Handbook of
Depression
and Anxiety
Second Edition, Revisedand Expanded

edited bySiegfried Kasper
University of Vienna
Vienna, Austria

Johan A. den Boer
Academic Hospital Groningen
Groningen, The Netherlands

J. M. Ad Sitsen
Academic Hospital Utrecht
Utrecht, The Netherlands

MARCELMARCEL DEKKER, INC.
D E K K ER

NEW YORK • BASEL

The ﬁrst edition was published as Handbook of Depression and Anxiety: A BiologicalApproach, edited by Johan A. den Boer and J. M. Ad Sitsen (Marcel Dekker, 1994).

Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress.
ISBN: 0-8247-0872-5
This book is printed on acid-free paper.
Headquarters
Marcel Dekker, Inc.
270 Madison Avenue, New York, NY 10016
tel: 212-696-9000; fax: 212-685-4540
Eastern Hemisphere Distribution
Marcel Dekker AG
Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland
tel: 41-61-260-6300; fax: 41-61-260-6333
World Wide Web
http:/ /www.dekker.com
The publisher offers discounts on this book when ordered in bulk quantities. For more
information, write to Special Sales/Professional Marketing at the headquarters address
above.
Copyright  2003 by Marcel Dekker, Inc. All Rights Reserved.
Neither this book nor any part may be reproduced or transmitted in any form or by anymeans, electronic or mechanical, including photocopying, microﬁlming, and recording,or by any information storage and retrieval system, without permission in writing fromthe publisher.
Current printing (last digit):
10 9 8 7 6 5 4 3 2 1
PRINTED IN THE UNITED STATES OF AMERICA

Medical Psychiatry
Series Editor Emeritus

William A. Frosch, M.D.
Weill Medical College of Cornell University
New York, New York, USA

Advisory Board

Jonathan E. Alpert, M.D., Ph.D.

Siegfried Kasper, M.D.

Massachusetts General Hospital andHarvard University School of Medicine
Boston Massachusetts, U S A

University Hospital for Psychiatry
and University of Vienna
Vienna, Austria

Bennett Leventhal, M.D.

Mark H. Rapaport, M.D.

University of Chicago School of Medicine
Chicago Illinois, USA

Cedars-Sinai Medical Center
Los Angeles California, USA

1 Handbook of Depression and Anxiety A Biological Approach, edited by Johan A. den Boer and J M Ad Sitsen
2 Anticonvulsants in Mood Disorders, edited by Russell T Joffe andJoseph R Calabrese
3 Serotonin in Antipsychotic Treatment Mechanisms and Clinical
Practice, edited by John M Kane, H -J Moller, and Frans Awouters
4 Handbook of Functional Gastrointestinal Disorders, edited by Kevin
W Olden
5 Clinical Management of Anxiety, edited by Johan A den Boer
6 Obsessive­Compulsive Disorders Diagnosis • Etiology • Treat­ment, edited by Eric Hollander and Dan J Stem
7 Bipolar Disorder Biological Models and Their Clinical Application,edited by L Trevor Young and Russell T Joffe
8 Dual Diagnosis and Treatment Substance Abuse and Comorbid
Medical and Psychiatric Disorders, edited by Henry R Kranzlerand
Bruce J Rounsaville
9 Geriatric Psychopharmacology, edited by J Craig Nelson
10 Panic Disorder and Its Treatment, edited by Jerrold F Rosenbaumand Mark H Pollack
11 Comorbidity in Affective Disorders, edited by Mauncio Tohen
12 Practical Management of the Side Effects of Psychotropic Drugs,edited by Richard Baton13. Psychiatric Treatment of the Medically Hi, edited by Robert G.
Robinson and William R. Yates
14. Medical Management of the Violent Patient' Clinical Assessment
and Therapy, edited by Kenneth Tardiff
15 Bipolar Disorders. Basic Mechanisms and Therapeutic Implica­
tions, edited by Jair C. Scares and Samuel Gershon
16 Schizophrenia A New Guide for Clinicians, edited by John G.
Csernansky
17 Polypharmacy in Psychiatry, edited by S. Nassir Ghaemi
18 Pharmacotherapy for Child and Adolescent Psychiatric Disorders­
Second Edition, Revised and Expanded, David R. Rosenberg,
Pablo A Davanzo, and Samuel Gershon
19 Brain Imaging In Affective Disorders, edited by Jair C. Scares
20 Handbook of Medical Psychiatry, edited by Jair C. Soares andSamuel Gershon
21 Handbook of Depression and Anxiety: Second Edition, Revisedand Expanded, edited by Siegfried Kasper, Johan A. den Boer, andJ. M. Ad Sitsen

ADDITIONAL VOLUMES IN PREPARATION

Aggression­ Psychiatric Assessment and Treatment, edited by EmilF. Coccaro
Autism Spectrum Disorders, edited by Eric Hollander

Depression in Later Life: A Multidisciplinary Approach, edited byJames Ellison and Sumer Verma
Handbook of Chronic Depression: Diagnosis and Therapeutic Man­
agement, edited by Maurizio Fava and Jonathan Alpert

Series Introduction

Depression and anxiety, both externally experienced and internally perceived, are part of
the normal human repertoire of response to stress. In my opinion, those who never experience such feelings are seriously ill, unable to recognize or respond appropriately to theimportance of danger and loss. On the other hand, the capacity to tolerate a “normal
expectable” level of each is a sign of mental health. Unfortunately, however, many of us
are unable to withstand the impact of the usual vicissitudes of life and are overwhelmedby excessive stress or chronic strain. The stressors may be as sudden as the events of
9/11, the diagnosis of a life-threatening disease, or the loss of someone we love, or they
may be an accumulation of the ordinary stresses of life at work and at home, with family
and friends. Symptoms of depression and/or anxiety may develop, sometimes assorted
into identiﬁable syndromes and, at times, representing speciﬁc disease states.
The chapters of this volume provide us with background information, such as theconceptual history of our understanding of anxiety and depression, their epidemiology
and genetics. They also provide insight into our current knowledge of the physiology andpathology of both anxiety and depression, and information about up-to-date treatment
approaches for both acute and chronic presentations.
This volume should be kept on our desks, readily accessible for consultation when
we need help with understanding the difﬁcult issues that bring people to us in search of
relief. It is a “vade-mecum”—a useful manual of what we now know about the biologicaland pharmacological treatments of depression and anxiety, and an invaluable resource for
all who care for the afﬂicted, important for general practitioners as well as for psychiatrists
and others in the mental health ﬁelds. The internationally renowned group of contributors
illustrate a growing consensus that anxiety and depression are both symptom and syndrome, and, in some instances, disease. It is time to apply this understanding to the practiceof medicine.
William A. Frosch, M.D.
Weill Medical College of Cornell University
New York, New Yorkiii

Preface

Anxiety and depression are complex emotional states in which cognitive evaluations andaffective and physiological responses are involved. Considering the complexity of these
emotions, which can be described in several scientiﬁc languages at different levels ofanalysis, there is no doubt that multiple neuronal systems in the brain are implicated in
the pathophysiology of these closely related disorders.
On a phenomenological level, there is a high degree of overlap between symptomsof anxiety and depression as well as a high degree of comorbidity. This does not imply,
however, that both syndromes are merely different phenotypical expressions of a genetically based constitution sharing similar biological underpinnings. The question of whether
anxiety and depression result from similar or different biological abnormalities cannot beanswered using one research strategy. On the one hand, psychophysiological research
provides evidence suggesting that anxiety and depression are clearly distinct disorders;on the other hand, some anxiety disorders and depressive syndromes respond to similar
pharmacological interventions. Thus, these conﬂicting ﬁndings from different biomedicalﬁelds of research present a challenge to all of us involved in the study of these very
common and often debilitating psychiatric illnesses.
Some investigators argue that distinguishing different subtypes among depressive
syndromes and anxiety disorders is a somewhat artiﬁcial practice. They reason that a
syndrome exists based upon a common underlying propensity toward ‘‘nervousness.’’
This (dimensional) viewpoint implies that the different diagnostic categories could be
merely phenotypical manifestations of an underlying vulnerability to anxiety or depression.
Over the last decade, our knowledge about the biological underpinnings of depression and anxiety disorders has increased substantially, particularly for anxiety disorders,and new insights are continually emerging from widely disparate ﬁelds, such as epidemiology, genetics, immunology, psychophysiology, and psychopharmacology. This volume
brings together these different disciplines and reviews the state of the art in research on
anxiety and depression and their interrelatedness.
We consider ourselves fortunate to have succeeded in getting so many internationally renowned contributors, who lend to this volume their knowledge and expertise inv

vi

Prefacethese disciplines. We hope that scientists and clinicians from many ﬁelds will be inspiredby the exciting ﬁndings presented in this book.
Siegfried Kasper
Johan A. den BoerJ. M. Ad Sitsen

Contents

Preface
Contributors

iii
xi

1. A Conceptual History of Anxiety and Depression
Gerrit Glas

1

2. Epidemiology of Depression and Anxiety
Borwin Bandelow

49

3. Comorbidity of Depression and Anxiety
Giovanni B. Cassano, Nicolò B. Rossi, and Stefano Pini

69

4. Anxiety, Depression, and Personality
Harald N. Aschauer and Monika Schlögelhofer

91

5. Is There a Common Etiology for Depression and Anxiety?
Dean F. MacKinnon and Rudolf Hoehn-Saric111

6. Measurements of Depression and Anxiety Disorders
Saena Arbabzadeh-Bouchez and Jean-Pierre Lépine127

7. Combining Psychotherapy and Pharmacotherapy for Depression andAnxiety
Robert H. Howland and Michael E. Thase
8. Genetics of Depression
Wolfgang Maier and Kathleen R. Merikangas

151

165

vii

viii

Contents

9.

Genetics of Anxiety
Wolfgang Maier

189

10.

Stress-Responsive Neurohormones in Depression and Anxiety
Andreas Ströhle and Florian Holsboer

207

11.

Neuropeptide Alterations in Depression and Anxiety Disorders
David A. Gutman, Dominique L. Musselman, and Charles B. Nemeroff

229

12.

Immunology in Anxiety and Depression
Norbert Müller and Markus J. Schwarz

267

13.

Brain Imaging in Depression and Anxiety
Peter S. Talbot, Sanjay J. Mathew, and Marc Laruelle

289

14.

Neurobiology of Anxiety and Depression
Philip T. Ninan and Thomas K Cummins

331

15.

Intracellular Signaling Transduction Dysregulation in Depression andPossible Future Targets for Antidepressant Therapy: Beyond theSerotonin Hypothesis
Andrea Trentani, S. Kuipers, G. J. Ter Horst, and Johan A. den Boer

349

16.

Norepinephrine in Depression and Anxiety
Pedro L. Delgado

387

17.

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands
Werner Sieghart

415

18.

Antidepressants for the Treatment of Depression and Anxiety Disorders:
Same Mechanism of Action?
R. Hamish McAllister-Williams and Stephen P. Tyrer

443

19.

Studies on the Neurobiology of Depression
Carlos A. Zarate, Jr. and Dennis S. Charney

457

20.

Animal Models of Subtypes of Depression
Paul Willner and Paul J. Mitchell

505

21.

Pathogenesis of Depression: Reconsideration of Neurotransmitter Data
by Depletion Paradigms
Alexander Neumeister and Anastasios Konstantinidis

545

Effects of Antidepressants on Speciﬁc Neurotransmitters: Are Such
Effects Relevant to Therapeutic Actions?
Brian Leonard

561

22.

Contentsix

23. Pharmacotherapy of Depression: The Acute and Long-Term Perspective
Robert J. Boland and Martin B. Keller583

24. Pharmacotherapy of Bipolar Disorder
Kenneth Thau and Anna Maria Streeruwitz

599

25. Development of New Treatment Options for Depression
Siegfried Kasper and Alan F. Schatzberg

615

26. The Depressed Patient: From Nonresponse to Complete Remission
Koen Demyttenaere and Jürgen DeFruyt

629

27. Pharmacogenetics of Mood Disorders: Is There a Future?
Bernard Lerer, Ofer Agid, and Fabio Macciardi

641

28. Theories of the Etiology of Anxiety
Trevor R. Norman, Graham D. Burrows, and James S. Olver657

29. Animal Models of Anxiety and Anxiolytic Drug Action
Dallas Treit, Aldemar Degroot, and Akeel Shah

681

30. Provocation of Anxiety States in Humans and Its Possible Signiﬁcancefor the Pathogenesis of These Disorders
Richard Balon, Robert Pohl, Vikram K. Yeragani, and Ravi K.
Singareddy

703

31. Pharmacotherapy of Anxiety Disorders
David S. Baldwin, David Bridle, and Anders Ekelund733

32. Pharmacotherapy of Mixed Anxiety/Depression Disorders
A. Carlo Altamura, Roberta Bassetti, Sara Fumagalli, Donato Madaro,
Daniele Salvadori, and Emanuela Mundo

757

33. New and Emerging Therapies for Anxiety
David J. Nutt and Spilios V. Argyropoulos

779

34. Scales Used in Depression and Anxiety ResearchHans-Jürgen Möller

789

Index

809

Contributors

Ofer Agid, M.D. Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
A. Carlo Altamura, M.D. Psychiatry, Department of Clinical Sciences ‘‘Luigi Sacco,’’University of Milan, Milan, Italy
Saena Arbabzadeh-Bouchez, M.D.
Paris, France

Department of Psychiatry, Hôpital Fernand Widal,

Spilios V. Argyropoulos, M.B.Ch.B., M.R.C.Psych
sity of Bristol, Bristol, England
Harald N. Aschauer, M.D.
Vienna, Austria

Department of Psychiatry, Univer-

Department of General Psychiatry, University of Vienna,

David S. Baldwin, M.B.B.S., F.R.Psych. University Department of Mental Health,Royal South Hants Hospital, and University of Southampton, Southampton, England
Richard Balon, M.D. Department of Psychiatry and Behavioral Neurosciences, University Psychiatric Center, Wayne State University School of Medicine, Detroit, Michigan,
U.S.A.
Borwin Bandelow, M.D., Ph.D. Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany
Roberta Bassetti, M.D. Psychiatry, Department of Clinical Sciences ‘‘Luigi Sacco,’’University of Milan, Milan, Italy
Robert J. Boland, M.D.

Department of Psychiatry and Human Behavior, Brown Unixi

xii

Contributors

versity, and Medical Director, Center for Behavioral and Preventive Medicine, Miriam
Hospital/LifeSpan, Providence, Rhode Island, U.S.A.
David Bridle, M.B., B.S., M.R.Psych.
Hospital, Southampton, England

Department of Psychiatry, Royal South Hants

Graham D. Burrows, M.D., Ch.B., B.Sc., FRANZCP Department of Psychiatry, Austin and Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria,
Australia
Giovanni B. Cassano, M.D.

Department of Psychiatry, University of Pisa, Pisa, Italy

Dennis S. Charney, M.D. National Institute of Mental Health, National Institutes of
Health, Bethesda, Maryland, U.S.A.
Thomas K Cummins, M.D. Department of Psychiatry and Behavioral Sciences, Emory
University School of Medicine, Atlanta, Georgia, U.S.A.
Jürgen DeFruyt, M.D.

University Hospital Gasthuisberg, Leuven, Belgium

Aldemar Degroot Department of Psychology, University of Alberta, Edmonton, Alberta, Canada
Pedro L. Delgado, M.D. University Hospitals of Cleveland and Case Western Reserve
University School of Medicine, Cleveland, Ohio, U.S.A.
Koen Demyttenaere, M.D., Ph.D.
Gasthuisberg, Leuven, Belgium

Department of Psychiatry, University Hospital

Johan A. den Boer, M.D., Ph.D. Division of Biological Psychiatry, Department of
Psychiatry, Academic Hospital Groningen, Groningen, The Netherlands
Anders Ekelund, M.B.Ch.B., Ph.D.
pital, Southampton, England

Department of Psychiatry, Royal South Hants Hos-

Sara Fumagalli, M.D. Psychiatry, Department of Clinical Sciences ‘‘Luigi Sacco,’’University of Milan, Milan, Italy
Gerrit Glas, M.D., Ph.D.

University of Leiden, Leiden, The Netherlands

David A. Gutman Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, U.S.A.
Rudolf Hoehn-Saric, M.D. Department of Psychiatry and Behavioral Sciences, Johns
Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.
Florian Holsboer, M.D., Ph.D.

Max Planck Institute of Psychiatry, Munich, Germany

Contributors

xiii

Robert H. Howland, M.D. Department of Psychiatry, University of Pittsburgh Schoolof Medicine, and Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania,
U.S.A.
Siegfried Kasper, M.D.
enna, Austria

Department of General Psychiatry, University of Vienna, Vi-

Martin B. Keller, M.D. Department of Psychiatry and Human Behavior, Brown University, Providence, Rhode Island, U.S.A.
Anastasios Konstantinidis, M.D.
enna, Vienna, Austria

Department of General Psychiatry, University of Vi-

S. Kuipers Division of Biological Psychiatry, Department of Psychiatry, Academic Hospital Groningen, Groningen, The Netherlands
Marc Laruelle, M.D. Columbia University College of Physicians and Surgeons, andNew York State Psychiatric Institute, New York, New York, U.S.A.
Brian Leonard, Ph.D., D.Sc., M.R.I.A.
sity of Ireland, Galway, Ireland

Department of Pharmacology, National Univer-Jean-Pierre Lépine, M.D. Department of Psychiatry, Hôpital Fernand Widal, Paris,
FranceBernard Lerer, M.D. Department of Psychiatry, Hadassah-Hebrew University Medical
Center, Jerusalem, Israel
Fabio Macciardi, M.D., Ph.D. Center for Addiction and Mental Health, University ofToronto, Toronto, Ontario, Canada
Dean F. MacKinnon, M.D. Department of Psychiatry and Behavioral Sciences, Johns
Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.
Donato Madaro, M.D. Psychiatry, Department of Clinical Sciences ‘‘Luigi Sacco,’’University of Milan, Milan, Italy
Wolfgang Maier, M.D. Department of Psychiatry, University of Bonn, Bonn, Germany
Sanjay J. Mathew, M.D.
U.S.A.

New York State Psychiatric Institute, New York, New York,R. Hamish McAllister-Williams, Ph.D., M.R.C.Psych. Department of Psychiatry,
University of Newcastle upon Tyne, Newcastle upon Tyne, England
Kathleen R. Merikangas, M.D. Department of Health and Human Services, National
Institutes of Health, Bethesda, Maryland, U.S.A.

xiv

Paul J. Mitchell, B.Sc., MIBiol, CIBiol, Ph.D.
cology, University of Bath, Bath, EnglandContributors

Department of Pharmacy and Pharma-Hans-Jürgen Möller, M.D. Department of Psychiatry, Ludwig Maximilian University,
Munich, Germany
Norbert Müller, M.D. Hospital for Psychiatry and Psychotherapy, Ludwig Maximilian
University, Munich, Germany
Emanuela Mundo, M.D. Psychiatry, Department of Clinical Sciences ‘‘Luigi Sacco,’’University of Milan, Milan, Italy
Dominique L. Musselman, M.D. Department of Psychiatry and Behavioral Sciences,
Emory University School of Medicine, Atlanta, Georgia, U.S.A.
Charles B. Nemeroff, M.D., Ph.D. Department of Psychiatry and Behavioral Sciences,
Emory University School of Medicine, Atlanta, Georgia, U.S.A.
Alexander Neumeister, M.D. Mood and Anxiety Disorders Program, National Instituteof Mental Health, National Institutes of Health, Bethesda, Maryland, U.S.A.
Philip T. Ninan, M.D. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, U.S.A.
Trevor R. Norman, B.Sc., Ph.D. Department of Psychiatry, Austin and Repatriation
Medical Centre, University of Melbourne, Heidelberg, Victoria, Australia
David J. Nutt, M.D., Ph.D., F.R.C.Psych., F. Med. Sci.
University of Bristol, Bristol, England

Psychopharmacology Unit,James S. Olver, M.B.B.S., M.P.M., FRANZCP Department of Psychiatry, Austin and
Repatriation Medical Centre, University of Melbourne, Heidelberg, Victoria, Australia
Stefano Pini, M.D., Ph.D. Department of Psychiatry, University of Pisa, Pisa, Italy
Robert Pohl, M.D. Department of Psychiatry and Behavioral Neurosciences, University
Psychiatric Center, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.
Nicolò B. Rossi, M.D. Department of Psychiatry, University of Pisa, Pisa, Italy
Daniele Salvadori, M.D. Psychiatry, Department of Clinical Sciences ‘‘Luigi Sacco,’’University of Milan, Milan, Italy
Alan F. Schatzberg, M.D. Department of Psychiatry and Behavioral Sciences, Stanford
University School of Medicine, Stanford, California, U.S.A.
Monika Schlögelhofer, M.A. Department of General Psychiatry, University of Vienna,
Vienna, Austria

Contributors

xv

Markus J. Schwarz, M.D. Hospital for Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany
Akeel Shah
CanadaDepartment of Psychology, University of Alberta, Edmonton, Alberta,

Werner Sieghart, Ph.D. Brain Research Institute, University of Vienna, Vienna, Austria
Ravi K. Singareddy, M.D. Department of Psychiatry and Behavioral Neurosciences,
University Psychiatric Center, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.
Anna Maria Streeruwitz, M.D. Department of Social Psychiatry and Evaluation Research, University of Vienna, Vienna, Austria
Andreas Ströhle, M.D. Max Planck Institute of Psychiatry, Munich, GermanyPeter S. Talbot, M.D., M.R.C.Psych. Division of Functional Brain Mapping, NewYork State Psychiatric Institute, New York, New York, U.S.A.
G. J. Ter Horst, Ph.D. Division of Biological Psychiatry, Academic Hospital Groningen, Groningen, The Netherlands
Michael E. Thase, M.D. Department of Psychiatry, University of Pittsburgh School of
Medicine, and Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania, U.S.A.
Kenneth Thau, M.D. Department of Social Psychiatry and Evaluation Research, University of Vienna, Vienna, Austria
Dallas Treit, Ph.D.
berta, Canada

Department of Psychology, University of Alberta, Edmonton, Al-

Andrea Trentani, Ph.D. Division of Biological Psychiatry, Department of Psychiatry,
Academic Hospital Groningen, Groningen, The Netherlands
Stephen P. Tyrer, M.B., B.Chir.DPM Division of Psychiatry, Royal Victoria Inﬁrmary, University of Newcastle upon Tyne, Newcastle upon Tyne, England
Paul Willner, M.S., Ph.D.

University of Wales Swansea, Swansea, Wales

Vikram K. Yeragani, M.D. Department of Psychiatry and Behavioral Neurosciences,
University Psychiatric Center, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.
Carlos A. Zarate, Jr., M.D. National Institute of Mental Health, National Institutes of
Health, Bethesda, Maryland, U.S.A.

1
A Conceptual History of Anxiety
and Depression
GERRIT GLAS
University of Leiden
Leiden, The Netherlands

I.

INTRODUCTION

For more than 2500 years, physicians have distinguished the clinical conditions we callaffective or anxiety disorder from such everyday feelings as fear, restlessness, and despondency. Contrary to what might be expected, case descriptions from the past often bear
remarkable resemblances to patients encountered in modern-day clinical practice. Whether
one consults Aristotle, Galen, Burton, or the 19th-century alienists, images of a suggestive
reality are evoked, images in which we can easily recognize the depressive, anxious, andmelancholic individual of our own era. These are similarities in symptomatology andcourse, as well as in the distinction between normality and pathology.
On the other hand, there are also considerable disparities in language and frame ofreference, conceptualization, and interpretation. From the time of Hippocrates until wellinto the 17th century, the description and interpretation of anxiety and depression were
dominated by the doctrine of bodily ﬂuids (humors). And, until quite recently, all mannerof ideas involving neural energy overshadowed discussions of phenomena such as neurasthenia, inhibition, and motor agitation.
These disparities have traditionally been given particular emphasis. The undeniably
impressive growth of our knowledge is seen as evidence of the superiority of contemporary
explanatory models. Conversely, ideas that were current from antiquity until the 19th
century are considered to be of no more than historical interest—simply a fanciful mythology for enthusiasts. The history of medicine has become a somewhat antiquated study,
pursued by a handful of specialists.
1

2

Glas

This may or may not be considered regrettable. However, these disparities once
again become relevant at a deeper level of discussion for clinicians as well as for scientiﬁcinvestigators. I refer here to the level of medicine’s basic concepts and to the cultural andideological strata from which these concepts derive their meaning.
A consideration of the foundations of medicine helps, for example, to put into perspective the already overly strict separation of symptoms and explanatory models. Symptoms are not natural phenomena in that they are not the invariable expressions of an
unchanging biological substratum. Whatever one’s concept of disease, what the patientsays is always based upon interpretation, at least to a certain extent. That interpretation
can be colored by whatever is considered to be normal or abnormal in a particular culture.
Explanatory models, on the other hand, are not simply conjured up out of the blue. They
are neither arbitrary nor coincidental, but are instead closely linked to whatever paradigms
are currently fashionable in the various branches of science. Moreover, they are always
interpretations of a reality that is already interpreted by the afﬂicted person and thosearound him.
Accordingly, we cannot pretend that depression and anxiety are natural phenomenathat have consistently been expressed and experienced in the same way down through thecenturies. The view according to which only the explanatory models have changed andnot the phenomena themselves should be rejected. Concentrating purely on differences atthe level of the explanatory models can easily turn the history of medicine into a studyof scientiﬁc folklore, as if, with the passage of time, only the explanatory models haveundergone change and not the signs and symptoms of the disorders. Notwithstanding theabove-mentioned similarities in clinical picture and course, the symptoms of anxiety anddepression also have changed (i.e., their relevance to what counts as disease and their
meaning as an expression of disease).
Seen from this point of view, the study of the history of medicine suddenly becomes
extremely relevant to a clear understanding of all sorts of current explanatory models.
The medical history of anxiety and depression is, therefore, not simply concerned withinternal scientiﬁc development. It also involves the interplay of cultural changes and psychopathological phenomena, including the scientiﬁc interpretations of such phenomena.
In this chapter, several leading concepts in the history of anxiety and depression will besummarized. Instead of delving into historical detail, the emphasis will be on concepts
and, particularly, on the paradigm shifts associated with the changes in conceptual content.
Anyone interested in the detail is referred to the existing literature on the history of medicine, particularly to the outstanding studies of Jackson [1] and Klibansky et al. [2]. Alsoof interest are the studies by Ackerknecht [3], Beek [4], Berrios [5,6], Flashar [7], Foucault[8], Gardiner et al. [9], King [10], Leibbrand and Wettley [11], Lewis [12], Roccatagliata[13], Rosen [14], Starobinski [15], and Zilboorg [16].
II. NOMENCLATURE
Before commencing with our historical review, a few comments about terminology. Firstof all, it should be realized that the generally accepted distinction between anxiety anddepression is of comparatively recent vintage. The ﬁrst nonphobic form of anxiety to takeits place in the description of disease did so as recently as the middle of the 19th century. Flemming’s Über Praecordialangst, which dates from 1848, was cited by SchmidtDegenhard [17] as the ﬁrst medico-psychiatric text exclusively devoted to a nonphobic
form of anxiety.

History of Anxiety and Depression

3

Of course, this does not mean that subtle variations in the spectrum of anxiety anddepressive disorders had not been observed and described prior to this. Evidently, however, there was no recognition of the need for a systematic distinction between anxiety
and depression. For a long time, both were encompassed by the broad concept of melancholia. Since the Corpus Hippocraticum (5th-century b.c.), fear and despondency havebeen referred to as the prominent characteristics of melancholia.
The terms melancholia (Greek: melaina cholè, black bile) and hypochondria (Greek:
hypochondrios, under the breastbone) are therefore of ancient vintage. The same applies
to the concept of mania. The word depression (Latin: deprimere, to press down) graduallycame into use during the 18th century [18].
Unlike the term phobia (Greek: phobos, fear), the term anxiety has neither Greek
nor Latin origins. The word anxiety (German: angst, worry) probably derives from the
Indo-Germanic root angh, which means to narrow, to constrict, or to strangulate [19–21].
This root reappears in the Greek word anchein, which means to strangle, to suffocate, orto press shut. The root angh has also survived in Latin, for example, in angor (suffocation;
feeling of entrapment) and anxietas (shrink back fearfully; being overly concerned). Fearderives from the German stem freisa or frasa. The term panic, on the other hand, has a
Greek background, namely, Pan or Panikos, the Greek god of the forest and of shepherds,
who was thought to have caused panic amongst the Persians at Marathon.
The boundaries of the different terms are rather vague. This is particularly true ofthe term melancholia, which covers practically all forms of nonorganically determined
psychopathology. In summary, however, it can be stated that despondency is a central
element in numerous terms for depression, whereas in terms referring to anxiety the emphasis is often on sensations of tightness and constriction in the region of the chest andthroat.
III. A HISTORY OF THE CONCEPTS OF ANXIETY AND DEPRESSION
BASED UPON THE CONCEPT OF MELANCHOLIA
A. Ancient Greece and Rome
Western psychiatry, just like somatic medicine, has its roots in Greek natural philosophy.
In this philosophy, the traditional explanations of mental illness, based upon the supernatural, gradually diminish in signiﬁcance. Clinical observation and reasoning become established practice. Natural philosophers attempt to elucidate the universal principle behindobserved phenomena. They observe heaven and earth, the orbits of heavenly bodies, andthe course of the seasons, as well as the cycle of ascension, splendor, and decline in theliving and the nonliving worlds. They are dissatisﬁed with demonological explanationsof mental illness, such as those found in the works of Homer, for example.
This does not mean that moments of speculation become a thing of the past (let us
consider, for example, the Corpus Hippocraticum). This work consists of a series of 70
medical texts dating from the 5th century B.C., which are attributed to Hippocrates andhis pupils. The Corpus contains the earliest formulation of the theory of the four humors
or bodily ﬂuids. This humoral theory was a modiﬁed version of the view ﬁrst encounteredin the works of Empedocles that the universe is made up of a mixture of four elements:
earth, ﬁre, air, and water. Empedocles himself was probably inﬂuenced by the Pythagorean
school’s doctrine of the “harmony of the spheres,” which placed strong emphasis on notions such as tuning and equilibrium. According to the humoral theory, disease resultsfrom a disturbance in the natural balance (dyscrasia) of the elements.

4

Glas

Blood, yellow bile, black bile, and phlegm are the four bodily ﬂuids or humors
distinguished in the Hippocratic texts. These ﬂuids were considered to be inﬂuenced by
the seasons. Accordingly, blood would increase in the spring, yellow bile in the summer,
black bile in the fall, and phlegm in the winter. In addition, each of the humors was
associated with a pair of primary qualities. Thus blood was associated with heat and wetness, yellow bile with heat and dryness, black bile with dryness and cold, and phlegmwith cold and wetness (see Fig. 1).
To the Greek physician, disease was caused by a disturbance in the natural balanceof the bodily ﬂuids. This balance was inﬂuenced by all sorts of factors, such as seasonalchanges, climate, geographical conditions, age, mental effort, as well as eating and drinking habits. The Greeks were well aware, for example, of the link between depressive
phenomenon and the fall. In addition to these factors, certain people were temperamentally
predisposed to melancholia. The term temperament refers to a personal’s humoral constitution. Due to an excess of black bile, or to an increased susceptibility of the black bile toheat or cold, some people could have a natural tendency toward melancholia.
This suggests that the balance between the humors reﬂects a much broader biopsychological and ecological equilibrium. This is indeed the case. The ancient concept ofdisease must be seen against the background of the then popular idea of a fundamental
likeliness of macrocosm and microcosm. Universe at large is a well-ordered macrocosm.
Its changes are reﬂected at the level of microcosm—the individual body, for instance.
This theme was to dominate the concept of disease for at least two millennia. It left noroom for the principle of linear (unidirectional) causality, which began to dominate medicine in the middle of the 18th century, nor can it be equated with the late 19th-century
concept of homeostasis, since this concept presupposes the idea of internal feedback, a
notion that is quite foreign to the ancient Greeks. In antiquity, disease was seen as adisorder reﬂected on all levels of existence, rather than as the consequence of an internal
disorder. The excess of black bile in melancholia was the analogue of changes in theseasons, in dietary habits, and in psychological constitution [22,23]. The origins and conclusion of disease were not conﬁned to the relative isolation of the body. Instead, disease
reﬂected changes on various levels within the macrocosm.

Figure 1 The four humors and their relation to the seasons, the elements, and the primary
qualities.

History of Anxiety and Depression

5

The ﬁrst-century reader may suspect that there are conceptual problems here; however, none seemed to exist for the Greek physician-philosopher, who seemed quite uninterested in the question of how all these different processes interacted with one another, andchose instead to ignore the problem. Some have suggested, for example, that the Greek
outlook could not accommodate a psychogenic cause of mental illness. This is factually
incorrect, since the literature of that time includes many examples of scholars becoming
depressed through excessive study, and of melancholics consumed by feelings of guilt,
hatred, or grief over a lost love. In addition, there is also a conceptual misunderstanding
here, such as occurs whenever modern ways of thinking begin to dominate the interpretation of humoral pathology. The humors are then reduced to purely biological phenomena(comparable to neurotransmitters) and the lovelorn state, or that of being overworked, tomere matters of psychology. Greek physicians undeniably thought of the melainè cholè
as a substance that was both visible and tangible, even though they had never actuallyseen it. Nevertheless, they persisted in associating this unseen substance with all kinds ofeffects at the psychological and behavioral levels. From a ﬁrst-century point of view, thisassociation could be seen as a metaphor. To the Greek physician, however, the notion of
atrabiliousness (black bitterness) was a condensation of all sorts of very real experiences
and perceptions. In short, even though the emphasis lay on what is now referred to as the
biological component, the psychological connotation still was implied by the terms forthe bodily ﬂuids.1 According to Aretaeus, bile means anger and black, much or furious:. . . in certain of these cases, there is neither ﬂatulence nor black bile, but mere anger andgrief, and sad dejection of mind; and these were called melancholics, because the terms bileand anger are synonymous in import, and likewise black with much and furious (Aretaeus;
via Jackson [24]).

For all that, black bile was the last substance to be ranked amongst the true bodily ﬂuids.
Initially interpreted as a breakdown product of yellow bile, black bile was ﬁrst described
as a natural constituent of the body in the Corpus Hippocraticum. Its change in status canprobably be attributed to the dark-colored urine and feces observed in malaria sufferers
and in patients with hepatic disease or gastric bleeding.
However, more than ﬁve centuries were to pass between this reference to black bilein the Hippocratic texts and the ﬁrst summarized description of its effects. This summary,which can be found in the medical works of Galen (131–201 a.d.), was to serve as amodel for medical thinking for centuries to come.
Galen owed a great deal to the work of Rufus of Ephesus (circa 100 a.d.), who wemust thank for a description of various melancholic delusions, amongst other things. One
such delusion was that of being an earthen pot, another was that of lacking a head. Rufus
also inﬂuenced Arabic medicine and, through it, the medicine of the Middle Ages. It was
Rufus from whom the great Ishaq ibn Imran, of 10th-century Baghdad, reputedly derived
his ideas about melancholia. The latter’s work was to become the direct source for De
Melancholia by Constantinus Africanus (11th century), a text that enjoyed great authority
during the Middle Ages and the Renaissance [25]. The distinction between the three formsof melancholia, which he may have derived from Rufus, was considered by Galen to beof particular signiﬁcance. He distinguished the following forms:
1. A generalized form of melancholia, with the blood being full of black bile
2. A cerebral form of melancholia, which only affected the brain
3. An hypochondrical form of melancholia involving the organs of the upper abdomen [26–28]

6

Glas

The ﬁrst form, unlike the second, could be accompanied by other phenomena (e.g., discoloration of the skin, cirrhosis of the liver, and the accumulation of ﬂuid). The mental manifestations of both the generalized and the cerebral forms were due to obstructed bloodvessels in the brain, as a result of a thickening of the blood. Galen suspected that thisobstruction led to a blockage of the channels through which the so-called pneuma animalis
ﬂowed. This pneuma was an etherlike substance, made up of small, lightweight, highly
animated particles. From ancient times until well into the 17th century, it has been associated with all kinds of mental functions, including perception and imagination. In othercases, according to Galen, black bile caused cerebral tissue damage, leading to the impairment of intellectual functions in particular. In the third form of melancholia, disease symptoms were not interpreted as resulting from black bile as such. Instead they were caused
by a vapor emanating from this ﬂuid, as a result of local warming in the hypochondrium.
This smoky vapor, according to Galen, rose up into the brain, obscuring thought. It was
this mental obscuration that explained the anxiety seen in melancholics. Galen compared
it to the darkness of night, which induces a causeless fear in many people:
As external darkness renders almost all persons fearful, with the exception of a few naturally
audacious ones or those who were specially trained, thus the color of the black bile induces
fear when its darkness throws a shadow over the area of thought [in the brain] [29].

Apart from generating this vapor, such local warming also converted one of the otherbodily ﬂuids to black bile, thereby producing an excess. Under circumstances such as this,melancholia would be characterized by heat rather than coldness. According to some later
writers of the Galenic school, this explained motor restlessness and behavioral disorders,an interpretation with which Burton concurred in 1621.
In terms of treatment, it was the distinction between the three forms of melancholiathat became of primary importance. Phlebotomy, the preeminent therapy for the generalized form, was ineffective in the treatment of the other two forms of melancholia, which
required alternative measures. Mention is made of changes in eating and drinking habits,
the use of emetics and laxatives, and attaining a correct balance between rest and physicalexercise.
Galen was aware that, while the manifestations of anxiety and depression are tremendously varied, the heart of melancholia consists of despondency and anxiety, especiallythe fear of death:
Although each melancholic patient acts quite differently than the others, all of them exhibit
fear or despondency. They ﬁnd fault with life and people; but not all want to die. For somethe fear of death is of principal concern during melancholy. Others again will appear to youquite bizarre because they dread death and desire to die at the same time.
Therefore, it seems correct that Hippocrates classiﬁed all their symptoms into twogroups: fear and despondency. Because of this despondency patients hate everyone whomthey see, are constantly sullen and appear terriﬁed, like children or uneducated adults in deepest darkness [30].

The link between melancholia and mania had already been established by Aretaeus of
Cappadocia, who lived around 150 a.d. [31]. However, in the work of Galen, this link isconspicuous by its very absence. In the Hippocratic texts, the term mania was frequently
used when referring to mental illness in general, even though the link with the action of
black bile had already been established. In the centuries that followed, mania and melancholia gradually became delineated as disorders having a certain periodicity, but with

History of Anxiety and Depression

7

contrasting outward expressions. Nevertheless, we must exercise caution, and not be overhasty in identifying these ailments with the present-day, bipolar disorder. The term melancholia still has very wide connotations, incorporating many different forms of psychosis
and all kinds of neurotic symptoms. Mania, on the other hand, speciﬁcally refers to thevarious forms of emotional restlessness and motor excitation.
In fact, mania and melancholia together encompass virtually the entire ﬁeld of prolonged psychopathology, that is, chronic diseases not associated with fever. The third formof mental illness, phrenitis, is both acute and associated with fever. The obvious comparison here is with delirious visions and acute psychoses. Epilepsy had a place all its own.
Viewed by the Greco-Roman world as a “sacred disease,” it includes forms that are transitional between classic epilepsy and melancholia.
B. The Middle Ages
During the Middle Ages, ideas about anxiety and depression actually changed very little.
Scholars continued to build upon the foundations created by the Hippocratic–Galenic
school. For many centuries, Alexandria, with its enormous library, was the center of research and contemplation. One area of Byzantine medicine, as it is known, is particularly
worthy of mention, particularly with respect to the work of compilers such as Oribasius
of Pergamon (325–403), Alexander of Tralles (525–605) and Paul of Aegina (625–690).
These scholars classiﬁed existing ideas from many different sources, without adding any
signiﬁcant contributions of their own.
At about the same time, the work of the Greek authors began to be translated into
the Semitic languages by Christians who had ﬂed the Byzantine Empire, as well as by
Arab authors. In this way Arabic medicine came to assimilate its Byzantine inheritance,in addition to inﬂuences from India and even China. By the end of the ﬁrst millennium,
writers from the Eastern Caliphate (Baghdad), such as Rhazes (865–923) and Avicenna(980–1037), had produced medical treatises of their own. Avicenna’s Canon of Medicine,in particular, was to dominate medical ideas for centuries to come. From Persia cameanother signiﬁcant ﬁgure, Ishaq ibn Imran (early 10th century), who has been referred topreviously. His work on melancholia inspired the great and inﬂuential treatises on thesubject by the encyclopedist Constantinus Africanus (1020?–1087). Originally from North
Africa, Constantinus subsequently lived in Salerno and later moved to Monte Cassano.
His work reﬂects that of Ishaq, in that he also devoted an extraordinary amount of consideration to psychogenic causes of melancholia. Later on, famous scholars from the Western
Caliphate (Spain), such as Averroes (1126–1198) and Maimonides (1135–1204), also
exerted an inﬂuence on medicine. In the late Middle Ages, however, authors dealing withmelancholia mainly referred to the works of Avicenna and Constantinus [32]. In the late
Middle Ages, medical knowledge was mainly concentrated in monasteries and in cathedral
schools. Moreover, various university medical schools were founded, the best known ofthese being Montpellier, Bologna, and Padua. In addition to continued classiﬁcation,some scholars now began to apply morality to humoral pathology [33]. This led to melancholics being described by some as degenerate, along with phlegmatics and cholerics.
Sanguinics, on the other hand, were considered to represent man, as God had intended
him to be, at the Creation. Melancholia was also associated with acedia, a type of listlessness and restless boredom, accompanied by a longing for change of environment. As
long ago as the 4th century, Cassianus described this condition in the monks of desertmonasteries not far from Alexandria. The afternoon demon would appear around the sixth

8

Glas

hour. It bred in the monks a loathing for their own cells, a disdain of the other brothers,
and a slothful unwillingness to take part in the routine activities of monastic life. Acedia,
in the guise of Sloth, was to become one of the Seven Deadly Sins of the Middle Ages
[34,35]. One particular development in the continuing systematization of humoral pathology was an accentuation of the difference between two forms of melancholia. In additon
to melancholia as a result of an excess of natural black bile, a second form was discerned,
caused by an excess of unnatural black bile. Unnatural black bile was thought to be produced by the combustion, or degeneration, of one of the four bodily ﬂuids.
In cases of an excess of natural black bile, the characteristics of the melancholic
temperament became more prominent. In such patients, mediation gave way to brooding.
Their previously sincere and caring attitude toward life plunged into one of anxiety andgloom. Those afﬂicted would stare at a single point, be incommunicative, and avoid allcontact. Beek, whose Waanzin in de Middeleeuwen (Madness in the Middle Ages) is,
unfortunately, not available in an English translation, summarizes the writings of many
authors as follows:
An excess of melancholic humor, which is thick and sediment-like, imparts a red color tothe head. The patient also experiences a feeling of heavy-headedness. He tastes a bitter-sweet
taste, the sediment of the humor. The pulse is weak and the veins full. The urine is thick andred-colored [36,37].

Although the combustion or degeneration of black bile presents a broadly similar picture,
there is the added element of preoccupation with death:
They become agitated about funerals. Believing that they are about to die, they lie on graves
and collect the bones of the dead. The pulse is hard and tense, the urine is lead-colored andthin [38].

The picture that developed as a result of burned yellow bile was one of mania. Patients
ranted, raved, and screamed all day long. Referring, once again, to Beek:
They lie awake. They exhibit excessive movement, jumping and running around. They arereckless and quarrelsome, wanting to beat those around them, preferably with an iron bar.
In the grip of the mania, they throw themselves through windows. The choleric temperamentis characterized by a lack of inhibition, wild behavior, recklessness, constant motion and rage.
Such patients have a lemon-colored complexion, their urine is thin and yellowish, the pulse
hard and rapid. It is thought that sufferers do not feel the cold because the combustion of
the bile keeps them warm [39].

Conversely, the combustion of blood produces feelings of happiness rather than of sadness:
They talk and laugh the whole time, wanting to dance and make merry all whole day long.
Their temperament type is one of happiness, laughter and loquacity. Their urine is thick andreddish brown [40].

Degeneration of phlegm, on the other hand:. . . induces apathy, inertia and absent-mindedness. Feeling heavy-headed, these patients neither move nor laugh, nor do they feel joy. In people with this type of temperament, inertia,
drowsiness and forgetfulness come to the fore. Characterized by a moist mouth and nostrils,
and a pale white complexion, they are referred to as lymphatics. Believing themselves to beﬁsh, they ask for water all day long and pine for river, or the sea. Their pulse is small andweak, their urine pale, whitish and of medium thickness [41].

History of Anxiety and Depression

9

In tracing the origins of melancholia, factors other than the humors (combusted or otherwise) must be taken into consideration. These were the complexio (the temperament andprimary qualities) of the brain and the condition of the rest of the body. A brain that isoverly dry, or excessively cold, has an increased susceptibility to disease. A weak heart
lowers the threshold against developing melancholia. Particular and frequent mention ismade of the relationship between heart and head. Heart palpitations, for example, are theexpression of an affection of the heart. Obviously, there is a relationship between themalfunctioning of this organ and a person’s state of mind. After all, did not the spiritus
vitalis ascend from the heart to the brain, where it inﬂuenced the spiritus animalis?
In medieval medicine, the nature of these inﬂuences was connected to the localization of functions in the different ventricles. The anterior (or lateral) ventricles were associated with imagination (imaginatio), the median (or third) ventricle with reasoning (ratio),and the posterior (or fourth) ventricle with memory (memoria). Melancholia was usually
linked with a disorder of the middle ventricle. Conditions that involve hallucinations anddelusions, such as mania and psychotic depression, were based upon disturbances to theequilibrium of the anterior ventricles.
Classiﬁcation was extended to include therapeutic procedures. Polypharmacy had
been popular even in ancient times, with leading roles being played by black hellebore
and extracts of mandragora. In addition, regulation of the so-called non-naturalia (externalor environmental factors) remained an important part of the therapeutic arsenal. Traditionally, six such factors were identiﬁed. These were:
Air: The patient should be kept in a warm, moist environment, the door of his houseshould preferably face east.
Rest and exercise: The aim should be to reduce sensory excitation and to achieve
relaxation. The patient should preferably be nursed in a dark room. The walls
should be bare of pictures, since these might overstimulate his imagination. A
not overly arduous walk, when the time is ripe, is beneﬁcial for the maintenanceof body temperature, as are massages and hot baths. An excess of body heat,
however, dries out the body and causes melancholia.
Waking and sleeping: The patient should sleep neither too little nor too much.
Food and drink: This sickness can result both from overeating and from excessive
fasting (as seen in the ascetics). Food must be easily digestible. Vegetables suchas lentils and beans give rise to ﬂatulence and therefore cause melancholia. Peppery spices, garlic, leeks, and onions must be avoided since they can burn the
humors. The same applies to both mature and salted meat, the meat of forest
animals, mature cheese, vinegar, and ﬁsh. A heavy wine, rich in sediment, causes
sickness, whereas a light, young wine can actually raise the spirits.
Retention and excretion: Melancholia can result from the accumulation of thosebodily ﬂuids which are normally discharged, such as menstrual blood, sperm, or
hemorrhoidal blood. The same is true of feces. Evacuation sometimes requires
mechanical assistance, for example, in constipation, the nonappearance of menstruation, or the nonbleeding of hemorrhoids. Coitus is generally to be recommended, although men with low potency should avoid overindulgence. Bathing,whether in a herbal bath or just with plain water, is an important therapeutic agent
that can also facilitate evacuation. However, excessively hot baths can induce
madness.

10

Glas

Passions of the soul: Excessive fear, hatred, and grief should be avoided. The same
applies to excessive study and to intense preoccupation with a particular task.
Nevertheless, anxious and inhibited melancholics can actually be cured by either
a ﬁerce rage or a sudden shock. Generally speaking, however, these passions
should be kept under control. Discussion and philosophical reading can both be
useful in calming the patient.2
C.

Intermezzo: Melancholia as a Characteristic of Genius

We have placed great emphasis on the continuity of the medical debates regarding melancholia. This continuous dialogue spans the centuries, from ancient times until the Middle
Ages and, as we shall see, even beyond. There are, in all, three closely related concepts:
1.
2.
3.

Natural black bile.
The disorder of melancholia, based on either an excess of natural black bile or
the combustion of one of the four body humors (melancholia adusta)
A chronic predominance of natural black bile in people with a melancholictype temperament.

In spite of the allegorizing and moralizing interpretations, the concept of melancholia
retained its link with humoral pathology. This doctrine, however, was not entirely undisputed in ancient times. The empirical school, for example, considered the theory of bodily
ﬂuids to be too speculative. There was also the methodist school, which sought refuge ina much simpler classiﬁcation of disease (involving the status strictus versus status laxusor, in other words, the respective contraction and relaxation of the so-called internal pores).
We also found that, with regard to the temperaments, there was some doubt about thenormalcy of the character variations (cf. Note 1).
There is another line that, in terms of the theme of this review, is even more important. This proceeds from Plato and Aristotle, via the Florentine School of the Middle Ages
(Marsilio Ficino) and Robert Burton [42] in the Renaissance, to William James [43] inthe present. It is a line of thought that regards the melancholic as exhibiting certain traits ofgenius. There is the famous opening line from the thirtieth book of Aristotle’s Problemata:Why is it that all those who have become eminent in philosophy or politics or poetry or thearts are so clearly of an atrabilious temperament, and some of them to such an extent as tobe affected by diseases caused by black bile, as is said to have happened to Heracles among
the heroes? [44]Aristotle seeks a natural explanation for this “madness which comes from the gods.” This
is in contrast with Plato’s Phaedrus [45], which offers a mythological description.3 Aristotle suggests that the eminence of the poets, politicians, and philosophers in question
could be ascribed to an optimum warmth of the black bile. Black bile, by its very nature,
was thought to be sensitive to changes of temperature. When cooled, it brought about“apoplexy or torpor or despondency or fear.” Heating induced “cheerfulness accompanied
by song and frenzy and the breaking forth of sores and the like” [46]. In the case of aman of genius, black bile, which is as such a pathogenic ﬂuid, is in an optimum state.
Such a person represents the normal within the abnormal or, in the words of Klibansky,
Panofsky, and Saxl, an “eucrasia within an anomaly” [47].
During the Renaissance, a time of revived interest in astrology, this association

History of Anxiety and Depression

11

between melancholia and genius acquired a special meaning. In antiquity, the planet Saturn
had been associated with Kronos, the son of Uranus (the god of Heaven) and Gaia (theEarth goddess), who had been banished to the underworld after the castration of his father.
Now, Saturn gradually turned into a symbol of the ambivalence of intellectual and artistic
life. According to ancient astrology, Saturn was the planet of gloom, desolation, decline,
and old age. However, the Neo-Platonists claimed that Saturn, as the highest planet, wasthe planet of the elevated, of ecstatic release from early things and happenings [48]. Marsilio Ficino (1433–1499), Neo-Platonist of the Florentine school as well as a priest andphysician, depicted Saturn at the heavenly body whose rays inﬂuenced the vital spirits ofthe brain (spiritus animalis), which were thought to connect the physical to the spiritual.
This inﬂuence was described as a kind of saturation process, one to which those bornunder the sign of Saturn were especially sensitive. Although enjoying intellectual powers
and creative talents far exceeding those of others, there was a tragic element to thesepeople. They spent their lives teetering on the very brink of catastrophe and they were
especially susceptible to melancholia. Black bile was identiﬁed with the earth, including
the very center of the planet itself, which meant that such people tended to have a deeply
penetrating understanding of existence. The association with Saturn, the highest of theplanets, meant that they aspired to higher planes of thought [49]. The novel element hereis the heightening of self-consciousness, the awareness of man’s vulnerability to catastrophe and decline. Their view of life took on a nostalgic and tragic tint. This outlook was
to recur in a variety of different forms in later periods, as, for example, in the Elizabethan
literature of the 16th and 17th centuries (Elizabethan Malady) [50].
D. The Renaissance, 17th, and 18th Centuries
The Renaissance was not only an age of heightened self-awareness and the era of Homoliteratus, with his knowledge of the classics, it was also the time of alchemy. This lent
impetus to the interpretation of disease in terms of chemical change, an approach thattexts on the history of medicine refer to as iatrochemistry. Substances such as salt, sulfur,
and silver became the focus of attention. Paracelsus (1493–1541) was one of the ﬁrst to
apply the newly gathered knowledge to medicine in an attempt to break down the hegemony of humoral pathology. He did not, however, renounce the doctrine of the temperaments
and the elements. Melancholia now became associated with the qualities of the chemicalelements, which are sharp and acidic. Thomas Willis (1621–1675), renowned for Two
Discourses Concerning the Soul of Brutes, expounded the theory that, in melancholia, theblood became “salino-sulphureous,” causing the spiritus animalis to adopt a different pattern of motion [51].
The high point of 17th century medical literature on melancholia, however, wasRobert Burton’s The Anatomy of Melancholy, published in 1621 [52]. This work, which
may seem somewhat bizarre to the modern reader, offered a compilation of all contemporary knowledge on the subject of melancholia. Greatly indebted to ancient medicine andphilosophy, Burton punctuated his arguments with references from ancient times. He subscribed to the dichotomy of the passions (derived from Thomas Aquinas), a doctrine thatwas generally accepted at the time. Here, the passions that predisposed one toward desire(passiones concupiscibiles) were distinguished from those which predisposed one toward
rage (passiones irascibiles). “Sorrow” and “fear,” emotions (perturbationes) belonging to
the latter category, were described by Burton as being directed at the evil that crossed

12

Glas

one’s path. Sorrow was related to disaster in the present, fear to disaster in the future.
Burton considered sorrow to be a major cause of melancholia, as well as one of its manifestations. It was:. . . an inseparable companion, the mother and daughter of melancholy, her epitome, symptom,
and chief cause [53].

The same was true of fear, the emotion most able to hold the imagination in thrall [54].
The imagination was:. . . medium deferens of the passions, by whose means they work and produce many times
prodigious effects [55].

Burton went on to add, however, that the converse was also true, since imagination serves
to enhance the impact of emotions.
In discussing the symptoms of melancholia, Burton considered fear and sorrow to
be two of a whole list of phenomena affecting those suffering from this condition. However, although these emotions were relatively nonspeciﬁc, this did not mean that they
were unimportant. Burton was acquainted with many of the forms of anxiety known today.
He made reference to fear of death, fear of losing those who are most important to us,
and paranoid anxiety. He also cited anxiety based on ideas and delusions of reference,fear associated with depersonalization, delusional depersonalization, and hypochondria.
Other forms that are mentioned include agoraphobia (!) and many other kinds of speciﬁc
phobias, such as fear of public speaking, fear of heights, claustrophobia, anticipatory fear,
and hyperventilation [56]. The physiology of emotions was strongly emphasized in RenéDescartes’ Les Passions de l’Âme (The Passions of the Soul), which was published about
a quarter of a century later [57–59]. This emphasis on physiology had a distinctly mechanistic ﬂavor in keeping with the contemporary trend toward a general mechanization of
the world view—a trend in medicine that really only took off in the 18th century and is
known as iatromechanics [60]. According to Descartes, passions not only prepare the body
but also predispose the soul to desire that for which the body is being prepared. The
physical manifestations of emotion therefore provide some degree of insight into the function of emotions.
Fear and anxiety did not rank highly amongst the passions [61]. Descartes considered
the emotion of fear to be quite useless. Nevertheless, his descriptions of the processes
that give rise to fear are worthy of mention, since they are representative of the 17th- and18th-century mechanistic view of disease. According to Descartes, the sight of a dangerous
animal caused certain particles (the “esprits animaux” or spiritus animalis referred to previously) to be released by the pineal gland. Although invisible, these rapidly moving particles were quite material in nature. They traversed the neural pathways to reach the heart,the leg muscles, and the circulatory system, and gave rise to the physiological componentof the ﬁght-or-ﬂight response. The altered distribution of blood then caused a rush of theseesprits animaux (animal spirits) to the brain. Here, the pores associated with fear wereopened, directing the esprits onward, back toward the periphery. Mental inﬂuences werenot, therefore, presumed to be involved in the generation of fear. Instead, fear was seen
as a complex, but purely physiological, reﬂex.
Although emotional perception was secondary, consisting of the registration of pineal gland movements, Descartes believed that such registration had a purpose, namely
evaluation. It facilitated the perception of objects in terms of their effects upon us, whether
beneﬁcial or otherwise.4 Properly employed, passions predispose the soul to desire thoseHistory of Anxiety and Depression

13

things which are naturally good for us. In this resigned adaptation to the eternal laws ofnature, one can detect the after-effects of the Stoa—after-effects that extend to the implicit
morality of certain modern-day forms of psychotherapy aiming at tolerance and cognitive
apprehension of the symptoms of anxiety and/or depression.
Descartes’ emphasis on mechanics was not accepted by the medical world until theclosing years of the 17th century. It enjoyed a brief ﬂowering in the period around 1750
before giving way to other interpretations. Those associated with iatromechanics, as it
was called, included men such as Pitcairn, Hoffmann, and Boerhaave (whose work reveals
traces of a humoral pathology, interpreted from the point of view of ﬂuid dynamics).
Boerhaave and Pitcairn favored a vasocentric approach seeking the origins of melancholia
in the modiﬁed ﬂow patterns and viscosity changes of liquids in the blood channels. Hoffmann was one of the ﬁrst to consider a neurocentric approach. He considered nerves tobe hollow tubes containing a ﬂowing liquid. Under normal circumstances, this neuralﬂuid was thin and volatile; however, if it thickened to an earthy, slimy consistency, thenmelancholia developed.
Under the inﬂuence of Isaac Newton, men such as Mead and Cullen (who was theﬁrst to use the term neurosis) speculated that this neural ﬂuid might also have electricalproperties. Cullen and others thought of this neural ﬂuid as a tenuous, highly mobile
substance that was related to ether. This etherlike substance did not actually ﬂow, buttransmitted motion to the various parts of the body by means of vibration. This caused
the ﬂuid hydraulics model of mental illness to be discarded. At the time, there was only
a vague notion of electrical phenomena. These were linked to the vitalistic interpretationof disease, the central concepts of which were tone and irritability. Cullen considered theirritability of the nervous system to be responsible for tissue tone [62].
Meanwhile, the clinical description of melancholia remained virtually unchanged.
Some still cited the Galenic trio of generalized, cerebral, and hypochondriacal melancholia. However, there were those (Boerhaave, for example) who interpreted this classicaltriad merely as stages on a continuous scale of severity. Some authors were inclined touncouple hypochondria from melancholia (of which it was the least serious form) andlink it instead with hysteria. According to Sydenham and Lorry, for example, hysteria in
women was equivalent to hypochondria in men.
The 18th century was a time bursting with tensions and contrasts, shifts and changes.
Humoralism gave way to solidism (the explanation of disease based on the properties ofthe organs and tissues). Iatrochemistry gave way to iatromechanics, which in turn was
replaced by concepts such as tone and irritability. Vasocentric views were replaced byneurocentric views. Meanwhile, vitalistic views of disease blended with speculation on
the electrical properties of neural ﬂuids. Each of these various approaches was considered
to be compatible, incompatible, or related to one another. The rational framework of theearly 18th century clearly offered medicine of that time the requisite intellectual freedom
with which to forge its principal concepts.
Toward the end of the century, this all began to change. Pathological anatomy had
expanded enormously, and greater emphasis was being given to clinical observation anddescription. It was a time of sensualism and fascination with sensory perception. Notions
such as irritability bear witness to a preoccupation with the hypersensitivity of the nervous
system and of the senses. The end of the 18th century saw the ﬁnal demise of humoralism.
During the same period, the notion that melancholia originated in the blood, or in thefunctions of the liver or spleen, was also dismissed. The central nervous system replaced
blood and abdominal organs. Today, the idea of temperament is all that remains of hu-

14

Glas

moralism. Although it has no place in the scientiﬁc view of character and personality, it
still exists as a metaphorical expression for the experience of despondent people.
E.

The 19th Century: Further Disintegration of the Conceptof Melancholia

The concept of partial insanity was popular in the nasographical schemes of the 18th
century and the ﬁrst decades of the 19th century [63]. As has been noted, medical scholarsof the late 18th century were fascinated with the sensitivity and irritability of the nervous
system. This, together with the fast-growing inﬂuence of faculty psychology (which
sharply distinguished between intellect, will, and imagination), may have contributed tothe popularity of the concept of partial insanity. This was not particularly novel, it wasmore the emphasis of an element of meaning found in descriptions of melancholia datingfrom ancient times (e.g., those of Aretaeus and Galen). For centuries it had been observedthat the thoughts and ideas of the melancholic were conﬁned to a single theme, often to
the extent that they became delusional. Melancholia was traditionally considered to be adelirium without fever, accompanied by fear, despondency, and additional phenomena
such as restlessness, insomnia, weariness, and discomfort in many parts of the body. In
addition, however, frequent reference was made to the monothematic content of the melancholia sufferer’s ideas and thoughts [64].
Late 18th-century medicine had a neurocentric orientation, one which tended tofocus upon sensitivity and cognitive capabilities. Perhaps this may have inﬂuenced theclassiﬁcation of mental illness into disorders in which the powers of judgment were completely incapacitated, and those in which they were partially impaired (partial insanity).
Melancholia was considered to fall within the latter category, a view that can be found,for example, in the Traité Médico-Philosophique sur l’Aliénation Mentale (Medical-Philosophical Treatise on Mental Disorder) by Philippe Pinel (1745–1826) [65]. Pinel also
considered mania to belong to this “melancholia with delirium.”This (temporary) identiﬁcation of melancholia with partial insanity completed thedecline of a concept that for centuries had dominated the description of mental illness.
Melancholia was divided up and its various parts were classiﬁed under other disorders.
A number of things contributed to this redistribution, such as resistance to humoral pathology, and its terminology; more detailed observation (as a side effect of growing institutionalization); and rationally inspired expectations regarding psychology’s ability to inﬂuencemental illness [66].
The ﬁrst line of demarcation was the idea of partial insanity itself. Some melancholics exhibit no signs of insanity (delirium) whatsoever; thus none of their thoughts andideas would be regarded as psychotic in the modern sense. In the Manual of Psychological
Medicine, which he wrote in collaboration with Bucknill, D. Hack Tuke (1827–1895)
distinguished between simple melancholia, in which the intellectual powers were intact,and complicated melancholia, in which they were not. The distinction applied by Henry
Maudsley (1835–1918) was essentially the same as Tuke’s, if somewhat wider in scope.
In addition to melancholia simplex (cf. Bucknill and Tuke’s simple melancholia), he distinguished not one, but two, forms of melancholia, both falling within the category ofideational insanity. These were melancholia as a form of general insanity and melancholia
as a form of partial insanity. In the ﬁrst case, intellectual derangement is complete, whereas
in the latter case it is only partial. There was also a parallel distinction in mania. However,
Maudsley went to great pains to emphasize the provisional nature of this theory [67].

History of Anxiety and Depression

15

Similarly, in France the signiﬁcance of the term melancholia declined considerably
under the inﬂuence of a nomenclature introduced in 1838 by Jean-Etienne-Dominique
Esquirol (1772–1840) in Des Maladies Mentales [68]. Since ancient times, the meaningof the term melancholia had encompassed both dejection and exultation. Finding this anunsatisfactory state of affairs, Esquirol substituted the term monomania for melancholia.
Monomania, which became an equivalent of the term partial insanity, was subdivided asfollows:
1. monomania, properly so-called, which is indicated by a partial delirium and a gay or exciting passion; this condition corresponded to maniacal melancholy, maniacal fury, or (. . .)melancholia complicated with mania; in ﬁne . . . (to) amenomania; and 2. monomania
coresponding to melancholy of the ancients, the tristimania of Rush and the delirium withmelancholy of Pinel [69].

Esquirol borrowed the terms amenomenia and tristimania from the work of Benjamin
Rush (1745–1813), the father of North American psychiatry. It was Rush who had linked
tristimania with hypochondria, alluding to the ancient hypochondriacal form of melancholia rather than to the diluted, 18th-century meaning of the term. Confusingly, besides
employing monomania in the broad sense mentioned above, Esquirol also used the term
to denote the manialike form of partial delirium. In this way, monomania became theequivalent of the ﬁrst form of monomania, the partial delirium with the “gay or exciting
passion.” The second, melancholic form of monomania was denoted by the term lypemania. In addition, Esquirol distinguished mania as a generalized insanity associated withexcitement and exultation. He occasionally tended to describe lypemania, monomania (inthe strict sense of the word), and mania as having progressive degrees of severity, thegreatest derangement occurring in mania and the least in lypemania.
Even in ancient times it was frequently pointed out that melancholia and mania
could occur in parallel, in sequence and in combination. However, it was not until 1854
that cyclical mood swings were speciﬁcally identiﬁed as the distinguishing criterion of a
subcategory of manic and depressive patients. In the same year, Jules Baillarger (1809–
1890) described la folie à double forme (the insanity with two forms), 10 days later followed by a commentary of Jean-Pierre Falret (1794–1870), in which he also discussed afolie circulaire (circular insanity). Some 40 years later, Kraepelin explicitly harked backto the work of these two French clinicians when he distinguished dementia praecox frommanic-depressive psychosis. Nonetheless, even by the middle of the 19th century, theterminological distinction between affective and schizophrenic psychopathology was byno means a fait accompli. Accordingly, Richard von Kraft-Ebing (1840–1902) declaredthat there were two forms of melancholia, namely simple melancholia and melancholiawith stupor. The latter form, also known as melancholia attonita or melancholia stupida,
was quite different from the partial delirium of French and English psychiatry. It was
related to a condition that, a few decades later, Kahlbaum was to call catatonia, which
could also be associated with reduced consciousness. With regard to simple melancholia,
von Kraft-Ebing distinguished between a mild form of melancholia that was not associatedwith delusions, melancholia associated with precordial pain, and melancholia associatedwith delusions and hallucinations. He placed strong emphasis on psychomotor inhibition
in all forms of melancholia, stating that in cases of melancholia attonita, this usually had
an organic cause, such as a blockage in the motor neuron pathways. Such inhibition could,
however, also be psychogenically induced. In practical terms, there were all kinds oftransitional states between the two major forms of melancholia. The difference between

16

Glas

these states lay in the relative degree to which mental and organic components were involved in the origin of the inhibition.
This shows that the ups and downs of 19th-century melancholia, as a concept, were
determined by a variety of different factors. In addition to attempts to distinguish newforms and the pursuit of ever-more precise classiﬁcation, there were also advocates ofcontinuity, who searched for transitional forms between the diverse clinical pictures. An
extreme example of this is provided by Wilhelm Griesinger (1817–1868), who strongly
defended the concept of a unitary psychosis (Einheitspsychose) in his Die Pathologie
und Therapie der psychische Krankheiten für Ärtzte und Studierende (The Pathology andTherapy of Mental Diseases for Physicians and Students). In this work, he cited both his
mentor, Zeller, and the Belgian alienist Guislain. According to Griesinger, the various
clinically deﬁned forms of mental illness could be reduced to the different stages of one
and the same disease. The ﬁrst of these successive states of mental depression was thestadium melancholicum—that is, the deterioration of normal emotions such as grief andjealousy. Next came hypochondria, the mildest form of insanity. This was followed bymelancholia in sensu stricto, which, although not necessarily associated with psychotic
phenomena, had a greater effect on the personality than did hypochondria. Finally, there
was mania, which caused the most pronounced mental derangement of any of the conditions listed here.
F.

Emil Kraepelin

The debate about the classiﬁcation of mood disorders, which continued on into the 20th
century, centered around the question of whether or not this group of disorders could be
subdivided. However, after 1900, the matter of whether mood disorders constituted a separate category of mental illness was hardly ever discussed.
This remarkable fact can be largely traced back to the work of one man, Emil
Kraepelin (1856–1926). It has often been pointed out that the term melancholia (alongwith related terms such as mania, partial delirium, and monomania) certainly cannot be
identiﬁed with what we currently refer to as affective disorder. The clinical pictures werealways those incorporating a variety of phenomena that would currently be regarded as
expressions either of schizophrenia or of a schizophreniform disorder. It is remarkable,
to say the least, that this age-old intermingling of psychotic and affective symptomatology
should have come to an end at the beginning of this century.
In his early years, Kraepelin worked with the neuroanatomist Flechsig. For a lengthy
period, he was also a research worked in Wundt’s psychological laboratory. Kraepelincannot simply be portrayed as a materialist, or as a somatologist; his ﬁeld of interest wasmuch too comprehensive for that [70]. Nevertheless, the idea that every psychiatric clinicalpicture could ultimately be reduced to an organic substratum in the brain was kept aliveby Kraepelin and many of his contemporaries. They were motivated by the discovery of
the cause of dementia paralytica, the confrontation with many cases of alcohol dementia,
and the aftermath of the theory of degeneration, formulated by Morel in the middle ofthe 19th century. Kraepelin accordingly established an anatomical laboratory in Heidelberg. He also brought in Nissl, a histopathologist, to assist him in the visualization of
the cerebral cortex. Their collaboration eventually bore fruit in the form of photographs(measuring from 50 to 75 cm) showing general views of the cerebral cortex [71].5
However, it was not these efforts that ultimately contributed to the lasting topicalityof Kraepelin’s work. Possibly inﬂuenced by Kahlbaum, Kraepelin became persuaded

History of Anxiety and Depression

17

about the importance of systematic clinical observation and description. This conviction
inspired him to amass a database of all the patients registered in Heidelberg. This databaseenabled him to follow the medical histories of his patients, in some cases for several
decades. It formed the basis for the separation of manic-depressive illness (‘das manischdepressive Irresein’) from schizophrenia (dementia praecox), which was ﬁrst described in
the ﬁfth (1896) and sixth (1899) editions of his famous textbook [72]–[74]. Although
there was always a bias toward neuroanatomy and localization, it gradually faded into thebackground and made way for a more functional and strictly empirical approach in whichclassﬁcation had less to do with diagnosis (i.e., the cause) and more to do with prognosis[75]. It was the course alone (rather than cause, symptoms, or periodicity) that proved
decisive in demarcating dementia praecox from manic-depressive illness. Dementia praecox led, by deﬁnition, to personality decline (Verblödung; dementia), whereas manicdepressive illness did not.
(. . .) the universal experience is striking, that the attacks of manic-depressive insanity within
the delimitation attempted here never lead to profound dementia (Verblödung, G.G.), noteven when they continue throughout life almost without interruption. Usually all morbid manifestations completely disappear; but where that is exceptionally not the case, only a rather
slight, peculiar psychic weakness develops, which is just as common to the types here taken
together as it is different from dementias in diseases of other kinds [76].

At the onset of the illness, it can be extremely difﬁcult to reach a correct diagnosis. Somethings to go by are age at onset (younger than 20 or beyond middle age) and a conﬁrmed
family history. There is also the premorbid character that, in the case of manic-depressive
illness, is weak, susceptible, dejected, and lacking in self-conﬁdence [77].
Meanwhile, the category of manic-depressive illness was very broad, encompassing
much more than the bipolar disorder, as it is called today:
Manic depressive insanity (. . .) includes on the one hand the whole domain of the so-called
periodic and circular insanity, on the other hand simple mania, the greater part of the morbid
states termed melancholia and also a not inconsiderable number of cases of amentia. Lastly,
we include here certain slight and slightest colorings of mood, some of them periodic, someof them continuously morbid, which on the one hand are to be regarded as the rudiment of
more severe disorders, on the other hand pass over without sharp boundary into the domainof personal predisposition. In the course of the years I have become more and more convincedthat all the above mentioned states only represent manifestations of a single morbid process [78].

In this deﬁnition, the bipolar disorder of our time coincides with “periodic and circularinsanity.” Here, manic derangement is characterized by the triad of rapid association ofideas, elated mood, and hyperactivity. Depression, on the other hand, is associated withthe triad of dejection or anxious moods, inhibition of thought, and reduced spontaneity.
In addition to the circular and simple disorders, amentia, and milder mood disorders,Kraepelin also refers to mixed pictures. These cases exhibit characteristics resembling themixed episodes of contemporary bipolar disorder. He also refers to the so-called “groundstates” (Grundzustände; predisposing personality traits), which form the basis for the development of mood disorders [79]. Kraepelin distinguished four ground states: depressive,
manic, irritable (erregbare), and cyclothymic. Finally, a distinction was made between
this group and the form of melancholia associated with a decline due to the effects ofaging (Rückbildungsalter; involution). In the latter case, inhibition was often absent whileanxiety and hypochondria were more prominent. Although Kraepelin was initially inclined

18

Glas

to keep this (involutional) melancholia separate from the others, he abandoned this idea
after the comprehensive study of this clinical picture by [80]. He subsequently included
this form of melancholia within manic-depressive psychosis (das manisch-depressive
Irresein). The debate about involutional melancholia was not ﬁnally settled until the 1970s
when this condition became just another form of depression.
Something that is common to all forms of manic-depressive illness is the absenceof an immediate cause, or at least a course that appears to be independent of possible
causes. A distinction should therefore be made between psychogenic depression and theconditions referred to above [81]. The most fundamental cause of manic-depressive psychosis is an hereditary, morbid predisposition. According to Kraepelin, of the 990 casesthat he studied in Heidelberg, he managed to establish that about 80% involved an hereditary defect [82].
Despite opposition [83,84], Kraepelin’s interpretations nevertheless enjoyed great
authority in German-speaking regions. For example, this is demonstrated by Eugen
Bleuler’s textbook, which was published in 1916. In describing the manic-depressive illness as a distinct disorder, this work relies heavily on the questions that Kraepelin had
raised on the subject [85]. The 13th edition of this book, published in 1975, exhibits somereservations about the heredity hypothesis and about the possibility of an airtight distinction between dementia praecox, on the one hand, and psychogenic disorders on the other.
Nevertheless, it still contains references to the old Kraepelinian classiﬁcation [86].
G.

Critique on Nosology: Reaction Type Versus Endogeny

The situation was different in the United States where, during the ﬁrst decade of the 20th
century, Adolf Meyer (1866–1950) expressed doubts about the value of the course criterion. He distinguished several forms of depression, such as constitutional depression, simple melancholia proper, other forms characterized by neurasthenic malaise or hypochondriacal complaints, depressive deliria, catatonic melancholia, and the so-called “delire denegation,” in which the patient believes he is nothing [87]. This was more than just adebate about classiﬁcation. Meyer was particularly uneasy about the coupling of heredity(endogeny) and manic-depressive psychosis, in the broad, Kraepelinian sense. He viewed
this link as nothing more than “neurologizing tautology,” which might easily give rise totherapeutic nihilism. Moreover, it did not do justice to the fact that mental illness is anattempt at adaptation, a reaction to the demands of a changing situation. Only when disease
is seen as an inadequate attempt at recovery, the search for what he called “modiﬁable
determining factors” could begin. We are then “in a live ﬁeld, in harmony with our instinctsof action, of prevention, of modiﬁcation and of an understanding doing justice to a desire
for directness” [88].
The question remains as to whether Meyer did justice to Kraepelin. In any event,Kraepelin cannot be accused of therapeutic nihilism. Under his direction, the enlarged
baths at Heidelberg achieved international fame and were visited by many foreign guests.
Nothing was too much trouble for him when it came to experimenting with new methodsof treatment. Of greater importance is the conceptual point at issue here. According to
Meyer, the debate on classiﬁcation should not be short-circuited by an appeal to suchideas as endogeny and heredity, about which nothing was empirically established. He did
not presume that biological processes should enjoy a privileged position in the list ofdetermining factors for mental illness. For this reason, Meyer substituted the term manicdepressive psychosis with the etiologically neutral term “affective reaction type.” Within

History of Anxiety and Depression

19

this reaction type, he distinguished a manic-depressive type, an anxious type, and simple
depressions [89].
Essentially the same view was held by Sir Aubrey Lewis who, in the 1930s, published an authoritative study of 61 cases investigated at the Maudsley Hospital in London[90–92]. According to Lewis, a total reaction of the organism is involved, even in cases
where the illness appears to be entirely without cause. Without doubt, there werechanges in the internal structure of the body, its chemical and vegetative regulation whichplay a great part in determining its course. But these are only part of the total reaction of
the organism, and it is by no means in denial of their fundamental importance in the illness
that one refuses them independent and preponderant signiﬁcance, either aetiological or as
part of the process of the illness [93].

According to Lewis, the more closely patients were studied, the less evidence there was fora nosological distinction between autonomous (endogenous) and reactive (psychogenic;
situational) depressions. Incidentally, the very same view had already been expressed 8
years earlier by Mapother, Lewis’ predecessor, on the basis of impressions obtained inclinical practice.
This established the scope of a debate which, since then, has been repeated withendless variations and which, even now, continues to exert a hold on psychiatry [94,95].
Ironically enough, the seeds of controversy were sown by Kraepelin, the very person who
most wanted to distance himself from the speculative impetus within the debate. In spiteof his empirical bias, Kraepelin continued to link the clinically descriptive course criterionwith the etiological hypothesis of endogeny. Through this, the reference to heredity became an established fact. In practical terms, Kraepelin’s coupling of the course criterionwith the idea of endogeny raised two mutually related issues, namely: (1) the role ofexogenic (biological and nonbiological) factors in the origin of depression and (2) thedemarcation of manic-depressive illness with respect to psychogenic depressions andmilder variants within the manic-depressive spectrum [96,97].
Both of these issues ultimately proved to be insoluble within the framework of theendogeny/exogeny dichotomy. In practice, it was quite impossible to distinguish between
depressions that were psychogenically induced and those in which psychological and situational factors merely played an instigating role. The responsiveness of the illness proved
to be of only limited signiﬁcance as a distinguishing criterion. Meanwhile, it should not
be forgotten that, in Kraepelin’s time, the term endogeny was also an expression of embarassment. At the end of the 19th century, Möbius introduced the twin concepts of endogeny
and exogeny. By about 1900, these concepts corresponded respectively to diseases whose
causes were still unknown and those whose causes had been well deﬁned. Causes whose
existence were (still) uncertain were described as endogenous. These were attributed, moreor less out of embarrassment, to innate personal qualities [98]. Exogenous causes included
bacteria, toxins, and tissue injury resulting from brain trauma. In 1910, Bonhoeffer devoted
a monograph to these so-called exogenic reactive types, and his name has been linked tothem ever since [99].
H. The Inﬂuences of Psychology and Psychoanalysis
After 1920, mainly because of changes in the use of the adjective “exogenous,” this debate
became even more complex. Originally this term was used only in relation to biologicalfactors; now it was extended to include intrapsychic and situational factors as well, thus

20

Glas

highlighting the demarcation between depression and neurosis. New dichotomies consequently arose, such as endogenous/reactive (Lange); autonomous/reactive (Gillespie);
endogenous/neurotic; psychotic/neurotic. After World War II, these were supplemented
by S (somatic) type/J ( justiﬁed) type (Pollitt); and vital depression/personal depression(van Praag). Of course, this shift in the debate cannot be dissociated from the inﬂuenceof Sigmund Freud (1856–1939) and the psychoanalytic school. In one of his early works,
the so-called Draft G, Freud had already addressed the neurological explanation of melancholia [100]. In 1917, he published an excellent, authoritative article on the link between
grief and melancholia [101]. In this article, he stated that, unlike grief, object loss inmelancholia was associated with unresolved feelings of ambivalence and regression of
the ego. Anger at being abandoned would then be directed toward the ego, which remained
narcissistically identiﬁed with the other. This internal “other” was then destroyed. Indeed,
Karl Abraham had already demonstrated self-destructive behavior and experiences in depressive patients [102]. From here, a line can be drawn via the work of Melanie Klein toauthors such as Lindemann [103] and Bowlby [104–106]. Klein distinguished a depressive
position as a phase in early childhood development. Lindemann wrote an inﬂuential article
on reactions to grief. Bowlby, as is well-known, worked extensively on the relationshipbetween psychopathology and the processes of attachment and separation.
The inﬂuence of the theory of emotions, developed by the philosopher Max Scheler(1874–1928) should also be mentioned. Scheler distinguished between four emotional
levels or strata: the level of sensory, physical (or vital), psychic, and spiritual feelings,
respectively [107]. This theory constitutes part of Scheler’s own moral philosophy withemphasis on values as nonsubjective realities that are expressed in the interaction between
a person and the environment. Scheler’s theory had the advantage of accounting for thefact that people are capable of experiencing more than one mood and/or emotion at atime. A person can be in a dejected mood while at the same time being angry with hisneighbor. Kurt Schneider applied this feeling theory to depression by stating that depression is based on a disorder in the vital sphere. Psychic feelings, such as feelings of guilt
and inadequacy, whould then be an “understandable reaction” to this vital disorder. The
vital feeling of being depressed would co-occur with psychic feelings of guilt and worthlessness. This theory of feelings was held, albeit temporarily, in high esteem. The adjective“vital” for endogenous depression, which until recently was in use in Europe, represents
the psychopathological remnant of this theory.
I.

Toward the Twin Pillars of DSM-III

Psychoanalysis enjoyed considerable inﬂuence for several decades, to such a degree that
there was barely any perceptible movement in the classiﬁcation debate. However, thisbegan to change with the discovery of the mechanisms of action of antidepressants, toward
the end of the 1950s. At that time, the effects of lithium had been known for 10 years
while ECT had been in use for more than 20 years. The advent of these new therapeutic
drugs raised the question of whether the biological active site of these drugs could belinked with speciﬁc target symptoms of depression (or mania). Gradually, it was acceptedthat this was indeed the case. Target symptoms, it was assumed, pointed to a given coredisorder in the spectrum of depressive symptomatology. The increasing use of advanced
statistical methods also had considerable impact on the debates. It enabled larger groupsof patients, taken from adjacent diagnostic categories, to be investigated for clustering ofHistory of Anxiety and Depression

21

symptoms (discriminant function analysis) and underlying factors or dimensions (factor
analysis).
The outcome of these developments was not immediately obvious [108]. In summary, the classiﬁcation debate gradually split into two separate debates after 1960. These
concerned (1) the distinction between manic-depressive psychosis and other forms of depression; and (2) the distinction between “endogenous” and neurotic depression.
The considerable overlap between these two debates served only to complicate matters, since the classiﬁcatory status of endogenous depression was central to both. When
highlighting some moments of this debate, mention should ﬁrst be made of the clinicaland genetic studies of Perris [109] and Angst [110]. Both workers found that depressives
with a previous history of mania had different hereditary proﬁles from those with no suchprevious history. On the basis of these ﬁndings, they concluded that the distinction between
unipolar and bipolar depressions, which was already defended on clinical grounds byLeonhard in 1959, was valid. This distinction became one of the basic assumptions of
the classiﬁcation of mood disorders in the DSM-III [111] and its subsequent editions[112,113].
Kendell, meanwhile, carried out a retrospective investigation of 1080 patients who
had been admitted to Maudsley Hospital [114]. He could ﬁnd no evidence of a bimodal
distribution in the symptom proﬁles of a heterogeneous group consisting of manic depressive patients, patients with neurotic depression, and patients with involutional melancholia. However, this kind of distribution was found in the Newcastle study. Somethingcommon to both studies was the relatively high loading of a “bipolar” factor.
As Kendell himself observed, his investigation did not negate the distinction between psychotic and neurotic depression. These could represent two poles of a continuum,with the psychotic pole displaying greater homogeneity than the neurotic pole. The simple
fact that the symptoms of the neurotic side are milder and fewer in number contributed
substantially to the reduced tendency toward clustering [115].
The lack of homogeneity at the neurotic depressive pole of the spectrum also foundexpression in the tri- and tetra-partite divisions of Klein [116] and Paykel [117], respectively. Klein distinguished an “endogenomorphic” depression, as well as a reactive anda (chronic) neurotic form. Paykel distinguished psychotic depressives as well as three othergroups: anxious depressives, hostile depressives, and young depressives with personality
disorder. Again, remarkably, some degree of consensus existed with respect to the psychotic or “endogenomorphic” end of the spectrum. The limited extent of this consensus
was due to the fact that, for the above-mentioned authors, the central issue was not bipolarity (cf. Perris, Angst, and Kendell), but rather vital phenomena and psychotic symptoms.
For this reason, it is not surprising that some clinicians opted for a center-periphery insteadof a continuum model. Mendels and Cochrane, for example, observed that:the so-called endogenous factor might represent the core of depressive symptomatology,
whereas the clinical features of the reactive factor may represent phenomenological manifestations of psychiatric disorders other than depression which ‘contaminate’ the depression syndrome [118].

Ultimately, however, with the advent of DSM-III(R), neither the center-periphery nor thecontinuum model was to gain the upper hand. Instead, the winner was a twin pillar model,
centering around the pillars of bipolar disorder and depressive disorder. In an article thatappeared in 1974, Klein articulated an important consideration regarding this shift [119].

22

Glas

He pointed out that endogenomorphic depressions (those which give the impression of
having arisen endogenously) occur particularly frequently in the group of neurotic depressives. As a result of epidemiological studies, less emphasis was placed upon the heterogeneity of neurotic depressions. Conversely, greater attention was paid to the chronicity
and severity of the disease. Finally, in the 1980s, genetic investigations not only favoredthe further demarcation of bipolar disorder—something which had already been advocatedon the basis of factorial analysis studies—but also the distinction of dysthymia (neurotic
depression) as a separate category.
In summary, it can be said that a consensus began to emerge in which the mostimportant demarcation line was drawn between bipolar disorder and unipolar depression.
In addition, within the group of unipolar depressive disorders, a subdivision was created,roughly corresponding to the distinction between endogenomorphic and chronic neurotic
depression as described by Klein. Ironically enough, the old concept of melancholia wasonce again called upon for assistance, namely, in the deﬁnition of the endogenomorphic(vital) form of major depression.
It should be noted, however, that this consensus was by no means universal. For
example, it still has not been decided whether or not the categorical distinction between
cyclothymia and dysthymia, on the one hand, and personality disorders, on the other, isan artifact. In addition, the debate about the demarcation between affective and anxiety
disorders has become of particular relevance in the past decade. Longitudinal, familiar,
and epidemiological studies have demonstrated that there is a high degree of comorbidity
between affective and anxiety disorders, both in the course of the illness and in relatives.
However, this discussion is beyond the scope of this chapter.
I switch now to a discussion of some highlights from the conceptual history ofanxiety and anxiety disorders.

IV. HIGHLIGHTS FORM THE CONCEPTUAL HISTORY OF ANXIETYAND ANXIETY DISORDERSA.

The Demarcation of Agoraphobia

As mentioned in Sec. II, prior to about 1850, anxiety was not considered to be a distinct
form of psychopathology in the medical literature. This is of particular importance to therecent debate on the demarcation between affective and anxiety disorders. For hundredsof years, the symptoms of anxiety had simply been seen as part of melancholia. In thecourse of the past century and the present one, the various forms of anxiety came to be
distinguished from depressive disorders, on a variety of grounds. In light of the centuryold merging of anxiety and depression, a reconsideration of these grounds is therefore amatter of considerable topical interest. Why the urge to merge the independent statusof various forms of anxiety within the total spectrum of psychopathological symptoms?
Historically, attention focused initially on phobias. Phobic anxiety, like other symptoms ofanxiety, had been described in other terminology in the Hippocratic texts. Burton describedagoraphobia, claustrophobia, and fear of public speaking. Errera [120] cites le Camus’Médecine de l’Esprit (Medicine of the Mind) from 1769 [121] and de Sauvages’ NosologieMéthodique (Methodical Nosology from 1770–1771 [122] as being the ﬁrst medical studies in the ﬁeld of phobia. The former includes a section on Des aversions (avoidance
behavior) while the latter lists many different types of phobias. The term phobia wasHistory of Anxiety and Depression

23

occasionally used in a diagnostic context even before 1850, as, for example, in the 1798
work of Benjamin Rush [123].
However, three publications that appeared around 1870 became particularly authoritative. The ﬁrst of these was a short article by Benedikt entitled Über Platzschwindel (Ondizziness on squares) [124]. Here, the author focused on a form of dizziness that, becauseof its characteristic symptomatology and treatability, in his opinion, merited a separate
classiﬁcation among the various forms of giddiness. This article was to go down in medical
history as one of the ﬁrst descriptions of agoraphobia. As just noted, this is in fact historically inaccurate. Furthermore, the term “Platzschwindel,” was invented by Griesinger, notBenedikt. Nevertheless, by according a separate classiﬁcation to the series of phenomena
currently referred to as agoraphobia, Benedikt’s article does mark a turning point.
Although Benedikt had observed anxiety in the patients he described, he believed
this to be secondary to the dizziness:. . . however, as soon as they enter a wider street or (especially) a square, they are overcome
by dizziness. They either become terriﬁed of collapsing mentally or else they are gripped bysuch tremendous fear that they will never dare to pass through such a place again [125].

Two years later, Westphal challenged the view that dizziness was of primary importance[126]. Westphal, who was the ﬁrst to use the term agoraphobia in a technical sense, believed that anxiety, rather than dizziness, was at the root of this phobia. It was anxiety
that caused the dizziness, not the other way around. Westphal’s observation was the forerunner of a debate that went full swing more than a century later [127]. This debate centersaround the provocative role of bodily sensations and their interpretation in the origin ofpanic attacks. Westphal based his hypothesis upon clinical observation, rather than ontheoretical considerations. He imputed Benedikt’s interpretation to the incompleteness of
his investigations [128].
Interestingly enough, Westphal himself was very much aware of the fact that thethree patients he described were certainly not afraid of streets or squares, as such. He
stressed the unfounded nature of their anxiety. Theirs was rather a fear of anxiety itself,
an anxiety that only much later is linked to particular situations. Modern-day authors who
point out that agoraphobic anxiety is not a fear of streets or squares and that it occurs
under all sorts of other circumstances ﬁnd an ally in Westphal.
B. Anxiety Under Circumstances of War
During the same period, Da Costa published an article on cardiac symptoms in exhausted
infantry soldiers during the Civil War [129]. Da Costa, himself a cardiologist, spoke ofan “irritable heart.” Observations of more than 300 patients led him to believe that thiscondition was caused by a heightened nervous irritability of the heart, which, in turn,was caused by prior overactivity, such as long marches or physical illness, for example.
During auscultation of the heart, Da Costa heard a weak and sometimes split ﬁrst sound,a pronounced second sound, and sometimes a systolic murmur. This systolic murmur
has recently been related to the midsystolic click of mitral valve prolapse. Da Costa
spoke of a sound “like the sudden motion of an only slightly elastic or cartilaginous substance” [130].
This classic article by Da Costa continued to stir things up among cardiologists,neurologists, and psychiatrists well into the middle of this century [131]. The debate became particularly intense during and after both world wars when, once again, tens of

24

Glas

thousands of those departing for the front lines were afﬂicted with the syndrome describedby Da Costa. Thomas Lewis gave a ﬁgure of 70,000 such cases among British soldiersduring World War I, 44,000 of whom subsequently received a war pension [132]. In
addition to a report on this subject, which he drew up for the Medical Research Committee
in 1917, in 1940 Lewis also published a monograph on the same theme [133]. By thattime, many agreed with Lewis that the term “irritable heart” was incorrect, since thisplaced a one-sided emphasis on heart palpitations and on pain in the region of the heart,which wrongly suggested that the complaints were cardiac in origin. However, despite
this consensus, there was still no unanimity about what actually lay behind the syndrome.
This lack of unanimity was also reﬂected in the nomenclature. Lewis introduced
the term effort syndrome in order to emphasize both the intolerance to physical exertionand the syndromal character of the picture described by Da Costa. While the clinicalpicture was indeed determined by cardiac symptoms, he found that only one-sixth of thepatients actually suffered from heart disease. Other terms that came into use were soldier’s
heart [134], war neurosis [135], Da Costa syndrome [136], neurocirculatory asthenia, andheart neurosis.
Following rejection of the cardiac hypothesis, the controversy over etiology mostly
centered on whether this picture was determined by psychic factors [137,138] or whether
it was a syndrome that could develop in more than one way [139–142].
Mackenzie, for example, blamed the confusion surrounding the condition (which
he termed soldier’s heart) on consideration of some individual symptoms to the exclusionof all else, and on the fact that this disorder had been named after its most prominent
symptom (in this case, heart palpitations and pain in the region of the heart). Becauseof this, less prominent symptomatology tended to be disregarded. Mackenzie states that,
according to the “law of associated phenomena,” local disorders are usually accompanied
by so-called reﬂex symptoms in other parts of the body (see Sec. IV. D). Moreover, long
before the formulation of the attribution theory, he already emphasized the inﬂuence of
medical terms on the way in which disease is perceived. By designating the systolic murmur associated with effort syndrome as an aortic or mitral valve defect, physicians could
turn their patients into invalids. Intolerance to exertion would then wrongly be labeled asheart disease.
The debate was settled provisionally by two collaborative studies by a number of
specialists from a section of the Maudsley Hospital, which was rehoused at Mill Hill
School during World War II. A special unit had been set up at the school for the purposeof studying patients with effort syndrome. One of these studies was an award-winningwork by Maxwell Jones, who later achieved fame as a champion of the therapeutic community [143]. In the other study, cardiologist Paul Wood concluded that the symptoms of
Da Costa syndrome were also prevalent in peace time and that they closely resembled thesymptoms of anxiety neurosis [144]. Although constitution, heavy exertion, and previous
infectious diseases could all be precipitating factors, effort syndrome was ultimately explicable in terms of (and maintained by) a neurotic mechanism. It affects those who, in their
youth, “clung too long to their mothers’ skirts” [145] and who, either due to parental
overconcern or to comments by their physician, learned to interpret various (normal) physiological changes as signs of physical impotence or even of danger.
Like Mackenzie, Wood placed great emphasis on the suggestibility of the patients,
particularly on their capacity to interpret, in a negative way, the normal physiologicalchanges that occur during physical exertion. Wood’s interpretation was partly based uponphysiological experiments that had demonstrated that peripheral sensation in effort syn-History of Anxiety and Depression

25

drome was founded neither upon local abnormalities like hypersensitivity of the central
nervous system (such as in hyperadrenalism), nor hyperventilation. Therefore, in his opinion, there was no speciﬁc pathophysiological mechanism that could be held responsible
for the physical symptoms. However, there did exist a speciﬁc psychological mechanismthat involved the association of exertion with all sorts of imaginary physical catastrophes.
Wood believed that this association was mediated by an emotion, usually anxiety, althoughpatients were generally not consciously aware of this. Therefore, the therapy consisted ofa form of psychoeducation in which people were informed of the physical manifestationsof emotions and of the fact that physical sensations were not, by deﬁnition, indicative ofa disorder in any particular organ.
Maxwell Jones concurred with this. He developed a form of group psychoeducation,using groups of about 100 patients, which later evolved into the ﬁrst therapeutic community. The aim of therapy was to teach patients to adopt a different attitude toward their
symptoms. In addition, Jones stressed the reality of intolerance to exertion, for which
extensive physiological studies failed to provide an explanation. He therefore spoke ofan effort phobia. Jones’ investigations had demonstrated that effort phobic patients quit
exerting themselves long before they reach their physiological limit, as expressed by aslightly smaller increase in the lactate level relative to a normal control group following
the subjective maximum of exertion.
The debate can be summarized by stating that the variation in nomenclature wasdetermined not only by all sorts of theoretical views concerning the causation of physicalsensations, but also by the immediate military importance of identifying and treating those
suffering from war neurosis. Wars have contributed greatly to our knowledge not only ofanxiety disorders but also, for example, of traumatic neuroses and terror psychoses[146,147]. In addition, they have propelled this knowledge in a speciﬁc direction. Lewis’choice of the term effort syndrome was signiﬁcant, as was his involvement in the development of exercise programs to increase the exertion tolerance of the soldiers he was treating.
Both can be seen as a direct reﬂection of the military importance of the capacity to deliver
physical effort [148]. Lewis’ effort syndrome is a splendid example of social inﬂuences
affecting psychiatric diagnosis. Regarding subsequent developments, it can be noted thatthe special relationship between anxiety phenomena and the heart persisted even after
1950. While consideration was being given on the sidelines to the psychiatric mode ofinterpretation, the somatic approach continued to play a dominant role. The 1960s saw
the development of somatic concepts such as hyperkinetic heart syndrome and hyperdynamic beta-adrenergic condition. In the 1980s and 1990s, the relationship between anxiety disorders and mitral valve prolapse has been the subject of debate, as has the so-called
fatigue syndrome [149,150].
C. Anxiety Psychosis
The frequent occurrence of anxiety with psychotic symptoms did not, of course, go unnoticed by 19th-century psychiatry. Wernicke, however, was the ﬁrst to use the term anxiety
psychosis. In Wernicke’s opinion, frightening cognitions, hallucinations, delusions, anddelusory ideas were the result, rather than the cause, of the emotion of anxiety. He explained the psychotic phenomena seen in anxiety psychosis by the intensity of the anxiety
itself. The reverse was true of alcohol hallucinosis, where anxiety was the result of thehallucinations. Melancholia also differed from anxiety psychosis. So-called agitated melancholia, on the other hand, which was actually a variant of anxiety psychosis, was totally

26

Glas

unrelated to melancholia [151]. The motor expressions that appeared in anxiety psychosis
were interpreted by Wernicke as complications, rather than as direct consequences ofanxiety. In the ensuing debate, criticism was leveled at the term anxiety psychosis[152,153]. Some questioned the worth of a classiﬁcation that was based on the content
of cognitions. Anxiety-dominated cognitions were not restricted to anxiety psychosis; theyalso occurred in a variety of other psychiatric disorders. Wernicke himself had alreadymade a distinction between anxiety psychosis, on the one hand, and anxiety in paranoiddelusions and in delusions of reference, on the other. The distinguishing criterion—
namely, that the cognition in anxiety psychosis must be a direct consequence of anxiety—proved not to be unequivocally applicable in practice.
Meanwhile, Specht’s interpretation differed considerably from that of Forster.
Specht felt that anxiety psychosis was a mixed (Kraepelinian) form of manic depressive
psychosis in which motor agitation was an expression of the manic component. Like Wernicke, he drew a sharp distinction between anxiety and agitation on the basis that theformer frequently occurred in depression, while the latter was commonly a feature ofmania. Specht’s view was that anxiety psychosis involved motor agitation as an expressionof the manic component, accompanied by the anxiety and inhibition of thought as a resultof the depressive component. For Wernicke, anxiety was the central characteristic of anxiety psychosis; for Specht it was agitation.
Forster, on the other hand, felt that the symptoms of anxiety psychosis could best
be seen either as a variant of melancholia (melancholia agitata) or as the early stage ofanother disorder. Not only did Forster not want to separate anxiety from agitation, he also
resisted Kraepelin’s separation of manic depressive psychosis from dementia praecox. In
his opinion, anxiety was not so much an emotion that was difﬁcult to deﬁne, but more acomplex series of cognitions that cannot be expressed in words. This formal characteristic,i.e., a special type of cognitive complexity, was determined by the “fundamental disorder”
that Forster placed at the level of the organic cerebral substratum [154].
In the ninth edition of Kraepelin’s textbook, anxiety psychosis was still included
under the Emotionelle Symptomenkomplexe (emotional symptom complexes). It was deﬁned as a dysphoric condition that cannot be sharply distinguished from depression. It
was associated with anxiety, motor restlessness, and psychotic symptoms [155]. As asymptom complex, it could occur in all types of psychiatric disorders, including manic
depressive psychosis and dementia praecox. It could also be age-related, as in presenility
and senility.
Two questions dominated this somewhat confusing debate surrounding anxiety psychosis. These concerned the relationships between emotions and cognition, and between
anxiety and (psycho)motor agitation. On the ﬁrst point, Wernicke considered the anxiety
emotion to be dominant, whereas Forster placed the cognition in the leading role. Specht’s
reference to the Kraepelinian idea of the manic depressive mixed condition suggested apreference for the view that the affective component was dominant. On the second point,
both Wernicke and Specht made a sharp distinction between anxiety and agitation. With
regard to a distinguishing criterion for anxiety psychosis, Wernicke emphasized the anxiety, Specht the agitation. Forster allowed anxiety, agitation, and desperation to intermingle,
since he believed that there were insufﬁcient empirical grounds for a sharp distinction
between anxiety disorders, manic depressive disorders, and psychotic disorders. Basically
Forster rejected the traditional classiﬁcation (derived from faculty psychology) into thinking disorders, feeling disorders, and disorders affecting the function of the will [156].

History of Anxiety and Depression

27

In the post-1910 literature, two publications are worthy of mention: G.E. Störring’s
Zur Psychopathologie und Klinik der Angstzustände (On the psychopathology and treatment of anxiety states) [157] and K. Conrad’s Die beginnende Schizophrenie (incipient
schizophrenia) [158]. Although neither work includes the term anxiety psychosis, both
point out the fundamental signiﬁcance of anxiety in the origin of psychosis. Both go on
to describe a period of depersonalization, anxiety, and anxious moods which often precedes the onset of psychosis. Conrad used the term trema to denote this anxious delusory
mood. Störring described how this anxious delusory mood could lead to so-called objectivation of anxiety, which nowadays is called projection. Feelings of anxiety are no longer
experienced internally, but transform into perceptions of a dreadful and mysteriously
changed world. In the case of psychosis, the background to this symptom is a disorderthat affects the sense of identity. Psychotics are no longer able to perceive themselves as
the source of meaningful experiences and activities. Feelings lose their natural bondwith the I. As a consequence, they take on an enigmatic and indeterminate character.
While the patient does not necessarily experience anxiety subjectively, the world nevertheless changes in an obscure way and appears to be terrifying, threatening, and gruesome.
Sometimes anxiety is experienced in ﬂashes, in which case, according to Störring, it makes
sense to speak of a delusory affect rather than of a delusory mood.
Meanwhile, with the virtual disappearance of the term anxiety psychosis from clinical usage, interest in anxiety symptoms in the context of psychosis had also faded [159].
However, studies pertaining to the occurrence of panic attacks in schizophrenia and inschizophreniform disorders are still published from time to time.
D. Neurasthenia
In the second half of the 19th century a new concept, neurasthenia, gained ground. George
M. Beard, the American advocate of this idea, considered neurasthenia to be a functional
disorder characterized by a deﬁciency of “nervous force.” This deﬁciency could express
itself in a multitude of symptoms, particularly at the level of the central nervous system,
the digestive tract, and the reproductive tract [160,161]. Although not highly prominent
among these symptoms, morbid fear and phobia were nevertheless ranked among the most
difﬁcult symptoms to cure [162,163]. Beard used analogies for nervous exhaustion suchas that of a furnace lacking in fuel and of a battery losing its charge [164]. Central to theconcept of neurasthenia was the lack of the strength and reserve to ﬁght the disturbancesof nervous function caused by stress. Beard’s neurasthenia concept was closely linked
with his vision of American society, which supposedly caused much greater overexcitationof the central nervous system than did European society. “American nervousness,” oneof Beard’s favorite synonyms for neurasthenia, was a typical product of an industrial
society in which the upper classes were doomed to a hectic lifestyle.
Beard experienced just as little difﬁculty with the conceptual difference between
the physical depletion of energy and the psychic feeling of exhaustion as did Freud adecade later [165]. He had observed that not only did neurasthenia patients tend to survive
their own physicians, but also they were capable of considerable mental effort. However,this did not cause him to reconsider the difference between subjective feelings of exhaustion and an actual deterioration in achievements resulting from a lack of physical reserves.
On the contrary, he stressed that, in a functional sense, there was actually something amiss,such as a hyperemia of the cerebrum, the stomach, or the prostate, for example.

28

Glas

Due to a lack of resistance, the functional disorder (which initially occurred locally)
became transmitted to other regions of the body (irradiation). It therefore had no opportunity to develop into a permanent local abnormality. In Beard’s opinion, this was not thecase in healthy people where occasionally local overexcitation could even result in death.
In the case of neurasthenia, the local functional disorder never exceeded the threshold ofintensity beyond which permanent defects could develop. Irradiation not only explained
the variable and migratory course, but also the multiplicity of symptoms. Among thesymptoms included by Beard were the “irritable heart,” all kinds of phobias, compulsions,
impotence, hyperesthesia, and a huge range of physical sensations.
The irradiation of the local functional disorder occurred reﬂectively, and Beard
thought that the sympathetic nerve played an important role here. This hypothesis of reﬂective nerve impulse transport was one of the three basic assumptions in Beard’s conceptof neurasthenia. In addition to the reﬂex theory, there was the idea of the electrical natureof nerve excitation and the law of conservation of energy [166].
Beard himself believed that it was open-minded observation that led him to thediscovery of neurasthenia, and his descriptions do indeed bear testimony to his extraordinary attention to detail. He would take even the most idiosyncratic, subjective sensationsquite seriously. The fact that neurasthenia had not been previously described was, in his
opinion, due to the fact that neurasthenic patients are not found in hospitals or mental
institutions. They should instead be sought elsewhere, neurasthenia being a disease of thestreet [167]. Nevertheless, Beard overestimated his inductive powers, as is demonstrated
by the above-mentioned three basic assumptions and the role they played in his work.
These assumptions constituted the guiding principle on which he based his attempts toforge a whole out of the positively exorbitant diversity of observations. Moreover, it wasquite common in those days to think of psychic disorders in terms of an excess or adeﬁciency of (nervous) energy. Furthermore, as we have previously seen, ideas such asasthenia and irritability were already fashionable a century earlier [168,169]. In 1848,
W.B. Carpenter explicitly suggested the idea of a close relation between nervous energy
and electricity. Thinkers such as Spencer, Fechner, and Darwin subsequently elaborated
this idea still further. Meanwhile, in the therapeutic sphere, the process of electriﬁcation
became quite popular [170]. Nor was Beard the ﬁrst to see a connection between lifestyleand functional changes in the central nervous system. The previously mentioned theoryof degeneration, which was very popular on the European continent at the time, provides
still more far-reaching examples. It is true to say that the fascination with the relationshipbetween nervous energy and electrical phenomena was not unconnected with developments in the natural sciences. Its origin, however, lay in the romantic period. The intellectuals of the romantic period are known to have been strongly captivated by the living
world’s organic urge to develop and evolve. Early in the 19th century, the concept ofnatural force encompassed not only physical forces, such as motion and heat, but also
biotic and psychic forces, such as the life force, growth energy, and the urge toward further
development. It is therefore not the case that the concept of physical energy was initially
discovered by physicists and only later applied, in a metaphorical sense, to psychic symptoms. In the second half of the 19th century, the prevailing climate of thought, which
was still dominated by the inﬂuence of the romantic period, swung in a materialistic andmechanistic direction. This transformation, which was associated with such names such
as H. Helmholtz, E. du Bois-Reymond, E.W. Brücke, and C. Ludwig, was triggered by
the discovery of the law of conservation of energy by Robert Mayer in 1842. It resulted

History of Anxiety and Depression

29

in a differentiation between physical and psychic force, which suddenly breathed new life
into the psychophysical problem. At the end of the 19th century, there was yet anotherswing, this time back in a neoromantic direction, whereby all sorts of vitalistic concepts
gained new ground. Beard’s concept of nervous force seemed to ﬁt in with this neoromantic pattern of a vitalistic mixture of psychic and physical forces. In summary, it can besaid that both Beard’s description of neurasthenia, as well as the temporary popularity ofthis concept, cannot be understood from a purely medical perspective. Instead, one must
consider the interaction between medical observations, theoretical opinions, philosophicaltraditions of thinking, and various social changes. However, the fact that medicine concerned itself with neurasthenic patients at all was, to a great extent, a social phenomenon.
When social pressure became too much for an individual’s resilience, neurasthenia offered
a medical excuse for taking it easy.
E.

Psychasthenia

One of the most remarkable studies in the history of the classiﬁcation of anxiety is Pierre
Janet’s Les obsessions et la psychasthénie (The obsessions and psychasthenia), datingfrom 1903 [171]. This work, written in an elegant and still readable style, not only offers
an overview of all possible manifestations of pathological anxiety, it also contains numerous vivid descriptions of conditions that are known today as depersonalization, somatoform disorder, hypochondria, stereotyped movement disorder, and chronic fatigue syndrome.
Janet argues against the tendency of many of his colleagues to divide symptom
clusters into separate diagnostic entities. Indeed, he presents a classiﬁcation of his own, by
making a distinction between three types of psychasthenia: obsessive thoughts, irresistable
movements (compulsions, tics, outbursts of temper as a result of the inability to complete
the compulsions), and visceral anxiety (generalized anxiety, panic, phobias, and even pain
syndromes). These types, in their turn, are subdivided into various clinical states. Janetnevertheless emphasizes the close ties between these states. In the course of their illness,many patients show symptoms of conditions belonging to different types. Moreover, suppression of the target symptoms of one type often leads to the emergence of symptoms
belonging to another type of psychasthenia. Blocking of the obsessions, for instance,heightens the anxiety and may induce compulsive behavior. Resisting one’s compulsions,on the other hand, often leads to cardiac palpitations and the sensation of suffocation.
The real innovative element of Janet’s study, however, is his attempt to ﬁt his numerous observations in a general theory of psychological functioning. In his Introduction,
Janet declares his sympathy with the French psychologist Ribot, who was one of his intellectual fathers and who had made a plea for the close collaboration between medicine
and psychology. Common to all patients, says Janet, is a disturbance in psychological
functioning, the so-called psychasthenic state or psychasthenia. This state is characterized
by three distinctive features, namely: (1) a sense of incompleteness (sentiment d’incomplétude); (2) a diminishing or loss of the sense (or function) of reality (la fonction dureel); and (3) exhaustion [172].
It is not easy to perceive exactly what Janet meant with the ﬁrst two of these features.
Roughly speaking, the sense of incompleteness refers to the subjective feeling that something is missing in one’s actions, feelings, or intellectual functioning. It is a sense of being
incapable and unsuccessful. Whatever one does, it seems useless and incomplete. Doubt,

30

Glas

hesitance, and endless rumination dominate one’s activities. Depersonalization, feelingsof doubleness and unreality, restlessness, apathy and disgust complete this list of manifestations.
With regard to the second feature, the diminishing of the sense (or function) of
reality, it is at ﬁrst sight even harder to imagine what Janet had in mind. Citing Spencer,
he deﬁnes it as “the coefﬁcient of reality of a psychological fact” [173]. Rephrasing thisstatement, one could say that certain classes of psychic functioning can be assessed withrespect to their degree of reality (i.e., to a certain quality of psychic functioning in relationto actual tasks and circumstances). In sum, the function of reality refers to the capacity
to be present, spontaneous, and effective, particularly in the domain of voluntary action,
attention, and perception.
Janet, after all, discerns ﬁve hierarchical levels of psychological functioning: thefunction of reality at the upper level; then indifferent activities (routine acts and vague
perceptions); the imagining function (memory, imagination, abstract reasoning, and day
dreaming) and visceral emotional reactions; and ﬁnally, at the lowest level, involuntarymuscular movements. The quality of psychological functioning is determined by the socalled psychological tension, the psychic correlate of the nervous energy, to which Beard
and Freud had alluded to. Lowering of this tension initially leads to a lack of attention,
concentration, and other synthetic mental functions—in other words, to a loss of “la fonction du réel” and subsequently to a disruption of routine activities at the second level.
The psychasthenic state is the result of precisely this lowering of psychic tension (abaissement de la tension psychologique) [174].
From this, it will become clear that anxiety is by no means the central symptom in
Janet’s account of the psychasthenic state. Anxiety occurs when psychic functioning is
disturbed from the upper level down to the fourth level, that of the visceral emotional
reactions. Anxiety, consequently, belongs to the most elementary of the mental functions:
Underneath the anger, fear and love, there is an emotion, that is not speciﬁc any more, thatis a sum-total of vague respiratory and cardiac complaints, which don’t evoke in the mind
the idea of any inclination or any particular action. That emotion is called anxiety, the mostelementary of the mental functions (translation by the author) [175].

Clearly, psychasthenia encompasses a broad range of clinical phenomena, including
the anxiety disorders of our time. The psychasthenic state, however, is determined by abreakdown of only the highest level of psychic functioning. This implies that even in thecase of phobias, obsessive-compulsive disorder, and panic attacks, a central role should
be assigned to feelings of unreality, incompleteness, ineffectiveness, and depersonalization, and not to feelings of fear and anxiety. Emotions and emotion theory play only asecondary role in Janet’s description and explanation of these disorders.
Janet does not deny the occurrence of panic attacks in some cases of psychasthenia[176]. But these can only be accounted for by the assumption of a temporary and more
severe collapse of the psychological tension, leading to disturbances at the third and fourthlevel. Fear, on the other hand, is a more complex and differentiated emotion, involving
psychic activity of the higher levels, such as imagination, perception and goal-directedbehavior. Fear as such, however, is the expression of activity at the fourth level of psychic
functioning.
From a psychological point of view, Janet was far ahead of his time, by pointing
to the importance of disturbances in the domain of attention and perception and theirHistory of Anxiety and Depression

31

relation to the sense of self. Psychology and psychiatry had to wait until the 80s before
attentional bias became a topic of some interest in empirical research of the anxiety disorders.
F.

Anxiety Neurosis

The history of the classiﬁcation of anxiety disorders since the time of Beard can be seen
as a peeling away of layers of the concept of neurasthenia. Anxiety neurosis was the ﬁrst
stratum to be laid bare under its surface. Next came all sorts of classiﬁcatory subdivisions
within anxiety neurosis [177].
Kahlbaum’s successor, Hecker, initiated the above-mentioned process in a classic
article on anxiety states in neurasthenia [178]. He had noticed that the anxiety attacks
experienced by many neurasthenia sufferers were not accompanied by any subjective feeling of anxiety. There were also patients who did not show anything like the full range ofphysical symptoms. Hecker used the term “larvirt” (larval; larvalike) to denote this absenceof a feeling of anxiety. The term “abortiv” was indicative of the interrupted, incomplete
nature of the attack in terms of the somatic symptomatology. The picture described byHecker bears a strong resemblance to the so-called limited symptom attacks in present-day
literature on panic disorder. Citing Lange, a Dane who had formulated an interpretation ofemotions that was practically identical to that of William James, Hecker stated that theabsence of subjective anxiety in the attack was based on a kind of misperception. The
physical symptoms were simply not recognized as expressions of anxiety. However, it
was also possible for an attack to commence with just one of the somantic symptoms
before radiating to other parts of the body. The way in which Hecker described this irradiation betrays a relationship with Beard’s reﬂex theory.
In 1895, Sigmund Freud, with reference to Hecker, joined the critics of Beard’s
broad concept of neurasthenia. However, in being more explicit about pathogenesis, Freudwent a step further than Hecker [179,180]. He believed that demarcation of neurasthenia
was essential since anxiety neurosis, because of its different pathogenesis, required different treatment. Neurasthenia was a disorder of the way in which the so-called somaticsexual excitation was released, whereas anxiety neurosis was primarily a disorder in thepsychic processing of such excitation. In the case of anxiety neurosis, Freud imaginedthat there was a buildup of pressure on the walls of the male seminal vesicles. When thispressure exceeded a given threshold, it was transformed into somatic energy and transmitted, via neural pathways, to the cerebral cortex. Under normal conditions, sexual fantasy
groups became charged with this energy, leading to sexual excitement (libido) and the
pursuit of release. Anxiety neurosis involved a blockage in the psychic processing of thissomatic sexual tension. Such a blockage might arise through abstinence, for example, or
due to the use of coitus interruptus, or because sexual fantasies had simply failed to takeshape. Somatic sexual tension was thus deﬂected away from the psyche (the cortex) anddirected to subcortical paths, ﬁnally expressing itself as inadequate actions, which occurred
most characteristically during an anxiety attack.
The pioneering article in which Freud detached anxiety neurosis from neurasthenia
includes a description of the symptomatology of the various forms of anxiety that is stillvalid today [181]. Freud cited anxious expectation as the core symptom of anxiety neurosis. He also distinguished between speciﬁc phobias agoraphobia, free-ﬂoating anxiety, andanxiety attacks. The latter were spontaneous in nature and were described as a purely

32

Glas

somatic phenomenon [182]. The aforementioned distinctions anticipated the now generally
accepted classiﬁcation of speciﬁc phobias, agoraphobia, generalized anxiety, and panic
disorders. Freud was not alone in anticipating DSM-IV. As the authors of DSM-IV haveacknowledged, striking similarities are also to be found in the sixth edition of Kraepelin’s
textbook [183,184]. Furthermore, it is interesting that Freud considered agoraphobia tobe characterized by a fear of panic attacks, and not by fear of streets or squares per se:“. . . ce que redoute ce malade c’est l’événement d’une telle attaque . . .” (. . . what thepatient fears is the occurrence of such an attack . . .) [185].
Freud’s reputation was not based upon his interpretations of anxiety neurosis, however. His second theory of anxiety, in which anxiety was interpreted as a signal of innerthreat, would ultimately have much greater inﬂuence [186].
This second theory had already announced its arrival by around 1895, albeit in asomatic guise. Freud asked why nonprocessed sexual excitation should express itself
speciﬁcally in the form of anxiety. In answering this question, a glimpse is afforded ofsomething that would later be more explcitly developed as a theme. Unlike real anxiety,which was based on the perception of an external threat, neurotic anxiety was a reaction
to inner threat. The core of this inner threat was an inability to process endogenously
created (sexual) excitation [187]. On another occasion, Freud put it as follows: “Anxiety
is the sensation of the accumulation of another endogenous stimulus, the stimulus tobreathing . . .” [188].
It is sometimes forgotten that elements of the above hypothesis also appeared in
Freud’s signal theory. There, also, the basis of all anxiety was biological helplessness(i.e., the helplessness of the child with respect to its own drive impulses) [189]. Although
the signal theory also concerns the satisfaction of needs, it does not relate primarily tosexual needs but rather to those associated with the instinct for self-preservation [190].
Object loss, the most clear-cut threat recognized by this instinct, becomes the psychological prerequisite for inducing the ego to give off a small quantum of anxiety in order torestore a favorable balance of pleasure and displeasure. The threat of object loss remains
linked to the biological state of being at the mercy of one’s drive impulses. This linkage
is mediated by remembrance symbols that, via separation and birth, ultimately refer to anarchaic inheritance of hereditary anxiety responses. In anxious patients, the symptom of
gasping for air is no longer seen as a mitigated orgasm but rather as the rudiment of thecry of a newborn child [191].
In a negative sense, Freud’s second theory of anxiety was of great signiﬁcance within
the classiﬁcation debate. His statement that anxiety was the “loose change” of the neurotic
conﬂict illustrates the nosologically nonspeciﬁc character gradually adopted by anxiety
in his interpretations.
This was partly the reason why the classiﬁcation of anxiety symptoms did not exactly
receive top priority in the period between 1930 and 1960. This is not, of course, meant
to detract from Freud’s exceptional merits. In the ﬁeld of anxiety theory, these merits lay
particularly in the concept of anxiety as a reaction to an inner threat. This idea, which
was without precedent in Freud’s days, permanently changed the face of psychiatry. Freudthereby gave a wholly individual treatment to the fundamental distinction between (objectless) anxiety and (object-linked) fear, a theme that for the rest was to ﬁnd its way into
psychiatry via another route.6
Freud’s approach was not limited to the psychoanalytic school. In its interpretationof anxiety, cognitive psychology (in the style of Beck) built upon Freud’s pioneering
concept of anxiety as an inner threat [192,193].

History of Anxiety and Depression

G.

33

Clinical Studies

After 1900, despite the almost universal recognition of the central position of anxiety inpsychopathology, relatively few psychiatric monographs were devoted exclusively to anxiety and anxiety disorders. One exception was the previously mentioned, exhaustive study
by Störring. Several authors occupied themselves with conceptual questions based on clinical observations. Goldstein [194] and Kronfeld [195] produced splendid articles that incorporated some fundamental concepts. Some other names that should be mentioned in thiscontext are those of Hoche [196], Kornfeld [197], and Oppenheim [198]. We alreadydiscussed Janet’s, “Les obsessions et al psychasthénie” (Obsessions and psychasthenia);
however, his “De l’angoisse à l’extase” (From anxiety to ecstasy) from 1926 is worthyof special mention too [199].
Next, reference should be made to several studies arising from particular theoreticalpoints of view. These include not only the psychoanalytical studies by Stekel [200], Bitter[201], and Riemann [202], but also the anthropological studies of von Gebsattel [203–205] and Tellenbach [206]. In addition, studies exclusively devoted to a particular formof anxiety, such as the innumerable publications on “Schreckneurosen” and “Schreckpsychosen” (from the German Schreck: terror), were carried out in the periods around bothworld wars [206–208].
Seen from a broader perspective, the conceptual framework within which the debate
on pathological anxiety took place was speciﬁcally determined by the intellectual legacy
bequeathed by scientists and philosophers such as Charles Darwin, W.B. Cannon, William
James, Sigmund Freud, and Max Scheler. It is no simple matter to illustrate just how thevarious interpretations and schools of thought inﬂuenced one another. Accordingly, I will
restrict my discussion to two themes, the role of bodily perceptions in the origin of anxiety
and the further determination of the distinction between anxiety and fear.
With regard to the ﬁrst theme, there seemed to be a signiﬁcant resistance among
clinicians to the James-Lange theory of emotions. Bodily changes, according to this theory,
instead of resulting from subjective feelings, were actually the cause of the emotional
coloring of sensory perceptions. Perception became emotion via the awareness of bodilychanges [210]. James himself was responsible for the subsequent confusion as to whether
a temporal-causal relationship existed between bodily changes and emotional perceptions,or whether both occurred simultaneously. It was usually assumed (probably not entirely
correctly) that James was postulating a temporal sequence between bodily changes andemotional perceptions. Clinicians, who also adopted this interpretation, criticized him on
this point by pointing out the immediacy of the experience of anxiety. According to Störring, the experience of anxiety was not mediated by prior bodily perception. However,
he was not entirely logical on this point since he consistently spoke of anxiety as a processing of, or a reaction to, sensations associated with speciﬁc organs [211]. Both Kornfeld(not to be confused with Kronfeld, who has been mentioned previously) and Hoche lodged
objections, on descriptive grounds, against the idea of a temporal sequence between bodilychange and emotional perception. Kornfeld, who himself suffered from neurasthenic complaints and panic attacks, enlivened his article with a description of one of his nightly
panic attacks. On awakening, he would ﬁrst experience a severe feeling of anxiety without
really knowing why he was frightened. Shortly afterward, he would become aware ofbodily sensations such as a feeling of constriction in the region of the heart, difﬁculty inbreathing, paraesthesia, and cold akra. This led him to conclude that a sharp distinction
should be made between feelings of anxiety and the perception of bodily changes. Al-

34

Glas

though Hoche thought along similar lines, like Hecker he formulated a sort of interoceptive
explanation for anxiety, in which anxiety was based on the misinterpretation of bodily
sensations. Kraepelin and Lange’s handbook ultimately rejected James’ theory of emotions
on theoretical grounds, both because of its psychophysical dualism and its disregard forcentral regulatory processes. An emotion such as fear of suffocation could be both somaticand psychological in origin. According to Kraepelin and Lange, the origin of this fear of
suffocation (whether lack of oxygen, hypercapnia, acidosis, or frightening events) was
irrelevant to the quality of the emotion itself. In all cases, the central issue was a threat
to the patient’s existence as a biological entity rather than any perception of bodily changes[212]. It should be noted, howver, that James was too much of a Darwinist to be accusedof psychophysical dualism.
In summary, it can be said that clinical psychiatrists mainly resisted the James-Langetheory because of their support for the primacy of clinical observation. Nevertheless, theantitheoretical sentiment in these convictions sometimes led to all sorts of nonexplicit
theoretical views being smuggled in through the back door.
In discussing the second theme, that of the further determination of the distinction
between anxiety and fear,6 consideration should ﬁrst be given to Kurt Goldstein’s observations of patients with organic brain damage. The majority of Goldstein’s patients werevictims of the World War I. He observed that, when faced with overly complex tasks,
these patients displayed a catastrophic reaction consisting of a wide range of physiologicaland psychomotor symptoms. Goldstein believed that even though it was not subjectively
experienced as such, this condition could best be interpreted as an expression of anxiety.
While Goldstein’s patients were unaware of the fact of their anxiety, the appearanceof their physical symptoms coincided with the failure to accomplish their tasks. Strictly
speaking, their anxiety was neither a reaction to failure nor a reaction to an awareness offailure. Anxiety—and this was the essence of Goldstein’s interpretation—was quite literally the actual manifestation of failure. Goldstein concludes that generally spoken anxiety
was the expression of a frustrated urge for self-realization.
This reference to the urge for self-realization was particularly popular among thosecontemporary authors who drew their inspiration from vitalism. Although similar references can also be found in Freud’s later work [213], it was actually the colossal presenceof Charles Darwin, behind the scenes, which inspired this line of thought. However,Goldstein was not thinking of the survival of the species, or that of the individual, in
purely Darwinian terms. The urge toward self-realization was more than a purely biological reality. It also found expression, for example, in the productive creativity shown by
children and adults in mastering the world. Anxiety was referred to as the “Erschütterung(des) Bestandes der Persönlichkeit” (disruption of the stability of personality) [214]. Ultimately, however, Goldstein failed to fully clarify the conceptual status of the propensity
for self-realization. The task of formulating more explicitly things that Goldstein merely
hinted at fell to other authors. Here we ﬁnd a scheme in which personality was divided
into an impersonal substructure and a personal superstructure. The substructure was described in vitalistic terms while the superstructure was analyzed in terms derived fromexistentialist phenomenology. Examples of this can be found in work by Arthur Kronfeld,
Felix Krueger, Philipp Lersch, and, to a lesser extent, H.C. Rümke. According to Kronfeld,
anxiety was based upon a deterioration of the personal superstructure. In extremely succinct terms, this disintegration was expressed as psychotic anxiety. However, the type ofanxiety that Kronfeld initially had in mind was existential rather than psychotic:

History of Anxiety and Depression

35

Anxiety is the mental expression of the existential annihilation of the integrity (“Einheitsform”) of the person. Its archetype is the fear of death, the anxiety related to vital destruction [215].

Such statements only become comprehensible when it is realized that Kronfeld rejected the link between anxiety and threat. Anxiety, in the true sense of the word, is not
the counterpart of safety, but of meaning, of being a person, of “one-ness,” of living. The
anxious person need not necessarily have a subjective awareness of this, however. Deathhas signiﬁcance long before it becomes a subjective reality. According to Kronfeld, thebiological aspect of anxiety consisted of life ﬂeeing from death. Such ﬂight is in vain,
however, and therein lies the source of all fear of life and of anxiety about fate. Therefore,
with anxiety, it is necessary to pose the question of meaning [216]. Kronfeld’s criticism
of the biologically inspired interpretation of anxiety was that it failed to do this.
In uncoupling anxiety from threat, Kronfeld may have gone a little too far, but his
remark that indescribable anxiety often has the quality of fear of living receives daily
conﬁrmation from the mouths of borderline patients.
H. From Dimension to Category
As has already been noted, the study of anxiety was not a high priority in the period from1930 to 1960. In addition to the previously mentioned inﬂuence of psychoanalysis, which
described anxiety as a nonspeciﬁc phenomenon, the assumption that anxiety occupied alow position in the hierarchy of psychiatric symptoms also had a part in this [217]. According to this line of thought, not only did anxiety occur in practically all psychopathological syndromes, it also marked the lower boundary of psychopathology, where this bordered on normality.
Jablensky adds to this that classiﬁcation had traditionally been an area of interestfor institutional psychiatry [218]. An explanation for the relative neglect of the classiﬁcation of anxiety disorders was that, as a rule, patients with neurotic anxiety were neverhospitalized. This status quo gradually changed toward the end of the 1950s. I shall summarize a number of these developments.
The psychophysiological investigation of emotions continued along the lines of theJames-Lange theory. In this context, Ax attempted to draw a distinction between the emotions of anxiety and anger on the basis of their peripheral physiological symptoms [219].
The anxiolytic effect of benzodiazepines was discovered, resulting in a ﬂood of
research into the effects of these chemicals on the central nervous system [220].
J. Wolpe introduced systematic desensitization as a form of behavior therapy,
thereby giving new impetus to the treatment of people with anxiety disorders [221].
The British psychiatrist M. Roth described a form of depersonalization associatedwith severe anxiety and phobic phenomena [222]. This was the so-called “phobic anxietydepersonalization syndrome.” Although it usually developed in the wake of a psychotrauma, this picture could sometimes occur spontaneously. The EEGs of just under onesixth of all patients revealed the presence of temporal-epileptic symptoms.
Finally, at the end of the 1950s, D.F. Klein (who has been referred to previously)
discovered that panic attacks in agoraphobic patients could be blocked using Imipramine[223,224]. This marked the beginning of a great ﬂood of experimental, pharmacological,
clinical, longitudinal, epidemiological, genetic, and familial research into the existence
and course of panic disorder.

36

Glas

With this boom in psychopharmacological research, increasingly stringent criteria
for the deﬁnition of psychiatric syndromes were drawn up. This was principally for thesake of comparability between research groups. Thus, psychopharmacological and biological psychiatric research constituted a powerful impetus for the development of the Feighner Criteria [225]. These, together with the Research Diagnostic Criteria [226] formed
the basis of the DSM-III and its further editions. The emphasis on descriptive precision
led to the demarcation of various forms of anxiety and to an abandonment of the conceptof neurosis, which was considered to be too vague. The depressive neurosis of DSM-II(1968) became dysthymia in DSM-III, falling under the affective disorders. Two types ofhysterical neurosis, hypochondria and depersonalization, were classiﬁed under somatoform and dissociative disorders, respectively. Neurasthenic neurosis was discarded. Anxiety neurosis, phobic neurosis, and obsessive-compulsive neurosis were combined under
the heading of anxiety disorders. Post-traumatic stress disorder, a newcomer, was added
to the anxiety disorders [227,228]. The anxiety neurosis was subsequently split up into
panic disorder and generalized anxiety disorder, while the phobic neuroses were divided
up into agoraphobia, simple phobias, and social phobia [229,230].
In spite of the nontheoretical nature of DSM-III, this change nevertheless heralded
in a fundamentally different approach to the psychopathology of anxiety. DSM-III bodefarewell not only to the psychodynamic conﬂict model, but also to a broader tradition inwhich anxiety was associated with disorders in personality structure. It was replaced by
a ﬁnely grained description and classiﬁcation of more superﬁcial symptomatology. Anxiety was no longer regarded as a consequence of the personality structure but primarily asa symptom in and of itself. This resulted in a switch from the predominantly dimensional
or dispositional approach, which characterized the neurosis model, to a typological or
categorical approach to psychopathology.
Panic disorder represents the most outstanding example of this development, becoming “a microcosm of many of the classic controversies surrounding psychiatric research”[231]. Biological, psychoanalytic, behavioral, and cognitive explanatory models now competed for priority in this debate [232–236]. At the moment, the question of what exactly
should be classiﬁed (patients? theoretical constructs? diseases?) is once again highly relevant [237].

V.

SUMMARY AND CONCLUSION

The preceding chapters cover only part of the history of anxiety and depression. While
this is partly attributable to the introductory nature of this review, the main reason is that
this discussion has been limited to concepts alone. Behind these concepts lies individual
suffering, the often ineffective concern of those around the patient, and the numerous
therapeutic efforts of physicians and paramedics. Although not covered here, this history
is at least as worthy of our consideration as the one described above.
In the Introduction, it was stated that the history of anxiety and depression should
be interpreted as the interplay of cultural changes and of changes not only in psychopathological symptoms per se, but also in their scientiﬁc interpretation. This interplay has, tosome extent, been reﬂected in the preceding chapters.
Viewed in the context of the microcosm–macrocosm theme, which was current bothin antiquity and in the renaissance, the mentally ill appeared as the personiﬁcation of aHistory of Anxiety and Depression

37

disruption in the subtle balance of cosmic forces. Such people were different, but not so
different as to warrant either ostracism or conﬁnement.
The moralizing and allegorizing of humoral pathology in the Middle Ages raised
the question of where disease ended and sin began. But it was difﬁcult to know where to
draw the line, as the 19th-century theory of degeneration made clear. According to thistheory, a transgression (due to alcoholism, for example) in one generation could lead toincreasingly serious forms of psychopathology in succeeding generations.
The idea that melancholics show traits of the exceptional and of genius is a common
thread running throughout history. Starting with Aristotle, it can be traced via Marsilio
Ficino, through Burton and the poets of the Elizabethan Era, and onward into the present
century in the work of William James. The fact that depressives’ weaker perceptual defenses allow them a more adequate perception of reality may, perhaps, be a pale reﬂectionof this very idea. The rationalization and mechanization of the world view in the postCartesian era ﬁnally resulted in a view of the mentally ill in which the irrational anduncontrollable elements of their behavior received special emphasis. The bestial side ofhuman nature revealed itself in such people. Right up to the present day, domination andcontrol have been key words in understanding the motivation behind medical concern forthe psychiatric patient. It is this very contrast with earlier treatment that illustrates theextent to which the medical domination of previously uncontrollable emotions has become
both the motive and guiding principle for current theoretical and therapeutic activity.
The current fascination of clinicians and researchers with the biological approach
therefore comes as no surprise. This approach seems to bring the promise of control andof tangible results, in contrast to the unpredictable and much less concrete results obtainedby psychological and social intervention. However, it is appropriate to issue a warning at
this point, since history has shown us how intractable psychopathological reality can be.
It is not without reason that clinicians repeatedly demonstrated an astonishing eclecticism
concerning the theoretical explanation of various insights. Clinicians showed reticencewhen it came to reasoning from preconceived theoretical points of view. I would remind
you of the reservations expressed against the James-Lange theory of emotions. This reticence cannot simply be attributed to an antiscientiﬁc attitude. It also stems from healthyclinical skepticism. The history of the classiﬁcation of anxiety and depression serves toemphasize the fact that such skepticism was often quite appropriate. Whenever attempts
were made to reﬁne a given theory, or combination of theories, clinical reality always
proved to possess an overabundance of elusiveness and unpredictability. Broadly speaking,longitudinal clinical observation advanced the classiﬁcation of anxiety disorders, and especially that of mood disorders, more than did any classiﬁcation based on preconceived
theoretical assumptions. In view of the controversy between the unitarians and the separatists, a combination of longitudinal and interdisciplinary (bio-psycho-social) researchwould seem to hold out particular promise for the future.
Finally, what has been said above should also be emphasized on epistemologicalgrounds. As scientiﬁc disciplines, neurobiology and pharmacology tackle problems abstractly and objectively. This implies that there is, by deﬁnition, a gap between the researchﬁndings in these disciplines and clinical reality. Furthermore, scientiﬁc constructs neverrelate to this reality in its entirety, but merely to aspects of the whole. Reiﬁcation (i.e.,
the identiﬁcation of these constructs with reality) can only lead to distortion. The conceptual history of anxiety and depression illustrates the repeated recurrence of forgotten ideas.
These were eliminated in the process of abstraction, only to return via the back door.

38

Glas

Scientiﬁc interpretations only bear fruit when the tension-ﬁlled gap separating them fromclinical reality, rather than being short-circuited, is kept open.

NOTES
1. Klibansky, Panofsky, and Saxl (1964, pp. 64–66 and 98–102) point out an irregularity in the classicalinterpretation of melancholia; this irregularity occurs in the theory of temperaments. In the strict humoralist
tradition, temperaments are reduced to disturbances in the balance between the bodily ﬂuids. These disturbances
initially appear to fall within the normal range, like the usual variations of character dispositions. However,changes in interpretation over the centuries become obvious: only blood is now considered to be an integral
part of the body, with the other three ﬂuids regarded as degeneration products. The signiﬁcance of these degeneration products (yellow bile, black bile, and phlegm) would, especially in the Middle Ages, take on a negative
connotation, as a result of which they would be considered to be responsible for all kinds of character abnormalities and immoral behavior.
The Galenic and Neo-Galenic theories of temperament, on the other hand, were originally oriented toward
the primary qualities (heat, cold, dryness, and wetness), and not so much toward the humors. The Galenictemperaments are not in fact real temperaments, that is to say temperaments in a biological (humoral) sense,
but rather disturbances in the balance between the primary qualities. Health was considered by Galen to be an
ideal state; every relative excess of a particular bodily ﬂuid was, to his mind, a disturbance and therefore alsoa disease. Thus the Galenic tradition had little inﬂuence on the development of a proper theory of temperament:
it could not deal with normal variation of character dispositions.
Behind this irregularity in the theory of temperaments lies a difference of opinion about disease: thestrict humoralistic tradition took a concrete and natural view of normality; whereas the Galenic tradition established itself on more abstract ideas, such as the primary qualities.
2. In scholastic medicine, the emotions of anxiety and rage are diametrically opposed. In rage, heat is
generated and ﬂoats to the periphery, the arms and legs display movement, the face becomes red, the pulse
strengthens, and the brain also comes to life again. In anxiety, the heat drains inward, peripheral parts become
cold and pale, the pulse rate decreases and the patient feels cold.
3. Plato distinguished four forms of godlike mania, namely, mania as the art of fortune telling (cf. theetymological relation between mania and mantikè, i.e., fortune telling); mania as ritual puriﬁcation and consecration leading to the relief of disease and grief; mania in the sense of ecstasy inspired by the Muses; and ﬁnallymania in the sense of being emotionally moved by memories when looking at beautiful things.
4. Cf. Descartes, 1647, article 52: “. . . qui nous importent . . .”; and Guéroult 1953, p. 253.
5. Kraepelin remained a dedicated experimental psychologist throughout his life. During his years in
Heidelberg (1891–1903), the work which he carried out included experiments on the function of will (taskperformance, level of fatigue), cognitive capacities (distractibility, attention, memory, ideational association), andexpressive functions (motor activity, handwriting, and language performance) (Kraepelin 1983, p. 71). During his
Münich years (1903–1922), much to his regret, he was no longer able to ﬁnd the time for experimental psychology, although he did give refresher courses for colleagues (ibidem, pp. 144, 145, 149).
6. The distinction between objectless anxiety and object-linked fear, which already had been formulatedby the philosopher Kierkegaard (1844), was to be introduced by Karl Jaspers in 1946, in the fourth edition of
his Allgemeine Psychopathologie (General Psychopathology). In the ensuing years, it was developed as a themein the anthropological school, which was oriented toward existential phenomenology.

REFERENCES
1. Jackson SW. Melancholia and Depression. From Hippocratic Times to Modern Times. New
Haven and London: Yale University Press, 1986.
2. Klibansky R, Panofsky RE, Saxl F. Saturn and Melancholy. Studies in the History of Natural
Philosophy, Religion and Art. London: Thomas Nelson and Sons Ltd, 1964 (Kraus Reprint,
Nendeln/Liechtenstein, 1979).
3. Ackerknecht EH. A Short History of Medicine. Baltimore & London: The Johns Hopkins
University Press, 1955 (revised edition 1968; reprint 1982).

History of Anxiety and Depression

39

4. Beek HH. Waanzin in de Middeleeuwen. Beeld van de gestoorde en bemoeienis met dezieke. Nijkerk/Haarlem: Callenbach/De Toorts, 1969.
5. Berrios GE. Melancholia and depression during the 19th century: a conceptual history. Br
J Psychiatry 1988; 153:298–304.
6. Berrios GE. The History of Mental Symptoms. Descriptive Psychopathology Since the Nineteenth Century. Cambridge: Cambridge University Press, 1996.
7. Flashar H. Melancholie und Melancholiker in den medizinischen Theorien der Antike. Berlin:
Walter de Gruyter and Co, 1966.
8. Foucault M. Madness and Civilization. A History of Insanity in the Age of Reason (translation of Histoire de la folie à l’age classique). New York: Random House, 1965/1973.
9. Gardiner HM, Metcalf RC, Beebe-Center J. Feeling and Emotion. A History of Theories.
Westport: Greenwood Press, 1937 (reprint 1970).
10. King LS. The Philosophy of Medicine. The Early Eighteenth Century. Cambridge, MA: Harvard University press, 1978.
11. Leibbrand W, Wettley A. Der Wahnsinn. Geschichte der abendländischen Psychopathologie.
Freiburg/München: Verlag Karl Albert, 1961.
12. Lewis AJ. Melancholia: A Historical Review. Mental Sci 1934; 80:1.
13. Roccatagliata G. A History of Ancient Psychiatry. New York: Greenwood Press, 1986.
14. Rosen G. Madness in Society. Chapters in the Historical Sociology of Mental Illness. New
York: Harper & Row, 1969.
15. Starobinski J. Geschichte der Melancholiebehandlung von den Anfängen bis 1900. Basel:
Geigy, 1960.
16. Zilboorg G. A History of Medical Psychology. New York: Norton and Company, 1941.
17. Schmidt-Degenhard M. Angst -problemgeschichtliche und klinische Aspekte. Fortschr Neurol Psychiatr 1986; 54:321–339.
18. Jackson SW. Melancholia and Depression. From Hippocratic Times to Modern Times. New
Haven and London: Yale University Press, 1986; 145–146.
19. von Baeyer W, von Baeyer-Katte W. Angst. Frankfurt am Main: Suhrkamp, 1971.
20. Häfner H. Angst, Furcht, historisches Wörterbuch der Philosophie. In: Ritter, J. ed., Band
I. Basel: Schwabe & Co, 1971:310–314.
21. Lewis A. Problems presented by the ambiguous word ‘anxiety’ as used in psychopathology.
Ann Psych Related Discipl 1967; 5:105–121.
22. Temkin O. Galenism. Rise and Decline of a Medical Philosophy. Ithaca/London: Cornell
University Press, 1973.
23. Temkin O. Health and Disease. The Double Face of Janus and Other Essays in the History of Medicine. Baltimore & London: The Johns Hopkins University Press, 1977:422–
425.
24. Jackson SW. Melancholia and Depression. From Hippocratic Times to Modern Times. New
Haven and London: Yale University Press, 1986:40.
25. Klibansky R, Panofsky E, Saxl F. Saturn and Melancholy. Studies in the History of Natural
Philosophy, Religion and Art. London: Thomas Nelson and Sons, Ltd (Kraus Reprint,
Nendeln/Liechtenstein, 1979), 1964:82.
26. Galenus, On the affected parts. In: Siegel RE, ed. Galen on the affected parts, translationfrom the Greek text with explanatory notes. Basel: Karger, 1976:89–94.
27. Jackson SW. Melancholia and Depression. From Hippocratic Time to Modern Times. New
Haven and London: Yale University Press, 1986:37.
28. Leibbrand W, Wettley A. Der Wahnsinn. Geschichte der abendländischen Psychopathologie.
Freiburg/München: Verlag Karl Albert, 1961:122–125.
29. Galenus. On the affected parts. In: Siegel RE, ed. Galen on the affected parts, translationfrom the Greek text with explanatory notes. Basel: Karger, 1976:93.
30. Galenus. On the affected parts. In: Siegel RE, ed. Galen on the affected parts, translationfrom the Greek text with explanatory notes. Basel: Karger, 1976:93.

40

Glas

31. Leibbrand W, Wettley A. Der Wahnsinn. Geschichte der abendländischen Psychopathologie.
Freiburg/München: Verlag Karl Albert, 1961:111–116.
32. Jackson SW. Melancholia and Depression. From Hippocratic Times to Modern Times. New
Haven and London: Yale University Press, 1986:63.
33. Klibansky R, Panofsky E, Saxl F. Saturn and Melancholy. Studies in the History of Natural
Philosophy, Religion and Art. London: Thomas Nelson and Sons Ltd (Kraus Reprint,
Nendeln/Liechtenstein, 1979), 1964:105–110.
34. Jackson SW. Melancholia and Depression. From Hippocratic Times to Modern Times. New
Haven and London: Yale University Press, 1986:65–77.
35. Klibansky R, Panofsky E, Saxl F. Saturn and Melancholy. Studies in the History of Natural
Philosophy, Religion and Art. London: Thomas Nelson and Sons Ltd (Kraus Reprint,
Nendeln/Liechtenstein, 1979), 1964:300.
36. Beek HH. Waanzin in de Middeleeuwen. Beeld van de gestoorde en bemoeienis met dezieke. Nijkerk/Haarlem: Callenbach/De Toorts, 1969:98 (my translation).
37. Klibansky R, Panofsky E, Saxl F. Saturn and Melancholy. Studies in the History of Natural
Philosophy, Religion and Art. London: Thomas Nelson and Sons Ltd (Kraus Reprint,
Nendeln/Liechtenstein, 1979), 1964:86–90.
38. Beek HH. Waanzin in de Middeleeuwen. Beeld van de gestoorde en bemoeienis met dezieke. Nijkerk/Haarlem: Callenbach/De Toorts, 1969:98 (my translation).
39. Beek HH. Waanzin in de Middeleeuwen. Beeld van de gestoorde en bemoeienis met dezieke. Nijkerk/Haarlem: Callenbach/De Toorts, 1969:98 (my translation).
40. Beek HH. Waanzin in de Middeleeuwen. Beeld van de gestoorde en bemoeienis met dezieke. Nijkerk/Haarlem: Callenbach/De Toorts, 1969:98 (my translation).
41. Beek HH. Waanzin in de Middeleeuwen. Beeld van de gestoorde en bemoeienis met dezieke. Nijkerk/Haarlem: Callenbach/De Toorts, 1969:98 (my translation).
42. Burton R. The anatomy of melancholy. Vol. I–III (AR Shilleto, Ed). London: George Belland Sons, 1621 (edition 1896).
43. James W. The varieties of religious experience. A study in human nature. New York: Longmans, Green and Co, 1902 (Penguin Books Ltd, 1982)
44. Aristotle. Problemata, 953a 10. In: J Barnes, ed. The complete works of Aristotle. Princeton:
Princeton University Press, 1984:1319.
45. Plato. Phaedrus, 244b-250. In: E Hamilton, E Cairns, eds. The collected dialogues of Plato.
Princeton: Princeton University Press, 1961:475.
46. Aristotle. Problemata, 954a 21–26. In: Barnes J, ed. The complete works of Aristotle.
Princeton: Princeton University Press, 1984:1320.
47. Klibansky R, Panofsky E, Saxl F. Saturn and Melancholy. Studies in the History of Natural
Philosophy, Religion and Art. London: Thomas Nelson and Sons Ltd (Kraus Reprint,
Nendeln/Liechtenstein, 1979), 1964:40.
48. Klibansky R, Panofsky E, Saxl F. Saturn and Melancholy. Studies in the History of Natural
Philosophy, Religion and Art. London: Thomas Nelson and Sons Ltd (Kraus Reprint,
Nendeln/Liechtenstein, 1979), 1964:133–195.
49. Klibansky R, Panofsky E, Saxl F. Saturn and Melancholy. Studies in the History of Natural
Philosophy, Religion and Art. London: Thomas Nelson and Sons Ltd (Kraus Reprint,
Nendeln/Liechtenstein, 1979), 1964:241–274.
50. Klibansky R, Panofsky E, Saxl F. Saturn and Melancholy. Studies in the History of Natural
Philosophy, Religion and Art. London: Thomas Nelson and Sons Ltd (Kraus Reprint,
Nendeln/Liechtenstein, 1979), 1964:228–240.
51. Jackson SW. Melancholia and Depression. From Hippocratic Times to Modern Times. New
Haven and London: Yale University Press, 1986:112.
52. Burton R. The Anatomy of Melancholy. Vol I–III. Shilleto AR, ed. London: George Belland Sons, 1621 (edition 1896).

History of Anxiety and Depression

41

53. Burton R. The Anatomy of Melancholy. Vol I–III Shilleto AR, ed. London: George Belland Sons, 1621 (edition 1896):298.
54. Burton R. The anatomy of Melancholy. Vol I–III. Shilleto AR, ed. London: George Belland Sons, 1621 (edition 1896):302.
55. Burton R. The Anatomy of Melancholy. Vol I–III. Shilleto AR, ed. London: George Belland Sons, 1621 (edition 1896):297.
56. Burton R. The Anatomy of Melancholy. Vol I–III. Shilleto AR, ed. London: George Belland Sons, 1621 (edition 1896):442–449.
57. Descartes R. Les passions de l’âme. Oeuvres de Descartes (Publiées par C Adam and P
Tannery), Tome XI, L. Paris: Cerf, Paris, 1649/1909:327.
58. Riese W. La théorie des passions à la lumière de la pensée médicale du XVIIe siècle. Basel/
New York: Karger, 1965.
59. O-Rorty A. From passions to emotions and sentiments. Philosophy 1982:57:157–172.
60. King LS. The Philosophy of Medicine. The Early Eighteenth Century. Cambridge MA: Harvard University Press, 1978.
61. Descartes R. Les passions de l’âme. Oeuvres de Descartes (publiées par C Adam and P
Tannery), Tome XI, L. Paris: Cerf, Paris, 1649/1909, articles 34–39, 58, 165, 174, 176.
62. López Pineiro J. Historical origins of the concept of neurosis (Berrios D transl.). Cambridge:
Cambridge University Press, 1983:12.
63. Starobinski J. Geschichte der Melancholiebehandlung von den Anfängen bis 1900. Basel:
Geigy 1960:55.
64. Jackson SW. Melancholia and partial insanity. J Hist Behav Sci 1983;19:173.
65. Pinel P. Traité médico-philosophique sur l’aliénation mentale. Paris, 1801.
66. Porter RR. A Social History of Madness. Stories of the Insane. London: Weidenfeld andNicolson, 1987:8–38; especially pp. 16–20.
67. Jackson SW. Melancholia and Depression. From Hippocratic Times to Modern Times. New
Haven and London: Yale University Press, 1986:170–171.
68. Esquirol JED. Des Maladies Mentales, 2 vols. Paris, 1838.
69. Esquirol JED, Des Maladies Mentales, 2 vols. Paris, 1838, p. 404 (English translation from
Jackson 1986, p. 152).
70. Kraepelin E. Lebenserinnerungen (herausgegeben von H Hippius, G Peters, D Ploog). Berlin:
Springer-Verlag, 1983:71, 144, 145, 149.
71. Kraepelin E. Lebenserinnerungen (herausgegeben von H Hippius, G Peters, D Ploog). Berlin:
Springer-Verlag, 1983:73.
72. Kraepelin E. Lebenserinnerungen (herausgegeben von H Hippius, G Peters, D Ploog). Berlin:
Springer-Verlag, 1983:68–69.
73. Kraepelin E. Einführung in die psychiatrische Klinik. Zweiunddreißig Vorlesungen (zweite,
durchgearbeitete Ausgabe). Leipzig: Verlag von Johann Ambrosius Barth, 1905 (compare
also 8th edition, 1913).
74. Kohl F. die Anfange von Emil Kraepelins Systematik der Psychosen. Psychiatrische Praxis
1999; 26:105–111.
75. Berrios GE, Hauser R. The early development of Kraepelin’s ideas on classiﬁcation, Psychol
Med 1988; 18:813.
76. Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte (achte, volständig umgearbeitete Auﬂage). Leipzig: Verlag von Johann Ambrosius Barth, 1913:1185 [(translation byThompson C, ed). The Origins of Modern Psychiatry. Chichester: John Wiley & Sons, 1987:
246–247.]
77. Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte (achte, volständig umgearbeitete Auﬂage). Leipzig: Verlag von Johann Ambrosius Barth, 1913:1387.
78. Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte (achte, volständig umgearbeitete Auﬂage). Leipzig: Verlag von Johann Ambrosius Barth, 1913:1183 (translation by

42

79.
80.

81.

82.
83.
84.
85.
86.
87.
88.
89.
90.

91.
92.
93.

94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.

Glas
Thompson C, ed]. The Origins of Modern Psychiatry. Chichester: John Wiley & Sons, 1987:
245.
Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte (achte, volständig umgearbeitete Auﬂage). Leipzig: Verlag von Johann Ambrosius Barth, 1913:1289, 1303.
Dreyfus GL. Die Melancholie, ein Zustandsbild des manisch-depressiven Irreseins. Ein klinisch Studie (mit einem Vorwort von Hofrat Prof. dr. Emil Kraepelin). Jena: Verlag von Gustav Fischer, 1907.
Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte (achte, volständig umgearbeitete Auﬂage). Leipzig: Verlag von Johann Ambrosius Barth, 1913:1389–1390; cf. also
pp. 1369–1370.
Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte (achte, volständig umgearbeitete Auﬂage). Leipzig: Verlag von Johann Ambrosius Barth, 1913:1353–1354.
Hoche AE. Pathologie und Therapie der nervösen Angstzustände. Dtsch Z Nervenheilk 1911,
41:94–204.
Jaspers K. Allgemeine Psychopathologie (sechste unveränderte Auﬂage). Berlin/Göttingen/
Heidelberg: Springer Verlag, 1953:471–479.
Bleuler E. Lehrbuch der Psychiatrie. Berlin: Verlag von Julius Springer, 1916:345.
Bleuler E. Lehrbuch der Psychiatrie (dreizehnte Auﬂage, neubearbeitet von ManfredBleuler). Berlin: Springer Verlag, 1975:457.
Winters, EE ed. The Collected Papers of Adolf Meyer, vol. 2. Baltimore: The Johns Hopkins
Press, 1951:566–567.
Winters, EE ed. The Collected Papers of Adolf Meyer, vol. 2. Baltimore: The Johns Hopkins
Press, 1951:599.
Winters, EE ed. The Collected Papers of Adolf Meyer, vol. 2. Baltimore: The Johns Hopkins
Press, 1951:600.
Lewis AJ. Melancholia: A clinical survey of depressive states. J Ment Sci 1934:80:277 (reprinted in: Lewis AJ. Inquiries in Psychiatry. Clinical and Social Investigations. London:
Routledge and Kegan Paul, 1967:118).
Lewis AJ. Melancholia: a prognostic study. J Ment Sci 1936; 82:488.
Lewis AJ. States of depression: clinical and aetiological differentiation. Brit Med J 1938; 2:
875.
Lewis AJ. Melancholia: a clinical survey of depressive states. J Ment Sci 1934; 80:277 (reprinted in Lewis AJ. Inquiries in Psychiatry. Clinical and Social Investigations. London:
Routledge and Kegan Paul, 1967:113).
Jablensky A. The conﬂict of nosologists: views on schizophrenia and manic-depressive illness in the early part of the 20th century. Schiz Res 1999; 39:95–100.
Pichot P. L’Avenir du Concept de Dépression. Acta Psych Belg 1996; 96:59–73.
Kendell RE. The Classiﬁcation of Depressive Illness. London/New York: Oxford University
Press, 1968:2.
Heron MJ. A note on the concept endogenous—exogenous. Br J Med Psychol 1965; 38:
241.
Lewis A. Endogenous and exogenous: a useful dichotomy? Psychol Med 1971; 1:191.
Bonhoeffer K. Zur Frage der Schreckpsychosen. Monatschrift für Psychiatrie und Neurologie
1919; 22:143–156.
Freud S. Draft G, Melancholia. Standard Edition, vol 1, 1895:200–206.
Freud S. Trauer und Melancholie. Gesammelte Werke, Band X, 1917:427–446.
Abraham K. Ansätze zur psychoanalytischen Erforschung und Behandlung des manischdepressiven Irreseins und verwandter Zustände. Zentral Psychoanalyse 1912; 2:302.
Lindemann E. Symptomatology and management of acute grief. Am J Psychiatry 1944; 101:
141.
Bowlby J. Attachment and Loss, vol I. Attachment, 2nd ed. New York: Basic Books,
1969.

History of Anxiety and Depression

43

105. Bowlby J. Attachment and Loss, vol II. Separation: Anxiety and Anger. London: Penguin
Books, 1973.
106. Bowlby J. Attachment and Loss, vol III. Loss: sadness and depression. London: Penguin
Books, 1981.
107. Scheler M. Der Formalismus in der Ethik und die materiale Wertethik II.V. Materiale Wertethik und Eudaimonismus. Halle, 1913/1916:344.
108. Akiskal HS, McKinney WT. Overview of recent research in depression. Integration of ten
conceptual models into a comprehensive clinical frame. Arch Gen Psychiatry 1975; 32:285.
109. Perris C, ed. A study of bipolar (manic-depressive) and unipolar recurrent depressive psychosis. Acta Psychiatrica Scand 1966; 42 (suppl 194).
110. Angst J. Zur Ätiologie und Nosologie endogener depressiver Psychosen. Ein genetische,soziologische und klinische Studie. Monographien aus der Gesamtgebiete der Neurologie
und Psychiatrie, Heft 112. Berlin: Springer-Verlag, 1966.
111. American Psychiatric Association Committee on Nomenclature and Statistics, Diagnostic
and Statistical Manual of Mental Disorders. Edition 3. Washington: American Psychiatric
Association, 1980.
112. American Psychiatric Association Committee on Nomenclature and Statistics, Diagnostic
and Statistical Manual of Mental Disorders. Edition 3 (revised). Washington: American Psychiatric Association, 1987.
113. American Psychiatric Association Committee on Nomenclature and Statistics, Diagnostic
and Statistical Manual of Mental Disorders. Edition 4. Washington: American Psychiatric
Association, 1994.
114. Kendell RE. The Classiﬁcation of Depressive Illness. London/New York: Oxford University
Press, 1968.
115. Kendell RE. The classiﬁcation of depressions: a review of contemporary confusion. Br J
Psychiatry 1976; 129:15.
116. Klein DF. Endogenomorphic depression. Conceptual and terminological confusion, ArchGen Psychiatry 1974; 31:447.
117. Paykel ES. Classiﬁcation of depressed patients: a cluster analysis derived grouping. Br J
Psychiatry 1971; 118:275.
118. Mendels J, Cochrane C. The nosology of depression: the endogenous-reactive concept, Am
J Psychiatry 1968; 124 (May Suppl.):1–6.
119. Klein DF. Endogenomorphic depression. Conceptual and terminological confusion. ArchGen Psychiatry 1974; 31:447.
120. Errera P. Some historical aspects of the concept of phobia. Psychiatric Q 1962; 36:325.
121. le Camus A. Des aversions. Méd l’Espr (Medicine of the Mind) 1769; 1:259–265.
122. de Sauvages FB. Nosologie Méthodique (Methodical Nosology). Paris: Hérissant, 1770–
1771:607–617.
123. Rush B. On the different species of phobia, 1798. In: Hunter R, McAlpine I, eds. Three
Hundred Years of Psychiatry 1535–1860. Oxford: Oxford University Press, 1963: 669–
670.
124. Benedikt M. Über “Platzschwindel.” Allgem Wien Med Z 1870; 15:488–489.
125. Benedikt M. Über “Platzschwindel.” Allgem Wien Med Z 1870; 15:488 (translation by theauthor).
126. Westphal C. Die Agoraphobie, eine neuropathische Erscheinung. Arch Psychiatr
Nervenkrank 1872; 3:138–161.
127. Kohl F. “Agoraphobie–Platzangst/Platzfurcht–Platzschwindel”. Die klassischen Beschreibungen der Platzangst von Carl Westphal und Emil Cordes und ihre Bedeutung fur die Konzeptgeschichte und aktuelle Diskussion der Angsterkrankungen. Psychiatr Praxis 2001; 28:
3–9.
128. Westphal C. Die Agoraphobie, eine neuropathische Erscheinung. Arch Psychiatr
Nervenkrank 1872; 3:153.

44

Glas

129. Da Costa JM. On irritable heart; a clinical study of a form of functional cardiac disorderand its consequences. Am J Med Sci 1871; 71:17–52.
130. Da Costa JM. On irritable heart; a clinical study of a form of functional cardiac disorderand its consequences. Am J Med Sci 1871; 71:26.
131. Skerritt P. Anxiety and the heart —a historical review. Psychol Med 1983; 13:17–25.
132. Lewis T. The tolerance of physical exertion, as shown by soldiers suffering from so-called“irritable heart.” Br Med J 1918; I:363–365.
133. Lewis T. Soldier’s Heart and the Effort Syndrome, 2nd ed. London: Shaw, 1940.
134. MacKenzie J. The soldier’s heart. Br Med J 1916; I:117–119.
135. MacKenzie J. The soldier’s heart and war neurosis: a study in symptomatology. Br Med J
1920; I: 491–494, 530–534.
136. Wood P. Da Costa’s syndrome (or effort syndrome). Br Med J 1941; 767–772, 805–811,
845–851.
137. Culpin M. The psychological aspect of the effort syndrome. The Lancet 1920; ii:84.
138. Wood P. Da Costa’s syndrome (or effort syndrome). Br Med J 1941; 767–772, 805–811,
845–851.
139. MacKenzie J. The soldier’s heart. Br Med J 1916; I:117–119.
140. MacKenzie J. The soldier’s heart and war neurosis: a study in symptomatology. Br Med J
1920; I:491–494, 530–534.
141. Jones M, Lewis A. Effort syndrome. The Lancet 1941; I:813–818.
142. Jones M. Physiological and psychological responses to stress in neurotic patients. J Ment
Sci 1948; 94:392–427.
143. Jones M. Physiological and psychological responses to stress in neurotic patients. J Ment
Sci 1948; 94:392–427.
144. Wood P. Da Costa’s syndrome (or effort syndrome). Br Med J 1941; 767–772, 805–811,
845–851.
145. Wood P. Da Costa’s syndrome (or effort syndrome). Br Med J 1941; 846.
146. Bonhoeffer K. Zur Frage der Schreckpsychosen Monatsch Psychiatr Neurol 1919; 22:143–
156.
147. Kleist K. Schreckpsychosen. Allgem Z Psychiatr 1918; 75:432–510.
148. Lewis T. The tolerance of physical exertion, as shown by soldiers suffering from so-called“irritable heart.” Br Med J 1918; I:363–365.
149. White P. Fatigue syndrome: neurasthenia revived. Br Med J 1989; 298:1199–1200.
150. Wessely S. Old wine in new bottles: neurasthenia and ‘ME.’ Psychol Med 1990; 20:35–53.
151. Wernicke C. Die Angstpsychose. Allgem Z Psychiatr 1895; 51:1020–1021.
152. Specht G. Ueber Angstaffekt im manisch-depressiven Irresein. Centralblatt Nervenheilk
Psychiatrie 1907; 30:529–533.
153. Forster E. Die klinische Stellung der Angstpsychose. Berlin: Karger, 1910.
154. Forster E. Die klinische Stellung der Angstpsychose. Berlin: Karger, 1910:252–260.
155. Kraepelin E, Lange J. Pychiatrie. Band I (neunte Auﬂage). Leipzig: Johann Ambrosius Barth,1927:611.
156. Forster E. Die klinische Stellung der Angstpsychose. Berlin: Karger, 1910:260.
157. Störring GE. Zur Psychopathologie und Klinik der Angstzustände. Abhandlungen aus dr
Neurologie, Psychiatrie, Psychologie und ihren Grenzgebieten. Beihefte zur Monatschrift für
Psychiatrie und Neurologie, Heft 72. Berlin: Kargr, 1934.
158. Conrad K. Die beginnende Schizophrenie. Stuttgart: Thieme, 1958.
159. Schmidt-Degenhard M. Angst -problemgeschichtliche und klinische Aspekte. Fortschr Neurol Psychiatr 1986; 54:321–339.
160. Beard GM. Sexual Neurasthenia [nervous exhaustion]. Its Hygiene, Causes, Symptoms, andTreatment. Rockwell Ad, ed. New York: EB Treat, 1884.
161. Beard GM. A Practical Treatise on Nervous Exhaustion (Neurasthenia). Its Symptoms, Nature, Sequences, Treatment. Rockwell, AD ed. London: HK Lewis, 1890.

History of Anxiety and Depression

45

162. Beard GM. Sexual Neurasthenia [Nervous Exhaustion]. Its Hygiene, Causes, Symptoms, andTreatment. Rockwell AD, ed. New York: EB Treat, 1884:52–53.
163. Beard GM. A Practical Treatise on Nervous Exaustion (Neurasthenia). Its Symptoms, Nature,
Sequences, Treatment. Rockwell AD, ed. London: HK Lewis, 1890:50–67.
164. Beard GM. Sexual Neurasthenia [Nervous Exhaustion]. Its Hygiene, Causes, Symptoms, andTreatment. Rockwell AD, ed. New York: EB Treat, 1884:60–61.
165. MacMillan MB. Beard’s concept of neurasthenia and Freud’s concept of the actual neuroses.
J Hist Behav Sci 1976; 12:376–390.
166. Rosenberg CE. The place of George M. Beard in nineteenth century psychiatry. Bull HistMed 1962; 36:245–259.
167. Beard GM. A practical treatise on nervous exhaustion (neurasthenia). Its symptoms, nature,
sequences, treatment. Rockwell AD, ed. London: HK Lewis, 1890:25–35.
168. Berrios GE. Feelings of fatigue and psychopathology: a conceptual history. Compr Psychiatry
1990; 31:140–151.
169. López Pineiro J. Historical Origins of the Concept of Neurosis. Berrios D, trans. Cambridge:
Cambridge University Press, 1983:64.
170. Russelman GHE. Van James Watt tot Sigmund Freud. De opkomst van het stuwmodel vande zelfexpressie. Deventer: Van Logham Slaterus, 1983:119–154.
171. Janet P. Les Obsessions et al Psychasthénie (The obsessions and psychasthenia). Paris: Alcan,
1903.
172. Janet P. Les Obsessions et la Psychasthénie (The obsessions and psychasthenia). Paris: Alcan,
1903:439.
173. Janet P. Les Obsessions et la Psychasthénie (The obsessions and psychasthenia). Paris: Alcan,
1903:487.
174. Janet P. Les Obsessions et la Psychasthénie (The obsessions and psychasthenia). Paris: Alcan,
1903:497.
175. Janet P. Les Obsessions et la Psychasthénie (The obsessions and psychasthenia). Paris: Alcan,
1903:486.
176. Janet P. Les Obsessions et la Psychasthénie (The obsessions and psyhasthenia). Paris: Alcan,
1903:247.
177. Tyrer PJ. Classiﬁcation in anxiety. Br J Psychiatry 1984;144:78–83.
178. Hecker E. Ueber larvirte und abortive Angstzustände bei Neurasthenie. Zentralb Nervenheilk
1893; 16:565–572.
179. Freud S. Über die Berechtigung, von der Neurasthenie einen bestimmten Symptomen-komplex als ‘Angstneurose’ abzutrennen. Gesammelte Werke, Band I, 1895:315–342.
180. Freud S. Zur Kritik der Angstneurose. Gesammelte Werke, Band I, 1895:355–376.
181. Freud S. Über die Berechtigung, von der Neurasthenie einen bestimmten Symptomen-komplex als ‘Angstneurose’ abzutrennen. Gesammelte Werke, Band I, 1895:315.
182. Freud S. Zur Kritik der Angstneurose. Gesammelte Werke, Band I, 1895:368–369.
183. Kraepelin E, Psychiatrie. Ein Lehrbuch für Studirende und Aertzte (sechste, voll-ständig
umgearbeitete Auﬂage). Leipzig: Johann Ambrosius Barth, 1899.
184. Spitzer RL, Williams JBW. Proposed revisions in the DSM -III Classiﬁcation of anxiety
disorders based on research and clinical experience. In: Tuma AH, Maser H, eds. Anxiety
and the Anxiety Disorders. Hillsdale/London: Lawrence Erlbaum, 1985:759–773.
185. Freud S. Obsessions et phobies. Gesammelte Werke, Band I, 1895:352.
186. Freud S. Hemmung, Symptom und Angst. Gesammelte Werke, Band XIV, 1926:111–205.
187. Freud S. Über die Berechtigung, von der Neurasthenie einen bestimmten Symptomen-komplex als ‘Angstneurose’ abzutrennen. Gesammelte Werke, Band I, 1895:338.
188. Freud S. Draft E, Standard Edition. Vol I, 1894:194.
189. Freud S. Hemmung, Symptom und Angst. Gesammelte Werke, Band XIV, 1926:68.
190. Freud S. Neue Folge der Vorlesungen zur Einfürung in die Psychoanalyse. Gesammelte
Werke, Band XV, 1933:100–101.

46

Glas

191. Freud S. Hemmung, Symptom und Angst. Gesammelte Werke, Band XIV, 1926:168.
192. Beck AT. Cognitive Therapy and the Emotional Disorders. New York: New American Library, 1976.
193. Beck AT, Emery G, with RL Greenberg. Anxiety Disorders and Phobias. A Cognitive Perspective. New York: Basic Books, 1985.
194. Goldstein K. Zum Problem der Angst. Allgem ärztliche Z Psychoth Psychische Hyg 1929;
2:409–437.
195. Kronfeld A. Über Angst. Nederlandsch Tijdschrift voor Psychologie 1935; 3:366–387.
196. Hoche AE. Pathologie und Therapie der nervösen Angstzustände. Dtsch Z Nervenheilk 1911;
41:194–204.
197. Kornfeld S. Zur Pathologie der Angst. Jahrbüch Psychiat Neurol 1902; 22:411–442.
198. Oppenheim H. Zur Psychopathologie der Angstzustände. Berl Klin Wochenschr 1909; 46:
1293–1295.
199. Janet P. De l’Angoisse à l’Extase. Paris: Alcan, 1926.
200. Stekel W. Nervöse Angstzustände und ihre Behandlung. Wien: Urban und Schwarzenberg,
1932.
201. Bitter W. Die Angstneurose. Entstehung und Heilung. Mit 2 Analysen nach Freud und Jung.
Bern: Hans Huber, 1948.
202. Riemann F. Grundformen der Angst und die Antinomien des Lebens. München/Basel: Ernst
Reinhardt Verlag, 1961.
203. Freiherr von Gebsattel VE. Anthropologie der Angst. In: Prolegomena einer medizinischen
Anthropologie. Ausgewählte Aufsätze. Berlin: Springer-Verlag, 1954:378–389.
204. Freiherr von Gebsattel VE. Zur Psychopathologie der Phobien. Die psychasthenische Phobie.
In: Prolegomena einer medizinischen Anthropologie. Ausgewählte Aufsätze. Berlin:
Springer-Verlag, 1954:42–74.
205. Freiherr von Gebsatte VE. Die Welt des Zwangskranken. In: Prolegomena einer medizinischen Anthropologie. Ausgewählte Aufsätze. Berlin: Springer-Verlag, 1954:74–128.
206. Tellenbach H. Melancholie. Problemgeschichte, Endogenität, Typologie, Pathogenese,
Klinik (dritte erweiterte Auﬂage). Berlin: Springer-Verlag, 1976.
207. Bonhoeffer K. Zur Frage der Schreckpsychosen. Monatsch Psychiatr Neurol 1919; 22:143–
156.
208. Kleist K. Schreckpsychosen. Allgem Z Psychiatr 1918; 75:432–510.
209. Panse F. Angst und Schreck in klinisch-psychologischer und sozialmedizinischer Sicht.
Dargestellt an Hand von Erlebnis-berichten aus dem Luftkrieg. Stuttgart: Georg Thieme Verlag, 1952.
210. James W. What is an emotion? Mind 1884; 9:189:204. Cf. also W James. Principles of
Psychology, 2 vols. New York: Dove, 1890:450.
211. Störring GE. Zur Psychopathologie und Klinik der Angstzustände. Abhandlungen aus der
Neurologie, Psychiatrie, Psychologie und ihren Grenzgebieten. Beihefte zur Monatschrift für
Psychiatrie und Neurologie, Heft 72. Berlin: Karger, 1934:24, 32.
212. Kraepelin E, Lange J. Psychiatrie. Band I (neunte Auﬂage), Leipzig: Johann Ambrosius
Barth, 1927:470.
213. Freud S. Neue Folge der Vorlesungen zur Einfürung in die Psychoanlyse. Gesammelte
Werke, Band XV, 1933.
214. Goldstein K. Zum Problem der Angst. Allgem Z Psychother Psych Hyg 1929; 2:415–416.
215. Kronfeld A. Über Angst. Nederland Tijdschr Psychol 1935; 3:378.
216. Kronfeld A. Über Angst. Nederland Tijdsch Psychologie 1935; 3:384. (Translation by theauthor of this chapter.)
217. Tyrer PJ. Classiﬁcation in anxiety. Br J Psychiatry 1984; 144:78–83.
218. Jablensky A. Approaches to the deﬁnition and classiﬁcation of anxiety and related disordersin European psychiatry. In Tuma AH, Maser J, eds. Anxiety and the Anxiety Disorders.
Hillsdale/London: Lawrence Erlbaum, 1985:735–758.

History of Anxiety and Depression

47

219. Ax A. The physiological differentiation between fear and anger in humans. Psychosom Med
1953; 15:433–442.
220. Sternbach LH. The benzodiazepine story. In: Priest RG, Vianna U Filho, Amrein R, Skreta
M, eds. Benzodiazepines. Today and Tomorrow. Lancaster: MTP Press Limited, 1980:5.
221. Wolpe J. Psychotherapy by Reciprocal Inhibition. Stanford: Stanford University Press, 1958.
222. Roth M. The phobic anxiety-depersonalization syndrome. Proc R Soc Med 1959; 52:587–
595.
223. Klein DF. Delineation of two drug-responsive anxiety syndromes. Psychopharmacologia
1964; 5:397–408.
224. Klein DF. Anxiety reconceptualized. Compr Psychiatry 1980; 21:411–427.
225. Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Munoz R. Diagnostic criteria
for use in psychiatric research. Arch Gen Psychiatry 1972; 26:57–63.
226. Spitzer, RL. Williams JBW. Proposed revisions in the DSM -III classiﬁcation of anxiety
disorders based on research and clinical experience. In: Tuma AH, Maser H, eds. Anxiety
and the Anxiety Disorders. Hillsdale/London: Lawrence Erlbaum, 1985:759–773.
227. Gersons BPR, Carlier IVE. Post-traumatic stress disorder: the history of a recent concept.
Br J Psychiat 1992; 161:742–748.
228. van der Kolk BA, Herron N, Hostetler A. The history of trauma in psychiatry. Psychiatr Clin
North Am 1994; 17:583–600.
229. Spitzer RL, Williams JBW. Proposed revisions in the DSM -III classiﬁcation of anxiety disorders based on research and clinical experience. In: Tuma AH, Maser H, eds. Anxiety andthe Anxiety Disorders. Hillsdale/London: Lawrence Erlbaum, 1985:759–773.
230. Pélissolo A, Lépine J-P. Les phobies socials: perspective historiques en conceptuelles.
L’Encéphale 1995; 21:15–24.
231. Gorman JM, Leibowitz MR, Fyer AJ, Stein J. A neuroanatomical hypothesis for panic disorder. Am J Psychiatry 1989; 146:148–161.
232. Tuma AH, Maser H, eds. Anxiety and the Anxiety Disorders. Hillsdale/London: Lawrence
Erlbaum, 1985.
233. Marks IM. Fears, Phobias and Rituals: Panic, Anxiety, and Their Disorders. Oxford: Oxford
University Press, 1987.
234. Barlow DH. Anxiety and Its Disorders. The Nature and Treatment of Anxiety and Panic.
New York: Guilford Press, 1988.
235. Glas G. Concepten van angst en angststoornissen. Een psychiatrische en vakﬁlosoﬁsche studie. Lisse/Amsterdam: Swets en Zeitlinger, 1991.
236. Glas G. Angst–beleving, structuur, macht. Amsterdam: Boom, 2001.
237. Blashﬁeld RK. Structural approaches to classiﬁcation. In: T Millon, G Klerman Eds. Contemporary directions in psychopathology. Toward the DSM-IV. New York: Guilford Press, 1986:
363–380.

2
Epidemiology of Depression
and Anxiety
BORWIN BANDELOW
University of GöttingenGöttingen, Germany

I.

INTRODUCTION

Epidemiological studies in psychiatry may help in assessing the importance of a certain
disorder in order to develop treatment strategies and in planning special health prevention
programs. They may provide information on the use of health services and the economic
impact of psychiatric disorders on the health-care system. Epidemiological research may
also help us to better understand the etiology of psychiatric diseases. For example, when
it is found that the prevalence rates of the anxiety disorders are more or less the same inmany different countries, despite different cultural and social environments, it seems lessprobable that these disorders can be attributed mainly to cultural or psychosocial causes.
If this is the case, neurobiological determinants that are distributed statistically among all
people, regardless of their sociocultural surroundings, must also be seen as a relevant
etiological factor.
A substantial underrecognition and undertreatment of anxiety disorders and depression have been shown. According to a WHO study, only approximately half of the casesof depression and anxiety have been recognized and only one-third were offered drug
treatment [1].
II. METHODOLOGY OF EPIDEMIOLOGICAL STUDIES
A. Prevalence Rates
In epidemiological studies, different kinds of prevalence rates are determined, and all havetheir advantages and disadvantages. The lifetime prevalence is the proportion of the sample
4950

Bandelow

who ever experienced a disorder in their life. Lifetime prevalence rates of disorders witha high mortality rate may be underestimated. The annual prevalence is the proportion ofprobands who experienced the disorder at some time in the 12 months prior to the interview. Disorders of longer duration are likely to be overrepresented in annual prevalence
rates compared to those of short duration. The more chronic a disease, the more similarities
between lifetime and 12-month prevalence rates should be found. The point prevalenceis the prevalence of a disorder on a certain effective day.
B.

Representativity

To determine the prevalence of mental disorders, large-scale, expensive, and complex
surveys have to be undertaken.
One relatively simple way to ﬁnd out how many people suffer from certain psychiatric disorders would be to make a survey among all patients who attend a number ofdifferent mental health services. However, by simply counting the individuals sufferingfrom panic disorder or major depression who consult a psychiatrist in a private practiceor a mental clinic, one would obtain prevalence rates that could be signiﬁcantly distorted,as they could be inﬂuenced by various factors such as specialty of the physician. Moreover,prevalence rates could be distorted because patients with certain psychiatric diseases tend
to have a high medical care utilization, such as somatization disorder patients, and others
may only rarely seek psychiatric help, such as patients with social phobia or severe cognitive dysfunctions. Finally, some patients in some countries can just simply not afford tosee a doctor, resulting in an underestimation of the prevalence of certain disorders in thispopulation.
The only way to obtain reliable prevalence rates is a so-called “knock-door” survey,
in which representative samples are collected by using methods known from population
polls. From a listing of all residential addresses, systematic samples are selected, and one
household member is addressed using a special procedure. Then, interviewers knock at thedoor of these households and interrogate the selected member using a structured interview.
To obtain a complete overview, representative surveys should also include patientscurrently hospitalized or in long-term facilities. However, not all studies have incorporated
this population.
Samples should be taken from different regions, including urban and rural sites. The
sample sizes of these surveys should be very large in order to obtain reliable and generalizable results, not only for frequent disorders but also for rare illnesses. The largest of thesestudies, the ECA study (see below), comprised 24,371 respondents.
When these large samples are investigated in population surveys, it is too expensive
to have the work done by experienced psychiatrists. Thus, these studies are usually conducted by professional interviewers who go through a speciﬁc training program for psychiatric interviews.
However, studies conducted in psychiatric outpatient services or in primary caresetting may also yield valuable information. Recently, a worldwide survey conducted by
the World Health Organization (WHO) explored the frequency of psychological problems
in primary care or general health settings [2].
In statistical investigations conducted with psychiatric inpatients, psychiatric disorders like depression, schizophrenia, or personality disorders are usually overrepresented
because certain features of these disorders require inpatient treatment, including suicid-

Epidemiology of Depression and Anxiety

51

ality, hostility, or reduced social integration. In these surveys, patients with anxiety disorders are generally underrepresented, as anxiety disorders rarely require inpatient treatment.
C. Diagnosis and Interview Technique
In order to obtain reliable diagnoses, interviews are usually based on the standard diagnostic tools, Diagnostic and Statistical Manual for Mental Disorders (DSM) [3] or International Classiﬁcation of Diseases (ICD-10) [4]. In order to structure the diagnostic process
and to obtain objective results, special interview manuals have been developed. These
include:The Structured Interview for DSM (SCID), which is a semistructured interview for
making the major axis I DSM diagnoses. It is administered by a clinician [5,6].
The Mini-International Neuropsychiatric Interview (M.I.N.I.), which is a short,structured diagnostic tool for DSM-IV and ICD-10 psychiatric disorders. Withan administration time of approximately 15 min, it was designed to meet the needfor a short, but accurate, structured psychiatric interview for multicenter clinical
trials and epidemiological studies [7].
The Diagnostic Interview Schedule (DIS), which is an interview schedule that allows
lay interviewers or clinicians to make psychiatric diagnoses according to DSM
criteria [8].
The Composite International Diagnostic Interview (CIDI) for DSM [9] or its modiﬁed version for ICD-10 [10], which combines questions from the DIS with Present
State Examination questions and is fully structured to allow administration by
lay interviewers and scoring of diagnoses by computer.
Some representative surveys have been conducted in recent years, using complex
sampling methods, well-deﬁned diagnostic criteria, elaborate questionnaires, and sophisticated statistical methods (see Table 1). The largest ones were the following:
In the Epidemiologic Catchment Area Program [11], a project conducted in the early
1980s, a probability sample of households was selected and one adult residing

Table 1 Lifetime and 6- or 12-Month Prevalence Rates for Major Depression, Sorted
by Lifetime Prevalence
Authors
Karam [21]Kessler et al. [12]Lépine et al. [86]Joyce et al. [87]Wittchen et al. [14]Bland et al. [17]Robins et al. [22]Canino et al. [88]Hwu et al. [13]Faravelli et al. [60]Lee et al. [89]

Site

N

Lifetime

12 months

6 months

Beirut, Lebanon
U.S. (NCS)
Paris, France
New ZealandWest Germany
Edmonton, Canada
U.S. (ECA)
Puerto Rico
TaiwanFlorence, Italy
Korea

526
8098
1746
1498
657
3258
18,5711551
11,004
1110
5100

19.0%
17.1%
16.4%
12.6%
9.0%
8.6%
5.2%
4.6%
1.5%
—
2.9

—
10.3%
4.5%
5.3%
—
—
3.0%
—
0.8%
5.2%
2.3%

—
—
—
3.0%
3.2%
—
3.0%
—
—

52

Bandelowin this household was interviewed in ﬁve U.S. communities; the DSM-III and the
DIS were used; it included 18,571 persons.
The National Comorbidity Survey (NCS) [12] was based on a stratiﬁed, multistage
probability sample of persons aged 15 to 54 years in 48 U.S. states and was
conducted from 1990 to 1992. DSM-III-R diagnoses were made with the CIDI;
8098 persons were interviewed. The interviewers were not clinicians, had an average of 5 years of prior interviewing and went through a 7-day study-speciﬁc training program for this survey.
The Taiwan Psychiatric Epidemiological Project was a representative survey andused the DSM-III and the DIS. It was conducted by trained lay interviewers inseven urban and rural regions in Taiwan [13]; 11,004 persons were interviewed
from 1982 to 1986.
Nonpsychiatrists sometimes express the opinion that prevalence rates for some mental disorders obtained in these studies are grossly exaggerated. For example, according to
the NCS study [12], every third woman suffers from an anxiety disorder once in her life.
It is a problem that the classiﬁcation systems DSM and ICD cannot reliably differentiate
between subthreshold cases and clinically signiﬁcant cases, which deﬁnitely need treatment. Some of the DSM and ICD criteria were decided by committee rather than being
empirically derived from ﬁeld studies. If a survey is carried out by lay interviewers, thereis the possibility that prevalence rates of some less well-deﬁned disorders may be inﬂated.
If a survey is conducted by psychiatrists (e.g., Ref. 14) or uses a general psychiatric outpatient sample (e.g., Ref. 15), the clinical cases will probably be identiﬁed more reliably.
Recently, a worldwide survey conducted by the WHO has explored the frequencyof psychiatric disorders in primary care [2]. In this kind of study, persons who are consulting health-care services are screened for psychological problems and psychiatric disorders, regardless of their reason for attending that service. This also means that persons
who consulted the doctor for a cold are included. These studies are not appropriate forobtaining representative prevalence rates for the reasons given above. However, they may
yield valuable information on the use of health services and the social and ﬁnancial impactof psychiatric disorders.
Even the representative population surveys show substantial discrepancies in prevalence rates. This may be attributed to various factors, including methodological differencesthat could distort the actual prevalence rates, for example:
Variation in the use of the diagnostic criteria (e.g., DSM-III or DSM-III-R).
Variation in the use of the interview manual (e.g., CIDI or DIS).
Type of interviewer (trained lay or psychiatrist/psychologist).
Interviewer instructions [16].
Language differences or translating problems.
Cultural differences in conveying psychiatric symptoms.
Differences in age range of the sample investigated [12].
Standardization of prevalence rates to the census population of each site instead ofto an identical population [17].
However, actual differences between the investigated populations may exist also and may
be due to:
Biological differences across races and ethnic groups.

Epidemiology of Depression and Anxiety

53

Culturally determined psychosocial differences (e.g., a different role of women insociety).
Traumatic stressors that inﬂuence whole nations or ethnic groups (e.g., war, poverty,
natural disasters, or suppression of minorities).
III. DEPRESSION
A. Prevalence
Lifetime and 6- or 12-month prevalence rates in different countries are listed in Table 1.
There was a wide variability in the rates of major depression across nations [18]. Thereis no simple explanation for this ﬁnding. The highest rates were found in war-shaken
Lebanon, but rates in the U.S. (NCS study) or Paris were almost the same. The lowest
rates were found in the Taiwan study. In this study, very low rates were also found for mostother psychiatric disorders, the reasons for which are unknown. It would be premature to
attribute these low rates to actual differences rather than to methodological biases (seeRefs. 19,20 for a discussion).
Women have higher depression rates than men across all countries. The female-tomale ratio is 2: 1 on average, ranging from 1.6: 1 in Taiwan and Lebanon [13,21] to 2.6
in the U.S. [22]. A number of reasons for the higher rates in women have been proposed
without a clear resolution. The higher occurrence of anxiety disorders in females thanmales beginning early in life might explain the higher female risk for major depression,as anxiety rates are also higher in women [23].
B. Course
The mean age at onset is very similar in most studies, ranging from 24.8 to 29.5 in the
majority of surveys—with the exception of Italy, where a mean age of 34.8 years wasfound [18]. Depression rates are highest in midlife. The highest 1-month prevalence rate
was found in the age group 25 to 44 (3.9%), followed by 18 to 24 (2.9%), 45 to 64 (2.6%),
and 0.9% in persons aged 65 and older [11]. However, these prevalence rates may havebeen inﬂuenced by high rates of suicidality for depressed patients.
IV. BIPOLAR DISORDER
In contrast to the high variability found in major depression, the lifetime rates for bipolar
disorder were rather consistent across the nations and varied between 0.3 and 0.9%, withthe exception of New Zealand, where a higher rate of 1.5% was found.
Although women have higher rates for major depression, for bipolar disorder the
opposite was found in some countries. In Canada, Puerto Rico, Korea, and New Zealand,
female-to-male ratios between 0.3: 1 and 0.7: 1 were registered. In the U.S. (ECA), therate was 1.2 :1, and in Taiwan rates were equal for men and women [18]. The mean age
at onset ranged between 17.1 in Canada to 29.0 in West Germany.
V.

DYSTHYMIA

A. Prevalence
The lifetime prevalence rates of dysthymia in different countries are listed in Table 2.
The average female-to-male ratio in these studies was 1.5 to 2.5. The highest 1-month54

Bandelow

Figure 1 Lifetime prevalence rates for anxiety disorders (Ref. 22).

Figure 2 Lifetime prevalence rates for anxiety disorders (Ref. 12). OCD: obsessivecompulsive disorder; GAD generalized anxiety disorder; PTSD: post-traumatic stress disorder.

Epidemiology of Depression and Anxiety

55

Figure 3 Lifetime prevalence rates for anxiety disorders (Ref. 17). OCD: obsessivecompulsive disorder.

Figure 4 Number of patients attending an anxiety disorders unit at the University of Goettingen, Germany in 6 months (May–Oct 1999). Diagnoses according to ICD-10 (Bandelow,
unpublished).

Table 2 Lifetime Prevalence Rates of Dysthymia
Refs.
Kessler et al. [12]Canino et al. [88]Wittchen et al. [14]Bland et al. [17]Robins et al. [22]Hwu et al. [13]SiteLifetime Prevalence

U.S. (NCS)
Puerto Rico
West Germany
Edmonton, Canada
U.S. (ECA)
Taiwan

6.4%
4.7%
4.0%
3.7%
3.0%
0.9–1.5%

56

Bandelow

prevalence rates were found in the age group 45 to 64 (5.4%), followed by 25 to 44 (5.1%)
in persons aged 65 and older (2.3%) and the age group 18 to 24 (2.2%) [11].

VI. ANXIETY DISORDERS
A.

Prevalence

Among all psychiatric disorders, the anxiety disorders are the most frequent [12]. Because
patients with anxiety disorders are mostly treated as outpatients, they probably receive
less attention from clinical psychiatrists than patients with other disorders that require
inpatient treatment but are much less frequent, such as mania or schizophrenia.
The prevalence rates of the anxiety disorders in three epidemiological studies arepresented in Figures 1 to 3.
In a special anxiety disorders unit, the numbers of patients seeking help differed
substantially from the actual prevalence rates in the population (Fig. 4). Panic disorderwith or without agoraphobia seems to be by far the most frequent reason for seeing ananxiety specialist psychiatrist, whereas patients with GAD were rare, and speciﬁc phobia
patients did not appear at all.
B.

Is There an Increase in the Prevalence of Anxiety Disorders?

Many newspaper articles start with the line “More and more people are suffering fromanxiety,” suggesting there has been a relative increase in anxiety disorders over the past
years. This tendency was already observed before the terrorist attacks in the U.S., whichshocked the world and may have made many people feel insecure. However, although
the question is of great interest and a general increase in media reports on anxiety disorders
has surely been observed in recent years, it is difﬁcult to prove a change in anxiety rates
over the years. Epidemiological data obtained before the introduction of classiﬁcation
systems such as the DSM-III are too imprecise to be compared with modern studies. To
verify the hypothesis that there is an increase or decrease in certain psychiatric disorders,
one would have to repeat large epidemiological surveys such as the ECA or NCS programs—in the same population using the same methodological setting—after an intervalof, for example, 30 years.
C.

Panic Disorder with or Without Agoraphobia

The prevalence of panic disorder is presented in Figures 1 to 3. For better clarity, therates for panic disorder and agoraphobia have been added up in the ﬁgures, although they
were reported separately in the surveys. In the majority of cases, the disorder starts withspontaneous panic attacks, with patients later developing agoraphobia as they learn to
avoid situations in which they might have spontaneous attacks, such as crowds, public
transport, or enclosed spaces. In a survey of outpatients [24] it was found that 60.4% of
the patients had panic disorder with agoraphobia, 28.9% panic disorder without agoraphobia, and 10.7% had agoraphobia without panic disorder. In a cross-national survey, 22.5
to 58.2% of panic patients had agoraphobia [19].
In a primary care setting, 0.9–1.7% of the patients attending a general practitioner
had panic disorder and 1.5 to 1.6% had agoraphobia [25]. It has consistently been foundthat more women than men suffer from panic disorder. Weissman et al. [19] found female-Epidemiology of Depression and Anxiety

57

to-male ratios between 1.3 :1 and 5.8 :1 in different countries. Relatively few studies haveinvestigated whether women with anxiety disorders have characteristics that are distinct
from those of men with the same disorders. The cause of the enhanced vulnerability toanxiety for women remains largely undetermined. Some data suggest that female reproductive hormones and related cycles may plan an important role [26]. There is some evidence
that the vulnerability to anxiety disorders may be genetically determined [27]. This genetic
vulnerability may manifest in neurobiological differences. For example, increased monoamine oxidase A activity in women has been found in female patients with panic disorder[28]. The role of women in society may also play a substantial role. Furthermore, it has
been discussed that prevalence rates for men are underestimated because it may be lesssocially acceptable for men to admit suffering from anxiety.
1. Course
According to the Cross-National Epidemiologic Study, the majority of studies found an
age at onset between 23.2 and 27.9 years, with two exceptions (32.1 years in Korea and35.5 in Germany) [19]. In a clinical sample of 322 patients with panic disorder from 6
countries, subjects indicated that they had a mean age at onset of panic disorder of 28.9
years. The average onset of agoraphobia was 6 months later [29].
Panic disorder seems to be rare in children before puberty. In a retrospective study,
343 adults with panic disorder were interviewed whether or not they fulﬁlled the criteria
for panic disorder before age 13. This was condirmed by only 1% of the panic patients[30]. During adolescence, the risk of developing panic disorder steadily increases. A representative survey among 388 high-school attendants revealed a lifetime prevalence of 4.7%
for the age period 12 to 19 [31].
Panic disorder has a waxing and waning course. As a whole, it follows a chronic
course if left untreated. However, “chronic” is a relative term, as spontaneous remission
is generally observed beginning after the age of 40 [11]. Mental health providers rarely
see typical panic patients after the age of 60. Bland et al. [32] reported a 6-month prevalence rate of 0.0% for the age of 65 and older. The age distribution of patients referred
to an anxiety disorders clinic shows that most patients are between 30 and 45 when they
are referred for treatment (Fig. 5). Only persons aged 16 and older were included in thisstudy.
2. Cross-Cultural Differences
Epidemiological data on panic disorder from community studies from 10 countries aroundthe world have been compared [19,33]. These studies were conducted in countries thatdiffer quite a lot in terms of culture, socioeconomic status, religion, and other aspects,
and included Canada, Germany, Italy, Korea, Lebanon, New Zealand, Puerto Rico, theU.S., and Taiwan. Although the various surveys differed in design, they were comparable,
as DSM-III/DMS-III-R and the interview manuals DIS or CIDI were used for all of them.
Some of the studies had very small samples sizes (e.g., 234 in Lebanon and 481 in Germany). Despite some limitations, there seemed to be high agreement in prevalence rates
of panic disorder across the majority of countries. Most studies found a lifetime prevalence
rate of 1.4 to 2.9%.
Only in the NCS, a high prevalence rate of 3.5 was found, probably because DSMIII-R was used, which has a broader deﬁnition of panic disorder. The other studies used
DSM-III. In the DSM-III-R criteria, patients are included if they have had only one attack

58

Bandelow

Figure 5 Age distribution of 512 patients with panic disorder with or without agoraphobia
referred to an anxiety disorders clinic (Ref. 92). Percentage of all men or all women, respectively. Mean age of all patients: 34.9 years.
in their life and then had “persistent worry about having a panic attack” for at least 1
month. In contrast, DSM-III requires at least 3 panic attacks in 3 weeks.
In Taiwan, very low rates were found for panic disorder, as was found also for manyother psychiatric disorders in the Taiwan study. This has been widely discussed (seeabove). It was hypothesized that culturally determined response bias might have lowered
the rates for panic disorder [19,20]. However, as rates for generalized anxiety were relatively high in Taiwan (3.7–10.5%) [13], it may also be speculated that differences inwording or lack of clinical experience of the lay interviewers led to an overestimation ofgeneralized anxiety and an underestimation of panic disorder. When the interview technique is imprecise, it might happen that panic patients are misdiagnosed as having generalized anxiety disorder because most panic patients roughly fulﬁll GAD criteria. On theother hand, panic disorder criteria are more exact so that it is less probable that GAD
patients are misdiagnosed as panic patients.
Still, it seems that the prevalence of panic disorder is relatively consistent in different
cultures. This may have consequences for assumptions on the etiology of panic disorder.
Neurobiological hypotheses on the etiology of anxiety disorder are getting some support
by these ﬁndings, whereas cultural inﬂuences may play a less important role.
D.

Speciﬁc Phobia

According to most studies, speciﬁc phobia is one of the most frequent anxiety disorders(Figs. 1 to 3). However, patients with isolated fears rarely seek professional help, probably

Epidemiology of Depression and Anxiety

59

because they do not have the same restrictions in quality of life as do patients with theother anxiety disorders (Fig. 4). Fear of animals, heights, and blood are most common.
The most prevalent speciﬁc fears were of animals (among women) and heights (amongmen) [34]. A female-to-male ratio of 2.3 :1 was found [12]. Speciﬁc phobia seems to havea chronic course. Despite treatment, 64% of speciﬁc phobia patients still had symptoms
after 10 to 16 years [35].
E.

Social Phobia (Social Anxiety Disorder)

Estimates for the lifetime prevalence of social anxiety disorder differ substantially (Figs.
1 to 3), ranging from 0.5% in Taiwan [13] to 14.4% in France [36]. Methodologicalreasons for different prevalence rates found in various countries have been discussed
above. Additionally, the DSM and ICD deﬁnitions for social phobia may not be appropriate for reliably differentiating between pathological fear of social situations and simple“shyness” or “stage fright.” For example, according to these deﬁnitions, someone who isafraid of having a single presentation at a university commission, which signiﬁcantly interferes with his academic functioning, would receive a diagnosis of social anxiety disorder.
There is a high rate of underrecognition in social anxiety disorder. In a study exploring the prevalence of social phobia in general health care, the disorder was diagnosed inonly 24.2% of the patients [36]. However, patients may also contribute to underrecognition, as one of the typical features of the disorder is being easily embarrassed when talking
about one’s psychiatric problems. Thus, only a minority of patients with social phobia
actively seek treatment (Fig. 6).
A female-to-male ratio of 1.4 :1 was found in the Edmonton [17] and NCS study[37]. Although more women suffer from social anxiety disorder, it appears that men are
more likely to seek treatment [38].
1. Course
Unlike other anxiety disorders, which tend to have an onset at the end of the 20s, themean age at onset for social anxiety disorder is in midadolescence (between age 15.2 and16.2) [39–41]. Onset after the age of 25 was uncommon [40]. Because of its early onset,
development of psychosocial behavior is impaired at an early stage, later leading to reduced social interaction, poor school performance, and poor employment status [42]. The
natural course of the disorder seems to be chronic and unremitting.

Figure 6 Out of 98 sufferers of social phobia, only a minority saw a doctor for psychological problems or admitted seeking help for social phobia (Ref. 42).

60

F.

Bandelow

Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) has previously been underestimated because of anumber of factors, including patients’ reluctance to spontaneously admit obsessions andcompulsions because of fear or shame [43]. Annual prevalence rates ranged between 1.1%
in Korea and New Zealand to 1.8% in Puerto Rico, according to a cross-national comparison. Again, Taiwan, where only 0.4% was found, was the exception [44]. The NCS study
did not address OCD. The female-to-male ratio ranges between 1.2 and 3.8 [11,44].
Consistent evidence shows the average age at onset to be in adolescence or early
adulthood [45,46]. OCD follows a chronic course. In patients with an illness duration ofat least 10 years, 27% were episodic and 73% chronic [47]. Steketee et al. [48] foundthat only approximately 20% of patients had full remission and 50% had partial remission
during a follow-up of up to 5 years. In a 40-year follow-up, Skoog et al. [49] foundimprovement in 83%, including recovery in 48% (complete recovery, 20%; recovery with
subclinical symptoms, 28%). Approximately one-half of the patients had obsessivecompulsive disorder for more than 30 years.
OCD in children is often underrecognized, as children often keep their OCD secretand do not easily request treatment [50]. Fifty percent of the childhood OCD cases havetheir onset by age 15 [51]. In a 9- to 14-year follow-up of patients with OCD onset duringadolescence, 6 of 14 patients retained their diagnosis [52].
G.

Post-Traumatic Stress Disorder

In two sites of the ECA study, lifetime prevalence rates of 1.0 and 1.3%, respectively,
were found [53,54] for post-traumatic stress disorder (PTSD). The 6-month prevalence
was found to be 0.44% [54]. In the NCS study, a lifetime rate of 7.8% was found (Fig.
2).
Notably, only a moderate percentage of persons exposed to trauma develop PTSD.
Risk factors, such as prior psychiatric history, a family history of psychiatric illness, andneurobiological factors inﬂuence vulnerability to the onset of the disorder [55]. In a study
by Norris [56], respondents in a representative sample were asked if they had ever experienced traumatic events. Rates of current PTSD varied by type of exposure and were highest
for sexual assault (14%), physical assault (13%), and motor vehicle accidents (12%). Someepidemiological studies have assessed survivors of speciﬁc types of traumas. Of men who
served in the Vietnam war, 15.2% met the criteria for PTSD. The rate for women was
8.5% [57]. Among women with a history of sexual assault, the PTSD rate was estimatedto be 3.7% compared to less than 1% for those with no such history [58]. Of respondents
who were exposed to hurricane Andrew, approximately 3% of males and 9% of females
met the criteria for PTSD [59].
H.

Generalized Anxiety Disorder

Prevalence rates for generalized anxiety disorder (GAD) found in the ECA and NCS studies are shown in Figures 1 and 2. In different countries, the following lifetime prevalence
rates were found: 4.0% in West Germany [14], 5.4% in Florence [60], 10.0% in Paris[15], and in 3.7 to 10.5% in different regions in Taiwan [13].
Of patients consulting a general practitioner for any kind of illness in different countries in Europe, 8.5% were identiﬁed as suffering from GAD [61]. However, it is surprisingthat patients with GAD were relatively rare as compared to panic patients in a special

Epidemiology of Depression and Anxiety

61

anxiety disorders outpatient department (Fig. 4). Possible explanations for this discrepancy
to epidemiological studies may be that the differentiation between GAD and anxious depression may be very difﬁcult in some cases because of the high comorbidity of these
conditions. The differential diagnosis may require all the experience of a well-trained
psychiatrist and may be asking too much of lay interviewers. Also, lay interviewers may
mistake panic disorder for GAD (see above).
Because of the 90.4% comorbidity of GAD with a wide spectrum of other mental
disorders, including depression and other anxiety disorders [62], it has been discussed
whether GAD is an independent diagnostic entity at all.
In most cases, GAD has its onset after the age of 25 years. For women, a substantial
increase in the incidence was observed after the age of 35, whereas in men an increase
occurred after the age of 45 [63]. According to all available studies, it follows a chronic
course.

VII. COMORBIDITY
Most studies show a high overlap between depression and anxiety syndromes. Relevant
data come from representative studies. In clinical settings, the relative proportion of comorbid cases is even higher than that found in representative population surveys because
individuals with two concomitant disorders, suffering from a high overall burden, are more
likely to seek treatment than individuals with only one disorder (Berkson’s paradox).
Both depression and anxiety syndromes also co-occur with other psychiatric conditions such as substance abuse or personality disorders.
A. Depression and Panic Disorder
Patients with anxiety of long standing are subject to melancholia
Aristotle, Epidemics, III

Of all anxiety disorders, panic disorder has been investigated most thoroughly with regard
to its association with depression. Frequently, both panic disorder and depression occur
simultaneously. Consistently, high estimates of the lifetime prevalence of major depression
in panic disorder between 22.5 and 68.2 have been reported [19,64–66]. Point prevalence
rates vary between 30 and 38% [67–70]. Conversely, high lifetime rates of panic disorderamong subjects with bipolar disorder or unipolar depression have been found. They varyfrom 10–59% [69,71–73]. Looking at different depression types, a lifetime prevalence
rate of panic disorder of 20.8% was observed among subjects with bipolar disorder, compared to 10.0% among subjects with unipolar depression and 0.8% among reference subjects [74].
Subjects with both panic and depression usually have worse symptoms than those
who had only one disorder [64,75–77]. The disorders begin earlier in life when they arecomorbid than when they occur singly [77,78].
Models explaining co-occurrence of panic disorder and depression include thehypotheses that the co-occurrence of panic attacks and major depression
1. Results from a common underlying pathogenic process.
2. Is a third disorder separate from panic disorder and depression.
3. Is a coincidence of two common psychiatric disorders by chance.

62

Bandelow4.
5.

May be explained in some cases by secondary depression due to demoralization
by panic attacks.
In other cases may be explained by major depression with secondary anxiety
symptoms.

From the available epidemiological, family, and neurobiological studies it is difﬁcult todecide which model is most appropriate to explain the high frequency of comorbidity ofpanic disorder and major depression (for details, see Refs. 75, 76, 79–82).
B.

Depression and Other Anxiety Disorders

In patients with major depression, comorbidity with simple phobia was found in 24.3%,
with social phobia in 27.1%, with post-traumatic stress disorder in 19.5%, and withobsessive-compulsive disorder in 5.4 to 10.9% [18,83]. Conversely, patients with these
disorders have a higher than expected rate for major depression. Of all anxiety disorders,
generalized anxiety disorder shows the highest comorbidity with major depression (e.g.,
62.4%) [62]. It can be assumed that the same comorbidity models apply for these anxiety
disorders as for panic disorder (see above).
C.

Is There a “General Neurotic Syndrome”?

It has been discussed that anxiety disorders (and probably “neurotic depression”) are notdiagnosed entities but are just different manifestations of a “general neurotic syndrome”[84] because there is such a high overlap between these disorders. Moreover, no biologicalmarkers have been found that are able to differentiate between these disorders and antidepressants seem to be effective in all of these conditions. However, it still seems to makesense to demarcate different diagnostic entities. Reasons for this include:
In most comorbid cases, one disorder can be identiﬁed which is in the foreground(see below).
Some features, such as symptomatology and age of onset (see above) seem to differ
quite substantially between these disorders.
There is some evidence for speciﬁcity in the genetic transmission.
D.

Comorbidity of Anxiety Disorders

Although comorbidity rates are very high (Table 3), the majority of patients still do nothave another anxiety disorder, underlining the fact that anxiety disorders should not beeasily lumped together.

Table 3 Overlap Between Anxiety Disorders (Lifetime Prevalence)
Comorbidity withFirst diagnosis

Panic disorder

GAD

Speciﬁc phobia

Social phobia

Panic disorder
GAD
Speciﬁc phobia
Social phobia

—
23.5%

23.5%
—
35.1%
13.3%

14.8%
16.0–35.1%—
37.6–44.5%

10.9%
13.3–34.4%
37.6%
—

10.9%

Source: Refs. 19, 37, 62, 90, 91.

Epidemiology of Depression and Anxiety

63

VIII. HEALTH-CARE UTILIZATION
Anxiety disorders show different patterns in health-care utilization, explaining why prevalence rates found in representative epidemiological surveys differ from statistical studies
in clinical settings. As shown in Figure 7, panic disorder has a relatively high proportionof individuals seeking professional help. Patients with panic disorder often assume thatthey have a medical rather than a psychiatric condition and tend to have themselves rechecked again and again in internal medicine or emergency wards.
In contrast, patients with social phobia tend to hide their problem. As shyness andshame are typical features of social anxiety, it is not surprising that patients are hesitant
to see a physician and to discuss their problem (Fig. 6).
Patients with speciﬁc phobia mostly can cope with their problem. Without major
restrictions in quality of life they can avoid having contact with the objects or situations
they fear, such as dogs, heights, or insects. Thus, these persons very rarely seek professional help.
These considerations may explain why psychiatrists or special anxiety disorders
units mostly see patients with panic disorder (Fig. 4), although speciﬁc and social phobia
are more frequent according to epidemiological studies. GAD patients were also underrepresented in the clinical setting, perhaps because they are overrepresented in representative
epidemiological studies (see above). The high health-care utilization of panic patients also
explains why more clinical studies have been conducted with panic disorder than withany other anxiety disorder, due to the easy access to high patient numbers needed forscientiﬁc studies. For example, a MEDLINE query found 2151 references for “panic disorder” and only 334 for “generalized anxiety disorder.”IX. CONCLUSIONS AND FUTURE PERSPECTIVES
The anxiety disorders and depression are among the most prevalent psychiatric disorders.
They are associated with a considerable degree of impairment, high health-care utilization,

Figure 7 Health-care utilization. Promotion of individuals with speciﬁc mental disorders
treated in any professional health-care service in 1 year (Ref. 93). For a comparison, thenumbers for somatization disorder and severe cognitive impairment are also given.

64

Bandelow

and an enormous economic burden for society. Epidemiological studies may help in planning treatment and prevention programs and they also may help us to better understandthe etiology of these disorders.
Future large epidemiological initiatives to investigate the prevalence of depression
and anxiety among different cultures are currently ongoing. They include the European
Study of Epidemiology on Mental Disorders (ESEMeD), which will involve 25,000 individuals, and the WHO World Mental Health 2000 study, which will comprise 100,000
interviews conducted in 23 countries around the world [85].
For more accurate projections of treatment need and further explication of rate discrepancies, data on clinical signiﬁcance (e.g., responses to questions on life interference
from, telling a professional about, or using medication for symptoms) should be taken
into account in mental disorder prevalence estimates [94].

REFERENCES
1. Sartorius N, Üstün TB, Lecrubier Y, Wittchen HU. Depression comorbid with anxiety: resultsfrom the WHO study on psychological disorders in primary health care. Br J Psychiatry Suppl
1996; 30:38–43.
2. Sartorius N, Üstün TB, Costa e Silva JA, Goldberg D, Lecrubier Y, Ormel J, Von Korff M,
Wittchen HU. An international study of psychological problems in primary care. Preliminary
report from the World Health Organization Collaborative Project on Psychological Problems
in General Health Care. Arch Gen Psychiatry 1993; 50:819–824.
3. APA. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington DC: American Psychiatric Press, 1994.
4. WHO. World Health Organisation. Tenth Revision of the International Classiﬁcation of Diseases, Chapter V (F): Mental and Behavioural Disorders (including disorders of psychologicaldevelopment). Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organization, 1991.
5. Spitzer RL, Williams JB, Gibbon M, First MB. The structured clinical interview for DSMIII-R (SCID). I: History, rationale, and description. Arch Gen Psychiatry 1992; 49:624–629.
6. Williams JB, Gibbon M, First MB, Spitzer RL, Davies M, Borus J, Howes MJ, Kane J, Pope
HG, Jr., Rounsaville B, et al. The structured clinical interview for DSM-III-R (SCID). II.
Multisite test-retest reliability. Arch Gen Psychiatry 1992; 49:630–636.
7. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker
R, Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development
and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin
Psychiatry 1998; 59(suppl 20):22–33; quiz 34–57.
8. Robins LN, Helzer JE, Croughan J, Ratcliff KS. National Institute of Mental Health Diagnostic
Interview Schedule. Its history, characteristics, and validity. Arch-Gen-Psychiatry 1981; 38:
381–389.
9. Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, Burke J, Farmer A, Jablenski A,
Pickens R, Regier DA. The Composite International Diagnostic Interview. An epidemiologic
Instrument suitable for use in conjunction with different diagnostic systems and in different
cultures. Arch Gen Psychiatry 1988; 45:1069–1077.
10. World Health Organization. Composite International Diagnostic Interview (CIDI). Version
1.0. Geneva: World Health Organization, 1990.
11. Regier DA, Boyd JH, Burke JD, Jr., Rae DS, Myers JK, Kramer M, Robins LN, George LK,
Karno M, Locke BZ. One-month prevalence of mental disorders in the United States. Basedon ﬁve Epidemiologic Catchment Area sites. Arch Gen Psychiatry 1988; 45:977–986.
12. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU,
Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in theEpidemiology of Depression and Anxiety

13.
14.

15.

16.

17.
18.

19.

20.

21.
22.
23.
24.
25.
26.
27.

28.

29.

30.
31.
32.
33.

65

United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51:
8–19.
Hwu HG, Yeh EK, Chang LY. Prevalence of psychiatric disorders in Taiwan deﬁned by the
Chinese Diagnostic Interview Schedule. Acta Psychiatr Scand 1989; 79:136–147.
Wittchen HU, Essau CA, von Zerssen D, Krieg JC, Zaudig M. Lifetime and six-month prevalence of mental disorders in the Munich Follow-up Study. Eur Arch Psychiatry Clin Neurosci
1992; 241:247–258.
Lépine JP, Pariente P, Boulenger JP, Hardy P, Zariﬁan E, Lemperiere T, Lellouch J. Anxiety
disorders in a French general psychiatric outpatient sample. Comparison between DSM-III
and DSM-IIIR criteria. Soc Psychiatry Psychiatr Epidemiol 1989; 24:301–308.
Robins LN, Helzer JE, Weissman MM, Orvaschel H, Gruenberg E, Burke JD, Jr., Regier DA.
Lifetime prevalence of speciﬁc psychiatric disorders in three sites. Arch Gen Psychiatry 1984;
41:949–958.
Bland RC, Orn H, Newman SC. Lifetime prevalence of psychiatric disorders in Edmonton.
Acta Psychiatr Scand Suppl 1988; 338:24–32.
Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG, Joyce PR, Karam
EG, Lee CK, Lellouch J, et al. Cross-national epidemiology of major depression and bipolar
disorder. JAMA 1996; 279:293–299.
Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S, Hwu HG, Joyce PR, Karam
EG, Lee CK, Lellouch J, et al. The cross-national epidemiology of panic disorder. Arch Gen
Psychiatry 1997; 54:305–309.
Compton WM, 3rd, Helzer JE, Hwu HG, Yeh EK, McEvoy L, Tipp JE, Spitznagel EL. New
methods in cross-cultural psychiatry: psychiatric illness in Taiwan and the United States. Am
J Psychiatry 1991; 148:1697–1704.
Karam EG. Depression et guerres du Liban: méthodologie d’une recherche. Ann Psychol Educ
Beirut, Université St. Joseph 1992:99–106.
Robins LN, Regier DA. Psychiatric Disorders in America: The Epidemiologic Catchment Area
Study. New York, N.Y.: The Free Press, 1991.
Breslau N, Schultz L, Peterson E. Sex differences in depression: a role for preexisting anxiety.
Psychiatry Res 1995; 58:1–12.
Bandelow B. Assessing the efﬁcacy of treatments for panic disorder and agoraphobia. II. The
Panic and Agoraphobia Scale. Int Clin Psychopharmacol 1995; 10:73–81.
Maier W, Linden M, Sartorius N. Psychische Erkrankungen in der Allgemeinpraxis. Ergebnisse und Schlußfolgerungen einer WHO-Studie. Deutsches Ärzteblatt 1996; 93:47–50.
Pigott TA. Gender differences in the epidemiology and treatment of anxiety disorders. J Clin
Psychiatry 1999; 60:4–15.
Kendler KS, Neale MC, Kessler RC, Health AC, Eaves LJ. The genetic epidemiology ofphobias in women. The interrelationship of agoraphobia, social phobia, situational phobia, andsimple phobia. Arch Gen Psychiatry 1992; 49:273–281.
Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D, Nothen MM, Maffei
P, Franke P, Fritze J, et al. Excess of high activity monoamine oxidase A gene promoter alleles
in female patients with panic disorder. Hum Mol Genet 1999; 8:621–624.
Bandelow B, Amering M, Benkert O, Marks I, Nardi AE, Osterheider M, Tannock C, Tremper
J, Versiani M. Cardio-respiratory and other symptom clusters in panic disorder. Anxiety 1996;
2:99–101.
Klein DF, Mannuzza S, Chapman T, Fyer AJ. Child panic revisited. J Am Acad Child Adolesc
Psychiatry 1992; 31:112–114; discussion 114–116.
Zgourides GD, Warren R. Prevalence of panic in adolescents: a brief report. Psychol Rep
1988; 62:935–937.
Bland RC, Newman SC, Orn H. Period prevalence of psychiatric disorders in Edmonton. Acta
Psychiatr Scand Suppl 1988; 338:33–42.
Katschnig H, Amering M. Panic attacks and panic disorder in cross-cultural perspective. Front
Clin Neurosci 1990; 9:67–80.

66

Bandelow

34. Curtis GC, Magee WJ, Eaton WW, Wittchen HU, Kessler RC. Speciﬁc fears and phobias.
Epidemiology and classiﬁcation. Br J Psychiatry 1998; 173:212–217.
35. Lipsitz JD, Mannuzza S, Klein DF, Ross DC, Fyer AJ. Speciﬁc phobia 10–16 years after
treatment. Depress Anxiety 1999; 10:105–111.
36. Weiller E, Bisserbe JC, Boyer P, Lepine JP, Lecrubier Y. Social phobia in general health care:an unrecognised undertreated disabling disorder. Br J Psychiatry 1996; 168:169–174.
37. Magee WJ, Eaton WW, Wittchen HU, McGonagle KA, Kessler RC. Agoraphobia, simple
phobia, and social phobia in the National Comorbidity Survey. Arch Gen Psychiatry 1996;
53:159–168.
38. Weinstock LS. Gender differences in the presentation and management of social anxiety disorder. J Clin Psychiatry 1999; 60(suppl 9):9–13.
39. Thyer BA, Parrish RT, Curtis GC, Nesse RM, Cameron OG. Ages of onset of DSM-III anxiety
disorders. Compr Psychiatry 1985; 26:113–122.
40. Schneier FR, Johnson J, Hornig CD, Liebowitz MR, Weissman MM. Social phobia. Comorbidity and morbidity in an epidemiologic sample. Arch Gen Psychiatry 1992; 49:282–288.
41. Turner SM, Beidel DC, Townsley RM. Social phobia: a comparison of speciﬁc and generalized
subtypes and avoidant personality disorder. J Abnorm Psychol 1992; 101:326–331.
42. Davidson JR, Hughes DL, George LK, Blazer DG. The epidemiology of social phobia: ﬁndings
from the Duke Epidemiological Catchment Area Study. Psychol Med 1993; 23:709–718.
43. Rasmussen SA, Eisen JL. The epidemiology and differential diagnosis of obsessive compulsive disorder. J Clin Psychiatry 1992; 53(suppl):4–10.
44. Weissman MM, Bland RC, Canino GJ, Greenwald S, Hwu HG, Lee CK, Newman SC, OakleyBrowne MA, Rubio-Stipec M, Wickramaratne PJ, et al. The cross national epidemiology ofobsessive compulsive disorder. The Cross National Collaborative Group. J Clin Psychiatry
1994; 55(suppl):5–10.
45. Lensi P, Cassano GB, Correddu G, Ravagli S, Kunovac JL, Akiskal HS. Obsessive-compulsive
disorder. Familial-developmental history, symptomatology, comorbidity and course with special reference to gender-related differences. Br J Psychiatry 1996; 169:101–107.
46. Berg CZ, Rapoport JL, Whitaker A, Davies M, Leonard H, Swedo SE, Braiman S, Lenane M.
Childhood obsessive compulsive disorder: a two-year prospective follow-up of a community
sample. J Am Acad Child Adolesc Psychiatry 1989; 28:528–533.
47. Perugi G, Akiskal HS, Gemignani A, Pfanner C, Presta S, Milanfranchi A, Lensi P, Ravagli
S, Maremmani I, Cassano GB. Episodic course in obsessive-compulsive disorder. Eur Arch
Psychiatry Clin Neurosci 1998; 248:240–244.
48. Steketee G, Eisen J, Dyck I, Warshaw M, Rasmussen S. Predictors of course in obsessivecompulsive disorder. Psychiatry Res 1999; 89:229–238.
49. Skoog G, Skoog I. A 40-year follow-up of patients with obsessive-compulsive disorder. ArchGen Psychiatry 1999; 56:121–127.
50. Rapoport JL, Inoff-Germain G. Treatment of obsessive-compulsive disorder in children andadolescents. J Child Psychol Psychiatry 2000; 41:419–431.
51. Karno M, Golding JM. Obsessive compulsive disorder. In: Robins LN, Regier DA, eds. Pediatric disorders in America. New York: Free Press, 1991:204–219.
52. Bolton D, Luckie M, Steinberg D. Long-term course of obsessive-compulsive disorder treatedin adolescence. J Am Acad Child Adolesc Psychiatry 1995; 34:1441–1450.
53. Helzer JE, Robins LN, McEvoy L. Post-traumatic stress disorder in the general population.
Findings of the epidemiologic catchment area survey. N Engl J Med 1987; 317:1630–1634.
54. Davidson JR, Hughes D, Blazer DG, George LK. Post-traumatic stress disorder in the community: an epidemiological study. Psychol Med 1991; 21:713–721.
55. McFarlane AC. Posttraumatic stress disorder: a model of the longitudinal course and the roleof risk factors. J Clin Psychiatry 2000; 61(suppl 5):15–20; discussion 21–23.
56. Norris FH. Epidemiology of trauma: frequency and impact of different potentially traumatic
events on different demographic groups. J Consult Clin Psychol 1992; 60:409–418.

Epidemiology of Depression and Anxiety

67

57. Kulka RA, Schlenger WE, Fairbank JA. Trauma and the Vietnam War Generation: Report ofﬁndings from the National Vietnam Veterans Readjustment Study. New York: Brunner &Mazel, 1990.
58. Winﬁeld I, George LK, Swartz M, Blazer DG. Sexual assault and psychiatric disorders among
a community sample of women. Am J Psychiatry 1990; 147:335–341.
59. Garrison CZ, Bryant ES, Addy CL, Spurrier PG, Freedy JR, Kilpatrick DG. Post-traumaticstress disorder in adolescents after Hurricane Andrew. J Am Acad Child Adolesc Psychiatry
1995; 34:1193–1201.
60. Faravelli C, Guerrini Degl’Innocenti B, Aiazzi L, Incerpi G, Pallanti S. Epidemiology of mooddisorders: a community survey in Florence. J Affect Disord 1990; 20:135–141.
61. Linden M, Maier W, Achberger M, Herr R, Helmchen H, Benkert O. Psychische Erkrankungen
und ihre Behandlung in Allgemeinarztpraxen in Deutschland [Psychiatric diseases and theirtreatment in general practice in Germany. Results of a World Health Organization (WHO)study]. Nervenarzt 1996; 67:205–215.
62. Wittchen HU, Zhao S, Kessler RC, Eaton WW. DSM-III-R generalized anxiety disorder in
the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51:355–364.
63. Carter RM, Wittchen HU, Pﬁster H, Kessler RC. One-year prevalence of subthreshold andthreshold DSM-IV generalized anxiety disorder in a nationally representative sample. Depress
Anxiety 2001; 13:78–88.
64. Breier A, Charney DS, Heninger GR. Major depression in patients with agoraphobia and panic
disorder. Arch Gen Psychiatry 1984; 41:1129–1135.
65. Stein MB, Tancer ME, Uhde TW. Major depression in patients with panic disorder: factors
associated with course and recurrence. J Affect Disord 1990; 19:287–296.
66. Lépine JP, Chignon JM, Teherani M. Suicide attempts in patients with panic disorder. ArchGen Psychiatry 1993; 50:144–149.
67. Buller R, Maier W, Benkert O. Clinical subtypes in panic disorder: their descriptive and prospective validity. J Affect Disord 1986; 11:105–114.
68. Lesser IM, Rubin RT, Rifkin A, Swinson RP, Ballenger JC, Burrows GD, Dupont RL, Noyes
R, Pecknold JC. Seconary depression in panic disorder and agoraphobia. II. Dimensions ofdepressive symptomatology and their response to treatment. J Affect Disord 1989; 16:49–58.
69. Sanderson WC, DiNardo PA, Rapee RM, Barlow DH. Syndrome comorbidity in patients diagnosed with a DSM-III-R anxiety disorder. J Abnorm Psychol 1990; 99:308–312.
70. Stein MB, Shea CA, Uhde TW. Social phobic symptoms in patients with panic disorder: practical and theoretical implications. Am J Psychiatry 1989; 146:235–238.
71. Coryell W, Endicott J, Winokur G. Anxiety syndromes as epiphenomena of primary major
depression: outcome and familial psychopathology. Am J Psychiatry 1992; 149:100–107.
72. Davidson J, Raft D, Pelton S. An outpatient evaluation of phenelzine and imipramine. J Clin
Psychiatry 1987; 48:143–146.
73. Leckman JF, Weissman MM, Merikangas KR, Pauls DL, Prusoff BA. Panic disorder andmajor depression. Increased risk of depression, alcoholism, panic, and phobic disorders infamilies of depressed probands with panic disorder. Arch Gen Psychiatry 1983; 40:1055–
1060.
74. Chen YW, Dilsaver SC. Comorbidity of panic disorder in bipolar illness: evidence from theEpidemiologic Catchment Area Survey. Am J Psychiatry 1995; 152:280–282.
75. Andrade L, Eaton WW, Chilcoat H. Lifetime comorbidity of panic attacks and major depression in a population-based study. Symptom proﬁles. Br J Psychiatry 1994; 165:363–369.
76. Coryell W, Endicott J, Andreasen NC, Keller MB, Clayton PJ, Hirschfeld RM, Scheftner WA,
Winokur G. Depression and panic attacks: the signiﬁcance of overlap as reﬂected in followup and family study data. Am J Psychiatry 1988; 145:293–300.
77. Grunhaus L, Pande AC, Brown MB, Greden JF. Clinical characteristics of patients withconcurrent major depressive disorder and panic disorder. Am J Psychiatry 1994; 151:541–
546.

68

Bandelow

78. Andrade L, Eaton WW, Chilcoat HD. Lifetime co-morbidity of panic attacks and major depression in a population-based study: age of onset. Psychol Med 1996; 26:991–996.
79. Crowe RR, Noyes R, Pauls DL, Slymen D. A family study of panic disorder. Arch Gen Psychiatry 1983; 40:1065–1069.
80. Noyes R, Jr., Crowe RR, Harris EL, Hamra BJ, McChesney CM, Chaudhry DR. Relationshipbetween panic disorder and agoraphobia. A family study. Arch Gen Psychiatry 1986; 43:227–
232.
81. Goldstein RB, Weissman MM, Adams PB, Horwath E, Lish JD, Charney D, Woods SW,
Sobin C, Wickramaratne PJ. Psychiatric disorders in relatives of probands with panic disorder
and/or major depression. Arch Gen Psychiatry 1994; 51:383–394.
82. Kendler KS, Heath AC, Martin NG, Eaves LJ. Symptoms of anxiety and symptoms of depression. Same genes, different environments? Arch Gen Psychiatry 1987; 44:451–457.
83. Kessler RC, Nelson CB, McGonagle KA, Liu J, Swartz M, Blazer DG. Comorbidity of DSMIII-R major depressive disorder in the general population: results from the US National Comorbidity Survey. Br J Psychiatry Suppl 1996:17–30.
84. Andrews G, Stewart G, Morris-Yates A, Holt P, Henderson S. Evidence for a general neurotic
syndrome. Br J Psychiatry 1990; 157:6–12.
85. Lepine JP. Epidemiology, burden, and disability in depression and anxiety. J Clin Psychiatry
2001; 62(suppl 13):4–10; discussion 11–12.
86. Lépine JP, Lellouch J, Lovell A. Anxiety and depressive disorders in a French population:
methodology and preliminary results. Psychiatr psychobiol 1989; 4:267–274.
87. Joyce PR, Oakley-Browne MA, Wells JE, Bushnell JA, Hornblow AR. Birth cohort trends
in major depression: increasing rates and earlier onset in New Zealand. J Affect Disord 1990;
18:83–89.
88. Canino GJ, Bird HR, Shrout PE, Rubio-Stipec M, Bravo M, Martinez R, Sesman M, Guevara
LM. The prevalence of speciﬁc psychiatric disorders in Puerto Rico. Arch Gen Psychiatry
1987; 44:727–735.
89. Lee CK, Kwak YS, Yamamoto J. Psychiatric epidemiology in Korea. I: gender and age differences in Seoul. J Nerv Ment Disord 1990; 178:242–246.
90. Van Ameringen M, Mancini C, Styan G, Donison D. Relationship of social phobia with otherpsychiatric illness. J Affect Disord 1991; 21:93–99.
91. Kessler RC, Stang P, Wittchen HU, Stein M, Walters EE. Lifetime co-morbidities betweensocial phobia and mood disorders in the US National Comorbidity Survey. Psychol Med 1999;
29:555–567.
92. Bandelow B. Panik und Agoraphobie - Ursachen, Diagnose und Behandlung. Wien: Springer,
2001.
93. Regier D, Narrow W, Rae D, Manderscheid R, Locke B, Goodwin F. The de facto U.S. mental
and addictive disorders service system. Arch Gen Psychiatry 1993; 50:85–94.
94. Narrow WE, Rae DS, Robins LN, Regier DA. Revised prevalence estimates of mental disorders in the United States: using a clinical signiﬁcance criterion to reconcile 2 survey’s estimates. Arch Gen Psychiatry 2002; 59:115–123.

3
Comorbidity of Depression andAnxiety
GIOVANNI B. CASSANO, NICOLÒ B. ROSSI, and STEFANO PINI
University of Pisa
Pisa, Italy

I.

INTRODUCTION: GENERAL CONCEPTS ON COMORBIDITY
AND DEFINITIONSPatients with anxiety or mood disorders often have features of multiple mental disorders,
but the extent and signiﬁcance of this comorbidity has received surprisingly little attention
in clinical practice or research in the past [1]. However, the comorbidity of psychiatricdisorders is emerging as a recent topic of major practical and theoretical signiﬁcance. As
more systematic attention has been devoted to psychiatric diagnosis in general, psychiatriccomorbidity has commanded increasing consideration, and the high frequency of multiple
diagnoses has discredited the previously popular assumption that a particular patient isunlikely to have more than one disorder. Parallel, the success of DSM-III [2] concept islargely the result of meeting the clinical research community’s need for a better diagnostic
system, addressing a conﬂuence of dissatisfaction with the DSM-I [3] and DSM-II [4],and meeting the need increasingly recognized in the late 1960s and the 1970s for anempirical knowledge base (e.g., Ref. 5). However, even after its ﬁne tuning through successive editions, the current edition, DSM-IV [6], represents only a fraction of clinicalreality. In DSM-IV and DSM-IV-TR [7], clinicians ﬁnd categories deﬁned appropriately
by descriptive, observable deﬁnitions; they also ﬁnd that the boundaries of any given
category are an inadequate match with the patients they treat. Comorbidity and the frequent
presentation of atypical and subclinical symptoms are the primary reasons for failure tomatch patients with the DSM-IV’s discrete, categorical, prototypes of mental illness [8].

69

70

Cassano et al.

Given the short history of the term comorbidity, there are a surprisingly large numberof deﬁnitions. Feinstein [9] coined the term comorbidity to mean “any distinct additional
clinical entity that has existed or that may occur during the clinical course of a patient
who has the index disease under study.” Strictly speaking, use of the term is restricted todiseases or disorders, not symptoms. Symptoms can associate or co-occur, but they are
not comorbid with disorders or with each other. In psychiatric epidemiology, the termcomorbid is used somewhat differently, the emphasis being on relative risk. When a patient
has a particular index disorder, there may be a relatively greater or lesser risk of otherdisorders being diagnosed or other symptoms observed.
Clinical studies also use the concept of comorbidity in the sense that more than one
disorder can be diagnosed in the same individual. In addition, any individual who meetsthe full diagnostic criteria for only one disorder may still have an increased frequency of
symptoms from other categories, but to an extent that is insufﬁcient to diagnose anotherdisorder. Diagnostic studies may identify symptoms or relationships between syndromesthat improve diagnostic precision by increasing the discriminant power of diagnostic
criteria.
Kaplan and Feinstein [10] also introduced a number of distinctions about types ofcomorbidity to clarify the concepts of comorbidity that arise in medicine in general and,possibly, in psychiatry. They distinguished between pathogenic, diagnostic, and prognostic
comorbidity. Pathogenic comorbidity arises when a particular disease leads to certain othercomplications or diseases, which are therefore considered to be etiologically related. For
an example of two diseases that are diagnostically comorbid, Kaplan and Feinstein citeda patient with polyuria, which is caused by diabetes and a coexisting renal ailment. Diagnostic comorbidity is likely whenever diagnostic criteria are based on patterns of symptoms that are individually nonspeciﬁc. Disorders that predispose the patient to develop
other disorders have prognostic comorbidity.
It is often difﬁcult to distinguish these subtypes of comorbidity, however, unlessthe pathogenesis of the disorder is well understood, which rarely happens with psychiatricdisorders. The proper terminology—comorbidity versus some other word or phrase—is
not unanimously accepted. Winokur [11], for example, prefers cosyndromal or use of
the primary–secondary distinction over comorbid. The multiple uses of the primary–secondary distinction have been discussed in Maser et al. [12], and Winokur refers only
to the chronological meaning of the primary–secondary distinction. In medical terms,
comorbidity conveys, at least in part, the notion of a disease process. Disease is producedby pathogens, but despite the suspicion of many, as said before, there are very few pathogens known to underlie the mental disorders described in DSM-IV. Cosyndromal is amore technically accurate term, and the temporal deﬁnition of the primary–secondary
distinction has value; but in line with current usage, we shall continue with the termcomorbid in relation to mental illnesses, even when there is no known pathogen.
In psychiatry, comorbidity appears to be the rule rather than the exception. Numerous studies of clinical samples of inpatients and outpatients [13–17] have demonstrated
the large proportion of patients who simultaneously meet diagnostic criteria for more thana single disorder, both within axis I and between axes I and II of the DSM-III-R [18].
Similarly, multiple diagnoses within individual subjects appear to be quite frequent in
epidemiological surveys conducted in the general population [19–21].
Two major approaches have been employed to classify multiple diagnoses within
a single individual: (1) assignment of a primary and secondary diagnosis based on orderof onset; and (2) application of hierarchical diagnostic systems in which one condition isComorbidity of Depression and Anxiety

71

inferred to supercede the other. The former approach is preferable because no preconceived etiological assumptions regarding the relationships between disorders are necessary. However, the primary–secondary distinction may be difﬁcult to apply to the assignment of retrospectively ascertained lifetime diagnoses, which require accurate
determination of the age of onset of disorders that often emerge in an insidious manner.
The latter approach has not been applied consistently across studies because of differencein the hierarchical structure of the diagnostic systems employed. Moreover, hierarchicalrelationships may often belie clinical data. The elimination of hierarchical relationships
between many of the disorders in the DSM-III-R [18] criteria facilitated the assessmentof relationships between two or more disorders.
II. BASIC CONCEPTS: SYNDROMAL AND SUBSYNDROMALCOMORBIDITY
During the last two decades, a large number of epidemiological studies conducted in thecommunity [20–23], general health-care sector [13,24], and clinical settings [14–17] havedocumented that comorbidity between different psychiatric disorders is a frequent phenomenon. Most of these studies focused on “threshold” comorbidities; that is, the coexistence of two or more mental disorders in the same individual in a deﬁned period of time(lifetime, 6 months, 1 month). Each disorder meets the diagnostic criteria for disorders
found in the DSM-IV [6] or the ICD-10 [25].
Whether the co-occurrence of two or more mental disorders in the same person
reﬂects the presence of pathophysiologically independent entities is far from clear. Highlevels of comorbidity raise questions about the speciﬁcity and the boundaries of certain
diagnostic categories and provide important clues to the etiology, pathophysiology, andphenomenology of both the index and comorbid disorders. Klein and Riso [26] argued
that there are at least four theoretical models of comorbidity that may explain the simultaneous co-occurrence of two or more mental disorders in the same individual: comorbidity
due to sampling bias, artifacts of diagnostic criteria, drawing boundaries in the wrong
place, and common etiological relationships (see Table 1). The concept of comorbidity
Table 1 Relationships Between Depression and Anxiety
Both depression and anxiety are reﬂection of the same phenomenon
1. Both conditions are reﬂections of the same phenomenon.
2. One of the two conditions is a mere reﬂection of the other.
3. One of the two induces changes that leads to the other.
Common factor for both anxiety and depression
1. Vulnerability hypothesis.
Artifact of diagnostic criteria
1. Comorbidity due to overlapping criteria.
2. Comorbidity due to one disorder encompassing the other.
Anxiety and depression are two separate entities
1. They can be either depression or anxiety.
2. They may appear together (comorbidity viewpoint).
3. Each can appear at threshold or subthreshold level. Any combination is possible (mixture
subsyndromal viewpoint).
4. Comorbidity is a common ﬁnal pathway of two distinct conditions.
Source: Adapted from Refs. 26 and 65.

72

Cassano et al.

is a valid and important clinical construct to capture and depict different components ofpsychopathology.
The amount of comorbidity may be inﬂuenced in different ways. First, the exclusionof hierarchical rules in the classiﬁcation of mental disorders and the separation of a morepervasive condition into more speciﬁc conditions may increase comorbidity rates. Second,
the period of time through an individual’s lifespan when a disorder is present can affectcomorbidity. Third, the deﬁnition of a threshold for a diagnosis may also sensitively affectlevels of comorbidity as low threshold tends to increase prevalence rates, while highthreshold tends to decrease prevalence rates.
Comorbidity and the classiﬁcations found in DSM-IV [6], the ICD-10 [25], andsimilar categorical systems are inextricably related. Without a categorical classiﬁcation
scheme, there is no reason to discuss comorbidity, and diagnostician would then quantify
attributes; syndrome categories, deﬁned by clusters of symptoms, would not exist, andtherefore, could not coexist. The DSM-IV disputes the claim that “each category of mental
disorder is a completely discrete entity with absolute boundaries” (p. xxii). However,
although its designers can make this statement with every honest intention, resarchers andinsurance companies act as if each category is a discrete entity. Moreover, DSM-IV does
not provide any standardization information about the frequency of co-occurrence of disorders, further suggesting that each category is discrete. The claim is also made that “there
is no assumption that all individuals described as having the same mental disorder are alikein all important ways” (p. xxii). They may differ in severity, impairment, and symptom
expression, and we will focus attention on the last of these possible differences. The DSMIV uses polythetic criteria sets, which means that a given individual may present with asubset of diagnostic criteria from a larger set. Thus, a person diagnosed as depressed musthave at least ﬁve symptoms out of the longer list of nine diagnostic criteria. Polythetic
criteria sets, however, speak to heterogenous clinical presentations only within a diagnostic
category. Consider adjustment disorders (DSM-IV, pp. 623–627) as a relatively understudied but common example seen in clinicians’ ofﬁces. Adjustment disorders are not usuallyconsidered a serious mental disorder (compared to schizophrenia, bipolar disorder, or
panic disorder). But, as we shall see, they can be serious enough when comorbidity, substance use, hospitalization, and suicide are taken into account.
The issue becomes even more problematic when considering “subthreshold” comorbidities. Clinical correlates of subthreshold forms of anxiety and their relationship withother mental disorders have not, to our knowledge, been investigated systematically. Epidemiological studies suggested that brief recurrent hypomania and mixed states, arising
within the setting of an attenuated bipolar spectrum, in some cases, may be detectable inthe context of co-occurring symptoms that fall below the threshold for a diagnosis of panicagoraphobia, generalized anxiety, social phobia, and obsessive-compulsive disorders [20].
However, differences in the outcome and treatment response are still not clear [27–29].
It has also been argued that in the majority of patients with a “neurotic syndrome,”
symptoms drawn from two or more diagnostic categories on the basis of predominantfeatures, would often be found. In such cases, the diagnostic groups may overlap or fadeinto another. Therefore, neurotic disorders have been hypothesized to occur generally
among individuals who show deviations along a number of independent dimensions, which
may predispose them to either anxiety, obsessive symptoms, or depressive disorders, aswell as other emotional disorders. In many cases, it may be difﬁcult to disentangle thespeciﬁc components of such neurotic syndromes [30,31].

Comorbidity of Depression and Anxiety

73

The DSM-IV [6] has tentatively recognized a disorder composed of symptoms fromtwo subclinical disorders: depression and anxiety. Mixed anxiety–depressive disorder,
however, has been placed in an appendix to the main text. It is one of a number of new
categories that were suggested by consultants for possible inclusion in the DSM-IV [6]or a future edition, but lacked sufﬁcient empirical backing to be included in the current
nomenclature. The term “mixed anxiety–depression states” has been also proposed andincorporated into the ICD-10 [25].
According to DSM-IV, persons with this disorder present with persistent or recurrent
dysphoric mood and a minimum of four of the following symptoms for at least 1 month:concentration or memory difﬁculties, sleep disturbance, fatigue or low energy, irritability,
worry, being easily moved to tears, hypervigilance, anticipating the worst, hopelessness
or pessimism about the future, and low self-esteem or feeling of worthlessness. If thecritiera for mood or anxiety disorders have ever met, then mixed anxiety–depressive disorder cannot be diagnosed. Both DSM-III-R and DSM-IV also mention “limited-symptom”
panic attacks, which have fewer than four somatic or cognitive symptoms.
The phenomenology, course, and the treatment outcome of less severe forms ofdepression have received greater attention than that of less severe forms of anxiety becauseof their high prevalence in the general population and in general health-care settings[32,33]. Patients with subthreshold depression were nevertheless found to have a family
psychiatric history and level of medical and psychiatric comorbidity similar to those ofpatients with depressive disorders [34].
A spectrum model of psychopathology is more adept at recognizing the subclinicalor threshold symptomatology that may occur concomitantly with core psychiatric disorders. The term spectrum has been traditionally used to underlie relationships among clusters of symptoms or to place deﬁned syndromes in relation to one another. In a broader
way the spectrum model can bring coherence to complex psychiatric symptoms, and include: (1) core, atypical, and subclinical symptoms of the primary axis I disorder; (2)signs, isolated symptoms, symptom cluster, and behavioral patterns related to the core
symptoms that may be prodromal, may represent a precursor of a not-yet fully expressed
condition, or may be sequelae of a previously full-ﬂedged disorder; and (3) temperamental
and/or personality traits. The spectrum model of psychiatric disorders evolved (initiallywith the “panic-agoraphobic spectrum”) at the University of Pisa, and has been further
developed in collaboration with researchers from the University of Pittsburgh and elsewhere in the United States [35]. This approach has the potential to answer to various
problems that arise by splitting disorders into narrow, distinct, nonoverlapping diagnostic
entities, like: (1) failure to encompass subthreshold and atypical symptomatology; (2)artiﬁcial enhancement of comorbid diagnosis; and (3) failure to replicate genetic markers
of narrow, restrictive phenotypes. It gives clinical weight to low-severity and isolated
symptoms that either appear alone or occur concomitantly with a major disorder. Suchsymptoms, even in the absence of syndromal illness, may lead to considerable sufferingand disability. In the presence of a syndromal axis I condition of another type (e.g., asmall number of, or even a single, panic–agoraphobic spectrum symptom in the presenceof syndromal major depression), they may have as signiﬁcant an impact on functioning
and treatment outcome as the comorbidity of two fully syndromal conditions [35,36].
Therefore, the identiﬁcation of these “spectrum phenomena” should be included as a routine part of clinical assessment because exclusive use of the categorical system and thevirtual exclusion of other broader concepts of psychiatric classiﬁcation have led to stereo-

74

Cassano et al.

Figure 1 Possible associations among spectrum disorders.

typical portraits of patients and have limited the available descriptive clinical information,
resulting in oversimpliﬁcation of multifaceted clinical proﬁles.
For example, a patient who presents with major depression, but with no complaintsof somatic manifestations of anxiety or phobias, differs signiﬁcantly from a patient who
exhibits precisely the same criterion symptoms of depression along with palpitations, gastrointestinal distress, and multiple phobias related to feelings of suffocation or entrapment(e.g., fears of elevators or highway driving). However, limiting the diagnostic workup to
DSM or ICD criteria would result in identical descriptions of these patients.
Spectrum symptomatology may be viewed as the part of the iceberg that is hidden
beneath the surface of the water, while the core, diagnostic criteria symptoms represent
the obvious, visible portion. Of course, the various conditions may evidence substantial
overlap in terms of individual symptoms, and symptoms of mood spectrum may overlap
with symptoms of panic spectrum, obsessive-compulsive spectrum, social phobia spectrum, bulimic-anorexic spectrum, as well as with what we have termed the separation
anxiety spectrum (Fig. 1).
Potential uses for the spectrum approach may include the improvement of treatment
selection, development of better strategies for outcomes measurement, monitoring thecourse of illnesses, strengthening of therapeutic alliances, and improvement in subtypingof patients for clinical, biological, and genetic research.
III. CLINICAL DESCRIPTIONS AND SYMPTOM CLUSTERS:COMORBIDITY AS A SPECIFIER FOR TREATMENT
The World Health Organization (WHO) Collaborative Study on Psychological Problems
in General Health Care indicated that anxiety and depressive disorders are the most common co-occurrence of psychiatric disorders [13]; of those patients with a current anxiety
disorder, about 45% also had a current depressive disorder, and 40% of those with acurrent depressive disorder had a current anxiety disorder [19].
Given the presence of multiple disorders, which disorder appeared ﬁrst? What implications does this knowledge have for treatment? These questions are the basis of an important debate, one that will ultimately be resolved by longitudinal data revealing the natural

Comorbidity of Depression and Anxiety

75

course of these disorders and the long-term outcome of treatment. Some believe, for example, that childhood separation anxiety is a prodrome (i.e., precursor or predictor) for adultpanic disorder. If we knew that separation anxiety disorder or an extreme sensitivity toseparation in adulthood preceded the onset of panic disorder, we could screen for thatdisorder, intervene when appropriate, and (theoretically) prevent the onset of panic. Similarly, if we knew that clinical or subclinical social phobia preceded the onset of depression,
we could screen for the anxiety disorder and take similar steps to those described forseparation/panic disorder. Knowledge about the course of illness will impact prevention
and treatment, and it will enhance our understanding of the origins of mental disorders.
Because longitudinal research is complex, tends to become dated, and requires stabilityof investigators, subjects, and funding, course of illness is not easily studied. In spite ofthese difﬁculties, such studies have been done and data exist. In this regard, consider three
data sets related to depression and anxiety: the National Institute of Mental Health (NIMH)
Collaborative Depression Study (CDS), the Munich Follow-up Study, and the Zurich Cohort Study of Young Adults. The CDS is a naturalistic clinical investigation of consecutive
patients who sought treatment at ﬁve major teaching hospitals in the United States. Patientswere periodically tracked and, at their 5-year follow-up, depression was found to precede
their anxiety disorders [16]. In a community epidemiological survey, Wittchen and Essau[37] followed patients in the German city of Munich to report that after 7 years, themajority of their subjects with both disorders experienced anxiety before depression. Thisis the opposite ﬁnding of Coryell and associates [16]. Subjects in the Munich Follow-up
Study came from both the community and a cohort of former psychiatric inpatients. In
Switzerland, Angst and colleagues [38] found that persons diagnosed 7 years earlier withpure anxiety tended to develop additional depressive disorders, but persons originally diagnosed with pure depression tended to retain that single diagnosis over the follow-up period.
That is, a diagnosis of pure depression remained relatively stable, whereas one of pureanxiety exhibited substantial instability as reﬂected in additional major or recurrent brief
depressions. There are several implications of these three sets of data, two of which (i.e.,
Munich and Zurich) agree that anxiety tends to precede depression. The Munich and Zurich surveys, as well as Epidemiologic Catchment Area (ECA) study [39], are more likely
to reﬂect true rates of pure and comorbid disorders. A second implication is that the DSMIV is most relevant when its individual diagnostic categories are applied to pure depression
found in community surveys. Pure depression subjects are less likely to seek treatment
and less likely to have additional mental illnesses during the course of their depression.
Conversely, clinicians seeing a patient with a pure anxiety disorder (i.e., no depression
or substance abuse) may expect additional disorders to appear if effective treatment forthe person is not promptly instituted. The degree to which treatments are effective inpreventing the appearance of these other disorders or in reducing their symptomatology
when they already exist concurrently is represented sparsely in the literature. A third implication is that mixed cases seem to have a worse outcome. Wittchen and Essau [37], foundthat subjects with mixed anxiety/depression were more severely impaired in psychosocial
functioning and evidenced more management problems in social roles than subjects witha pure disorder. In terms of remission rates, Wittchen and Essau’s mixed group evidenced
lower rates than those individuals with pure depression. An unfavorable, chronic course
was found in 44.1% of the mixed anxiety/depression group but in only 26.3% of thepure depression group. The clinical study found depressive symptoms to be more severe,
persistent, and recurrent when the patients had a coexisting anxiety syndrome than when
depression occurred among patients with anxiety [16,40]. Moreover, mood-congruent de-

76

Cassano et al.

lusions and the delusional subtype of depression are more frequent among patients withboth depression and panic disorder than in patients with depression only [40]. Obsessions
and compulsions clearly had the gravest prognosis when they were present in a depressed
patient, but the presence of any anxiety syndrome predicted a worse outcome than was
projected for patients without a comorbid anxiety syndrome. A common limitation ofthese three studies is the lack of any assessment of temperament as a maker of moodvulnerability. Savino and colleagues [27], for example, studied 140 panic patients andshowed that high rates of temperamental dysregulation often co-occur (over a lifetime)with anxiety disorders and may represent the only manifestation of a mood lability preceding the onset of an anxiety disorder. In this perspective, any data lacking informationon temperamental features appear incomplete for characterizing the temporal relationshipbetween anxiety and mood disorders. A limitation of the report by Coryell and colleagues[16] is that it is a clinical, not a community, study. As such, it may not be a valid representation of the natural course of illness. Berkson [41] demonstrated an often replicated rulein epidemiological research: persons seeking treatment for a medical problem usually havean additional medical diagnosis, and prevalences recorded in clinical settings do not reﬂect
the base rate for either diagnosis in the community. Most of the subjects entered the
NIMH-CDS seeking treatment for existing comorbidities. Perhaps this particular set ofpatients was unusual in having their depression precede anxiety. Perhaps this progressionis the more severe and drives people into a clinic. The answers are not yet clear, but thepatients who entered the proband group of the Collaborative Depression Study and who
were reported on in the Coryell study probably reﬂect what practicing clinicians see.
A.

Bipolar Depression

Lifetime diagnoses of anxiety disorders are very common in bipolar patients, but researchis still limited in this ﬁeld for two main reasons: the relative underdiagnosis of bipolar II
disorders, often misdiagnosed as unipolar or personality disorders [42], and the lack ofutilization of structured interviews for the diagnosis of anxiety disorders in hypomanic
patients [43], or bipolarity in anxious patients [44].
Recent data from the Stanley Foundation Bipolar Treatment Outcome Network [45]report a lifetime comorbid anxiety disorder in 42% of 288 bipolar patients, while 30% ofthem have a current comorbid anxiety disorder. In the National Comorbidity Survey(NCS), patients who had a bipolar disorder in the past 12 months had a 95% frequencyof lifetime anxiety disorders, with a reported risk of comorbid panic disorder and social
phobia higher in bipolar disorder (odds ratios of 11.0 vs. 4.6) compared to unipolar disorder (odds ratios of 7.0 vs. 3.6) [21]. Chen and Dilsaver [14], using the Epidemiological
Catchment Area (ECA) data, found that the prevalence of panic disorder among bipolar
patients was higher than in unipolars (20.8% and 10.0%, respectively) and that the riskof having panic disorder was 2.1 times higher for a bipolar patient than for patients withunipolar depression. Furthermore, panic disorder was frequently found to be associatedwith obsessive-compulsive disorder comorbidity in bipolar and unipolar patients [15].
Savino et al. [27], in a clinical sample of panic patients, found a prevalence of 47.8% ofbipolar spectrum disorders and 22.9% of unipolar depression.
Comorbidity rates of obsessive-compulsive disorder with bipolar disorder have beenfound to range between 7.3 and 21.1% [28, 46, 47]. A reanalysis of the ECA data showeda higher prevalence of obsessive-compulsive disorder comorbidity in bipolar patients thanin unipolar depressives (21.0% and 12.2%, respectively), with a risk of having obsessive-Comorbidity of Depression and Anxiety

77

compulsive disorder two times greater for bipolar than for unipolar depressives [15]. By
contrast, Krueger et al. [48] found a similar lifetime prevalence of obsessive-compulsive
disorder in bipolar (35.1%) and unipolar depressives (35.2%). These two studies suggestthat the incidence of this disorder in bipolar disorder was higher than had previously beenthought.
Wittchen et al. [49] reported a rate of comorbidity of generalized anxiety disorder(GAD) with bipolar disorder of 10.5%, lower than with major depression (62.4%). In a
recent clinical trial, Pini et al. [28] reported higher lifetime rates of generalized anxiety
disorder in bipolar subjects (31.6%) even if still lower than in unipolar depressives(37.1%). These ﬁndings support the hypothesis that bipolar disorder has a strong connection to panic and obsessive-compulsive disorders, while GAD may be related to affective
disorder.
B. Major Depression
A high proportion of patients receiving a diagnosis of depression also manifest a varietyof anxiety symptoms that fulﬁll the criteria for one or more concomitant anxiety disorders.
Several epidemiological and clinical studies indicate that comorbidity of major depression
and anxiety disorders range from 21% to 91% [20, 22, 28, 50] (Table 2). The concomitanceof anxiety disorders with depression has important prognostic and therapeutic implications
for clinical practice. Although there has been controversy in recent years as to whether
anxiety and depressive disorders are continuous and merged insensibly with each otheror whether they constitute distinct entities, it is clinically evident that the co-occurrenceof the two conditions has been found to be associated with greater overall psychopathology, high risk of chronicity of illness, greater social and occupational impairment, highrisk of suicide, and poor prognosis [48, 51, 52].
1. Enquiries into the Relationship Between the Anxiety Disorders
and Depressive Disorders in Clinical Samples
Panic Disorder. The rate of panic disorder in the general population is estimatedto be between 1.4 to 2.9%. Individuals with panic disorder have high rates of comorbidity
with mood and other disorders. Epidemiological studies estimate that 74 to 90% of subjects
with a history of panic also meet criteria for at least one other mental disorder and 56 to
73% have had a lifetime history of major depression [22,53]. Similar rates have beenreported in clinical samples. In approximately one-third of cases, the onset of panic precedes the onset of major depression; in one-third, major depression has a primary onset;
and in the remaining one-third, the two conditions occur in close temporal relationship[23,54]. Predictors of subsequent episodes of major depression in patients with panic disorder include prior history of major depression, presence of generalized anxiety disorder,
and the severity of agoraphobia, with the latter two factors signiﬁcant after controlling
for lifetime history of depression [55].
Social Phobia. The prevalence of social phobia in the general population is reported to be around 1.7 to 3.8% [56,57]. Social phobia is estimated to precede the onsetof major depression in two-thirds of cases [57,58]. Furthermore, percentage ranging from67 to 92% of individuals with a lifetime history of social phobia meet criteria for at least
one other psychiatric disorder and, of these, 15 to 20% had a lifetime comorbid major
depressive disorder. Higher rates of comorbidity between major depression and social

78

Table 2Comorbidity Between Depression and Anxiety: Prevalence and Chronology of Onset

Diagnosis

PrevalenceAnxiety disordercomorbid with any
psychiatric disorder

Panic disorderSocial phobia
GAD
PTSD

1.4%–2.9%
1.7%–3.8%
1.9%–6.6%
1%–13.8%

74%–90%67%–92%80%–90%73%–83%

Anxiety disordercomorbid withMDD

MDD comorbidwith anxiety
disorderOnset of anxiety
disorderprecedes MDD

56%–73%
15%–21%62%–67%
37%–48%

10%
27%
17%
20%

29%
65%
63%
53%–78%Source: Adapted from Ref. 66.

Cassano et al.

Comorbidity of Depression and Anxiety

79

phobia have been reported by Cassano et al. [52] in clinical samples, including cohortsof subjects with psychotic depression. Results of genetic epidemiological studies suggestthat genetic factors may contribute to the development of social phobia, with heritability
estimated at approximately 30% [59].
2. The Relevance of Treatment Response for Relationship Between
Depression and Anxiety Disorders
There is an extensive literature that testiﬁes that both tricyclic antidepressants and MAOI
compounds are effecting in alleviating the symptoms of panic-agoraphobic and generalanxiety disorder. More recently, the SSRIs have also been demonstrated to be effectivein the treatment of agoraphobia and related panic attacks. On the basis of a meta-analytic
review of the literature, it has been reported that these drugs had proven superior to imipramine and to alprazolam in treating panic disorder [60]. However, the interpretation ofthese results testifying to the unity of anxiety and depressive disorders is far from clear.
The way in which patients with panic-agoraphobic spectrum conditions respond to eachof these groups of drugs differs from the response of depressive patients. In the initial
phases of treatment of patients with anxiety disorders, anxiety and tension are initiallyexacerbated. It is plausible that effects in anxiety disorders are probably achieved along
a different pharmacodynamic route than along which changes are induced in patients withdepressive illness. Further, the similarity of treatment response of two or more groups ofdisorders with distinct proﬁles does not signify an identical etiology or pathogenesis. The
wide range of efﬁcacy of corticoid compounds and of antibiotics are illustrative of thispoint. Any classiﬁcations of disease based on similarity of therapeutic response to eitherof these compounds, would prove chaotic and meaningless.
Differences in treatment response are more informative. Most clinical trials in depression have not evaluated the efﬁcacy of antidepressant treatment for comorbid anxiety
disorders and symptoms. Only a handful of studies have examined this issue but none
have sought to evaluate the relative efﬁcacy of one treatment over another. In an open
study, response to ﬂuoxetine for the treatment of depression was investigated in a large
cohort of depressed patients with, versus without, comorbid anxiety disorders [61]. The
results indicated that patients with comorbid anxiety disorders were more likely to be
nonresponders. In a naturalistic study of 30 outpatients with major depression, who also
met the criteria for at least one current comorbid anxiety disorder, ﬂuvoxamine was foundto be effective in reducing both depressive and anxiety symptoms [62]. A limitation ofthese studies was that neither a placebo nor an alternative treatment was utilized, making
it difﬁcult to know if there was a speciﬁc antianxiety effect and whether ﬂuvoxamine wassuperior to other antidepressants in treating depression with comorbid anxiety disorders.
More recently, ﬂuoxetine, sertraline, and paroxetine were found to be equally effective
in depressed patients with high levels of anxiety [63]. However, in this comparative study,
only anxiety symptoms as measured by several items on the Hamilton Rating Scale forDepression were used, making it unclear if a broader range of anxiety symptoms would
also respond to these treatments. Similarly, because no comorbid anxiety diagnoses were
made, we cannot know whether these treatments would be effective in depressed patientswith anxiety disorders.
We conducted a 4-month multicenter, open, controlled clinical trial to compare the
efﬁcacy and safety of paroxetine and moclobemide in patients with major depression withcurrent comorbid anxiety disorders. In this study, we addressed several limitations of theprevious research: that is, comorbid anxiety diagnoses were made, a more comprehensive

80

Cassano et al.

assessment of anxiety symptoms was used, and two antidepressant medications werestudied.
Both moclobemide and paroxetine produced signiﬁcant improvement in symptoms
of depression and anxiety. However, we found that compared to moclobemide, paroxetine
showed greater efﬁcacy in patients with depressive disorders and comorbid panic disorderin reducing depressive and anxiety symptomatology; furthermore, paroxetine was more
rapid than moclobemide in improving anxiety symptoms. Interestingly, this effect of paroxetine was not found in the subgroup of depressed patients with comorbid generalized
anxiety disorder.
Although not directly comparable with our data, Fava et al. [63] found no differencesin efﬁcacy and tolerability of ﬂuoxetine, sertraline, and paroxetine in the treatment ofdepressed patients with high levels of baseline anxiety, as assessed by the six items of
the anxiety factor on the 17-item HDRS. These results suggest that for at least someanxious symptoms, there may be no difference between the three antidepressants studied.
However, in light of the results reported here, it is plausible that a diagnostic characterization of comorbid anxiety diagnoses (e.g., using the DSM system) could have revealed
differences in the efﬁcacy of these three drugs. Given the high rate of anxiety comorbidity
in patients requiring treatment for depression, the most appropriate drug will be the onethat shows the highest and earliest efﬁcacy in both conditions. This property will enableclinicians to limit the use of drug combination or of benzodiazepines in those cases ofdepression associated with anxiety conditions. In the future, a better clinical proﬁle characterization of new drugs should be obtained through protocols speciﬁcally designed forpatients with comorbid mood and anxiety disorder, as well as the adoption of multiple
disorder outcome measures either in their full-ﬂedged or subthreshold manifestations [36].
Our study suggests that two drugs of proven efﬁcacy in depression and anxiety, moclobemide and paroxetine, perform differentially depending on speciﬁc comorbid anxiety diagnosis. In light of the fact that panic disorder, GAD, and obsessive-compulsive disordercan co-occur in patients with depression [22,28,64,65], and not all antidepressants may
be equally effective, it is important that clinicians choose a treatment that would be mosteffective in treating both types of disorders.
C.

Dysthymic Disorder

There is considerable evidence that patients with a principal diagnosis of dysthymic disorder manifest a variety of nondepressive symptoms typically associated with anxiety[17,66,67]. Studies conducted in community samples [68] and in clinical settings[17,28,69] show rates of anxiety comorbidity ranging from 20% to 40% in patients withdysthymia. Generalized anxiety disorder, panic disorder, and social phobia are the mostfrequently associated conditions [28]. Recently, Klein et al. [70] conducted a prospective,
longitudinal follow-up study of 86 outpatients with early-onset of dysthymic disorder and39 outpatients with episodic major depressive disorder. They found that 36% of dysthymic
patients had a concurrent anxiety disorder compared to 17.9% of counterparts. During thecourse of the follow-up, patients with dysthymic disorder exhibited signiﬁcantly greaterlevels of symptoms and lower functioning than patient with episodic major depressive
disorder. Haykal and Akiskal [71] have suggested that anxious features may often complicate the course of dysthymia and may contribute to make dysthymia less responsive totreatment interventions.

Comorbidity of Depression and Anxiety

81

Tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), reversible inhibitors of monoamine oxidase (RIMA), and benzamides have all proven efﬁcacy in dysthymia [72]. In a double-blind study, moclobemide (300 mg/day) was found tobe superior compared to ﬂuoxetine (20 mg/day) in treating dysthymia with superimposed
depression [73]. On the other hand, Haykal and Akiskal [71] reported more satisfactory
results with ﬂuoxetine than with imipramine in patients categorized as pure dysthymic,
the difference being much more pronounced in females than in males. In these studies,
the impact of associated anxiety component on treatment outcome was not investigated.
Indeed, speciﬁc patterns of anxiety comorbidity may play a role in rendering partiallyinconsistent the results of different clinical trials in patients with dysthymia. In Haykal
and Akistal’s study, for example, dysthymic subjects with axis I comorbid anxiety disorders that dominated the clinical picture were excluded from the trial. On the contrary, in
Duarte et al.’s study [73], a substantial number of subjects with dysthymia had comorbid
anxiety syndromes.
Comorbidity of dysthymia with various discrete anxiety disorders was rarely taken
into account in comparative clinical trials, despite being commonly encountered in psychiatric practice and being suggested to be more prone to develop chronicity [74]. Recently,
we compared moclobemide (effective in dysthymia [72,73]) and paroxetine (effective ina broad spectrum of anxiety disorders [75,76]), in a population of dysthymic patients with
anxiety comorbidity and without superimposed major depression (unpublished data). Our
analyses showed that paroxetine and moclobemide were in general effective both on depressive and anxious symptoms in patients affected by primary dysthymia comorbid with
anxiety disorders. However, paroxetine was found to be signiﬁcantly superior to moclobemide in reducing depressive and anxious symptomatology in patients with dysthymia withcomorbid panic disorder, suggesting that speciﬁc pattern of anxiety comorbidity may substantially affect treatment-response of patients with depressive disorders [24,36,77].
In conclusion, our data suggest that speciﬁc anxiety comorbidity patterns such as
panic disorder may affect treatment response, predict different antidepressant efﬁcacy,
and indicate best treatments in dysthymic patients.
D. Spectrum Comorbidity: Diagnostic and Therapeutic Implications
The difﬁculty, if not the impossibility, of classifying many patients with multiple disorders
into one of the DSM categories has spawned a variety of other procedures to cope withclinical reality [12]. These include use of the primary–secondary distinction, multiple
diagnoses, use of both axes I and II, associated features of a disorder, and the spectrumof a disorder concept [78]. In this section we describe the concept of spectrum as anadditional perspective for the clinical evaluation of concomitant psychiatric disorders. The
necessity of this additional conceptual tool to describe mental disorder phenomenology
derived from similar observations that gave rise to other coping mechanisms: sharply
divided categorical systems of classiﬁcation do not capture the complex and variable psychopathology seen in most patients. Usually this complex phenomenology is simplisticallyattributed to premorbid personality traits, to personality disorder, or to residual symptoms
and/or maladaptive behavior residual to a previous axis I disorder. The deﬁnition of spectrum includes a range of subclinical and/or atypical symptoms and isolated behavioralfeatures that are partial or subclinical expressions of a categorical disorder. These areusually overlooked by clinicians. The spectrum itself is not a diagnostic category. A good

82

Cassano et al.

example of this concept was given by Cassano and Savino [78], who described the panicagoraphobic spectrum as an expansion of panic disorder phenomenology described in
DSM-III-R. It included symptoms and behavioral features belonging to the following areas: panic attacks; anxious expectation; polyphobic features; avoidant behavior; reassurance sensitivity; help-seeking behavior; maladaptive behavior; predisposing or prodromal
factors; and physiological sensitivity to chemical substances. When adhering to a DSMIV diagnosis, co-occurring symptoms and subclinical or atypical manifestations of otherdisorders that cut across different diagnostic categories are often seen as associated features of the primary disorder. However, when even a few isolated or subclinical symptoms
are present, there may be signiﬁcant impairment in the patient’s social functioning [79],and the phenomenology of the axis I disorder may be signiﬁcantly modiﬁed, thereby delaying and misleading the diagnosis. For example, symptoms of an overlooked comorbid
anxiety and bipolar II disorder can often be observed within the categories of borderline
personality disorder and atypical depression. In these cases, feelings of insecurity andagitation and episodes of dyscontrol brought about by atypical panic symptoms co-occurring with depressive episode in a bipolar patient may be easily confused with the impulsivity and aggressivity of borderline patients. In the same way, unrecognized, subclinical,
or isolated panic symptoms may bring atypical features such as mood reactivity to a depressive episode. The high rates of comorbidity between panic disorder and bipolar disorders found by Savino and associates [27] and Chen and Dilsaver [14] support these observations. Higher rates of comorbidity could be reasonably expected if subjects were selectedusing a symptomatic extension of DSM-IV criteria. The impact of a mild, subtle, andlong-lasting psychopathology on parents’ quality of life was very clear to Sir Aubrey
Lewis, who wrote in 1936 [80]: ‘‘It may be said, simply, that severe emotional upsets
ordinarily tend to subside, but that mild emotional states, when often provoked or long
maintained, tend to persist, as it were, autonomously. Hence the paradox that a grossblatant psychosis may do less damage in the long run than some meager neurotic incubus:
a dramatic attack of mania or melancholia, with delusions, wasting, hallucinations, wild
excitement and other alarms, may have far less effect on the course of a man’s life thansome deceptively mild affective illness which goes on so long that it becomes inveterate.
The former comes as a catastrophe, and when it has passed the patient takes up his life
again, while with the latter he may never get rid of his burden (p. 998).”
Detection of subtle, long-lasting, underlying psychopathology is more difﬁcult when
it is concomitant with an axis I disorder. Description of a clinical reality that includes acomplex array of symptoms belonging to different disorders and their proper treatment led
us to speak in terms of subclinical and atypical spectrum comorbidity. Early recognition ofspectrum comorbidity (observed over a lifetime) leads to a signiﬁcant improvement indiagnostic accuracy, choice of a more appropriate treatment strategy, management of treatment, control over the potential for substance abuse, and prediction of outcome [35].
Moreover, clinical experience shows that the adoption of a proper treatment strategy covering both the axis I disorder and the lifetime occurrence of spectrum symptoms often
produces dramatic changes in the lifestyle of the patient, who feels free from psychopathological features that the clinician and even the patient believed were stable personality
traits. Unrecognized spectrum symptoms occurring at one time in the patient’s life may
impact his or her personality and the presentation of any psychopathology at some future
time. An example might be of a young man who, at the age of 20, experiences one or
two mild panic attacks. He seeks no treatment, but the attacks change his life in certain
ways. Prior to the mild panic attacks, he was described as energetic, open to new experi-

Comorbidity of Depression and Anxiety

83

ences, and socially outgoing with a hyperthymic temperament. Following the onset ofpanic symptoms, he becomes increasingly pavid, dependent, socially avoidant, and worried about his health. These features become stable and traitlike. When this patient is seen
by a clinician at age 40 for a depressive episode, his panic symptoms have long beenforgotten, and he presents as a fearful person, somewhat hypochondriacal, and dependent
on others to such an extent that he tends to avoid remaining alone. Now the recognitionof distinct symptoms of the panic spectrum and the consequent adoption of a well-targeted
treatment strategy become fundamental. If the clinician attempts to treat only the depressive episode, he or she will miss the main reason for the patient’s 20 years of fearfulness, dependency, avoidness, and hypochondriasis, which were initiated and maintainedby a partial expression of panic disorder.
It is not clear how a psychosocial treatment would deal therapeutically with theclinical case described above, but in terms of medications, a drug such as imipramine (orparoxetine) is much more likely to treat both the depression and residual symptoms of
the panic attacks than compounds such as nortriptyline, which are targeted at depression
alone [81]. Also, the clinician–patient relationship, the cornerstone of any treatment strategy, can be signiﬁcantly improved by adopting the spectrum approach. Providing clinicians with new keys with which to interpret the patient’s behavior, this approach enables
an easy identiﬁcation of individualized psychopathological proﬁles, capturing mild symptoms and details of patients’ lifestyles. In some proﬁles, patients often recognize themselves. Receiving credible, practical, and clear interpretation of their long-lasting problems
helps patients establish a positive and reassuring relationship with their therapist. Withthe quick establishment of preferential channels of communication, patients usually feel
syntonic with the therapist and, in return, they comply more completely with the therapeutic plan. There are diagnostic and therapeutic implications of a lifetime presence of spectrum symptoms in a patient with an axis I disorder. Referring to the sample above, missing
the spectrum comorbidity means overlooking potential complications related to the concomitance of panic disorder and depression—that is, greater severity of illness [40,82],
poorer prognosis [37,83], higher rates of chronicity [84], decreased patient complianceand responsiveness to treatment [85,86], poorer psychosocial functioning [87], increased
family loading [88], higher risk for substance abuse [88,89], and elevated odds ratios for
suicide attempts [90,91]. From a therapeutic perspective, this patient will beneﬁt mainly
from a drug or other treatment modality acting on both the axis I disorder and the spectrum
symptoms. A common example is that of two patients presenting with the same severityof depressive episode. Presume that the clinician prescribes the same antidepressant (e.g.,clomipramine) to both patients. After 10 to 15 days, one patient improves as expected,
whereas the other now evidences panic attacks as well as depression. Without asking about
the spectrum of symptoms, even those that may have occurred much earlier in the patient’s
lifetime, a therapist will have difﬁculty understanding these dramatically different outcomes. With the spectrum approach used as a magnifying lens on the patient’s psychopathology, it is possible to solve the problem. The patient who improved may have chronic,
mild obsessive traits, such as perfectionism, which makes clomipramine the drug of ﬁrst
chice. On the other hand, the patient who developed panic attacks may reveal a previous
trait of separation and loss sensitivity, which exlains his or her adverse reaction to theclomipramine. The patient who worsened had an overlooked panic vulnerability. Whenthe spectrum reveals such a panic proﬁle, the patient’s hypersensitivity to antidepressantsand to benzodiazepine withdrawal should be taken into account. Finally, the patient willprobably need reassurance and cognitive support, as do most panic patients. A similar

84

Cassano et al.

example is that of a depressed, grieving patient who does not recover unless the clinician
gives an antidepressant with antipanic action. An abnormal grief reaction reﬂects a particular vulnerability to separation, which in most cases belongs to the panic-agoraphobic spectrum. Besides the same panic habitus is often expressed by extremely intense and tightinterpersonal relationships and dependency on others, characteristics typical of panic patients.
IV. IMPLICATIONS FOR TREATMENT AND SUGGESTEDGUIDELINES FOR CLINICIANS
Comorbidity is clearly important in patient management and treatment. Feinstein [9] notedthat researchers try to exclude patients with associated disease from therapeutic trials fora given disease. However, ﬁndings in such presumably homogeneous samples may not
apply to routine clinical practice. Failure to classify and analyze comorbid disease cancreate misleading medical statistics and may cause spurious comparisons during the planning and evaluation of treatment for patients. Comorbidity can alter the clinical courseof patients with the same diagnosis by affecting the time of detection, prognostic anticipations, therapeutic selection, and post-therapeutic outcome of an index diagnosis [10]. Also,
the presence of soft signs and symptoms belonging to the spectrum of other disorders(observed over a lifetime) is systematically overlooked, leading to an opposite bias of aheterogeneous sample, which may raise doubts and questions about the reliability of suchstudies in the light of a more descriptive approach. For example, in a hypothetical trial
for an antipanic medication, a panic patient, who has obsessive symptoms but lacks one
symptom to fulﬁll the criteria for OCD, is included in the trials as well as a patient withoutobsessive traits. Practical consequences may include poor knowledge about the spectrumof action of the treatment, difﬁculty in predicting response to the treatment, and/or atypicaloutcomes.
The DSM-IV does not suggest speciﬁc treatments for each disorder category andsubcategory. However, modern treatment researchers—psychosocial and psychopharmacological—have attempted to design treatments tailored to speciﬁc DSM categories. The
strategy links treatment to diagnosis, and we may expect this strategy to succeed to theextent that the targeted DSM-IV classiﬁcation is valid. It is possible that treatment researchers will successfully design treatments that ﬁt DSM-IV categories but fail to treat
their patients successfully because the categories do not completely represent the patients.
To the extent that comorbidity presents a challenge to the ofﬁcial nomenclature, it presents
a similar challenge to treatments designed and targeted for DSM categories.
If not treated properly, patients with comorbid anxiety and depression have a worse
outcome than patients with either illness alone [92], and have more severe and a greaternumber of symptoms than those diagnosed with depression. Furthermore, they are more
likely to have low mood, panic attacks, and suicidal ideation, with greater disruption tosocial, work and family life [93,94]. Thus, the most effective treatment requires attention
to symptoms of both anxiety and depression. Usually, diagnostic theories inform treatment
protocol, but since the newer antidepresssants are successful for treating not only depression but also anxiety disorders, there may be less need to employ different medications
for each disorder. After identifying the patient’s speciﬁc disorder(s) and/or subdiagnostic
symptoms, the ideal treatment for depression and comorbid anxiety should take the formof a single drug that is efﬁcacious in the treatment of both disorders. Drugs that achieve
an effective dosage through once-daily administration and with a good tolerability should

Comorbidity of Depression and Anxiety

85

be preferred to aid patient compliance. Safety in overdose is also important because of
the higher risk of suicide in depressed patient with associated anxiety than in those withdepression alone [94–96].
As both depression and anxiety disorders tend to be chronic and recurring, treatment
should be effective in the long term and should prevent relapse of the condition. Patientsthen need to be educated about the time it takes to heal, the potential side effects oftreatment, the fact that most side effects will resolve with time, and the collaborative
approach to treatment, which will lead to signiﬁcant relief of symptoms and recovery.
V.

CONCLUSIONS

Clinicians who seek only the diagnostic criteria for a speciﬁc disorder, with rigid adherence to the DSM-IV diagnostic criteria, and by extension, the DSM-IV categories, willprobably miss a more global perspective of the entire pathology. Such a narrow perspective
is mainly justiﬁed in research, but is unacceptable in clinical practice. The DSM-IV wasconceived, at least in part, as a research tool, allowing common, standardized, and atheoretical communication among clinical investigators. But the DSM-IV is also used as a clinicalmanual when the practitioner is face to face with the client/patient. In such a nonstandardized, unstructured setting, the clinician more often than not sees the DSM-IV as ameans to collect payment from a third party and focuses on the predominant symptom
picture as the diagnosis. A more integrative approach that takes comorbidity into accountshould not only reﬂect a more valid psychiatric classiﬁcation, but should also improvetreatment and treatment outcome.
Evidence for the dramatic intrusion of comorbidity phenomena (axis I and spectrum
comorbidity) in psychiatry has been derived from several sources, including epidemiological, pharmacological, clinical, and genetic studies. Despite this broad body of evidence,
proponents of the categorical approach mostly conceive subclinical symptomatology thatcoexists with the disorder as background noise, overlooking the complex degree of overlap, both phenomenological and neurobiological, among the different symptoms. In fact,
speciﬁc patterns of comorbidity appear to be stable, as if there were common neuronal
networks that probably represent functional loci minoris resistentiae. We have discussed
the diagnostic improvement brought about by the punctual and reﬁned recognition of
subclinical and atypical comorbidity. Another relevant consequence involves therapeuticstrategy, as comorbid syndromes often require different acute, continuation, and maintenance doses as well as a distinct timing of administration and suspension of the treatment.
It is not difﬁcult to believe that drug targets in the brain are different in different patients;for example, a patient with a pure disorder compared to a patient with the same disorderplus spectrum symptoms of panic, obsessive-compulsive disorder, and related symptomatology. However, ofﬁcial guidelines for the therapy of depression and bipolar disorders
still do not provide clinicians and researchers with any treatment-speciﬁc indications, devoting relatively little attention to the clinical importance of comorbidity, treatment strategies, and outcome. Also, the reliability of clinical trials can be questioned in light of amore descriptive approach as pharmacological trials are usually conducted with patients
whose symptomatology ﬁts a particular diagnosis coded by standardized criteria.
Diagnostic procedures should attempt to combine descriptive, categorical, and dimensional approaches, devoting more attention to the cross-sectional and longitudinal
analysis of nuclear, subclinical, and atypical symptoms that may represent a pattern offull-blown and partially expressed comorbidity. Within this conceptual framework, psycho-

86

Cassano et al.

pathology can be more speciﬁcally approached in clinical terms of either individualized
treatment or prevention. Further, some traditional points of weakness of clinical psychiatry
and psychology, such as the chronic forms of illness and the treatment-resistant disorders,
may be contrasted more successfully.

REFERENCES
1. Caron C, Rutter M. Comorbidity in child psychopathology: concepts, issues and research strategies. J Child Psychol Psychiatry 1991; 32:1053–1080.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rded. (DSM-III). Washington, DC: American Psychiatric Association, 1980.
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 1sted. (DSM-I). Washington, DC: American Psychiatric Association, 1952.
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 2nded. (DSM-II). Washington, DC: American Psychiatric Association, 1968.
5. Katz M, Cole JO, Barton WE. The role of methodology of classiﬁcation in psychiatry andpsychopathology (No. HSM 72-9015). Washington, DC: Department of Health, Education andWelfare, 1968.
6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4thed. (DSM-IV). Washington, DC: American Psychiatric Association, 1994.
7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4thed. Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association, 2000.
8. Maser JD, Cassano GB, Michelini S. Treatment implications of comorbid mental disorders.
In: Wetzler S, Sanderson WC, eds. Treatment Strategies for Patients with Psychiatric Comorbidity. New York: Wiley & Son Inc., 1997; 3–18.
9. Feinstein AR. The pre-therapeutic classiﬁcation of co-morbidity in chronic disease. J Chronic
Dis 1970; 23:455–468.
10. Kaplan MH, Feinstein AR. The importance of classifying initial co-morbidity in evaluating
the outcome of diabetes mellitus. J Chron Dis 1974; 27:387–404.
11. Winokur G. The concept of secondary depression and its relationship to comorbidity. Psychiatric Clin North Am 1990; 13:567–583.
12. Maser JD, Weise R, Gwirtsman H. Depression and ist boundaries with selected Axis I disorders: implication of comorbidity. In Beckham EE, Leber WR, eds. Handbook of Depression,
2nd ed. New York: Guilford Press, 1995:86–106.
13. Sartorius N, Ustun TB, Lecrubier Y, Wittchen HU. Depression comorbid with anxiety: resultsfrom the WHO study on psychological disorders in primary health care. Br J Psychiatry 1996;
30:338–343.
14. Chen YW, Dilsaver SC. Comorbidity of panic disorder in bipolar illness: evidence from theEpidemiologic Catchment Area Survey. Am J Psychiatry 1995; 152(2):280–282.
15. Chen YW, Dilsaver SC. Comorbidity for obsessive-compulsive disorder in bipolar and unipolar disorders. Psychiatry Res 1995; 59(1–2):57–64.
16. Coryell W, Endicott J, Winokur G. Anxiety syndromes as epiphenomena of primary major
depression: outcome and familial psychopathology. Am J Psychiatry 1992; 149(1):100–107.
17. Sanderson WC, Beck AT, Beck J. Syndrome comorbidity in patients with major depression
or dysthymia: prevalence and temporal relationships. Am J Psychiatry 1990; 147:1025–1028.
18. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 3rded., rev. (DSM-III-R). Washington, DC: American Psychiatric Association, 1987.
19. Lecrubier Y. The impact of comorbidity in the treatment of panic disorder. J Clin Psychiatry
1998; 59(suppl 8): 11–16.
20. Angst J, Merikangas KR, Preisig M. Subthreshold syndromes of depression and anxiety inthe community. J Clin Psychiatry 1997; 58(suppl 8):6–10.

Comorbidity of Depression and Anxiety

87

21. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU,
Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the
United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994;
51(1):8–19.
22. Kessler RC, Nelson CB, McGonagle KA, Liu J, Swartz M, Blazer DG. Comorbidity of DSMIII-R major depressive disorder in the general population: results from the US National Comorbidity Survey. Br J Psychiatry 1996; 168(suppl 30):17–30.
23. Kessler RC, Stang PE, Wittchen HU, Ustun TB, Roy-Burne PP, Walters EE. Lifetime panicdepression comorbidity in the National Comorbidity Survey. Arch Gen Psychiatry 1998; 55(9):801–808.
24. Pini S, Perkonnig A, Tansella M, Wittchen HU. Prevalence and 12-month outcome of threshold and subthreshold mental disorders. J Affect Disord 1999; 56:37–48.
25. World Health Organization. International Classiﬁcation of Disease, 10th ed. (ICD-10). Geneva, Switzerland: World Health Organization, 1992.
26. Klein DN, Riso LR. Psychiatric disorders: problems of boundaries and comorbidity. In: Costello C, ed. Basic Issues in Psychopathology. New York: Guilford Press, 1993: 19–66.
27. Savino M, Perugi G, Simonini E, Soriani A, Cassano GB, Akiskal HS. Affective comorbidity
in panic disorder: is there a bipolar connection? J Affect Disord 1993; 23(3):155–163.
28. Pini S, Cassano GB, Simonini E, Savino M, Russo A, Montgomery SA. Prevalence of anxiety
disorders comorbidity in bipolar depression, unipolar depression and dysthymia. J Affect Disord 1997; 42(2–3):145–153.
29. Perugi G, Akiskal HS, Pfanner C, Presta S, Gemignani A, Milanfranchi A, Lensi P, Ravagli
S, Cassano GB. The clinical impact of bipolar and unipolar affective comorbidity on obsessivecompulsive disorder. J Affect Disord 1997; 46(1):15–23.
30. Roth M, Argyle N. Anxiety, panic and phobic disorders: an overview. J Psychiatr Res 1988;
22(suppl 1):33–54.
31. Tyrer P, Seivewright N, Murphy S, Ferguson B, Darling C, Kingdon D, Brothwell J, Johnson
AL. Nottingham study of neurotic disorder. Lancet 1989; 1(8632):277.
32. Ustun TB, Sartorius N, eds. Mental Illness in General Health Care. An International Study.
New York: John Wiley, 1994.
33. Ormel J, VonKorff M, Ustun TB, Pini S, Korten A, Oldehinkel T. Common mental disorders
and disability across cultures. Results from the WHO collaborative study on psychologicalproblems in general health care. JAMA 1994; 272:1741–1748.
34. Sherbourne CD, Wells KB, Hays RD, Rogers W, Burman MA, Judd LL. Subthreshold depression and depressive disorders: clinical characteristics of general medical and mental healthspecialty outpatients. Am J Psychiatry 1994; 151;1777–1784.
35. Cassano GB, Michelini S, Shear MK, Coli E, Maser JD, Frank E. The panic-agoraphobic
spectrum: a descriptive approach to the assessment and treatment of subtle symptoms. Am J
Psychiatry 1997; 154(6 Suppl):27–38.
36. Frank E, Shear K, Rucci P, Cyranowsky JM, Endicott J, Fagiolini A, Grochocinski VJ, HouckP, Kuper DJ, Maser JD, Cassano GB. Inﬂuence of panic-agoraphobic spectrum on treatment
response in patients with recurrent major depression. Am J Psychiatry 2000; 157:1101–1107.
37. Wittchen HU, Essau CA. Comorbidity of anxiety disorders and depression: does it affectcourse and outcome? Psychiatry Psychobiol 1989; 4:315–323.
38. Angst J, Vollrath M, Merikangas KR, Ernst C. Comorbidity of anxiety and depression in the
Zurich cohort study of young adults. In: Maser JD, Cloninger CR, eds. Comorbidity of Moodand Anxiety Disorders. Washington, DC: American Psychiatric Press, 1990: 123–137.
39. Robins LN, Regier DA. Psychiatric Disorders in America. New York: Free Press, 1991.
40. Pini S, Goldstein RB, Wickramaratne PJ, Weissman MM. Phenomenology of panic disorderand major depression in a family study. J Affect Disord 1994; 30:257–272.
41. Berkson J. Limitation of the application of fourfold table analysis to hospital data. Biometric
Bull 1946; 2:47–53.

88

Cassano et al.

42. Akiskal HS. The prevalent clinical spectrum of bipolar disorder: beyond DSM-IV. J Clin
Psychopharmacol 1996; 16(suppl 3):117–122.
43. Angst J. The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord
1998; 50:143–151.
44. Himmelhoch JM. Social anxiety, hypomania and the bipolar spectrum: data, theory and clinicalissues. J Affect Disord 1998; 50:203–213.
45. McElroy SL, Altshuler LL, Suppes T, Keck PE Jr, Frye MA, Denicoff KD, Nolen WA, Kupka
RW, Leverich GS, Rochussen JR, Rush AJ, Post RM. Axis I psychiatric comorbidity and its
relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry
2001; 158(3):420–426.
46. Pigott TA, L’Heureux F, Dubbert B, Bernstein S, Murphy DL. Obsessive compulsive disorder:
comorbid conditions. J Clin Psychiatry 1994; 55(suppl):15–27; discussion 28–32.
47. Strakowski SM, Tohen M, Stoll AL, Faedda GL, Goodwin DC. Comorbidity in mania at ﬁrst
hospitalization. Am J Psychiatry 1992; 149(4):554–556.
48. Krueger S, Cooke RG, Hasey GM, Jorna T, Persad E. Comorbidity of obsessive-compulsive
disorder in bipolar disorder. J Affect Disord 1995; 34:117–120.
49. Wittchen HU, Zhao S, Kessler RC, Eaton WW. DSM-III-R generalized anxiety disorder in
the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51(5):355–364.
50. Cosoff SJ, Hafner RJ. The prevalence of comorbid anxiety in schizophrenia, schizoaffective
disorder and bipolar disorder. Aust NZ J Psychiatry 1998; 32:67–72.
51. Strakowsky SM, Tohen M, Stoll AL, Faedda GL, Mayer PV, Kolbrener ML, Goodwin DC.
Comorbidity in psychosis at ﬁrst hospitalization. Am J Psychiatry 1993; 150:752–757.
52. Cassano GB, Pini S, Saettoni M, Dell’Osso L. Multiple anxiety disorder comorbidity in patients with mood spectrum disorders with psychotic features. Am J Psychiatry 1999; 156:474–
476.
53. Dick CL, Bland RC, Newman SC. Epidemiology of psychiatric disorders in Edmonton. Panic
disorder. Acta Psychiatr Scand 1994; 376(suppl):45–53.
54. Roy-Byrne PP, Stang P, Wittchen HU, Ustun B, Walters EE, Kessler RC. Lifetime panicdepression comorbidity in the National Comorbidity Survey. Association with symptoms, impairment, course and help-seeking. Br J Psychiatry 2000; 175:229–235.
55. Ball SG, Otto MW, Pollack MH, Rosenbaum JF. Predicting prospective episodes of depression
in patients with panic disorder: a longitudinal study. J Consult Clin Psychol 1994; 62(2):359–
365.
56. Weissman MM, Bland RC, Canino GJ, Greenwald S, Lee CK, Newman SC, Rubio-Stipec M,
Wickramaratne PJ. The cross-national epidemiology of social phobia: a preliminary report.
Int Clin Psychopharmacol 1996; 11(suppl 3):9–14.
57. Faravelli C, Zucchi T, Viviani B, Salmoria R, Perone A, Paionni A, Scarpato A, Vigliaturo
D, Rosi S, D’adamo D, Bartolozzi D, Cecchi C, Abrardi L. Epidemiology of social phobia:
a clinical approach. Eur Psychiatry 2000; 15(1):17–24.
58. Merikangas KR, Angst J. Comorbidity and social phobia: evidence from clinical, epidemiologic, and genetic studies. Eur Arch Psychiatry Clin Neurosci 1995; 244(6): 297–303.
59. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. The genetic epidemiology of phobias in women. The interrelationship of agoraphobia, social phobia, situational phobia andsimple phobia. Arch Gen Psychiatry 1992; 49(4):273–281.
60. Boyer W. Serotonin uptake inhibitors are superior to imipramine and alprazolam in alleviating
panic attacks: a meta-analysis. Int Clin Psychopharmacol 1995; 10(1):45–49.
61. Fava M, Uebelacker LA, Alpert JE, Nierenberg AA, Pava JA, Rosembaum JF. Major depressive subtypes and treatment response. Biol Psychiatry 1997; 42:568–576.
62. Sonawalla SB, Spillmann MK, Kolsky AR, Alpert JE, Nierenberg AA, Rosenbaum JF, Fava
M. Efﬁcacy of ﬂuvoxamine in the treatment of major depression and comorbid anxiety disorders. J Clin Psychiatry 1999; 60:580–583.
63. Fava M; Rosenbaum JF, Hoog SL, Tepner RG, Kopp JB, Nilsson ME. Fluoxetine versus

Comorbidity of Depression and Anxiety

64.
65.
66.
67.
68.

69.

70.
71.
72.
73.
74.

75.

76.

77.
78.

79.
80.
81.

82.
83.
84.
85.

89

sertraline and paroxetine in major depression: tolerability and efﬁcacy in anxious depression.
J Affect Disord 2000; 59:119–126.
Cassano GB, Perugi G, Musetti L, Akiskal HS. The nature of depression presenting concomitantly with panic disorder. Compr Psychiatry 1989; 30(6): 473–482.
Kaufman J, Charney D. Comorbidity of mood and anxiety disorders. Depress Anxiety 2000;
13(suppl 1):69–76.
Markowitz JC, Moran ME, Kocsis JH, Frances AJ. Prevalence and comorbidity of dysthymic
disorder among psychiatric outpatients. J Affect Disord 1992; 24:63–71.
Howland RH. General health, health care utilization, and medical comorbidity in dysthymia.
Int J Psychiatry Med 1993; 23:211–238.
Kessler RC. The prevalence of psychiatric comorbidity. In: Wetzler S, Sanderson WC, eds.
Treatment strategies for patients with psychiatric comorbidity. New York: Wiley & Sons, Inc.,
1997:23–48.
Versiani M, Nardi E. Dysthymia: clinical picture, comorbidity, and outcome. In: Akiskal HS,
Cassano GB, eds. Dysthymia and the Spectrum of Chronic Depressions. New York: Guilford
Press, 1997: 35–43.
Klein DN, Schwartz JE, Rose S, Leader JB. Five-year course and outcome of dysthymic disorder. A prospective, naturalistic follow-up study. Am J Psychiatry 2000; 157:931–939.
Haykal RF, Akiskal HS. The long-term outcome of dysthymia in private practice: clinicalfeatures, temperament, and the art of management. J Clin Psychiatry 1999; 60:508–518.
Versiani M. Pharmacotherapy of dysthymic and chronic depressive disorders: overview withfocus on moclobemide. J Affect Disord 1998; 51:323–332.
Duarte A, Mikkelsen H, Delini-Stula A. Moclobemide versus ﬂuoxetine for double depression:a randomized double-blind study. J Psychiatr Res 1996; 30:453–458.
Cassano GB, Pini S, Miniati M, Savino M. Dysthymia: implications for continuity and chronicity of mood disorders. In: Bolis CL, Licinio J, eds. Public Health Aspects of Dysthymia in
the Field of Neuroscience. Geneva, Switzerland: World Health Organization, 2000; 73–86.
Ballenger JC, Wheadon DE, Steiner M, Bushnell W, Gergel IP. Double-blind, ﬁxed-dose,placebo-controlled study of paroxetine in the treatment of panic disorder. Am J Psychiatry
1988; 155:36–42.
Stein MB, Liebowitz MR, Lydiard RB, Pitts CD, Bushnell W, Gergel I. Paroxetine treatmentof generalized social phobia (social anxiety disorder): a randomized controlled trial. JAMA
1998; 280:708–713.
Levine J, Cole DP, Chengappa RKN, Gershon S. Anxiety disorders and major depression,
together or apart. Depress Anxiety 2001; 14:94–104.
Cassano GB, Savino M. Symptomatology of panic disorder. An attempt to deﬁne the panicagoraphobic spectrum phenomenology. In: Montgomery S, ed. Psychopharmacology of Panic.
London: Oxford University Press, 1993: 38–57.
Klerman GL, Weissman MM, Ouellette R, Johnson J, Greenwald S. Panic attack in the community. Social morbidity and health care utilization. JAMA 1991; 13;265(6): 742–746.
Lewis A. Prognosis in the manic-depressive psychosis. Lancet 1936; 2:997–999.
Cassano GB, Michelini S. Pharmachological treatment of depression and comorbid anxiety
disorders. In: Gessa G, Fratta W, Pani L, Serra G, eds. Depression and Mania: From Neurobiology to Treatment. New York: Raven Press, 1995; 113–125.
Angst J, Dobler-Mikola A. The Zurich Study. VI. A continuum from depression to anxiety
disorders? Eur Arch Psychiatry Neurol Sci 1985; 235(3):179–186.
Hecht H, von Zerssen D, Krieg C, Possl J, Wittchen HU. Anxiety and depression: comorbidity,
psychopathology, and social functioning. Compr Psychiatry 1989; 30(5):420–433.
Stavrakaki C, Vargo B. The relationship of anxiety and depression: a review of the literature.
Br J Psychiatry 1986; 149:7–16.
Albus M, Scheibe G. Outcome of panic disorder with or without concomitant depression: A
2-year prospective follow-up study. Am J Psychiatry 1993; 150(12):1878–1880.

90

Cassano et al.

86. Van Valkenburg C, Akiskal HS, Puzantian V, Rosenthal T. Anxious depressions. Clinical,
family history, and naturalistic outcome—comparisons with panic and major depressive disorders. J Affect Disord 1984; 6(1):67–82.
87. Reich J, Warshaw M, Peterson LG, White K, Keller M, Lavori P, Yonkers KA. Comorbidityof panic and major depressive disorder. J Psychiatr Res 1993; 27(suppl 1):23–33.
88. Clayton PJ. The comorbidity factor: establishing the primary diagnosis in patients with mixed
symptoms of anxiety and depression. J Clin Psychiatry 1990; 51(suppl):35–39.
89. Merikangas KR, Risch NJ, Weissman MM. Comorbidity and co-transmission of alcoholism,
anxiety and depression. Psychol Med 1994; 24(1)69–80.
90. Bronisch T, Wittchen HU. Suicidal ideation and suicide attempts: comorbidity with depression,anxiety disorders, and substance abuse disorder. Eur Arch Psychiatry Clin Neurosci 1994;
244(2):93–98.
91. King MK, Schmaling KB, Cowley DS, Dunner DL. Suicide attempt history in depressed patients with and without a history of panic attacks. Compr Psychiatry 1995; 36(1):25–30.
92. Lepine JP, Gastpar M, Mendlewicz J on behalf of the DEPRES Steering Committee and Tylee
A. Depression in the community: the ﬁrst pan-European study DEPRES (Depression Researchin European Society). Int Clin Psychopharmacol 1997; 12;19–29.
93. Tylee A. Treatment of coexisting depression and anxiety: the Depression Research in European
Society (DEPRES) Survey. Primary Care Psychiatry 1999; 5: S9–S11.
94. Tylee, A, Gastpar, M, Lépine J-P, Mendlewicz J. Identiﬁcation of depressed patient types in
the community and their treatment needs: ﬁndings from the DEPRES II (Depression Researchin European Society II) survey. Int Clin Psychopharmacol 1999; 14:153–165.
95. Wunderlich U, Bronisch T, Wittchen HU. Comorbidity patterns in adolescents and young
adults with suicide attempts. Eur Arch Psychiatry Clin Neurosci 1998; 248:87–95.
96. Fawcett J. Targeting treatment in patients with mixed symptoms of anxiety and depression.
J Clin Psychiatry 1990; 50(suppl 1):40–43.

4Anxiety, Depression, and Personality
HARALD N. ASCHAUER and MONIKA SCHLÖGELHOFER
University of Vienna
Vienna, Austria

I.

INTRODUCTION

Biological variations, social inﬂuences, psychological and cognitive factors, childhood
experience, individual goals and choices, and other aspects of personality have been described by various researchers as components of personality [1]. People differ markedly
from one another in multiple quantiﬁable dimensions of personality—the dynamic organization of the psychobiological system that moderates adaptation to experience [2]. Fora long time scientists such as Freud, Adler, Jung, Rogers, Catell, Allport, Bandura, andMichel, explored personality and developed various theories about it. But there is no consensus in the ﬁeld about which model should guide personality research [1].
Rapid progress is being made in understanding the neurobiology of human personality. This has been facilitated by using questionnaires that assess multiple dimensions of
personality quantitatively and reliably. Hypothesis-driven research has mapped models
with ﬁve to seven dimensions of personality to results from recent work on the biology ofthese personality dimensions. These reliable personality inventories permit tests of speciﬁchypotheses about regional brain activity, neurophysiology, neurochemistry, and neurogenetics [2]. People’s responses to such questionnaires are remarkably stable, even over several decades. Human personality is currently approached by a number of dimensional
personality traits. The underlying assumption is that describing the individual’s personality
proﬁle (i.e., his or her score on each of the selected traits) is enough to provide a relevant
description of that individual’s personality. We can accept that the thousands of adjectives
with which we characterize people can be reduced to a few dimensions. But it should be
noted that mathematical or theoretical analyses do not provide only one unique solution—
an inﬁnite number of different solutions seem possible [3].
91

92Aschauer and Schlögelhofer

II. PERSONALITYA.

Personality Models

Interest in the study of personality has existed for a long time, but theories differ and are
innumerable. Jung [4] described the personality dimensions of introversion and extroversion, Kretschmer [5] deﬁned the dimensions of schizothymia and cyclothymia. Biologicalmechanisms are proposed as the basis of Gray’s [6] two-dimensional model of personality,with reward and punishment mechanism traits. Eysenck [7,8] has proposed three major
factors of personality: neuroticism versus emotional stability, extroversion versus introversion, and psychoticism versus superego control. He argues that these three dimensions
are biologically determined. They exist in animals and in people from many countries
with vastly diverse cultures, which supports the idea that they are caused by a fundamental
biological variability.
Cloninger’s psychobiological theory proposed seven basic dimensions of personalitythat are based on inherited biological differences—the dimensions of temperament (novelty seeking, harm avoidance, reward dependence, and persistence) and character (selfdirectedness, cooperativeness, and self-transcendence). Temperament refers to automatic
emotional responses to experience that are moderately heritable and stable throughout life.
In contrast, character refers to self-concepts and individual differences in goals and values,
which inﬂuence voluntary choices, intentions, and the meaning of what is experienced inlife. Differences in character are moderately inﬂuenced by sociocultural learning and mature in progressive steps throughout life. Each of these aspects of personality interacts
with one another to motivate adaptation to life experiences and to inﬂuence susceptibility
to emotional and behavioral disorders. There are weak correlations within the domainsof temperament and character and moderate, nonlinear correlations between temperamentand character. In other words, each possible temperament proﬁle is associated with two
or more possible character proﬁles and vice-versa [2]. According to Cloninger, “each of
the temperament dimensions corresponds to a speciﬁc neurotransmitter: dopamine (in low
levels, for novelty seeking), serotonin (in high levels, for harm avoidance), and norepinephrine (in low levels, for reward dependence).” Accumulating clinical and biologicalresearch ﬁndings from laboratories throughout the world are now conﬁrming the crosscultural validity of this seven-factor model for both normal and abnormal personality. The
drugs that psychiatrists use to treat various disorders have biological effects that ﬁt themodel [1]. Harm avoidance is the inhibition of approach behaviors, and the enhancementof escape behaviors, and these are principally served by the serotonin system. The trait
has resemblance to neuroticism and perhaps depression. Novelty seeking, the increased
tendency to respond with approach to novel and promising situations, is principally servedby the dopamine system. Rewarding activities increase domapine release or inhibit its
uptake. Reward dependence reﬂects the persistence of behavior that is likely to be intermittently rewarded, so that a key subscale of reward dependence is persistence [9].
In contrast to Cloninger, Fiske [10] introduced by linear factor analysis ﬁve uncorrelated dimensions, a model he called the “Big Five” personality factors model. Studies
were conducted to determine what dimensions people use when they describe themselves
and one another. The data showed that extroversion, agreeableness, conscientiousness,
neuroticism, and openness were the personality dimensions most used. Most of the variability in normal adult personality can be described by these terms, but probably morethan ﬁve are needed to be comprehensive [2].

Anxiety, Depression, and Personality

93

B. Biological Aspects of Personality
Relationships between personality and biology have been suggested since ancient Greek
times when Hippocrates proposed his humoral theory. Hippocrates claimed that each person’s temperament reﬂects the balance of the body ﬂuids: blood—sanguine (optimistic,
hopeful); black bile—melancholic (depressed, sad); yellow bile—choleric (angry, irascible); phlegm—phlegmatic (unemotional, apathetic) [11]. Psychologists such as Eysenckhave documented psychometric dimensional factors in personality; these factors have been
hypothesized to reﬂect a genetic and biological basis [12]. Current theories emphasize theimportance of the brain and neurotransmitter systems. Neurotransmitters have speciﬁcfunctions and, depending upon how these various systems are balanced, the result may
correspond to personality variations, such as impulsiveness, easy arousal, and so on[13,14]. From what we know about the functioning of various parts of the brain, it is
tempting to speculate that neural differences predispose people to develop differences inpersonality.
In recent research, factor-analytical-derived personality dimensions are shown to be
more biologically heterogeneous than the seven dimensions proposed by Cloninger, simply because interactive biological systems are unlikely to be uncorrelated. For example, high neuroticism scores can result from either high harm avoidance or low selfdirectedness. However, the biological correlates of harm avoidance differ from thoseof self-directedness, just as anxiety disorders (which are high in harm avoidance) differ
from personality disorders (which are low in self-directedness) [2].
1. Biology, Genetics, and Environment in Personality
Many twin- and adoption studies conﬁrm that hereditary factors inﬂuence the developmentof personality. The ﬁeld of behavioral genetics studies the impact of heredity on personality and other behavior. It assesses the heritability of traits; that is, the extent to which they
are genetically determined. Heritabilities of 25 to 50% for personality traits are commonly
reported. Many twin studies have been conducted [15–17]. Loehlin [16] showed the heritability of the “Big Five” personality traits (extroversion, agreeableness, conscientiousness,
neuroticism, and openness). Genetics accounted for approximately 28 to 46% of the variability of these traits. Other scientists try to conﬁrm the heritability with different personality models in twin studies. Tellegen et al. [17] report heritabilities of 0.39 to 0.58 using
the Multidimensional Personality Questionnaire (MPQ).
Several ﬁndings seem to be consistent: 25% of variation is transmissible from parent
to child, another 25% of variation is dependent on nonlinear interaction among multiple
genes. Consequently, the correlation between sibs for a speciﬁc personality trait is usually
about 0.15 to 0.30. Multiple genes contribute to each dimension so individual genes areunlikely to explain more than 3 to 10% of the total variance in a trait. Therefore, there
are often inconsistencies about the importance of a particular candidate gene when comparisons are made between different populations, particularly when the samples studied aresmall [2].
However, all these heredity studies permit an estimation of environmental effects.
The crucial point to research in this area is to distinguish genetic and environmental effects.
However, environment is, after all, more difﬁcult to quantify than genetic relationship.
For example, anxiety might develop from having an anxious parent, but it might also
result because the parent creates a frightening world. Adoption studies are useful to esti-

94

Aschauer and Schlögelhofer

mate these effects. There is some evidence that the shared family environment inﬂuences
some areas more than others. Loehlin [18] found strong inﬂuences for conservatism andreligiosity. Hoffman [19] reported that family environment also inﬂuences whether siblings develop common interests, such as an interest in music. But there is also evidence
that siblings who grow up together tend to have greater differences in speciﬁc personality
characteristics. “Dependency is one such characteristic,” according to Cloninger; “a variety of factors, including birth order and illness, work to make one sibling the dependent
one and to prevent the expression of dependency in the others [19].” Scarr [15] notes that
heredity and environment can combine in various ways. Sometimes heredity inﬂuences
people to select or pay attention to particular facets of environment.
In molecular genetics, many have studied human personality (linkage disequilibrium in families, association in case-control designs, systematic genome scan). The ﬁrst
genome-wide scan of personality traits detected signiﬁcant linkage between the trait harm
avoidance and a locus on chromosome 8p21-23 that explained 38% of the trait variance.
There was signiﬁcant evidence of epistatis between the locus on 8p and others on chromosomes 18p, 20p, and 21q. These oligogenic interactions explained most of the variancein harm avoidance [20].
Extensive work has been carried out with particular candidate genes, including polymorphisms related to the serotonin transporter, serotonin 1b receptor, serotonin 2c receptor, dopamine transporter, dopamine D3 receptor, dopamine D4 receptor, and catecholO-methyltransferase [2]. For example, the role of the serotonin transporter in temperamentand character has been studied in detail in many laboratories since the initial report by
Lesch et al. [21] of association and linkage with anxiety-related personality traits like harm
avoidance. Lesch et al. demonstrated an association between the short form (containing a
44 bp deletion) of the serotonin transporter promotor region polymorphism (5-HTTLPR)
and anxiety-related traits such as neuroticism and harm avoidance. Heritabilities in the
30 to 50% range are typical [22]. The ﬁnding has been replicated in some studies, but
not in others. Subsequent studies analyzed the association between 5-HTTLPR and the
TCI dimensions of cooperativeness and self-directedness in a group of healthy volunteers[23]. Contrary to Cloninger’s theory Hamer et al. [23] found a strong association between
5-HTTLPR and the character traits of self-directedness and cooperativeness. In that study,
the short allele was associated with lower scores in self-directedness as well as in cooperativeness compared to the long allele. On the other side, the linkage and association areeven stronger with the character traits of self-directedness and cooperativeness than withharm avoidance.
Association studies between novelty seeking and the dopamine D4 receptor haveshown for the ﬁrst time the importance of interactions among multiple genes [3,24]. It
was shown to be positive in most large studies, but there are some negative ﬁndings [2].
The dopamine D4 receptor (DRD4) was the ﬁrst common genetic polymorphism (theseven repeat of the dopamine D4 receptor) providing evidence of an association with anormal human personality dimension [9,25]. It is clear now that novelty seeking is abehavior that depends on the epistatic interaction of multiple gene loci, not just the average
effect of a single gene. In addition to the dopamine D4 receptor locus, variation in novelty
seeking has also been found to be inﬂuenced by variation at the dopamine transporter
gene and at the dopamine D3 receptor locus. The same gene may interact with multiple
other genes, creating partly overlapping sets of epistatic systems. For example, dopamine
D4 receptor variation inﬂuences novelty seeking, but it also interacts with polymorphisms

Anxiety, Depression, and Personality

95

in the serotonin 2c receptor locus to inﬂuence the level of reward dependence and persistence [9].
Another dopamine receptor that has been examined for a role in personality traitsis the dopamine 3 receptor (DRD3), which was associated in a study with high scores inneuroticism and behavioral inhibition [26]. Another investigation showed an associationof DRD3 and novelty seeking in bipolar patients [27]. A particularly exciting development
is the possibility that the role of genes in human temperament could be recognized very
early in development at a time when environmental inﬂuences are minimum [22].
In brain imaging studies it has been shown that individual differences in speciﬁchuman temperament traits are associated with speciﬁc differences in regional cerebral
blood ﬂow. Novelty seeking was shown to be positively correlated with activity of theparalimbic cortex; in contrast, harm avoidance and reward dependence were negatively
correlated with different regions [2]. Another study using the distinction between extroversion and introversion (novelty seeking is moderately correlated with introversion; highextroversion corresponds primarily to low harm avoidance) came out with highly convergent ﬁndings [2]. But brain systems are necessarily interactive with one another and therefore partially overlapping.
Another approach is to correlate the regional brain distribution of speciﬁc ligands(dopamine transporter, dopamine D2 receptor binding in positron emission tomography)
with measures of personality. Studies found a negative correlation of detachment scores(Karolinska scales of personality) with striatal dopamine transporter binding [2]. Detachment scores resemble low novelty seeking and reward dependence. But such studies in
resting states could be more fully evaluated in activation.
In neurophysiology studying event-related potentials, low P300 amplitude in an auditory task was associated with high harm avoidance and low novelty seeking [2]. But
the functional signiﬁcance of P300 as an indicator of executive functions and behavioral
inhibition, as well as the interplay of temperament and character in these cognitive functions, must further be evaluated. Further studies focused on the positive correlation of
pupil reactivity to the noradrenergic alpha-1 agonist challenge and fear of dangerous or
risky situations (resembles harm avoidance).
Pharmacological challenges were also tested in relation to personality traits (e.g.,high harm avoidance has been associated with differences in serotonergic function: low
plasma tryptophan availability, blunted prolactin response to d-fenﬂuramine, low platelet
5HT2 receptor sensitivity). Novelty seeking is related to both dopaminergic and noradrenergic processes (amphetamine and norepinephrine-dependent testosterone and prolactin
levels). Personality proﬁles show consistent relationships with risk for cardiovascular disease (blood pressure, epinephrine levels, lipids, cholesterol). Blood lipid levels, diet, activity and personality appear to interact in a complex interdependent manner [2].
Progress is being made in understanding the biology of human personality at every
level of observation, brain imaging, neurophysiology, neurochemistry, and neurogenetics.
Multidimensional models of human personality help to facilitate investigation of the architecture of relationships at each of these levels. When we get to the level of molecular
genetics, we ﬁnd extensive epistatic interaction among multiple loci inﬂuencing variationin each trait and also partial overlap. There is some speciﬁcity in relationships, but there
is universal interrelatedness at every observable level. This interactive relatedness meansthat we will need to shift away from linear causal thinking about one or two variables at
a time and certainly give up exclusive reliance on categorical labeling of personality disor-

96

Aschauer and Schlögelhoferders [2]. Impressive progress is being made in understanding the organization of the psychobiological system that regulates our adaptation to experience.
C.

Psychosocial Aspects of Personality

Scientists agree that personality is a dynamic process that develops over time [1]. Environment, society, culture, etc., inﬂuence the development of personality. Longitudinal studies
illustrate continuity of personality and change over time. Cloninger states: “Continuity
across life span has been found for various characteristics, including ego control, shyness,
dependency, and ill temper. Change occurs, too, especially when life roles change or when
education breaks maladaptive patterns” [1]. In this context, Erikson [28] proposed thateight developmental stages from infancy, early childhood to adulthood, and old age. Cloninger reports that this “psychological theory” describes the relationship between the psychological development of the individual and the social context in which this development
occurs: “At each stage, the developing ego strength is in conﬂict with its opposite: trustwith mistrust, and so on. We achieve a healthy balance if our strengths prevail over theiropposites. It is best not to extinguish mistrust, shame and other negative characteristics,
however, because we need them to keep a realistic equilibrium: the person who trusts
everyone or who never feels ashamed cannot function in the real world” [1]. Various
stages of life (infancy, childhood, adolescence, adulthood, old age) can inﬂuence the development of personality. For example, during infancy secure attachment to the parent becomes the basis for later social relationship. Acklin et al. [29] reported that psychiatricoutpatients with inadequate relationships in early memories showed a higher degree ofpathology measured with various clinical scales. In recent studies [30], researchers foundthat attachment was associated with higher performance on commonly used intelligencetests for the next decade. Furthermore, the ﬁndings from Acklin et al. [31] indicate that
undergraduates who experienced lack of control or difﬁculties in relationships in earlychildhood showed higher scores on a questionnaire measure of depression.
D.

Assessment of Personality

There are many instruments to assess the personality differences among individuals. Measurements are sometimes categorical and called qualitative measurements. More often,
personality is expressed as quantitative measurements. But qualitative measurements aswell as quantitative measurements must be reliable (the measurement is dependable) andvalid (the test measures what the rater is trying to measure). Some often-used instruments
are the Tridimensional Personality Questionnaire (TPQ), Temperament and Character Inventory (TCI), Minnesota Multiphasic Personality Inventory (MMPI), the Myers-Briggs
Type Indicator (MBTI), and the Rorschach inkblot test [1]. A widely used questionnaire
based on the consensual “Big Five” model, is the Revised NEO Personality Inventory(NEO-PI-R). Although reliance on self-report may seem unsound, the self-report versionof the NEO is stable over time, and the factor structure replicates in different cultures
around the world [9].
Some personality inventories take a different approach, basing themselves on speciﬁc psychological or biological theories rather than the neutral mathematical techniqueof factor analysis. A recent example that has proved of heuristic value in psychiatry is the
Tridimensional Personality Questionnaire (TPQ). The TPQ was developed by Cloninger tomeasure the dimensions of his psychobiological theory. It draws on human and animal
work to suggest that behavior is mediated by certain neurotransmitters that underlie threeAnxiety, Depression, and Personality

97

basic and largely heritable dimensions (novelty seeking, harm avoidance, and reward dependence). TPQ harm avoidance is highly correlated with NEO neuroticism, and TPQ
novelty seeking is positively correlated with extroversion and negatively correlated withconscientiousness. Reward dependence is the TPQ term for attachment to others, sentimentality, and warmth; its opposites are pragmatism and tough-mindedness [9]. A key
subscale of reward dependence is persistence. The Temperament and Character Inventory(TCI) was further developed by Cloninger after the TPQ for assessment in clinical settings
and to test speciﬁc predictions based on a seven-dimensional model of psychobiology of
personality. The TCI measures seven dimensions of personality, including three character
dimensions (self-directedness, cooperativeness, and self-transcendence) in addition to thefour dimensions of temperament measured by the TPQ (harm avoidance, novelty seeking,reward dependence, persistence) [2].
III. PERSONALITY DISORDERS
Pinel [32] was the ﬁrst to distinguish personality disorders from mental illness. With theterm “manie sans délire” he described people who had no delusions but were susceptible
to unexplainable, sudden violent behaviors. Other classiﬁcations of personality disorders
were gradually developed during the 19th century. In Germany, in the late 1920s, Kraepelin [33] ﬁnally endorsed the term “psychopathic personality” and described seven different
types of personality disorders. The main importance of the psychopathology for the conception of personality disorders was indicated by Schneider [34]. He regarded abnormal
personalities as “constitutional variants that are highly inﬂuenced by personal experiences”
and identiﬁed 10 speciﬁc classes of “psychopathic personality.” The classiﬁcation system
inﬂuenced the DSM-IV [35] and ICD-10 classiﬁcation system [36]. A comparison [37]shows that some types of personality disorders identiﬁed by Schneider are similar to typesof personality disorders described in the DSM-IV and ICD-10 classiﬁcation systems.
In general, deﬁnition of personality disorders, according to the ICD-10 [36] andDSM-IV [35] diagnostic guidelines include three key concepts:
1. A main disorder of characteristic constitution and behavior that concerns different ﬁelds of personality.
2. An onset in childhood or adolescence. (A diagnosis of personality disorder before age of 16 or 17 is inappropriate.)
3. Mostly related with personal and social impairments.
Table 1 lists the speciﬁc personality disorders as classiﬁed in DSM-IV.
A. Prevalence of Personality Disorders
There is evidence that up to 10% of the population shows an abnormal personality [38].
In the international WHO-study (716 psychiatric patients from 12 different countries)
Loranger et al. [39] diagnosed in 39.5% of patients a personality disorder according to
ICD-10 diagnostic criteria. Table 2 [40] shows the prevalence rates in populations, ranging
from 0.1%, found by Lin et al. [41] to 9.8%, found by Langner and Michael [42]. Few
studies provide information about temporal trends in the prevalence of personality disorders [43]. In a 15-year follow-up study, Lin et al. [41] reported that there was no increasein the prevalence of personality disorders over the years using an unstructured psychiatricinterview. Two other studies [39,44] showed a marked increase of personality disorders

98

Aschauer and Schlögelhofer

Table 1 Personality Disorders According to DSM-IV
Cluster A

301.0:
Paranoid Personality Disorder301.20Schizoid Personality Disorder301.22
Schizotypal Personality Disorder

Cluster B

301.50Histrionic Personality Disorder
301.7
Antisocial Personality Disorder
301.81
Narcissistic Personality Disorder
301.83
Borderline Personality Disorder

Cluster C

301.4
Obsessive-Compulsive Personality Disorder
301.6
Dependent Personality Disorder
301.82
Avoidant Personality Disorder
301.9
Personality Disorder, not otherwise speciﬁed.

Source: American Psychiatric Association, 1994/1996.

in psychiatric inpatients over 10 years and 15 years, respectively [43]. However, further
studies are needed to evaluate temporal trends in the prevalence of personality disorders.
B.

Psychopharmacological Drugs and Personality Disorders

In principal, treatment with psychopharmacological agents in patients with personality
disorders can be focused on speciﬁc symptoms or syndromes (e.g., cognitive dysfunctions,mood disorders, impulsive behavior, or anxiety) but only partly on personality disorders
as a whole [45]. On the other hand, treatment can be directed against complications of
personality disorders (suicide, aggression, or a lack of social adjustment) [45]. Finally,
comorbid axis I disorders (depression, anxiety, etc.) in patients with personality disorders
can be treated with psychopharmacotherapy. Psychopathological symptoms of axis I disorders will be reduced, but personality disorders can be treated in addition with interventionsof different psychotherapeutic techniques. Tables 3 and 4 give an overview of studies inwhich patients with personality disorders received pharmacological interventions [45].
We will present in more detail a few studies selected at random using antidepressantsfrom the group of selective serotonin reuptake inhibitors (SSRIs). Fava et al. [46], forexample, treated patients with depressive disorder and personality disorders with ﬂuoxe-

Prevalence of Personality Disorders in Epidemiological Surveys

Author(s)Country

Date ofsurveySize ofsampleMethod ofassessment

Prevalence(%)

1969–70
1963–7050465 a1468

Clinical interview using ICD-8 criteria
Clinical interview using ICD-8 criteria b

2.7
1.0

1939–441080

9.4

1975–79
1980–84

1536
1666

Clinical interview using Scandinavian
criteria
Clinical interview
CIS using ICD-8 criteria (1975–79),
and ICD-9 and DSM-III-R criteria(1980–84)
Clinical interview using ICD-8 criteria
Clinical interview using Scandinavian
criteria; informants
Clinical interview d using American criteria
Speciﬁc interview schedule e using
DSM-I criteria
Clinical interview using European criteria; informants
Clinical interview

Allebeck et al. (1988)
Bash and Bash-Liechti(1987)
Bremer (1951)

SwedenIslamic Republicof Iran
NorwayDilling et al. (1989)

Germany

Essen-Moller (1956)
Helgason (1981)

SwedenIceland1957–772550 c5395

Langner and Michael(1963)
Leighton (1959)

USA

1954

1660

Canada1952

1010

Lin et al. (1989)

China (Provinceof Taiwan)
India

1946–48
1961–63

19931
39024
2691

Sethi et al. (1972)

6.4
2.8

6.4
4.6

Anxiety, Depression, and Personality

Table 2

9.8
0.1
0.1
0.1
0.1

Source: Adapted from Ref. 40.
aRefers to a survey of male military conscripts aged 18–20 years.
b
Diagnoses were recoded using ICD-9 criteria.
c
The Lundby study: a community survey of an entire population from Lund.
d
The clinical interview was based on symptom questionnaires such as the Minnesota Multiphasic Inventory, the Cornell Medical Index, and the World War II Screening Neuropsychiatric Adjunct.
e
The interview schedule was partly based on the Health and Opinion Survey.

99

100

Table 3

Double-Blind, Placebo-Controlled Treatment Studies with Neuroleptics in Various Personality Disorders

AuthornMedication

42

Flupenthixol 20 mg i.m. every 4 weeks

50

Thioridazine 5–40 mg

Cowdry and Gardner(1988)
Soloff et al. (1993)

16

Triﬂuoperazine 7.8 mg (n ⫽ 7 for 3 weeks)

36
38
34
15 (open study)

Haloperidol 4 mg/d
Phenelzine 60 mg/d
Placebo
Clozapine 253.3 ⫹/⫺ 163.7 mg/d for 2–9
monthsChengappa et al. (1995)

1 (casuistic)

Clozapine 300 mg/d

Khouzam and Donnelly(1997)
McDougle et al. (1997)

1 (casuistic)

Risperidone 4 mg/d18 (12 weeks)

Risperidone 1.8 ⫹/⫺ 1.0 mg/d

Frankenburg andZanarini (1993)

Source: Adapted from Ref. 45.

Signiﬁcant reduction of suicide attempts after 6
weeks
Signiﬁcant drug–placebo differences were foundon “illusions,” “psychoticism,” “obsessivecompulsive symptoms” but not on “depression”
Improvement of behavioral control, anxiety, and depression
Superior efﬁcacy for phenelzine, followed by placebo and haloperidol on measures of depression,anxiety, anger, and hostility
Twelve of 18 symptoms as rated by the brief psychiatric rating scale (BPRS) decreased signiﬁcantly; global assessment score increased
Impulsivity and self-injurious behavior signiﬁcantly
decreased
Impulsivity in combination with self-injurious
behavior decreased
Reduction of aggressive and impulsive behavior,improvement in social behavior

Aschauer and Schlögelhofer

Montgomery andMontgomery (1982)
Goldberg et al. (1986)

ResultDouble-Blind, Placebo-Controlled Treatment Studies with Antidepressants in Various Personality Disorders

AuthornMedication

ResultSoloff et al. (1986)

60

Cowdry and Gardner (1988)

12

Liebowitz et al. (1984)

60

Amitriptyline 147 mg,
Haloperidol 4.8 mg
Tranylcypromine 40 mg/d
on average
Phenelzine, imipramine

Parsons et al. (1989)?

Phenelzine, imipramine

Soloff et al. (1993)

Markovitz (1995)
Simeon et al. (1997)

38
36
34
22
17

Phenelzine 60 mg/d
Haloperidol 4 mg/d
PlaceboFluoxetine 80 mg/d
Fluoxetine 55 mg/d

Coccaro and Kavoussi (1997)40

Fluoxetine 20–60 mg/d

Signiﬁcant improvement in depression with haloperidol incomparison to amitriptyline
In comparison to triﬂuoperazine, carbamazepine, and placebo, improvement on mood
Response rate with phenelzine was 67%, signiﬁcanthigher rates on dysphoric features than imipramine andplacebo
Improvement with phenelzine in comparison to imipramine
Superior efﬁcacy for phenelzine, on measure of depression, anxiety, anger, and hostility in comparison to haloperidol and placebo
Signiﬁcant improvement in anxiety and depression
Fluoxetine was signiﬁcantly superior to placebo in thetreatment of skin picking
Signiﬁcant reduction on irritability, aggressive and impulsive behavior during week 6 and 12; no inﬂuence on
the self-report.

Anxiety, Depression, and Personality

Table 4

Source: Adapted from Ref. 45.

101

102

Aschauer and Schlögelhofertine for 8 weeks. The presence of a cluster B diagnosis before treatment predicted positive
outcome for depression. Following treatment, they found reductions in the frequency ofmost individuals’ personality disorder diagnoses and total Personality Disorder Questionnaire (PDQ-R) scores. Patients with cluster B personality disorders may experiencechanges in measures of personality function in response to treatment, regardless of changes
in depression or symptoms associated with depression.
In a placebo-controlled study, Salzman et al. [47] treated borderline personality disorder volunteers with ﬂuoxetine for 13 weeks. The most striking ﬁnding from this study
was a clinically and statistically signiﬁcant decrease in anger among ﬂuoxetine recipients,
independent of changes in depression. But possibly this result cannot be duplicated inseverely ill patients.
Coccaro et al. [48] performed a double-blind, placebo-controlled trial of ﬂuoxetinein personality-disordered patients with current histories of impulsive aggressive behaviors
and irritability. Over 3 months of treatment, ﬂuoxetine demonstrated an antiaggressive
effect on these individuals, suggesting a therapeutic role for ﬂuoxetine or other SSRIs in
personality disorders.
Eskelius et al. [49] reported a trial with sertraline and citalopram in patients withmajor depressive disorder in whom a personality disorder measure was performed. Following treatment, reductions in the frequency of paranoid, borderline, avoidant, and dependent personality disorder diagnoses were seen in both treatment groups. Reduction ofdepression scores accounted for 0 to 8.4% of the observed variance. Therefore, they conclude that in depressed patients SSRIs signiﬁcantly affect personality traits.
Studies from the 1980s found that patients with both depressive disorder and personality disorder were less likely to receive medication [50] and received antidepressants fora shorter time period [51]. More recent studies [52] indicate that patients with both anaffective disorder and a personality disorder were as likely as patients without a personality
disorder to receive pharmacotherapy. Regarding psychotherapy, individuals with depression and a comorbid personality disorder were signiﬁcantly more likely than those withouta personality disorder to have received psychotherapy in the past.
Phillips et al. [53] in a longitudinal study (1991 to 1996) were the ﬁrst to examine
the relationship between comorbid personality disorders and treatment received in patientswith anxiety disorders. The results of this study showed that anxiety disorder patients witha personality disorder were just as likely to receive medication, and they received a higher
number of drugs compared to patients without a personality disorder. Individuals with aborderline personality disorder were more likely to receive heterocyclic antidepressantsand interventions characteristic of psychodynamic psychotherapy and cognitive therapy.
Notable is that in this study the percentage of personality-disordered patients who received
medication, and the number of medications received, did not increase over a span of 5
years. According to Phillips et al., “the reason for this stability is unclear, but it may
reﬂect clinicians’ impressions that while medications are often beneﬁcial for personality
disorders, their effects are often modest” [53].
IV. PERSONALITY DISORDERS AND DEPRESSION
It is well established that there is a relationship between personality disorders and comorbid axis I disorders [54]. Cluster A personality disorders associate with schizophrenia;
cluster B personality disorders with substance abuse, eating disorders; and somatization
disorders; and cluster C personality disorders are related with anxiety and mood disorders.
Sanderson et al. [55] investigated whether the type and prevalence of personality

Anxiety, Depression, and Personality

103

disorders differed among outpatients with dysthymia (n ⫽ 63), major depression (n ⫽197), and dysthymia plus major depression (n ⫽ 32) diagnosed by the Structured ClinicalInterview for DSM-III-R (SCID-I and SCID-II). Fifty percent of patients with major depression, 52% of patients with dysthymia, and 69% of patients with a major depression
and dysthymia received a clinical diagnosis of at least one personality disorder. Sanderson
et al. [55] also reported that patients with a personality disorder had signiﬁcantly higherscores on the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) in
comparison to patients without a personality disorder. The most frequently diagnosed personality disorders were from DSM-III-R cluster C (avoidant, dependent, obsessive-compulsive, and passive-aggressive personality disorders); personality disorders from cluster
B (histrionic, narcissistic, antisocial, and borderline personality disorders) were less frequent; and personality disorders from cluster A (paranoid, schizoid, and schizotypal personality disorders) were rare. Similar results found Kool et al. [56]. The authors investigated the incidence of personality disorders among individuals with both major depression
and dysthymia and patients with major depression without dysthymia. Approximately 60%
of patients with depressive disorders (n ⫽ 211) suffered from one or more personality
disorders (diagnosed by the personality questionnaire, VKP) in comparison to a control
group. The most common personality disorders are those in cluster C (anxious/fearful).
The literature suggests higher incidence of personality disorders in patients with seasonalaffective disorder compared to normal populations [57,58]. These studies found up to 23%of the depressed patients with seasonal disorder to meet DSM-IV criteria for personality
disorder, mostly cluster C personality disorders. But the prevalence of personality disorders seems to be lower than in patients with nonseasonal depressive disorder [59,60].
Notable in this context is that patients with personality disorders have signiﬁcantly more
symptoms (assessed with the Symptom Check List SCL-90) than patients without these
disorders. Regarding predictive value of personality disorders and the development andrelapses of major depression, borderline personality disorders and dependency personality
traits predicted relapses of major depression in a 6-year follow-up study [61]. Fava et al.
[62] reported that patients with early onset of major depression in comparison to thosewith late onset of depression had a signiﬁcantly higher prevalence of avoidant, histrionic,
narcissistic, and borderline personality disorders.
Hirschfeld [63] reviews the literature with respect to comorbidity of personality
disorders and depression. Personality disorders may precede the development of depression, depression may precede the personality disorder, or there may be an interface between both. Contrary to expectation, with respect to treatment, the presence of the personality disorders did not affect the rate of response to pharmacotherapy for chronic
depression (dysthymia, chronic major depression, double depression). For acute depressive
states, personality disorders are prevalent and are likely to adversely affect response totreatment. Furthermore, data strongly support the hypothesis that successful treatment for
depression is associated with improvement of the personality disorder as well. The resultsof O’Leary et al. [64] support the view that the presence of a personality disorder andhigh neuroticism scores modify the short-term course to remission onset in depression:
longer time to remission onset is associated with a high neuroticism score.
V.

PERSONALITY DISORDERS AND ANXIETYOver the years, there has been an increasing interest in the prevalence of patients with
anxiety disorders and personality disorders [65]. Several studies have found high rates of
personality disorder diagnoses among patients with anxiety disorders such as panic disor-

104

Aschauer and Schlögelhofer

der and agoraphobia [66,67], obsessive-compulsive disorder [68], generalized anxiety disorder [69], and social phobia [70]. But is there a relationship between certain personality
disorders and anxiety disorders in general, or between certain personality disorders andcertain anxiety disorders? In this context, Sanderson et al. [71] investigated the prevalenceof personality disorders of patients with anxiety disorders and compared the prevalence
within each speciﬁc anxiety disorder. The ﬁndings indicate that 35% of patients with
anxiety disorders were diagnosed with at least one personality disorder. The prevalence
rate ranged from 12% (simple phobia) to 49% (generalized anxiety disorder) and 61%(social phobia) among the different anxiety disorders. It is not surprising that 71% of all
patients with a personality disorder were from the “anxious/fearful” cluster C of personality disorders. Dyck et al. [72] found particularly consistent results in their study. Twentyfour percent of 622 individuals with at least one past or current episode of one or moreanxiety disorders had one or more personality disorders. The most commonly diagnosed
personality disorders were avoidant, obsessive-compulsive, dependent, and borderline personality disorders. Patients with social phobia and generalized anxiety disorders had thehighest rates of one or more personality disorders. These ﬁndings suggest that the development of social phobia and generalized anxiety disorder is probably more closely linked
to personality disorders than panic disorder and agoraphobia [72]. But there are divergent
ﬁndings for speciﬁc associations between particular anxiety disorders and personality disorders, although each of these studies used structured interviews (SCID II) as the basis
for diagnosis. For example, Brooks et al. [65] and Nesdadt et al. [73] associated obsessivecompulsive personality disorders with general anxiety disorders. In contrast, Mauri et al.
[74] found a connection between dependent personality disorder and generalized anxiety
disorder. However, understanding comorbidity patterns of anxiety and personality disorders is complicated further by the frequent co-occurrence of depressive disorders inanxiety-disordered patients.
VI. PERSONALITY AND DEPRESSION
Tellenbach [75] described the melancholic type (“typus melancholicus”) of personality asa premorbid personality structure predisposing to episodes of melancholia. von Zerssen[76] conceived the manic type as its counterpart (i.e., a premorbid marker of predisposition
to the manic component of a bipolar disorder). Hecht et al. [77] investigated in this context
the personality features in patients with affective disorder (unipolar depression, bipolar I,
and bipolar II), in a high-risk group (ﬁrst-degree relatives) and a control group. Featuresof the melancholic personality type are more pronounced in patients with unipolar depression in comparison to controls. In the bipolar I group with mainly manic episodes, personality features do not differ from those of controls. Regarding personality in healthy
relatives, melancholic personality features tend to be somewhat more pronounced inhigh-risk subjects. It was concluded that premorbid typus manicus and typus melancholicus predicted, respectively, a predominant manic and a predominant depressive course of
an affective disorder. Other investigators addressed the same questions using different
measures and found that high neuroticism predicted increases in depressive symptoms
across time. Additionally, high conscientiousness predicted increases in manic symptoms
across time. Therefore, they concluded that speciﬁc personality traits may assist in predicting bipolar symptoms [78].
Several reports have shown that anxiety-related personality traits are related to depression [9]. A large female twin study showed that neuroticism (and not self-esteem)

Anxiety, Depression, and Personality105

was a predictor of risk for major depression. Hansenne et al. [79] studied the role playedby the TCI character dimensions in depression. Depressed patients exhibited higher harm
avoidance and self-transcendence scores as well as lower self-directedness and cooperativeness scores as compared to healthy controls. Among the depressed group, harm avoidance, self-directedness, and cooperativeness dimensions are related to the severity of depression.
Furthermore, Bagby et al. [80] found higher scores in the openness dimension inseasonal affective disorder (SAD) patients compared to both nonseasonal depressive patients and healthy controls, using the NEO-PI-R [81]. In a twin study, Jang et al. [82] foundmoderate, but signiﬁcant, associations between seasonality and neuroticism in healthy
volunteers, using the Five-Factor Inventory [81], and these associations seem to be attributable to common genetic factors rather than being inﬂuenced by environmental factors[83]. A recent study [84] failed to show a correlation between the severity of neuroticism
and seasonality, using the NEO-PI-R in a sample of SAD patients. Sher et al. [85] foundthe 5-HTTLPR polymorphism to be independent in its effect on both seasonality andneuroticism in a sample of healthy patients [85].
Poor response rate to bright light therapy has shown to be associated with cluster
C personality disorders and high scores in the harm avoidance scale in the Tridimensional
Personality Questionnaire [58].
SAD patients showed a decrease in neuroticism scores after successful bright lighttherapy, correlating with changes in the total score in the Hamilton Depression Rating
Scale [60]. Lilie et al. found personality abnormalities in 60% of a small number of SAD
patients during winter, but only in 35% during summer [59]. The character dimension
self-directedness was shown to be susceptible to the state effects of depression in major
depressive disorder [86]. Similarly, recent ﬁndings suggest that SAD patients exhibit signiﬁcantly lower scores in the factors of agreeableness, surgency, and emotional stability,
and signiﬁcantly higher in conscientiousness, during the nondepressed state when compared to healthy controls using the Five-Factor model of personality [87].
TPQ scales were also used to predict response to treatments with antidepressants.
Scores on the novelty seeking and reward dependence dimensions were not affected bydepressed state or treatment response status. However, scores on the harm avoidance dimension were signiﬁcantly lower in antidepressant responders and were altered by depressed state [88]. TPQ scales also accounted for 35% of the variance in treatment responsecompared to less than 5% predicted by clinical variables in a study by Joyce et al. [89].
They treated depressed patients with double-blind clomipramine or desipramine (tricyclic
antidepressants) for 6 weeks.
Curiously, although harm avoidance or neuroticism has been associated in somestudies with the short 5-HTTLPR allele, no ﬁrm association between this polymorphismand major depression could be reported. Serretti et al. [90] showed that 5-HTTLPR has
not a major inﬂuence on the depressive symptomatology in mood disorder subjects. Only
the short 5-HTTLPR variant was marginally associated with higher psychic anxiety scores.
A study conducted by Rosenthal [91] showed an association between seasonal affective
disorder and the 5-HTTLPR short allele. However, these ﬁndings could not be replicatedin more recent studies [92,93]. The study by Willeit et al. [92] resulted in an association
between the polymorphism in the serotonin transporter and the melancholic type of seasonal affective disorder [92]. A meta-analysis, however, showed an association between
this polymorphism and bipolar disorder [9].
In suicide victims, impulsivity (prominent in the novelty-seeking personality trait)106

Aschauer and Schlögelhofer

is an important personality proﬁle. Association was observed between suicidal ideation and
COMT gene locus (catechol-O-methyltransferase). COMT contributes to novelty seeking
along with the DRD4 and 5-HTTLPR polymorphisms. The polymorphism in the promoter
region of the serotonin transporter gene (5-HTTLPR) was shown to be associated withviolent suicide behavior [92]. A polymorphism in the tryptophan hydroxylase gene (important in the serotonergic pathway) has also been linked to suicide and other impulsivity
disorders such as violence associated with alcoholism [9].

VII. PERSONALITY AND ANXIETY
It has been shown that subjects with higher harm avoidance scores have a greater probability of being affected by cluster C personality disorders and comorbid mood and anxiety
disorders [9]. However, no association was observed between panic disorder and the 5HTTLPR short allele, the so-called “anxiety gene.”
We studied a sample of detoxiﬁed alcohol dependents with TPQ and found that
harm avoidance was the only dimension of TPQ inﬂuenced by anxiety. Depressive symptoms did not change TPQ scores. High anxiety measures were associated with high harm
avoidance [94]. Keeping in mind that harm avoidance is theoretically associated with theserotonergic neurotransmitter system, this could explain the positive therapeutic effects
of serotonergic drugs on anxiety disorders.
A substantially increased score was found on the harm avoidance dimension in bothpanic disorder patients and patients with general anxiety disorder, but it did not differ
with regard to TPQ scores [95]. This latter ﬁnding is in agreement with the ﬁndings that
panic disorder and general anxiety disorder do not differ signiﬁcantly with respect to theassociated personality disorders.
In general, individuals with various anxiety disorders are all expected to be high inharm avoidance. They are usually about average or low in novelty seeking. Social phobics
are also reported to be low in reward dependence. Panic disorder patients were found tobe lower in persistence than controls [96]. Persistence was average in obsessionals compared to the general population. The stability of harm avoidance has been examined in alongitudinal study of panic disorder patients undergoing treatment with drugs and/or behavior therapy. Despite reductions in panic attacks, harm avoidance remained stable during
a 6-month follow-up. This suggested that harm avoidance may reﬂect susceptibility togeneralized anxiety independent of panic states.

REFERENCES
1. Cloniger SC. Personality: Description, Dynamics and Development, 1st ed. Baltimore: W.H.
Freeman and Company, 1996.
2. Cloniger CR. Biology of personality dimensions. Curr Opinion Psychiatry 2000; 13:611–616.
3. Ebstein RP, Novick O, Umansky R, Priel B, Osher Y, Blaine D, Bennet ER, Nemanov L,
Katz M, Belmaker RH. D4DR exon III polymorphism associated with the personality trait ofnovelty seeking in normal human volunteers. Nat Genet 1996; 12:78–80.
4. Jung CG. Psychologische Typen. Zürich: Rascher, 1921.
5. Kretschmer E. Körperbau und Charakter, 24th ed. Berlin: Springer, 1991.
6. Gray JA. Elements of a Two-Process Theory of Learning. New York: Academic Press, 1975.
7. Eysenck HJ. Biological dimensions of personality. In: Pervin LA, ed. Handbook of Personality:
Theory and Research. New York: Guilford, 1990:224–276.

Anxiety, Depression, and Personality

107

8. Eysenck HJ. Genetic and environmental contributions to individual differences: The threemajor dimensions of personality. J Personal 1990; 58:245–261.
9. Ebstein RP, Benjamin J, Belmaker RH. Genetics of personality dimensions. Curr Opin Psychiatry 2000; 13:617–622.
10. Fiske DW. Consistency of factorial structures of personality ratings from different sources. J
Abnorm Soc Psychol 1949; 44:329–344.
11. Merenda PF. Toward a four-factor theory of temperament and/or personality. J Person Assess
1987; 51:367–374.
12. Eysenck HJ. The Biological Basis of Personality. Springﬁeld, IL: Charles C Thomas, 1967.
13. Derryberry D, Tucker DM. The adaptive base of the neural hierarchy: Elementary motivational
controls on network function. In: Dienstbier R, ed. Nebraska Symposium on Motivation. Lincoln: University of Nebraska Press, 1990:69–164.
14. Lester D. A neurotransmitter basis for Eysenck’s theory of personality. Psychol Rep 1989;
64:189–190.
15. Scarr S. Personality and experience: Individual encounters with the world. In: Aronoff J, Rabin
SI, Zucker RA, eds. The Emergence of Personality. New York: Springer, 1987:49–87.
16. Loehlin JC. Genes and environment in personality development. Newbury Park, CA: Sage,
1992.
17. Tellegen A, Lykken DT, Bouchard TJ, Wilcox KJ, Segal NL, Rich S. Personality similarity
in twins reared apart and together. J Person Soc Psychol 1988; 54:1031–1039.
18. Loehlin JC. Twin studies, environment differences, age changes. Behav Brain Sci 1987; 10:30–31.
19. Hoffman LW. The inﬂuence of the family environment on personality: Accounting for sibling
differences. Psychol Bull 1991; 110:187–203.
20. Cloninger CR, Van Eerdewegh P, Goate A et al. Anxiety proneness linked to epistatic lociin genome scan of human personality traits. Am J Med Genet 1998; 81:313–317.
21. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR,
Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in theserotonin transporter gene regulatory region. Science 1996; 274:1527–1531.
22. Ebstein RP, Benjamin J, Belmaker RH. Personality and polymorphisms of genes involved inaminergic neurotransmission. Eur J Pharmacol 2000; 410:205–214.
23. Hamer DH, Greenberg BD, Sabol SZ, Murphy DL. Role of serotonin transporter gene intemperament and character. J Person Disord 1999; 33:31–36.
24. Benjamin J, Greenberg B, Murphy DL, Li L, Patterson C, Hamer D. Mapping personality
traits to genes: population and family association between the D4 dopamine receptor and measures of novelty seeking. Nat Genet 1996; 12:81–84.
25. Gebhardt C, Leisch F, Schüssler P, Fuchs K, Stompe T, Sieghart W, Hornik K, Kasper S,
Aschauer HN. Non-association of dopamine D4 and D2 receptor genes with personality inhealthy individuals. Psychiatric Genet 2000; 10:131–137.
26. Hendersen AS, Korten AE, Jorm AF, Jacomb PA, Christensen H, Rodgers B, Tan X, Easteal
S. COMT and DRD3 polymorphisms, environmental exposures and personality traits related
to common mental disorders. Am J Med Genet 2000; 96:102–107.
27. Staner L, Hilger C, Hentges F, Monreal J, Hoffmann A, Couturier M, Le Bon, O, Stefos G,
Souery D, Mendlewicz J. Association between novelty seeking and the dopamine D3 receptor
gene in bipolar patients: a preliminary report. Am J Med Genet 1998; 81:192–194.
28. Erikson EH. Identity and the life cycle. Selected papers. Psychological Issues. New York:International University Press, 1959.
29. Acklin MW, Bibb JL, Boyer P, Jain V. Early memories as expressions of relationship paradigms: A preliminary investigation. J Person 1991; 57:177–192.
30. Jacobson T, Edelstein W, Hofmann V. A longitudinal study of the relation between representations of attachment in childhood and cognitive functioning in childhood and adolescence. Devel Psychol 1994; 30:112–124.

108

Aschauer and Schlögelhofer

31. Acklin MW. Rorschach classic in contemporary perspective: Series introduction. J Person
Assess 1993; 61:196–197.
32. Pinel P. Traité médico-philosophique sur l’aliénation mentale, 2nd ed. Paris: Brossons, 1809.
33. Kraepelin E. Manic depressive insanity and paranoia. Barclay RM, trans. Textbook of Psychiatry, 8th ed. Edinburgh: Churchill Livingstone, 1921.
34. Schneider K. Die Psychopathischen Persönlichkeiten. Berlin: Springer, 1923.
35. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4thed. Washington DC: American Psychiatric Press, 1980.
36. World Health Organization. The ICD-classiﬁcation of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines. Geneva: WHO, 1992.
37. Nissen G. Persönlichkeitsstörungen: Ursachen, Erkennung, Behandlung. Stuttgart: W. Kohlhammer GmbH, 2000:15.
38. Nissen G. Persönlichkeitsstörungen: Ursachen, Erkennung, Behandlung. Stuttgart: W. Kohlhammer GmbH, 2000:16–20.
39. Loranger AW, Sartorius N, Andreoli A. The international personality disorders examination.
Arch Gen Psychiatry 1994; 51:215–224.
40. de Girolamo G, Reich JH. Personality Disorder. Geneva: World Health Organization, 1993,
pp 16–17.
41. Lin TY, Chu HM, Rin H, Hsu CC, Yeh EK, Chen CC. Effects of social change on mental
disorders in Taiwan: observation based on a 15-year follow-up survey of general populationsin three communities. Acta Psychiatr Scand 1989; 79:11–34.
42. Langner TS, Michael ST. Life Stress and Mental Health. The Midtown Manhattan Study.
London: Collier, MacMillan, 1963.
43. deGirolamo G, Reich JH. Personality Disorder. Geneva: World Health Organization, 1993:
37–38.
44. Dilling H, Weyrer S, Fichter M. The upper Bavarian studies. Acta Psychiatr Scand 1989; 79:
113–140.
45. Gaeble W, Klimke A. Neuroleptika bei nichtpsychotischen Störungen. Berlin: SpringerVerlag, 1999:194–203.
46. Fava M, Boufﬁdes E, Pava JA, McCarthy MK, Steingard RJ, Rosenbaum JF. Personality
disorder comorbidity with major depression and response to ﬂuoxetine treatment. Psychother
Psychosom 1994; 62:160–167.
47. Salzman C, Wolfson AN, Schatzberg A, Looper J, Henke R, Albanese M, Schwartz J,
Miyawaki E. J Clin Psychopharmacol 1995; 15:23–29.
48. Coccaro EF, Kavoussi RJ. Fluoxetine and impulsive aggressive behaviour in personalitydisordered subjects. Arch Gen Psychiatry 1997; 54:1081–1088.
49. Eskelius L, von Knorring L. Changes in personality traits during treatment with sertraline orcitalopram. Br J Psychiatry 1999; 174:444–448.
50. Charney DS, Nelson JC, Quinlan DM. Personality traits and disorders in depression. Am J
Psychiatry 1981; 138:1601–1604.
51. Pfohl B, Coryell W, Zimmerman M, Stangl D. Prognostic validity of self-report and interview
measures of personality disorder in depressed inpatients. J Clin Psychiatry 1987; 48:468–472.
52. Downs NS, Swerdlow NR, Zisook S. The relationship of affective illness and personality
disorders in psychiatric outpatients. Ann Clin Psychiatry 1992; 4:87–94.
53. Phillips KA, Shea TS, Warshaw M, Dyck I, Bruce S, Keller M. The relationship between
comorbid personality disorders and treatment received in patients with anxiety disorders. J
Person Disord 2001; 15:157–167.
54. Tyrer P, Gunderson J, Lyons M, Tohen M. Special feature: Extend of comorbidity between
mental state and personality disorders. J Person Disord 1997; 11:242–259.
55. Sanderson WC, Wetzler S, Beck AT, Betz F. Prevalence of personality disorders in patientswith major depression and dysthymia. Psychiatr Res 1992; 42:93–99.

Anxiety, Depression, and Personality

109

56. Kool S, Dekker J, Duijsens IJ, de Jonghe F. Major depression, double depression and personality disorder. J Person Disord 2000; 14:274–281.
57. Schulz PM, Goldberg S, Wehr TA, Sack DA, Kasper S, Rosenthal NE. Personality as a dimension of summer and winter depression. Psychopharmacol 1988; 24:360–362.
58. Reichborn-Kjennerud T, Lingjaerde O, Dahl AA. Personality disorders in patients with winterdepression. Acta Psychiatr Scand 1994; 90:413–419.
59. Lilie JK, Lahmeyer HW, Watel LG, Eastman CI. The relation of personality to clinical outcome in SAD. Soc Light Treatment Biol Rhythmus 1990; 2:213.
60. Sachs GS, Jain U, Truman CJ, Blais MA, Otto MW, Hirschfeld D. Seasonal affective disorderand personality characteristics: Assessing personality traits of pre-treatment and post-treatment
phases of seasonal depression. Soc Light Treatment Biol Rhythms 1996; 8:36.
61. Alnaes R, Torgersen S. Personality and personality disorders predict development and relapsesof major depression. Acta Psychiatr Scand 1997; 95:336–342.
62. Fava M, Alpert JE, Borus JS, Nierenberg AA, Pava JA, Rosenbaum JF. Patterns of personality
disorder comorbidity in early-onset versus late-onset major depression. Am J Psychiatry 1996;
153:1308–1312.
63. Hirschfeld RMA. Personality disorders and depression: comorbidity. Depression Anxiety
1999; 10:142–146.
64. O’Leary D, Costello F. Personality and outcome in depression: an 18-month prospective follow-up study. J Affect Disord 2001; 63:67–78.
65. Brooks RB, Baltazar PL, Munjack DJ. Co-occurrence of personality disorders with panic disorder, social phobia, and generalized anxiety disorder: A review of the literature. J Anxiety
Disord 1989; 3:259–285.
66. Reich JH, Noyes R. A comparison of DSM-III personality disorders in acutely panic anddepressed patients. J Anxiety Disord 1986; 1:123–131.
67. Friedman CJ, Shear MK, Frances A. DSM-III personality disorders in panic patients. J Person
Disord 1987; 1:132–135.
68. Baer L, Jenike MA, Ricciardi JN. Standardized assessment of personality disorders inobsessive-compulsive disorder. Arch Gen Psychiatry 1990; 47:826–830.
69. Sanderson WC, Wetzler S, Kaplan M. Chronic anxiety and generalized anxiety disorders.
Issue in comorbidity. In: Rapee RM, Barlow DH, eds. Chronic Anxiety, Generalized Anxiety
Disorder and Mixed Anxiety Depression. New York: Guilford Press, 1991:119–136.
70. Turner SM, Beidel DC, Borden JW, Stanley MA, Jacob RG. Social phobia: Axis I and II
correlates. J Abnorm Psychol 1991; 100:102–106.
71. Sanderson WC, Wetzler S, Beck AT, Betz F. Prevalence of personality disorders among patients with anxiety disorder. Psychiatry Res 1993; 51:167–174.
72. Dyck IR, Phillips KA, Warshaw MG, Dolan RT, Shea MT, Stout RL, Massion AO, Zlotnick
C, Keller MB. Patterns of personality pathology in patients with generalized anxiety disorder,
panic disorder with and without agoraphobia, and social phobia. J Person Disord 2001; 15:
60–71.
73. Nesdadt MB, Romanoski AJ, Samuels JF, Folstein MF, McHugh PR. The relationship between
personality and DSM-III axis I disorders in the population: results from an epidemiologic
survey. Am J Psychiatry 1992; 149:1228–1233.
74. Mauri M, Sarno N, Rossi VM, Armani A, Zambotto S, Cassano GB, Akiskal HS. Personality
disorders associated with generalized anxiety, panic, and recurrent depressive disorders. J Person Disord 1992; 6:162–167.
75. Tellenbach H. Melancholie, 1st ed. Berlin: Springer, 1961.
76. von Zerssen D. Premorbid personality and affective psychoses. In: GD Burrows, ed. Handbookof Studies on Depression. Amsterdam: Excerpta Medica, 1977:79–103.
77. Hecht H, Calker D, Berger M, von Zerssen D. Personality in patients with affective disorders
and their relatives. J Affect Disord 1998; 51:33–43.

110

Aschauer and Schlögelhofer

78. Lozano BE, Johnson AL. Can personality traits predict increases in manic and depressive
symptoms? J Affect Disord 2001; 63:103–111.
79. Hansenne M, Reggers J, Pinto E, Kjiri K, Ajamier A, Ansseau M. Temperament and character
inventory (TCI) and depression. J Psychiatric Res 1999; 33:31–36.
80. Bagby RM, Schuller DR, Levitt AJ, Joffe RT, Harkness KL. Seasonal and non-seasonal depression and the ﬁve-factor-model of personality. J Affect Disord 1996; 38:89–95.
81. Costa PT, McCrae RR. NEO-PI-R: Professional Manual: Revised NEO Personality Inventory(NEO PI-R) and NEO Five-Factor Inventory (NEO-FFI). Psychol Assessment Resources(Odessa, FL), 1992.
82. Jang KL, Lam RW, Livesley WJ, Vernon PA. The relationship between seasonal mood change
and personality: more apparent than real? Acta Psychiatr Scand 1997; 95:539–543.
83. Jang KL, Lam RW, Harris RW, Vernon PA, Livesley WJ. Seasonal mood change and personality: an investigation of genetic co-morbidity. Psychiatry Res 1998; 78:1–7.
84. Gordon T, Keel J, Hardin TA, Rosenthal NE. Seasonal mood change and neuroticism: thesame construct? Compr Psychiatry 1999; 40:415–417.
85. Sher L, Greenberg BD, Murphy DL, Rosenthal NE, Sirota LA, Hamer DH. Pleiotropy of theserotonin transporter gene for seasonality and neuroticism. Psychiatr Genet 2000; 10:125–
130.
86. Black KJ, Sheline YI. Personality disorder scores improve with effective pharmacotherapy ofdepression. J Affect Disord 1997; 43:11–18.
87. Lingjaerde O, Foreland AR, Engvik H. Personality structure in patients with winter depression,assessed in a depression-free state according to the ﬁve factor model of personality. J Affect
Disord 2001; 62:165–174.
88. Joffe RT, Bagby RM, Levitt AJ, Regan JJ, Parker JD. The tridimensional personality questionnaire in major depression. Am J Psychiatry 1993; 150:959–960.
89. Joyce PR, Mulder RT, Cloninger CR. Temperament predicts clomipramine and desipramine
response in major depression. J Affect Disord 1994; 30:35–46.
90. Serretti A, Cusin C, Lattuada E, DiBella D, Catalano M, Smeraldi E. Serotonin transporter
gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders. Mol
Psychiatry 1999; 4:280–283.
91. Rosenthal NE, Mazzanti CM, Barnett RL, Hardin TA, Turner EH, Lam GK. Role of serotonintransporter promoter repeat polymorphism (5-HTTLPR) in seasonality and seasonal affective
disorder. Mol Psychiatry 1998; 3:175–177.
92. Willeit M, Praschak-Rieder N, Neumeister A, Zill P, Stastny J, Leisch F, Hilger E, deJonge
S, Thierry N, Konstantinidis A, Winkler D, Bondy B, Fuchs K, Sieghart W, Aschauer HN,
Ackenheil M, Kasper S. A polymorphism (5-HTTLPR) in the serotonin transporter promotor
gene is associated with DSM-IV depression subtypes in seasonal affective disorder. MolecularPsychiatry, in press.
93. Johansson C, Smedh C, Partonen T, Pekkarinen P, Paunio T, Ekholm J, Peltonen L, Lichtermann D, Palmgren J, Adolfsson R, Schilling M. Seasonal affective disorder and serotoninrelated polymorphism. Neurobiol Dis 2001; 8:351–357.
94. Meszaros K, Willinger U, Fischer G, Schönbeck G, Aschauer HN. The tridimensional personality Model: inﬂuencing variables in a sample of detoxiﬁed alcohol dependents. Comprehens
Psychiatry 1996; 37:109–114.
95. Starcevic V, Uhlenhuth EH, Fallon S, Pathak D. Personality dimensions in panic disorder andgeneralized anxiety disorder. J Affect Disord 1996; 37:75–79.
96. Cloninger CR, Pryzbeck TR, Svrakic DM. The Temperament and Character Inventory (TCI):A Guide to Its Development and Use. St. Louis: Washington University Center for Psychobiology of Personality, 1994.

5
Is There a Common Etiology for
Depression and Anxiety?
DEAN F. MacKINNON and RUDOLF HOEHN-SARIC
Johns Hopkins University School of Medicine
Baltimore, Maryland, U.S.A.

I.

INTRODUCTION

Depression and anxiety coexist so often in patients that it is natural to question whether
they have a common etiology. Distinct clinical syndromes may have the same etiology(e.g., the clinical syndrome caused by pneuomococcal infection depends on whether it
occurs in the lung, meninges, or elsewhere). At the same time, two disorders that occur
together might have distinct etiologies. For example, lung cancer and alcoholic cirrhosis
might frequently occur together because drinkers tend to smoke. The debate over whether
pathological anxiety and depression constitute different aspects of the same disorder [1]or distinct, although often overlapping, conditions [2] is not new, but remains unresolved.
In this chapter we review evidence pertinent to the question at hand from methodologies
of epidemiology, neuroscience, pharmacology, and psychophysiology. While many of theresults of these studies pertain more to the question of common pathophysiology than ofcommon etiology of anxiety and depression, a thorough understanding of the former may
be necessary to present an informed response as to the latter.

II. ANXIETY AND DEPRESSION: NORMAL AND ABNORMAL
In discussing the etiologies of anxiety and depression, one must distinguish normal affective responses from exaggerated affective responses as seen in emotionally labile persons, and from categorically deﬁned anxiety and depressive disorders. In the most common
sense of the term, “etiology” implies a pathological cause. Normal emotional responses,
111

112

MacKinnon and Hoehn-Saric

therefore, do not have an etiology, but it may be enlightening to examine shared mechanisms of normal anxiety and sadness as a way to explain pathological emotions. Exaggerated emotional responses are pathological in function, but not form; the pathology exists
not in the emotional response, but in the vulnerability to exaggerated response. The fundamental question posed by the common coexistence of anxiety and depression in patientsis whether pathological forms of anxiety and depression have the same pathological cause.
As affects, anxiety and depression are experienced in everyday life and serve important biological functions. Normal anxiety improves motivation and performance on tasks.
Anxious feelings act as a warning to focus on potentially dangerous situations and toformulate plans to deal with them. Moreover, since anxiety is an unpleasant emotion fromwhich we like to escape, it motivates us to master or avoid anxiety-provoking situations.
Normal depression, akin to grief, occurs after a loss, either real or perceived. The biologicalusefulness of depression may be thus to promote afﬁliative behavior. Some aspects ofdepression may be useful as a means of energy conservation; in this regard, symptomsof seasonal depression (lethargy, increased sleep, carbohydrate craving) may seem adaptive in a wintertime agrarian or hunter–gatherer economy.
In normal as well as pathological states, depression and anxiety may intermingle.
The perception of imminent, but potentially correctable, danger often coexists or alternateswith the perception of hopelessness. Distressed persons often experience mixed feelingsof anxiety and depression, whether or not they have a psychiatric disease. In the oldnomenclature, patients with exaggerated, but not necessarily pathological depression oranxiety were seen to exhibit different forms of neurosis. Thus, the psychological etiology
or trigger of anxiety and depression may be the same because the same source of stress
may lead to both kinds of symptoms.
The difference between normal and abnormal anxiety and depression is in part a
matter of degree but is mainly a categorical question. Some emotional expressions are so
intense as to interfere with a patient’s ability to cope with the stress that triggered theemotion. Cases in which the emotional response is understandable, albeit extreme, are to
be differentiated from cases in which the emotional response is not related to or is out of
proportion to an understandable cause and is associated with a cluster of other stereotypic
symptoms deﬁning a clinical syndrome. In the former cases, the underlying biologicalcause of the disorder is a patient’s vulnerability to experience an exaggerated emotional
response of some sort. In the latter cases, the emotional response is only one of a set ofsymptoms that tend to emerge simultaneously with or without an apparent source of stress.
The difﬁculty in sorting out whether a pathological anxiety or mood state is anextreme on a dimensional scale or a categorically deﬁned disease entity is one of thecritical dilemmas in clinical psychiatry. Frequent overlap of anxiety and depressive symptoms further confounds this dilemma. An estimated 20 to 90% of patients in surveys
experience both anxiety and depression [3]. Numerous studies have shown that anxiety
disorders may contain an element of depression and vice versa [4,5]. Therefore, many
anxiety rating scales contain subscales of depression, and depression scales also include
subscales describing psychic and somatic symptoms of anxiety (e.g., Refs. 6,7). Rating
instruments that measure both mood states simultaneously have been useful in the recognition of how clinicians have separated nonpsychotic anxiety patients from nonpsychotic
depressive patients. While patients with “anxiety neurosis” tend to score high mainly on
scales measuring anxiety, patients with “depressive neurosis” score high both on scales
measuring the degree of anxiety and depression [8]. Thus, patients with depressive neurosis were as anxious, but more depressed, than patients with anxiety neurosis.

Depression and Anxiety: Common Etiology?

113

Not all patients with anxiety and depressive disorders exhibit mixed features. Somepatients with anxiety disorders are free of clinically signiﬁcant depression and some patients with depressive disorders do not experience signiﬁcant levels of anxiety. However,the frequent co-occurrence of symptoms of both anxiety and depression in a substantial
subset of patients indicates that identiﬁcation of mixed anxiety and depressive disorders
is an important ﬁrst step toward discovering a common etiology. Differentiation of a mixed
anxiety-depressive disorder has been slow to come to the diagnostic nomenclature [9,10],
possibly because of mixed data on clinical response to treatment [11,12].
III. CLINICAL AND EPIDEMIOLOGICAL STUDIES
Reliable data on the boundaries and stability of psychiatric diagnosis awaited the development of a widely accepted, categorical deﬁnition of diagnostic entities. Soon after theadvent of the Diagnostic and Statistical Manual of Mental Disorders (DSM), 3rd ed. [13],however, it became clear that diagnostic reliability had a limitation. Not all patients could
be cleanly assigned to a single diagnostic category according to the guidelines of themanual [2,14,15]. Later editions of the DSM have employed three strategies to accountfor such complex forms of disorder: hierarchies, comorbidity, and speciﬁers. Hierarchies
in the deﬁnitions of certain disorders specify that the disorder is not diagnosed if it occurs
only in the context of another disorder (e.g., generalized anxiety disorder is not diagnosed
if the syndrome appears only when the patient also has a major depression syndrome).
Comorbidity accounts for multiple disorders by simply listing all disorders for which apatient meets diagnostic criteria whether or not one disorder is the same as, or secondary
to, the other (e.g., a patient may have both major depression and panic disorder). In older
nomenclatures, speciﬁers such as “endogenous” versus “reactive” or “neurotic” depression
implied the diagnostician had knowledge about the cause of the depression. Speciﬁers in
DSM are used with some disorders to denote a phenomenologically distinct subtype (e.g.,major depressive disorder with atypical features). However, none of the speciﬁers available for mood disorders deﬁne an anxious subtype or account for anxiety symptoms.
Therefore, for the most part our discussion of the unity or differentiation of anxiety fromdepressive diagnoses will focus on comorbidity data.
Comorbidity, however, has limitations as a concept, in large part because it has anumber of deﬁnitions that are used erratically across studies. In some studies of anxiety
and depression, the term indicates that anxiety and depressive symptoms coexist simultaneously. In other studies, however, the term denotes that one condition frequently follows
the other. Earlier studies on comorbidity were mostly descriptive; more recent studies
have tried to explore biological relations between disorders that frequently show comorbidity. Some investigators have proposed that anxiety and depression are biologically separate disorders [2]. If this is true, we should ﬁnd little overlap in their clinical pictures. It
is also conceivable that symptoms of anxiety and depression represent different aspectsof the same disorder [1]. Here, symptoms of anxiety and depression could occur simultaneously or alternate. A third possibility is that one condition (e.g., anxiety) induces changes
that lead to another condition, namely depression. In this model, pathological depression isthe consequence of pathological anxiety and should not lead to anxiety disorders. Finally,
comorbidity may be the ﬁnal common pathway of two originally independent conditions;however, without enhanced knowledge of pathophysiology this possibility is hard to support.
Longitudinal studies have suggested that anxiety is often a prodromal form of de-114

MacKinnon and Hoehn-Saricpressive disorder. Whereas depression without anxiety tends to maintain diagnostic stability over time, individuals with anxiety disorders and mixed anxiety-depressive disorders
at baseline often are found to have depressive disorders later in life [16–19]. While patients
who had originally suffered from anxiety disorders often subsequently developed depressive disorders, patients who were diagnosed as having depressive disorders withoutanxiety rarely developed an anxiety disorder. Thus, depression maintained a diagnostic
stability over time, but this was not true for anxiety disorders.
Studies on comorbidity with various anxiety disorders have shown an inconsistentpicture as to the associated risk of depressive disorder. Anxiety disorders have been foundto occur in as many as the majority of individuals in treatment for depression, with social
phobia as the most common disorder [20]. Results of most studies suggest that panic
disorder and depression are frequently associated or that depression emerges in the courseof panic disorder [21]. Indeed, panic disorder is an extremely common, albeit not universal,
condition in patients with both depressive [22] and manic depressive [23] disorders. Generalized anxiety disorder (GAD), as mentioned above, overlaps so often with depressionthat it is not considered a comorbid condition; indeed, it is not diagnosed at all if it occurs
only with depression. Breslau and Davis [24] reported a high incidence of major depression
in surveyed mothers who carried the primary diagnosis of GAD. A lifetime history ofmajor depression can be diagnosed in anywhere from 6 to 46% of patients with GAD,
depending on the methodology (reviewed in Ref. 25); however, Angst et al. [17] rarely
found coexisting depression in their GAD groups. Variant ﬁndings may be explained bydifferences in patient population, diagnostic criteria, and assessment methods. Nevertheless, taking at face value the positive reports of a chronological priority of one disorderto another does not resolve the question as to whether the two disorders derive from thesame etiology, or whether one disorder produces the other.
Family studies address directly the question of a shared etiology of anxiety anddepression by examining shared familial risk for these disorders. If anxiety disorder (ordepressive disorder) in a family member raises the risk for both anxiety and affective
disorder in relatives, then this may be evidence for a shared etiology. If anxiety and depressive disorders “breed true” (i.e., if anxiety only raises the familial risk for anxiety
and depression for depression), then this argues against a common genetic etiology. The
empirical results are complex. Looking at anxiety broadly, patterns of comorbidity suggesting a speciﬁc risk in some families are not apparent. Angst et al. [17] found thatparents of patients with pure anxiety or depressive disorders and mixed anxiety-depressive
disorders had comparable histories of anxiety and depressive disorders. Noyes et al. [26]and Crowe [27] demonstrated that the risk of having an anxiety neurosis was six times
higher in relatives of probands with that disorder than in relatives of controls. The speciﬁcity of transmission of anxiety disorders is also suggested by the work of Cloninger et al.
[28] and Dealy et al. [29], whose studies showed that relatives of probands with anxiety
disorders, but not depressive disorders, exhibited an increased risk of anxiety neurosis.
On the other hand, twin studies support the hypothesis that pure depression and mixed
anxiety–depression are etiologically similar disorders, whereas pure anxiety disorders differ etiologically from depressive and mixed disorders [30]. These discrepant results aswell as others that show a lack of crossover familial risk of one anxiety disorder to another[26] suggest that it may not be possible to talk about the genetic etiology of anxiety ingeneral, but rather about each speciﬁc type of anxiety disorder.
In a similar way, it may not be possible to speak about the etiology of depression
in general, as opposed to depression as part of a mood disorder syndrome [31]. A case

Depression and Anxiety: Common Etiology?

115

in point is panic disorder. Weissman et al. [32] have used a family study approach tomeasure the risk of pure and comorbid panic and major depressive disorders in the relativesof probands with each disorder alone, of probands with combined panic and major depression, and of unaffected control probands. They concluded that panic and early-onset major
depressive disorder were speciﬁc and independent disorders, and that combined depression
and panic disorder were probably not a disorder distinct from the simple types. The relationship of panic and bipolar disorders, however, suggests a different story. MacKinnon
et al. [33] found that the risk for panic combined with bipolar disorder was elevated inrelatives of probands with combined panic and bipolar disorder compared to bipolar andpanic disorder alone. Thus, one possible account of the etiological relationship of anxiety
and mood is that familial bipolar affective disorder and panic disorder may have common
etiological factors, at least in some families. Major depression and panic together do notappear to constitute a subtype of illness, but may be related at a higher level (i.e., panic
may arise as a complication of depression, or vice versa).
Pursuit of a common genetic etiology of depression and anxiety shows promise, but
has not yet yielded a molecular basis for comorbidity. Linkage and association studies
support a complex genetic basis for many psychiatric disorders [34]. Thus, it is possible—
indeed probable—that a common genetic basis for two related psychiatric disorders will
exist in the form of a common genetic vulnerability of several genes involved in thepathogenesis of the various disorders. Anxiety, for example, may be the result when one
has variants of two of the genes A, B, and C, while depression may be produced byvariants of two of the genes C, D, and E. Combinations including a variant of gene C
will produce comorbidity by a common mechanism, while other combinations produce
comorbidity via distinct mechanisms. A potential crossover candidate gene is the serotonintransporter gene. Functional polymorphisms in this gene have been associated or linked
with anxiety-related traits in several studies [35,36] and with depression [37]; however,results have been inconsistent [38].
Longitudinal and family studies provide mixed support for the hypothesis that depressive and anxiety disorders may have common etiological risk factors. In longitudinalstudies, it appears that anxiety often may be an early manifestation of a disease processthat leads later in life to clear depression. In family studies, it appears that some, but notall, of the genetic alleles related to bipolar and panic disorder may be the same; however,there is little evidence that other anxiety and depressive disorders share genetic risk factors.
Without detailed knowledge of pathophysiological mechanisms, it may not be possible
to say whether anxiety and depressive disorders associated epidemiologically are also
associated etiologically. This knowledge may come from molecular genetics or from studies of brain structure and function.
IV. IMAGING STUDIES
Changes in cerebral blood ﬂow and metabolism, seen in imaging studies, emphasize differences between anxiety and depressive disorders rather than features common to both typesof disorders. Moreover, subtypes of anxiety disorders and subtypes of depressive disorders
exhibit speciﬁc imaging patterns that indicate biological differences not only between
anxiety and depression per se but also between the subtypes. For example, panic disorderpatients at rest, but not other anxiety disorder patients, show increased metabolism andblood ﬂow in the right parahippocampal region [39,40] while obsessive-compulsive patients at rest exhibit higher cerebral blood ﬂow in right prefrontal cortex [41]. Under

116

MacKinnon and Hoehn-Saric

symptom provocation, three different anxiety disorders, namely, obsessive-compulsive
disorder, speciﬁc phobia, and post-traumatic stress disorder, showed as a common characteristic increased cerebral blood ﬂow in the right inferior frontal cortex, the right posterior
medial orbitofrontal cortex, the bilateral insular cortex, the bilateral lenticulate nuclei, andbilateral brain stem foci [42]. This ﬁnding indicates a widespread activation of the brain
during heightened anxiety. In contrast to anxiety disorders, depressive disorders generally
show decreased metabolism and blood ﬂow in the dorsolateral and medial-prefrontal cortex, basal ganglia, and the cingulate, reversed with successful pharmacotherapy [43,44].
However, a group of unipolar patients with positive family history of depression exhibited
increased blood ﬂow in portions of the orbital frontal cortex and amygdala [45]. Thus,
imaging studies not only fail to support the hypothesis of a common etiology of anxiety
and depressive disorder but indicate a biological diversity in subgroups of disorders.
V.

PSYCHOPHYSIOLOGICAL STUDIES

Similarities in patterns of autonomic and neurovegetative functioning between individuals
with anxiety and depressive disorders may implicate common pathophysiological mechanisms that in turn reﬂect a common etiological factor for these disorders. Findings of acommon psychophysiological abnormality would serve as a potentially valuable clue, butwould not deﬁnitively establish a common etiology until more is understood about thelinkage of etiology and pathological mechanisms. A number of studies have examined
the question of whether the physiology of sleep and autonomic arousal is similar or distinct
in subjects with depression and anxiety.
Sleep disturbance is a common complication of anxiety and depressive disorders;
however, different disorders tend to have different sleep complaints. Whereas insomnia
in anxious patients tends to occur early, reﬂecting hyperarousal, patients with depression
tend to have middle or late insomnia, indicating a fundamental disturbance of sleep architecture and regulation. These differences are reﬂected in sleep encephalographic studies,
which consistently show in depression abnormal sleep continuity and shortened REM
latency [46] as well as microarchitectural abnormalities, including decreased delta amplitude or incidence [47]. Despite common complaints of early insomnia in panic disorder[48], reports of sleep architectural changes have been inconsistent [49,50] and distinct
from EEG patterns seen in depression [51]. Similarities in sleep architecture disturbance
between subjects with GAD and dysthymia support the notion that these may be variantsof the same disorder [52].
Several investigators have focused on quantitative encephalographic asymmetry asa means of discriminating anxious from depressed emotional states in normal subjects.
Observation of a shift to the right in brain activity [53] in dysphoric states is consistent
with many other lines of evidence on cerebral asymmetry [54]. Electrodermal activity,
which reﬂects sympathetically controlled sweat gland activity, is often decreased in depressed persons [55]. Patterns of electrodermal activity have been found as well to correlate with differential activation of right versus left brain, dependent on the degree of anxious and depressed temperament in the individual [56]. Studies of electrodermal activity
and/or quantitative EEG activation in patients with mood and anxiety disorders tend toﬁnd patterns of asymmetry, however, with inconsistent patterns across studies [57–59].
Evidence that major depressive disorder and panic are distinct disorders is derived
from panic provocation studies using lactate or carbon dioxide, which consistently differentiate panic from other anxiety disorders [60,61] and, generally, from major depressiveDepression and Anxiety: Common Etiology?

117

disorder [62–65]. Mechanisms for panic vulnerability have not been worked out in detail,but have been hypothesized to involve faulty regulation of respiration [66] or hypersensitivity of the amygdala-related structures involved in the generation of a fearful response [67].
Other evidence that anxiety and depression may be related pathophysiologicallyand thus etiologically can be sought in measures of autonomic nervous system arousal.
Cardiovascular activity measures such as basal forearm blood ﬂow, heart rate, and bloodpressure are similar in patients with chronic anxiety and with agitated depression, in contrast to normal controls and patients with “nonagitated depression” [68]. Individuals with
anxiety and depressive disorders, as well as other dysphoric emotional states, have beenfound to have diminished heart rate variability, possibly through a mechanism involving
decreased vagal tone [69]. Empirically, however, no consistent abnormalities in vagal tone
have been found in anxiety disorders or depression [70].
In summary, studies of sleep architecture and symptom provocation offer evidence
for differential mechanisms of depressive and anxious symptomatology, while studies ofquantitative electroencephalography and cardiovascular regulation suggest a greater degree of physiological overlap. Heightened speciﬁcity of physiological measures correlatedwith emotional symptoms may yield evidence in time of overlapping disease mechanisms
for speciﬁc subtypes of anxiety and depressive disorders.
VI. NEUROENDOCRINE MECHANISMS
The hypothesis that psychiatric disorder results from stress, as mediated by the hypothalamic–pituitary–adrenal (HPA) axis, has long provenance and mixed heuristic value andempirical support. Proponents of this hypothesis connect childhood trauma to affective
and anxiety psychopathology via corticotropin-releasing factor (CRF) hypersecretion induced by the early stressful conditions [71]. These ﬁndings parallel biochemical and behavioral ﬁndings in animal models [72]. It is unclear, however, how applicable this hypothesis may be to affective and anxiety disorder patients who do not have a history of trauma
and/or evidence of cortisol dysregulation. It is also unclear whether this hypothesis addresses the etiology of depressive and anxiety disorders, or whether hypersecretion ofstress hormones reﬂects a response to the stress of having psychiatric symptoms rather
than a root cause of psychiatric symptoms. While cortisol elevation is seen during acutestress, it is not found in chronic anxiety disorders. On the contrary, patients in some anxiety
disorders, for instance in PTSD, have cortisol levels that are lower than in nonanxious
individuals [73].
Challenge studies have been used to test whether cortisol dysregulation plays a rolein psychiatric disorder. For a short while, it appeared that the challenge studies would
have diagnostic and prognostic value in depression and anxiety disorders. Unfortunately,
these neurohormonal manifestations lack speciﬁcity. Changes in the HPA axis, leading
to hypercortisolemia and nonsuppression of cortisol in the dexamethasone suppression
test (DST), are found in approximately 50% of patients with major depression [31: 448].
Some evidence suggests that normalization of HPA nonsuppression is a prerequisite for
antidepressant response in depression [74]. The test, however, is not speciﬁc to depression
as it gives positive results in alcohol withdrawal, psychotropic drug withdrawal, acuteweight loss, or physical exercise, and is frequently positive in schizophrenia and dementias[75]. It also has been found positive, although to a lesser degree, in anxiety disorders. In
the studies he has surveyed, Heninger [76] reported that panic disorder patients had a

118

MacKinnon and Hoehn-Saric

median nonsuppression rate of 18%, which places them between the rate of normal persons(approximately 10%) and that of major depression. Hospitalized panic disorder patientswere more frequently nonsuppressed, which suggests that nonsuppression is linked to theseverity of the disorder. Elevation of cortisol levels has been found to be elevated in thesaliva of patients experiencing an acute spontaneous panic attack [77] and in the serumof subjects who demonstrate vulnerability to panic provocation with lactate [78]. Cortisol
nonsuppression using the DST has also been reported in GAD and in obsessive-compulsive
disorder [75]. Interestingly, in one study of GAD patients, the nonsuppression normalized
after successful nondrug behavioral treatment [79].
Dysfunction in the HPA axis might reside in the mechanism by which ACTH isreleased by CRF. In animal models, CRF has been shown to stimulate amygdala structures
putatively involved in the generation of fear and anxiety responses [80]. Amygdala CRF,
in turn, has been shown to be selectively stimulated by circulating glucocorticoids [81].
Diminished ACTH response to CRF has been demonstrated in major depression and panic
disorder in comparison to normal controls [76,82]. However, while CRF has been foundincreased in depressed patients and, in some studies, in anxiety patients [83], these ﬁndings
were not consistently seen in anxiety patients [72,84]. Since CRF is under partial controlof the noradrenergic system, the effect of challenges on the system are reﬂected in thecortisol response. The cortisol response to the α 2-noradrenergic agonist clonidine and to
the α 2-noradrenergic antagonist yohimbine were similar in both disorders. Thus, overactivity of the HPA axis occurs in subsets of depressive and anxiety disorders and, therefore,lacks speciﬁcity. Twenty-four-hour monitoring of cortisol levels in psychotic versus nonpsychotic depressed patients, for example, revealed higher cortisol levels in the psychotic
patients, who also had greater illness chronicity, again suggesting higher cortisol as apossible effect of prolonged stress rather than a cause of illness [85].
The serotonergic system is even more complex and less well understood than thenoradrenergic and HPA systems. At least 16 receptors with different functions have been
described, making interpretation difﬁcult [86]. Challenge studies of the serotonergic system are also difﬁcult to interpret. An infusion of the serotonin precursor tryptophan induced a normal prolactin response in panic patients, but a blunted response in major depression [87]. The same group [76:393] reported that prolactin responses to the serotonin
1c agonist m-chlorophenylpiperazine (mCPP) were normal in both conditions. Kahn etal. [88] found, however, that small doses of mCPP caused anxiety and, compared withnormals, heightened cortisol secretion in panic disorder, but not in major depression. The
authors interpreted their ﬁndings as evidence for postsynaptic serotonin oversensitivity inpanic disorder, but not in depression. Their study did not rule out a subsensitivity of theserotonergic system in depression. mCPP also caused transitory increases in obsessivecompulsive symptoms, without a differential effect on hormonal levels in patients withobsessive-compulsive disorder [89]. Since serotonin modulates areas of the brain that are
involved in anxiety and depression, one cannot conclude a common mechanism. Serotonin
may affect different brain functions in each disorder.
VII. CLINICAL PHARMACOLOGY
A discussion of the common pharmacological mechanisms of antidepressant and antianxiety response must begin with the caveat that the relationship between pharmacologicalmechanisms and etiology is likely to be indirect. Medications in the antidepressant classthat work both on anxiety and depression may begin to alter neurotransmission with theDepression and Anxiety: Common Etiology?

119

ﬁrst dose, while the therapeutic effect may not be evident for several weeks. In contrast,
medications that work immediately, such as benzodiazepines that act through the γ-aminobutyric acid (GABA) receptor to lower anxiety, particularly the physiological manifestations of anxiety, are generally not effective in the treatment of depression per se, except
by lowering anxiety in agitated depression [90]. Antidepressants that block the reuptakeof norepinephrine and serotonin reduce depression and block panic attacks, but have noacute effect on generalized anxiety [91,92]. Prolonged administration of norepinephrine
and/or serotonin reuptake inhibitors reduces panic attacks, possibly by inhibiting locus
coeruleus activity. However, only antidepressants with serotonin reuptake–inhibiting
properties reduce psychic symptoms, such as ruminations, in GAD [91,93], psychic symptoms in panic disorder [94,95], and obsessions and compulsions [96–98], possibly throughreduction of frontal lobe activity [99]. Not all antidepressants have anxiolytic effects. For
instance, buproprion, an antidepressant that may exercise its effects through the dopaminergic system, does not reduce panic attacks [100] nor has it been found useful in treatmentof other anxiety disorders.
Thus, some medications reduce anxiety without affecting depression. Some, but notall, antidepressants have in addition anxiolytic effects but they differ in their effectiveness.
Since antidepressants alter functions of various, but not necessarily the same, brain areas
their anxiolytic effects may be coincidental and cannot be taken as evidence of brain
mechanisms common to anxiety and depression.
The development and application of receptor-speciﬁc drugs will enhance our understanding of biological mechanisms of anxiety and depression. Clonidine, a fairly speciﬁc
α 2-noradrenergic agonist, for instance, blocks panic attacks and has a stabilizing effecton ﬂuctuations in anxiety. However, after an initially sedating effect, it has only a modest
effect on generalized anxiety and has no effect on depression [101]. Particularly interesting are drugs that affect speciﬁc serotonergic receptors. Although a general blockade ofserotonin reuptake suppresses panic attacks, relieves depression, decreases obsessivecompulsive symptoms, and, after prolonged administration, decreases psychic symptoms
of generalized anxiety, speciﬁc serotonin receptor agonists and antagonists have either
anxiety-inducing or anxiolytic [102] effects and may lower depression [103].
In summary, pharmacotherapeutic interventions suggest complex, but different,mechanisms for anxiety and depressive disorders. Moreover, mechanisms differ in subgroups of the disorders. Some symptoms of anxiety and depression are ameliorated by
the same medication. This may indicate overlapping mechanisms in certain disorders. On
the other hand, many drugs have a broad spectrum of actions and may affect several
independent mechanisms. Systematic investigations of the disorders with receptor-speciﬁc
drugs promise to widen our understanding of these disorders.
VIII. CONCLUSIONS
A survey of research ﬁndings linking anxiety and depression reveals some evidence ofcommon pathophysiology and some evidence of divergent pathophysiology. The pathophysiological relationship among depression and anxiety disorders varies by the anxiety
disorder. Some chronic anxiety disorders—especially phobias and generalized anxiety
disorder—are difﬁcult to differentiate from depressive disorders and thus in some instances may be variants of affective disorder. These disorders may, in a sense, converge to
a common etiology. Some anxiety disorders (e.g., panic disorder and obsessive compulsive
disorder) do not have signiﬁcant symptomatic overlap, but do have signiﬁcant comorbidity

120

MacKinnon and Hoehn-Saric

with affective disorders. These disorders may share some, but not all, biochemical or
physiological markers with affective disorders; thus they appear to be distinct disorders
but related at some unknown level. If they are related etiologically, it is likely to be via
a complex chain of causation with some links in common. One might conceive of thisrelationship as either parallel or intersecting, depending on whether the disorders arise
from common etiological elements or, alternatively, one disorder arises as a complicationof another.
What sort of conceptual model of brain function might account for this complex
picture of depression entwined with anxiety but in many details distinct from anxiety
disorders? The brain can be conceptualized as a multimodular system. These modules havedistinct functions, but being closely interconnected with other modules, their functions areconstantly modiﬁed. The clinical differences in anxiety and depressive disorders can be
explained by differences in the degree to which certain modules are pathologically affected
and inﬂuence other modules. Some modules may be activated only in anxiety disorders,
others only in depression, leading to “pure” disorders. However, in many subtypes ofanxiety or depressive disorders, modules activated in pure anxiety interact with those
activated in pure depression, leading to various types of anxiety-depressive disorders. This
interaction between modules may be caused by a genetic predisposition, as suggested byfamily studies. They may be caused by early environmental inﬂuence, particularly earlylife trauma, which affects cerebral response patterns, sometimes permanently, as seen inanimal models and in patients who have experienced severe trauma. In a more subtle way,these emotional patterns may manifest in “neurotic” individuals who respond with highdegrees of anxiety and depression when faced with everyday stressors. Certain severe
forms of one sort of disorder seem to recruit modules of another; thus patients with agitateddepression complain of anxious mood and restless energy, or patients with severe agoraphobic social avoidance may become constricted in behavior to the point of inertia resembling melancholia. Therefore, rather than search for a common etiology of anxiety anddepression, we need to search for the etiology of subgroups of anxiety and depressive
disorders and the effects of these disturbances on the biology of the brain with respect tothe interactions between modules.
REFERENCES
1. Lewis A. Melancholia: A clinical survey of depressive states. J Ment Sci 1934; 80:277–378.
2. Roth M, Mountjoy CQ, Caetano D. Further investigations into the relationship between depressive disorders and anxiety state. Pharmacopsychiatria 1982; 15:135–141.
3. Wetzler S, Katz MM. Problems with the differentiation of anxiety and depression. J Psychiatr
Res 1989; 23:1–12.
4. Rickels K, Schweizer E. The clinical course and long-term management of generalized anxiety disorder. J Clin Psychopharmacol 1990; 10:101S–110S.
5. Coryell W, Endicott J, Andreasen NC, Keller MB, Clayton PJ, Hirschfeld RM, Scheftner
WA, Winokur G. Depression and panic attacks: the signiﬁcance of overlap as reﬂected infollow-up and family study data. Am J Psychiatry 1988; 145:293–300.
6. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32:50–
55.
7. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62.
8. Hoehn-Saric R. Affective proﬁles of chronically anxious patients. Hillside J Clin Psychiatry
1983; 5:43–56.
9. Zinbarg RE, Barlow DH, Liebowitz M, Street L, Broadhead E, Katon W, Roy-Byrne P,Depression and Anxiety: Common Etiology?

10.
11.
12.
13.
14.

15.
16.
17.

18.

19.

20.
21.

22.

23.
24.
25.
26.
27.

28.

29.
30.

121

Lepine JP, Teherani M, Richards J. The DSM-IV ﬁeld trial for mixed anxiety-depression.
Am J Psychiatry 1994; 151:1153–1162.
Boulenger JP, Fournier M, Rosales D, Lavallee YJ. Mixed anxiety and depression: fromtheory to practice. J Clin Psychiatry 1997; 58(suppl 8):27–34.
Clayton PJ, Grove WM, Coryell W, Keller M, Hirschfeld R, Fawcett J. Follow-up and family
study of anxious depression. Am J Psychiatry 1991; 148:1512–1517.
Joffe RT, Bagby RM, Levitt A. Anxious and nonanxious depression. Am J Psychiatry 1993;
150:1257–1258.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
3rd ed. Washington, DC: APA Press, 1980.
Detre TP. Is the grouping of anxiety disorders in DSM-III based on shared beliefs or data?
In Tuma AH, Maser JD, eds. Anxiety and Anxiety Disorders. Hillsdale, NJ: Erlbaum, 1985:
783–786.
Tyrer P. Classiﬁcation of Neurosis. New York: Johns Wiley & Sons, 1989.
Kendell RE. The stability of psychiatric diagnosis. Br J Psychiatry 1974; 124:352–356.
Angst J, Vollrath M, Merikangas KR, Ernst C. Comorbidity of anxiety and depression in
the Zurich Cohort Study of Young Adults. In: Maser JD, Cloninger CR, eds. Comorbidityof Mood and Anxiety Disorders. Washington, DC: American Psychiatric Press, 1990:123–
138.
Pine DS, Cohen P, Gurley D, Brook J, Ma Y. The risk for early-adulthood anxiety anddepressive disorders in adolescents with anxiety and depressive disorders. Arch Gen Psychiatry 1998; 55:56–64.
Stein MB, Fuetsch M, Muller N, Hoﬂer M, Lieb R, Wittchen HU. Social anxiety disorderand the risk of depression: a prospective community study of adolescents and young adults.
Arch Gen Psychiatry 2001; 58:251–256.
Zimmerman M, McDermut W, Mattia JI. Frequency of anxiety disorders in psychiatric outpatients with major depressive disorder. Am J Psychiatry 2000; 157:1337–1340.
Leckman JF, Clubb MM, Pauls DL. Comorbidity of panic disorder and major depression:
A review of epidemiological and genetic data. In: Ballenger JC, ed. Clinical Aspects of Panic
Disorder. New York: Wiley-Liss, 1990:141–149.
Stang P, Wittchen HU, Ustun B, Walters EE, Kessler RC. Lifetime panic-depression comorbidity in the National Comorbidity Survey. Association with symptoms, impairment, courseand help-seeking. Br J Psychiatry 2000; 176:229–235.
Chen YW, Dilsaver SC. Comorbidity of panic disorder in bipolar illness: evidence from theEpidemiologic Catchment Area Survey. Am J Psychiatry 1995; 152:280–282.
Breslau N, Davis GC. Further evidence on the doubtful validity of generalized anxiety disorder. Psychiatry Res 1985; 16:177–179.
Noyes R. Comorbidity in generalized anxiety disorder. Psychiatr Clin North Am 2001; 24:
41–55.
Noyes R, Clarkson C, Crowe RR, Yates WR, McChesney CM. A family study of generalized
anxiety disorder. Am J Psychiatry 1987; 144:1019–1024.
Crowe RC, Pauls DL, Slymen DJ, Noyes R. A family study of anxiety neurosis. Morbidity
risk in families of patients with and without mitral valve prolapse. Arch Gen Psychiatry
1980; 37:77–79.
Cloninger CR, Martin RL, Guze SB. A blind follow-up and family study of anxiety neuroses:
Preliminary analysis of the St. Louis 500. In: Klein DF, Rabkin J, eds. Anxiety: New Research and Changing Concepts. New York: Raven Press, 1981:137–154.
Dealy RS, Ishiki DM, Avery DH, Wilson LG, Dunner DL. Secondary depression in anxiety
disorders. Compr Psychiatry 1981; 22:612–618.
Torgersen S. A twin-study perspective of the comorbidity of anxiety and depression. In:
Maser JD, Cloninger CR, eds. Comorbidity of Mood and Anxiety Disorders. Washington,
DC: American Psychiatric Press, 1990:367–378.

122

MacKinnon and Hoehn-Saric

31. Goodwin FK, Jamison KR. Manic Depressive Illness. New York: Oxford University Press,
1990.
32. Weissman MM, Wickramaratne P, Adams PB, Lish JD, Horwath E, Charney D, Woods SW,
Leeman E, Frosch E. The relationship between panic disorder and major depression. A new
family study. Arch Gen Psychiatry 1993; 50:767–780.
33. MacKinnon DF, McMahon FJ, Simpson SG, McInnis MG, DePaulo JR. Panic disorder withfamilial bipolar disorder. Biol Psychiatry 1997; 42:90–95.
34. Stoltenberg SF, Burmeister M. Recent progress in psychiatric genetics-some hope but nohype. Hum Mol Genet 2000; 9:927–935.
35. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR,
Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in theserotonin transporter gene regulatory region. Science 1996; 274:1527–1531.
36. Mazzanti CM, Lappalainen J, Long JC, Bengel D, Naukkarinen H, Eggert M, Virkkunen M,
Linnoila M, Goldman D. Role of the serotonin transporter promoter polymorphism inanxiety-related traits. Arch Gen Psychiatry 1998; 55:936–940.
37. Collier DA, Arranz MJ, Sham P, Battersby S, Vallada H, Gill P, Aitchison KJ, Sodhi M,
Li T, Roberts GW, Smith B, Morton J, Murray RM, Smith D, Kirov G. The serotonin transporter is a potential susceptibility factor for bipolar affective disorder. Neuroreport 1996; 7:
1675–1679.
38. Minov C, Baghai TC, Schule C, Zwanzger P, Schwarz MJ, Zill P, Rupprecht R, Bondy B.
Serotonin-2A-receptor and -transporter polymorphisms: lack of association in patients withmajor depression. Neurosci Lett 2001; 303:119–122.
39. Reiman EM, Raichle ME, Butler FK, Herscovitch P, Robins E. A focal brain abnormality
in panic disorder, a severe form of anxiety. Nature 1984; 310:683–685.
40. Nordahl TE, Stein MB, Benkelfat C, Semple WE, Andreason P, Zametkin A, Uhde TW,
Cohen RM. Regional cerebral metabolic asymmetries replicated in an independent group ofpatients with panic disorders. Biol Psychiatry 1998; 44:998–1006.
41. Harris GJ, Hoehn-Saric R, Lewis RB, Pearlson GD, Streeter C. Mapping of SPECT regional
cerebral perfusion abnormalities in obsessive-compulsive disorder. Human Brain Mapping
1994; 1:237–248.
42. Rauch SL, Savage CR, Alpert NM, Fischman AJ, Jenike MA. The functional neuroanatomyof anxiety: a study of three disorders using positron emission tomography and symptom
provocation. Biol Psychiatry 1997; 42:446–452.
43. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell
JL, Martin CC, Lancaster JL, Fox PT. Reciprocal limbic-cortical function and negative mood:converging PET ﬁndings in depression and normal sadness. Am J Psychiatry 1999; 156:
675–682.
44. Kennedy SH, Evans KR, Kruger S, Mayberg HS, Meyer JH, McCann S, Arifuzzman AI,
Houle S, Vaccarino FJ. Changes in regional brain glucose metabolism measured with positronemission tomography after paroxetine treatment of major depression. Am J Psychiatry 2001;
158:899–905.
45. Drevets WC. Prefrontal cortical-amygdalar metabolism in major depression. Ann NY Acad
Sci 1999; 877:614–637.
46. Mendlewicz J, Kerkhofs M. Sleep electroencephalography in depressive illness. A collaborative study by the World Health Organization. Br J Psychiatry 1991; 159:505–509.
47. Armitage R. Microarchitectural ﬁndings in sleep EEG in depression: diagnostic implications.
Biol Psychiatry 1995; 37:72–84.
48. Mellman TA, Uhde TW. Electroencephalographic sleep in panic disorder. A focus on sleeprelated panic attacks. Arch Gen Psychiatry 1989; 46:178–184.
49. Lydiard RB, Zealberg J, Laraia MT, Fossey M, Prockow V, Gross J, Ballenger JC. Electroencephalography during sleep of patients with panic disorder. J Neuropsychiatry Clin Neurosci
1989; 1:372–376.

Depression and Anxiety: Common Etiology?

123

50. Ferini-Strambi L, Bellodi L, Oldani A, Bertella S, Smirne S, Battaglia M. Cyclic alternating
pattern of sleep electroencephalogram in patients with panic disorder. Biol Psychiatry 1996;
40:225–227.
51. Lauer CJ, Krieg JC, Garcia-Borreguero D, Ozdaglar A, Holsboer F. Panic disorder and major
depression: a comparative electroencephalographic sleep study. Psychiatry Res 1992; 44:41–
54.
52. Arriaga F, Paiva T. Clinical and EEG sleep changes in primary dysthymia and generalized
anxiety: a comparison with normal controls. Neuropsychobiology 1990; 24:109–114.
53. Isotani T, Tanaka H, Lehmann D, Pascual-Marqui RD, Kochi K, Saito N, Yagyu T, Kinoshita
T, Sasada K. Source localization of EEG activity during hypnotically induced anxiety andrelaxation. Int J Psychophysiol 2001; 41:143–153.
54. Davidson RJ, Sutton SK. Affective neuroscience: the emergence of a discipline. Curr Opin
Neurobiol 1995; 5:217–224.
55. Christie MJ, Little BC, Gordon AM. Peripheral indices of depressive states. In: van Praag
HM, Lader MH, Raphaelson OJ, eds. Handbook of Biological Psychiatry. Part II: Brain
Mechanisms and Abnormal Behavior Psychophysiology. New York: Marcel Dekker, 1980:
145–182.
56. Papousek I, Schulter G. Associations between EEG asymmetries and electrodermal lability
in low vs. high depressive and anxious normal individuals. Int J Psychophysiol 2001; 41:
105–117.
57. Kopp M, Gruzelier J. Electrodermally differentiated subgroups of anxiety patients and controls. II: Relationships with auditory, somatosensory and pain thresholds, agoraphobic fear,
depression and cerebral laterality. Int J Psychophysiol 1989; 7:65–75.
58. Kano K, Nakamura M, Matsuoka T, Iida H, Nakajima T. The topographical features of EEGs
in patients with affective disorders. Electroencephalogr Clin Neurophysiol 1992; 83:124–
129.
59. Kentgen LM, Tenke CE, Pine DS, Fong R, Klein RG, Bruder GE. Electroencephalographic
asymmetries in adolescents with major depression: inﬂuence of comorbidity with anxiety
disorders. J Abnorm Psychol 2000; 109:797–802.
60. Papp LA, Klein DF, Martinez J, Schneier F, Cole R, Liebowitz MR, Hollander E, Fyer AJ,
Jordan F, Gorman JM. Diagnostic and substance speciﬁcity of carbon-dioxide-induced panic.
Am J Psychiatry 1993; 150:250–257.
61. Perna G, Bertani A, Arancio C, Ronchi P, Bellodi L. Laboratory response of patients withpanic and obsessive-compulsive disorders to 35% CO 2 challenges. Am J Psychiatry 1995;
152:85–89.
62. Buller R, von Bardeleben U, Maier W, Benkert O. Speciﬁcity of lactate response in panic
disorder, panic with concurrent depression and major depression. J Affect Disord 1989; 16:
109–113.
63. Targum SD. Differential responses to anxiogenic challenge studies in patients with major
depressive disorder and panic disorder. Biol Psychiatry 1990; 28:21–34.
64. Perna G, Barbini B, Cocchi S, Bertani A, Gasperini M. 35% CO 2 challenge in panic andmood disorders. J Affect Disord 1995; 33:189–194.
65. Kent JM, Papp LA, Martinez JM, Browne ST, Coplan JD, Klein DF, Gorman JM. Speciﬁcityof panic response to CO 2 inhalation in panic disorder: a comparison with major depression
and premenstrual dysphoric disorder. Am J Psychiatry 2001; 158:58–67.
66. Klein DF. False suffocation alarms, spontaneous panics, and related conditions. An integrative hypothesis. Arch Gen Psychiatry 1993; 50:306–317.
67. Gorman JM, Kent JM, Sullivan GM, Coplan JD. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry 2000; 157:493–505.
68. Kelly D. Anxiety and Emotions. Springﬁeld, IL: Charles C Thomas, 1980.
69. Gorman JM, Sloan RP. Heart rate variability in depressive and anxiety disorders. Am HeartJ 2000; 140:77–83.

124

MacKinnon and Hoehn-Saric

70. Lehofer M, Moser M, Hoehn-Saric R, McLeod D, Liebmann P, Drnovsek B, Egner S, Hildebrandt G, Zapotoczky HG. Major depression and cardiac autonomic control. Biol Psychiatry
1997; 42:914–919.
71. Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, Miller AH, Nemeroff CB.
Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abusein childhood. JAMA 2000; 284:592–597.
72. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotropin-releasing
factor in depression and anxiety disorders. J Endocrinol 1999; 160:1–12.
73. Golier J, Yehuda R. Neuroendocrine activity and memory-related impairments in posttraumatic stress disorder. Dev Psychopathol 1998; 10:857–869.
74. Steckler T, Holsboer F, Reul JM. Glucocorticoids and depression. Baillieres Best Pract Res
Clin Endocrinol Metab 1999; 13:597–614.
75. Lamberts SW. Neuro-endocrine aspects of the dexamethasone suppression test in psychiatry.
Life Sci 1986; 39:91–95.
76. Heninger GR. A biological perspective on comorbidity of major depressive disorders andpanic disorders. In: Maser JD, Cloninger CR, eds. Comorbidity of Mood and Anxiety Disorders. Washington, DC: American Psychiatric Press, 1990:381–401.
77. Bandelow B, Wedekind D, Pauls J, Broocks A, Hajak G, Ruther E. Salivary cortisol in panic
attacks. Am J Psychiatry 2000; 157:454–456.
78. Coplan JD, Goetz R, Klein DF, Papp LA, Fyer AJ, Liebowitz MR, Davies SO, Gorman JM.
Plasma cortisol concentrations preceding lactate-induced panic. Psychological, biochemical,
and physiological correlates. Arch Gen Psychiatry 1998; 55:130–136.
79. Tiller JW, Biddle N, Maguire KP, Davies BM. The dexamethasone suppression test andplasma dexamethasone in generalized anxiety disorder. Biol Psychiatry 1988; 23:261–270.
80. Gray TS. Amygdaloid CRF pathways. Role in autonomic, neuroendocrine, and behavioral
responses to stress. Ann NY Acad Sci 1993; 697:53–60.
81. Schulkin J, Gold PW, McEwen BS. Induction of corticotropin-releasing hormone gene expression by glucocorticoids: implication for understanding the states of fear and anxiety andallostatic load. Psychoneuroendocrinology 1998; 23:219–243.
82. Holsboer F, von Bardeleben U, Buller R, Heuser I, Steiger A. Stimulation response tocorticotropin-releasing hormone (CRH) in patients with depression, alcoholism and panic
disorder. Horm Metab Res Suppl 1987; 16:80–88.
83. Boyer P. Do anxiety and depression have a common pathophysiological mechanism? Acta
Psychiatr Scand 2000; (suppl 406):24–29.
84. Fossey MD, Lydiard RB, Ballenger JC, Laraia MT, Bissette G, Nemeroff CB. Cerebrospinal
ﬂuid corticotropin-releasing factor concentrations in patients with anxiety disorders and normal comparison subjects. Biol Psychiatry 1996; 39:703–707.
85. Posener JA, DeBattista C, Williams GH, Kraemer HC, Kalehzan BM, Schatzberg AF. 24hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major
depression. Arch Gen Psychiatry 2000; 57:755–760.
86. Murphy DL, Andrews AM, Wichems CH, Li Q, Tohda M, Greenberg B. Brain serotonin
neurotransmission: an overview and update with an emphasis on serotonin subsystem heterogeneity, multiple receptors, interactions with other neurotransmitter systems, and consequent
implications for understanding the actions of serotonergic drugs. J Clin Psychiatry 1998;
59(suppl)15:4–12.
87. Charney DS, Heninger GR. Serotonin function in panic disorders. The effect of intravenous
tryptophan in healthy subjects and patients with panic disorder before and during alprazolam
treatment. Arch Gen Psychiatry 1986; 43:1059–1065.
88. Kahn RS, Kalus O, Wetzler S, Cahn W, Asnis GM, van Praag HM. Effects of serotonin
antagonists on m-chlorophenylpiperazine-mediated responses in normal subjects. Psychiatry
Res 1990; 33:189–198.
89. Murphy DL, Zohar J, Benkelfat C, Pato MT, Pigott TA, Insel TR. Obsessive-compulsiveDepression and Anxiety: Common Etiology?

90.
91.

92.

93.

94.
95.
96.

97.

98.
99.
100.

101.
102.

103.

125

disorder as a 5-HT subsystem-related behavioural disorder. Br J Psychiatry 1989; (suppl 8):
15–24.
Schatzberg AF, Cole JO. Benzodiazepines in depressive disorders. Arch Gen Psychiatry
1978; 35:1359–1365.
Hoehn-Saric R, McLeod DR, Zimmerli WD. Differential effects of alprazolam and imipramine in generalized anxiety disorder: somatic versus psychic symptoms. J Clin Psychiatry
1988; 49:293–301.
Kahn RJ, McNair DM, Lipman RS, Covi L, Rickels K, Downing R, Fisher S, Frankenthaler
LM. Imipramine and chlordiazepoxide in depressive and anxiety disorders. II. Efﬁcacy inanxious outpatients. Arch Gen Psychiatry 1986; 43:79–85.
McLeod DR, Hoehn-Saric R, Porges SW, Kowalski PA, Clark CM. Therapeutic effects ofimipramine are counteracted by its metabolite, desipramine, in patients with generalized anxiety disorder. J Clin Psychopharmacol 2000; 20:615–621.
den Boer JA, Westenberg HG. Behavioral, neuroendocrine, and biochemical effects of 5hydroxytryptophan administration in panic disorder. Psychiatry Res 1990; 31:267–278.
Hoehn-Saric R, McLeod DR, Hipsley PA. Effect of ﬂuvoxamine on panic disorder. J Clin
Psychopharmacol 1993; 13:321–326.
Mavissakalian M, Jones B, Olson S, Perel JM. The relationship of plasma clomipramine andN-desmethylclomipramine to response in obsessive-compulsive disorder. Psychopharmacol
Bull 1990; 26:119–122.
Leonard HL, Swedo SE, Rapoport JL, Koby EV, Lenane MC, Cheslow DL, Hamburger SD.
Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children
and adolescents. A double-blind crossover comparison. Arch Gen Psychiatry 1989; 46:1088–
1092.
Pigott TA, Seay SM. A review of the efﬁcacy of selective serotonin reuptake inhibitors inobsessive-compulsive disorder. J Clin Psychiatry 1999; 60:101–106.
Hoehn-Saric R, Lipsey JR, McLeod DR. Apathy and indifference in patients on ﬂuvoxamineand ﬂuoxetine. J Clin Psychopharmacol 1990; 10:343–345.
Sheehan DV, Davidson J, Manschreck T, Van Wyck FJ. Lack of efﬁcacy of a new antidepressant (bupropion) in the treatment of panic disorder with phobias. J Clin Psychopharmacol
1983; 3:28–31.
Hoehn-Saric R, Merchant AF, Keyser ML, Smith VK. Effects of clonidine on anxiety disorders. Arch Gen Psychiatry 1981; 38:1278–1282.
Kahn RS. Serotonin in the pathogenesis of anxiety. In: Hoehn-Saric R, McLeod D, eds.
Biology of Anxiety Disorders: Recent Developments. Washington, DC: American Psychiatric Press, 1993:61–102.
Klieser E, Strauss WH. Study to establish the indication for the selective S2 antagonist
ritanserin. Pharmacopsychiatry 1988; 21:391–393.

6
Measurements of Depression
and Anxiety Disorders
SAENA ARBABZADEH-BOUCHEZ and JEAN-PIERRE LÉPINE
Hôpital Fernand Widal
Paris, France

The extensive use of standardized methods of evaluation and quantitative psychopathology
are relatively recent phenomena in psychiatry. The main goal of quantitative psychopathology is to standardize diagnostic categories in order to improve diagnostic accuracy andscreening of psychiatric cases, assessment of severity of symptoms or disorders, and evaluation of treatment effects.
Diagnostic categories are reliable to the extent that clinicians can agree with eachother on whether or not a given disorder is present in a patient. There are no absolute
criteria against which psychiatric diagnoses can be validated. Hence scientiﬁc progress in
psychiatry has been based on establishing a consensus among clinicians about the signs
and symptoms that constitute speciﬁc psychiatric disorders and operationalizing clinicalpractice. The need for diagnostic reliability is of particular importance in the follow-up
of patients in treatment, and to assure the homogeneity of patient populations in clinicalresearch.
The main sources of poor reliability for inter-rater evaluations are information variance (i.e., differences in the type or quantity of information obtained), interpretation variance (i.e., differences in interpretation of clinical information in terms of psychopathological signiﬁcance), and criteria variance (i.e., differences in the criteria used to deﬁne mental
disorders).
Structured and semistructured diagnostic instruments reduce the information variance by standardizing the information-gathering process. Interpretation variance is de127

128

Arbabzadeh-Bouchez and Lépine

creased by use of a detailed glossary of psychopathological terms along with the instrument, as well as extensive training of interviewers. Finally, explicit and standardized
diagnostic criteria diminish the criteria variance by use of a uniform set of criteria for agiven diagnosis.
There are two principal types of psychopathological evaluations: categorical anddimensional evaluations. Categorical assessments are qualitative assessments and establish
a category of diagnosis based on the presence or absence of certain attributes in a patient.
On the other hand, dimensional evaluations are quantitative and aimed at assessing theintensity of the disorder. The dimensional evaluation can assess several factors and is amore sensitive instrument in the evaluation of treatment effects. Categorical and dimensional assessments, although conceptually distinct, are not entirely separable. Between
these two classiﬁcation types, there is an ordinal classiﬁcation, using ordered sets of categories such as mild, moderate, and severe. Moreover, a cut-off point can be used withany continuous scale to indicate a threshold for a corresponding category.
The psychometric properties of psychiatric instruments can be considered under theheadings of reliability and validity. The reliability of an instrument refers to the reproducibility of measurements. A reliable instrument is one that reproduces the same results on
repeated administrations. The validity of an instrument is deﬁned as the extent to which
an instrument measures what it claims to measure.
In the following section, we will ﬁrst discuss categorical (diagnostic) instruments
mainly used in adult subjects to assess depression and anxiety disorders. Next, we turnto dimensional instruments providing an assessment of the severity of anxiety disorders
and depression.
I.

DIAGNOSTIC INSTRUMENTS FOR DEPRESSION
AND ANXIETY DISORDERS

All the instruments presented here provide diagnosis of depressive or anxiety disorders.
Most of them are clinician-administered interviews, requiring trained clinicians with agood knowledge of psychopathology. However, two of the interviews (CIDI and DIS) canbe administered by trained nonclinical or lay interviewers and are used in epidemiologicalstudies.
We will also present two primary care interviews that combine both self-report andfollow-up examination designed for use as screening instruments by nonpsychiatric physicians. All the instruments presented differ in the extent of their coverage of axis I disorders
and the degree of structure imposed. Some of them are wedded to one set of diagnostic
criteria, whereas others can generate diagnosis according to multiple types of criteria. Oneof the limitations of these interviews is that they are all time consuming and expensive,
especially those that should be administered by a clinician.
The Schedule for Affective Disorders and Schizophrenia (SADS) [1] was initiallydeveloped in an effort to reduce information variance in both the descriptive and diagnostic
evaluation of the subjects for the National Institute of Mental Health Clinical Research
Branch Collaborative Program on the Psychobiology of Depression. This instrument canbe used in clinical or nonclinical settings. SADS is a semistructured instrument, whichshould be administered by a clinician. It evaluates mental disorders according to the Research Diagnostic Criteria (RDC) [2] which is a precursor of DSM-III. The RDC covers
23 major diagnostic categories including mood disorders and anxiety disorders. The instru-

Measurements of Depression and Anxiety

129

ment consists of two sections: the ﬁrst covers the symptoms of current mental disorders
and the second covers the lifetime history of mental disorders before the year preceding theinterview. Individual symptoms and other aspects of current affective (mood) disorders,
psychotic disorders, and anxiety disorders are rated in detail in scales of severity. Symptoms are rated according to their most severe level during the current episode and at thelevel they were experienced in the week before the interview. Clinically signiﬁcant symptoms of lifetime disorders are rated as present or absent. The time required for administering the instrument is typically 1 to 3 h depending on the symptoms present. Different
versions of SADS include SADS-L (lifetime), SADS-LB (speciﬁcally intended to evaluate
bipolar disorders), and SADS-LA (anxiety disorders). It is important to note that this
instrument does not generate diagnoses according to the DSM-IV criteria; it seems to bevery useful in that it provides for (1) a detailed description of the features of the current
episodes of illness when they were at their most severe; (2) a description of the level ofseverity of manifestations of major dimensions of psychopathology during the week preceding the evaluation, which can be used as a measure of change; (3) a progression ofquestions and criteria, which provides information for making diagnoses; and (4) a detailed
description of past psychopathology and functioning relevant to an evaluation of diagnosis,
prognosis, and overall severity of disturbance. Test–retest reliability of summary scalescores from Part I of the SADS is good [3]. Test–retest reliability of disorders shows
good agreement (kappa ⬎ 0.65) for most disorders and subtypes of affective disorders.
Finally, SADS item and scale scores are shown to be sensitive to change in placebocontrolled medication studies.
The Structured Clinical Interview for DSM (SCID) [4] was initially developed toprovide a broad coverage of psychiatric diagnoses according to DSM. It was designed tobe more efﬁcient and simpler to use than other existing instruments and, consequently,
to require less time for training and administration.
SCID-I is a semistructured instrument that needs to be administered by a clinician
and generates diagnoses according to DSM-IV criteria. This instrument can be used withpsychiatric patients or with nonpatient community subjects who are undergoing evaluation
for psychopathology. SCID-I includes nine diagnostic modules: mood episodes, psychotic
symptoms, psychotic disorders differential, mood disorders differential, substance use,anxiety, somatoform disorders, eating disorders, and adjustment disorders. Two versionsof SCID are available: SCID-I (research version) [5] and SCID-CV (clinical version) [6].
The majority of diagnoses generated by this instrument are made on a lifetime (ever present) and current (meets diagnosis criteria in the past month) basis. This instrument also
allows evaluation of subthreshold diagnosis. The time required to administer the instrument can range from 1 to 3 h depending on the clinical symptoms of the subject.
The Schedules for Clinical Assessment in Neuropsychiatry (SCAN) [7] were developed internationally for the study of psychopathology. It forms the basis for collaborative
studies of the causes, risk factors, outcomes, and consequences of mental disorders. This
instrument is an outgrowth of the Present State Examination (PSE) [8], which was ﬁrst
developed in the early 1960s and has undergone nine revisions. Its purpose is to assess
the psychopathology and behavior associated with a broad range of major psychiatricdisorders in adult life. The SCAN can be used to make psychiatric diagnoses in clinicalsamples according to Diagnostic Criteria for Research (ICD-10-DCR), DSM-IV, and othersystems. It is important to note that this instrument can also provide dimensional ratingsof symptoms and syndromes that are not wedded to any single classiﬁcation or diagnostic

130

Arbabzadeh-Bouchez and Lépine

system. This instrument can be administered by interviewers who should be well trainedin assessing the signs and symptoms of psychopathology. It provides current and lifetime
diagnoses.
Several brief screens are available to help identify mental disorders in primary care.
In choosing among them, an investigator must consider the clinical research setting, thesampling framework, and the strategy used to assess the reliability and validity of the
instruments. We chose to describe here the PRIME-MD and the SDDS-PC that are often
used in primary care practice to screen patients for psychiatric symptoms.
PRIME-MD [9] is intended for use by general practitioners and is designed for the
diagnosis of mental disorders that are most commonly encountered in general practice. This
instrument was speciﬁcally designed for use by nonpsychiatric primary care physicians.
Because of its simplicity and efﬁciency, it can be used as a quick assessment tool for psychiatrists evaluating patients with anxiety, depression, or somatic symptoms. Its limitations
are that it covers only a few of the psychiatric diagnoses encountered in psychiatric settingsand it ignores certain aspects of the criteria for the disorders that it does cover, such as
impairment and differential diagnosis criteria. It consists of two sections: a 1-page patientquestionnaire, which is completed by the patient prior to seeing the physician and a 9-pageevaluation guide for the clinician, which is a structured interview. The Clinical Evaluation
Guide generates ﬁve types of diagnoses according to the DSM-IV criteria (mood, anxiety,alcohol use/abuse, eating disorders, and somatic disorders). The average time required foradministering PRIME-MD is typically less than 20 min. Spitzer and colleagues assessed thevalidity and utility of PRIME-MD [9] in a sample of 1000 adult patients assessed by 31
primary care physicians. In this study there was good agreement between PRIME-MD diagnoses and those of independent mental health professionals [for the diagnosis of any PRIMEMD disorder (kappa ⫽ 0.71; overall accuracy rate ⫽ 88%)]. The sensitivity of the PRIMEMD was very good for detecting any psychiatric diagnosis (0.83) and at least satisfactoryfor detecting any diagnosis with a particular diagnostic module.
The Symptom-Driven Diagnostic System for Primary Care (SDDS-PC) [10] wasdeveloped as a computerized instrument to improve diagnosis of mental disorders in primary care practice. It consists of three components: (1) a 29-item patient self-report screening questionnaire; (2) a diagnostic interview guide with six diagnosis modules plus a
module assessing suicide risk; and (3) a longitudinal tracking form. It provides diagnoses
according to the DSM-IV. The SDDS-PC is intended for use by primary care physicians
and nurse practitioners, with little or no speciﬁc training in its use. It takes approximately
5 min for patients to complete the screening form. Each diagnostic module can take between 5 and 10 min to administer.
This instrument has not been tested in mental health settings and has limited diagnostic coverage for general use in psychiatric practice. The SDDS-PC covers ﬁve disorders(major depression, panic disorder, alcohol abuse or dependence, generalized anxiety disorder, and obsessive-compulsive disorder, as well as suicidal ideation. Patients who screen
positive for a disorder receive the corresponding diagnostic interview module. Patients
who meet mental disorder criteria on the diagnostic interview module are then followedwith the longitudinal tracking form.
A cross-validation study was carried out by the instrument developers [11] andshowed an overall sensitivity for any disorder of 0.88 and a fair concordance (kappa ⫽0.47) between diagnoses of depressive disorders made by primary care physicians and
SCID diagnoses made by trained mental health interviewers. In this study, the kappa values

Measurements of Depression and Anxiety

131

ranged from 0.11 (generalized anxiety disorder) to 0.48 (suicidal ideation); the overall
kappa for any diagnosis was 0.50.
The Diagnosis Interview Schedule (DIS) [12] is a structured interview developedfor use by lay interviewers or clinicians in subjects in community or in clinical samples.
DIS generates current as well as lifetime diagnoses according to DSM-III criteria. DIS has
undergone several revisions. The fourth version, DIS-IV, generates diagnoses according to
DSM-IV criteria. DIS-IV also provides information about symptom duration, remission,and associated impairment and treatment received. This instrument is being used in a setof epidemiological studies sponsored by the National Institute of Mental Health Center
for Epidemiological Studies.
The DIS is the precursor to the Composite International Diagnostic Interview (CIDI)[13]. The latter was developed in order to allow evaluation of mental disorders in different
cultural settings and according to the International Classiﬁcation of Disease (ICD) andthe DSM criteria. The DIS has been revised several times, and the latest version, DIS-IV[14] yields diagnoses on the basis of DSM-IV diagnostic criteria. DIS-IV also provides
information about symptom duration, remission, and recency and about associated impairment and treatment received. The DIS begins with a demographic section, followed by
19 diagnostic modules, and concludes with an open-ended question the interviewer may
not have covered and a section for rating observations of the subject’s speech, affect, andbehavior. Additions made to version IV of the DIS have increased administration time toapproximately 90 to 120 min. This instrument has been administered to 220 psychiatricpatients by lay interviewers to compare the diagnoses obtained by the DIS to clinicaldiagnoses [15]. Kappas for agreement between DIS and chart diagnoses ranged from 0.39
to ⫺0.03 and averaged 0.14 for 13 diagnostic categories. Agreement was best for affective,obsessive-compulsive, and schizophrenic disorders and was poorest for phobias where
patients overemphasized fears.
The Composite International Diagnostic Interview (CIDI) [13] was designed at therequest of the World Health Organizations/US Alcohol, Drug Abuse, and Mental HealthAdministration Task Force on Psychiatric Assessment Instruments. This instrument combines questions from the DIS with questions designed to elicit PSE items.
The CIDI is a highly structured instrument, which can be administered by nonclinicians. It generates diagnoses according to the DSM-IV and ICD-10 criteria. Most of the
major ICD and DSM axis I diagnostic classes are addressed by the most recent CIDI
(version 2.1). The 11 diagnostic modules included in the CIDI roughly correspond to themodules that cover adult axis I disorders in the DIS, with some modest differences interminology and content. An alternative version of the CIDI was developed for use in the
National Comorbidity Survey (NCS) in the United States in the early 1990s. For both the
DIS and the CIDI, interviewers proceed through a series of questions formatted according
to a ﬂowchart. When the subject answers in the afﬁrmative a question about whether asymptom has ever been experienced, the interviewer asks whether the subject has (1) tolda doctor or other professional about the symptom; (2) taken medication for it; or (3) experienced signiﬁcant interference with life or activities as a result of it. The time required toadminister this instrument is approximately 75 min and its most recent version is CIDI 2.1
The Mini-International Neuropsychiatric Interview [16] is a short, structured diagnostic interview, developed jointly by psychiatrists and clinicians in the United States andFrance, for DSM-IV abd ICD-10 psychiatric disorders. With an administration time of
approximately 15 min, it was designed to meet the need for a short, but accurate, structured

132

Arbabzadeh-Bouchez and Lépine

psychiatric interview for multicenter clinical trials and epidemiological studies and to be
used as a ﬁrst step in outcome tracking in nonresearch clinical settings. The diagnoses
generated are lifetime and present. The disorders assessed by this instrument are mooddisorders, anxiety disorders, eating disorders, and psychotic disorders.
The Newcastle Diagnostic Scales [17] for affective disorders include several short,
10-item scales useful for the assessment of depressed patients. One of the ﬁrst scales
published was designed to make the difference between endogenous and exogenous depression through a structured interview. The same year (1965) the authors published another scale designed to predict the response to electroconvulsive therapy. These two scales
have only two items in common, which assess anxiety and weight loss. These scales areeasy to administer and their reliability is good. They are designed to be completed by apsychiatrist but short training could allow family practitioners to use of these scales. Davidson et al. [18] assessed the validity and the reliability of this instrument. Good interrater reliability was obtained for diagnostic category and for item scores in 36 patients.
The scale showed construct validity with reference to the Hamilton and Montgomery–
Asberg rating scales. Concurrent validity was shown relative to other diagnostic scalesof endogenous depression.
Several diagnostic instruments not covered in this chapter have been designed speciﬁcally for use in special patient populations. The Diagnostic Interview for Genetic Studies (DIGS) [19] is a comprehensive and lengthy instrument designed as a diagnostic assessment tool in genetic studies. For patients with anxiety disorders, the Anxiety Disorders
Interview Schedule (ADIS-R) [20] provides DSM diagnosis of anxiety disorders by DSM
criteria, with additional coverage of mood, somatoform, and substance abuse disorders.
II. DIMENSIONAL ASSESSMENT OF ANXIETY
There are two main types of instruments for dimensional assessment of anxiety, namely,
self-evaluation scales (designed to be completed by the subject) and hetero-evaluation
scales (intended for use by an interviewer).
A.

Self-Assessment Scales for Anxiety

The main categories of self-assessment scales used in the evaluation of anxiety are scales
assessing general psychopathology including anxiety, such as the General Health Questionnaire (GHQ) [21,22] the Symptom Check List-90 Revised (SCL-90R) [23], and theBrief Symptom Inventory (BSI) [24]; scales assessing the general anxiety (e.g., the Beck
Anxiety Inventory [25], and the Hospital Anxiety and Depression (HAD) [26] and, ﬁnally,
scales assessing speciﬁc dimensions of anxiety such as the Fear Questionnaire [27] andthe Penn State Worry Questionnaire (PSWQ) [28].
B.

General Psychopathology Scales Assessing Anxiety

In this chapter we are going to examine the most commonly used measures of general
psychiatric symptoms. These scales are intended as screening instruments to identify individuals likely to have psychopathology, not as speciﬁc diagnostic measures to identify
particular axis I disorders. These instruments also focus on the impact of the psychopathology on the individual’s ability to function. The GHQ assesses levels of mental health ingeneral clinical practice, the SCL-90-R goes further in assessing speciﬁc symptoms with

Measurements of Depression and Anxiety

133

nine symptom constructs. Finally, the BSI is a multidimensional symptom inventory derived for brevity from the SCL-90-R.
The GHQ [21,22] was developed to evaluate the psychological components of ill
health, assessing the subject’s ability to carry out daily functions. This measure is notdesigned for psychiatric diagnosis but rather as a screening device. It may be seen as
a complement to a formal psychiatric interview. This instrument is a self-administeredquestionnaire that takes 3 to 15 min to complete.
There are four versions of the GHQ, which include 60, 30, 28, or 12 items, respectively. The GHQ-28 is a scaled version of the GHQ designed on the basis of resultsfrom principal components analysis, indicating a total score with four subscales: somatic
symptoms (scale A), anxiety/insomnia (scale B), social dysfunction (scale C), and severe
depression (scale D). These subscales are dimensions of symptomatology rather than distinct diagnosis.
The GHQ is highly acceptable to the general population, as evidenced by its frequent
use in large-scale surveys in clinical and nonclinical settings. This instrument has beenused most commonly to estimate the prevalence, presentation, detection, and outcome ofpsychiatric disorders among primary care attenders.
The SCL-90-R [23] is a 90-item self-administrated questionnaire assessing the discomfort created by each symptom during the past week. This instrument contains only
minor revisions from the SCL-90 that are the replacement of two items and minor changes
to seven other items. The SCL-90-R is constituted by nine symptom constructs: somatization, obsessive-compulsive symptoms, interpersonal sensitivity, depression, anxiety, hostility, phobic-anxiety, paranoid ideation, and psychoticism. It takes about 12 to 20 min tocomplete. This instrument can be used as a screening instrument of global psychologicaldistress and as a multidimensional measure of symptom proﬁles. This instrument is often
used in randomized clinical trials assessing antidepressants and anxiolytics, and also inclinical studies evaluating anxiety and depressive disorders. Schmitz et al. [29] investigated the screening properties of the GHQ-12 and the SCL-90-R in a primary care settingin Germany. A randomly selected sample (n ⫽ 408) of adult outpatients from 18 primarycare ofﬁces was screened using the German versions of the GHQ-12 and the SCL-90-R.
A structured diagnostic interview (SCID) and an impairment rating (IS) were used as agold standard to which both questionnaires were compared. There was no difference inthe performance of the general scores of the two questionnaires. Both instruments wereable to detect cases. Analyses conﬁrmed that the SCL-90-R subscales “anxiety” and “depression” showed acceptable concurrent validity for the diagnostic groups anxiety anddepression (according to DSM-III-R). In this study, GHQ-12 and SCL-90-R appeared to
be useful tools for identifying mental disorders in primary care practice and research.
The Brief Symptom Inventory (BSI) [24] is derived from the SCL-90-R. This instrument is a multidimensional symptom inventory designed to assess the psychological symptom patterns of respondents in the community, medical, and psychiatric settings. The BSI
is a 53-item form of the SCL-90-R requiring 8 to 10 min to be completed. It reﬂects
psychopathology and psychological distress in terms of the same nine symptom dimensions of the SCL-90-R. The BSI may be used as a single, one-time assessment of thepatient’s clinical status. It may also be used repeatedly to document formal outcomes orquantify pre- and post-treatment responses. This instrument is therefore useful both inscreening primary care patients and in planning treatment and evaluating outcome.
Collectively, the sum of studies using the BSI demonstrates the instruments to be

134

Arbabzadeh-Bouchez and Lépine

broadly sensitive to the manifestations of psychological distress and interventions acrossa wide range of contexts.
C.

Scales Assessing General Anxiety

Principal instruments providing broad coverage of anxiety symptomatology are describedin this part. Usually, these instruments are used in situations in which a clinician does
not want to assess a speciﬁc type of anxiety disorder or in patients with clinically signiﬁcant anxiety that falls below the minimum threshold set by the anxiety disorder criteria.
These broader measures should not be confused, as they often are, with measures of generalized anxiety disorder, which is a speciﬁc DSM diagnosis.
HADS [26] is 14-item self-report scale originally designed to screen for the presenceof a mood disorder in medically ill patients. Seven items of the instrument assess anxiety
and seven items assess depression. Factor analysis of the instrument has revealed that allseven items assessing depression correspond to a single factor (depression factor), whereas
the items assessing anxiety correspond to two factors—motor anxiety and psychologicalanxiety. This instrument is a good screening device for the presence of depressive disorderin nonpsychiatric populations.
Zigmond and Snaith [26] found item-total correlations (r) ranging from 0.30 to 0.60
in 50 patients in a general outpatient clinic. An exploratory factor analysis of the HAD
was carried out in 568 cancer patients by Moorey et al. [30]. Two distinct, but correlated,factors emerged that corresponded to the questionnaire’s anxiety and depression subscales.
The factor structure proved stable when subsamples of the total sample were investigated.
The internal consistency of the two subscales was also high. The validity of this instrument
was assessed in adolescents by White et al. [31].
The HADS was given to 248 schoolchildren, to 48 psychiatric outpatients, and to
38 deliberate self-harm inpatients aged 12 to 17, and validated against ICD-10 diagnoses
for the outpatients. In this study, the HADS has adequate test–retest reliability and factor
structure, and discriminates between adolescents diagnosed with depressive or anxiety
disorders and those without these diagnoses.
Finally, the construct validation of the Hospital Anxiety and Depression Scale wasassessed with clinical populations by Johnston et al. [32]. Data from patients with breastdisease, myocardial infarction, and stroke were examined using factor analytic and psychometric analyses. The HADS showed high levels of internal consistency and there waslittle evidence that removing items would improve it.
The Beck Anxiety Inventory (BAI) [25] assesses anxiety, with a focus on somatic
symptoms. This instrument was speciﬁcally developed to discriminate between anxiety
and depression. The BAI is a 21-item self-report questionnaire assessing symptoms ofanxiety such as nervousness, inability to relax, dizziness or light-headedness, and heart
pounding or racing. Patients record how much they have been bothered by each symptom
during the past week, including the day the questionnaire was administered. It takes approximately 5 min to complete this instrument. This questionnaire is a reliable and wellvalidated measure of somatic anxiety symptoms found across anxiety disorders and also
in depression. However, it is important to note that this instrument does not assess worry,
which is an important symptom in the GAD, nor does it focus on the other DSM-IV
symptoms of this speciﬁc anxiety disorder. Moreover, BAI does not discriminate well
between speciﬁc anxiety disorders.
The Beck Anxiety Inventory was administered to 105 outpatients who were diag-Measurements of Depression and Anxiety

135

nosed with various types of psychiatric disorders by Steer et al. [33]. A principal factor
analysis was performed, and two factors were found to represent subjective and somatic
symptoms of anxiety. Results of this study supported the use of the inventory for evaluating self-reported anxiety in outpatients adolescents.
D. Instruments Assessing Speciﬁc Dimensions of Anxiety
The Fear Questionnaire [27] is a self-report instrument developed to assess the severityof common phobias (mainly agoraphobia, social phobia, and blood-injury phobia) andassociated anxiety and depression. The FQ agoraphobia and social phobia subscales may
be useful as brief screening instruments for symptoms of agoraphobia and social phobia.
Cox et al. [34] conducted a conﬁrmatory factor analysis using the Fear Questionnaire
responses of 122 social phobia patients. The results indicated that the proposed three-factor
model of the scale (agoraphobia, social phobia, and blood/injury dimensions) provided agood ﬁt of data. These data provided strong support for the validity of the scale.
The Penn State Worry Questionnaire (PSWQ) [28] was designed to assess trait
symptoms of pathological worry. This instrument was created to assess the tendency ofan individual to worry, and the tendency for the worrying to be generalized and not restricted to one or a small number of situations. The PSWQ is a 16-item self-report questionnaire assessing the frequency and intensity of worry symptoms. It takes approximately
5 min to complete this instrument. The PSWQ showed good convergence with other measures of worry in nonclinical populations. The use of this instrument is recommended asa measure of severity of pathological worry and change. It may be useful as a screening
tool to detect pathological worry, but it cannot be used to diagnose generalized anxiety
disorder in nonclinical populations because worry could be related to many disorders
besides generalized anxiety disorder.
Brown et al. [35] assessed the psychometric properties and utility of the PSWQ ina clinical sample of 436 anxiety disorders patients and 32 normal controls. Factor analysis
indicated that the PSWQ assesses a unidimensional construct. Furthermore, the PSWQ
evidenced quite favorable internal consistency using GAD patients and each of the otheranxiety disorder groups and normal controls. The validity of the PSWQ was supported
by an analysis indicating that the measure distinguished GADs from each of the otheranxiety disorder groups including those with obsessive-compulsive disorder. Collectively,
the ﬁndings speak favorably to the PSWQ in research examining the nature and treatmentof GAD and the processes of normal and pathological worry.
E.

Hetero-Evaluation Scales Assessing Anxiety

The Hamilton Anxiety Rating Scale (HARS) [36] is a 14-item clinician-administered rating scale providing an overall measure of global anxiety, including psychic (cognitive)
and somatic symptoms. The symptoms assessed are anxious mood, tension, fear, insomnia,
intellectual (cognitive) symptoms, depressed mood, behavior at interview, somatic (sensory) symptoms, cardiovascular symptoms, respiratory symptoms, gastrointestinal symptoms, genitourinary symptoms, autonomic symptoms, and somatic (muscular) symptoms.
It takes approximately 15 to 30 min to administer this instrument. The HARS can be used
to assess the severity of overall anxiety in patients meeting criteria for anxiety or depressive disorders but this instrument does not distinguish symptoms of a speciﬁc anxiety
disorder or distinguish an anxiety disorder from an anxious depression.
The Tyrer’s Brief Scale for Anxiety [37] is a 10-item clinician-administered scale

136

Arbabzadeh-Bouchez and Lépine

designed to assess anxiety among mentally ill patients. This instrument is derived fromthe CPRS (Comprehensive Psychopathological Rating Scale) [38], which assesses general
psychopathology.
This instrument includes 10 speciﬁc items for generalized anxiety; eight items correspond to reported symptoms and two to the observed ones. The cognitive symptoms ofanxiety are assessed by four items, whereas the somatic symptoms of anxiety are assessedby ﬁve items. It takes approximately 15 min to complete this instrument. This instrument
has been used in pharmacological trials assessing the efﬁcacy of anxiolytic drugs.
The Association for Methodology and Documentation in Psychiatry (AMDP-System) [39] is composed of two parts: a part on history data (AMDP-1 to ⫺3) and a parton the present psychiatric and somatic state (AMDP-4 and ⫺5). The psychopathology
scale contains 100 items ⫹ 15 “French” items (mainly on anxiety); the somatic scale, 40⫹ 7 items, all graded from 0 to 4. The interview and the completion of the two scales
take approximately 45 to 60 min. Presently there are two systems derived from the AMDP:
one for gerontopsychiatry (the AGP System) and one for forensic psychiatry (the FPDS
System).
Gebhardt et al. [40] carried out a study assessing the validity of the syndrome scales
in the AMDP-system. In order to assess this validity, various diagnostic groups as deﬁned
by the ICD were described by these scales and distinguished from each other by discriminant analyses. As a comparison, the same diagnostic groups were distinguished using the
syndrome scales of the AMP system. The analyses using the AMDP system were performed in a sample of 659 patients of the Psychiatric Clinic of the Free University of
Berlin during 1979 to 1980, the analyses with the AMP system in a sample of 2269
patients of the same clinic during the period 1971 to 1976. It could be shown that different
endogenous and organic psychoses as well as neuroses can be described in their psychopathology and discriminated from each other by means of the syndrome scales of the AMDP
system. The validity of the syndrome scales in relation to this criterion could be proved.
Moreover, a high similarity between the results with the AMDP system and the resultswith the AMP system was found, which demonstrates that the two systems compare well.
III. INSTRUMENTS FOR THE EVALUATION OF SPECIFICANXIETY DISORDERS
Use of different scales allows better appreciation of the various clinical dimensions of a
speciﬁc anxiety disorder. For panic disorders, the available instruments include the PanicAssociated Symptom Scale [41], the Panic Disorder Severity Scale (PDSS) [42], and Anxiety Sensitivity Index (ASI) [43]. For social phobia, the available instruments include Liebowitz Social Anxiety Scale (LSAS) [44], the Brief Social Phobia Scale (BSPS) [45], andthe Social Phobia and Anxiety Inventory (SPAI) [46]. For obsessive-compulsive disorders,the available scales include: the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) [47],and The Leyton Obsessional Inventory [48], and the Mausley Obsessional Compulsive
Inventory [49]. Finally, instruments assessing the post-traumatic stress disorder that we
describe in this chapter are Impact of Event Scale (IES) [50], the Mississippi Scale (MSS)[51], the Clinician-Administered PTSD Scale (CAPS) [52], and the Posttraumatic Stress
Diagnostic Scale (PDS) [53].
A.

Instruments Assessing Panic Disorder and Agoraphobia

The Panic-Associated Symptom Scale (PASS) [41] is a 14-item self-rating scale with a
0 to 3 scoring. The 14 items assess several panic attack symptoms and the patient is asked

Measurements of Depression and Anxiety

137

to determine the severity of each symptom during the worst moment of the panic attack.
This instrument is frequently used in studies comparing patients with panic disorder interms of clinical features and outcome.
The Panic Disorder Severity Scale (PDSS) [42] is a clinician-administered instrument developed to provide a simple way of measuring the overall severity of DSM-IV
panic disorder. This instrument consists of seven items assessing panic frequency, distressduring panic, panic-focused anticipatory anxiety, phobic avoidance of situations, phobic
avoidance of physical sensations, impairment in work functioning, and impairment insocial functioning. It takes between 5 to 10 min to complete the PDSS. This instrument
is useful in assessing overall panic disorder severity at baseline, and it provides a proﬁleof severity of the different panic disorder symptoms. It is important to note that the PDSS
is not a diagnostic instrument; it could be used to monitor the outcome of panic disorderspeciﬁcally.
Shear et al. [54] assessed reliability and validity of the PDSS and tried to provide
an estimate of a cut-off score discriminating the presence or absence of current DSM-IV
panic disorder, and to determine the factor structure of the instrument. One-hundred-four
psychiatric outpatients, including 54 with current panic disorder, underwent structured
diagnostic assessment and the PDSS interview. The PDSS was repeated within 3 to 17
days. The reliability and the validity of the PDSS were conﬁrmed and a one-factor solution
ﬁt the data. A cut-off score of eight identiﬁes patients with current panic with a sensitivityof 83.3% and a speciﬁc of 64%.
The Panic and Agoraphobia Scale [55] was developed to assess the degree of severity of these disorders after a diagnosis has been made according to the criteria of the
DSM-III-R/IV or the ICD-10. This instrument was specially developed for use in clinicaldrug trials. Factors that impair the quality of life in panic disorder and agoraphobia patients(panic attacks, phobic avoidance, anticipatory anxiety, impairment in social relationships
and work, assumption of somatic disease) were considered in the development of thisscale so that the efﬁcacy of a certain drug therapy on each of these factors can be assessed
separately. It takes few minutes to complete this instrument. The PAS is a useful tool forassessing the severity of PDA.
The Anxiety Sensitivity Index (ASI) [43] assesses fear of anxiety symptoms or consequences, evaluating the degree to which individuals interpret symptoms of anxiety as
threatening. This instrument is a 16-item self-report questionnaire that could be used asa measure of symptom type and severity at baseline, and a clinical outcome measure inpatients with panic disorder. Although the ASI is not a diagnostic measure, this instrument
could be used to distinguish patients with panic disorder from patients with other anxiety
disorders.
Since the development of the 16-item Anxiety Sensitivity Index ASI, there has been
considerable controversy in the literature about whether it should be conceptualized as an
unidimensional or multidimensional measure. ASI responses were collected by Cox et al.
[56] from 216 panic disorder patients and 365 undergraduate students. Conﬁrmatory factor
analysis results for both the patient and student data strongly supported the view that the
ASI is a multidimensional measure.
The Mastery of Your Anxiety and Panic II [57] is a method for recording selfmonitored panic attacks. Any panic attacks had to be recorded as soon as the attacks
are over providing measure of frequency, intensity, and duration of panic episodes. This
instrument could be used as the main outcome measure in studies of panic disorder. Panic
frequency data can be collected over any speciﬁed period, although a minimum of 2 weeks
is recommended to establish a baseline for the panic attack.

138

Arbabzadeh-Bouchez and Lépine

The Mobility Inventory for Agoraphobia (MI) [58] is a self-report questionnaire
designed to assess the frequency of panic attacks and the severity of agoraphobic avoidance behavior both in situations where the patient is accompanied by a trusted companion
and where the patient is alone. It takes about 20 min to complete this instrument. The MIseems to be the best available measure of agoraphobic avoidance to data.

B.

Instruments Assessing Social Phobia

The Liebowitz Social Anxiety Scale [44] is a clinician-administered semistructured interview designed to assess the social phobia as determined by DSM-IV criteria. The LSAS
includes 24 items, 13 describing performance situations and 11 describing social interactional situations. The LSAS yields four subscales: fear-social, avoidance-social, fear-performance, and avoidance-performance. It takes approximately 15 to 20 min to complete
this instrument. The Liebowitz scale covers a broad range of potentially fearful situations.
Heimberg et al. [59] assessed the reliability, validity, and treatment sensitivity of
the Liebowitz Social Anxiety Scale. Three hundred and eighty-two patients from several
studies of the treatment of social phobia were evaluated. An independent assessor administered the LSAS to each patient prior to the initiation of treatment. Patients also completed
other measures of social anxiety and avoidance, although the speciﬁc measures varied
across the samples. The LSAS and its subscales were normally distributed and demonstrated excellent internal consistency. The convergent validity of the LSAS was demonstrated via signiﬁcant correlations with other commonly used measures of social anxiety
and avoidance. These correlations also tended to be larger than correlations with measuresof depression, especially after treatment. However, the pattern of correlations of LSAS
subscales with one another and with the other measures suggest that the fear subscales
and the avoidance subscales may not be sufﬁciently distinct in clinical samples. The LSAS
was also demonstrated to be sensitive to the effects of pharmacological treatments of social
phobia over time. In conclusion, the LSAS appeared to be a reliable, valid, and treatmentsensitive measure of social phobia.
The Brief Social Phobia Scale (BSPS) [60] is a semistructured instrument assessing
severity and treatment response in social phobia as deﬁned by DSM criteria. The BSPS
consists of 11 items. The ﬁrst seven items assess the severity of avoidance for each of
the following situations: public speaking, talking to people in authority, talking to strangers, being embarrassed or humiliated, being criticized, social gatherings, and doing something while being watched. The second part contains four items assessing physiologicalsymptoms (i.e., blushing, trembling, palpitations, and sweating) experienced by the patient
while being confronted with the social situations. It takes approximately 10 to 15 min tocomplete this instrument. The BSPS should not be used as a diagnostic instrument. It does
not provide information about the duration of social phobia symptoms or the degree of
distress or interference they cause. Finally, this instrument demonstrates acceptable interrater and test–retest reliability, internal consistency, concurrent validity against other measures of social phobia, and the ability of patients to change as a result of treatment. It canalso detect differences between active treatment and placebo treatment.
Davidson et al. [45] assessed the psychometric properties of the BSPS in a sample
of social phobia patients. The results yielded a high level of reliability and validity. Test–
retest reliability was excellent, as was internal consistency. The fear and avoidance subscales demonstrated highly signiﬁcant correlations with remaining items totals; however,the physiological subscale did not. The BSPS also demonstrated signiﬁcant relationships

Measurements of Depression and Anxiety

139

with other established scales that assess anxiety and disability, and it proved sensitive totreatment effects in a trial of 5-HT3 antagonist and placebo.
The Social Phobia and Anxiety Inventory [46] is a self-report questionnaire assessing speciﬁcally social phobia as deﬁned in DSM. This instrument is composed of two
subscales that are the 32-item social phobia scale and the 13-item agoraphobia scale.
Twenty-one of the 32 social phobia items assess the degree of distress in different social
settings. Other social phobia items assess the degree to which respondents experiencesomatic and cognitive symptoms in social situations. Average administration time is between 20 and 30 min.
Beidel et al. [61] examined the correlation of the SPAI with daily social behavior ofa clinic sample of social phobics. The results indicated that the SPAI provides a reasonableindication of the distress experienced during daily social encounters in three dimensions:behavior, cognitions, and overall distress. They also examined the validity of the SPAI
with reference to the somatic response and avoidance behavior of social phobics. The
results indicated that the somatic items of the SPAI are related to the somatic responseof social phobics and that performance of the SPAI is associated with avoidance behavior
in an anxiety-producing task.
C. Instruments Assessing the Obsessive-Compulsive Disorders
The Yale-Brown Obsessive Compulsive Scale [47] was designed to remedy the problemsof existing rating scales by providing a speciﬁc measure of the severity of symptoms ofobsessive-compulsive disorder that is not inﬂuenced by the type of obsessions or compulsions present. This instrument measures the severity of obsessive-compulsive symptoms
in patients with obsessive-compulsive disorder. Both obsessions and compulsions are rated
in terms of time spent, interference with functioning, distress, resistance, and control. This
instrument is a clinician-administered interview, divided into two subscales: the obsessions
subscale and the compulsions subscale. It takes approximately 10 to 15 min to administer
the Y-BOCS.
The Y-BOCS is currently a standard for the assessment of obsessive-compulsive
symptoms. It provides a good measure of overall obsessive-compulsive disorder severity
and it is well suited for assessing changes with treatment. It can be used as a screening
instrument, but it is not a diagnostic instrument because it does not speciﬁcally assess
whether the diagnostic criteria for DSM-IV obsessive-compulsive disorder are met or not.
Goodman et al. [47] assessed the validity of the Y-BOCS and its sensitivity tochange. Convergent and discriminant validity were examined in baseline ratings fromthree cohorts of patients with obsessive-compulsive disorder (n ⫽ 81). The total YaleBrown Scale score was signiﬁcantly correlated with two of three independent measuresof obsessive-compulsive disorder and weakly correlated with measures of depression andanxiety in patients with obsessive-compulsive disorder with minimal secondary depressive
symptoms. These results indicate that this is a reliable and valid instrument for assessing
obsessive-compulsive disorder symptom severity.
The Leyton Obsessional Inventory [48] is a 69-item self-administered instrument
designed to assess obsessive and compulsive symptoms among patients. First, the subject
must answer each item, checking the presence or absence of obsessive or compulsive
symptoms. Then the patient is asked to choose answers regarding the interference of thesymptoms with daily life and the degree of the patient’s resistance to each symptom. This
instrument is often used in clinical settings, but it cannot be used as a screening instrument
or in epidemiological studies.

140

Arbabzadeh-Bouchez and Lépine

The Leyton Obsessional Inventory was administered to 73 obsessive-compulsive
patients by Murray et al. [62] and their responses were compared with those of 100 normal
subjects. The ratio of the mean patient to normal scores ranged from 2.4 :1 for obsessional
traits and 3.2 :1 for symptoms to 6.2 :1 for resistance and 12.5:1 for interference withother activities. A principal components analysis on the patients’ replies produced three
unitary components (household order, personal contamination, and doubting plus two bipolar components (checking/parsimony and desire for closure/unpleasant ruminations).
These components appeared to be quite stable and have also been identiﬁed in normal
subjects, suggesting that obsessional neurotics differ from normal subjects quantitatively
rather than qualitatively.
The Maudsley Obsessional Compulsive Inventory (MOCI) [49] is a 30-yes/no-item
instrument assessing obsessional and compulsive symptoms such as checking, cleaning,
slowness, and doubting. The psychometric characteristics and relationship among the Leyton Obsessional Inventory, the MOCI, and the Y-BOCS were examined in a sample of
30 obsessive-compulsive patients diagnosed using a structured interview [63]. The majority of the subscales of the various measures were found to have a good internal consistency
across gender and the mean scores were similar to those reported in other studies.
D.

Instruments Assessing the Post-Traumatic Stress Disorder (PTSD)

The Impact of Event Scale (IES) [50] is a 15-item self-report questionnaire originallydeveloped to measure the psychological response to speciﬁc traumatic stressors or stressful
life events. More precisely, it was intended to capture symptoms of intrusion and avoidance. Clinical, ﬁeld, and experimental studies of potentially stressful life events give concordant ﬁndings: there is a general human tendency to undergo episodes of intrusive thinking and periods of avoidance. The IES can be employed with any stressful life events.
This instrument is composed of two scales, the 7-item intrusion subscale and the 8-item
avoidance subscale. Respondents rate how frequently they experienced each of the 15 IES
symptoms during the prior 7 days on a 4-point scale. It is important to notice that the IES
does not assess hyperarousal symptoms (e.g., irritability and exaggerated startle response)that are part of the DSM-IV diagnostic criteria for post-traumatic stress disorder. It takes
about 5 to 10 min to administer the IES. Although the IES is not a diagnostic instrument,
it provides a brief, reliable, assessment of intrusion and avoidance symptoms associatedwith post-traumatic stress disorder.
Sundin and Horowitz [64] reviewed studies that evaluated the psychometric properties of the IES. The results indicate that the IES’s two-factor structure is stable over different types of events, that it can discriminate between stress reactions at different times
after the event, and that it has convergent validity with observer-diagnosed post-traumaticstress disorder. The use of IES in many psychopharmacological trials and outcome studies
is supportive of the measure’s clinical relevance.
The Mississippi Scale (MSS) [51] is a 35-item self-report assessing the severity of
trauma-related symptoms on the basis of the DSM-III criteria for post-traumatic stressdisorder. It takes 5 to 20 min to complete the MSS. This instrument seems to be a useful
self-report measure of baseline post-traumatic stress disorder principal symptoms. It is
important to note that the MSS is not a diagnostic measure but provides an assessmentof the severity of this speciﬁc anxiety disorder.
Lauterbach et al. [65] assessed the psychometric properties of the Civilian Mississippi Posttraumatic Stress Disorder Scale. The Mississippi is internally consistent (alphaMeasurements of Depression and Anxiety

141

approximately ⫽ 0.89, split-half r approximately ⫽ 0.80), and it can discriminate between
traumatized and nontraumatized respondents. However, its relationship with measures of
PTSD was weaker than its relationship with measures of depression and anxiety, suggesting that it may be more of a general measure of distress.
The Clinician-Administered PTSD Scale [52] is a structured interview assessing thetype and severity of DSM-III-R Post-traumatic stress disorder symptoms. The CAPS consists of 17 interviewer-rated items that cover the principal symptoms of PTSD according
to the DSM criteria, which are reexperiencing the traumatic event, presence of intrusive
thoughts, ﬂashbacks, distressing dreams, avoidance of stimuli related to the trauma, numbing of general responsiveness, efforts to avoid trauma-related thoughts or situations, andrestricted affect and increased arousal with sleep problems, irritability and hypervigilance.
It takes approximately 45 to 60 min to administer this instrument. This scale could be
used as a diagnostic instrument, as a measure of baseline severity of post-traumatic stressdisorder and as a treatment outcome measure.
The Posttraumatic Stress Diagnostic Scale (PDS) [53] is a 49-item self-report scale
developed to provide a reliable DSM-IV diagnosis of post-traumatic stress disorder andfor quantifying the symptom severity. The score provides a proﬁle of diagnosis, symptom
severity, symptom description, and level of impairment. It takes 10 to 15 min to complete
this instrument.
IV. INSTRUMENTS ASSESSING DEPRESSION
The goal of assessing depression is to measure the severity of depressive symptoms interms of both the severity of individual symptoms and the total number of depressive
symptoms that have been present. Most of the depressive self-rating scales could be usedas screens and can indicate the presence of depressive symptoms. However, unless thescreens were used in a patient with an earlier determined diagnosis of depressive disorder,
the clinician would still need to completely assess the patient before diagnosing depressive
disorder.
A. Self-Assessment Scales
The Beck Depression Inventory (BDI) [66] is a self-administered instrument developed
to assess the behavioral manifestations of depression. This instrument provides a standardized assessment of depression severity in patients with previously diagnosed depressive
illness. The BDI is one of the most used self-rating scales for measuring depression. A
second use of the BDI is to screen patients who may have depressive illness and may
require intervention, but in this case, the BDI should be followed up with a diagnostic
instrument or a clinical interview. It takes 5 to 10 min to complete the BDI. Richter et
al. [67] discussed validity aspects of the BDI on the basis of meta-analyses of studies on
the psychometric properties. Shortcomings of the BDI are its high item difﬁculty, lack ofrepresentative norms, and thus doubtful objectivity of interpretation, controversial factorial
validity, instability of scores over short time intervals (over the course of 1 day), and poor
discriminant validity against anxiety. Advantages of the inventory are its high internalconsistency, high content validity, validity in differentiating between depressed and nondepressed subjects, sensitivity to change, and international propagation.
The Center for Epidemiologic Studies Depression Scale (CES-D) [68] is a 20-item
self-report instrument developed in order to measure symptoms of depression in commu-

142

Arbabzadeh-Bouchez and Lépinenity populations. This instrument has also been used in many studies as a screen for thepresence of depressive illness. The items assess the depressed mood, feelings of worthlessness, feelings of hopelessness, loss of appetite, poor concentration, and sleep disturbance. The scale does not include items for increased appetite or sleep, anhedonia, psychomotor agitation or retardation, guilt or suicidal thoughts.
Weissman et al. [69] presented data from psychiatric populations and a community
sample on the CES-D. Results showed that the scale is a sensitive tool for detecting depressive symptoms and change in symptoms over time in psychiatric populations, andthat it agreed quite well with more lengthy self-report scales used in clinical studies andwith clinician interview ratings. Although a symptom scale cannot differentiate between
diagnostic groups, the CES-D has demonstrated its validity as a screening tool for detecting depressive symptoms in psychiatric populations.
The Zung Self-Rating Depressive Scale (Zung SDS) [70] is a 20-item self-report
instrument providing a measure of depression severity. Items are selected to tap affective,
cognitive, behavioral, and physical aspects of depression. Although there is coverage formost DSM-IV symptom criteria, there is no item assessing psychomotor retardation or
symptoms that are more common in atypical depressions such as increased appetite, weight
gain, or hypersomnia.
Biggs et al. [71] assessed the validity of the ZSDS. This instrument correlated well(0.69) with the treating physician’s global rating in 26 depressed outpatients during the
6 weeks of treatment with a tricyclic antidepressant. In a larger sample of 41 patients, ahigh correlation was found between the ZSDS and the Hamilton Rating Scale. The sensitivity of the ZSDS was found to be adequate. The scale was able to differentiate, at the
0.05 level, four severity groups classiﬁed on the basis of the global rating. This study
indicated that the ZSDS is a valid and sensitive measure of clinical severity in depressed
patients and supported its continued use as a research instrument.
This self-administered Beﬁndlichkeits-Skala (BFS) [72] includes 28 pair of antonymous adjectives designed to assess mood. The BFS provides an assessment of mood variations. For each adjective pair, the patient is asked to choose between three answers. This
scale is easy to complete and is not time consuming. It could be easily used in clinicalsettings.
B.

Hetero-Evaluation Scales

The Hamilton Rating Scale for Depression (Ham-D) [73] is a 17-item interviewer-administered scale providing an assessment of the severity of depressive symptoms in patientswith primary depressive illness. This instrument is also useful for monitoring changes in
depressive symptoms with treatment. The Ham-D is probably the most commonly used
observer-rated depressive symptom rating scale. It takes about 15 to 20 min to administer
the Ham-D. It is important to note that because this instrument was developed before the
DSM-III and the Research Diagnostic Criteria, it does not include symptoms like anhedonia, and reverse neurovegetative symptoms (oversleeping and overeating), and thus may
underestimate depressive severity in patients with atypical features. Several other versionsof this instrument (21 items, 23 items, and 26 items) are also available.
Ratings of 54 English and 52 Swedish patients on a 65-item comprehensive psychopathology scale were used to identify the 17 most commonly occurring symptoms in primary depressive illness in the combined sample. Ratings on these 17 items for the patients
participating in studies of four different antidepressant drugs were used to create a depres-Measurements of Depression and Anxiety

143sion scale consisting of the 10 items that showed the largest changes with treatment andthe highest correlation to overall change. This new scale was the Montgomery-Asberg
Depression Ratings Scale (MADRS) [74].
MADRS is a 10-item interviewer-administered scale designed to assess the overall
severity of depressive symptoms in patients with depressive disorder. The main goal ofthis instrument is to assess treatment changes with good sensitivity. It takes approximately
15 min to administer the MADRS. The inter-rater reliability of this scale is high. Scoreson the scale correlate signiﬁcantly with scores on a standard rating scale for depression,
the Hamilton Rating Scale for Depression (Ham-D), indicating its validity as a generalseverity estimate. Its capacity to differentiate between responders and nonresponders toantidepressant treatment is better than the Ham-D, indicating greater sensitivity to change.
Davidson et al. [75] assessed the reliability and the validity of the MADRS in 44
depressed inpatients. All items on the scale occurred frequently in the sample; the scale
exhibited construct validity (internal homogeneity) and concurrent validity relative to the
Hamilton Depression Scale and the concepts of endogenous and nonendogenous depression. Sleep disturbance, reduced appetite, and suicidal thoughts correlated poorly with theremainder of the scale. Finally, inter-rater reliability was demonstrated between a psychiatrist and a nurse on individual item and total scores.
The Scale of Psychomotor Retardation [76] assesses only one dimension of depression, that is, psychomotor retardation, whereas most of the instruments provide an assessment of several dimensions of this mood disorder. This interviewer-rated 14-item instrument describes the motor, verbal, hedonic, and cognitive behavior of the depressed patient.
This scale could be used in assessing the efﬁcacy of antidepressant drugs.
The CORE system [77] is an 18-item clinician-rated instrument assessing psychic
and motor signs in depressed patients. Retardation, agitation, and lack of interaction are
the three main dimensions of the CORE System. Each item is scored 0 to 3, with a total
score of 54. A single cut off score of 8 is used to allocate patients to either a “melancholic”
or “nonmelancholic” class.
The Bech-Rafaelsen Melancholia Scale [78] is an 11-item interviewer-administeredinstrument providing an assessment of cognitive and somatic symptoms in depressed patients. This scale is derived from the Hamilton 17-item scale and from the CronholmOttoson Depression Scale. This instrument should be administered at a precise time, inthe morning, between 8:00 and 9:30 am. It takes approximately 15 to 30 min to complete
this instrument. The Bech-Rafaelsen Melancholia Scale seems to be a good instrument
in assessing the depressive disorder, among in- or outpatients. It could also be used inpharmacological and epidemiological studies. It is important to note that even though thename of this scale refers to melancholia, this instrument could be used among patientswith minor, nonmelancholic depression.
Finally, depression scales developed for use in special populations are also available.
We are going to describe one scale usually used in postpartum women, one used in elderly
people, and one used in schizophrenic patients.
The Edinburgh Postnatal Depression Scale [79] was designed to identify patientswith postpartum depression. This instrument is a 10-item self-report questionnaire providing a probable diagnosis of depression on the basis of Research Diagnostic Criteria (RDC).
It takes approximately 10 min to complete this instrument. This scale seems to be well
accepted and it appears to be helpful for aiding general practitioners in detecting major
and minor depressive disorder occurring in the postpartum period. It also has the advantagethat many usual somatic features in postpartum women, including changes in sleep and144

Arbabzadeh-Bouchez and Lépine

energy, are not scored as pathological. In addition to performing as a screening tool, theEPDS measures the severity of depression.
The Geriatric Depression Scale (GDS) [80] was developed to assess depression in
geriatric populations. Most of the currently available symptom scales were developed andvalidated in samples of medically healthy younger adults. However, it is important to
notice that sleep difﬁculties, decreased energy, and decreased libido are frequently foundin nondepressed elderly persons. Thus, there is a need to use a different set of symptom
descriptors when assessing depression in geriatric populations. In constructing the GDS,
a 100-item questionnaire was administered to normal and severely depressed subjects.
The 30 questions most highly correlated with the total scores were then selected andreadministered to new groups of elderly subjects. These subjects were classiﬁed as normal,
mildly depressed, or severely depressed on the basis of Research Diagnostic Criteria(RDC). The GDS, Ham-D, and SDS are all found to be internally consistent measures,and each of the scales was correlated with the subject’s number of RDC symptoms.
The GDS was designed to provide a reliable screening test for depression that would
be easy to score and simple to administer. The items reﬂect a variety of symptoms relevant
to depression, including lowered mood, poor self-image, poor motivation, past versus
future orientation, cognitive problems, obsessive traits, and agitation. This instrument isa 30-item self-report scale used to screen for depressive illness in geriatric patients andalso used to assess the severity of depression for monitoring change over time or withtreatment. The authors suggest that the GDS represents a reliable and valid self-rating
depression screening scale for elderly populations.
Lyons et al. [81] assessed the reliability, validity, and temporal stability of the Geriatric Depression Scale (GDS) in 69 elderly patients who underwent surgery for broken
hips. The GDS demonstrated internal consistency, reliability, and concurrent validity with
the Hamilton Depression Rating Scale. In addition, the GDS was stable across the hospital
stay and thus appeared to be less inﬂuenced by the patients’ acute health status.
The Calgary Depression Scale for Schizophrenia (CDSS) [83] was developed toassess symptoms of major depressive disorder in patients with schizophrenia. Rating scales
developed to assess depressive symptoms have questionable validity in schizophrenic patients. The CDSS proposes to address this problem. This instrument consists of nine items:
depressed mood, hopelessness, self-deprecation, guilty ideas of reference, pathologicalguilt, depression worse in the morning, early wakening, suicide, and observed depression.
The items on the CDSS are all typical depressive symptoms and do not appear to overlap
with the negative symptoms of schizophrenia. These items are selected from the Hamilton
Depression Rating Scale and the Present State Examination. The time frame is typically
2 weeks prior to the interview. It takes 15 to 20 min to administer this instrument. The
CDSS is potentially useful in screening patients with schizophrenia to identify those withpossible major depressive disorder. This instrument is also useful in monitoring the response of depressive symptoms to treatment.
V.

CONCLUSION

The ﬁrst step when choosing an instrument in psychopathology is to determine whether
one intends to use the instrument for diagnosis or to evaluate the severity of a given
disorder. If the main aim of the evaluation is diagnosis, a categorical instrument is suitable.
On the other hand, if the severity of the disorder is being assessed, a dimensional instrument is appropriate. Next, one must consider who will administer the instruments. Certain

Measurements of Depression and Anxiety

145

instruments can only be used by psychiatrists or clinical psychologists (e.g., SADS),
whereas others (e.g., CIDI or DIS) can be used by trained lay interviewers.
Clinical studies, including randomized controlled trials, often rely on specialized
instruments that can only be administered by psychiatrists or clinical psychologists. Epidemiological studies, however, make use of instruments that can be used by trained lay
interviewers. Finally, some instruments are particularly suitable for screening of patientsin the primary care setting (PRIME-MD).
In case of dimensional evaluations, certain instruments are intended for evaluationof general psychopathology, including anxiety (e.g., GHQ, SCL90R), whereas others assess only general anxiety (e.g., BAI, HAD). Another group of instruments evaluate speciﬁc
dimensions of general anxiety (e.g., Fear Questionnaire, PSWQ). A ﬁnal group of dimensional instruments (e.g., PASS, PDSS, Y-BOCS) assess speciﬁc anxiety disorders suchas panic disorder or obsessive-compulsive disorder.
The use of standardized instruments in clinical practice can improve the collection,
synthesis, and reporting of information as compared with the use of unstructured clinicalexaminations. Standardized assessments can ensure that relevant topics are covered inappropriate depth and decrease the likelihood of omitting important domains of information. These instruments also allow categorization and quantiﬁcation of symptoms according to an agreed-upon system and provide consistency of assessments across examiners.
REFERENCES
1. Endicott J, Spitzer RL. A diagnostic interview: the Schedule for Affective Disorders andSchizophrenia. Arch Gen Psychiatry 1978; 35(7): 837–844.
2. Spitzer RL, Endicott J, Robins E. Research Diagnostic Criteria: Biometrics Research. New
York: New York State Psychiatric Institute, 1978.
3. Andreasen NC, Grove WM, Shapiro RW, Keller MB, Hirschfeld RM, McDonald-Scott P.
Reliability of lifetime diagnoses. A multicenter collaborative perspective. Arch Gen Psychiatry
1981; 38(4): 400–405.
4. Spitzer RL, Williams JB, Gibbon M, First MB. The Structured Clinical Interview for DSM
III R (SCID). I: History, rationale, and description. Arch Gen Psychiatry 1992; 49(8): 624–
629.
5. First MB, Spitzer RL, Williams JBW, et al. Structured Clinical Interview for DSM IV (SCIDI) (User’s Guide and Interview) Research Version. New York: New York Psychiatric Institute,
1995.
6. First MB, Spitzer RL, Williams JBW, et al. Structured Clinical Interview for DSM IV-Clinician Version (SCID-CV) (User’s Guide and Interview). Washington, DC: American Psychiatric Press, 1997.
7. Wing JK, Babor T, Brugha T, Burke J, Cooper JE, Giel R, Jablenski A, Regier D, Sartorius
N. SCAN: Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 1990;
47(6): 589–593.
8. Wing JK, Cooper JE, Sartorius N. The measurement and Classiﬁcation of Psychiatric Symptoms. London: Cambridge University Press, 1974.
9. Spitzer RL, Williams JB, Kroenke K, Linzer M, deGruy FV 3rd, Hahn SR, Brody D, Johnson
JG. Utility of a new procedure for diagnosing mental disorders in primary care. The PRIMEMD 1000 study. JAMA 1994; 14; 272(22): 1749–1756.
10. Olfson M, Leon AC, Broadhead WE, Weissman MM, Barrett JE, Blacklow RS, Gilbert TT,
Higgins ES. The SDDS-PC: a diagnostic aid for multiple mental disorders in primary care.
Psychopharmacol Bull 1995; 31(2): 415–420.

146

Arbabzadeh-Bouchez and Lépine

11. Weissman MM, Olfson M, Leon AC, Broadhead WE, Gilbert TT, Higgis ES, Barrett JE,
Blacklow RS, Keller MB, Hoven C. Brief diagnostic interviews (SDDS-PC) for multiple mental disorders in primary care. A pilot study. Arch Fam Med 1995; 4(3): 220–227.
12. Robins LN, Helzer JE, Croughan J, Ratcliff KS. National Institute of Health Diagnostic Interview Schedule. Its history, characteristics, and validity. Arch Gen Psychiatry 1981; 38(4):381–389.
13. Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF, Burke J, Farmer A, Jablenski A,
Pickens R, Regier DA, et al. The Composite International Diagnostic Interview. An epidemiologic instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Arch Gen Psychiatry 1988; 45(12): 1069–1077.
14. Robins LN, Marcus L, Reich W, et al. Diagnostic Interview Schedule, Version IV. St Louis,
MO: Washington School of Medicine, 1996.
15. Erdman HP, Klein MH, Greist JH, Bass SM, Bires JK, Machtinger PE. A comparison of the
Diagnostic Interview Schedule and clinical diagnosis. Am J Psychiatry 1987; 144(11): 1477–
1480.
16. Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker
R, Dunbar GC: The Mini-International Neuropsychiatric Interview (MINI): the development
and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin
Psychiatry 1998; 59(20): 22–33.
17. Carney MWP, Roth M, Garside RF. The diagnosis of depressive syndromes and the predictionof ECT response. Br J Psychiatry 1965; 111:659–674.
18. Davidson J, Strickland R, Turnbull C, Belyea M, Miller RD. The Newcastle Endogenous
Depression Index: validity and reliability. Acta Psychiatr Scand 1984; 69(3): 220–230.
19. Nurnberger JI, Jr, Blehar MC, Kaufmann CA, York-Cooler C, Simpson SG, Harkavy-Friedman J, Severe JB, Malaspina D, Reich T. Diagnostic interview for genetic studies. Rationale,unique features, and training. NIMH Genetics Initiative. Arch Gen Psychiatry 1994; 51(11):849–859.
20. Di Nardo P, Moras K, Barlow DH, Rapee RM, Brown TA. Reliability of DSM-III-R anxiety
disorder categories. Using the Anxiety Disorders Interview Schedule-Revised (ADIS-R). ArchGen Psychiatry 1993; 50(4): 251–256.
21. Goldberg DP. The detection of psychiatric illness by questionnaire. Oxford, England: Oxford
University press, 1972.
22. Goldberg DP, Williams P. User’s guide to the General Health Questionnaire. Berkshire, England: Nfer-Nelson, 1991.
23. Derogatis LR. SCL-90-R (revised) Version Manual I. Baltimore, MD: Johns Hopkins University School of Medicine, 1977.
24. Derogatis LR, Melisaratos N: The Brief Symptom Inventory: an introductory report. Psychol
Med 1983; 13(3): 595–605.
25. Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988; 56(6): 893–897.
26. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand
1983; 67(6): 361–370.
27. Marks IM, Mathews AM. Brief Standard self-rating for phobic patients. Behav Res Ther 1979;
17(3): 263–267.
28. Meyer TJ, Miller ML, Metzger RL, Borkovec TD. Development and validation of the Penn
State Worry Questionnaire. Behav Res Ther 1990; 28(6): 487–495.
29. Schmitz N, Kruse J, Heckrath C, Alberti L, Tress W. Diagnosing mental disorders in primarycare: the General Health Questionnaire (GHQ) and the Symptom Check List (SCL-90-R) as
screening instruments. Soc Psychiatry Epidemiol 1999; 34(7): 360–366.
30. Moorey S, Greer S, Watson M, Gorman C, Rowden L, Tunmore R, Robertson B, Bliss J. The
factor structure and factor stability of the Hospital Anxiety and Depression Scale in patientswith cancer. Br J Psychiatry 1991; 158: 255–259.

Measurements of Depression and Anxiety

147

31. White D, Leach C, Sims R, Atkinson M, Cottrell D. Validation of the Hospital Anxiety andDepression Scale for use with adolescents. Br J Psychiatry 1999; 175: 452–454.
32. Johnston M, Pollard B, Hennessey P. Construct validation of the Hospital Anxiety and Depression Scale with clinical populations. J Psychosom Res 2000; 48(6): 579–584.
33. Steer RA, Kumar G, Ranieri WF, Beck AT. Use of the Beck Anxiety Inventory with adolescent
psychiatric outpatients; Psychol Rep 1995; 76(2): 459–465.
34. Cox BJ, Parker JD, Swinson RP. Conﬁrmatory factor analysis of the Fear Questionnaire withsocial phobia patients. Br J Psychiatry 1996; 168(4): 497–499.
35. Brown TA, Antony MM, Barlow DH. Psychometric properties of the Penn State Worry Questionnaire in a clinical anxiety disorders sample. Behav Res Ther 1992; 30(1): 33–37.
36. Hamilton M. The Assessment of anxiety states by rating. Br J Med Psychol 1959; 32, 50–
55.
37. Tyrer P, Owen RT, Ciccheti DV. The Brief scale for anxiety: a subdivision of the comprehensive psychological rating scale. J Neurol Neurosurg Psychiatry 1984; 47(9): 970–975.
38. Asberg M, Montgomery SA, Perris C, Shalling D, Sedvall G. A comprehensive psychopathological rating scale. Acta Psychiatr Scand 1978; (suppl 271): 5–27.
39. Bobon DP, ed. Le Système AMDP. Collection Psychologie Sciences Humaines, 2nd ed. Liège:
Mardaga, 1981.
40. Gebhardt R, Pietzcker A. Validity of the syndrome scales in the AMDP-system. Arch Psychiatr
Nervenkr 1983; 233(6): 509–523.
41. Argyle N, Deltito J, Allerup P, Maier W, Albus M, Nutzinger D, Rasmussen S, Ayuso JL,
Bech P. The Panic-Associated Symptom Scale: measuring the severity of panic disorder. Acta
Psychiatr Scand 1991; 83(1):20–26.
42. Shear MK, Brown TA, Barlow DH, Money R, Scholomskas DE, Woods SW, Gorman JM,
Papp LA. Multicenter collaborative panic disorder severity scale. Am J Psychiatry 1997;
154(11): 1571–1575.
43. Reiss S, Peterson RA, Gursky DM, McNally RJ. Anxiety sensitivity, anxiety frequency andthe prediction of fearfulness. Behav Res Ther 1986; 24(1): 1–8.
44. Liebowitz MR. Social phobia. Mod Probl Pharmacopsychiatry 1987; 22: 141–173.
45. Davidson JR, Miner CM, De Veaugh-Geiss J, Tupler LA, Colket JT, Potts NL. The Brief
Social Phobia Scale: a psychometric evaluation. Psychol Med 1997; 27(1): 161–166.
46. Turner SM, Beidel DC, Dancu CV, Stanley MA. An empirically derived inventory to measuresocial fears and anxiety: the Social Phobia and Anxiety Inventory. Psychol Assess 1989; 1:
35–40.
47. Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR, Charney DS.
The Yale-Brown Obsessive-Compulsive Scale. I and II. Arch Gen Psychiatry 1989; 46(11):1006–1016.
48. Cooper J. The Leyton obsessional inventory. Psychol Med 1970; 1(1): 48–64.
49. Hodgson RJ, Rachman S. Obsessional-compulsive complaints. Behav Res Ther 1977; 15(5):389–395.
50. Horowitz M, Wilner N, Alvarez W. Impact of Event Scale: a measure of subjective stress.
Psychosom Med 1979; 41(3): 209–218.
51. Keane TM, Caddell JM, Taylor KL. Mississippi Scale for Combat-Related PosttraumaticStress Disorder: three studies in reliability and validity. J Consult Clin Psychol 1988; 56(1):85–90.
52. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, Keane TM.
The development of a Clinician–Administered PTSD Scale. J Trauma Stress 1995; 8(1): 75–
90.
53. Foa EB, Cashman L, Jaycox L et al. The validation of the self-report measure of posttraumatic stress disorder: the Post-traumatic Diagnostic Scale. Psychol Assess 1997; 9: 445–
451.
54. Shear MK, Rucci P, Williams J, Frank E, Grochocinski V, Vanjer BJ, Houck P, Wang T.

148

55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.

70.
71.
72.

73.
74.
75.
76.
77.
78.
79.

Arbabzadeh-Bouchez and Lépine
Reliability and validity of the panic disorder severity scale: replication and extension. J
Psychiatr Res 2001; 35(5):293–296.
Bandelow B. Assessing the efﬁcacy of treatments for panic disorder and agoraphobia. II. The
Panic and Agoraphobia Scale. Int Clin Psychopharmacol 1995; 10(2): 73–81.
Cox BJ, Parker JD, Swinson RP. Anxiety sensitivity: conﬁrmatory evidence for a multidimensional construct. Behav Res Ther 1996; 34(7): 591–598.
Rapee RM. A case of panic disorder treated with breathing retraining. J Behav Ther Exp
Psychiatry 1985; 16(1): 63–65.
Chambless DL, Caputo GC, Jasin SE, Gracely EJ, Williams C. The Mobility Inventory for
Agoraphobia. Behav Res Ther 1985; 23(1): 34–44.
Heimberg RG, Horner KJ, Juster HR, Safren SA, Brown EJ, Schneier FR, Liebowitz MR.
Psychol Med. 1999; 29(1): 199–212.
Davidson JR, Potts NL, Richichi EA, Ford SM, Krishnan KR, Smith RD, Wilson W. The
Brief Social Phobia Scale. J Clin Psychiatry 1991; 52(suppl): 48–51.
Beidel DC, Borden JW, Turner SM, Jacob RG. The Social Phobia and Anxiety Inventory:
concurrent validity with a clinical sample. Behav Res Ther 1989; 27(5): 573–576.
Murray RM, Cooper JE, Smith A. The Leyton Obsessional Inventory: an analysis of the responses of 73 obsessional patients. Psychol Med 1979; 9(2): 305–311.
Richter MA, Cox BJ, Direnfeld DM. A comparison of three assessment instruments for obsessive-compulsive symptoms. J Behav Ther Exp Psychiatry 1994; 25(2): 143–147.
Sundin EC, Horowitz MJ. Impact of Event Scale: psychometric properties. Br J Psychiatry
2002; 180: 205–209.
Lauterbach D, Vrana S, King DW, King LA. Psychometric properties of the civilian versionof the Mississippi PTSD Scale. J Trauma Stress 1997; 10(3): 499–513.
Beck AT, Ward CH, Mendelson M et al. An inventory of measuring depression. Arch Gen
Psychiatry 1961; 4: 53–63.
Richter P, Werner J, Heerlein A, Kraus A, Sauer H. On the validity of the Beck Depression
Inventory. A review. Psychopathology 1998; 31(3): 160–168.
Radloff LS. The CES-D scale: a self report depression scale for research in the general population, Appl Psychol Meas 1977; 1: 385–401.
Weissman MM, Sholomskas D, Pottenger M, Prusoff BA, Locke BZ. Assessing depressive
symptoms in ﬁve psychiatric populations: a validation study. Am J Epidemiol 1977; 106(3):203–214.
Zung WWK. A self-rating depression scale. Arch Gen Psychiatry 1965; 12: 63–70.
Biggs JT, Wylie LT, Ziegler VE. Validity of the Zung Self-Rating Depression Scale. Br J
Psychiatry 1978; 132: 381–385.
von Zerssen D, Koeller DM, Rey ER. A scale for the objective evaluation of the state ofsubjective well-being as a method for longitudinal studies. Arzneimittelforschung 1970; 20(7):915–918.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiat 1960; 23: 56–62.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br
J Psychiatry 1979; 134: 382–389.
Davidson J, Turnbull CD, Strickland R, Miller R, Graves K. The Montgomery-Asberg Depression Scale: reliability and valdity. Acta Psychiatr Scand 1986; 73(5): 544–548.
Widlocher D. Psychomotor retardation: clinical, theoretical, and psychometric aspects. Diagnosis and treatment of affective disorders. Psychiatric Clin North Am 1983; 6(1): 27–40.
Parker G, Hadzi-Pavlovic D. Melancholia: a disorder of movement and mood. Cambridge:
University Press, 1996.
Bech P, Rafaelsen OJ. The use of rating scale exampliﬁed by a comparison of the Hamilton
and the Bech-Rafaelsen melancholia scale. Acta Psychiatr Scand 1980; 285(62): 128–131.
Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10item Edinburg Postnatal Depression Scale. Br J Psychiatry 1987; 150: 782–786.

Measurements of Depression and Anxiety

149

80. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, Leirer VO. Development andvalidation of a geriatric depression screening scale: a preliminary report, J Psychiatr Res 1982–
1983; 17(1): 37–49.
81. Lyons JS, Strain JJ, Hammer JS, Ackerman AD, Fulop D. Reliability, validity, and temporalstability of the Geriatric Depression Scale in hospitalized elderly. Int J Psychiatry Med 1989;
19(2): 203–209.
82. Addington D, Addington J, Schissel B. A depression rating scale for schizophrenics. Schizophr
Res 1990; 3(4): 247–251.

7
Combining Psychotherapy andPharmacotherapy for Depression
and Anxiety
ROBERT H. HOWLAND and MICHAEL E. THASE
University of Pittsburgh School of Medicine
Western Psychiatric Institute and Clinic
Pittsburgh, Pennsylvania, U.S.A.

I.

INTRODUCTION

Depressive and anxiety disorders are clinically and neurobiologically heterogeneous conditions [1,2]. One consequence of heterogeneity is that it is implausible that a single typeof treatment will be universally effective. Because depression and anxiety often occur attimes of grief or life stress; affect how the sufferer feels about his or her self, world, past,and future; and disproportionately afﬂict those with histories of early trauma or personality
difﬁculties, psychotherapy has long been considered a reasonable and useful treatment[3]. Since the 1950s, however, many drug therapies have been studied and are now commonly used in the treatment of depression and anxiety [4,5]. Moreover, during the past
20 years, greater emphasis has been placed on the theoretical and clinical developmentof time-limited structured psychotherapies that are speciﬁcally tailored toward core psychopathologies found in the depressive and anxiety disorders [6–8], although the speciﬁcity of different psychotherapies has been debated [9]. Given the wide variety of effective
psychotherapies and drug therapies that are currently available for treating depression andanxiety, a clinically and scientiﬁcally important question is whether the combination of
psychotherapy and pharmacotherapy is more effective than either treatment modality
alone. In this chapter, we will review the use of combination psychotherapy and pharmacotherapy for depression and anxiety, discuss some of the clinical and methodological problems with these studies, and suggest directions for future research in this area.
151

152

Howland and Thase

II. REASONS FOR COMBINING PSYCHOTHERAPY AND
PHARMACOTHERAPY
Various psychotropic drugs, especially antidepressants, have been found to be effective
not only in the treatment of depression [10], but also in the treatment of different anxiety
disorders, including panic disorder with or without agoraphobia [11], generalized anxiety
disorder [12], obsessive-compulsive disorder [13], social anxiety disorder [14], and posttraumatic stress disorder [15]. In addition, interpersonal psychotherapy (IPT), cognitive
behavioral therapy (CBT), and various forms of behavioral therapy (BT) are effective
treatments for depression [6]. Modiﬁed forms of CBT and BT have been better studied
than IPT for anxiety [16–18], and they have been found to be effective in the treatment
of different anxiety disorders [7], including panic disorder [19], generalized anxiety
disorder [20], obsessive-compulsive disorder [21], social anxiety disorder [22], and posttraumatic stress disorder [23].
Despite the effectiveness of drug therapy, patients may experience residual symptoms, may not be fully compliant in taking medication, may have deﬁcient interpersonal
and problem-solving skills, may have underlying maladaptive personality or temperamental traits, and may face ongoing life stressors [24,25]. Most patients and psychiatric practitioners also strongly prefer the use of psychotherapy to drug therapy [26–28]. Combining
psychotherapy and pharmacotherapy for the treatment of depression and anxiety is commonly done in clinical practice and often is recommended by clinical practice guidelines[29–31]. Together with drug therapy, the use of psychotherapy can instill hope and reestablish patient morale, increase levels of social and physical activity, help develop appropriate
coping behaviors, address medication noncompliance, mobilize psychosocial resources,
and provide practical psychosocial skills development [32].
Although the majority of patients will clearly show clinical improvement with pharmacotherapy or psychotherapy alone, only a signiﬁcant minority will experience a fullremission with treatment [33]. Because psychotherapy and pharmacotherapy likely havedifferent mechanisms of action, combining them might have additive or synergistic therapeutic effects that lead to a greater overall clinical outcome [6,34,35]. Drug therapy ismore likely to target underlying biological abnormalities and to improve somatic symptoms [4,5]. Psychotherapy is more likely to affect psychological and cognitive processes
and to improve psychosocial functioning [30,36,37]. However, successful drug therapy is
associated with concomitant improvements in psychological and psychosocial functioning[38]. Successful psychotherapy has also been associated with normalization of abnormal
regional brain metabolism [39,40]. Thus, pharmacotherapy and psychotherapy each may
have primary and secondary effects on the underlying biological pathophysiology of depression and anxiety, as well as associated psychosocial impairment, which may reciprocally enhance and complement their therapeutic effects [41,42].
There is also some evidence that the clinical effects of pharmacotherapy may work
more quickly, whereas the effects of psychotherapy may be delayed but more durable
over time [43,44]. For example, antidepressants have been shown to have more rapid
therapeutic beneﬁts compared to psychotherapy [45,46]. By contrast, several studies reported that the therapeutic beneﬁts of psychotherapy were more durable after treatment
discontinuation than those observed in depressed patients withdrawn from antidepressants[47–50]. As a result, short- and long-term clinical effects of combining psychotherapy
and pharmacotherapy may complement each other.
Drug therapy may facilitate the use of psychotherapy in other ways [51]. Because

Combining Psychotherapy and Pharmacotherapy

153

the use of psychotherapy depends on adequate cognitive functioning (e.g., concentration,verbal comprehension, and memory), severe depression and anxiety states may be associated with impaired neuropsychological functioning, making it difﬁcult for a patient to use
psychotherapy effectively [52]. By improving underlying neuropsychological functioning,
drug therapy may improve the cognitive skills necessary to engage in psychotherapy. Also,
psychotherapy may facilitate adherence to pharmacotherapy, especially early in treatment
when side effects are more likely to occur before substantial clinical improvement [53].
For example, in a recent study of chronic depression, subjects treated with a combinationof psychotherapy and pharmacotherapy were less likely to drop out of treatment becauseof adverse drug effects compared to subjects treated with pharmacotherapy alone [46]. In
addition, another recent study of bereavement-related major depression found that subjects
receiving combined treatment were less likely to drop out compared to subjects receiving
psychotherapy, pharmacotherapy, or placebo [54].
III. EFFICACY OF COMBINED TREATMENT FOR DEPRESSION
AND ANXIETYPrevious reviews of studies comparing psychotherapy and pharmacotherapy in the treatment of depressive and anxiety disorders have concluded that the two modalities weregenerally comparably effective [6,7], although these studies and their conclusions havebeen criticized [55]. Most studies investigating the efﬁcacy of combined treatment havebeen conducted in depressive rather than anxiety disorders.
A. Depressive Disorders
One of the earliest studies on depression contrasted IPT and amitriptyline, each alone andin combination, against a minimal-contact control group [56]. Not only did the effects ofboth IPT and amitriptyline surpass those of the minimal contact control group, but there
also was a small additive effect favoring the group receiving both active therapies, suggesting that each modality has unique or complementary therapeutic effects. However,most other early studies of psychotherapy and antidepressant combinations failed to demonstrate statistically signiﬁcant additive effects [57–61]. More recently, a research groupstudying late-life major depression found that approximately 80% of subjects showed afull response during open treatment with the combination of IPT and the antidepressantnortriptyline [62], a response rate signiﬁcantly higher than is usually seen in antidepressanttreatment studies. This group has also compared IPT and nortriptyline, singly and combined, in a group of older adults with grief-related major depressive episodes [54]. The
investigators found a signiﬁcant effect for nortriptyline (versus placebo), but not for IPT(versus placebo). They observed several trends suggesting an advantage for the IPT andnortriptyline combination versus nortriptyline alone, although these modest effects were
not statistically signiﬁcant because of the small sample sizes of the treatment groups.
Surprisingly, newer generation antidepressants have not been well studied in combination with psychotherapy. Recently, Ravindran et al. [63] compared group CBT andsertraline, each alone and in combination, in a placebo-controlled multicenter study ofdysthymic disorder. Sertraline was signiﬁcantly more effective than placebo or group
CBT, whereas group CBT was not signiﬁcantly more effective than placebo. Several nonsigniﬁcant trends suggested an additive effect for group CBT and sertraline, but the study
was too small to determine if this modest advantage was clinically signiﬁcant.

154

Howland and Thase

Thase et al. [64] reported the results of a pooled analysis of a series of 595 depressed
outpatients treated with psychotherapy alone (using CBT or IPT) or the combination of
IPT and tricyclic antidepressants. Patients receiving combined therapy had a 14% greater
remission rate than those treated with psychotherapy alone. Moreover, there was a large
difference (41%) in the subgroup of patients with more severe, recurrent depressive episodes. These results support the general ﬁnding that psychotherapy and pharmacotherapy
have modest additive effects for a broad range of depressed patients and a large advantage
for selected subgroups (e.g., more severe depressions).
A large multicenter, randomized clinical trial evaluated the cognitive behavioral
analysis system of psychotherapy (CBASP), which is a modiﬁed form of CBT, and theantidepressant nefazodone, singly and in combination, in 681 patients with chronic major
depression [46]. Nefazodone and CBASP were each associated with signiﬁcant reductionsof depressive symptoms after 12 weeks of treatment, but the combination group had signiﬁcantly greater proportions of responders and fully remitted patients. Nefazodone alone
and combined with CBASP was more rapidly effective than CBASP alone. Subjects
treated with combination therapy appeared to beneﬁt from both the more rapid effects ofnefazodone and the slower emerging beneﬁts of CBASP. Patients receiving combination
therapy also were less likely to relapse during 16 weeks of continuation treatment compared to CBASP or nefazodone alone [65].
Two controlled studies have examined the efﬁcacy of IPT combined with the antidepressants imipramine [66] or nortriptyline [67] for prevention of recurrent major depression. In both studies, sustained remission was initially achieved during acute treatment
with the combination of IPT and medication. Following 4 months of continuation therapy,
the next stage of treatment was random assignment to maintenance pharmacotherapy,
psychotherapy, or a combination of both. In the ﬁrst study [66], patients receiving imipramine alone or combined with IPT had signiﬁcantly better outcomes compared to placebo,
IPT alone, or IPT plus placebo during 3 years of maintenance treatment. There was noadvantage for the patients who received combined treatment. In the second study [67],older patients receiving nortriptyline alone, IPT alone, or combination therapy had signiﬁcantly better outcomes compared to placebo during maintenance treatment. This study,
however, found an additive effect in the group receiving the combination of IPT andpharmacotherapy.
Several studies have examined the sequential use of combined psychotherapy andpharmacotherapy after an initial monotherapy treatment trial of depression. These studies
suggested that adding CBT or IPT to pharmacotherapy after completion of acute-phase
pharmacotherapy alone leads to better clinical outcomes [68–70]. A recent study in womenwith recurrent major depression found that adding pharmacotherapy in patients who did
not fully respond to an initial course of IPT alone resulted in a greater remission rate(79%) compared to those patients who had received combined treatment initially (66%)[71]. Moreover, some studies have found that the sequential addition of psychotherapy
after an initial course of pharmacotherapy not only improves residual depressive symptoms, but also will improve psychological symptoms and psychosocial functioning[70,72]. Hence, combined therapy may be especially useful for patients who have showna partial response to psychotherapy or pharmacotherapy alone [32].
Mood-stabilizing medications are considered the mainstay of treatment for bipolar
disorder, but there is developing evidence that the use of speciﬁc psychosocial interventions together with pharmacotherapy may lead to a better clinical outcome [73]. For example, family-focused psychoeducational treatment was effective in reducing relapses andCombining Psychotherapy and Pharmacotherapy

155

improving depressive symptoms in bipolar disorder [74]. In addition, modiﬁed forms of
IPT and CBT have been shown to improve compliance, reduce depressive symptoms, andincrease psychosocial functioning [75–79].
B. Anxiety Disorders
Studies comparing psychotherapy and pharmacotherapy in the treatment of anxiety disorders have generally found that the two modalities are effective [7], although there has
been some debate about their relative efﬁcacy [55]. Compared to depression, however,the use of combined treatment for various anxiety disorders has not been as well studied[7,43].
Panic disorder with or without agoraphobia can be effectively treated either withdrug therapy, typically antidepressants, or with psychotherapy, usually some form of CBTor BT such as exposure therapy [30]. Earlier meta-analyses of treatments for panic disorder
did not ﬁnd substantial or consistent evidence that combined therapy is better than psychotherapy or pharmacotherapy alone [80–82], but various methodological problems withthese studies prevent any deﬁnitive conclusions [55]. More recently, a large multicenter
randomized double-blind placebo-controlled clinical trial evaluated CBT and the antidepressant imipramine, singly and in combination, in 312 patients with panic disorder [83].
This study found that imipramine and CBT alone were signiﬁcantly better than placebo
on most measures during acute and maintenance treatment. There was a trend for greater
improvement with combined therapy compared to CBT or imipramine alone during acutetreatment, but combined therapy showed a substantial advantage by the end of maintenance treatment. Studies with newer generation antidepressants such as paroxetine [84]and ﬂuvoxamine [85] have found that combined therapy may be more effective than psychotherapy alone. Similar to studies in depression, there is developing evidence that adding
psychotherapy to pharmacotherapy may be useful for treating residual symptoms [86] orpreventing relapse [7,87] in panic disorder. Finally, studies of agoraphobia have foundthat the combination of imipramine and exposure BT is superior to either therapy alone [7].
Generalized anxiety disorder can be effectively treated with various drug therapies,
including antidepressant drugs, or with psychotherapy, usually CBT [20,12]. Psychotherapy may also successfully treat comorbid conditions commonly found in generalized anxiety disorder [88]. Unfortunately, there are no systematic studies comparing the efﬁcacy
of combined therapy to psychotherapy or pharmacotherapy alone [7,89].
Obsessive-compulsive disorder can be effectively treated either with drug therapy(i.e., clomipramine or a serotonin reuptake–inhibiting antidepressant) or with some formof CBT or BT such as exposure and response prevention therapy [13,90,91]. An earlier
meta-analysis of treatments for obsessive-compulsive disorder suggested that combined
therapy is better than psychotherapy or pharmacotherapy alone [21], but the methodologyof this analysis has been criticized [55]. Other recent studies have not found substantial
or consistent evidence that combined therapy is superior [92,93], although the study by
Hohagen et al. [94] suggested that obsessional and depressive symptoms may improve
more with the combination of BT and the antidepressant ﬂuvoxamine.
Social anxiety disorder can be effectively treated with various drug therapies, primarily antidepressants, or with psychotherapy, usually CBT [14,22]. Although there areno systematic studies comparing the efﬁcacy of combined therapy to psychotherapy or
pharmacotherapy alone, the differential short-term and long-term effects of pharmacotherapy and psychotherapy have suggested that they may have especially useful synergistic

156

Howland and Thase

effects when combined [22,95]. Also, given the substantial comorbidity found in social
anxiety disorder [96], combination treatment may lead to a better overall clinical outcome.
The treatment of post-traumatic stress disorder has not been as extensively investigated as depression and other anxiety disorders, although recent studies have shown signiﬁcant beneﬁts with the use of antidepressants [15] and different forms of CBT, especially
exposure therapy [23]. Because of the diverse and complex symptoms often found in posttraumatic stress disorder [97], reﬂecting underlying psychological and neurobiologicalprocesses, it is likely that combining psychotherapy and pharmacotherapy will be more
effective than either therapy alone, but this has not been systematically studied [98,99].
C.

Conclusions and Recommendations About the Use of Combined
Treatment

The research studies reviewed here generally support the conclusion that combined treatment is at least as effective as psychotherapy or pharmacotherapy alone in the treatment
of depression. This contradicts the notion that pharmacotherapy might interfere with theeffects of psychotherapy or vice versa [51]. Additive effects have been observed in someof the studies evaluating psychotherapy and pharmacotherapy combinations, but thelargest effects have been shown in patients with more severe and chronic illnesses. Surprisingly, virtually all studies of combined therapy have used older tricyclic antidepressantdrugs. Additional studies investigating the use and effectiveness of combined therapy withnewer generation medications are needed.
There also is some developing evidence that partial responders to psychotherapy or
pharmacotherapy alone will improve by using combined treatments. These ﬁndings suggest that the sequential strategy of combining treatments only after failing an adequate
monotherapy might be more efﬁcacious and cost effective than using combination therapy
for all patients at the beginning of treatment. This issue deserves further study, especially
examining different sequence patterns of combined treatments (e.g., pharmacotherapy
added to psychotherapy versus psychotherapy added to pharmacotherapy) as well as examining the efﬁcacy of different treatment components (i.e., different types of medications
and different forms of psychotherapy). These studies also need to speciﬁcally and prospectively investigate possible clinical and biological predictors of treatment response.
Because medications may work more quickly, whereas psychotherapy may havemore delayed but sustained effects, it is possible that combination therapy might havegreater long-term beneﬁts. Combination therapy has not been as well studied during longterm treatment, however, but combined treatment can reduce the risk of recurrent depression in older patients. In addition, psychotherapy can not only target mood and anxiety
symptoms, but also improve psychological and psychosocial functioning. Hence, there isa need to study further the long-term effects of combined treatment not only on illness
symptoms and recurrence risk but also on psychosocial functioning. Along with this, theoverall cost effectiveness of combined treatment compared to psychotherapy or pharmacotherapy alone can be assessed [9,100].
The failure to demonstrate a more signiﬁcant advantage with combined treatment
may be due to the relatively small sample sizes of most studies. In addition, age, gender,
type of treatment, and diagnostic subgroups might also be potential confounding factors
in studies comparing the effects of psychotherapy, pharmacotherapy, and their combination. For example, younger and older depressed cohorts respond differently to different
types of antidepressant drugs [101,102]. Men and women also have differential responseCombining Psychotherapy and Pharmacotherapy

157

rates to different types of antidepressants and different forms of psychotherapy [103,104].
Response rates to medications and psychotherapy may also vary according to depressive
subtype [45,105–108].
Another potential problem in treatment studies of combined therapy is the adequacyof pharmacotherapy or psychotherapy. The adequacy of pharmacotherapy is relatively
easy to quantify (e.g., dose, duration, and compliance). Recent efforts at quantifying theadequacy of psychotherapy have found that the quality of therapy [109], therapeutic alliance [9,110], and investigator allegiance [111] may all affect the response to psychotherapy. It is also likely that psychotherapy and pharmacotherapy engender different therapeutic expectations as well [112–114], which might affect treatment outcome.
Compared to depression, the use and effectiveness of combination therapy has notbeen as well studied in anxiety disorders. Studies of panic disorder have provided thestrongest evidence that combination therapy may be superior to psychotherapy or pharmacotherapy alone. There is clearly a need for additional research in other anxiety disorders,
as well as studies investigating different drug and psychotherapy combinations, the useof sequential treatment strategies, clinical and biological predictors of treatment response,
and the long-term effects of combination therapy on symptomatic and psychosocial outcomes. Moreover, because anxiety affects the treatment response to pharmacotherapy andpsychotherapy in major depression [115,116], formal combined treatment studies of comorbid depression and anxiety are needed.
Based on this review, not all patients with depression and anxiety will necessarily
require or greatly beneﬁt from combined treatment using pharmacotherapy together witha rigorous course of psychotherapy (such as IPT or CBT). Several particular subgroupsof patients might be more likely to beneﬁt from combined treatment, especially those withmore severe [64], chronic [46,117], or treatment-resistant [32] depression and anxiety.
The presumed beneﬁt in reducing the high level of suffering and disability in these patients
is more likely to justify the added cost and expenditure of limited therapists’ time inproviding combined treatment. The choice of treatment, however, will ultimately dependon patient and provider preferences as well as the availability of appropriately trained
psychotherapists and pharmacotherapists.

REFERENCES
1. Howland RH, Thase ME. Affective disorders: biological aspects. In: Millen T, Blaney PH,
Davis RD, eds. Oxford Textbook of Psychopathology. New York: Oxford University Press,
1999:166–202.
2. Marshall RD, Klein DF. Diagnostic classiﬁcation of anxiety disorders: historical context andimplications for neurobiology. In: Charney DS, Nestler EJ, Bunney BS, eds. Neurobiology
of Mental Illness. New York: Oxford University Press, 1999:437–450.
3. Eysenck HJ. The effects of psychotherapy: an evaluation. J Consult Psychol 1952; 16:319–
324.
4. Howland RH, Thase ME. Mood disorders: therapeutic armamentarium. In: D’Haenen H, denBoer JA, Wilner P, eds. Textbook of Biological Psychiatry. London: John Wiley & Sons,
Ltd. 2002:861–875.
5. Goddard AW, Coplan JD, Gorman JM, Charney DS. Principles of the pharmacotherapy ofanxiety disorders. In: Charney DS, Nestler EJ, Bunney BS, eds. Neurobiology of Mental
Illness. New York: Oxford University Press, 1999:548–563.
6. Rush AJ, Thase ME. Psychotherapies for depressive disorders: a review. In: Maj M, Sartorius

158

7.
8.
9.

10.
11.
12.
13.
14.

15.

16.
17.
18.
19.
20.
21.

22.
23.
24.
25.

26.
27.

28.

Howland and Thase
N, eds. WPA Series. Evidence and Experience in Psychiatry. Volume 1: Depressive Disorders. Chichester: John Wiley & Sons, 1999:161–206.
Barlow DH, Lehman CL. Advances in the psychosocial treatment of anxiety disorders: implications for national health care. Arch Gen Psychiatry 1996; 53:727–735.
James I, Blackburn I-M. Psychological approaches to anxiety disorders. Curr Opin Psychiatry
1997; 10:481–485.
Kopta SM, Lueger RJ, Saunders SM, Howard KI. Individual psychotherapy outcome andprocess research: challenges leading to greater turmoil or a positive transition. Ann Rev
Psychol 1999; 50:441–469.
Thase ME. Do we really need all these new antidepressants? Weighing the options. J Practical
Psychiatry Behav Health 1997; 3:3–17.
Boyer W. Serotonin uptake inhibitors are superior to imipramine and alprazolam in alleviating panic attacks: a meta-analysis. Int Clin Psychopharmacol 1995; 10:45–49.
Davidson JRT. Pharmacotherapy of generalized anxiety disorder. J Clin Psychiatry 2001;
62:46–50.
Micallef J, Blin O. Neurobiology and clinical pharmacology of obsessive-compulsive disorder. Clin Neuropharmacol 2001; 24:191–207.
Brunello N, den Boer JA, Judd LL, Kasper S, Kelsey JE, Lader M, Lecrubier Y, Lepine JP,
Lydiard RB, Mendlewicz J, Montgomery SA, Racagni G, Stein MB, Wittchen HU. Social
phobia: diagnosis and epidemiology, neurobiology and pharmacology, comorbidity and treatment. J Affect Disord 2000; 60:61–74.
Stein DJ, Seedat S, van der Linden GJH, Zungu-Dirwayi N. Selective serotonin reuptake
inhibitors in the treatment of post-traumatic stress disorder: a meta-analysis of randomized
controlled trials. Int Clin Psychopharmacol 2000; 15:S31–S39.
Bewin CR. Theoretical foundations of cognitive-behavior therapy for anxiety and depression.
Ann Rev Psychol 1996; 47:33–57.
Weissman MM, Markowitz JC. Interpersonal psychotherapy: current status. Arch Gen Psychiatry 1994; 51:599–606.
Lipsitz JD, Markowitz JC, Cherry S, Fyer AJ. Open trial of interpersonal psychotherapy forthe treatment of social phobia. Am J Psychiatry 1999; 156:1814–1816.
Shear MK, Weiner K. Psychotherapy for panic disorder. J Clin Psychiatry 1997; 58:38–
45.
Borkovec TD, Ruscio AM. Psychotherapy for generalized anxiety disorder. J Clin Psychiatry
2001; 62:37–42.
van Balkom AJLM, van Oppen P, Vermeulen AW, van Dyck R. A meta-analysis on thetreatment of obsessive compulsive disorder: a comparison of antidepressants, behavior, andcognitive therapy. Clin Psychol Rev 1994; 14:359–381.
Heimberg RG. Current status of psychotherapeutic interventions for social phobia. J Clin
Psychiatry 2001; 62:36–42.
Foa EB. Psychosocial treatment of posttraumatic stress disorder. J Clin Psychiatry 2000; 61:
43–48.
Thase ME, Howland RH. Refractory depression: relevance of psychosocial factors and therapies. Psychiatr Ann 1994; 24:232–240.
Fava GA, Rafanelli C, Ottolini F, Ruini C, Cazzaro M, Grandi S. Psychological well-being
and residual symptoms in remitted patients with panic disorder and agoraphobia. J Affect
Disord 2001; 65:185–190.
Seligman MEP. The effectiveness of psychotherapy. The Consumer Reports study. Am Psychol 1995; 50:965–974.
Benkert O, Graf-Morgenstern M, Hillert A, Sandmann J, Ehmig SC, Weissbecker H, Kepplinger HM, Sobota K. Public opinion on psychotropic drugs: an analysis of the factors
inﬂuencing acceptance or rejection. J Nerv Ment Dis 1997; 185:151–158.
Sullivan M, Verhulst J, Russo J, Roy-Byrne PP. Psychotherapy vs. pharmacotherapy: areCombining Psychotherapy and Pharmacotherapy

29.
30.
31.
32.
33.
34.
35.
36.
37.

38.

39.

40.

41.
42.
43.
44.

45.
46.

47.
48.
49.

159

psychiatrists polarized? A survey of academic and clinical faculty. Am J Psychother 1993;
47:411–423.
Persons JB, Thase ME, Crits-Christoph P. The role of psychotherapy in the treatment ofdepression: review of two practice guidelines. Arch Gen Psychiatry 1996; 53:283–290.
Work Group on Panic Disorder. Practice Guideline for the treatment of patients with panic
disorder. Am J Psychiatry 1998; 155:1–34.
Foa EB, Davidson JRT, Frances A. The expert consensus guideline series: treatment of posttraumatic stress disorder. J Clin Psychiatry 1999; 60:1–76.
Thase ME, Friedman ES, Howland RH. Management of treatment-resistant depression: psychotherapeutic perspectives. J Clin Psychiatry 2001; 62:18–24.
Ballenger JC. Clinical guidelines for establishing remission in patients with depression andanxiety. J Clin Psychiatry 1999; 60:29–34.
Lader M. Bio-psycho-social interactions in anxiety and panic disorders: a speculative perspective. J Psychol Med 1991; 8:154–159.
Middleton HC. Panic disorder: a theoretical synthesis of medical and psychological approaches. J Psychosom Res 1998; 44:121–132.
Jarret RB. Psychosocial aspects of depression and the role of psychotherapy. J Clin Psychiatry
1990; 51(suppl 26):35–38.
Fava GA, Rafanelli C, Cazzaro M, Conti S, Grandi S. Well-being therapy. A novel psychotherapeutic approach for residual symptoms of affective disorders. Psychol Med 1998; 28:
475–480.
Hirschfeld RM, Montgomery SA, Keller MB, Kasper S, Schatzberg AF, Moller HJ, Healy
D, Bladwin D, Humble M, Versiani M, Montenegro R, Bourgeois M. Social functioning in
depression: a review. J Clin Psychiatry 2000; 61:268–175.
Brody AL, Saxena S, Stoessel P, Gillies LA, Fairbanks LA, Alborzian S, Phelps ME, Huang
S-C, Wu H-M, Ho ML, Mai K, Scott C, Maidment K, Baxter L, Lewis R. Regional brain
metabolic changes in patients with major depression treated with either paroxetine or interpersonal therapy: preliminary ﬁndings. Arch Gen Psychiatry 2001; 58:631–640.
Schwartz JM, Stoessel PW, Baxter LR, Martin KM, Phelps ME. Systematic changes in cerebral glucose metabolic rate after successful behavior modiﬁcation treatment of obsessivecompulsive disorder. Arch Gen Psychiatry 1996; 53:109–113.
Kandel ER. A new intellectual framework for psychiatry. Am J Psychiatry 1998; 155:457–
469.
Eisenberg L. Is psychiatry more mindful or brainier than it was a decade ago? Br J Psychiatry
2000; 176:1–5.
Lader MH, Bond AJ. Interaction of pharmacological and psychosocial treatments of anxiety.
Br J Psychiatry 1998; 173(suppl 34):42–48.
Manning DW, Francis AJ. Combined therapy for depression: critical review of the literature.
In: Manning DW, Frances AJ, eds. Combined Pharmacotherapy and Psychotherapy for Depression. Washington, DC: American Psychiatric Press, Inc., 1990:3–36.
Watkins JT, Leber WR, Imber SD, et al. Temporal course of change of depression. J Consult
Clin Psychol 1993; 61:858–864.
Keller MB, McCullough JP, Klein DN, et al. A comparison of nefazodone, the cognitive
behavioral-analysis system of psychotherapy, and their combination for the treatment ofchronic depression. N Engl J Med 2000; 342:1462–1470.
Evans MD, Hollon SD, DeRubeis RJ, et al. Differential relapse following cognitive therapy
and pharmacotherapy for depression. Arch Gen Psychiatry 1992; 49:802–808.
Kovacs M, Rush AJ, Beck AT, Hollon SD. Depressed outpatients treated with cognitive
therapy or pharmacotherapy. A one-year follow-up. Arch Gen Psychiatry 1981; 38:33–39.
Simons AD, Murphy GE, Levine JL, Wetzel RD. Cognitive therapy and pharmacotherapy
for depression. Sustained improvement over one year. Arch Gen Psychiatry 1986; 43:43–
48.

160

Howland and Thase

50. Blackburn IM, Eunson KM, Bishop S. A two-year naturalistic follow-up of depressed patientstreated with cognitive therapy, pharmacotherapy and a combination of both. J Affect Disord
1986; 10:67–75.
51. Klerman GL. Ideological conﬂicts in integrating pharmacotherapy and psychotherapy. In:
Beitman BD, Klerman GL, eds. Integrating Pharmacotherapy and Psychotherapy. Washington, DC: American Psychiatric Press, Inc., 1991:3–19.
52. Thase ME, Dube S, Bowler K, Howland RH, Myers JE, Friedman E, Jarrett DB. Hypothalamic-pituitary-adrenocortical activity and response to cognitive behavior therapy in unmedicated, hospitalized depressed patients. Am J Psychiatry 1996; 153:886–891.
53. Ward NG. Psychosocial approaches to pharmacotherapy. In: Beitman BD, Klerman GL, eds.
Integrating Pharmacotherapy and Psychotherapy. Washington, DC: American PsychiatricPress, Inc., 1991:69–104.
54. Reynolds CF, Miller MD, Pasternak RE, Frank E, Perel JM, Cornes C, Houck PR, Mazumdar
S, Dew MA, Kupfer DJ. Treatment of bereavement-related major depressive episodes in later
life: a controlled study of acute and continuation treatment with nortriptyline and interpersonal psychotherapy. Am J Psychiatry 1999; 156:202–208.
55. Klein DF. Flawed meta-analyses comparing psychotherapy with pharmacotherapy. Am J
Psychiatry 2000; 157:1204–1211.
56. DiMascio A, Weissman MM, Prusoff BA, Neu C, Zwilling M, Klerman GL. Differential
symptom reduction by drugs and psychotherapy in acute depression. Arch Gen Psychiatry
1979; 36:1450–1456.
57. London P, Klerman G. Evaluating psychotherapy. Am J Psychiatry 1982; 139:709–717.
58. Hollon SD, DeRubeis RJ, Evans MD, et al. Cognitive therapy and pharmacotherapy for
depression singly and in combination. Arch Gen Psychiatry 1992; 49:774–781.
59. Murphy GE, Simons AD, Wetzel RD, Lustman PJ. Cognitive therapy and pharmacotherapy.
Singly and together in the treatment of depression. Arch Gen Psychiatry 1984; 41:33–41.
60. Blackburn IM, Bishop S, Glen AIM, Whalley LJ, Christie JE. The efﬁcacy of cognitive
therapy in depression: a treatment trial using cognitive therapy and pharmacotherapy, eachalone and in combination. Br J Psychiatry 1981; 139:181–189.
61. Beck AT, Hollon SD, Young JF, Bedrosian RC, Budenz D. Treatment of depression withcognitive therapy and amitriptyline. Arch Gen Psychiatry 1985; 42:142–148.
62. Miller MD, Wolfson L, Frank E, Cornes C, Silberman R, Ehrenpreis L, Zaltman J, Malloy
J, Reynolds CF. Using interpersonal psychotherapy (ITP) in a combined psychotherapy/medication research protocol with depressed elders: a descriptive report with case vignettes. J
Psychother Pract Res 1998; 7:47–55.
63. Ravindran AV, Anisman H, Merali Z, et al. Treatment of primary dysthymia with groupcognitive therapy and pharmacotherapy: clinical symptoms and functional impairments. Am
J Psychiatry 1999; 156:1608–1617.
64. Thase ME, Greenhouse JB, Frank E, et al. Treatment of major depression with psychotherapy
or psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry 1997; 54:1009–
1015.
65. Kocsis JH, Arnow B, Borian FE, Dunner DL, et al. Nefazodone, CBAS-Psychotherapy andtheir combination for the continuation treatment of chronic major depression. American Psychiatric Association Annual Meeting, New Orleans, LA, 2001.
66. Frank E, Kupfer DJ, Perel JM, et al. Three-year outcomes for maintenance therapies in recurrent depression. Arch Gen Psychiatry 1990; 47:1093–1099.
67. Reynolds CF, Perel JM, Frank E, et al. Three-year outcomes of maintenance nortriptyline
treatment in late-life depression: a study of two ﬁxed plasma levels. Am J Psychiatry 1999;
156:1177–1181.
68. Fava GA, Grandi S, Zielezny M, Canestrari R, Morphy MA. Cognitive behavioral treatmentof residual symptoms in primary major depressive disorder. Am J Psychiatry 1994; 151:
1295–1299.

Combining Psychotherapy and Pharmacotherapy

161

69. Paykel ES, Scott J, Teasdale JD, et al. Prevention of relapse in residual depression by cognitive therapy. Arch Gen Psychiatry 1999; 56:829–835.
70. Markowitz JC. Psychotherapy of the postdysthymic patient. J Psychother Pract Res 1993;
2:157–163.
71. Frank E, Grochocinski VJ, Spanier CA, Buyesse DJ, Cherry CR, Houck PR, Staph DM,
Kupfer DJ. Interpersonal psychotherapy and antidepressant medication: evaluation of a sequential treatment strategy in women with recurrent major depression. J Clin Psychiatry
2000; 61:51–57.
72. Scott J, Teasdale JD, Paykel ES, Johnson AL, Abbott R, Hayhurst H, Moore R, Garland A.
Effects of cognitive therapy on psychological symptoms and social functioning in residual
depression. Br J Psychiatry 2000; 177:440–446.
73. Swartz HA, Frank E. Psychotherapy for bipolar depression: a phase-speciﬁc treatment strategy? Bipolar Disord 2001; 3:11–22.
74. Miklowitz DJ, Simoneau TL, George EL, Richards JA, Kalbag A, Sachs-Ericsson N, Suddath
R. Family-focused treatment of bipolar disorder: 1-year effects of a psychoeducational program in conjunction with pharmacotherapy. Biol Psychiatry 2000; 48:582–592.
75. Fava GA, Bartolucci G, Rafanelli C, Mangelli L. Cognitive-behavioral management of patients with bipolar disorders who relapsed while on lithium prophylaxis. J Clin Psychiatry
2001; 62:556–559.
76. Zaretsky AE, Segal ZV, Gemar M. Cognitive therapy for bipolar depression: a pilot study.
Can J Psychiatry 1999; 44:491–494.
77. Patelis-Siotis I, Young LT, Robb JC, Marriott M, Bieling PJ, Cox LC, Joffe RT. Group
cognitive behavioral therapy for bipolar disorder: a feasibility and effectiveness study. J Affect Disord 2001; 65:145–153.
78. Patelis-Siotis I. Cognitive-behavioral therapy: applications for the management of bipolar
disorder. Bipolar Disord 2001; 3:1–10.
79. Frank E, Swartz HA, Kupfer DJ. Interpersonal and social rhythm therapy: managing thechaos of bipolar disorder. Biol Psychiatry 2000; 48:593–604.
80. van Balkom AJLM, Bakker A, Spinhoven P, Blaauw BMJW, Smeenk S, Ruesink B. A metaanalysis of the treatment of panic disorder with or without agoraphobia: A comparison of
psychopharmacological, cognitive-behavioral, and combination treatments. J Nerv Mental
Dis 1997; 185:510–516.
81. Clum GA, Clum GA, Surls R. A meta-analysis of treatments for panic disorder. J Consult
Clin Psychol 1993; 61:317–326.
82. Gould RA, Otto MW, Pollack MH. A meta-analysis of treatment outcome for panic disorder.
Clin Psychol Rev 1995; 15:819–844.
83. Barlow DH, Gorman JM, Shear MK, Woods SW. Cognitive-behavioral therapy, imipramine,or their combination for panic disorder: a randomized controlled trial. JAMA 2000; 283:
2529–2536.
84. Oehrberg S, Christiansen PE, Behnke K, Borup AL, Severin B, Soegaard J, Calberg H, Ohrstrom JK, Judge R, Manniche PM. Paroxetine in the treatment of panic disorder: a randomized, double-blind, placebo-controlled study. Br J Psychiatry 1995; 167:374–379.
85. de Beurs E, van Balkom AJLM, Lange A, Koele P, et al. Treatment of panic disorder withagoraphobia: comparison of ﬂuvoxamine, placebo, and psychological panic management
combined with exposure and of exposure in vivo alone. Am J Psychiatry 1995; 152:683–
691.
86. Pollack MH, Otto MW, Kaspi SP, Hammerness PG, et al. Cognitive behavior therapy fortreatment-refractory panic disorder. J Clin Psychiatry 1994; 55:2000–205.
87. Wiborg IM, Dahl AA. Does brief dynamic psychotherapy reduce the relapse rate of panic
disorder? Arch Gen Psychiatry 1996; 53:689–694.
88. Borkovec TD, Abel JL, Newman H. Effects of psychotherapy in comorbid conditions ingeneralized anxiety disorder. J Consult Clin Psychol 1995; 63:479–483.

162

Howland and Thase

89. Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Borkovec TD, Rickels K, Stein DJ,
Wittchen HU. Consensus statement on generalized anxiety disorder from the International
Consensus Group on Depression and Anxiety. J Clin Psychiatry 2001; 62:53–58.
90. Schwartz JM. Neuroanatomical aspects of cognitive-behavioral therapy response in obsessive-compulsive disorder: an evolving perspective on brain and behavior. Br J Psychiatry
1998; 173:38–44.
91. Franklin ME, Abramowitz J, Kozak MJ, Levitt JT, Foa EB. Effectiveness of exposure andritual prevention for obsessive-compulsive disorder: randomized compared with nonrandomized samples. J Consult Clin Psychol 2000; 68(4):594–602.
92. Van Balkom AJLM, De Haan E, Van Oppen P, Spinhoven P, Hoogduin KAL, Van Dyck
R. Cognitive and behavioral therapies alone versus in combination with ﬂuvoxamine in thetreatment of obsessive-compulsive disorder. J Nerv Ment Dis 1998; 186(8):492–499.
93. Kozak M, Liebowitz MR, Foa EB. Cognitive behavior therapy and pharmacotherapy forobsessive-compulsive disorder: the NIMH-sponsored collaborative study. In: Goodman WK,
ed. Obsessive-Compulsive Disorder: Contemporary Issues in Treatment. Personality andClinical Psychology Series. Mahwah: Lawrence Erlbaum Associates, Inc., 2000:501–530.
94. Hohagen F, Winkelmann G, Rasche-Rauchle H, Hand I, Konig A, Munchau N, Hiss H,
Geiger-Kabisch C, Kappler C, Schramm P, Rey E, Aldenhoff J, Berger M. Combination of
behaviour therapy with ﬂuvoxamine in comparisons with behaviour therapy and placebo:
result of a multicenter study. Br J Psychiatry 1998; 173(35S):71–78.
95. Liebowitz MR, Heimberg RG, Schneier FR, Hope DA, Davies S, Holt CS, Goetz D, Juster
HR, Lin S-H, Bruch MA, Marshall RD, Klein DF. Cognitive-behavioral therapy versus phenelzine in social phobia: long term outcome. Depression Anxiety 1999; 10:89–98.
96. Pollack MH. Comorbidity, neurobiology, and pharmacotherapy of social anxiety disorder. J
Clin Psychiatry 2001; 62(suppl 12):24–29.
97. Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Foa EB, Kessler RC, McFarlane AC,
Shalev AY. Consensus statement on posttraumatic stress disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry 2000; 61(suppl 5):60–66.
98. Shalev AY, Bonne O, Eth S. Treatment on posttraumatic stress disorder: a review. Psychosom
Med 1996; 58(2):165–182.
99. Marshall RD, Cloitre M. Maximizing treatment outcome in post-traumatic stress disorder by
combining psychotherapy with pharmacotherapy. Curr Psychiatry Rep 2000; 2(4):335–340.
100. Hersh EK, Lazar SG. Cost-effectiveness of psychotherapy for depression. In: Spiegel D, ed.
Efﬁcacy and Cost-Effectiveness of Psychotherapy. Washington, DC: American PsychiatricPress, Inc., 1999:125–132.
101. Brent DA, Ryan N, Dahl R, Birmaher B. Early-onset mood disorder. In: Bloom FE, Kupfer
DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press,
1995:1631–1642.
102. Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA, Hughes CW, Carmody T, Rintelmann
J. A double-blind, randomized, placebo-controlled trial of ﬂuoxetine in children and adolescents with depression. Arch Gen Psychiatry 1997; 54:1031–1037.
103. Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, Gelenberg AJ, Davis SM, Harrison WM, Keller MB. Gender differences in treatment response tosertraline versus imipramine in chronic depression. Am J Psychiatry 2000; 157:1445–1452.
104. Thase ME, Frank E, Kornstein S, Yonkers KA. Gender differences in response to treatmentsof depression. In: Frank E, ed. Gender and Its Effects on Psychopathology. Washington, DC:
American Psychiatric Press, Inc., 2000:103–129.
105. Elkin I, Gibbons RD, Shea MT, et al. Initial severity and differential treatment outcomein the National Institute of Mental Health Treatment of Depression Collaborative Research
Program. J Consult Clin Psychol 1995; 63:841–847.
106. Klein DF, Ross DC. Reanalysis of the National Institute of Mental Health Treatment ofCombining Psychotherapy and Pharmacotherapy

107.

108.

109.

110.

111.
112.
113.
114.
115.

116.

117.

163

Depression Collaborative Research Program general effectiveness report. Neuropsychopharmacology 1993; 8:241–251.
Shea MT, Pilkonis PA, Beckham E, et al. Personality disorders and treatment outcome in
the NIMH treatment of depression collaborative research program. Am J Psychiatry 1990;
147:711–718.
Stewart JW, Garﬁnkel R, Nunes EV, Donovan S, Klein DF. Atypical features and treatment
response in the National Institute of Mental Health Treatment of Depression Collaborative
Research Program. J Clin Psychopharmacol 1998; 18:429–434.
Frank E, Kupfer DJ, Wagner EF, McEachran AB, Cornes C. Efﬁcacy of interpersonal psychotherapy as a maintenance treatment of recurrent depression. Contributing factors. ArchGen Psychiatry 1991; 48:1053–1059.
Krupnick JL, Collins J, Pilkonis PA, et al. Therapeutic alliance and clinical outcome in the
NIMH treatment of depression collaborative research program: preliminary ﬁndings. Psychotherapy 1994; 31:28–35.
Luborsky L, Diguer L, Seligman DA, et al. The researcher’s own therapy allegiances: a “wildcard” in comparisons of treatment efﬁcacy. Clin Psychol Sci Pract 1999; 6:95–106.
Wilkins W. Psychotherapy: the powerful placebo. J Consult Clin Psychol 1984; 52:570–
573.
Parloff MB. Placebo controls in psychotherapy research: a sine qua non or a placebo forresearch problems? J Consult Clin Psychol 1986; 54:79–87.
Horvath P. Placebos and common factors in two decades of psychotherapy research. Psychol
Med 1988; 104:214–225.
Brown C, Schulberg HC, Madonia MJ, Shear MK, Houck PR. Treatment outcomes for primary care patients with major depression and lifetime anxiety disorder. Am J Psychiatry
1996; 153(10):1293–1300.
Frank E, Shear MK, Rucci P, Cyranowski JM, Endicott J, Fagiolini A, Grochocinski VJ,
Houck P, Kupfer DJ, Maser J, Cassano GB. Inﬂuence of panic-agoraphobic spectrum symptoms on treatment response in patients with recurrent major depression. Am J Psychiatry
2000; 157(7):1101–1107.
Howland RH. Psychosocial therapies for dysthymia. In: The Hatherleigh Guide to Managing
Depression. New York: Hatherleigh Press, 1996:225–241.

8
Genetics of Depression
WOLFGANG MAIER
University of Bonn
Bonn, Germany
KATHLEEN R. MERIKANGASNational Institutes of Health
Bethesda, Maryland, U.S.A.

The hereditary nature of emotional behavior was recognized even in ancient times. In
particular, speciﬁc features of temperaments were observed to run in families. Thus, immediately after the introduction of the modern concepts of affective and emotional disorders
by Falret and later by Kraepelin, familial etiology was discussed and investigated: formore than 100 years it has been evident that at least some subtypes of manic depressive
disorders were familial and genetic. Although the ﬁrst family and twin studies were performed without standardized and criteria-based diagnoses in the absence of structured
interviews, their results were clearly replicated in subsequent methodologically more reﬁned and valid studies. Currently, the ﬁeld is intensively searching for DNA variants thatpredispose to mood disorders with only limited success.

I.

GENETIC EPIDEMIOLOGY OF MOOD DISORDERS

A. Familial Clustering
For many years, family studies dominated the research ﬁeld of genetics of affective disorders. Numerous studies demonstrated the familial nature of unipolar depression and bipolar
disorder (Table 1).
Overall, ﬁrst-degree relatives of probands with unipolar depression are at an increased risk for unipolar depression; the mean relative risk
165

166

Table 1

Proportion of First-Degree Relatives of Bipolar (BP) and Unipolar Depressive (UP) Disorder Probands with a Lifetime History of
Bipolar and Unipolar Depressive Disorder
Rates/100
Subtype in relatives by proband subtype

Sample
Refs.
2

3
4
5

6

Probands (n)BPUPControls
BP
UP
Controls
UP
Controls
BP
UP
Controls
BP
UP
Controls

54
16
75
130
30
43
133
82
100
225
160
80
108
80

Ratio weighted for sample size.
Source: Ref. 1.

Relatives (n)

411
113
619
739
166
265
810
591
230
500
543
504
306
221
Total rates/100
Relative risk (vs. controls)

BP–BP

BP–UP

UP–BP

UP–UP

Controls–BP

Controls–UP

19.6

11.5

11.0

20.1

0.2

0.5

21.9

2.6

8.0

3.0

0.4

5.7

—

—

1.5

3.2

1.5

4.1

21.2

1.9

11.9

2.3

0.2

4.8

7.1

17.1

1.3

19.0

0.9

7.7

6.2
10.3

12.2
3.2

2.2
3.5

13.6
3.6

0.6

3.8

Maier and Merikangas

DisorderGenetics of Depression

λ⫽

167

risk among first-degree relatives
risk among controls

is 1.9 [7]. The degree of familial aggregation of bipolar disorder is substantially stronger
with a mean relative risk of 7.9 [8]. No gender effect was found for these relative risks.
Speciﬁcally, a continuum mode of familial genetic liability to unipolar depression using
gender-speciﬁc thresholds to explain the higher prevalence in females (a higher liability
for males is requested for expressing the disease resulting in reduced prevalence) has been
ruled out [9].
What is the familial relationship between unipolar depression and bipolar disorder?
There is consistent evidence across a large number of family studies that unipolar depression is also more common among relatives of probands with bipolar disorder than expectedfrom general population prevalence rates; relative risks for unipolar depression among
relatives is very similar between probands with unipolar depression and with bipolar disorder (relative risk of 1.9). On the other hand, most family studies in probands with unipolar
depression did not ﬁnd elevated risks for bipolar disorder among biological relatives, although there are a minority of family studies reporting a substantially increased risk for
bipolar disorder among relatives of probands with unipolar depression [5,10,11]. It isdifﬁcult to decide if these latter studies are false positives. Therefore, it is difﬁcult todecide if
1. Unipolar depression and bipolar disorder are located on a familial genetic continuum of liability in a two-threshold model. Bipolar disorder has a stronger
familial genetic determination transmitting the risk for both disorders (higher
threshold in the model); however, unipolar depression, with the reduced familial
risk, is also a familial condition, with a lower familial risk for bipolar disorders(with a lower threshold in the model) [12: 106]; an increased risk for bipolar
disorder in families of probands with unipolar depression can be expected fromthis model, but is difﬁcult to be detected because of the low prevalence rate ofbipolar disorder.
2. Unipolar depression is etiologically heterogeneous with only a small minorityof cases carrying an increased risk for bipolar disorder: a smaller subgroup of
unipolar depression in the familial context of bipolar disorder versus a larger
subgroup of unipolar depression in absence of a familial relationship to bipolar
disorder.
Unfortunately, the currently available body of evidence does not prove either possibility.
B. Genetic Determination
Unipolar depression has been most widely investigated by twin studies (Table 2) in both
hospital- as well as population-based samples. All published twin studies (population- or
hospital-based) on unipolar depression suggest a genetic inﬂuence ranging between 30 to
50% with a mean of 37% [7]. The degree of heritability is comparable between males
and females. Thus, sex-speciﬁc genetic factors cannot explain the higher prevalence ofdepression among females. A reduced female–male to same-sex concordance in dizygotic
twins suggests that genes may exist that act differently on the risk of depression in males
and females [24].

168

Maier and Merikangas

Table 2 Twin Studies in Bipolar Disorder and Unipolar Depression
Sample size
Disorders

Refs.

Sample
H/C—country a

Bipolar disorder

13
14
15
16
17
18

H-Norway
H-U.S.
H-Denmark
H-Norway
H-Sweden
H-U.K.

6
5
34
4
13
22

Unipolar depression

19
19
20
21
22
23

H-Sweden
C-Sweden
H-U.K.
C-U.S.
C-Australia
C-U.S.

57
97
68
1874
1323
1368

a

MZ
pairs

DZ
pairs

Concordance
MZ

DZ

—
15
37
6
22
27

67%
20%
62%
75%
39%
36%

—
0%
8%
0%
5%
7%

157
169
109
1498
1339
2422

41%
54%
46%
23%
42%
39%

27%
33%
20%
14%
35%
30%

Sample ascertained from Hospital (H), Community (C) population.

The majority of twin studies on unipolar depression further decomposed the nongenetic component into a component shared by both twins and an individual-speciﬁc component. Consistently across all studies the individual-speciﬁc component was substantiallystronger than the shared environmental component, and exceeded the impact of the genetic
component by magnitude; in most studies the shared environmental component was negligible in the model-based variance analysis [20,25,26].
As a limitation, the individual-speciﬁc environmental component also includes variance because of the measurement error that might be substantial in lifetime assessmentof depressive episodes (because of memory problems). Twin studies with a follow-up
component (two distant time points of clinical lifetime assessments) can estimate the relative impact of the measurement error; using this strategy, Kendler et al. [27] extracted
the variance emerging from measurement error by a model-based analysis of heritabilityon the remaining variance in the Virginia twin study in females. As a result, the magnitudeof the individual-speciﬁc environmental component decreased considerably, and the estimate for the heritability was doubled and raised to 70%.
In contrast to unipolar depression, the number of twin and adoption studies on bipolar disorder is relatively small; however, results are more equivocal and genetic factors
deﬁne most of the proportion of variance. The heritability of bipolar disorder as evidenced
in twin studies was estimated as 0.59% [8]. Given the overwhelming evidence of a major
genetic component, bipolar disorder became the ﬁrst psychiatric disorder to be submitted
to linkage analysis 30 to 40 years ago.
Adoption studies are another tool used to demonstrate genetic determination of adisorder. This method received little attention during the past decade and available samples
are small. The two major adoption studies of bipolar disorder found an approximately
three-fold increased risk of bipolar disorder among biological compared to adoptive relatives of probands [28,29]. The results of two adoption studies conducted on unipolar depression yielded evidence for signiﬁcantly increased rates of mood disorders after adoption[29,30]. In contrast, a third study in unipolar depression did not ﬁnd evidence for increased

Genetics of Depression

169

rates of mood disorders among biological compared to adoptive relatives of adopted mooddisorder probands [31]; however, this study suffers from methodological insufﬁciencies(no personal interviews).
C. Modiﬁers of Familial Genetic Inﬂuences on Unipolar Depression
Severity and course of mood disorders is interindividually variable, stimulating speculations on a familial genetic inﬂuence. Thus, three study questions have been explored:
1. Familiality of and genetic inﬂuence on severity of symptoms.
2. Familiality of and genetic inﬂuence on age at onset.
3. Familiality of and genetic inﬂuence on recurrency or chronicity of the courseof the disease.
Heritability to unipolar depression apparently varies along a dimension of severity
indexed by number of symptoms and degree of impairment, with more severe cases carrying a stronger genetic component: A recent, population-based telephone interview twin
study proposed that depression with mild or only modest degree of severity is under genetic control [21]. This conclusion is supported by prior twin studies [16], but not byanother large population-based twin study [27,32]. A hospital-based twin study argues fora universal genetic inﬂuence on unipolar depression [20]; given that hospital care is delivered to more severe cases, this observation is compatible with the variation of the magnitude of the genetic component along a dimension of severity in population-based studies.
On the other hand, low severity of depression is likely to be correlated with under-reportingand measurement error; thus, heritability of low-severity depression might be underestimated. A series of family studies proposed a reciprocal relationship between age at onset
across the lifespan and degree of familial loading: (1) it has been demonstrated that lateonset depression goes together with a lower familial risk [33–35]; (2) however, it remains
unclear if this reciprocal linear relationship between age at onset and familial loading also
extends to childhood and adolescence.
Twin studies with a high proportion of young adults provide no conclusive evidence
for this relationship [32:21]. Assuming the inverse linear relationship, a higher familialloading among adolescent probands with depression would be the consequence. This assumption is supported by a recent German study in adolescents using the family history
method yielding the maximal relative risk in relatives (parents) for unipolar depression:
the relative risk for depression in parents of depressed probands was increased by an odds
ratio of 2.7 (with conﬁdence interval 2.1–3.5) [36]. However, Klein et al. [37], using themore valid and reliable family study method reported an odds ratio of 1.8 for the risk,
which is not higher than the mean relative risk found in the family studies in adults. Some
prospective studies in adolescents were also unable to conﬁrm a stronger familial genetic
impact on early-onset depression [38,39].
Two reasons might contribute to the inconsistencies across studies with regard to
the impact of early age at onset:
1. The concept of early-onset depression might be inappropriate: genetic inﬂuence
was observed to be stronger in adolescent than in prepubertal depression, withthe latter showing a pattern of familial clustering that is similar to adult-onset
cases [40,41].
2. Greater heterogeneity in early-onset cases: prospective studies demonstrated alack of longitudinal speciﬁcity of unipolar depression (in contrast to bipolar

170

Maier and Merikangas

disorder); early-onset unipolar depression is strongly intraindividually associated with anxiety disorders and often subsequently develops into pure anxiety
disorder [41]; however, Klein et al. [40] did not observe greater familial riskin adolescent depression.
In sum, the concept of early-onset major depression needs further familial genetic
study before early onset can be considered as an indicator of greater familial genetic risk.
A relationship between increased familial genetic risk and early onset has not yet been
convincingly established because of the lack of sufﬁcient study.
Some studies proposed a linear relationship between recurrence and familial risk inunipolar depression [32,42]. Other factors predictive for the familial variant of unipolar
depression are longer duration of episodes and recurrent thoughts of death and suicide [32].
In bipolar disorder, a differential familial genetic background of early versus lateonset subtypes was proposed and empirically supported [43]. In addition, intrafamilial
association of the age at onset in bipolar disorder proposes direct or indirect genetic inﬂuence [44].
D.

Subtypes of Affective Disorders

The search for disease genes in some complex disorders took an enormous advantage ofmore homogeneous clinical subgroups with greater genetic risk and Mendelian modes oftransmission (e.g., Alzheimer’s disease and breast cancer with early-onset cases deﬁning
those homogeneous groups).
Classic clinical concepts of unipolar depression proposed a dichotomy between two
subtypes: one being biologically and genetically determined, and another being of psychosocial origin without biological etiology. According to this distinction, two different patterns of familial aggregation of depression should be observable. Andrew et al. [45] tested
this hypothesis in a hospital-based twin series and were able to reject it. Maier et al. [46]and Fanous et al. [47] explored whether melancholia deﬁnes a distinct familial genetic
subtype and found no support for a stronger familial determination. Thus, although there
might be a quantitative variation of the magnitude of genetic determination along thevarious clinical and biological correlates of unipolar depression, clinical distinctions basedon the melancholia/endogenous depression concept or absence/presence of psychosocial
risk factors are not reﬂecting this putative variation.
Dysthymia is a chronic low-grade form of unipolar depression characterized by disturbed mood and vegetative functions, whereas depressive personality disorders describe
persistent depressionlike cognitive sets of low self-esteem and negative anticipation andpessimism. Both conditions are familial and belong to a unipolar depressive spectrumwith shared familial liability [48]. Each of the chronic variants shows diagnostic speciﬁcity
as well as nonspeciﬁcity in familial aggregation; in particular, the chronic variants, dysthymia and depressive personality disorders, go together whereas the risk for dysthymia infamilies of probands with depressive episodes in absence of dysthymia is only slightly
increased [49]. One extended twin sample proposed a modest genetic inﬂuence on dysthymia comparable by magnitude to unipolar depression [21].
Bipolar disorder requires the presence of full-blown depressive and manic episodes(bipolar I disorder). Milder variants of manic episodes are called hypomania and deﬁnebipolar II disorder (full depressive episodes and separated hypomanic episodes). Highlyrecurrent hypomanic and recurrent subthreshold depression deﬁne cyclothymia. Are thesesubtypes genetically distinct entities, or are all of them variants of bipolar I with similar

Genetics of Depression

171

familial patterns of aggregation? Unfortunately, systematic twin studies exploring thesequestions have not been published. However, some family studies addressing these issues
are available. Those family studies [3,6,50,57] report bipolar II disorder to be familial
and observed a coaggregation with bipolar I disorder and unipolar depression. The familial
pattern of aggregation among bipolar II probands is more similar to bipolar I than to
unipolar depression probands. Simultaneously, bipolar II was most common among relatives of bipolar II probands, which supports bipolar II as being a partially distinct category
in a familial genetic perspective. In this vein, some pedigree analyses support familial
homogeneity of bipolar II disorder without coaggregation of bipolar I disorder [52]. Thus,
it remains unclear if bipolar I and II are alternative expressions of the same liability. A
familial relationship between cyclothymia and bipolar disorder was also reported. The
familial relationship to unipolar depression seems to be less strong [53–55].
Affective disorders, particularly bipolar disorder, are strongly associated with suicidal ideation and behavior. However, this association cannot explain that suicidal ideation
and behavior is familial and genetically inﬂuenced. Adoption and twin studies have convincingly demonstrated that the familial genetic basis of suicidal behavior is in large part
independent of associated familial mental disorders. Schulsinger et al. [56] and Wender
et al. [29] were the ﬁrst to propose this hypothesis on the basis of a small Danish adoption
study covering multiple psychiatric diagnoses. In the meantime, two extended twin studies(one in the U.S. by Fu et al. [57], and one in Australia by Statham et al. [58]) supported thishypothesis and demonstrated that suicidal ideation and suicidal attempts are geneticallyinﬂuenced but most of the variance was explained by shared and nonshared environmental
factors. Both studies differ in the magnitude of genetic inﬂuence on suicidal attempts vs.
ideation. Twin studies also demonstrated that completed suicide is under genetic control[59]. Another family study demonstrated familial genetic links between completed suicideand suicide attempts [60]. Thus, affective disorders with suicidal ideation or behavior
might deﬁne a genetically distinct and even more complex group than affective disorders
as a whole.
E.

Familial Genetic Relationship to Other Disorders

Nearly all family studies observed a lack of familial speciﬁcity for affective disorders.
Most nonspeciﬁcity was reported for offspring of probands with affective disorders(mainly bipolar disorder) [61]; cosegregation was particularly observed for various anxiety
disorders, attention deﬁcit hyperactivity, and other behavioral problems.
Historically, the relationship between affective and psychotic disorders received
most attention. The family and twin studies dedicated to this study question can be summarized by the following conclusions:
1. Schizoaffective disorders are not only at a higher risk for affective disorders
but also for a higher risk for psychotic disorders (including schizophrenia) [62].
2. Affective disorders with psychotic symptoms (beyond schizoaffective disorder)
were reported to be more common among relatives of probands with schizophrenia than would be expected by chance [63].
3. Most family studies were unable to ﬁnd a familial relationship between nonpsychotic affective disorders and schizophrenia. In contrast, some controlled family
studies propose an elevated risk of nonpsychotic unipolar depression among
relatives of probands with schizophrenia but not with bipolar disorder [62,64].
4. Recently, a British twin study ignoring diagnostic hierarchies proposed a rela-172

Maier and Merikangas

tionship between schizophrenia and mania [65]. An excess of schizophrenia
among relatives of probands with affective disorders is not reported in any ofthe larger controlled family studies, although speculations on anticipation operating in bipolar disorder suggested increased risk of schizophrenia among
offspring [66].
Thus, there is some evidence of overlapping familial genetic conditions between
affective disorders, on one hand, and psychotic disorders, on the other hand. Linkage
studies recently shed new light on this relationship (see below).
The family studies in bipolar disorder proposed a familial genetic subset of patientswith comorbid panic disorder (or panic attacks) [67]. The combined diagnosis revealed
strong familial clustering but was not associated with increased familial risk for pure panic
disorder. This constellation suggests that the comorbid diagnosis deﬁnes an etiologicallydistinct entity and not just the combination of two familial conditions. In those families,
panic disorder was similarly intraindividually combined with bipolar I and bipolar II disorders. The validity of this comorbid subtype was further supported by subsequent linkage
and association studies (see below). The familial genetic relationship of unipolar depression to anxiety disorders is discussed in more detail in Chapter 9.
The relationship between mood disorders and alcoholism has been explored extensively during the last three decades mainly by family studies. Intraindividual co-occurrenceis high not only among the index cases but also among relatives. Overall, the links ofalcoholism with bipolar disorder seem to be stronger than with unipolar depression. The
conclusions on shared familiality are diverse. Some studies found intrafamilial cosegregation of bipolar disorder or unipolar depression, respectively, and alcoholism [68–70],
whereas the majority of investigators were unable to observe this relationship [11,71–76].
One study came to divergent conclusions depending on the mode of data analysis [77].
Furthermore, an extended twin study in the general population found that the observed
comorbidity between major depression and alcoholism (with an odds ratio of 2) is nearlyexclusively due to common genetic factors [78]. Thus, if there is any communality offamilial genetic risk factors between mood disorders and alcoholism, it is of limited degree
and, therefore, difﬁcult to detect.
It has been speculated that speciﬁc diagnostic subgroups of unipolar depression
reveal a stronger familial genetic link to alcoholism; for example, Winokur et al. [79]proposed to subdivide unipolar depression into three groups according to family history—
familial loading with unipolar depression only, with alcoholism, and with absence of familial loading. Although the diagnostic distinctions received some subsequent support by thesame group [68] they did not hold up in other family studies [80].
Finally, the excess comorbidity between eating disorders and affective disorders
stimulated familial genetic inquiries; they often go together in a complex neurobiologicalrelationship. Interest in this relationship recently emerged from the detection of the orphasin gene (with functions in affect, eating, and sleeping). As expected, there is not only
cosegregation in families but also a genetic relationship; twin studies have also demonstrated that unipolar depression has similar genetic determinants as anorexia [81]; therelationship to bulimia seems to be less strong [82].
F.

Interplay Between Genes and Environment

Epidemiological and clinical research identiﬁed several environmental and personal risk
factors for unipolar depression [83–86]: (1) female gender; (2) critical life events andGenetics of Depression

173

daily hustles in the temporal context of the depressive episode; (3) early emotional environment (e.g., parental warmth); (4) early traumas during childhood; (5) head injury inearly adulthood; (6) lack of social support; (7) depressionlike personality factors such asincreased neuroticism; and (8) previous psychiatric and somatic diseases (e.g., anxiety
disorders, alcoholism, or cardiovascular diseases).
Genetic as well as environmental factors contribute to affective disorders. The modeof their interplay is extensively explored for unipolar depression. Different mechanisms
to combine environmental and genetic factors can mediate depressive episodes:
1. Are these risk factors operating independent of the genetic risk factors (independent relationship)?
2. Does their impact depend on the amount of genetic risk (interaction)?
3. Some of these risk factors are genetically inﬂuenced: do those genetic inﬂuences
on risk factors contribute to the hereditary basis of depression (correlation)?
All of these possible mechanisms operate for speciﬁc environmental factors in unipolar depression:
1. Independence: Gender as a risk factor neither interacts nor correlates with thegenetic risk for depression [87].
2. Interaction: The effect of critical life events on depression is stronger in thepresence of increased genetic risk; one family study even found that life events
only induce depression in the presence of a history of emotional disorders inparents [41,88].
3. Correlation: Life events reveal some heritability pointing at the genetic mediation of life events that are dependent on the proband’s behavior [83]. It has also
been shown that this is the case particularly for life events that increase the riskfor depression [84]. In addition, the fact that speciﬁc environmental risk factors
operate independently cannot be excluded.
Which environmental factors have a powerful impact on major depression in the absenceof substantial genetic risk? One strategy to approach this question is to compare two
discordant monozygotic twins; the rationale is that strong genetic factors would most likely
be associated with the presence of depression in both twins. The comparison between
affected and unaffected monozygotic twins proposed childhood vulnerability and interpersonal difﬁculties as most inﬂuential environmental determinants [89]; pregnancy and perinatal complications might be of relevance for early-onset bipolar disorders [90].
Thus, the biometric analyses reveal that the interaction of genetic and environmental
factors is extremely complex. Further reﬁnement of this puzzle can be expected once
speciﬁc susceptibility genes have been identiﬁed. However, the search for susceptibility
genes is severely hampered by the interaction with environmental factors.
II. SEARCH FOR SUSCEPTIBILITY GENES ON A DNA LEVEL
The search for disease genes on a DNA level starts with localization on the genome. For
this purpose, two strategies are available: linkage analysis in families with multiple affecteds, and linkage disequilibrium/association studies in case-control or nuclear family samples. Genetic variability occurs so frequently on the genome on a population level that avariant at a speciﬁc polymorphic site is in linkage disequilibrium (association) with variants at multiple other loci in close neighborhood. Thus, linkage to a locus or association

174

Maier and Merikangas

with an allele or haplotype does not mean that the linked/associated locus/allele is involved in the etiology of the disease; instead, such a ﬁnding identiﬁes a candidate regionand stimulates extensive ﬁne mapping and, subsequently, functional studies in order to
identify the disease gene.
The most direct approach in the search for disease genes relies on the knowledgeof pathophysiology and of involved gene products (candidate-gene approach). Given thelinkage disequilibrium along the genome, a genome-wide search for disease genes is possible using high-throughput techniques [91], yet it is technically difﬁcult to perform. In thenear future, genome-wide association studies will be technically feasible but will requirehuge sample sizes. Currently, a genome-wide strategy is only technically feasible withthe linkage approach because of the lower spatial resolution of this method (⬃500 appropriately placed markers required). Unfortunately, genes with minor effect (odds ratio
1: 2) have only a low chance of being detected by the linkage strategy. In contrast, thelinkage disequilibrium/association strategy is substantially more powerful for small geneeffects [92].
Thus, a most promising research strategy is to combine these possibilities and (1)to identify linked candidate regions on the genome by linkage analyses; (2) replicate thelinkage ﬁnding and, in the positive case, (3) ﬁnemap the region using a linkage disequilibrium strategy to further narrow down candidate interval.
A.

Genome-Wide Linkage Analysis

Given the stronger genetic inﬂuence, bipolar disorder was until now the most frequently
investigated affective disorder with regard to linkage analysis. Bipolar disorder was eventhe ﬁrst psychiatric disorder where linkage analysis was applied. As early as 1969, bipolar
disorder was reported to be linked to a monogenic disease, color blindness, and/or to
glucose-6-phosphate dehydrogenase deﬁciency with genes located on chromosome Xq2628 [93,94]. In multiple subsequent studies, this ﬁnding was only partly replicated [95].
However, a recent linkage scan in a single extended Finnish pedigree proposed linkage
to a nearby locus Xq25-26 [96], raising the possibility of genetic heterogeneity. Early
enthusiasm motivated by the upcoming molecular genetic opportunities was particularly
dampened by the nonreplication of the linkage to chromosome 11p initially reported in
an isolate pedigree (Amish population) [97,98].
Meanwhile genome-wide linkage analyses using informative marker systems likemicrosatellites became feasible. Twelve genome-wide linkage scans have been published;for summary of all studies published till early 2001, see Refs. 99, 100. The chromosomal
regions suggested to be linked to bipolar disorder are broad, usually covering 20 to 40 cM.
The strength of linkage for all proposed candidate loci is moderate at best, with mostly“suggestive” linkage according to the criteria of Lander and Kruglyak [101]. The maximal
lod score observed for bipolar disorder is 3.8 to 10p [100]. Not a single linkage to a
speciﬁc region received support from all or even the majority of scans. However, at least
some of the genome scans found suggestive linkage to some region. Loci emerging fromat least two of the published linkage scans are: 1q21-42, 4p16, 10q21-26, 12q23-24,
13q11-32, 18p11, 22q11-12 [102]. Two very recently published genome scans [100,103]
provided further support to some of these linkages.
The vast majority of implicated studies are samples of affected pairs of siblings
recruited in outbreed populations. Although it is believed that these samples are particularly informative, linkage analysis in isolate families with a high density of affected cases

Genetics of Depression

175

might accelerate the detection of susceptibility genes: given the homogeneous population
background and the possibility that the disease was introduced to the isolate by a single
or only a few founders, fewer susceptibility genes, but with stronger effects, are likely tocontribute to the disease. Haplotype analysis can efﬁciently narrow down candidate regions to regions covering less than 10 cM in extended multiplex families. A linkage study
in a French-Canadian isolate pedigree demonstrates these putative advantages [104–106].
Limitations of statistical power inherent in the available linkage analyses propose
a combination of family samples or a meta-analysis (combination of P values) to select“true” candidate regions. Badner and Gershon [99] performed a meta-analysis across 11
published linkage scans and found strongest evidence for susceptibility loci for bipolar
disorder on chromosome 13q11-32 ( p ⬍ 6 ⫻ 10⫺6 ) and on chromosome 22q11-12 (p ⬍1 ⫻ 10⫺5 ). The other candidate loci did not receive strong support for linkage; on theother hand, a meta-analysis cannot exclude linkage to these regions.
The broad variation of results and high inconsistency between various studies is not
an argument against the validity of the linkage approach. Two main reasons explain thediversity of results across studies:1. The available sample sizes are too small to create consistent results. If multiple
genes contribute, the sample size required for the detection of linkage to anyof the susceptibility genes is substantially smaller than the sample size required
to replicate this speciﬁc ﬁnding [107]; thus, given the limitations of power andsample size inherent in the published scans, a high rate of nonreplications canbe expected.
2. Disorders that are under the inﬂuence of multiple genes are likely to be genetically heterogeneous. The genes contributing and their effect sizes might differ
across the population of affecteds (e.g., between severe and less severe cases)
and by the genetic population background; another possibility is pleiotropy (i.e.,
multiple different genetic constellations produce the same phenotype). Thus,
samples of pairs of affected siblings might differ partly between recruiting sites
even within the same country, between countries, and ethnicities. In addition,
etiologically different subgroups might be driven by different susceptibility
genes as has been recently proposed by Rotondo et al. [108] for bipolar disorderin combination with panic disorder. The variation of proportions of speciﬁc
subtypes across samples might produce divergent linkage results.
Despite these ambiguities it can be concluded from these results that bipolar disorder
is not inﬂuenced by a single major gene; instead, multiple susceptibility genes each with
only a mild-to-modest effect are likely to operate.
Some of the candidate regions detected for bipolar disorders are overlapping withcandidate regions linked to schizophrenia [109]. Some authors interpret this constellation
as a hint in favor of a common genetic basis for affective disorder and schizophrenia.
Yet, this conclusion is premature. Because there are thousands of genes in these regions,overlap of candidate regions cannot be interpreted as identity of genes being involved forboth disorders. On the other hand, the degree of overlap cannot be explained by random
ﬂuctuation alone.
Up to now, no genome-wide linkage scan has been performed in unipolar depression;
yet, currently, two major linkage efforts are in progress. The only reported linkage studies
in unipolar depression focus on candidate genes with no evidence of statistically signiﬁcantlinkage [101] in a sample with “pure depressive disorder” with recurrent episodes [110].

176

B.

Maier and Merikangas

From Candidate Regions to Candidate Genes

Given the higher power and the ﬁner spatial resolution of association/linkage disequilibrium studies, this technique has to be applied to polymorphic candidate genes located inregions linked to the disease (positional candidates). In this context, candidate genes thatare functionally involved in the pathophysiology of bipolar disorder according to the current knowledge are of interest (positional as well as functional candidates). Some candidates in the linked regions are of particular functional interest and have therefore been
explored recently:
1.
2.
3.

4.

Myo-inositol monophosphatase (IMPA2), a key enzyme of lithium on chromosome 18p11.2 [111,112].
G-protein-coupled receptor kinase-3 on chromosome 22q11, which is differentially expressed in an animal model for psychotic mania [113].
Gene coding with multiple mutations for Wolfram syndrome (WFS1), an autosomal recessive disease that is characterized by frequent comorbidity withaffective disorders and located on chromosome 4p16 [114–117].
Gene coding for Darier’s disease, an autosomal dominant dermatological disease with frequent comorbidity with affective disorders on chromosome 12q2324; this gene expresses the protein calcium-ATPase in the endoplasmic reticulum [118].

Although a few of these studies reported borderline signiﬁcant associations, a relationship of any of these candidate genes to bipolar disorder has not as yet been established.
C.

Genetic Association Studies

Numerous association studies (mainly case-control comparisons) were conducted in affective disorders with a broad range of candidate genes. Recent research preferentially
focused on genes coding for receptors, transporters, and enzymes involved in monoaminergic transmission. The results are extremely conﬂicting with multiple claims for associationthat could not be replicated. Given the small magnitude of genetic effects to be identiﬁed
and limitations in sample size, perfect consistence of multiple replication tests cannot be
expected even for a “true” positive ﬁnding. Meta-analyses are useful under this condition
or at least a considerable proportion of successful replication tests of an initially positiveﬁnding. In this perspective, several genetic variants of candidate genes reveal some evidence for an association with affective disorders.
The strongest association to bipolar disorder is reported for a variant of the monoamine oxidase A (MAO-A) gene. MAO-A operates as a candidate, given the efﬁcacy of
MAO-A inhibitors in antidepressant treatment. There has been suggestive evidence foran association between bipolar disorder and a CA repeat variant in intron 2 [119], although
not all replication tests unequivocally conﬁrm this overall (e.g., Refs 120, 121). Unfortunately, association to functional genetic promoter variants was excluded in moderate-sized
samples [122].
Most frequently, the relationship to the promoter polymorphism of the serotonintransporter gene has been studied. The polymorphism is functionally relevant, and an
association of affective disorders to the short allele has been proposed [123]. A former
meta-analysis proposed a small effect of this variant in bipolar disorder [124], with anincreased odds ratio of 1.2, but subsequent studies were mainly negative [120,125,126].

Genetics of Depression

177

The evidence for association of this genetic variant to unipolar disorder is less conclusive.
However, heterogeneity might prohibit consistent results (e.g., an association of the smallallele with the clinical subtype of seasonal depression was reported [127,128]). The associations of the short allelic variant to the personality factor “neuroticism” appear to be morestable [129–131].
Unfortunately, neither of these two candidate genes with variants in suggestive association with bipolar disorder are located in any of the candidate regions for bipolar disorderfound by linkage analysis.
Other polymorphisms, such as the tyrosine hydroxylase (TH) gene, the tryptophanhydroxylase (TPH) gene, the COMT gene, or the serotonin and dopamine receptor genes,
provided only inconclusive or negative results in association studies with bipolar disorder
or unipolar depression [132].
The view that unipolar depression is under the control of the same genes independentof the age at onset has recently been challenged by an inquiry in late-onset depression:
this condition was associated with a mutation in the methylenetetrahydrofolate reductase
enzyme gene (MTHFR) in contrast to early-onset depression. The same mutation is predisposing to cerebrovascular diseases and is associated with increased plasma homocysteine
and folate deﬁciencies which were also reported for late-onset depression [133].
D. Cytogenetic Techniques
Besides the main stream of linkage and genetic association studies, a few groups usedcytogenetic techniques to search for gene loci that implicate the disease through chromosomal abnormalities (particularly translocations and deletions). A series of regions were
found which, unfortunately, did not overlap with regions linked to the disease (for overview see Ref. 132). Of particular interest is a Scottish family with several psychoses,
bipolar disorder, and unipolar depression with a balanced translocation between two genes(chromosomes 1q42, 11q14.3). A gene in 11q14.3 disrupted in affected family members(DISC1) with up-to-now unknown function was detected and needs further investigation[134].
E.

Search for Genes Using Speciﬁc Modes of Transmission

Speciﬁc features of the familial aggregation of affective disorders have been proposed.
1. Anticipation
According to some family studies, the vertical transmission of bipolar disorder from one
generation to the next goes together with a decrease of the age at onset [135]. This phenomenon can be explained by multiple mechanisms. One possibility in this context is genetically mediated anticipation that can be caused by expansion of trinucleotide repeats at the
mutated disease gene locus (dynamic mutations). This kind of mutation codes for the socalled polyglutamine disease (like Huntington’s), which shows anticipation on a phenotype level. Using the repeat expansion detection (RED) method, the maximal lengths oftrinucleotide alleles were compared for the whole genome between probands with bipolar
disorder and controls in multiple studies. Conclusive results were not obtained [136,137].
This negative conclusion does not rule out the hypothesis because the RED method might
be too insensitive to detect the majority of dynamic mutations across the genome.

178

Maier and Merikangas

2. Parent-of-Origin Effects
Patients with bipolar disorder have more mothers than fathers with the same disease [135].
Although multiple nongenetic causes might explain this constellation in complex diseases,
two genetic mechanisms might account for this pattern:
1.

2.

F.

Genetic imprinting: DNA methylization might operate speciﬁcally for speciﬁcmaternal alleles of maternal decent with the consequence that the mutated paternal mutations at a disease locus are preferentially expressed. Indeed, at least oneof the proposed linkages to bipolar disorder—18p11—is limited to paternallytransmitted pedigrees; however, this speciﬁc linkage is not very strong andmight be a false positive.
Mitochondrial transmission: genetic information is also transported by mitochondria which are exclusively transmitted from the mother. Furthermore, mitochondrial dysfunction is also proposed by other lines of evidence [138]. The
whole mitochondrial genome was sequenced in several studies [132,139,140]
without a consistently conﬁrmed signiﬁcant result. Yet, one variant (the 10398A
polymorphism) has been found with increased frequency in two studies. However, causal mechanisms might also arise from different haplotype patterns andnot only from variations at a single site; this possibility [139] has to be further
evaluated.

Pharmacogenetics

The broad interindividual variation of response to treatment is partly due to the interindividual variability: multiple functional sequence variation sites in metabolizing enzymes
and transport, target, and effector proteins are likely to inﬂuence individual side effects
and effectiveness [141]. Empirical evidence supports this assumption. Response to longterm lithium treatment in multiple cases within the family was found to be correlated. Also,
plasma levels of most antidepressants are inﬂuenced by the cytochrome P450 metabolizing
system, which reveals broad genetic variation (e.g., resulting in pure and fast metabolizers); plasma levels have some impact on side effects and effectiveness (although a linear
relationship or a “therapeutic window” has not been detected).
The ﬁeld of pharmacogenetics promises to provide DNA markers and haplotypes
for prediction of drug response, and to improve the opportunity for individualized treatment [142]. However, progress of knowledge with regard to antidepressants is slow because of the lack of appropriately sized prospective controlled pharmacological treatment
programs with a pharmacogenetic component (which are accessible to the academic community). Up to now, few pharmacogenetic studies investigated the impact of the variationin the serotonin receptor or transporter genes and their promoters on response to selective
serotonin reuptake inhibitors (SSRIs) and to lithium. The short allele in the promoter ofthe serotonin transporter gene was associated with poor responses to SSRIs, according
to Zanardi et al. [143]; Kim et al. [144] reported a conﬂicting result with regard to thehomozygotes for the short allele. The same allele was associated with response tolithium [145].
Despite the currently disappointing results in the search for genetic predictors ofantidepressants, major progress can be expected with the advent of informative clinical
trials and new genotyping techniques.

Genetics of Depression

179

III. CONCLUSIONS
The detection of genes coding for mood disorders turned out to be substantially more
difﬁcult than anticipated. This constellation is currently identical for all genetically complex disorders, and the consequences are also the same. The growing opportunities emerging from the progress of human genomics, neurosciences, biostatistics, and epidemiology
justify optimistic perspectives. The current research trends in psychiatric genetics support
this view.
1. The application of the opportunities for DNA genotyping (e.g., SNPs or chiptechnology) will increase efﬁciency, reduce costs, and encourage new strategies
as genome-wide case-control studies for the search of susceptibility genes [91];
the huge case-control samples needed for this new approach are currently recruited in many places.
2. The growing knowledge on linkage disequilibrium across the genome and therelevance of population backgrounds will inform the search for disease genes
and improve the understanding of the variation of results across samples andpopulations (for an overview, see Refs. 146, 147). New methods using the diversity of haplotypes across the genome have already been successful in unravelingthe genetic basis of complex diseases (e.g., Crohn’s disease) [148].
3. The extraction of genetically relevant phenotypes that are more closely related
to the genes underlying the disease [149] will accelerate the successful searchfor disease genes; the clinical diagnosis will not remain the only way to deﬁne
the phenotype. Clinical subtyping of diagnostic entities is also a new and promising approach to extract biologically meaningful phenotypes (e.g., Ref. 150).
4. The progress of the functional genetics and genomics, of transgenic and proteomic methods allow the detection of new pathways, and improves the understanding of gene function in the brain; new candidate gene families emerge fromthose innovative research activities (for an overview, see Ref. 151).
5. The emerging collaboration between genetics, neuroscience, epidemiology, andclinical research [1] will replace the small groups of investigators, and will
shift the ﬁeld from a purely hypothesis-free genome-wide search to an informed
genome-wide search for disease genes (without focusing on well-establisheddisease genes).
Thus, the lack of knowledge of fully conﬁrmed susceptibility genes for unipolar
depression or bipolar disorder will not discourage further research aimed at the geneticarchitecture of mood disorders. Furthermore, the emerging discipline of pharmacogenetics
will contribute to an improvement of antidepressant treatment.
REFERENCES
1. Merikangas KR, Chakravarti A, Moldin S, Araj H, Blangero J, Burmeister M, Crabbe J,
DePaulo R, Foulks E, Freimer N, Koretz D, Lichtenstein W, Mignot E, Reiss A, Risch N,
Takahashi J. Future of genetics of mood disorders research. Workgroup on Genetics for
NIMH Strategic Plan for Mood Disorders. Biol Psychiatry, in press.
2. Gershon ES, Mark A, Cohen N, Belizon N, Baron M, Knobe K. Transmitted factors in
the morbid risk of affective disorders: a controlled study. J Psychiatr Res 1975; 12:283–
299.

180

Maier and Merikangas

3. Gershon ES, Hamovit J, Guroff JJ, Dibble E, Leckman JF, Sceery W, Targum SD, Nurnberger JI Jr, Goldin LR, Bunney WE Jr. A family study of schizoaffective, bipolar I, bipolarII, unipolar, and normal control probands. Arch Gen Psychiatry 1982; 39:1157–1167.
4. Weissman MM, Kidd KK, Prusoff BA. Variability in rates of affective disorders in relativesof depressed and normal probands. Arch Gen Psychiatry 1982; 39:1397–403.
5. Tsuang MT, Faraone SV, Fleming JA. Familial transmission of major affective disorders.
Is there evidence supporting the distinction between unipolar and bipolar disorders? Br J
Psychiatry 1985; 146:268–271.
6. Heun R, Maier W. The distinction of bipolar II disorder from bipolar I and recurrent unipolar depression: results of a controlled family study. Acta Psychiatr Scand 1993; 87:279–284.
7. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: review andmeta-analysis. Am J Psychiatry 2000; 157:1552–1562.
8. Tsuang MT, Faraone SV. The Genetics of Mood Disorders. Baltimore: John Hopkins, 1990.
9. Merikangas KR, Weissman MM, Pauls DL. Genetic factors in the sex ratio of major depression. Psychol Med 1985; 15:63–69.
10. Weissman MM, Gershon ES, Kidd KK, Prusoff BA, Leckman JF, Dibble E, Hamovit J,
Thompson WD, Pauls DL, Guroff JJ. Psychiatric disorders in the relatives of probands withaffective disorders. The Yale University–National Institute of Mental Health Collaborative
Study. Arch Gen Psychiatry 1984; 41:13–21.
11. Preisig M, Fenton BT, Stevens DE, Merikangas KR. Familial relationship between mooddisorders and alcoholism. Compr Psychiatry 2001; 42:87–95.
12. Faraone S, Tsuang MT, Tsuang DW. Genetics of Mental Disorders. New York: Guilford,
1999.
13. Kringlen E. Hereditary and environment in the functional psychoses. London: Heinemann,
1967.
14. Allen MG, Cohen S, Pollin W, Greenspan SI. Affective illness in veteran twins: a diagnostic
review. Am J Psychiatry 1974; 131:1234–1239.
15. Bertelsen A, Harvald B, Hauge M. A Danish twin study of manic-depressive illness. Br J
Psychiatry 1977; 130:330–351.
16. Torgersen S. Genetic factors in moderately severe and mild affective disorders. Arch Gen
Psychiatry 1986; 43:222–226.
17. Kendler KS, Pedersen NL, Johnson L, Neale MC, Mathé AA. A pilot Swedish twin studyof affective illness including hospital- and population-ascertained subsamples. Arch Gen Psychiatry 1993; 50:699–706.
18. Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ, Venturi P,
Jones LA, Lewis SW, Sham PC, Gottesman II, Farmer AE, McGufﬁn P, Reveley AM, Murray RM. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series.
Arch Gen Psychiatry 1999; 56:162–168.
19. Kendler KS, Pedersen NL, Neale MC, Mathé AA. A pilot Swedish twin study of affective
illness including hospital- and population-ascertained subsamples: Results of model ﬁtting.
Behav Genet 1995; 25:217–232.
20. McGufﬁn P, Katz R, Watkins S, Rutherford J. A hospital-based twin register of the heritability of DSM-IV unipolar depression. Arch Gen Psychiatry 1996; 53:129–136.
21. Lyons MJ, Eisen SA, Goldberg J, True W, Lin N, Meyer JM, Toomey R, Faraone SV, MerlaRamos M, Tsuang MT. A registry-based twin study of depression in men. Arch Gen Psychiatry 1998; 55:468–472.
22. Bierut LJ, Heath AC, Bucholz KK, Dinwiddie SH, Madden PAF, Statham DJ, Dunne MP,
Martin NG. Major depressive disorder in a community-based twin sample: are there different
genetic and environmental contributions for men and women? Arch Gen Psychiatry 1999;
56:557–563.
23. Kendler KS, Prescott CA. A population-based twin study of lifetime major depression inmen and women. Arch Gen Psychiatry 1999; 56:39–44.

Genetics of Depression

181

24. Kendler KS, Gardner CO, Neale MC, Prescott CA. Genetic risk factors for major depression
in men and women: similar or different heritabilities and same or partly distinct genes? Psychol Med 2001; 31:605–616.
25. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. A population-based twin studyof major depression in women. The impact of varying deﬁnitions of illness. Arch Gen Psychiatry 1992; 49:257–266.
26. Lyons MJ, True WR, Eisen SA, Goldberg J, Meyer JM, Faraone SV, Eaves LJ, Tsuang MT.
Differential heritability of adult and juvenile antisocial traits. Arch Gen Psychiatry 1995; 52:
906–915.
27. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. The lifetime history of major
depression in women. Arch Gen Psychiatry 1993; 50:863–870.
28. Mendlewicz J, Rainer JD. Adoption study supporting genetic transmission in manicdepressive illness. Nature 1977; 268:327–329.
29. Wender PH, Kety SS, Rosenthal D, Schulsinger F, Ortmann J, Lunde I. Psychiatric disorders
in the biological and adoptive families of adopted individuals with affective disorders. ArchGen Psychiatry 1986; 43:923–929.
30. Cadoret RJ. Evidence for genetic inheritance of primary affective disorder in adoptees. Am
J Psychiatry 1978; 135:463–466.
31. Von Knorring AL, Cloninger CR, Bohman M, Sigvardsson S. An adoption study of depressive disorders and substance abuse. Arch Gen Psychiatry 1983; 40:943–950.
32. Kendler KS, Gardner CO, Prescott CA. Clinical characteristics of major depression that predict risk of depression in relatives. Arch Gen Psychiatry 1999; 56:322–327.
33. Weissman MM, Wickramaratne P, Merikangas KR, Leckman JF, Prusoff BA, Caruso KA,
Kidd KK, Gammon GD. Onset of major depression in early adulthood. Increased familialloading and speciﬁcity. Arch Gen Psychiatry 1984; 41:1136–1143.
34. Price RA, Kidd KK, Weissman MM. Early onset (under age 30 years) and panic disorderas markers for etiologic homogeneity in major depression. Arch Gen Psychiatry 1987; 44:434–440.
35. Maier W, Lichtermann D, Minges J, Heun R, Hallmayer J, Klingler T. Unipolar depression
in the aged: determinants of familial aggregation. J Affect Disord 1991; 23:53–61.
36. Lieb R, Isensee B, Hoﬂer M, Pﬁster H, Wittchen HU. Parental major depression and therisk of depression and other mental disorders in offspring: a prospective-longitudinal community study. Arch Gen Psychiatry 2002; 59:365–374.
37. Klein DN, Lewinsohn PM, Rohde P, Seeley JR, Durbin CE. Clinical features of major depressive disorder in adolescents and their relatives: impact on familial aggregation, implications for phenotype deﬁnition, and speciﬁcity of transmission. J Abnorm Psychol 2002; 111:
98–106.
38. Silberg J, Pickles A, Rutter M, Hewitt J, Simonoff E, Maes H, Carbonneau R, Murrelle L,
Foley D, Eaves L. The inﬂuence of genetic factors and life stress on depression among adolescent girls. Arch Gen Psychiatry 1999; 56:225–232.
39. Avenevoli S, Stolar M, Li J, Dierker L, Ries Merikangas K. Comorbidity of depression inchildren and adolescents: models and evidence from a prospective high-risk family study.
Biol Psychiatry 2001; 49:1071–1081.
40. Klein DN, Lewinsohn PM, Seeley JR, Rohde P. A family study of major depressive disorderin a community sample of adolescents. Arch Gen Psychiatry 2001; 58:13–20.
41. Silberg J, Rutter M, Neale M, Eaves L. Genetic moderation of environmental risk for depression and anxiety in adolescent girls. Br J Psychiatry 2001; 179:116–121.
42. Maier W. Onset and course of affective disorders in subjects at risk: a prospective family
study. Psychiatr Ann 1996; 26:315–319.
43. Schurhoff F, Bellivier F, Jouvent R, Mouren-Simeoni MC, Bouvard M, Allilaire JF, Leboyer
M. Early and late onset bipolar disorders: two different forms of manic-depressive illness?
J Affect Disord 2000; 58:215–221.

182

Maier and Merikangas

44. Leboyer M, Bellivier F, McKeon P, Albus M, Borrman M, Perez-Diaz F, Mynett-Johnson
L, Feingold J, Maier W. Age at onset and gender resemblance in bipolar siblings. Psychiatry
Res 1998; 81:125–131.
45. Andrew M, McGufﬁn P, Katz R. Genetic and non-genetic subtypes of major depressive
disorder. Br J Psychiatry 1998; 173:523–526.
46. Maier W, Hallmayer J, Lichtermann D, Philipp M, Klingler T. The impact of the endogenous
subtype on the familial aggregation of unipolar depression. Eur Arch Psychiatry Clin Neurosci 1991; 240:355–362.
47. Fanous AH, Walsh D, Kendler KS. Do endogenous features in depression predict the riskof psychiatric illness in relatives? Acta Psychiatr Scand 1996; 94:56–59.
48. Klein DN. Depressive personality in the relatives of outpatients with dysthymic disorder andepisodic major depressive disorder and normal controls. J Affect Disord 1999; 55:19–27.
49. Donaldson SK, Klein DN, Riso LP, Schwartz JE. Comorbidity between dysthymic and major
depressive disorders: a family study analysis. J Affect Disord 1997; 42:103–111.
50. Coryell W, Endicott J, Reich T, Andreasen N, Keller M. A family study of bipolar II disorder.
Br J Psychiatry 1984; 145:49–54.
51. Fieve RR, Go R, Dunner DL, Elston R. Search for biological/genetic markers in a long-term
epidemiological and morbid risk study of affective disorders. J Psychiatr Res 1984; 18:425–
445.
52. Heun R, Maier W. Bipolar II disorders in six ﬁrst-degree relatives. Biol Psychiatry 1993;
34:274–276.
53. Klein DN, Depue RA, Slater JF. Cyclothymia in the adolescent offspring of parents withbipolar affective disorder. J Abnorm Psychol 1985; 94:115–127.
54. Klein DN, Depue RA, Slater JF. Inventory identiﬁcation of cyclothymia. IX. Validation in
offspring of bipolar I patients. Arch Gen Psychiatry 1986; 43:441–445.
55. Klein DN, Clark DC, Dansky L, Margolis ET. Dysthymia in the offspring of parents withprimary unipolar affective disorder. J Abnorm Psychol 1988; 97:265–274.
56. Schulsinger F, Kety SS, Rosenthal D, Wender PH. A family study of suicide. In: Schou M,
Strömgren E, eds. Origin, Prevention and Treatment of Affective Disorders. Orlando, FL:
Academic Press, 1979:278–287.
57. Fu Q, Heath AC, Bucholz KK, Nelson EC, Glowinski AL, Goldberg J, Lyons MJ, Tsuang
MT, Jacob T, True MR, Eisen SA. A twin study of genetic and environmental inﬂuenceson suicidality in men. Psychol Med 2002; 32:11–24.
58. Statham DJ, Heath AC, Madden PA, Bucholz KK, Bierut L, Dinwiddie SH, Slutske WS,
Dunne MP, Martin NG. Suicidal behavior: an epidemiological and genetic study. Psychol
Med 1998; 28:839–855.
59. Roy A, Segal NL, Centerwall BS, Robinette CD. Suicide in twins. Arch Gen Psychiatry
1991; 48:29–32.
60. Brent DA, Bridge J, Johnson BA, Connolly J. Suicidal behavior runs in families. A controlledfamily study of adolescent suicide victims. Arch Gen Psychiatry 1996; 53:1145–1152.
61. Merikangas KR, Angst J. The challenge of depressive disorders in adolescence. In: RutterM, ed. Psychosocial Disturbances in Young People: Challenges for Prevention. New York:
Cambridge University Press, 1995:131–165.
62. Maier W, Lichtermann D, Minges J, Hallmayer J, Heun R, Benkert O, Levinson D. Continuity and discontinuity of affective disorders and schizophrenia. Results of a controlled family
study. Arch Gen Psychiatry 1993; 50:871–883.
63. Kendler KS, McGuire M, Gruenberg AM, O’Hare A, Spellman M, Walsh D. The Roscommon Family Study. IV. Affective illness, anxiety disorders, and alcoholism in relatives. ArchGen Psychiatry 1993; 50:952–960.
64. Gershon ES, DeLisi LE, Hamovit J, Nurnberger JI Jr, Maxwell ME, Schreiber J, Dauphinais
D, Dingman CW 2nd, Guroff JJ. A controlled family study of chronic psychoses. Schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 1988; 45:328–336.

Genetics of Depression

183

65. Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGufﬁn P. A twin study of genetic relationships between psychotic symptoms. Am J Psychiatry 2002; 159:539–545.
66. Crow TJ. The continuum of psychosis and its implication for the structure of the gene. Br
J Psychiatry 1986; 149:419–429.
67. MacKinnon DF, Zandi PP, Cooper J, Potash JB, Simpson SG, Gershon E, Nurnberger J,
Reich T, DePaulo JR. Comorbid bipolar disorder and panic disorder in families with a highprevalence of bipolar disorder. Am J Psychiatry 2002; 159:30–35.
68. Winokur G, Coryell W, Endicott J, Akiskal H. Further distinctions between manic-depressive
illness (bipolar disorder) and primary depressive disorder (unipolar depression). Am J Psychiatry 1993; 150:1176–1181.
69. Grant BF, Hasin DS, Dawson DA. The relationship between DSM-IV alcohol use disorders
and DSM-IV major depression: examination of the primary-secondary distinction in a general
population sample. J Affect Disord 1996; 38:113–128.
70. Rende R, Weissman M, Rutter M, Wickramaratne P, Harrington R, Pickles A. Psychiatricdisorders in the relatives of depressed probands. II. Familial loading for comorbid nondepressive disorders based upon proband age of onset. J Affect Disord 1997; 42:23–28.
71. Dunner DL, Hensel BM, Fieve RR. Bipolar illness: factors in drinking behavior. Am J Psychiatry 1979; 136:583–585.
72. Schuckit MA. The clinical implications of primary diagnostic groups among alcoholics. ArchGen Psychiatry 1985; 42:1043–1049.
73. Merikangas KR, Risch NJ, Weissman MM. Comorbidity and co-transmission of alcoholism,
anxiety and depression. Psychol Med 1994; 24:69–80.
74. Nelson E, Rice J, Rochberg N, Endicott J, Coryell W, Akiskal HS. Affective illness in family
members and matched controls. Acta Psychiatr Scand 1995; 91:146–151.
75. Harrington R, Rutter M, Weissman M, Fudge H, Groothues C, Bredenkamp D, Pickles A,
Rende R, Wickramaratne P. Psychiatric disorders in the relatives of depressed probands. I.
Comparison of prepubertal, adolescent and early adult onset cases. J Affect Disord 1997;
42:9–22.
76. Kendler KS, Davis CG, Kessler RC. The familial aggregation of common psychiatric andsubstance use disorders in the National Comorbidity Survey: a family history study. Br J
Psychiatry 1997; 170:541–548.
77. Maier W, Merikangas K. Co-occurrence and cotransmission of affective disorders and alcoholism in families. Br J Psychiatry Suppl 1996; 30:93–100.
78. Kendler KS, Heath AC, Neale MC, Kessler RC, Eaves LJ. Alcoholism and major depression
in women. A twin study of the causes of comorbidity. Arch Gen Psychiatry 1993; 50:690–
698.
79. Winokur G, Rimmer J, Reich T. Alcoholism IV. Is there more than one type of alcoholism?
Br J Psychiatry 1971; 118:525–531.
80. Merikangas KR, Leckman JF, Prusoff BA, Pauls DL, Weissman MM. Familial transmissionof depression and alcoholism. Arch Gen Psychiatry 1985; 42:367–372.
81. Wade TD, Bulik CM, Neale M, Kendler KS. Anorexia nervosa and major depression: shared
genetic and environmental risk factors. Am J Psychiatry 2000; 157:469–471.
82. Kendler KS, Walters EE, Neale MC, Kessler RC, Heath AC, Eaves LJ. The structure of thegenetic and environmental risk factors for six major psychiatric disorders in women. Phobia,
generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism. ArchGen Psychiatry 1995; 52:374–383.
83. Kendler KS, Neale M, Kessler R, Heath A, Eaves L. A twin study of recent life events anddifﬁculties. Arch Gen Psychiatry 1993; 50:789–796.
84. Kendler KS, Kessler RC, Neale MC, Heath AC, Eaves LJ. The prediction of major depression
in women: toward an integrated etiologic model. Am J Psychiatry 1993; 150:1139–1148.
85. Bulik CM, Prescott CA, Kendler KS. Features of childhood sexual abuse and the development of psychiatric and substance use disorders. Br J Psychiatry 2001; 179:444–449.

184

Maier and Merikangas

86. Holsinger T, Steffens DC, Phillips C, Helms MJ, Havlik RJ, Breitner JC, Guralnik JM, Plassman BL. Head injury in early adulthood and the lifetime risk of depression. Arch Gen Psychiatry 2002; 59:17–22.
87. Kendler KS, Thornton LM, Prescott CA. Gender differences in the rates of exposure to stressful life events and sensitivity to their depressogenic effects. Am J Psychiatry 2001; 158:587–
593.
88. Kendler KS, Karkowski LM, Prescott CA. Causal relationship between stressful life eventsand the onset of major depression. Am J Psychiatry 1999; 156:837–841.
89. Kendler KS, Gardner CO. Monozygotic twins discordant for major depression: a preliminary
exploration of the role of environmental experiences in the aetiology and course of illness.
Psychol Med 2001; 31:411–423.
90. Foley DL, Thacker LR 2nd, Aggen SH, Neale MC, Kendler KS. Pregnancy and perinatal
complications associated with risks for common psychiatric disorders in a population-based
sample of female twins. Am J Med Genet 2001; 105:426–431.
91. Risch NJ. Searching for genetic determinants in the new millennium. Nature 2000; 405:847–
856.
92. Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science
1996; 273:1516–1517.
93. Reich T, Clayton PJ, Winokur G. Family history studies: V. The genetics of mania. Am J
Psychiatry 1969; 125:1358–1369.
94. Winokur G, Tanna VL. Possible role of X-linked dominant factor in manic depressive disease. Dis Nerv Syst 1969; 30:89–94.
95. Gershon ES, Goldin LR, Martinez MM, Hoehe MR. Detecting discrete genes for susceptibility to bipolar disorder or schizophrenia. In: Gershon ES, Cloninger CR, eds. Genetic
Approaches to Mental Disorders. Washington, DC: American Psychiatric Press, 1994:205–
230.
96. Pekkarinen P, Terwilliger J, Bredbacka PE, Lonnqvist J, Peltonen L. Evidence of a predisposing locus to bipolar disorder on Xq24-q27.1 in an extended pedigree. Genome Res 1995; 5:
105–115.
97. Egeland JA, Gerhard DS, Pauls DL, Sussex JN, Kidd KK, Allen CR, Hostetter AM, Housman
DE. Bipolar affective disorders linked to DNA markers on chromosome 11. Nature 1987;
325:783–787.
98. Kelsoe JR, Ginns EI, Egeland JA, Gerhard DS, Goldstein AM, Bale SJ, Pauls DL, Long
RT, Kidd KK, Conte G, Housman DE, Paul SM. Re-evaluation of the linkage relationshipbetween chromosome 11p loci and the gene for bipolar affective disorder in the Old Order
Amish. Nature 1989; 342:238–243.
99. Badner JA, Gershon ES. Meta-analysis of whole-genome linkage scans of bipolar disorderand schizophrenia. Mol Psychiatry 2002; 7:405–411.
100. Cichon S, Schumacher J, Müller DJ, Hurter M, Windemuth C, Strauch K, Hemmer S, Schulze
TG, Schmidt-Wolf G, Albus M, Borrmann-Hassenbach M, Franzek E, Lanczik M, Fritze J,
Kreiner R, Reuner U, Weigelt B, Minges J, Lichtermann D, Lerer B, Kanyas K, Baur MP,
Wienker TF, Maier W, Rietschel M, Propping P, Nöthen MM. A genome screen for genes
predisposing to bipolar affective disorder detects a new susceptibility locus on 8q. Hum Mol
Genet 2001; 10:2933–2944.
101. Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting andreporting linkage results. Nat Genet 1995; 11:241–247.
102. DeLisi LE, Craddock NJ, Detera-Wadleigh S, Foroud T, Gejman P, Kennedy JL, Lendon
C, Macciardi F, McKeon P, Mynett-Johnson L, Nurnberger JI Jr, Paterson A, Schwab S, Van
Broeckhoven C, Wildenauer D, Crow TJ. Update on chromosomal locations for psychiatricdisorders: report of the interim meeting of chromosome workshop chairpersons from theVIIth World Congress of Psychiatric Genetics, Monterey, California, October 14–18, 1999.
Am J Med Genet 2000; 96:434–449.

Genetics of Depression

185

103. Bennett P, Segurado R, Jones I, Bort S, McCandless F, Lambert D, Heron J, Comerford C,
Middle F, Corvin A, Pelios G, Kirov G, Larsen B, Mulcahy T, Williams N, O’Connell R,
O’Mahony E, Payne A, Owen M, Holmans P, Craddock N, Gill M. The Wellcome trust UKIrish bipolar affective disorder sibling-pair genome screen: ﬁrst stage report. Mol Psychiatry
2002; 7:189–200.
104. Morissette J, Villeneuve A, Bordeleau L, Rochette D, Laberge C, Gagne B, Laprise C, Bouchard G, Plante M, Gobeil L, Shink E, Weissenbach J, Barden N. Genome-wide search forlinkage of bipolar affective disorders in a very large pedigree derived from a homogeneous
population in quebec points to a locus of major effect on chromosome 12q23-q24. Am J
Med Genet 1999; 88:567–587.
105. Badenhop RF, Moses MJ, Scimone A, Mitchell PB, Ewen KR, Rosso A, Donald JA, Adams
LJ, Schoﬁeld PR. A genome screen of a large bipolar affective disorder pedigree supports
evidence for a susceptibility locus on chromosome 13q. Mol Psychiatry 2001; 6:396–403.
106. Degn B, Lundorf MD, Wang A, Vang M, Mors O, Kruse TA, Ewald H. Further evidence
for a bipolar risk gene on chromosome 12q24 suggested by investigation of haplotype sharing
and allelic association in patients from the Faroe Islands. Mol Psychiatry 2001; 6:450–455.
107. Suarez BK, Hampe CL, Van Eerdewegh P. Problems of replicating linkage claims in psychiatry. In: Gershon ES, Cloninger RC, eds. Genetic Approaches to Mental Disorders. Washington, D.C.: American Psychiatric Press, 1994:23–46.
108. Rotondo A, Mazzanti C, Dell’Osso L, Rucci P, Sullivan P, Bouanani S, Gonnelli C, Goldman
D, Cassano GB. Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. Am J Psychiatry 2002; 159:23–29.
109. Berrettini WH. The human genome: susceptibility loci. Am J Psychiatry 2001; 158:865.
110. Wang Z, Crowe RR, Tanna VL, Winokur G. Alpha 2 adrenergic receptor subtypes in depression: a candidate gene study. J Affect Disord 1992; 25:191–196.
111. Yoshikawa T, Padigaru M, Karkera JD, Sharma M, Berrettini WH, Esterling LE, DeteraWadleigh SD. Genomic structure and novel variants of myo-inositol monophosphatase 2(IMPA2). Mol Psychiatry 2000; 5:165–171.
112. Detera-Wadleigh SD. Lithium-related genetics of bipolar disorder. Ann Med 2001; 33:272–
285.
113. Niculescu AB 3rd, Segal DS, Kuczenski R, Barrett T, Hauger RL, Kelsoe JR. Identifying
a series of candidate genes for mania and psychosis: a convergent functional genomics approach. Physiol Genom 2000; 4:83–91.
114. Furlong RA, Ho LW, Rubinsztein JS, Michael A, Walsh C, Paykel ES, Rubinsztein DC. A
rare coding variant within the wolframin gene in bipolar and unipolar affective cases. Neurosci Lett 1999; 277:123–126.
115. Evans KL, Lawson D, Meitinger T, Blackwood DH, Porteous DJ. Mutational analysis of
the Wolfram syndrome gene in two families with chromosome 4p-linked bipolar affective
disorder. Am J Med Genet 2000; 96:158–160.
116. Middle F, Jones I, McCandless F, Barrett T, Khanim F, Owen MJ, Lendon C, Craddock N.
Bipolar disorder and variation at a common polymorphism (A1832G) within exon 8 of theWolfram gene. Am J Med Genet 2000; 96:154–157.
117. Ohtsuki T, Ishiguro H, Yoshikawa T, Arinami T. WFS1 gene mutation search in depressive
patients: detection of ﬁve missense polymorphisms but no association with depression or
bipolar affective disorder. J Affect Disord 2000; 58:11–17.
118. Jacobsen NJ, Franks EK, Elvidge G, Jones I, McCandless F, O’Donovan MC, Owen MJ,
Craddock N. Exclusion of the Darier’s disease gene, ATP2A2, as a common susceptibility
gene for bipolar disorder. Mol Psychiatry 2001; 6:92–97.
119. Furlong RA, Ho L, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein DC. Analysis of themonoamine oxidase A (MAOA) gene in bipolar affective disorder by association studies,
meta-analyses, and sequencing of the promoter. Am J Med Genet 1999; 88:398–406.

186

Maier and Merikangas

120. Frisch A, Postilnick D, Rockah R, Michaelovsky E, Postilnick S, Birman E, Laor N, Rauchverger B, Kreinin A, Poyurovsky M, Schneidman M, Modai I, Weizman R. Association of
unipolar major depressive disorder with genes of the serotonergic and dopaminergic pathways. Mol Psychiatry 1999; 4:389–392.
121. Schulze TG, Muller DJ, Krauss H, Scherk H, Ohlraun S, Syagailo YV, Windemuth C, Neidt
H, Grassle M, Papassotiropoulos A, Heun R, Nöthen MM, Maier W, Lesch KP, Rietschel
M. Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder. Am J Med Genet 2000; 96:801–803.
122. Preisig M, Bellivier F, Fenton BT, Baud P, Berney A, Courtet P, Hardy P, Golaz J, Leboyer
M, Mallet J, Matthey ML, Mouthon D, Neidhart E, Nosten-Bertrand M, Stadelmann-Dubuis
E, Guimon J, Ferrero F, Buresi C, Malafosse A. Association between bipolar disorder andmonoamine oxidase A gene polymorphisms: results of a multicenter study. Am J Psychiatry
2000; 157:948–955.
123. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR,
Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in theserotonin transporter gene regulatory region. Science 1996; 274:1527–1531.
124. Furlong RA, Ho L, Walsh C, Rubinsztein JS, Jain S, Paykel ES, Easton DF, Rubinsztein
DC. Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar
and unipolar affective disorders. Am J Med Genet 1998; 81:58–63.
125. Ohara K, Nagai M, Tsukamoto T, Tani K, Suzuki Y, Ohara K. Functional polymorphismin the serotonin transporter promoter at the SLC6A4 locus and mood disorders. Biol Psychiatry 1998; 44:550–554.
126. Serretti A, Cusin C, Lattuada E, Di Bella D, Catalano M, Smeraldi E. Serotonin transporter
gene (5-HTTLPR) is not associated with depressive symptomatology in mood disorders. Mol
Psychiatry 1999; 4:280–283.
127. Rosenthal NE, Mazzanti CM, Barnett RL, Hardin TA, Turner EH, Lam GK, Ozaki N, Goldman D. Role of serotonin transporter promoter repeat length polymorphism (5-HTTLPR) in
seasonality and seasonal affective disorder. Mol Psychiatry 1998; 3:175–177.
128. Sher L, Hardin TA, Greenberg BD, Murphy DL, Li Q, Rosenthal NE. Seasonality associatedwith the serotonin transporter promoter repeat length polymorphism. Am J Psychiatry 1999;
156:1837.
129. Greenberg BD, Li Q, Lucas FR, Hu S, Sirota LA, Benjamin J, Lesch KP, Hamer D, Murphy
DL. Association between the serotonin transporter promoter polymorphism and personality
traits in a primarily female population sample. Am J Med Genet 2000; 96:202–216.
130. Jorm AF, Prior M, Sanson A, Smart D, Zhang Y, Easteal S. Association of a functional
polymorphism of the serotonin transporter gene with anxiety-related temperament and behavior problems in children: a longitudinal study from infancy to the mid-teens. Mol Psychiatry
2000; 5:542–547.
131. Osher Y, Hamer D, Benjamin J. Association and linkage of anxiety-related traits with afunctional polymorphism of the serotonin transporter gene regulatory region in Israeli sibling
pairs. Mol Psychiatry 2000; 5:216–219.
132. Kato T. Molecular genetics of bipolar disorder. Neurosci Res 2001; 40:105–113.
133. Hickie I, Scott E, Naismith S, Ward PB, Turner K, Parker G, Mitchell P, Wilhelm K. Lateonset depression: genetic, vascular and clinical contributions. Psychol Med 2001; 31:1403–
1412.
134. Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, Devon RS,
Clair DM, Muir WJ, Blackwood DH, Porteous DJ. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet 2000; 9:1415–1423.
135. McMahon FJ, Stine OC, Chase GA, Meyers DA, Simpson SG, DePaulo JR Jr. Inﬂuence ofclinical subtype, sex, and lineality on age at onset of major affective disorder in a family
sample. Am J Psychiatry 1994; 151:210–215.
136. O’Donovan MC, Guy C, Craddock N, Murphy KC, Cardno AG, Jones LA, Owen MJ,

Genetics of Depression

137.

138.
139.

140.

141.
142.
143.

144.
145.
146.
147.

148.

149.
150.
151.

187

McGufﬁn P. Expanded CAG repeats in schizophrenia and bipolar disorder. Nat Genet 1995;
10:380–381.
Guy CA, Bowen T, Jones I, McCandless F, Owen MJ, Craddock N, O’Donovan MC.
CTG18.1 and ERDA-1 CAG/CTG repeat size in bipolar disorder. Neurobiol Dis 1999; 6:
302–307.
Kato T, Kato N. Mitochondrial dysfunction in bipolar disorder. Bipolar Disord 2000; 2:180–
190.
Kirk R, Furlong RA, Amos W, Cooper G, Rubinsztein JS, Walsh C, Paykel ES, Rubinsztein
DC. Mitochondrial genetic analyses suggest selection against maternal lineages in bipolar
affective disorder. Am J Hum Genet 1999; 65:508–518.
McMahon FJ, Chen YS, Patel S, Kokoszka J, Brown MD, Torroni A, DePaulo JR, Wallace
DC. Mitochondrial DNA sequence diversity in bipolar affective disorder. Am J Psychiatry
2000; 157:1058–1064.
Evans WE, Relling MV. Pharmacogenomics: Translating functional genomics into rational
therapeutics. Science 1999; 286:487–491.
Roses AD. Pharmacogenetics and the practice of medicine. Nature 2000; 405:857–865.
Zanardi R, Serretti A, Rossini D, Franchini L, Cusin C, Lattuada E, Dotoli D, Smeraldi E.
Factors affecting ﬂuvoxamine antidepressant activity: inﬂuence of pindolol and 5-HTTLPR
in delusional and nondelusional depression. Biol Psychiatry 2001; 50:323–330.
Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG, Carroll BJ. Serotonin transporter
gene polymorphism and antidepressant response. Neuroreport 2000; 11:215–219.
Serretti A, Lilli R, Mandelli L, Lorenzi C, Smeraldi E. Serotonin transporter gene associatedwith lithium prophylaxis in mood disorders. Pharmacogenom J 2001; 1:71–77.
Goldstein DB. Islands of linkage disequilibrium. Nat Genet 2001; 29:109–111.
Reich DE, Cargill M, Bolk S, Ireland J, Sabeti PC, Richter DJ, Lavery T, Kouyoumjian R,
Farhadian SF, Ward R, Lander ES. Linkage disequilibrium in the human genome. Nature
2001; 411:199–204.
Johnson GC, Esposito L, Barratt BJ, Smith AN, Heward J, Di Genova G, Ueda H, Cordell
HJ, Eaves IA, Dudbridge F, Twells RC, Payne F, Hughes W, Nutland S, Stevens H, Carr
P, Tuomilehto-Wolf E, Tuomilehto J, Gough SC, Clayton DG, Todd JA. Haplotype tagging
for the identiﬁcation of common disease genes. Nat Genet 2001; 29:233–237.
Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J. Psychiatric genetics: search for phenotypes. Trends Neurosci 1998; 21:102–105.
Niculescu AB 3rd, Akiskal HS. Proposed endophenotypes of dysthymia: evolutionary, clinical and pharmacogenomic considerations. Mol Psychiatry 2001; 6:363–366.
Pandey A, Mann M. Proteomics to study genes and genomes. Nature 2000; 405:837–846.

9Genetics of Anxiety
WOLFGANG MAIER
University of Bonn
Bonn, Germany

I.

INTRODUCTION

Anxiety disorders are common. Like all other common diseases, anxiety disorders arefamilial and genetically inﬂuenced. In contrast to other psychiatric disorders, the familial
genetic nature of anxiety disorders were detected recently, with a delay of several decades.
It was only about two decades ago—after the advent of the ﬁrst criteria-based deﬁnitionsof speciﬁc anxiety disorders in DSM-III—that intensive genetic–epidemiological research
on anxiety disorders started. It became evident at the same time that anxious behavior inanimals reveals strong similarities to that in human behavior, and anxious behavior inanimals is under genetic control. Given the face validity of the animal phenotype, genetic
animal research became a model for understanding the genetic basis of human anxiety
and anxiety disorders.

II. GENETIC EPIDEMIOLOGY BY FAMILY AND TWIN STUDIES
During the last two decades, a series of family and twin studies documented the familial
aggregation and genetic determination of generalized anxiety disorders, panic disorders,and phobic disorders. Adoption studies had not been conducted. Recent review studies
reported the current evidence in this ﬁeld [1,2]. Thus, this chapter brieﬂy summarizes thecurrent state of knowledge in Tables 1 and 2.
Although the prevalence rates for anxiety disorders in families of affected subjects
and of controls vary considerably across samples, the odds ratios and heritability estimates
are less variable. Heterogeneity tests for odds ratios were conducted, and for the heritability rates in twin samples without revealing inconsistencies across samples [2].
189

190

Maier

Table 1 Family Studies: Meta-Analysis

Disorders
Generalized anxiety disorders
Panic disorders

Agoraphobia
Social phobia (generalized)

Simple phobias

Refs.
4
5
6
5
7
8
9
6
10
11
12
3—parents
10

Risk (%) amongﬁrst-degree relatives Controls
19.5
8.9
17.3
13.2
7.9
11.0
9.5
11.6
10.0
16.0
26.4
22.4
31.0

3.5
1.9
4.2
0.9
2.3
1.8
3.0
4.2
3.0
6.0
2.7
12.2
9.0

OR
compared
to controls
6.6
5.0
4.8
15.6
3.6
6.7
3.4
3.0
3.5
2.9
12.9
4.7
4.4

Source: Refs. 2 and 3.

Table 2 Twin Studies: Meta-Analysis

Disorders

Refs.

Samplegender

Generalized anxiety disorders

13
14
15
15
16
13
17
18
14
19
20
19
20
21
19
20
19
20
22
20

males/females
males
males
femalesmales/females
males/females
males/females
femalesmales
femalesmales
femalesmales
males/females
femalesmales
femalesmales
femalesmales

Panic disorders

Agoraphobia
Social phobia
Simple phobias”, animal”””, situational”””, medical””
Source: Ref. 2.

Probandwise
concordance
(%)
MZ
DZ
60.0
—
22.9
38.1
30.8
41.7
73.0
20.7
—
23.2
12.2
24.4
12.6
13.0
25.9
15.9
22.2
21.2
—
15.6

14.3
—
19.5
40.6
0.0
16.7
0.0
14.5
—
15.3
12.2
15.3
9.8
8.0
11.0
7.7
23.7
6.5
—
4.1

Heritability
0.37
0.22
0.22

0.37
0.43
0.39
0.37
0.30
0.20
0.32
0.35
—
0.25
—
0.28

Genetics of Anxiety

191

Two main conclusions can be drawn:
1. Altogether, consistent evidence emerge that all anxiety disorders are strongly
familial. The odds ratios indicate an at least threefold excess of morbid risk forany anxiety disorder among ﬁrst-degree relatives of affected individuals (Table1). For each of the listed diagnostic categories, the reported odds ratios evenexceed the odds ratios for unipolar depression (ranging between 2 and 3) [1].
2. Twin studies clearly demonstrate that all anxiety disorders are under genetic
inﬂuence (Table 2). The magnitudes of the genetic components range between
0.2 and 0.4 and are comparable by magnitude across the various disorders witha trend for panic disorder showing maximal heritability rates; maximal heritability was reported for panic disorder by Scherrer et al. [14], with 0.43 in males,
whereas lowest heritability estimates (15–22%) were calculated for one twin
study in generalized anxiety disorder based on only a modest familial aggregation rate [15]. Unipolar depression is inﬂuenced by genes to a similar extent. In
contrast, schizophrenia and bipolar disorders, as well as dimensional personality
traits like neuroticism, are under stronger genetic control (heritability ⬎ 0.5).
Overall, the heritability estimates are lower than 50%. Thus, a nongenetic environmental component is apparently more relevant for the manifestation of anxiety disorders
than genetic factors. This conclusion might be inappropriate as the environmental component also includes (1) all the measurement errors and (2) the variance due to gene–environment interaction. Consequently, the magnitude of the genetic component is likely to be
an underestimate.
The analysis of twin study data allows additional reﬁnements: variance component
analysis of twin studies enables the decomposition of the origin of variation because ofnongenetic factors in shared and in individual-speciﬁc environmental components. Although those calculations are model-dependent, they allow a rough impression on therelevance of putative risk-factor components. Counter to expectancy, the nongenetic variance is nearly exclusively due to individual-speciﬁc determinants in anxiety disorders ofadults [2]. Common environment, however, might be more relevant in childhood or adolescent anxiety disorders; e.g., a recent twin study [23] found substantial impact for sharedenvironment on separation anxiety disorder, particularly in boys, which decreased withage.
As a limitation, this variance-analytic strategy is not sensitive enough to detect contributions of shared environment of only very modest magnitude (⬍ 10%); e.g., although
no impact of shared environment was observed in the global variance analysis in a Virginia
sample with more than 2000 twins, the analysis of the speciﬁc risk factor “deﬁcient parenting” (coldness, overprotectiveness/rejection, and authoritarianism) revealed a modest, but
signiﬁcant, contribution to the risk of generalized anxiety disorder, phobia, and panic
disorder [24]. In this line, a family study in social phobia [3] reported only a borderline
signiﬁcance for parental style. Merikangas et al. [25] were also unable to ﬁnd a signiﬁcance
impact on parental style (beyond the parental psychopathology) on anxiety disorders inoffspring. Thus, also the analysis of speciﬁc environmental factors detected only minor
effects of environment but could not prove a major contribution of shared nongenetic
family inﬂuences.
In summary, we can conclude that the family aggregation of anxiety disorders is
mainly attributable to genetic factors but not to a common environment. Even without
the speciﬁcation of genes and environments in family and twin studies, these results con-

192

Maier

tribute to the classic discussions on the origin of anxiety disorders; e.g., it was proposedthat anxious behavior and particularly social anxiety were learned by modeling (modellearning hypothesis), and that children, in particular, learn this behavior from their parents.
According to this hypothesis, children would be exposed to a common, shared risk factor
emerging as shared variance from twin studies. Given the lack of evidence for sharednongenetic components in twin studies, the model-learning hypothesis cannot explain asubstantial proportion of the variance.
III. MODIFIERS OF THE MAGNITUDE OF RELATIVE RISK
The magnitude of familial loading is broadly varying across families for each anxiety
disorder. What are the determinants? Gender, age at onset, and comorbidity with selecteddisorders have been explored as risk-modifying factors.
Anxiety disorders are generally more common among females than males. Consequently, female relatives of affected probands are more vulnerable to anxiety disorders
than male relatives. However, the relative risks of any anxiety disorder are comparable
between female and male relatives of affected probands across the various family studies.
Similarly, the heritability estimates are not gender-dependent (Tables 1 and 2) [15].
The familial risk of most psychiatric disorders is positively correlated to the age at
onset. Similarly, in anxiety disorders, Goldstein et al. [26] observed higher familial loadingfor early-onset panic disorder. This issue has not been pursued in other anxiety disorders.
Comorbidity of panic disorder with agoraphobia has been proposed to indicate increased severity associated with increased familial risk to panic disorder and agoraphobia[6]. Further research was unable to support this hypothesis [7,27].
Comorbidity of panic disorder with major depression is also considered an indicatorof high severity. Despite of earlier contradicting reports, the familial risk for anxiety disorders is apparently unchanged by comorbidity with depression [27].
IV. MODE OF TRANSMISSION
The mode of intrafamilial transmission remains unclear for all anxiety disorders as is thecase for all psychiatric and all common diseases. Previous reports on segregation analyses
for panic disorders proposing a major gene effect or even a dominant transmission [28]were not replicable in subsequent segregation studies [29]. Thus, all anxiety disorders canbe considered genetically complex disorders without a Mendelian mode of transmission.
The most reasonable assumption for all anxiety disorders is that multiple genes areinteracting with each other and with environmental factors to produce the disorder (multiple susceptibility/vulnerability genes). Given the results of genome-wide linkage studies
in panic disorders (see below), genes with a major effect are unlikely to operate in the
majority of families affected by panic disorders (see below). In agreement with this transmission model, Merikangas et al. [25] observed a gene-dose effect: the risk among offspring doubles if both parents suffer from anxiety disorders. More speciﬁc knowledge
about the transmission of anxiety disorders is only feasible after speciﬁc impacting vulnerability genes are identiﬁed.
A.

The Structure and the Boundaries of the Transmitted Phenotype

What is the genetic architecture of the inherited phenotype? Given that the deﬁnitions ofanxiety disorders emerge from clinical conventions, it is unlikely that these diagnostic

Genetics of Anxiety

193

entities are transmitted in families as distinct phenotypes; a one-to-one relationship between a combination of genetic factors and a speciﬁc anxiety disorder cannot be expected.
It would come as a surprise if the conventional clinical boundaries would map into distinct
genetic entities. Instead, the phenotypes transmitted in families are only correlated to anxiety disorders. Empirical evidence supports this suggestion.
1.
2.
3.
4.

Anxiety disorders might be transmitted as part of a continuum.
Anxiety disorders might not operate as genetically distinct entities.
Anxiety disorders might share susceptibility genes with other disorders.
Neurophysiological and neurochemical indicators might be genetically related
to anxiety disorders, and present as more direct cues to the susceptibility genes.

1. Transmission of an Anxiety-Related Continuum
Anxiety disorders might be considered as extremes on a continuum of liability to anxious
behavior that is driven by a common genetic predisposition (quantitative trait loci—QTL);
thus, subthreshold anxiety disorders, anxiety symptoms, and anxious behavior are also
inﬂuenced by the same genetic variation as anxiety disorders; either a lower environmental
or genetic load or the presence of protective genes or environment prevent these subdiagnostic features from becoming more severe and presenting as anxiety disorders.
Empirical research using individual symptoms or dimensional measures of phobia
and panic provided only limited evidence for a familial genetic basis for subthresholdconditions. In this context, the magnitude of the relative risk of subsyndromal anxiety inrelatives of patients with panic/phobic disorders, and of the heritability estimates remains
controversial: particular phobic symptoms have not been found to be highly transmissible
by interview-based family studies [30,31]; similarly, only very modest heritability wasreported for individual phobic/panic symptoms and factors in a twin study using questionnaires [32]. However, there is also conﬂicting evidence [33–36]. Several twin studies
report heritability estimates for symptoms of speciﬁc phobic fears (between 0.45 and 0.55)
comparable to phobic disorders particularly among children. Despite these twin studies,
it remains uncertain if the number of anxiety symptoms represents a trait that is as heritable
as anxiety disorders.
More basic and more traitlike symptoms may produce unpleasant, adverse, or harmful consequences (anxiety sensitivity). Recent research demonstrated that anxiety sensitivity is an antecedent risk factor for panic and anxiety symptoms [37]. A new twin study
using a new scale to measure anxiety sensitivity revealed a very substantial heritability
rate of nearly 50% [38]. The genetic architecture of this trait, however, remains to be
explored.
2. Diagnostic Speciﬁcity in Transmission of Speciﬁc Anxiety Disorders?
The familial genetic relationship between speciﬁc phobias remains ambiguous: on the one
hand, a family study in probands with panic disorder and phobia (in absence of comorbidity with nonanxiety disorders) found a diagnosis-speciﬁc familial contribution to panic
disorder with agoraphobia, social phobia, and simple phobia [10] without excluding partial
overlap of the familial components between each of these disorders (especially betweensocial and simple phobias). Another family study found familial coaggregation of social
phobia and agoraphobia in probands with panic disorder in the absence of comorbidity
with major depression; however, the coaggregation of both conditions is not a consequence

194

Maier

of shared familial genetic factors; instead, social phobia presents more of a consequenceof preestablished agoraphobia in relatives [8].
The genetic relationship between panic disorder and phobias has been extensively
explored with ambiguous results. A prior family study by Noyes [6] also found panic
disorder with agoraphobia and panic disorder without agoraphobia to breed true. Subsequent studies were unable to replicate this relationship [7,27]. Partial identity of genetic
vulnerability factors for phobias and panic disorder (as well as bulimia) was also reported
in two independent population-based twin studies [14,39]. In contrast, the genes impacting
on generalized anxiety disorder and depression did not reveal substantial overlap withgenes inﬂuencing the manifestation of phobias and panic disorder according to Hickie etal. (40) and Kender et al. [41]. Phobias were not further speciﬁed in these two large-scalestudies, leaving space for divergent relationships on the level of speciﬁc phobias. Anotherstudy in offspring of patients found evidence for a familial genetic link between social
phobia and depression [3]. A recent twin study by Scherrer et al. [14], however, suggested
that at least half of the genetic liability for panic disorder overlapped with generalized
anxiety disorder. Thus, it cannot be excluded that speciﬁc phobias show differential effects.
Apparently, there is diagnostic speciﬁcity as well as unspeciﬁcity with regard to thesubtype in a family-genetic perspective. Panic disorder and phobic disorder are considerably overlapping whereas generalized anxiety disorder shows the highest degree of distinctness.
3. Genetic Relationship to Other Disorders
Anxiety disorders and depression: The familial genetic relationship between generalized
anxiety and depression was the topic of intensive study in several population-based twin
studies [42–46]. A very strong genetic relationship between generalized anxiety disorderand major depression emerged from these twin studies: both disorders share the same
genetic vulnerability factors; the differential alternative expression as anxiety or as depression is due to distinct environmental factors that still have to be identiﬁed. If anxiety anddepression are considered quantitatively as two continua, with the disorders deﬁning theextreme of the continuum, the close genetic relationship between both psychopathologicalconditions was replicated in other population-based twin studies [42–44]. Anxiety disorders and depression in childhood are even more closely correlated than in adulthood[25,47].
There is also consensus in more recent family and twin studies that panic disorders
and major depression are not strongly related genetically. Controlled family studies report
only modest or insigniﬁcant excess of major depression in families of probands with panic
disorder without a history of major depression [27,48]. Twin studies [39] report absenceof a substantial genetic correlation between panic disorder (and phobias), on the one hand,and depression, on the other hand. In contrast, a family-genetic relationship between bipolar disorder and panic disorder seems to be closer [49].
The observed diagnostic unspeciﬁcity of anxiety disorders and depression with regard to familial aggregation has been considered under the model of age-speciﬁc expression of common risk factors: anxiety is preferentially expressed in childhood, and depression is preferentially expressed in adulthood [50–52].
Another model, derived from the analysis of a large Australian twin study, proposesthat anxiety (mainly in males) and depression (mainly in females) are variable expressions

Genetics of Anxiety

195

of a heritable trait of neuroticism (which revealed heritability estimates of more than 50%
in multiple twin studies) [53].
The genetic correlations between liabilities to phobias and panic disorder and between generalized anxiety disorder and depression may explain a substantial proportionof the intraindividual comorbidity between these disorders as observed in epidemiologicalstudies [54]. However, genetic factors cannot account for the excess comorbidity between
panic disorder and major depression.
Anxiety disorders and addiction: The relationship between anxiety disorders andalcoholism is particularly complex. It is indisputable that an excess rate of alcoholism(abuse or dependence) can be encountered in families of probands with any anxiety disorder. The relationship to anxiety disorders in family studies, however, is heterogeneous:(1) alcoholism in relatives of probands with social phobia is mainly secondary to therelative’s primary social anxiety disorder [55]; (2) several studies report that a partly
shared genetic-familial diathesis underlies alcoholism and panic disorder [55–57]. However, twin studies only attribute a very modest common genetic component to panic disorder and alcoholism [39].
4. Genetically Correlated Neurobiological Indicators
Diagnostic categories are based on a consensus that does not refer to pathogenic mechanisms or aim at deﬁning the most appropriate phenotype emerging from underlying genes.
Genes inﬂuence the behavior through multiple complex neurobiological mechanisms (molecular mechanisms, neurotransmitter systems, neurophysiological mechanisms, brain circuits); nongenetic forces do impact those pathways. Thus, the relationship between vulnerability genes and the behavioral phenotype is only indirect, and the effect of a single
genetic mutation is likely to inﬂuence multiple behavioral qualities simultaneously. Given
that genes exert their inﬂuence on behavior through neurobiological mechanisms, neurochemical and the neurophysiological indicators represent intermediate phenotypes that areclosely related intraindividually to the genetically more complex behavioral phenotype ofanxiety. These hypothetical indicators of the genetic diathesis to the disease (1) should
occur more often among subjects with increased genetic risk even if these subjects are
not affected with the disease, and (2) should be under genetic control. Those vulnerability
indicators can be considered as endophenotypes [58] and are most useful for the searchof speciﬁc underlying genes that also impact on the correlated disorders.
Indicators of particular interest of a diathesis for anxiety are somatic and behavioral
reactions to stimuli like lactate infusion, hyperventilation, and CO 2 inhalation [59,60] forpanic disorder and phobia, or reactions to the unfamiliar or novelty in children [61] forsocial phobia, and reactions to threat- and fear-related stimuli (startle) [25] for panic andphobia in children and adults. These response patterns have been shown to precede thedevelopment of anxiety disorders (mainly panic disorders and phobias) as indicators ofincreased risk.
Given that anxiety disorders are familial, the high-risk approach exploring childrenof affected parents is a particularly promising strategy to evaluate disease-related vulnerability indicators. These indicators have been explored in a series of high-risk studies.
1. Children at high risk for anxiety disorders have increased startle reﬂex underbaseline but even more under various aversive conditions, and increased galvanic skin response particularly subsequent to threat-related stimuli [25].

196

Maier

2.

3.

Behavior inhibition to unfamiliar stimuli or situations is associated with shyness
among children and occurs consistently more commonly in offspring of parents
with social anxiety and other variants of anxiety disorders [51,62]; thus, thisreaction type among children was proposed to reﬂect constitutional “anxiety
diathesis” that is familial and predictive of liability to social phobia and panic
disorder [63].
Sensitivity to CO 2 challenge measured by autonomic reactions is well supported
as a vulnerability indicator of anxiety, particularly of panic disorder. Healthy
relatives of probands with panic disorder have increased sensitivity [64]. In
addition, Bellodi et al. [65] demonstrated genetic inﬂuence on this trait by atwin study in healthy volunteers. Response to CO 2 inhalation has been proposed
to be associated with the functional promoter polymorphism of the serotonintransporter gene [66]. On this basis, interactive gene x psychological risk factor
models have been proposed to explain the pathogenesis of anxiety in vulnerable
subjects [66].

Another putative vulnerability indicator is the reaction to lactate infusion that provokes panic attacks in affected subjects. However, in contrast to CO 2 , relatives of probands
with panic disorder do not consistently respond with panic attacks to lactate [67].
Physiological vulnerability indicators for generalized anxiety disorders have not yet
been developed. Automatic (e.g., heart-rate variability) activity and reactions are particularly promising in this respect but have not yet been fully explored as vulnerability indicators.
Besides these physiological functions, behavioral trait measures as anxiety sensitivity or personality traits like neuroticism may also reﬂect the underlying liability to anxiety
disorders more appropriately than the diagnostic categories (see above).
What can be concluded for the transmitted phenotype?
1.

2.

3.

B.

Apparently, various categories of anxiety disorders do not breed true, although
there is some diagnostic speciﬁcity; generalized anxiety is genetically most distinct whereas panic disorders and phobias share genetic risk factors.
The diagnostic boundaries are not supported by a differential genetic etiology;
the boundary between depression and generalized anxiety is not reﬂected in
distinct genetic etiologies; on the contrary, genetic components for both disorders are strongly correlated. Thus, in a genetic perspective, generalized anxiety
is closer to depression than to the other anxiety disorders.
Several physiological and behavioral dimensional traits that are closely related
to the manifestation of phobias and panic disorder are apparently inﬂuenced by
the same genes as the anxiety disorders; they might serve as alternative, more
appropriate phenotypes from a genetic perspective.

Search for Predisposing Genes

Two major strategies for mapping disease genes are feasible: linkage analysis and association studies. In either case, polymorphic loci on the genome are used as markers. The ﬁrst
strategy applies to families with multiple affected subjects, and explores whether genetic
markers are transmitted together with the disease. The second strategy applies either toindependent cases in comparison to controls or, alternatively, to nuclear families (affectedindex case with both parents using the not transmitted parental alleles as controls); theGenetics of Anxiety

197

association strategy tests whether a genetic variant (allele) at a speciﬁc locus is morecommon among affecteds compared to controls.
The linkage strategy can be used in a hypothesis-free manner by using a genomewide approach with a limited number of densely and appropriately placed informative
markers; markers linked with the disease indicate a broad candidate region that is likely
to host a disease gene. A genome-wide approach by association studies will be technicallyfeasible in forthcoming years; in addition, very extensive case-control samples are needed.
Currently, the association strategy is still restricted to a candidate-gene approach.
Candidate genes express gene products (e.g., proteins) that are involved in the pathophysiology or treatment of the disease.
The two strategies have certain advantages and disadvantages: The success of theassociation strategy depends on the knowledge of the neurobiology of anxiety disorders.
Given the limitations of the speciﬁc progress in this ﬁeld, most candidate genes are notyet known. Observed associations with a genetic variant must also be interpreted withcaution: two markers in close distance on the same chromosome are in linkage disequilibrium and, therefore, in association; an associated variant, therefore, does not necessarily
represent the “true” susceptibility gene variant but may just indicate that a genetic variant
in linkage disequilibrium inﬂuences the risk. On the other hand, the linkage strategy can
only localize genes with a major or at least substantial effect and may be futile in disorders
driven by an operation of multiple genes with only small effects that can be detected moreeasily by the association strategy.
The most critical issue in searching predisposing genes is the appropriate phenotype
deﬁnition. Up to now, published studies relied nearly exclusively on clinical diagnoses(only exception being anxiety disorders) [68]. However, there are serious uncertainties
about the utility of clinical diagnoses in gene-mapping studies (see above). Latent behavioral and/or biological traits (like anxiety sensitivity or reaction to CO 2 inhalation) might
be more appropriate.
1. Genome-Wide Linkage
In an inﬂuential paper, Risch [69,70] demonstrated that linkage studies for mapping of
disease genes using pairs of affected siblings are more powerful the higher the relativerisk of the disease among ﬁrst-degree relatives. Given that the odds ratio is higher than
3.0, all anxiety disorders are promising candidates for genome-wide linkage analysis; inthis respect they are better suited for linkage studies than unipolar depression with lower
relative risk.
Three genome-wide linkage scans were conducted in samples of families with panic
disorder: in 23 families by Knowles et al. [71], which were extended to 34 families by
Weissman et al. [72]; in 23 families by Crowe et al. [73]; and in 20 pedigrees by Gelernter
et al. (74). Linkage signals with only modest effects were found in each of these studies,
proposing that only genes with a small or modest effect inﬂuence panic disorder. Consequently, multiple susceptibility genes with small to modest effects impact on the manifestation of panic disorder.
The signals found in one family sample were, unfortunately, not replicable in thetwo other family samples, although very similar selection criteria for probands and families
and similar tools for phenotype characterization were applied. Given the difﬁculties ofreplication of small or modest linkage signals under the condition of relatively small family
samples, this inconsistency does not come as a surprise [75]. However, the comparisonof two of the three studies brought some consensus: a locus on chromosome 7p showed

198

Maier

suggestive linkage in two samples: maximal lod score in Knowles’ et al. sample 1.71 [71],in Crowe et al.’s sample 2.23 [73]; similarly, another locus on chromosome 1 revealed
suggestive linkage in Crowe et al.’s sample [73] with a maximal lod score of 1.1, and of
2.0 in Gelernter et al.’s sample [74]. Despite not reaching the level of statistical signiﬁcance, and despite the lack of incomplete consensus between the three genome scans,these results are remarkable given the low likelihood of obtaining overlapping signals in
different genome scans with very limited sample sizes. These promising candidate regions
await additional replication as well as ﬁne-mapping, particularly in candidate genes located in these areas; unfortunately, current knowledge does not propose interesting
positional candidate genes. Linkage studies for other anxiety disorders are currently notavailable.
Two innovative approaches to linkage deserve special attention, although the empirical results are not yet replicated. In the sample of families with multiple members withpanic disorder recruited for linkage [72] coincidence of panic disorder with a series ofsomatic diseases (affecting kidney, bladder, thyroid, and mitral valve) in individual family
members was noticed. After restriction of the sample to families with at least one member
reporting panic together with one of these somatic diseases, the lod score at a single locus
on chromosome 13 went up to a highly signiﬁcant magnitude.
Motivated by the observation of the excess comorbidity between panic disorder andjoint laxity in a speciﬁc population, Gratacos et al. [76] collected families with a highprevalence of panic disorder or phobias and joint laxity. Before starting the genome scan,
an initial cytogenetic examination in family members with both disorders was performed;
an interstitial duplication on chromosome 15q (DUP25) was found in the majority ofaffected subjects. At the DUP25 locus, a highly signiﬁcant linkage signal was detectedin the multiplex families. The proposed vulnerability gene variant DUP 25 is of particularinterest because of its non-Mendelian transmission [76].
2. Candidate Genes
The selection of candidate genes primarily focuses on neurochemical hypotheses to thedisease. Anxiety and its disorders are thought to be related to serotonin. Other candidate
genes refer to targets of anxiety-provoking agents.
Serotonin transporter genes. The serotonin transporter is instrumental in the regulation of serotonergic activity. The polymorphism in the promoter region of the serotonintransporter gene is a most promising candidate for negative emotions, anxiety, as well asanxiety disorders. After the ﬁrst report of an association of the allele with reduced in vitrotransporter expression with neuroticism and other personality-bound, anxiety-related traits[77], a bulk of studies tried to replicate the results with limited success: in favor of theoriginal ﬁnding [78–80]; partly in favor [81]; not in favor [82–84]. Using clinical diagnoses (panic disorder) as phenotypes, neither linkage nor association have been found infamily-based studies [85].
Serotonin receptor genes. Another candidate is the serotonin receptor 5HT2c asagonists to this receptor may provoke anxiety (e.g., mCPP) whereas antagonists (e.g.,ritanserine) are anxiolytic agents. Deckert et al. [86] identiﬁed polymorphisms in regulatory units of this gene and found a signiﬁcant association of one variant with panic disorderin one but not in another population.
Animal studies (knockout models), in particular, propose the 5HT1a receptor as a
candidate for genetic studies [87]. However, common variants of this gene have not beenfound up to now which could explain a relevant proportion of the genetic variance [88].

Genetics of Anxiety

199

Serotonin-metabolizing enzymes: monoamine oxidase and COMT genes. Monoamine oxidase inhibitors are powerful drugs for panic disorder and social phobia. Although
the relationship between MAO and anxiety disorders remains obscure [89], the genes
coding for the two variants of MAO are promising candidates; both genes carry functional
genetic variants in their regulatory units. Deckert et al. [90] ﬁrst reported an association
between a promoter variant for MAO-A on the X-chromosome and panic disorder in two
independent populations. A subsequent replication test in a family-based association sample was unable to support the initial report [91].
The gene encoding another monoamine-metabolizing enzyme, catechol-O-methyltransferase (COMT), carries a functionally relevant variant that is hypothesized to impact
on several psychiatric disorders and their clinical presentations. Until now, there has been
no evidence for an association with anxiety disorders [92]. Lack of evidence for association
with the COMT variants was also reported for the anxiety-related traits of behavior inhibition and neuroticism [93].
Target of anxiolytic drugs: GABA and its receptors. The GABAergic systems are
implicated in the pathophysiology and treatment of anxiety disorders: GABA-A agonists
like benzodiazepines are anxiolytic and there is evidence for a decreased benzodiazepine
receptor function in anxious patients; in temporal correlation with the onset of anxiolytic
action, mRNA of speciﬁc GABA-receptor subunits is expressed by benzodiazepines incritical areas in the brain. The genes of GABA-receptor subunits carry multiple polymorphisms. Unfortunately, candidate gene studies of GABA-receptor subunits did not form
replicable associations with panic disorder [94]. However, recently an association study
with behavior inhibition, an anxiety-related phenotype, found modest evidence that an
isoform of the glutamic acid decarboxylase (GAD65) was less common in affected subjects. While this ﬁnding requires replication, it is noteworthy that the GAD65 knock-out
mouse revealed increased anxiety-like behavior [68].
Anxiety-provoking substances and their targets: CKK and adenosine receptors.
Cholecystokinin-tetrapeptide triggers panic attacks in patients with panic disorder more
often than in controls; this effect can be blocked by antipanic substances (e.g., imipramine). The CKK gene carries a polymorphism in the promoter region. It has been tested
for association with panic disorder with positive results [95], which were not consistently
replicable [96]. Caffeine can also provoke anxiety in panic disorder probands through its
binding to adenosine receptors. Several silent mutations were identiﬁed in the two subtypesof adenosine receptors A1 and A2 AR. Some evidence for an association with A2 AR genevariants was found by Deckert et al. [97] for panic disorder. A replication test could not
conﬁrm the initial result [98].
C. Genetic Animal Models
Anxiety as a reaction to threatening situations is not unique to humans. Avoidance andanxiety-like behavior is a physiological reaction in all rodents and serves a protectivefunction; anxiety behavior is an evolutionary conserved phenotype (in contrast to depression). Thus, we can use animal models in order to understand mechanisms underlying
human anxiety. Multiple behavioral models in animals were developed in the past withthe following results: as in humans, there is a broad variation of anxiety-related behavior
among members of the same species and the same strain; selective breeding experiments
have clearly demonstrated that genetic factors control the degree of anxiety-like behavior
also among mice and rats. Because of the apparent homology between human and animal

200

Maier

behavior, these studies provided valid animal models for anxiety disorders by deﬁning
extreme behavioral variants as pathological anxiety. In this context, anxiety-like behavior
can be observed and quantiﬁed by avoidance behavior and behavior inhibition in aversive
conditions, and by conditioned fear and potential startle [99].
More recently, the inactivation of speciﬁc genes became feasible among mice usingtransgenic technology (knock-out lines) in order to study the impact of a speciﬁc geneon the behavior and underlying neurobiological circuits. By these means, new promising
candidate genes can be identiﬁed beyond our current knowledge of the pathophysiologyof the disease (what is particularly advantageous, given the limited knowledge on thepathophysiology of anxiety disorders). A large number of genes contributing to neuronalmessengers, receptors, and intracellular regulations have been targeted in knock-out lines
and tested for anxiety-like behavior (see overview, Ref. 100). Apart from conﬁrming the
involvement of serotonin, gamma-aminobutyric acid, and corticotropin-releasing hormone
as major mediators of anxiety and stress-related behaviors, two novel groups of anxietyrelevant molecules have been revealed. The ﬁrst group consists of neurotrophic-type molecules, such as interferon-gamma, neural cell adhesion molecule, and midkine, which play
important roles in neuronal development and cell-to-cell communication. The second
group comprises regulators of intracellular signaling and gene expression, which emphasizes the importance of gene regulation in anxiety-related behaviors. Defects in these molecules are likely to contribute to the abnormal development and/or function of neuronal
networks, which leads to the manifestation of anxiety disorders.
V.

CONCLUSION

All anxiety disorders are under genetic control probably with multiple genes impacting
on all disorders. The contributing genes still have to be identiﬁed. The search for susceptibility genes is hampered by the uncertainty of what is transmitted in families. The familial
genetic transmission reveals diagnostic speciﬁcity as well as unspeciﬁcity between thevarious subcategories of anxiety disorders as well as with depression and alcoholism.
Thus, diagnostic subcategories, even if they are diagnosed with maximal precision andreliability, will not present the most appropriate phenotypes for the detection of the underlying genes. The availability of the expanding technical potentials to map the variabilityof the human genome, and to explore the relationship to genetically inﬂuenced phenotypes,
will not automatically result in a successful identiﬁcation of genes accounting for anxiety
disorders. In order to reduce the complexity of the phenotype-genotype relationship andto use forthcoming technical potentials, two critical steps have to be achieved: (1) the
development of a genetic nosology [1] using behavioral and neurobiological vulnerability
indicators and endophenotypes; [2] the recruitment of large samples of nuclear families(with affected index cases) and/or of cases and controls in order to use the new prospectsof genome-wide association studies.
REFERENCES
1. Smoller JW, Tsuang MT. Panic and phobic anxiety: deﬁning phenotypes for genetic studies.
Am J Psychiatry 1998; 155:1152–1162.
2. Hettema JM, Neale MC, Kendler KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 2001; 158:1568–1578.
3. Lieb R, Wittchen HU, Hoﬂer M, Fuetsch M, Stein MB, Merikangas KR. Parental psychopa-

Genetics of Anxiety

4.
5.

6.

7.
8.

9.

10.
11.
12.

13.
14.

15.
16.
17.
18.
19.

20.
21.

22.

23.

24.

201

thology, parenting styles, and the risk of social phobia in offspring: a prospective-longitudinal
community study. Arch Gen Psychiatry 2000; 57:859–866.
Noyes R Jr, Clarkson C, Crowe RR, Yates WR, McChesney CM. A family study of generalized anxiety disorder. Am J Psychiatry 1987; 144:1019–1024.
Mendlewicz J, Papadimitriou GN, Wilmotte J. Family study of panic disorder: comparison
with generalized anxiety disorder, major depression and normal subjects. Psychiatr Genet
1993; 3:73–78.
Noyes R Jr, Crowe RR, Harris EL, Hamra BJ, McChesney CM, Chaudhry DR. Relationshipbetween panic disorder and agoraphobia: a family study. Arch Gen Psychiatry 1986; 43:
227–232.
Maier W, Lichtermann D, Minges J, Oehrlein A, Franke P. A controlled family study inpanic disorder. J Psychiatr Res 1993; 27 (suppl 1):79–87.
Horwath E, Solk SI, Goldstein RB, Wickramaratne P, Sobin C, Adams P, Lish JD, Weissman
MM. Is the comorbidity between social phobia and panic disorder due to familial contransmission or other factors? Arch Gen Psychiatry 1995; 52:574–582.
Fyer AJ, Mannuzza S, Chapman TF, Lipsitz J, Martin LY, Klein DF. Panic disorder andsocial phobia: effects of comorbidity on familial transmission. Anxiety 1996; 2:173–
178.
Fyer AJ, Mannuzza S, Chapman TF, Martin LY, Klein DF. Speciﬁcity in familial aggregationof phobic disorders. Arch Gen Psychiatry 1995; 52:564–573.
Mannuzza S, Schneier FR, Chapman TF, Liebowitz MR, Klein DF, Fyer AJ. Generalizedsocial phobia: reliability and validity. Arch Gen Psychiatry 1995; 52:230–237.
Stein MB, Chartier MJ, Hazen AL, Kozak MV, Tancer ME, Lander S, Furer P, Chubaty D,
Walker JR. A direct-interview family study of generalized social phobia. Am J Psychiatry
1998; 155:90–97.
Skre I, Onstad S, Torgersen S, Lygren S, Kringlen E. A twin study of DSM-III-R anxiety
disorders. Acta Psychiatr Scand 1993; 88:85–92.
Scherrer JF, True WR, Xian H, Lyons MJ, Eisen SA, Goldberg J, Lin N, Tsuang MT. Evidence for genetic inﬂuences common and speciﬁc to symptoms of generalized anxiety andpanic. J Affect Disord 2000; 57:25–35.
Hettema JM, Prescott CA, Kendler KS. A population-based twin study of generalized anxiety
disorder in men and women. J Nerv Ment Dis 2001; 189:413–420.
Torgersen S. Genetic factors in anxiety disorders. Arch Gen Psychiatry 1983; 40:1085–1089.
Perna G, Caldirola D, Arancio C, Bellodi L. Panic attacks: a twin study. Psychiatry Res
1997; 66:69–71.
Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Panic disorder in women: a population-based twin study. Psychol Med 1993; 23:397–406.
Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. The genetic epidemiology ofphobias in women: the interrelationship of agoraphobia, social phobia, situational phobia,
and simple phobia. Arch Gen Psychiatry 1992; 49:273–281.
Kendler KS, Myers J, Prescott CA, Neale MC. The genetic epidemiology of irrational fears
and phobias in men. Arch Gen Psychiatry 2001; 58:257–265.
Carey G, Gottesman II. Twin and family studies of anxiety, phobic, and obsessive disorders.
In: Klein DF, Rabkin J, eds. Anxiety: New Research and Changing Concepts. New York:
Raven, 1981: 117–136.
Neale MC, Walters EE, Eaves LJ, Kessler RC, Heath AC, Kendler KS. Genetics of bloodinjury fears and phobias: a population-based twin study. Am J Med Genet 1994; 54:326–
334.
Feigon SA, Waldman ID, Levy F, Hay DA. Genetic and environmental inﬂuences on separation anxiety disorder symptoms and their moderation by age and sex. Behav Genet 2001;
31:403–411.
Kendler KS, Myers J, Prescott CA. Parenting and adult mood, anxiety and substance use

202

25.
26.

27.

28.
29.
30.

31.
32.

33.
34.
35.
36.
37.
38.
39.

40.
41.
42.
43.

44.
45.

Maier
disorders in female twins: an epidemiological, multi-informant, retrospective study. Psychol
Med 2000; 30:281–294.
Merikangas KR, Avenevoli S, Dierker L, Grillon C. Vulnerability factors among children
at risk for anxiety disorders. Biol Psychiatry 1999; 46:1523–1535.
Goldstein RB, Wickramaratne PJ, Horwath E, Weissman MM. Familial aggregation and phenomenology of “early”-onset (at or before age 20 years) panic disorder. Arch Gen Psychiatry
1997; 54:271–278.
Weissman MM, Wickramaratne P, Adams PB, Lish JD, Horwath E, Charney D, Woods SW,
Leeman E, Frosch E. The relationship between panic disorder and major depression. A new
family study. Arch Gen Psychiatry 1993; 50:767–780.
Pauls DL, Bucher KD, Crowe RR, Noyes R Jr. A genetic study of panic disorder pedigrees.
Am J Hum Genet 1980; 32:639–644.
Vieland VJ, Goodman DW, Chapman T, Fyer AJ. New segregation analysis of panic disorder. Am J Med Genet 1996; 67:147–153.
Fyer AJ, Mannuzza S, Gallops MS, Martin LY, Aaronson C, Gorman JM, Liebowitz MR,
Klein DF. Familial transmission of simple phobias and fears. A preliminary report. ArchGen Psychiatry 1990; 47:252–256.
Fyer AJ, Mannuzza S, Chapman TF, Liebowitz MR, Klein DF. A direct interview family
study of social phobia. Arch Gen Psychiatry 1993; 50:286–293.
Kendler KS, Walters EE, Truett KR, Heath AC, Neale MC, Martin NG, Eaves LJ. A twinfamily study of self-report symptoms of panic-phobia and somatization. Behav Genet 1995;
25:499–515.
Torgersen S. The nature and origin of common phobic fears. Br J Psychiatry 1979; 134:
343–351.
Rose R, Ditto W. A developmental-genetic analysis of common fears from early adolescence
to early adulthood. Child Dev 1983; 54:361–368.
Stevenson J, Batten N, Cherner M. Fears and fearfulness in children and adolescents: a genetic analysis of twin data. J Child Psychol Psychiatry 1992; 33:977–985.
Thapar A, McGufﬁn P. Are anxiety symptoms in childhood heritable? J Child Psychol Psychiatry 1995; 36:439–447.
Taylor S. Anxiety Sensitivity: Theory, Research, and Treatment of the Fear of Anxiety. Mahwah, NJ: Erlbaum, 1999.
Stein MB, Jang KL, Livesley WJ. Heritability of anxiety sensitivity: a twin study. Am J
Psychiatry 1999; 156:246–251.
Kendler KS, Walters EE, Neale MC, Kessler RC, Heath AC, Eaves LJ. The structure of thegenetic and environmental risk factors for six major psychiatric disorders in women. Phobia,
generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism. ArchGen Psychiatry 1995; 52:374–383.
Hickie I, Kirk KM, Martin NG. Unique genetic and environmental determinants of prolonged
fatigue: a twin study. Psychol Med 1999; 29:259–268.
Kendler KS, Karkowski LM, Prescott CA. Fears and phobias: reliability and heritability.
Psychol Med 1999; 29:539–553.
Jardine R, Martin NG, Henderson AS. Genetic covariation between neuroticism and thesymptoms of anxiety and depression. Genet Epidemiol 1984; 1:89–107.
Kendler KS, Heath A, Martin NG, Eaves LJ. Symptoms of anxiety and depression in a volunteer twin population. The etiologic role of genetic and environmental factors. Arch Gen Psychiatry 1986; 43:213–221.
Kendler KS, Heath AC, Martin NG, Eaves LJ. Symptoms of anxiety and symptoms of depression. Same genes, different environments? Arch Gen Psychiatry 1987; 44:451–457.
Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Major depression and generalized
anxiety disorder. Same genes, (partly) different environments? Arch Gen Psychiatry 1992;
44:451–457.

Genetics of Anxiety

203

46. Roy MA, Neale MC, Pedersen NL, Mathe AA, Kendler KS. A twin study of generalized
anxiety disorder and major depression. Psychol Med 1995; 23:1037–1049.
47. Eley TC, Stevenson J. Exploring the covariation between anxiety and depression symptoms:
a genetic analysis of the effects of age and sex. J Child Psychol Psychiatry 1999; 40:1273–
1282.
48. Maier W, Minges J, Lichtermann D. The familial relationship between panic disorder andunipolar depression. J Psychiatr Res 1995; 29:375–388.
49. MacKinnon DF, McMahon FJ, Simpson SG, McInnis MG, DePaulo JR. Panic disorder withfamilial bipolar disorder. Biol Psychiatry 1997; 42:90–95.
50. Sylvester C, Hyde T, Reichler R. Clinical psychopathology among children of adults withpanic disorder. In: Dunner D, Gershon E, Barrett J, eds. Relatives at Risk for Mental Disorder.
New York: Raven, 1988:87–102.
51. Biederman J, Rosenbaum JF, Bolduc EA, Faraone SV, Hirshfeld DR. A high risk study ofyoung children of parents with panic disorder and agoraphobia with and without comorbid
major depression. Psychiatry Res 1991; 37:333–348.
52. Last CG, Hersen M, Kazdin A, Orvaschel H, Perrin S. Anxiety disorders in children andtheir families. Arch Gen Psychiatry 1991; 48:928–934.
53. Martin NG, Jardine R, Andrews G, Heath AC. Anxiety disorders and neuroticism: are there
genetic factors speciﬁc to panic? Acta Psychiatr Scand 1988; 77:698–706.
54. Merikangas KR, Angst J, Eaton W, Canino G, Rubio-Stipec M, Wacker H, Wittchen HU,Andrade L, Essau C, Whitaker A, Kraemer H, Robins LN, Kupfer DJ. Comorbidity andboundaries of affective disorders with anxiety disorders and substance misuse: results of aninternational task force. Br J Psychiatry 1996; 168 (suppl 30):58–67.
55. Merikangas KR, Stevens DE, Fenton B, Stolar M, O’Malley S, Woods SW, Risch N. Comorbidity and familial aggregation of alcoholism and anxiety disorders. Psychol Med 1998;
28:773–788.
56. Maier W, Minges J, Lichtermann D. Alcoholism and panic disorder: co-occurrence and cotransmission in families. Eur Arch Psychiatry Clin Neurosci 1993; 243:205–211.
57. Maier W, Merikangas K. Co-occurrence and cotransmission of affective disorders and alcoholism in families. Br J Psychiatry 1996; 168 (suppl 30):93–100.
58. Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J. Psychiatric genetics: search for phenotypes. Trends Neurosci 1998; 21:102–105.
59. Balon R, Jordan M, Pohl R, Yeragani VK. Family history of anxiety disorders in control
subjects with lactate-induced panic attacks. Am J Psychiatry 1989; 146:1304–1306.
60. Antony MM, Brown TA, Barlow DH. Response to hyperventilation and 5.5% CO 2 inhalationof subjects with types of speciﬁc phobia, panic disorder, or no mental disorder. Am J Psychiatry 1997; 154:1089–1095.
61. Kagan J, Snidman N, Arcus D. Childhood derivatives of high and low reactivity in infancy.
Child Dev 1998; 69:1483–1493.
62. Rosenbaum JF, Biederman J, Gersten M, Hirshfeld DR, Meminger SR, Herman JB, Kagan
J, Reznick JS, Snidman N. Behavioral inhibition in children of parents with panic disorderand agoraphobia. A controlled study. Arch Gen Psychiatry 1988; 45:463–470.
63. Rosenbaum JF, Biederman J, Hirschfeld DR, Bolduc EA, Chaloff J. Behavioral inhibitionin children: a possible precursor to panic disorder or social phobia. J Clin Psychiatry 1991;
52 (suppl):5–9.
64. Perna G, Bertani A, Caldirola D, Bellodi L. Family history of panic disorder and hypersensitivity to CO 2 in patients with panic disorder. Am J Psychiatry 1996; 153:1060–1064.
65. Bellodi L, Perna G, Caldirola D, Arancio C, Bertani A, Di Bella D. CO 2-induced panic
attacks: a twin study. Am J Psychiatry 1998; 155:1184–1188.
66. Schmidt NB, Storey J, Greenberg BD, Santiago HAT, Li Q, Murphy DL. Evaluating gene
⫻ psychological risk factor effects in the pathogenesis of anxiety: a new model approach.
J Abnorm Psychol 2000; 109:308–320.

204

Maier

67. Reschke AH, Mannuzza S, Chapman TF, Lipsitz JD, Liebowitz MR, Gorman JM, Klein DF,
Fyer AJ. Sodium lactate response and familial risk for panic disorder. Am J Psychiatry 1995;
152:277–279.
68. Smoller JW, Rosenbaum JF, Biederman J, Susswein LS, Kennedy J, Kagan J, Snidman N,
Laird N, Tsuang MT, Faraone SV, Schwarz A, Slaugenhaupt SA. Genetic association analysis of behavioral inhibition using candidate loci from mouse models. Am J Med Genet 2001;
105:226–235.
69. Risch N. Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum
Genet 1990; 46:222–228.
70. Risch N. Linkage strategies for genetically complex traits. II. The power of affected relative
pairs. Am J Hum Genet 1990; 46:229–241.
71. Knowles JA, Fyer AJ, Vieland VJ, Weissman MM, Hodge SE, Heiman GA, Haghighi F,
de Jesus GM, Rassnick H, Preud’homme-Rivelli X, Austin T, Cunjak J, Mick S, Fine LD,
Woodley KA, Das K, Maier W, Adams PB, Freimer NB, Klein DF, Gilliam TC. Results ofa genome-wide genetic screen for panic disorder. Am J Med Genet 1998; 81:139–147.
72. Weissman MM, Fyer AJ, Haghighi F, Heimann G, Deng Z, Hen R, Hodge SE, Knowles
JA. Potential panic disorder syndrome: clinical and genetic linkage evidence. Am J Med
Genet 2000; 96:24–35.
73. Crowe RR, Goedken R, Samuelson S, Wilson R, Nelson J, Noyes R Jr. Genomewide surveyof panic disorder. Am J Med Genet 2001; 105:105–109.
74. Gelernter J, Bonvicini K, Page G, Woods SW, Goddard AW, Kruger S, Pauls DL, Goodson
S. Linkage genome scan for loci predisposing to panic disorder or agoraphobia. Am J Med
Genet 2001; 105:548–557.
75. Suarez BK, Hampe CL, Van Eerdewegh P. Problems of replicating linkage claims in psychiatry. In: Gershon ES, Cloninger RC, eds. Genetic Approaches to Mental Disorders. Washington, D.C.: American Psychiatric Press, 1994: 23–46.
76. Gratacos M, Nadal M, Martin-Santos R, Pujana MA, Gago J, Peral M, Armengol L, Ponsa
I, Miro R, Bulbena A, Estivill X. A polymorphic genomic duplication on human chromosome
15 is a susceptibility factor for panic and phobic disorders. Cell 2001; 106:367–379.
77. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR,
Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in theserotonin transporter gene regulatory region. Science 1996; 274:1527–1531.
78. Mazzanti CM, Lappalainen J, Long JC, Bengel D, Naukkarinen H, Eggert M, Virkkunen M,
Linnoila M, Goldman D. Role of the serotonin transporter promoter polymorphism in anxiety-related traits. Arch Gen Psychiatry 1998; 55:936–940.
79. Murakami F, Shimomura T, Kotani K, Ikawa S, Nanba E, Adachi K. Anxiety traits associatedwith a polymorphism in the serotonin transporter gene regulatory region in the Japanese. J
Hum Genet 1999; 44:15–17.
80. Greenberg BD, Li Q, Lucas FR, Hu S, Sirota LA, Benjamin J, Lesch KP, Hamer D, Murphy
DL. Association between the serotonin transporter promoter polymorphism and personality
traits in a primarily female population sample. Am J Med Genet 2000; 96:202–216.
81. Melke J, Landen M, Baghei F, Rosmond R, Holm G, Bjorntorp P, Westberg L, Hellstrand
M, Eriksson E. Serotonin transporter gene polymorphisms are associated with anxiety-related
personality traits in women. Am J Med Genet 2001; 105:458–463.
82. Gelernter J, Kranzler H, Coccaro EF, Siever LJ, New AS. Serotonin transporter protein gene
polymorphism and personality measures in African American and European American subjects. Am J Psychiatry 1998; 155:1332–1338.
83. Jorm AF, Henderson AS, Jacomb PA, Christensen H, Korten AE, Rodgers B, Tan X, Eastseal
S. An association study of a functional polymorphism of the serotonin transporter gene withpersonality and psychiatric symptoms. Mol Psychiatry 1998; 3:449–451.
84. Flory JD, Manuck SB, Ferrell RE, Dent KM, Peters DG, Muldoon MF. Neuroticism is notGenetics of Anxiety

85.

86.

87.
88.

89.

90.

91.

92.
93.

94.

95.
96.

97.

98.

99.
100.

205

associated with the serotonin transporter (5-HTTLPR) polymorphism. Mol Psychiatry 1999;
4:93–96.
Hamilton SP, Heimann GA, Haghighi F, Mick S, Klein DF, Hodge SE, Weissman MM,
Fyer AJ, Knowles JA. Lack of genetic linkage or association between a functional serotonintransporter polymorphism and panic disorder. Psychiatr Genet 1999; 9:1–6.
Deckert J, Meyer J, Catalano M, Bosi M, Sand P, DiBella D, Ortega G, Stober G, Franke
P, Nothen MM, Fritze J, Maier W, Beckmann H, Propping P, Bellodi L, Lesch KP. Novel5′-regulatory region polymorphisms of the 5-HT2C receptor gene: association study withpanic disorder. Int J Neuropsychopharmacol 2000; 3:321–325.
Gingrich JA, Hen R. Dissecting the role of the serotonin system in neuropsychiatric disorders
using knockout mice. Psychopharmacology 2001; 155:1–10.
Ohara K, Xie DW, Ishigaki T, Deng ZL, Nakamura Y, Suzuki Y, Miyasato K, Ohara K.
The genes encoding the 5HT1D alpha and 5HT1D beta receptors are unchanged in patientswith panic disorder. Biol Psychiatry 1996; 39:5–10.
Whitﬁeld JB, Pank D, Bucholz KK, Madden PA, Heath AC, Statham DJ, Martin NG. Monoamine oxidase: associations with alcohol dependence, smoking and other measures of psychopathology. Psychol Med 2000; 30:443–454.
Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D, Nothen MM, Maffei
P, Franke P, Fritze J, Maier W, Propping P, Beckmann H, Bellodi L, Lesch KP. Excess ofhigh activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 1999; 8:621–624.
Hamilton SP, Slager SL, Heiman GA, Haghighi F, Klein DF, Hodge SE, Weissman MM,
Fyer AJ, Knowles JA. No genetic linkage or association between a functional promoter polymorphism in the monoamine oxidase-A gene and panic disorder. Mol Psychiatry 2000; 5:
465–466.
Ohara K, Nagai M, Suzuki Y, Ochiai M, Ohara K. No association between anxiety disorders
and catechol-O-methyltransferase polymorphism. Psychiatry Res 1998; 80:145–148.
Henderson AS, Korten AE, Jorm AF, Jacomb PA, Christensen H, Rodgers B, Tan X, Eastseal
S. COMT and DRD3 polymorphisms, environmental exposures, and personality traits related
to common mental disorders. Am J Med Genet 2000; 96:102–107.
Crowe RR, Wang Z, Noyes R jr, Albrecht BE, Darlison MG, Bailey ME, Johnson KJ, Zoega
T. Candidate gene study of eight GABAA receptor subunits in panic disorder. Am J Psychiatry 1997; 154:1096–1100.
Kennedy JL, Bradwejn J, Koszycki D, King N, Crowe R, Vincent J, Fourie O. Investigationof cholecystokinin system genes in panic disorder. Mol Psychiatry 1999; 4:284–285.
Hamilton SP, Slager SL, Helleby L, Heiman GA, Klein DF, Hodge SE, Weissman MM, Fyer
AJ, Knowles JA. No association or linkage between polymorphisms in the genes encoding
cholecystokinin and the cholecystokinin B receptor and panic disorder. Mol Psychiatry 2001;
6:59–65.
Deckert J, Nothen MM, Franke P, Delmo C, Fritze J, Knapp M, Maier W, Beckmann H,
Propping P. Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease. Mol Psychiatry 1998; 3:81–85.
Yamada K, Hattori E, Shimizu M, Sugaya A, Shibuya H, Yoshikawa T. Association studiesof the cholecystokinin B receptor and A2a adenosine receptor genes in panic disorder. J
Neural Transm 2001; 108:837–848.
Plomin R, Owen MJ, McGufﬁn P. The genetic basis of complex human behaviors. Science
1994; 264:1733–1739.
Wood SJ, Toth M. Molecular pathways of anxiety revealed by knockout mice. Mol Neurobiol
2001; 23:101–119.

10
Stress-Responsive Neurohormones
in Depression and Anxiety
ANDREAS STRÖHLE and FLORIAN HOLSBOER
Max Planck Institute of Psychiatry
Munich, Germany

I.

INTRODUCTION

Stress is classically deﬁned as a threatening of homeostasis to which the organism, inorder to survive, responds with a large number of adaptive responses. According to workby Cannon, this mainly implicates the sympathetic nervous system and hormones of theadrenal medulla. Selye was the ﬁrst to suggest that neuroendocrine factors play a decisiverole and he considered the pituitary adrenal system to be the major organizer of the nonspeciﬁc responses to stress. Any type of emotional or physical stressor sets into motion acascade of processes that ﬁne-tune the adaptive response according to speciﬁc demands.
Sympathetic pathways are activated to allow for enhanced alertness and focused attention,
whereas vegetative functions such as feeding, sleep, and sexual drive are decreased. Peripherally, the humoral and neural systems support the most pressing requirements byelevating heart rate, blood pressure, respiratory rate, and gluconeogenesis. An integral
part of adaptation to a stressor is the protection of the organism against an overreaction
and the curtailment of the response following termination of the stressor. If the organism
is incapable of terminating the reponse to stress at the end of the exposure, or if it is
exposed to chronic stress, adaptive mechanisms can lead to pathological changes. Defects
in this counterregulatory mechanism may be either genetically encoded, acquired during
premorbid life, or they may be a scar imprinted by previous disease episodies or traumatic
events. Whatever their origin, there is plausible evidence that changes in stress-adaptive
mechanisms are involved in the development, treatment, and prevention of depression andanxiety disorders.
207

208

Ströhle and Holsboer

II. THE STRESS RESPONSE
In response to acute physical or psychological stress, parvocellular neurons of the paraventricular hypothalamus (PVN) produce increased amounts of corticotropin-releasing hormone (CRH), which is released into portal vessels activating the secretion of corticotropin(ACTH) from anterior pituitary cells. In turn, ACTH enters the circulation and elicits
corticosteroids from the adrenal cortex. This rapid activation of the hypothalamic pituitaryadrenocortical (HPA) system can be life sustaining because of the metabolic effect ofelevating blood glucose levels. Other stress-related responses needed for life-sustaining
adaptations encompass a number of behavioral reﬂexes elicited by activation of the HPA
system, presumably by an increase in CRH release. Activation of the stress response may
be affected by ascending aminergic input from the locus coeruleus and the raphé nuclei.
However, limited direct input to the PVN and dense innervations of central limbic structures further suggest indirect pathways in the modulation of the stress response. In addition, GABA-, glutamate-, and possibly acetylcholine-containing neurons play a role inexcitation of the PVN.
A.

Corticotropin-Releasing Hormone (CRH), CRH Receptors,
and Natriuretic Peptides

CRH is a 41-residue peptide originally isolated by Vale and colleagues from ovine hypothalamus [1]. Sequences for human and rat CRH were subsequently determined and foundto be identical to each other, and they differed from ovine CRH in 7 of the 41 amino acidresidues [2]. Two important CRH-containing neuronal tracts originate in the PVN of the
hypothalamus: CRH neurons with an endocrine role coproduce arginine vasopressin(AVP) and terminate at the median eminence. CRH neurons involved in autonomic functions produce CRH alone and project to the brain stem and the spinal cord. CRH is also
found in the cerebrocortex, limbic system, locus coeruleus, and olfactory bulb, although
at lesser concentrations. Besides its role as the principal secretagogue of ACTH, CRH
has neurotransmitter-like actions outside the hypothalamus as well. Of note, CRH neurons
innervate noradrenergic centers in the pons (locus coeruleus) and the central nucleus of
the amygdala, areas of recognized importance in anxiety and stress response.
The effects of CRH are mediated by two speciﬁc G-protein-coupled seven-transmembrane domain receptors called CRH-R1 and CRH-R2. Furthermore, two splice variants of the CRH-R2 receptor have been characterized in the rat brain [3]. A nearly exclusive expression of CRH-R1 has been observed in frontal cortical areas, the cholinergic
basal forebrain, the brainstem cholinergic nuclei, and superior colliculus, the basolateral
nucleus of the amygdala, the cerebellum, the trigeminal nuclei, and the anterior pituitary.
CRH-R2α, on the other hand, is more strongly expressed in the paraventricular nucleus,
the lateral septum, the cortical and medial nuclei of the amygdala, and the serotonergicraphe nuclei. Mixed receptor populations have been reported for the olfactory bulb, thehippocampus, the entohirnal cortex, the bed nuclei of the stria terminalis and the periaqueductal gray [4]. Interestingly, low-to-moderate CRH-R1 signals have further been reported
for the central nucleus of the amygdala and the substantial nigra [5]. Moreover, recent
evidence points toward expression of CRH-R1 in the locus coeruleus, at least in the nonhuman primate brain [6]. However, differences among species have to be considered when
predictions about clinical implications of drugs acting at CRH receptor subtypes are basedon manipulations of rodent CRH receptors [7].

Stress-Responsive Neurohormones

209

Most studies exploring behavioral effects of CRH in animals have used intracerebroventricular or site-speciﬁc effects of CRH, and all agree that CRH mediates numerous
anxiogenic and fear-related aspects of stress. These include the CRH-induced potentiationof acoustic startle, suppression of social interaction, and an increase in stress-induced
freezing behavior [8]. This is further supported by transgenic mice overexpressing CRH.
These mice have deﬁcits in emotionality and were used as a genetic model of anxiogenic
behavior [9]. As shown in Figure 1, most of the signs and symptoms induced by CRH
administration correspond to symptoms of today’s diagnostic algorithms for depression
and anxiety disorders.
Decreased CRH neurotransmission has been studied by administering antisense oligodeoxynucleotides corresponding to the start-coding region of CRH mRNA. The application of this kind of gene therapy to stressed rats produced a decrease in CRH biosynthesis
and led to the reduction of anxiety-related behavior [10]. Comparison of the behavioral
effects of antisense probes that were either directed against CRH-R1 or against R2-receptor
mRNA suggested that CRH-R1 is more likely to convey anxiety and, possibly, depressionrelated signaling [11,12]. Complementary evidence was provided by the generation of
CRH-R1-receptor-deﬁcient mouse mutants, which proved to be less anxious than normal

Figure 1 Animal studies in which CRH was injected intracerebroventricularly or CRH
synthesis was disrupted (knockout mice or antisense oligodeoxynucleotide treatment ofrats) or CRH receptor function was manipulated through antagonists, gene therapy or genetargeting are in accord with indirect clinical evidence that many signs and symptoms present
in major depression can be attributed to enhanced central activity of CRH (according toRef. 7).

210

Ströhle and Holsboer

mice [13,14]. Conﬂicting results with respect to anxiety-like behavior were described for
CRH-R2-receptor knockout mice [15,16].
Whereas several peptides besides AVP are known to act synergistically with CRH,
the only peptide candidate in humans that inhibits the HPA system at all regulatory levelsof the system seems to be atrial natriuretic peptide (ANP). ANP has been shown to inhibit
the stimulated release of CRH and ACTH in vitro and in vivo. This can be observed inhumans as well, where ANP inhibits the CRH-induced ACTH [17], prolactin [18], andcortisol secretion [19]. ANP is not only synthesized by atrial myocytes [20] and released
into the circulation, but also is found in neurons of different brain regions [21] where
speciﬁc receptors have been found. ANP receptors and immunoreactivity have been foundin periventricular and paraventricular hypothalamic nuclei, the locus coeruleus, and thecentral nucleus of the amygdala. HPA modulation by ANP is shown in Figure 2.
Intracerebroventricular administration of ANP elicited anxiolytic activity in the
open-ﬁeld, social interaction, and elevated plus-maze tests [22,23]. The effects of central
and peripheral administration of atriopeptin-II, a 23-amino-acid residue peptide of ANP(Ser103-Arg125), was furthermore investigated in the elevated plus-maze test in rats previously exposed to a social defeat stress. Results show that the intracerebroventricular, intraamygdala, and intraperitoneal administration of atriopeptin-II produced anxiolytic effects
without affecting spontaneous locomotor activity [24]. In line with opposite endocrine
effects of C-type natriuretic peptide (CNP) [25], intracerebroventricular administration of
CNP had a clear anxiogenic effect in the elevated plus-maze [26]. The blockage of thisanxiogenic effect of CNP by a CRH receptor antagonist [27] gives further evidence for

Figure 2 Preclinical and clinical studies show that ANP inhibits the HPA system at the
hypothalamus, the pituitary, and the adrenal cortex. ANP is released from the heart but isfound in the CNS as well. GR, glucocorticoid receptor; MR, mineralocorticoid receptor.

Stress-Responsive Neurohormones

211

a bidirectional interaction of CRH and natriuretic peptides, with respect not only to the
HPA-system, but also to anxiety-related behavior.
B. Glucocorticoids, Glucocorticoid Receptors, and Neuroactive
Steroids
Corticosteroids act on neurons by two principal mechanisms: (1) genomic actions, where
the steroid enters the cell and binds to cognate receptors that transform into transcription
factors, modulating the expression of steroid hormone-regulated genes; and (2) nongenomic actions, where steroids bind to sites at synaptic membranes, affecting ion conductance(Figure 3).
The central role of corticosteroids in the maintenance of basic functions and in
adaptation and survival under stressful conditions has led to the evolution of two distinct
receptor systems, the mineralocorticoid receptors (MR) and the glucocorticoid receptors(GR) [28]. These two receptors, the MR with about 10-fold higher afﬁnity to cortisol thanthe GRs, provide sufﬁcient control over tonic (MR) and stress-response (GR) mechanisms
in the hippocampus allowing for physiological responsiveness over a wide concentration
range of cortisol. Under baseline conditions, the MRs are 90% occupied by cortisol,

Figure 3 Nongenomic and genomic effects of neuroactive steroids. The list in the upper
left-hand corner of the ﬁgure shows steroids that fulﬁll the criteria for neuroactive steroids.
The lower list gives neurotransmitter receptors that are targets for steroid modulation. The
right-hand side of the ﬁgure describes the classical model of steroid-hormone activation via
the steroid-receptor cascade at the genomic level, which takes place over minutes to hours.
The list on the right-hand side of the diagram gives typical steroid hormones. BDZ, benzodiazepines; ER, estrogen receptor, G, G-protein; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; PS, pregnenolone sulfate; R, receptor. (From Ref. 33.)

212

Ströhle and Holsboer

whereas the GRs are only 50% occupied. In the early morning, when HPA activation
occurs, or following stress, the GRs become more fully occupied in order to curtail HPAactivating mechanisms. Continuing corticosteroid hypersecretion leads to overexposureof GRs and MRs which in turn are downregulated. The most important control mechanismof the HPA system is an autoregulatory feedback by corticosteroids that can inhibit ACTH
secretion, both directly and indirectly by rapid (within minutes) and delayed (more than
2 h) effects [29]. At the DNA level, where positive and a few negative (including ACTH
suppression) gene regulations occur, GR and MR bind as heterodimers. Whenever colocalyzed as in the case in hippocampal cells, GR and MR can heterodimerize, which expands
the repertoire of cellular responses to ﬂuctuating corticoid levels [30].
In the last decade, considerable evidence has emerged indicating that certain steroids
may alter neuronal excitability via their action at the cell surface via interaction withcertain neurotransmitter receptors. For steroids with these particular properites, the term
“neuroactive steroids” has been used (31–33). Other authors use the term neurosteroids,
which can be misconstrued, because these steroids are not speciﬁcally synthesized in neurons. Whereas it seems attractive to differentiate genomic from nongenomic actions uponneurons, it could be demonstrated that transitions may also exist between these two modesof action [34]. Steroids that are believed to have limited effects at membrane sites, such asallopregnanolone (3α,5α-THP) and allotetrahydrodeoxycorticosterone (3α,5α-THDOC),
can be oxidized intracellularly and then exert genomic actions through progesterone receptors. Thus, the steroid molecule provides a rather ﬂexible structure that can be modiﬁed,
depending on the tissue, to satisfy speciﬁc demands.
The ﬁrst behavioral observations related to these steroids date back to Selye, who,
over 50 years ago, reported that progesterone and deoxycorticosterone (DOC) have astrong sedative action through their A-ring-reduced metabolites. These two steroids,
3α,5α-THP and 3α,5α-THDOC, bind at γ-aminobutyric acidA (GABAA) receptors to enhance GABA-induced chloride currents. In rats, 3α,5α-THDOC and 3α,5α,THP are elevated in cortical and hypothalamic tissue after stress [32], and they have been shown
to be anxiolytic and hypnotic, respectively, as predicted by electrophysiology, where abenzodiazepine-like action was demonstrated [34]. Several other neuroactive steroids have
opposite effects. For example, the sulfated form of pregnenolone has been observed toantagonize GABAA-receptor-mediated chloride currents by reducing the channel open frequency [31] and therefore being proconvulsant. Interestingly, 3α,5α-THP dampens theactivity of the HPA system and counteracts CRH-induced anxiety. In addition, neonatal
treatment of rats with 3α,5α-THDOC abolishes the behavioral and neuroendocrine consequences of adverse early life events [35].
III. DEPRESSION AND ANXIETY DISORDERS
Today, there is a trend to create an increasing number of diagnostic categories, which is
reﬂected by the fact that the ofﬁcial diagnostic manual of the American Psychiatric Association for diagnoses released in the 1950s (DSM-I) contained 106 diagnostic categories,
while the current version of this manual (DSM-IV) has been expanded to over 400 categories. In this light, any attempt to validate a psychiatric diagnosis with laboratory ﬁndings
must be frustrating. Instead of syndromes or diagnoses being contrasted with HPA measures, the latter should be considered as one of the features of the clinical phenotype.
Ideally, these abnormalities should be incorporated as signs and symptoms into a
multiaxial diagnostic scheme [36].

Stress-Responsive Neurohormones

213

A. Major Depression
Approximately 50 to 60% of patients with major depression show distinct baseline changes
in ACTH and cortisol secretion. Studying the pulsatile activity and circadian rhythmicity,
it can be demonstrated that in depression the number of ACTH pulses is increased, while
for cortisol it was not the number but the amount released per burst that was increased[37]. The coincidence of increased ACTH burst frequency and enhanced cortisol secretory
amplitude is probably a secondary consequence of the hypersensitivity of the adrenal
glands, which is further supported by increased cortisol surges after ACTH administration[38], the normal cortisol response despite blunted ACTH secretion following CRH stimulation [39] and an enlarged adrenal size during depression [40].
The dexamethasone suppression test (DST) has received considerable attention in
psychiatric research because of its ease of use and its suggested potential for identifying
patients with endogenous or melancholic depression. A large number of studies haveshown that depressives frequently escape from the suppressive effect of 1 to 2 mg dexamethasone (DEX) [41–43], but to date the DST is no longer regarded as a diagnostic test[44]. The most promising application of the DST remains its use as a state marker, which
can be applied longitudinally to follow-up treatment response [44].
After CRH became available for clinical studies, several groups consistently reported that ACTH response was blunted, regardless of whether ovine or human CRH wasused [39,45] (Fig. 4). In some studies, an inverse relationship was found between baseline
cortisol concentration and post-CRH ACTH concentrations, and it was concluded thatelevated baseline cortisol concentrations account for ACTH blunting via negative feedback. However, other factors, such as CRH receptor desensitization of corticotrophs, altered processing and storage of ACTH precursors and alternative processing of POMC
may also contribute to this phenomenon.
A surprising ﬁnding emerged when patients with depression were given DEX andwere then challenged with CRH in the afternoon of the following day. Inadequately suppressed cortisol concentrations and DEX together should be additive in blunting ACTH
release via negative feedback. Against expectation, depressed patients showed a paradoxical pattern insofar as DEX pretreatment resulted in increased ACTH and cortisol responses
to CRH despite combined endogenous (cortisol) and exogenous (DEX) glucocorticoid
concentrations [46,47] (Fig. 4). This abnormality disappears after successful antidepressant treatment [48]. In those patients where the neuroendocrine abnormalities persisted,
the risk of relapse was much higher [49,50]. The combined DEX/CRH test proved particularly useful as a predictor of increased risk for relapse [48–53]. Results of a study inwhich different doses of DEX were administered prior to CRH showed that ACTH andcortisol suppression occurs at higher DEX dosages in the depressives than in matched
controls [54]. This shift of the dose-response curve to higher DEX dosages corroborates
the view that negative feedback mechanisms through glucocorticoid receptors to which
DEX binds are impaired in major depression [55].
In major depression as well as in chronic stress there is a shift to a gradually intensifying vasopressinergic regulation of the HPA system. Dexamethasone, which does notbind to corticosteroid-binding globulins, exerts its effect on the HPA system primarily at
the pituitary corticotrophs and does not suppress the expression of hypothalamic CRH andvasopressin as effectively as endogenous corticosteroids. A transient GR desensitization
gradually develops, and vasopressin expression, which reacts differentially to changes inglucocorticoid concentrations than does CRH expression, becomes less efﬁciently sup-214

Ströhle and Holsboer

Figure 4 Patients with major depression usually have a blunted ACTH reponse to CRH,
which is believed to be secondary to desensitized CRH1 receptors (left). After pretreatment
with a low dose of dexamethasone, healthy controls do not show a substantial ACTH release, whereas the ACTH response in patients with major depression is comparable to the
response of healthy controls not pretreated with dexamethasone (right).

pressed than CRH by circulating corticosteroids. In control subjects, only CRH and AVP
administered together are able to override DEX suppression of the HPA system [56]. In
patients with major depression, corticosteroid receptor function is genetically altered, as
the Munich Vulnerability Study [57,58] suggests, or acquired as a result of impaired coping with stress, and this is why patients with major depression show a much less restrained
release of central ACTH stimulants than healthy controls or depressive patients in remission.
The consequences of impaired regulation of cortisol concentrations are manifold,ranging from untoward effects in peripheral tissues (e.g., osteoporosis) to changes in thecentral nervous system. The latter are believed to comprise effects on morphology as wellas on cognitive function [59]. Studies by Sheline et al. [60,61] and Bremner et al. [62]suggest that recurrent major depression is associated with hippocampal volume loss andthat the degree of this change is determined by the duration of the illness. It has been
proposed that the neuroendocrine changes in depression may account for the changes inhippocampal volume. Importantly, these reductions in hippocampal volume, which arealso seen in patients with schizophrenia [63], a disease not particularly associated withhypercortisolemia, do not necessarily reﬂect cell death [62]. Moreover, in post-traumaticstress disorder, decreased hippocampal volume is associated with normal or even reduced
plasma and urine cortisol concentrations [64]. Factors other than glucocorticoids also account for stress-induced reversible or permanent morphological changes in the hippocampus. For example, a study in nonhuman primates, where high dosages of glucocorticoids
were given for 12 months to aged macaques no evidence was found for decreased hippocampal volume, subﬁeld volumes, subﬁeld neuronal density, and subﬁeld total neuronalnumber [65]. This ﬁnding is in accordance with a report of postmortem brains of patients

Stress-Responsive Neurohormones

215

with major depression and of patients treated with synthetic corticosteroids, where morphological changes or signs of cell death were absent [66].
B. Panic Disorder
Only subtle changes in baseline HPA activity occur in panic disorder patients. Abelson
and Curtis [67] showed that panic disorder patients tend to show elevated cortisol concentrations at night, a greater amplitude of ultradian secretory episodes, but a similar numberof secretion pulses compared to controls. Interestingly, these HPA system alterations inpanic disorder patients are modulated by illness severity and treatment-seeking behavior:patients who were actively in treatment had higher cortisol concentrations than patients
who were enrolled in the study through advertisement. Most studies, however, show thatcompared to patients with major depression, panic disorder patients have decreased [68]and, compared to control subjects, unchanged baseline cortisol concentrations [69]. Studies in panic disorder patients with agoraphobia have been more inconsistent: some studies
demonstrate mild hypercortisolism while other studies do not [70,71].
Compared to patients with major depression, lower rates of nonsuppression following a standard DST has been found in panic disorder patients. Furthermore, compared tocontrol subjects, panic disorder patients in general do not have a higher rate of nonsuppression in the DST [71,72]. Like patients with major depression, panic disorder patients
have a blunted ACTH response to CRH [73,74], although it has been suggested that thisattenuation has different reasons [75]. After DEX pretreatment, panic disorder patients
have higher CRH-induced ACTH and cortisol concentrations than control subjects andlower levels than a reference group of depressed patients [76]. CSF concentrations of
CRH are not altered in patients with panic disorder [77].
Although it seems unlikely that CRH is not secreted during panic attacks, there areno empirical data demonstrating this release directly. Only few investigations have managed to study the HPA system during naturally occurring panic attacks: while spontaneous
panic attacks in the laboratory are not accompanied by an increase in cortisol concentrations [78], spontaneous attacks in the natural environment are reported to be accompanied
by increased cortisol concentrations [79]. In the context of exposure therapy, situationallytriggered panic attacks were not accompanied by an increase in cortisol concentrations[80]. Panic disorder patients who experience a panic attack in response to lactate demonstrate signiﬁcantly higher plasma cortisol concentrations immediately preceding lactate
infusion compared with nonpanicking patients and normal control subjects [81]. This activation of the HPA system correlates with self-reported fear, and may be related to anticipatory anxiety. While lactate-induced panic attacks are not accompanied by an activated
HPA system, cholecystokinin tetrapeptide (CCK-4)-induced panic attacks are accompanied by an exaggerated ACTH secretion [82], providing evidence for an enhanced pituitary
ACTH secretion during panic attacks despite unchanged cortisol concentrations and points
to a possible role of CRH in these attacks.
Negative feedback loops seem to be involved in the HPA-system alterations of patients with panic disorder as well. Compared to patients with major depression, panic
disorder patients have a signiﬁcantly increased number of lymphocyte glucocorticoid receptors [83]. Furthermore, a signiﬁcantly accelerated ANP release has been described inpatients with lactate-induced panic attacks [84] and it has been suggested that this increase
contributes to the paradoxical blunting of ACTH and cortisol secretion during lactateinduced and most likely spontaneous panic attacks as well.

216

C.

Ströhle and Holsboer

Post-Traumatic Stress DisorderCompared with normal controls and in contrast to other psychiatric disorders, patientswith post-traumatic stress disorder (PTSD) have lower mean 24-h urinary cortisol secretion [85], lower baseline plasma cortisol concentrations [86], increased glucocorticoid
binding in lymphocytes [84], and increased sensitivity to the HPA-suppressive effects of
DEX [87], which, taken together, indicate enhanced negative feedback capacity in thesepatients. Further studies will have to clarify whether these abnormalities are a consequenceof the trauma and the disorder or whether they represent premorbid alterations, increasing
the risk for PTSD after trauma exposure. Preliminary data demonstrated that a history ofa previous assault leads to attenuated cortisol concentrations in the immediate aftermathof a subsequent rape in women [88].
Like patients with major depression, PTSD patients have increased CSF CRH concentrations [89] and a blunted ACTH response to the CRH stimulation test [90]. Further
evidence for a hypersecretion of CRH in PTSD comes from a study showing an increased
ACTH release in response to metyrapone [91], which impedes adrenal steroidogenesis byblocking the conversion of 11-deoxycortisol to coritsol. This ﬁnding further underscores
the role of increased sensitivity of the glucocorticoid receptors in HPA-system abnormalities in PTSD.
IV. STRESS-RESPONSIVE NEUROHORMONES IN THE TREATMENT
OF DEPRESSION AND ANXIETYGABAA-receptor modulation by benzodiazepines has long been practiced in the shortterm treatment of depression and anxiety disorders. However, side effects, tolerance development, and dependence limit their use to highly selected patients in the early phase of
drug treatment as an adjunct to antidepressants [92]. Inhibition of CRH release by benzodiazepines has been described in the hypothalamus [93] and the median eminence [94].
In panic disorder patients, benzodiazepine treatment resolves pretreatment HPA-systemabnormalities [95]. Although neuroimaging studies are indicative of changes in benzodiazepine–GABAA-receptor function in panic disorder [96–98], the hypothesized shift in the
benzodiazepine receptor “set-point” [99] could not be substantiated [100,101]. At the moment, long-term pharmacological treatment of depression or anxiety disorders is best performed with antidepressants. Their effects on stress-responsive neurohormones and possible new treatment approaches will be reviewed in more detail.
A.

Antidepressant Treatment

Antidepressants are clinically effective not only in depression, but also in panic disorderand PTSD. In contrast to their clinical effectiveness, elucidation of the mechanisms ofaction of these drugs has been less successful. The hypothesis that has dominated the ﬁeld
is based on the assumption that a biogenic amine-deﬁciency underlies mood disorders andthat this can be remedied by inhibition of presynaptic reuptake transporters of serotonin
and/or norepinephrine, thus increasing the transmitter concentrations at presynaptic sites.
This hypothesis, however, does not explain why it takes at least weeks before antidepressants become effective, whereas reuptake inhibition occurs immediately. Two new hypotheses, which are complementary rather than mutually exclusive, have been forwarded to
explain how antidepressants work. One hypothesis, developed by Duman et al. [102],
focuses on the effects of activation of the cAMP cascade through cell membrane receptors,

Stress-Responsive Neurohormones

217

followed by enhanced induction of CREB and hippocampal brain-derived neurotrophic
factors (BDNF). The other hypothesis submits that antidepressants act through improving
GR function [57,103]. In the CNS, these modulations also affect brain regions not or only
indirectly connected to the peripheral HPA system, which regularly stabilizes under theinﬂuence of antidepressants.
In vivo experiments showed that rats, when treated chronically with antidepressants,
displayed decreased baseline and stress-induced levels of plasma ACTH and corticosterone. Upon analyzing the capacity of MR and GR in the hippocampus of these rats, it
was found that the ﬁrst change was seen in MR binding, which increased after 1 weekof treatment [104,105]. In the light of inhibitory effects of MRs on HPA activity, whichis reﬂected by studies employing MR antagonists in rats and humans or MR antisense inrats [106], the observed upregulation of MR capacity seems to be the ﬁrst step necessary
for the inhibition of hypothalamic CRH neurons. This effect is followed by increased GR
transcription capacity [104,105,107]. The MR upregulating effects of antidepressants andthe subsequent reduction of HPA overactivity in depressed patients underscore the importance of appropriate MR function. This is further supported by a clinical trial in whichantidepressant response to amitriptyline in major depression was impared by coadministration of spironolactone, an MR antagonist (Hundt et al., unpublished results,
cited in Ref. 7).
The effects of antidepressants on GR function have also been studied usingtransgenic mice expressing GR antisense: after long-term treatment with moclobemide, areversible MAO-A inhibitor, these mutated mice not only show normalized HPA activity
but also changes in several tests of anxiety and memory [108]. These ﬁndings support
the notion that antidepressants act by improving the negative feedback capacity of the
HPA system at various levels and that the setpoint of the HPA-system activity is modiﬁed
in a way that “buffers” the hormonal response to stressors. This may represent one mechanism by which patients who have recovered from depression or an anxiety disorder may
be protected by long-term antidepressant treatment against further stress-induced relapses.
A new line of research in regard to the mechanisms of antidepressants was stimulatedby the observation that in animal studies the selective serotonin reuptake inhibitor (SSRI)
ﬂuoxetine, which is widely used for the treatment of depression and anxiety, may enhance
the concentrations of 3α,5α-THP in the rat brain [109]. At the molecular level, it has been
demonstrated that SSRIs shift the activity of the 3α-hydroxysteroid oxidoreductase, whichcatalyzes the conversion of 5α-DHP into 3α,5α-THP, toward the reductive direction,
thereby enhancing the formation of 3α,5α-THP [110]. Additionally, 3α,5α-THP has beensuggested to possess antidepressant-like effects in mice using the Porsolt forced swim test
[111]. These preclinical ﬁndings suggest that 3α-reduced neuroactive steroids such as
3α,5α-THP may play a role in the treatment with antidepressant drugs. Indeed, the concentrations of GABA-agnostic neuroactive steroids 3α,5α-THP and 3α,5β-THP were reducedin plasma of depressed patients, while there was an increase in 3β,5α-THP, an antagonistic
isomer of 3α,5α-THP [112,113], as shown in Figure 5. In contrast to preclinical data,also tri- and tetracyclic antidepressants interfered with the composition of neuroactive
steroids in a similar way as did SSRIs [112]. In addition, antidepressants do not generally
shift the activity of the 3α-hydroxysteroid oxidoreductase toward the reductive direction.
The concentrations of 3α,5α-THDOC were elevated during depression, probably as aconsequence of hypercortisolemia, and reduced by ﬂuoxetine [114], but not by tri- or
tetracyclic antidepressants [115]. Thus, the effects of antidepressants on neuroactive steroids also appear to be substance substrate-speciﬁc. So far no data are available whether

218

Ströhle and Holsboer

Figure 5 Mean plasma concentrations of progesterone, 3α,5α-THP, 3α,5β-THP and
3β,5α-THP in patients with major depression during ﬂuoxetine treatment and in control subjects. (From Ref. 112.)
similar effects on the concentrations of neuroactive steroids can be achieved by nonpharmacological interventions such as electroconvulsive treatment or psychotherapy. Furthermore, no clinical data on the potential antidepressant activity of 3α-reduced neuroactive
steroids are available.
While no data on the role of a 3α-reduced neuroactive steroids in the treatment of
PTSD are published until now, in panic disorder patients, opposite changes to those seen
in major depression emerged. At baseline, patients with panic disorder had signiﬁcantly
increased concentrations of the positive allosteric modulators 3α,5α-THP and 3α,5β-THP
together with signiﬁcantly decreased concentrations of 3β,5α-THP, a functional antagonist
for GABAA-agonistic steroids, which might result in an increased GABA-ergic tone. SSRI
treatment did not inﬂuence these changes of neuroactive steroid concentrations [116].
Most strikingly, during experimentally induced panic attacks, drastic changes of neuroactive steroid concentrations occur, paralleling psychopathological changes and resulting ina dramatically reduced GABA-ergic tone [117] supporting the idea that the increased
baseline concentrations of GABAA-agonistic neuroactive steroids may serve as a counterregulatory mechanism against the occurrence of spontaneous panic attacks. Major depression and panic disorder show distinct changes in the concentrations of neuroactive steroids
and the effects of antidepressant treatment. When attempting to pharmacologically modify
the equilibrium of neuroactive steroids as a treatment for psychiatric disorders [118], consideration should also be given to baseline concentrations and possible counterregulatory
mechanisms.
C.

Possible Treatment Approaches

If one assumes that normalization of an altered HPA setpoint is an essential mechanism
for antidepressant drug action, the question arises as to how this goal is achieved. An
alternative treatment approach would, therefore, be either to suppress the behavioral symptoms of enhanced CRH by CRH receptor antagonists or ANP receptor agonists or to block

Stress-Responsive Neurohormones219

the many untoward effects of excessive corticosteroid secretion by administration of GR
antagonists. Furthermore, modulation of the concentration of neuroactive steroids has beensuggested as a new psychopharmacological tool as well [33,119].
The most straightforward strategy to restrain the depressionogenic and anxiogenic
effect of excessive CRH production and relase is the administration of CRH-R1 antagonists. One of these compounds (R121919), a pyrazolopyrimidine has been tested [7]. The
ﬁrst open-label trial with this substance in depressed patients signiﬁcantly reduced depression and anxiety scores as was seen in both clinican and patient ratings, suggesting that
this type of compound may have considerable therapeutic potential [120]. The questionof whether CRH-R1 antagonists resolve the entire depressive syndrome or only several
stress-related symptoms, such as pathological anxiety, loss of appetite and sexual drive,
sleep disturbance, psychomotor and cardiovascular changes, etc., as found in animal experiments, remains to be validated in controlled clinical trials. Although especially promising
until now, there are no data on the therapeutic potential of CRH-R1 antagonists in thetreatment of panic disorder or PTSD.
In preclinical studies with two selectively bred rat lines, in high-anxiety-related behavior (HAB) R121919 reduced anxiety-related behavior in a dose-dependent manner,
whereas it had virtually no behavioral effect in low-anxiety-related behavior (LAB) rats
[121]. In contrast, the stress-induced activity of the HPA system, as determined by simultaneously measured plasma ACTH levels, was similarly blunted by R121919 in both HAB
and LAB animals. Because CRH gene expression was observed to be increased in thelocus coeruleus of HAB rats and activation of the brain area is associated with stress andanxiety in rats, the anxiolytic effect of R121919 is consistent with an action of the CRHR1 antagonist at this brainstem locus [122].
An alternative approach focuses upon reduction of cortisol either by cortisol synthesis inhibitors or by blocking their action by antagonizing their effects at receptors. To
date, only few studies with small sample size exist, which limit their clinical acceptance.
Of particular interest is the use of metyrapone, which results in an inhibition of hydroxylation at position C11 of the steroid molecule, thus preventing the synthesis of cortisol.
Metyrapone treatment has produced antidepressant-like behavioral changes in two frequently used rodent models for screening antidepressive compounds, the forced swimtest and the olfactory-bulbectomized rat [123]. Numerous exploratory studies and one
small placebo-controlled trial suggest that metyrapone has antidepressant potential [124].
This clinical effect seems to contradict the notion that decreased cortisol-mediated feedback may elicit increased CRH in all those brain areas where CRH gene expression iscontrolled by GR. However, the additional bioavailability of non-C11-hydroxylated adrenal steroids increases the pool of neuroactive steroids [125], which can exert a numberof neuroendocrine and behavioral symptoms such as a reduction of anxiety-like behavior
and suppression of CRH expression [35,126]. Ketoconazole, in addition to blocking adrenal steroid synthesis, inhibits cytochrome P450-dependent enzymes and has direct inhibitory effects on other pituitary cells than corticotrophs [127], thus, for example, affecting
gonadal steroid secretion as well. Consistent with predictions from open-label studies, a
recent placebo-contolled trial suggested that ketoconazole is superior to placebo among
hypercortisolemic depressed patients [128]. Again, it is difﬁcult to dissociate the effects
of ketoconazole from the effects of other adrenal steroids that are produced at much higher
rates because of the enzyme blockade.
Blockade of GR as a treatment strategy has been poorly studied due to the lack of
speciﬁc antagonists. Preliminary results suggested that mifepristone (RU486) may be a

220

Ströhle and Holsboer

Figure 6 Normed CCK-4-induced increase in the API score, and the anxiety and somatic
sub-scores in patients with panic disorder. Compared to placebo, ANP inhibits the CCK-4
induced increase in the API score and the anxiety and somatic subscores, giving evidence
for an anxiolytic activity of ANP in patients with panic disorder. (From Ref. 131.)

useful treatment approach in major depression [129]. At the moment it is not fully clear
how disturbed corticosteroid-receptor signaling can be inﬂuenced therapeutically. Conservatively, administration of a CRH-R1 antagonist is expected to shorten the onset of coadministered antidepressants. Such drugs may also work as antidepressants when administered as monotherapy [120]. Similarly, GR antagonists might not be effective enough asmonotherapy, but they may be a worthwhile adjunct to antidepressants. Perhaps the mostintriguing approach is the administration of GR antagonists to patient with psychotic depression. It has been submitted by Schatzberg and coworkers [130] that hypercortisolemia
enhances dopaminergic transmission to an extent that results clinically in psychotic symptoms. Thus suppressing cortisol effects at GR may limit this dopamine excess and thus
resolve psychotic symptoms. It is of note that psychotic depression is almost always associated with HPA overactivity.
Natriuretic peptides are speciﬁcally involved in the modulation of the HPA system
at all regulatory levels [19]. Neuroanatomical distribution of the natriuretic peptide system
supports a role of these peptides in anxiety modulation as well. And indeed, in rodents
ANP was found to be anxiolytic [24], whereas CNP was anxiogenic [26,27]. In patientswith panic disorder, basal ANP concentrations are lower when compared to healthy control
subjects, but ANP concentrations are faster and more pronounced during experimentallyinduced panic attacks [17]. In line, there is recent evidence for an anxiolytic activity of
ANP in humans: ANP decreases CCK-4-induced panic anxiety in patients with panic
disorder [131] (Fig. 6) and healthy control subjects and attenuates the HPA-system activity
by decreasing ACTH and cortisol stimulation [132]. Nonpeptidergic ANP receptor ligands
may ultimately be used in the pharmacological treatment of anxiety disorders, like panic
disorder.

Stress-Responsive Neurohormones

221

VIII. SUMMARY
Clinical and preclinical studies have gathered substantial evidence that stress-response
alterations play a major role in the development of major depression, panic disorder, andpost-traumatic stress disorder. The stress response, the hypothalamic pituitary adrenocortical (HPA) system and its modulation by CRH, corticosteroids, and their receptors, as wellas the role of natriuretic peptides and neuroactive steroids, are described. We review therole of the HPA system in major depression, panic disorder, and post-traumatic stressdisorder, as well as its possible relevance for treatment. Impaired glucocorticoid-receptor
function in major depression is associated with an excessive release of neurohormones,
like CRH, to which a number of signs and symptoms characteristic of depression can be
ascribed. In panic disorder, a role of central CRH in panic attacks has been suggested.
Atrial natriuretic peptide (ANP) is involved in sodium lactate-induced panic attacks. Furthermore, preclinical and clinical data on its anxiolytic activity suggest that nonpeptidergic
ANP-receptor ligands may ultimately be used in the treatment of anxiety disorders. Recent
data further suggest a role of 3α-reduced neuroactive steroids in major depression, panic
attacks, and panic disorder. Post-traumatic stress disorder is characterized by a peripheral
hyporesponsive HPA system and elevated CRH concentrations in CSF. This dissociation
is probably related to an increased risk for this disorder. Antidepressants are effective
both in depression and anxiety disorders and have major effects on the HPA system,
especially on glucocorticoid and mineralocorticoid receptors. Normalization of HPA-system abnormalities is a strong predictor of the clinical course, at least in major depression
and panic disorder. CRH-R1 or glucocorticoid-receptor antagonists and ANP-receptor agonists are currently being studied and may provide future treatment options more closely
related to the pathophysiology of the disorders.
REFERENCES
1. Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic
peptide that stimulates secretion of corticotropin and β-endorphine. Science 1981; 213:1394–
1397.
2. Rivier J, Rivier C, Vale W. Synthetic competitive antagonists of corticotropin-releasing factor: effect of ACTH secretion in the rat. Science 1984; 224:889–891, 1984.
3. Lovenberg TW, Liaw CW, Grigoriadis DE, Clevenger W, Chalmers DT, deSouza EB,
Oltersdorf T. Cloning and characterization of a functionally distinct corticotropin-releasing
factor receptor subtype from rat brain. Proc Natl Acad Sci USA 1995; 92:836–840.
4. Chalmers DT, Lowenberg TW, de Souza EB. Localization of novel corticotropin-releasing
factor receptor (CRF2) mRNA expression to speciﬁc subcortical nuclei in rat brain: Comparison with CRF1 receptor mRNA expression. J Neurosci 1995; 15:6340–6350.
5. Ambrosio E, Sharpe LG, Pilotte NS. Regional binding to corticotropin releasing factor receptors in brain of rats exposed to chronic cocaine withdrawal. Synapse 1997; 25:272–
276.
6. Sánchez MM, Young LJ, Plotsky PM, Insel TR. Autoradiographic and in situ hybridization
localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain.
Comp Neurol 1999; 408:365–377.
7. Holsboer F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists
to treat depression and anxiety. J Psychiatr Res 1999; 33:181–214.
8. Dunn AJ, Berridge CW. Physiological and behavioral responses to corticotropin releasing
factor administration: Is CRF a mediator of anxiety or stress response. Brain Res Rev 1990;
15:71–100.

222

Ströhle and Holsboer

9. Stenzel-Poore MP, Heinrichs SC, Rivest S, Koob GF, Vale WW. Overproduction of corticotropin-releasing factor in transgenic mice: a genetic model of anxiogenic behavior. J Neurosci
1994; 14:2579–2584.
10. Skutella T, Montkowski T, Stöhr T, Probst JC, Landgraf R, Holsboer F, Jirikowski GF.
Corticotropin-releasing hormone (CRH) antisense oligodeoxynucleotide treatment attenuatessocial defeat-induced anxiety in rats. Cell Mol Neurobiol 1994; 14:579–588.
11. Liebsch F, Landgraf R, Engelmann M, Lörscher P, Holsboer F. Differential behavioral effects
of chronic infusion of CRH1 and CRH2 receptor antisense oligonucleotides into the rat brain.
J Psychiatr Res 1999; 33:153–163.
12. Skultella T, Probst JC, Renner U, Holsboer F, Behl C. Corticotropin-releasing hormone receptor (type I) antisense targeting reduces anxiety. Neuroscience 1998; 85:795–805.
13. Smith GW, Aubry J-M, Dellu F, Contarino A, Bilezjian LM, Gold LH, Hause C, Bentley
CA, Sawchenko PE, Koob GF, Vale W, Lee K-F. Corticotropin-releasing factor receptor 1deﬁcient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 1998; 20:1093–1102.
14. Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JMHM, Stalla GK, Blanquet V, Steckler
T, Holsboer F, Wurst W. Impaired stress response and reduced anxiety in mice lacking afunctional corticotropin-releasing hormone receptor 1. Nature Genet 1998; 19:162–166.
15. Kishimoto T, Radulovic M, Lin CR, Hooshmand F, Hermanson O, Rosenfeld MG, Spiess
J. Deletion of the CRH2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-23. Nature Gen 2000; 24:415–419.
16. Bale TL, Contarino A, Smith GW, Chan R, Gold LH, Sawchenko PE, Koob GF, Vale WW,
Lee KF. Mice deﬁcient for corticotropin-releasing hormone receptor-2 display anxiety-likebehavior and are hypersensitive to stress. Nature Gen 2000; 24:410–414.
17. Kellner M, Wiedemann K, Holsboer F. ANF inhibits the CRH-stimulated secretion of ACTH
and cortisol in man. Life Sci 1992; 50:1835–1842.
18. Wiedemann K, Herzog L, Kellner M. Atrial natriuretic hormone inhibits corticotropin-releasing hormone induced prolactin release. J Psychiatr Res 1995; 29:51–58.
19. Ströhle A, Kellner A, Holsboer F, Wiedemann K. Atrial natriuretic hormone decreases endocrine response to a combined dexamethasone corticotropin-releasing hormone test. Biol Psychiatry 1998; 43:371–375.
20. de Bold AJ. Atrial natriuretic factor a hormone produced by the heart. Science 1985; 230:
767–770.
21. Tanaka I, Misono KS, Inagami T. Atrial natriuretic factor in rat hypothalamus, atria andplasma: Determinations by speciﬁc radioimmunoassay. Biochem Biophys Res Commun
1984; 124:663–668.
22. Biro E, Sarnyai Z, Penke B, Szabo G, Telegdy G. Role of endogenous corticotropin-releasing
factor in mediation of neuroendocrine and behavioral response to cholecystokinin octapeptide
sulfate ester in rats. Neuroendocrinology 1999; 57:340–345.
23. Bhattacharya SK, Chakrabarti A, Sandler M, Glover V. Anxiolytic activity of intracerebroventricularly administered atrial natriuretic peptide in the rat. Neuropsychopharmacology
1996; 15:199–206.
24. Ströhle A, Jahn H, Montkowski A, Liebsch G, Boll E, Landgraf R, Holsboer F, Wiedemann
K. Central and peripheral administration of atriopeptin is anxiolytic in rats. Neuroendocrinology 1997; 65:210–215.
25. Kellner M, Diehl I, Knaudt K, Schüle C, Jahn H, Wiedeman K. C-type natriuretic peptide
excerts stimulatory effects on the corticotropin-releasing hormone induced secretion of hormones in normal man. Eur J Endocrinol 1997; 136:388–393.
26. Montkowski A, Jahn H, Ströhle A, Poettig M, Holsboer F, Wiedemann K. C-type natriuretic
peptide exerts opposing effects to atrial natriuretic peptide on anxiety-related behaviour in
rats. Brain Res 1998; 792:358–360.

Stress-Responsive Neurohormones

223

27. Jahn H, Montkowski A, Knaudt K, Ströhle A, Kiefer A, Schick M, Wiedemann K. Alphahelical-corticotropin-releasing hormone reverses anxiogenic effects of C-type natriuretic peptide in rats. Brain Res 2001; 893:21–28, 2001.
28. de Kloet ER. Brain corticosteroid receptor balance and homeostatic control. Front Neuroendocrinol 1991; 12:95–164.
29. Keller-Wood ME, Dallman MF. Corticosteroid inhibition of ACTH secretion. Endocr Rev
1984; 5:1–24.
30. Trapp T, Rupprecht R, Castrén M, Reul JMHM, Holsboer F. Heterodimerization between
mineralocorticoid and glucocorticoid receptor: A new principle of glucocorticoid action in
the CNS. Neuron 1994; 13:1457–1462.
31. Majewska MD, Harrison NL, Schwart RD, Barker JL, Paul SM. Steroid hormone metabolites
are barbiturate-like modulators of the GABA receptor. Science 1986; 232:1004–1007.
32. Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992; 6:2311–2322.
33. Rupprecht R, Holsboer F. Neuroactive steroids: Mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci 1999; 22:410–416.
34. Rupprecht R, Reul JMHM, Trapp T, van Steensel B, Wetzel C, Damm K. Progesterone
receptor-mediated effects of neuroactive steroids. Neuron 1993; 11:523–530.
35. Patchev VK, Montkowski A, Rouskova D, Koranyi L, Holsboer F, Almeida O. Neonatal
treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of advers early life events. J Clin
Invest 1997; 99:962–966.
36. Holsboer F. Antidepressant drug discovery in the postgenomic era. World J Biol Psychiatry(in press).
37. Deuschle M, Schweiger U, Weber B, Gotthart U, Korner A, Schmider J, Lammer CH, Heuser
I. Diurnal activity and pulsatility of the hypothalamus-pituitary-adrenal system in male depressed patients and healthy controls. J Clin Endocrin Metab 1997; 82:234–238.
38. Amsterdam JD, Winokur A, Abelman E, Lucki I, Rickels K. Cosyntropin (ACTH 1-24) stimulation test in depressed patients and healthy subjects. Am J Psychiatry 1983; 140:907–909.
39. Holsboer F, von Bardeleben U, Gerken A, Stalla GK, Müller OA. Blunted corticotropin andnormal cortisol response to human corticotropin-releasing factor in depression. N Engl J Med
1984; 1984:1127.
40. Rubin RT, Phillips JJ, Sado TF, McCracken JT. Adrenal gland volume in major depression.
Increase during the depressive episode and decrease with successful treatment. Arch Gen
Psychiatry 1995; 52:213–218.
41. Rubin RT, Poland RE, Lesser IM. Neuroendocrine aspects of primary endogenous depression. 1987; 44:328–336.
42. Carroll BJ, Feinberg M, Greden JF. A speciﬁc laboratory test for the diagnosis of melancholia. Arch Gen Psychiatry 1981; 38:15–22.
43. Holsboer, Philipp M, Steiger A, Gerken A. Multisteroid analysis after DST in depressed
patients—a controlled study. J Affect Disord 1986; 10:241–249.
44. Holsboer F, Liebl R, Hofschuster E. Repeated dexamethasone suppression test during depressive illness. Normalization of test result compared with clinical improvement. J Affect
Disord 1982; 4:93–101.
45. Gold PW, Chorousos G, Kellner C, Post R, Roy A, Augerinos P, Schulte H, Ohlﬁeld E,
Loriaux DI. Psychiatric implications of basic and clinical studies with corticotropin-releasing
factor. Am J Psychiatry 1984; 141:619–627.
46. von Bardeleben U, Holsboer F. Cortisol response to a combined dexamethasone-human corticotropin-releasing hormone challenge in patients with depression. J Neuroendocrinol 1989;
1:485–488.
47. von Bardeleben U, Holsboer F. Effect of age upon the cortisol response to human CRH in
depressed patients pretreated with dexamethasone. Biol Psychiatry 1991; 29:1042–1050.

224

Ströhle and Holsboer

48. Holsboer-Trachsler E, Strohler R, Hatzinger M. Repeated administration of the combined
dexamethasone-human corticotropin releasing hormone stimulation test during treatment ofdepression. Psychiatry Res 1991; 38:163–171.
49. Zobel AW, Yassouridis A, Frieboes R-M, Holsboer F. Cortisol response to the combined
dexamethasone-CRH test predicts medium-term outcome in patients with major depression.
Am J Psychiatry 1999; 156:949–951.
50. Zobel A, Nickel T, Sontag A, Uhr M, Holsboer F, Ising M. Cortisol response in the combined
dexamethasone/CRH test as predictor of relapse in patients with remitted depression: a prospective study. J Psychiatr Res 2001; 35:83–94.
51. Holsboer F, von Bardeleben U, Wiedemann K, Müller OA, Stalla GK. Serial assessment ofcorticotropin-releasing hormone response after dexamethasone in depression—Implications
for pathophysiology of DST nonsuppression. Biol Psychiatry 1987; 22:228–234.
52. Holsboer-Trachsler E, Hemmeter U, Hatzinger M, Seifritz E, Gerhard U, Hobi V. Sleep
deprivation and bright light as potential augmenters of antidepressant drug treatment-neurobiological and psychomethric assessment of course. J Psychiatr Res 1994; 28:381–399.
53. Heuser IJE, Schweiger U, Gotthardt U, Schmider J, Lammers CH, Dettling M, Yassouridis A,
Holsboer F. Pituitary-adrenals-system regulation and psychopathology during amitriptyline
treatment in elderly depressed patients and in normal comparison subjects. Am J Psychiatry
1996; 153:93–99.
54. Modell S, Yassouridis A, Huber J, Holsboer F. Corticosteroid receptor function is decreased
in depressed patients. Neuroendocrinology 1997; 65:216–222.
55. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology
2000; 23:477–501.
56. von Bardeleben U, Holsboer F, Stalla GK, Müller OA. Combined administration of humancorticotropin-releasing factor and lysine vasopressin induces cortisol escape from dexamethasone suppression in healthy subjects. Life Sci 1985; 37:1613–1618.
57. Holsboer F, Lauer CJ, Schreiber W, Krieg J-C. Altered hypothalamic-pituitary-adrenocorticalregulation in healthy subjects at high familial risk for affective disorders. Neuroendocrinology 1995; 62:340–347.
58. Modell S, Lauer CJ, Schreiber W, Huber J, Krieg J-C, Holsboer F. Hormonal response patternin the combined DEX-CRH test is stable over time in subjects at high familial risk for affective disorders. Neuropsychopharmacology 1998; 18:253–262.
59. Belanoff JK, Gross K, Yager A, Schatzberg AF. Corticosteroids and cognition. J Psychiatr
Res 2001; 35:127–145.
60. Sheline YI, Wang PW, Gado MH, Hsernansky JG, Vanier MW. Hippocampal atrophy inrecurrent major depression. Proc Natl Acad Sci USA 1996; 93:3908–3913.
61. Sheline YI, Shanghavi M, Mintun MA, Gado MH. Depression duration but not age predicts
hippocampal volume loss in medically healthy women with recurrent major depression. J
Neurosci 1999; 19:5034–5043.
62. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal
volume reduction in major depression. Am J Psychiatry 2000; 157:115–118.
63. Nelson MD, Saykin AJ, Flashman LA, Riordan HJ. Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging. A meta-analytic study. Arch Gen Psychiatry 2000; 55:433–440.
64. Bremner JD. Does stress damage the brain. Biol Psychiatry 1999; 45:797–805.
65. Leverenz JB, Wilkinson CW, Wamble M, Corbin S, Grabber JE, Raskind MA, Peskind ER.
Effect of chronic high-dose exogenous cortisol on hippocampal neuronal number in aged
nonhuman primates. J Neurosci 1999; 19:2356–2361.
66. Müller MB, Lucassen PJ, Yassouridis A, Hoogendijk WJG, Holsboer F, Swaab DE. The
human hippocampus in major depression or following administration of glucocorticoids: No
evidence major structural alterations. Soc Neurosci Abstr 1998; 24:990.

Stress-Responsive Neurohormones

225

67. Abelson JL, Curtis CG. Hypothalamic-pituitary-adrenal axis activity in panic disorder 24hour secretion of corticotropin and cortisol. Arch Gen Psychiatry 1996; 53:323–331.
68. Kathol RG, Anton R, Noyes R, Gehris T. Direct comparison of urinary free cortisol excretionin patients with depression and panic disorder. Biol Psychiatry 1989; 25:873–878.
69. Uhde T, Joffe RT, Jimerson DC, Post RM. Normal urinary free cortisol and plasma MHPG
in panic disorder: Clinical and theoretical implications. Biol Psychiatry 1988; 23:575–585.
70. Kathol RG, Noyes R, Lopez AL, Reich JH. Relationship of urinary free cortisol levels inpatients with panic disorder to symptoms of depression and agoraphobia. Psychiatry Res
1988; 24:211–221.
71. Curtis GC, Cameron OG, Neese RM. The dexamethasone suppression test in panic disorderand agoraphobia. Am J Psychiatry 1982; 139:1043–1046.
72. Lieberman JA, Bremner R, Lesser M, Coccaro E, Borenstein M, Kane MJ. Dexamethasone
suppression test in patients with panic disorder. Am J Psychiatry 1983; 140:917–919.
73. Holsboer F, von Bardeleben U, Buller R, Heuser I, Steiger A. Stimulation response to corticotropin-releasing hormone (CRH) in patients with depression alcoholism and panic disorder.
Horm Metab Res 1987; 19:80–88.
74. Roy-Byrne PP, Uhde TW, Post RM, Gallucci W, Chousos GP, Gold PW. The corticotropinreleasing hormone stimulation test in patients with panic disorder. Am J Psychiatry 1986;
143:896–899.
75. Kellner M, Yehuda R. Do panic disorder and posttraumatic stress disorder share a common
psychoneuroendocrinology? Psychoneuroendocrinology 1999; 24:485–504.
76. Schreiber W, Lauer CJ, Krumrey K, Holsboer F, Krieg JC. Dysregulation of the hypothalamic-pituitary-adrenocortical system in panic disorder. Neuropsychopharmacology 1996; 15:
7–15.
77. Jolkonen J, Lepola U, Bissett G, Nemeroff C, Riekkinen P. CSF corticotropin-releasing factor
is not affected in panic disorder. Biol Psychiatry 1987; 33:136–138.
78. Cameron OG, Lee MA, Curtis GC, McCann DS. Endocrine and physiological changes during‘spontaneous’ panic attacks. Psychoneuroendocrinology 1987; 12:321–331.
79. Bandelow B, Wedekind D, Pauls J, Broocks A, Hajak G, Ruther E. Salivary cortisol in panic
attacks. Am J Psychiatry 2000; 157:454–456.
80. Woods SW, Charney DS, McPherson CA, Gradman AH, Heninger GR. Situational panic
attacks Behavioral, physiologic, and biochemical characterization. Arch Gen Psychiatry
1987; 44:365–375.
81. Coplan JD, Goetz R, Klein DF, Papp LA, Fyer AJ, Liebowitz MR, Davies SO, Gorman JM.
Plasma cortisol concentrations preceeding lactate-induced panic. Arch Gen Psychiatry 1998;
55:130–136.
82. Ströhle A, Holsboer F, Rupprecht R. Increased ACTH concentrations associated with cholecystokinin tetrapeptide-induced panic attacks in patients with panic disorder. Neuropsychopharmacology 2000; 22:251–256.
83. Yehuda R, Boisneau D, Mason JW, Giller EL. Relationship between lymphocyte glucocorticoid receptor number and urinary free cortisol excretion in mood, anxiety, and psychotic
disorder. Biol Psychiatry 1993; 34:18–25.
84. Kellner M, Herzog L, Holsboer F, Widemann K. A possible role of atrial natriuretic hormone
in pituitary-adrenocortical unresponsiveness in lactate-induced panic. Am J Psychiatry 1995;
152:1365–1367.
85. Yehuda R, Kahana B, Binder-Byrnes K, Southwick SM, Mason JW, Giller EL. Low urinary
cortisol excretion in Holocaust survivors with posttraumatic stress disorder. Am J Psychiatry
1995; 152:982–986.
86. Yehuda R, Teicher MH, Levengood RA, Trestman RL, Siever LJ. Circadian regulation ofbasal cortisol levels in posttraumatic stress disorder. Ann N Y Acad Sci 1994; 746:378–380.
87. Yehuda R, Southwick SM, Krystal JH, Bremner D, Charney DS, Mason JW. Enhanced sup-

226

88.
89.

90.

91.

92.

93.

94.

95.
96.

97.
98.
99.

100.
101.

102.
103.
104.

105.

106

Ströhle and Holsboer
pression of cortisol following dexamethasone administration in posttraumatic stress disorder.
Am J Psychiatry 1993; 150:83–86.
Resnick HS, Yehuda R, Pitman RK, Foy DW. Effect of previous trauma on acute plasma
cortisol level following rape. Am J Psychiatry 1995; 152:1675–1677.
Bremner JD, Licinio J, Darwell A, Krystal JH, Owens MJ, Southwick SM, Nemeroff CB,
Charney DS. Elevated CSF corticotropin-releasing factor concentrations in posttraumaticstress disorder. Am J Psychiatry 1997; 154:624–629.
Smith MA, Davidson J, Ritchie JC, Kudler H, Lipper S, Chappell P, Nemeroff CB. The
corticotropin-releasing hormone test in patients with posttraumatic stress disorder. 1989; 26:
349–355.
Yehuda R, Schmeidler J, Elkin A, Houshmand E, Siever L, Binder-Byrnes K, Wainberg
M, Aferiot D, Lehman A, Guo LS, Yang RK. Phenomenology and psychobiology of theintergenerational response to trauma. In Danieli Y, ed. International Handbook: Multigenerational Legacies of Trauma. New York: Plenum, 1997.
Goddard AW, Brouette T, Almai A, Jetty P, Woods SW, Charney D. Early administrationof clonazepam with sertraline for panic disorder. Arch Gen Psychiatry 2001; 58:681–
686.
Kalogeras, Calogero AE, Kuribayashi T. In vitro and in vivo effects of the trialzolobenzodiazepine alprazolam on hypothalamic-pituitary-adrenal function: pharmacological and clinicalimplications. J Clin Endocrinol Metab 1990; 70:1462–1471.
Owens MJ, Bissette G, Nemeroff CB. Acute effects of alprazolam and adinazolam on
the concentrations of corticotropin-releasing factor in the rat brain. Synapse 1989; 4:196–
202.
Curtis GC, Abelson JL, Gold PW. Adrenocorticotrophic hormone and cortisol responses inpanic disorder and effects of alprazolam treatment. Biol Psychiatry 1997; 41:76–85.
Schlegel S, Steiner H, Bokisch A, Hahn K, Schlosser R, Benkert O. Decreased benzodiazepine receptor binding in panic disorder measured by iomazenil SPECT: a preliminary report.
Eur Arch Psychiatry Clin Neurosci 1994; 224:49–51.
Malizia A, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ. Decreased brain GABAA
benzodiazepine receptor binding in panic disorder. Arch Gen Psychiatry 1998; 47:917–925.
Kaschka W, Feistel H, Ebert D. Reduced benzodiazepine receptor binding in panic diordermeasured by iomazenil SPECT. J Psychiatry Res 1995; 29:423–427.
Nutt DJ, Glue P, Lawson C, Wilson S. Flumazenil provocation of panic attacks. Evidence
for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry 1990;
47:917–925.
Ströhle A, Kellner M, Yassouridis A, Holsboer F, Wiedemann K. Effect of ﬂumazenil in
lactate-sensitive patients with panic disorder. Am J Psychiatry 1998; 155:610–612.
Ströhle A, Kellner M, Holsboer F, Wiedemann K. Behavioral, neuroendocrine and cardiovascular response to ﬂumazenil: No evidence for an altered benzodiazepine receptor sensitivity
in panic disorder. Biol Psychiatry 1999; 45:321–326.
Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. ArchGen Psychiatry 1997; 54:597–606.
Holsboer F, Barden N. Antidepressants and hypothalamic-pituitary-adrenocortical regulation.
Endocr Rev 1996; 17:187–205.
Reul JMHM, Stec I, Söder M, Holsboer F. Chronic treatment of rats with the antidepressantamitriptyline attenuates the activity of the hypothalamic-pituitary-adrenocortical system. Endocrinology 1993; 133:312–320.
Reul JMHM, Labeur M, Grigoriadis DE, de Souza EG, Holsboer F. Hypothalamic-pituitaryadrenocortical axis changes in the rat after long-term treatment with reversible monoamineoxidase-A inhibitor moclobemide. Neuroendocrinology 1994; 60:509–519.
Reul JMHM, Probst JC, Skutella T, Hirschmann M, Stec IS, Montkowski A, Landgraf R,
Holsboer F. Increased stress-induced adrenocorticotropin response after long-term intracere-Stress-Responsive Neurohormones

107.

108.

109.

110.
111.
112.

113.

114.

115.

116.

117.

118.

119.
120.

121.

122.

123.

227

broventricular treatment of rats with antisense mineralocorticoid receptor oligodeoxynucleotides. Neuroendocrinology 1997; 65:189–199.
Brady LS, Witﬁeld HJ, Fox RJ, Gold PW, Herkenham M. Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid
receptor gene expressin in rat brain. J Clin Invest 1991; 87:831–837.
Montkowski A, Barden N, Wotjak C, Stec I, Ganster J, Meaney M, Engelman M, Reul
JMHM, Landgraf R, Holsboer F. Long-term antidepressant treatment reduces behaviouraldeﬁcits in transgenic mice with impaired glucocorticoid receptor function. J Neuroendocrinol
1995; 7:841–845.
Uzunov DP, Cooper TB, Costa E, Guidotti A. Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography. Proc Natl Acad Sci USA 1996;
93:12599–12604.
Grifﬁn LD, Mellon SH. Selective serotonin reuptake inhibitors indirectly alter activity ofneurosteroidogenic enzymes. Proc Natl Acad Sci 1999; 96:13512–13517.
Khisti RT, Chopde CT, Jain SP. Antidepressant-like effect of the neurosteroid 3α-hydroxy5α-pregnan-20-one in mice forced swim test. Pharmacol Biochem Behav 2000; 67:137–143.
Romeo E, Ströhle A, de Michele F, Spaletta G, Hermann B, Holsboer F, Pasini A, Rupprecht
R. Effects of antidepressant treatment on neuroactive steroids in major depression. Am J
Psychiatry 1998; 155:910–913.
Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A. Increasein the cerebrospinal ﬂuid content of neurosteroids in patients with unipolar major depression
who are receiving ﬂuoxetine or ﬂuvoxamine. Proc Natl Acad Sci USA 1998; 95:3239–3244.
Ströhle A, Pasini A, Romeo E, Hermann B, Spalletta G, de Michele F, Holsboer F, Rupprecht
R. Fluoxetine decreases concentrations of 3α,5α-tetrahydrodeoxycorticosterone (3α,5αTHDOC) in major depression. J Psychiat Res 2000; 34:183–186.
Ströhle A, Romeo E, Hermann B, di Michelle F, Spaletta G, Pasini A, Holsboer F, Rupprecht
R. Concentrations of 3α-reduced neuroactive steroids and their precursors in plasma of patients with major depression and after clinical recovery. Biol Psychiatry 1999; 45:274–
277.
Ströhle A, Romeo E, di Michele F, Pasini A, Yassouridis A, Holsboer F, Rupprecht R.
GABAA receptor modulatory neuroactive steroid composition in panic disorder and duringparoxetine treatment. Am J Psychiatry 2002; 159:145–147.
Ströhle A, Romeo E, di Michele F, Pasini A, Hermann B, Gajewsky G, Holsboer F, Rupprecht R. Induced panic attacks shift GABAA receptor modulatory neuroactive steroid composition. Arch Gen Psychiatry (in press).
Guidotti A, Costa E. Can the antidysphoric and anxiolytic proﬁles of selective serotonininhibitors be related to their ability to increase brain 3α,5α-tetrahydroprogesterone (allopregnanolone) availability? Biol Psychiatry 1988; 44:865–873.
Rupprecht R. The neuropsychopharmacological potential of neuroactive steroids. J Psychiatr
Res 1997; 31:297–314.
Zobel AW, Nickel T, Künzel HE, Ackl N, Sonntag A, Ising M, Holsboer F. Effects of thehigh-afﬁnity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the ﬁrst 20 patients treated. J Psychiatr Res 2000; 34:171–181.
Keck ME, Welt T, Wigger A, Renner U, Engelmann M, Holsboer F, Landgraf R. The anxiolytic effect of the CRH1 receptor antagonist R121919 depends on innate emotionality in rats.
Eur J Neurosci 2001; 13:373–380.
Plotsky PM, Zurich KJ, Mathys C, Sanchez MM, Thrivikraman KV, Holsboer F, Wigger
A, Landgraf R. Region-speciﬁc alterations in corticotropin releasing factor (CRF) mRNA
distribution and CRF-R2 bindings in rats bred for high anxiety-related behavior (HAB). Soc
Neurosci Abstr 2000; 26:206–207.
Healy DG, Harkin A, Cryan JF, Kelley JP, Leonhard BE. Metyrapone displays antidepressant-like properties in preclinical paradigms. Psychopharmacology 1999; 145:303–308.

228

Ströhle and Holsboer

124. O’Dwyer AM, Lightman SL, Marks M, Checkley SA. Treatment of major depression withmetyrapone and hydrocortisone. J Affect Disord 1995; 33:123–128.
125. Rupprecht R, Ströhle A, Hermann B, de Michele F, Spaletta G, Pasini A, Holsboer F, Romeo
E. Neuroactive steroid concentrations following metyrapone administration in depressed patients and healthy volunteers. Biol Psychiatry 1998; 44:912–914.
126. Patchev VK, Hassan AH, Holsboer F, Almeida OFX. The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus. Neuropsychopharmacology 1996; 15:
533–540.
127. Stalla HK, Stalla J, von Werder K. Nitroimidazole derivates inhibit anterior pituitary cellfunction apparently by a direct effect on the catalytic subunit of the adenylate cyclase holoenzyme. Endocrinology 1989; 155:699–706.
128. Wolkowitz OM, Reus VI, Chan T, Manfredi F, Raum W, Johnson R, Canick J. Antiglucocorticoid treatment of depression: double blind ketokonazole. Biol Psychiatry 1999; 45:1070–
1074.
129. Murphy BEP, Filipini D, Ghardirian AM. Possible use of glucocorticoid receptor anragonists
in the treatment of major depression: Preliminary results using RU486. J Psychiatry Neurosci
1993; 18:209–213.
130. Schatzberg AF, Rothschild AJ, Langlais PJ, Bird ED, Cole JO. A corticosteroid/dopamine
hypothesis for psychotic depression and related states. J Psychiatr Res 1984; 19:57–64.
131. Ströhle A, Kellner M, Holsboer F, Wiedemann K. Anxiolytic activity of atrial natriuretic
peptide in patients with panic disorder. Am J Psychiatry 2001; 158:1514–1516.
132. Wiedemann K, Jahn H, Yassouridis A, Kellner M. Anxiolytic activity of atrial natriuretic
peptide on cholecystokinin tetrapeptide-induced panic attacks. Arch Gen Psychiatry 2001;
58:371–377.

11
Neuropeptide Alterations in Depression
and Anxiety Disorders
DAVID A. GUTMAN, DOMINIQUE L. MUSSELMAN, andCHARLES B. NEMEROFF
Emory University School of Medicine
Atlanta, Georgia, U.S.A.

I.

INTRODUCTION

In the search for the underlying pathophysiology of the major psychiatric disorders, neuropeptides, in general, and hypothalamic-releasing factors, in particular, have been scrutinized closely. Our growing understanding of the brain over the past few decades has
suggested complex interactions between classic monoamine neurotransmitters, such as
dopamine (DA), norepinephrine (NE), and serotonin (5HT), and the growing numbers ofneuropeptides found throughout the brain. Neuropeptides—molecules that contain two or
more amino acids linked by peptide bonds—function as critical chemical messengers andare heterogeneously distributed through the peripheral and central nervous system (CNS).
Many of these peptides exert diverse actions, functioning as hypothalamic hypophysiotropic-releasing factors, neuromodulators, and/or neurotransmitters. As understanding of
the behavioral effects of these neuropeptides continues to grow, it has become increasingly
apparent that dysregulation of the proper functioning of neuropeptide systems may be
relevant to particular psychiatric disorders. In this chapter, we brieﬂy review basic neuropeptide neurobiology most relevant to psychiatric disorders and summarize preclinicaland clinical studies implicating neuropeptide alterations in the pathophysiology of moodand anxiety disorders.

229

230

Gutman et al.

II. RATIONALE FOR EXPLORING NEUROPEPTIDE MODULATION
IN AFFECTIVE AND ANXIETY DISORDERS
Undoubtedly one early rationale for the intensive study of neuropeptide systems in patientswith primary psychiatric disorders was the higher than expected psychiatric morbidity inpatients with primary endocrine disorders such as Addison’s disease or Cushing’s syndrome. Disturbances in the feedback regulation of the hypothalamic–pituitary–end-organ
axes are of considerable interest. Because hypothalamic hypophysiotropic neuropeptides
ultimately control the activity of these neuroendocrine axes, considerable effort has been
expended into the search for evidence of dysfunction in these systems. However, outsideof the neuroendocrine axes, the ongoing discovery and characterization of new neuropeptides and multiple subtypes of neuropeptide receptors and their heterogeneous distribution
have often suggested these peptides may modulate behaviors directly relevant to psychiatric disease. Because neuropeptides account for neurotransmission at a large percentageof CNS synapses and indirectly or directly modulate the activity of a diverse number ofhormones and neurotransmitters that have been implicated in the pathogenesis of affective
and anxiety disorders, their scrutiny may allow for elucidation of the primary pathophysiological deﬁcits in these devastating illnesses.
One of the primary motivations for the continuing investigation of the major endocrine axes is the so-called “neuroendocrine window strategy.” This strategy is based ona large literature that indicates that the secretion of the target endocrine organs (e.g., theadrenal cortex or thyroid) is largely controlled by their respective pituitary trophic hormones, which in turn are controlled primarily by the secretion of their respective hypothalamic release and/or release-inhibiting hormones. There is now considerable evidence thatthe secretion of these hypothalamic hypophysiotropic hormones is controlled, at least inpart, by the classic neurotransmitters including 5HT, acetylcholine (ACh), and NE, allpreviously posited to play a preeminent role in the pathophysiology of affective, anxiety,and/or psychotic disorders.
However, the hypothesis that one can infer information about higher CNS neuronal
activity as, for example, the activity of serotonergic neurons in a particular disease state
solely by measuring the function of a speciﬁc endocrine axis, is, however far from provenand fraught with difﬁculty. Many factors other than a single neurotransmitter system affectthe activity of the various endocrine axes. Nevertheless, taken together with other measuresof neurotransmitter function, this approach can indeed provide useful information.
The contrasting behavioral and neurobiological effects of antidepressants [tricyclic
antidepressants or monoamine oxidase inhibitors (MADs)], anxiolytics (SSRIs, SNRIs,
and benzodiazepines), and antipsychotics as well as those drugs which induce or worsen
depression (such as reserpine), anxiety (ﬂumazenil, cholecystokinin), and psychosis (psychostimulants, phencyclidine) have provided yet another impetus for scrutiny of neuroendocrine and neuropeptide pathophysiology in the major psychiatric illnesses because virtually all of these agents alter the activity of one or more endocrine axis. This second coreassumption, the “psychopharmacological bridge technique” posits that if a drug produces
therapeutic effects and has speciﬁc biochemical actions, an etiological relationship between the therapeutic effects, biochemical changes, and the primary cause of the syndrome
may exist [1]. For example, tricyclic antidepressants block reuptake of NE and 5HT, MAO
inhibitors inhibit the metabolism of catecholamines and 5HT and, moreover, downregulation (decrease in the number) of β-adrenergic receptors that is associated with most antidepressant treatments occurs in association with the clinically successful treatment of de-Neuropeptide Alterations

231

pression. The pharmacological bridge technique and “neuroendocrine window strategy”
together suggest that alterations of a variety of endocrine axes exist within patients withmajor psychiatric disorders, and that many clinically efﬁcacious agents act upon one ormore of the neuropeptide circuits in the CNS. The pharmacological bridge technique alsosuggests altered neurotransmitter transporter or receptor-mediated signal transduction in
depression and other psychiatric disorders. Whether alterations in peripheral endocrineorgan hormone secretion contribute primarily to the pathogenesis of psychiatric disorders,
and/or whether altered secretion of pituitary and hypothalamic hormones primarily contribute to the signs and symptoms of a speciﬁc mental illness remains a subject of considerable controversy. In this chapter, we brieﬂy outline the major ﬁndings concerning theputative roles of neuropeptides and hypothalamic-release factors in mood and anxiety
disorders.
III. CURRENT STRATEGIES FOR EVALUATING A SPECIFIC ROLE
FOR NEUROPEPTIDES IN PSYCHIATRIC DISORDERS:PRECLINICAL AND CLINICAL STUDIES
A. Preclinical Studies
Preclinical studies have been essential in providing useful and novel peptide circuit targets
for drug discovery and in understanding some of the possible roles of neuropeptides andtheir interactions with other brain systems. Most of these studies involve directly injecting
the peptide of interest into the brains of laboratory animals and studying its effect on
behavior and on other known peptide and hormonal systems. One example of the usefulness of this strategy is in identifying potential behavioral effects of cholecystokinin(CCK), which was originally discovered in the gastrointestinal tract. CCK injections inlaboratory animals can induce many behavior responses characteristic of panic attacks,
which has led to scrutiny of a potential role for CCK and its receptor systems in panic
disorder.
B. Clinical Studies
As noted above, during the 1970s and 1980s peripheral neuroendocrine markers were
often used to indirectly assess CNS function because the brain was relatively inaccessible
for study, with the exception of cerebrospinal ﬂuid (CSF) and postmortem studies. With
the emergence of the monoamine theories of mood disorders and schizophrenia, many
investigators attempted to draw conclusions about the activity of speciﬁc neurotransmittercircuits in patients with various psychiatric disorders by measuring the basal and stimulated secretion of pituitary and end-organ hormones in plasma. Clinical studies, however,are often confounded by the normal circadian rhythms and the pulsatile release of manyof the hypothalamic–pituitary–end-organ axes components that are often not taken into
account when these experiments are designed. Further, differences in assay sensitivity,
gender, inclusion criteria for patients, and severity of symptoms all may potentially generate confounding or at least quite variable results. Nevertheless, considerable progress about
the neurobiology of psychiatric disorders has been discovered through such an approach.
Before proceeding into a review of the relevant clinical literature, a brief overview
of the most common methodologies employed merits discussion. Most clinical studies inhumans are based on one of three methodologies: (1) postmortem studies in which theconcentration of neuropeptides and neuropeptide receptors are measured; (2) studies mea-

232

Gutman et al.

suring the concentrations of peptides in biological ﬂuids such as plasma and CSF; and(3) studies measuring the biological and behavioral changes following administration of
the neuropeptides (i.e., challenge tests).
Postmortem studies are advantageous in that they allow peptide levels to be sampleddirectly in brain tissue and from distinct brain regions. Methodologically there are major
obstacles to overcome in obtaining and studying postmortem tissue. Because peptides andtheir receptors and mRNA are degraded postmortem, differences between the elapsed time
between death of the subject and harvesting of the tissue, and hence in postmortem decay,
as well as other neurochemical confounds associated with preserving and handling thetissue render conclusions concerning the relations between peptide circuit alterations andpsychiatric disorders tentative and unable to stand on their own.
Many investigators have measured peptides in plasma and CSF. The concentrationof neuropeptides in CSF is thought by some, but not all, investigators to accurately measure extracellular ﬂuid concentration in brain, and therefore has an advantage over postmortem studies that are thought to measure both the releasable and nonreleasable poolsof neuropeptides. Although CSF concentrations may be an index of the mean activity of aneuropeptide system, they may not accurately represent regional variations in extracellularavailability of these peptides that may be of great pathophysiological importance. Plasma
concentrations of neuropeptides are also commonly determined, although they are confounded by the presence of binding proteins as, for example, with corticotropin-releasing
factor (CRF), and the impossibility of differentiating between CNS and peripheral sourcesof the neuropeptide being measured.
Another important strategy has been the administration of neuropeptides or synthetic
neuropeptide agonists or antagonists directly to patients with affective and anxiety disorders, and measuring subsequent neuroendocrine and/or behavioral changes. In these socalled stimulation or provocation tests, hypothalamic and/or pituitary-derived factors or
their synthetic analogs are exogeneously administered, and the hormonal response to this“challenge” is assessed. For example, in the standard CRF stimulation test, a 1 µg/kg
dose of human or ovine CRF is administered intravenously, and the adrenocorticotropin(ACTH) and cortisol response is measured over a period of 2 or 3 h. This test is a very
sensitive measure of hypothalamic–pituitary–adrenal (HPA) axis activity, and changes
in the magnitude and/or duration of the response relative to normal control values arecharacteristic of one or another type of dysregulation of the HPA axis. One must be cautious, however, about making assumptions about what, if any, CNS deﬁcits are responsible
for the pattern of HPA axis activity observed.

IV. CORTICOTROPIN-RELEASING FACTOR IN MOOD AND ANXIETYDISORDERSA.

Basic Biology

The HPA axis has been extensively scrutinized in patients with psychiatric diseases. An
abundance of evidence dating back over 100 years has demonstrated that dysfunction of
the HPA axis may lead to speciﬁc psychiatric disturbances. At the pinnacle of this systemis the neuropeptide CRF, also known as corticotropin-releasing hormone (CRH), a 41amino-acid peptide that, as a hypothalamic-releasing factor, controls the activity of the
HPA axis.

Neuropeptide Alterations

233

Figure 1 Diagram of the neurovascular anatomy of the hypothalamic-pituitary axis. PVN,
paraventricular nucleus. SON, supraoptic nucleus. POA, preoptic area. ARC, arcuate
nucleus. PT, pars tuberalis. PI, pars intermedia. PD, pars distalis. PN, pars nervosa, MB,mamillary body, OC, optic chiasm.

Within the hypothalamus, CRF is primarily synthesized in the parvocellular neurons
located in the paraventricular nucleus (PVN) [2]. CRF neurons in the PVN (Fig. 1) receive
input from a variety of brain nuclei, including the amygdala, bed nucleus of the stria
terminalis, and other brain stem nuclei [2]. Hypothalamic CRF-containing neurons, inturn, project to the median eminence [3]. In response to stress, this neural circuit is activated releasing CRF from the median eminence into the hypothalamo-hypophyseal portal
system where it binds to CRF receptors on corticotrophs in the anterior pituitary, which
promotes the synthesis of propiomelanocortin (POMC) and the release of its post-translation products, adrenocorticotropic hormone (ACTH), β-endorphin, and others. ACTH released from the anterior pituitary into the systemic circulation then stimulates the production and release of cortisol by acting on ACTH receptors in the adrenal cortex. (For ageneral schematic of HPA axis regulation, see Fig. 2.).
Although Saffron and Schally identiﬁed a crude extract that promoted the releaseof ACTH from the pituitary in 1955 [4], CRF was not isolated and chemically characterized until 1981. Working with extracts derived from 500,000 sheep hypothalami, Valeand colleagues at the Salk institute isolated, synthesized, and elucidated the structure of234

Gutman et al.

Figure 2 Overview of the common organizational motif of the neuroendocrine axis. The
neurosecretion of hypothalamic factors into hypophyseal portal vessels is regulated by aset point of activity from higher brain centers. Neurohormones released from the hypothalamus into hypophyseal portal vessels in turn stimulate cells in the pituitary. These adenohypophyseal hormones then regulate the hormone output from the end-organ. The end organ
then exerts negative feedback effects at the pituitary and hypothalamus to prevent further
neurohormone and pituitary hormone release via “long-loop” negative feedback. Short-loop
negative feedback may also occur where pituitary hormones feed back directly on hypothalamic neurons to prevent further neurohormone release.

CRF [5]. This discovery led to the availability of synthetic CRF, which ﬁnally permitted
a more comprehensive assessment of HPA axis activity to be developed. It is now clearthat CRF coordinates the endocrine, immune, autonomic, and behavioral responses ofmammals to stress.
Two CRF receptor subtypes, CRF1 and CRF2, with distinct anatomical localization
and receptor pharmacology, have been identiﬁed [6–10] in rats and humans. Both receptors are G-protein-coupled receptors and are positively coupled to adenylyl cyclase via
Gs. The CRF1 receptor is predominantly expressed in the pituitary, cerebellum, and neocortex in the rat [11]. A growing body of evidence from animal studies has shown that CRF1
receptors may speciﬁcally mediate some of the anxiogenic-like behaviors observed afteradministration of CRF [12,13]. The CRF2 receptor family is composed of two primary
splice variants, CRF2A and CRF2B. The CRF2A receptor is more prevalent in subcorticalregions, such as the ventromedial hypothalamus, lateral septum, and dorsal raphe nucleus,
whereas CRF2B is more abundantly expressed in the periphery. In addition to CRF, several
other endogeneous peptide ligands for CRF receptors have recently been discovered including urocortin [14], urocortin II, and urocortin III, and perhaps others [15,16]. With
the discovery of several new putative endogenous ligands, much of the pharmacology
and functional interactions between these ligands and receptors remains to be discovered[17,18].

Neuropeptide Alterations

235

B. HPA Axis Abnormalities in Depression
Evidence linking HPA axis abnormalities and psychiatric symptoms, as noted above, dates
back more than 100 years. The greater than expected prevalence of depression and otherpsychiatric symptoms in both Cushing’s and Addison’s disease served as an impetus forresearchers to scrutinize HPA axis function in patients with psychiatric disorders. Basedon the work of research groups led by Board, Bunney, and Hamburg, as well as by Carroll,
Sachar, Stokes, and Besser, literally thousands of studies were conducted in this area,
most during the 1970s.
Some of the earliest studies demonstrated abnormalities in glucocorticoid function
in depressed patients, including elevated plasma and CSF cortisol concentrations in depressed patients [19,20], increased 24-h urinary free cortisol concentrations, and increased
levels of cortisol metabolites in urine [21]. One of the major advances, of course, camewith the discovery of the chemical identity of the neuropeptide CRF, the primary physiological secretagogue of ACTH, and ultimately of cortisol (Table 1).
In order to accurately assess HPA axis function, several functional challenge tests
have been developed, both provocative and suppression tests. The most commonly used
test to measure HPA axis function is the dexamethasone suppression test (DST). In thisstandardized test, 1 mg of dexamethasone is administered orally at 11 P.M., and blood
samples are obtained at 8 A.M. the following morning for cortisol measurement. Dexamethasone is a synthetic steroid similar to cortisol; it suppresses ACTH secretion andsubsequently cortisol release in healthy volunteers. Nonsuppression of plasma glucocorticoid levels following the administration of dexamethasone is common in depressed patients. The rate and magnitude of cortisol nonsuppression after dexamethasone administration generally correlates with the severity of depression [22]; in fact, nearly all patientswith major depression with psychotic features exhibit DST nonsuppression [23,24]. Since
Carroll’s initial report [25,26] and subsequent claims for diagnostic utility [27], the dexamethasone suppression test has generated considerable controversy [28] as to its diagnostic
utility. Diagnostic issues notwithstanding, the overwhelming conclusion from a myriadof studies demonstrates that a sizeable percentage of depressed patients exhibit HPA axis
hyperactivity.
Shortly after the isolation and characterization of CRF, a standardized CRF stimulation test was developed to further assess HPA axis activity. In this paradigm, CRF (ovineor human) is administered intravenously (usually in a ﬁxed dose of 100 µg or as a 1 µg/
kg dose), and the ensuing ACTH (or β-endorphin) and cortisol response is measured at
30-min intervals over a 2 to 3-h period [29]. Numerous studies have now demonstrated

Table 1 HPA Axis Changes in Depression↑ Corticotropin-releasing factor (CRF) concentrations in cerebrospinal ﬂuid a↓ Adrenocorticotropic hormone response (ACTH) to CRF stimulation↓ Density of CRF receptors in frontal cortex of suicide victims
Enlarged pituitary gland in depressed patients a
Adrenal gland enlargement in suicide victims and depressed patients↑ Plasma cortisol during depression a↑ Urinary free cortisol concentrations a
Nonsuppression of plasma cortisol and ACTH after dexamethasone administrationaaState-dependent.

236

Gutman et al.

a blunted ACTH and β-endorphin response to exogenously administered ovine CRF(oCRF) or human CRF (hCRF) in depressed patients when compared to nondepressedsubjects, though the cortisol response in depressed patients and nondepressed control subjects does not consistently differ [30–34]. The blunted ACTH response to CRF occurs in
depressed DST nonsuppressors, but not in DST suppressors [35]. The attenuated ACTH
response to CRF is presumably because of either chronic hypersecretion of CRF fromnerve terminals in the median eminence, which results in downregulation of CRF receptors
in the anterior pituitary, and/or to chronic hypercortisolemia. This receptor downregulation
results in a reduced responsivity of the anterior pituitary to CRF, as has been demonstrated
in laboratory animals [36–40]. Following recovery from depression, the documented disturbances in the HPA axis generally remit.
A combined dexamethasone/CRF test has also been developed by Holsboer andcolleagues. In this test, 1.5 mg of dexamethasone is administered orally at night (23:00h), and subjects receive an IV bolus of 100 µg of human CRF at 15:00 h the following
day. Patients with HPA axis dysfunction, which is frequently encountered in 40 to 60%
of depressed patients, display a paradoxically increased release of ACTH and cortisol
following CRF challenge relative to controls. These abnormalities disappear following
remission of depression, and normalization of HPA axis function seems to precede fullclinical remission [41,42]. The combined DEX/CRF test appears to have much higher
sensitivity for detecting subtle alterations in HPA axis function; approximately 80% of
patients with major depression exhibit an abnormal response to the DEX/CRF test. In
contrast, only approximately 44% of patients with major depression demonstrate an abnormal response when the dexamethasone suppression test is administered alone [41,42].
Furthermore, otherwise healthy individuals with ﬁrst-degree relatives with an affective
illness, which greatly increases their own risk for psychiatric disorders, demonstrated cortisol and ACTH responses to the DEX/CRF test that were higher than a control group, butless than patients currently suffering from major depression. One interpretation of theseﬁndings is that a genetically transmittable defect in corticosteroid receptor function may
render these individuals more susceptible to developing affective disorders by increasingbaseline and evoked HPA axis activity [43].
C.

Extrahypothalamic CRF and Depression

The studies thus far discussed focused primarily on dysregulation of the HPA axis, but
perhaps of even greater relevance to psychiatric disorders is the fact that CRF controls
not only the neuroendocrine, but also the autonomic, immune, and behavioral responses
to stress in mammals. Moreover, results from both clinical studies, and a rich body ofliterature conducted primarily in rodents and lower primates, have indicated the importance of extrahypothalamic CRF circuits [13,44]. In rodents, primates, and humans, CRF
and its receptors have been heterogeneously localized in a variety of regions including
the amygdala, thalamus, hippocampus, and prefrontal cortex, and others [45–48]. Thesebrain regions are known to be important in regulating many aspects of the mammalianstress response, and in regulating affect. The presence of CRF receptors in both the dorsal
raphe (DR) and locus coeruleus (LC), the major serotonergic and noradrenergic cell-bodycontaining regions in the brain, respectively, also deserve comment. Because most available antidepressants, including the tricyclics and selective serotonin reuptake inhibitors(SSRI), are believed to act primarily via modulation of noradrenergic and/or serotonergicNeuropeptide Alterations

237

systems, the neuroanatomical proximity of CRF and monoaminergic systems provides
plausibility for interaction between CRF systems and antidepressants.
Involvement of extrahypothalamic CRF systems in the pathophysiology of depression is suggested by numerous studies showing elevated CRF concentrations in the cerebrospinal ﬂuid (CSF) of drug-free depressed patients [49–53], although a discrepant report
has appeared [54]. Elevated cisternal CSF CRF concentrations have also been detected
in depressed suicide victims [49]. A reduction in concentrations of CRF in CSF has been
observed in healthy volunteers treated with the tricyclic antidepressant desipramine [55]and in depressed patients following treatment with ﬂuoxetine [56] or amitryptiline [57],providing further evidence of a possible interconnection between antidepressants, noradrenergic neurons, and CRF systems. Similar effects have been reported after electroconvulsive therapy (ECT) in depressed patients [58]. Elevated CSF CRF concentrations appear
to represent a state, rather than a trait, marker of depression (i.e., a marker of the state ofdepression rather than a marker of vulnerability to depression) [58]. Furthermore, highand/or increasing CSF CRF concentrations, despite symptomatic improvement of major
depression during antidepressant treatment, may be the harbinger of early relapse [59],as our group previously reported for DST nonsuppression [60].
While the exact mechanism contributing to CRF hyperactivity remains obscure,studies from our group and others have documented long-term persistent increases in HPAaxis activity and extrahypothalamic CRF neuronal activity after exposure to early untoward life events—for example, neglect, and child abuse, respectively, in both laboratory
animals (rat and nonhuman primates) and patients [43,61–63]. Early-life stress apparently
permanently sensitizes the HPA axis and leads to a greater risk of developing depression
later in life. To measure HPA axis responsivity to stress in humans, the Trier Social Stress
Test (TSST) was developed. This laboratory paradigm involves a simulated 10-min public
speech and a mental arithmetic task. The TSST has been validated as a potent activatorof the HPA axis in humans [64]. Recently, our group has reported increased plasma ACTH
and cortisol concentrations, presumably because of hypersecretion of CRF, after exposure
to the TSST in women (both depressed and nondepressed) who were exposed to severe
physical and emotional trauma as children [65]. The depressed women both with andwithout early-life stress exhibited a blunted ACTH response to CRF, whereas the womenwith early trauma alone exhibited an exaggerated ACTH response. These data provide
further evidence for functional hyperactivity of CRF systems that may be inﬂuenced byearly adverse life events.
D. CRF and Anxiety Disorders
Involvement of CRF in anxiety disorders has been well documented in both animal andhuman studies. As reviewed by Arborelius and colleagues [66], patients with post-traumatic stress disorder (PTSD) (i.e., Vietnam combat veterans) exhibit signiﬁcantly elevated
CSF CRF concentrations [67,68], as well as alterations in the ACTH response to CRF
challenge [69]. A recent elegant study using an in-dwelling catheter in the lumbar space,which allows repeated sampling of CSF for several hours after the initial, and presumably
stressful, lumbar puncture, demonstrated elevated CSF CRF levels in PTSD combat veterans [68]. In contrast, low serum cortisol and urinary free cortisol levels have been repeatedly, yet unexpectedly, detected in PTSD, especially after dexamethasone administration[70,71]. One possible mechanism that has been proposed by Yehuda and colleagues to238

Gutman et al.

explain these ﬁndings is heightened negative glucocorticoid feedback within the HPA axis
in chronic PTSD patients [72].
Although CSF CRF concentrations are not increased in panic disorder patients[73,74], a diminished ACTH response to CRF administration has been observed [75].
Increased [76] or normal concentrations [74,77] of CSF CRF have been documented inpatients with obsessive-compulsive disorder (OCD), although signiﬁcant decreases in CSF
CRF concentrations occur with a therapeutic response to clomipramine [78]. Patients withgeneralized anxiety disorder (GAD), however, exhibit similar CSF CRF concentrations
in comparison to normal controls [74,79]. Not surprisingly increased concentrations of
CSF CRF occur in alcohol withdrawal, a condition of sympathetic arousal and increased
anxiety [80,81]. In contrast, CSF CRF concentrations are reduced [82] or are normal [83]in abstinent chronic alcoholics with normal plasma cortisol concentrations. Although HPA
axis hyperactivity exists in patients with certain anxiety disorders, such perturbations do
not exist in the patterns suggestive of CRF hypersecretion as documented in patients withmajor depression [66]. Moreover, in the majority of these studies, careful assessment ofcomorbidity of mood and anxiety syndromes and symptoms has not been conducted.
E.

CRF in Depression and Anxiety: Conclusions

Space constraints do no permit an extensive review of the preclinical literature; however,
several additional points are worth highlighting. Numerous studies have documented thatwhen CRF is directly injected into the CNS of laboratory animals, it produces effects
reminiscent of the cardinal symptoms of depression, including decreased libido, reduced
appetite and weight loss, sleep disturbances, and neophobia. Based on this premise, newly
developed CRF1 receptor antagonists represent a novel putative class of antidepressants.
Such compounds show activity in nearly every preclinical screen for antidepressants andanxiolytics currently employed. Recently, a small open-label study exmaining the effectiveness of R121919, a CRF1 receptor antagonist, in major depression was completed [84]in which standard severity measures of both anxiety and depression were reduced in the
depressed patients after R121919 treatment. Although this drug is no longer in clinicaldevelopment, it is clear that CRF1 antagonists potentially represent a new class of psychotherapeutic agents to treat anxiety and affective disorders. Finally, the early trauma dataraises the question of whether childhood physical and sexual abuse, common among depressed patients, is responsible for some or all of the changes reported in the HPA axis
and CRF circuits in patients with major depression.
V.

THYROTROPIN-RELEASING FACTOR, THE THYROID AXIS,AND DEPRESSIONA.

Biology

Dysfunction of the HPT axis has been associated with numerous psychiatric disturbances,
ranging from mild depression to overt psychosis. The HPT axis controls the release of
thyroid hormones, T3 and T4, and is regulated by two peptide hormones, thyrotropinreleasing hormone (TRH), a tripeptide, and thyroid-stimulating hormone (TSH) or thyrotropin, a large protein. TRH was the ﬁrst of the hypothalamic-releasing hormones to beisolated and characterized. TRH is synthesized predominantly in the paraventricular nucleus in the hypothalamus and stored in nerve terminals in the median eminence where
it is released into the vessels of the hypothalamic-hypophyseal portal system. TRH is thenNeuropeptide Alterations

239

transported to the sinusoids in the anterior pituitary, where it binds to TRH receptors on
thyrotropes and promotes the release of TSH into the systemic circulation.
TSH is a 28-kDA glycoprotein composed of two noncovalently linked protein
chains, TSH-α, which is identical to the α subunit contained in other pituitary hormones,
including follicle-stimulating hormone, luteinizing hormone, human chorionic gonadotropin, and TSH-β. Upon stimulation by TSH, the thyroid gland releases the iodinated aminoacids L-triiodothyronine (T3) and thyroxine (T4). Beside their well-known metabolic effects, T3 and T4 provide feedback to the hypothalamus and adenohypophysis to regulate
the synthesis and release of TRH and TSH, respectively [85]. Following its initial isolation,
the heterogeneous distribution of TRH in extrahypothalamic sites strongly suggested a role
for this peptide as a neurotransmitter or neuromodulator, as well as a releasing hormone. It
is now established that TRH itself can produce direct effects on the CNS independent of
its actions on pituitary thyrotrophs.
B. Psychiatric Manifestations of Thyroid Dysfunction
Primary thyroid axis disorders are often associated with numerous psychiatric manifestations ranging from mild depression and anxiety to overt psychosis. Regardless of the
etiology, hypothyroidism leads to a number of clinical manifestations, including slowed
mentation, forgetfulness, decreasing hearing, cold intolerance, and ataxia. Decreased energy, weight gain, depression, cognitive impairment, or overt psychosis (“myxedema madness”) may also result. Because of the overlapping symptoms with depression, thyroid
hormone deﬁciency must be ruled out when evaluating patients with depression.
Early studies from the late 1960s and early 1970s scrutinized psychiatric comorbidity in patients with hypothyroidism, and a substantial number of these patients demonstrated signs of depression, anxiety, and/or cognitive disturbances [86,87]. Furthermore,these symptoms were often improved or resolved following resolution of the thyroid condition alone. Later studies have demonstrated varying degrees of cognitive disturbance in up
to 48% of psychiatrically ill hypothyroid cases [88], and approximately 50% of unselected
hypothyroid patients have symptoms characteristic of depression [88]. Anxiety symptoms
are also common, occurring in up to 30% of unselected patients. Mania and hypomanic
states have rarely been reported in hypothyroid patients. Finally, although psychosis is
the most common reported symptom in the case literature on hypothyroidism (52.9%), it
only accounts for approximately 5% of the psychiatric morbidity in an unselected sample[88], presumably because more severe symptoms are more likely to be documented in
the clinical literature.
C. TRH and TSH in Depression
Considerable evidence has revealed an increased incidence of HPT axis dysfunction inpatients with major depression (Table 2). More than 25 years ago research groups led

Table 2 Hypothalamic-Pituitary-Thyroid (HPT) Axis Alterations in Depression↑ CSF TRH concentrations in depressed patients↓ Nocturnal plasma TSH
Blunted or exaggerated TSH in response to TRH stimulation
Presence of antithyroglobulin and/or antimicrosomal thyroid antibodies

240

Gutman et al.

by Prange [89] and Kastin demonstrated that approximately 25% of patients with major
depression exhibit a blunted TSH response to TRH [89,90]. This is clearly not secondary
to hyperthyroidism but presumably because of hypersecretion of TRH from the medianeminence, which leads to TRH receptor downregulation in the anterior pituitary and reduced sensitivity of the pituitary to exogeneously administered TRH. This hypothesis
seems plausible in light of evidence showing elevated TRH concentrations in CSF of drugfree depressed patients [91] and an inverse relationship between the blunted TSH responseto TRH and CSF TRH concentrations [92]. Depressed patients have also been shown tohave an increased prevalence rate of symptomless autoimmune thyroiditis (SAT), deﬁned
by the abnormal presence of antithyroglobulin and/or antimicrosomal thyroid antibodies
consistent with grade 4 hypothyroidism [93].
Although there is a preponderance of evidence suggesting elevated TRH release insome depressed patients, as of yet it is unclear what precise role this factor plays in depression. Interestingly, a lumbar intrathecal infusion of 500 µg of TRH into medication-free
inpatients with depression produced a clinically robust, but short-lived, improvement inmood and suicidality, which led the authors to propose that elevated TRH levels might
be a compensatory response in depression [94]. Although this work is preliminary, it raises
the interesting possibility that a systematically administered TRH receptor agonist may
represent a novel class of antidepressant agents.
D.

Bipolar Disorder and HPT Abnormalities

HPT axis abnormalities have also been reported in bipolar disorders. Both elevated basal
plasma concentrations of TSH and an exaggerated TSH response to TRH have been demonstrated [95,96]. There is also evidence that bipolar patients with the rapid cycling subtype have a higher prevalence rate of hypothyroidism (grades I, II, and III) than bipolar
patients who do not [97,98]. A blunted or absent evening surge of plasma TSH, a blunted
TSH response to TRH [99,100], and the presence of antithyroid microsomal and/or antithyroglobulin antibodies [101,102] have also been demonstrated in bipolar patients.
E.

Thyrotropin-Releasing Hormone Alterations in Anxiety Disorders

Evidence demonstrating alterations of TRH circuits in anxiety disorders is relatively limited. A blunted TSH response to TRH has been observed in panic disorder patients[103,104]. However, in one of these studies, this effect was only demonstrated in patientswith concurrent major depression [104]. Another study indicated that the TSH reponse to
TRH is normal in panic disorder patients [105]. CSF TRH concentrations in patients withpanic disorder, generalized anxiety disorder, or obsessive-compulsive disorder are unchanged compared to control subjects [106].

VI. ARGININE-VASOPRESSIN
A.

Biology

Arginine-vasopressin (AVP), also known as antidiuretic hormone (ADH), is a nonapeptide
synthesized in the lateral magnocellular neurons of the paraventricular and supraoptic
nuclei of the hypothalamus, and is released directly into the bloodstream from axon terminals in the posterior pituitary [107]. These AVP-containing neurons terminate in the neuro-Neuropeptide Alterations

241

hypophysis and secrete AVP into the systemic circulation, although they send collaterals
to the hypothalamo-hypophyseal portal system as well. Another group of AVP-containing
neurons project from the medial parvocellular subdivision of the paraventricular nucleus(PVN) to the median eminence. Within the median eminence, the parvocellular-derived
AVP is released from axon terminals, secreted into the hypothalamo-hypophyseal portal
circulation, and carried to the anterior lobe of the pituitary gland [3]. Moreover extrahypothalamic AVP-containing neurons lie within limbic structures such as the septum andamygdala, as well as in the brainstem and spinal cord [108]. AVP-containing neurons also
receive afferent innervations from many different neuronal cell groups and send axonal
projections from the cerebral cortex throughout the CNS. It is thought that AVP and theother well-known posterior pituitary hormone, the nonapeptide oxytocin (OT), play a rolein modulating neural activity in hypothalamic, limbic, and autonomic circuits.
AVP has prominent roles in controlling ﬂuid balance via its effects on the kidney, in
regulating blood pressure by its vasoconstrictive effects on blood vessels, and can directly
promote the sensation of thirst. AVP also can act synergistically with CRF to promote
the release of pituitary POMC-derived peptides (i.e., ACTH and β-endorphin) in humans[109] and animals [110] following stressful stimuli [111]. Chronic stress or adrenalectomy
increases the activity of the parvocellular AVP system [112,113]. CRF and AVP are colocalized in the parvocellular cells of the human hypothalamus and may be secreted together
into the human hypothalamic-hypophyseal portal circulation [114]. The ratio of AVP and
CRF released into the hypothalamic-hypophyseal portal circulation varies in different species [110] and according to the nature of the stress [115,116].
B. AVP in Anxiety and Depression
Similar to the clinical investigations regarding CRF, a variety of patient groups have beenstudied. Alterations of CSF AVP concentrations have been reported in patients with major
depression, bipolar disorder, schizophrenia, anorexia, obesity, alcoholism, Alzeheimer’s
disease, and Parkinson’s disease [117,118]. CSF AVP concentrations in patients with major depression are reportedly reduced in comparison to control subjects, although thesource of CSF AVP is likely extrahypothalamic and not an index of PVN AVP secretion[119–121]. Basal plasma concentrations of AVP in depressed patients are also reportedly
decreased in comparison to age-matched controls [122], although others have found nodifference [123]. Interestingly AVP secretion in response to an infusion of hypertonic
saline is diminished in depressed patients as compared to controls [123].
A mildly blunted ACTH response to exogenous AVP administration has been reported in depressed patients [33], but the ﬁnding was not replicated in two other studies[124,125]. Remarkably, an increase in the number of PVN AVP neurons colocalized with
CRF cells has been reported in depressed patients compared to controls in a postmortem
tissue study [126,127]. This is of interest in view of the ability of AVP to potentiate theactions of CRF at the corticotrope. In contrast to the ﬁndings suggestive of diminishedhypothalamic-vasopressinergic activity in depressed patients are the ﬁndings suggestiveof hypersecretion of AVP in bipolar patients during their manic phase. Elevations in CSF
AVP concentrations have been documented in manic patients [118], as well as signiﬁcant
increases of plasma AVP in comparison to patients with unipolar depression and controls[128]. Clearly, hypothalamic and extrahypothalamic AVP circuits are regulated independently. Whether the perturbations of AVP secretion in patients with neuropsychiatric disorders are state- or trait-dependent requires further elucidation.

242

Gutman et al.

VII. ENDOGENOUS OPIOID PEPTIDES
A.

Biology

The rationale for studying opioids in depression and anxiety disorders is based on theobservation that opiates possess antidepressant and anxiolytic effects. Opium has been
known to have mood-elevating properties, and Krapelin proposed opium as a treatment
for depressed patients as early as 1905. It is now known that the endogenous opioid peptide
system is composed of three groups of peptides, including methionin-enkephalin andleucine-enkephalin [129], β-endorphin [130], and the dynorphins [131]. These peptides
have been shown to play a variety of physiological roles, including regulation of pain,mood, respiration, cardiovascular function, gastrointestinal activity, satiety, sexual behavior (see review, Ref. 132).
At the genomic level, there are three genes responsible for the precursors of opioid
peptides: pro-opiomelanocortin (POMC), proenkephalin, and prodynorphin. Consequently, there are at least three classes of opioid peptides with different biosynthetic andneuronal pathways: the endorphins, enkephalins, and dynorphins. In the adenohypophysis[133], POMC is processed to yield only ACTH and β-lipotropin. β-lipotropin is thenprocessed to yield at least three compounds, including β-γ, and α-endorphin. The second
endogenous opioid system is composed of met- and leuenkephalin, whose precursor isproenkephalin. Derivatives of prodynorphin are the third group of endogenous opioid peptides, including dynorphin A, dynorphin B, and neoendorphin, which are located almost
exclusively in the posterior pituitary.
B.

Opioids in Depression

Early open trials with β-endorphin indicated an improvement in depressed patients following intravenous β-endorphin administration [134], which were later substantiated by controlled clinical trials [135,136]. However, these results were not conﬁrmed, and there is
conﬂicting evidence as to whether intravenously administered β-endorphin permeates the
blood-brain barrier (see Ref. 137 for a comprehensive review of these studies). Also,
the highly addictive nature of opioids limits their usefulness as a potential treatment for
depression. Several studies have also shown that the potent mu opiate receptor antagonist
naloxone does not directly affect mood [138–140], further weakening a strong role of theendogenous opioid system in affective disorders. Two later studies, using very high doses,
showed an increase in anxiety in normal controls [141] or an augmentation of symptom
severity in depressed patients. Nevertheless, these studies did not provide evidence for arole for opioid peptide systems in depression.
The studies investigating CSF β-endorphin immunoreactivity in depression and anxiety disorders by and large also have not substantiated any major role for endogenous
opioid peptides in depression or anxiety disorders. Most investigators [142–146], but not
all [147], have reported normal concentrations of CSF β-endorphin in patients with major
depression. One study also showed elevated CSF β-endorphin levels in patients diagnosed
with panic disorder [148], although this effect was not demonstrated in a later study [149].
Because of these negative ﬁndings and a lack of corroborating evidence, extensive scrutinyof CSF enkephalin and dynorphin concentrations in patients with affective disorder has
not been conducted.
Numerous studies have also measured plasma concentrations of β-endorphin in patients with affective disorders. Because both ACTH and β-endorphin are coreleased from

Neuropeptide Alterations

243

the pituitary following stress and share a common precursor, POMC, these studies are
particularly interesting in light of the consistent alterations in HPA axis function seen in
depression [150]. Studies investing plasma levels of β-endorphin have yielded somewhat
discrepant results. Some investigators have shown increased concentrations [147,151,152],
whereas others have found normal concentrations [34,153–156].
Not surprisingly, similar to the ACTH response to i.v. CRF challenge (vida supra),the β-endorphin response to exogenously administered oCRF is blunted in depressed patients compared to normal subjects [34]. Morever, nonsuppression of plasma β-endorphin
occurs in depressed patients in a manner similar to cortisol nonsuppression after dexamethasone administration. β-endorphin nonsuppression to dexamethasone has been observed
even in those patients whose baseline β-endorphin levels were similar to those of normal
controls [156–158]. In these patients, postdexamethasone levels of cortisol and β-endorphin were strongly correlated [156,158]. In contrast, depressed patients have been reported
to exhibit increased secretion of β-endorphin in response to cholinergic stimulation[147], thyrotropin-releasing hormone (TRH), and luteinizing-hormone-releasing-hormone(LHRH) in comparison to controls [159].

VIII. NEUROPEPTIDE Y
Originally cloned from a pheochromocytoma by Minth and colleagues in 1984, neuropeptide Y (NPY) is a 36 amino acid–containing peptide whose gene is expressed in cells
derived from the neural crest [160]. Neurons displaying NPY immunoreactivity are abundant within several of the limbic areas of the CNS [161,162]. NPY is also present withinneurons of the hypothalamus, brainstem, and spinal cord. Present in most sympathetic
nerve ﬁbers, NPY can be detected in vascular beds throughout the body and occurs inparasympathetic nerves as well [163]. Receptors for NPY are also widely distributed. Not
only do NPY-containing neurons innervate CRF-containing cells of the PVN [164], but
NPY administration increases hypothalamic CRF levels [165] and promotes its release as
well [166]. The relationship of NPY to CRF is further substantiated by the partial blockadeof the NPY-stimulated ACTH response by a CRF receptor antagonist. Moreover, NPY
potentiates the effects of exogenously administered CRF in animals [167]. NPY itself may
have anxiolytic properties. Recently developed NPY overexpressing mice have demonstrated an attenuated sensitivity to the behavioral consequences of stress [168].
Although an initial investigation [169] did not ﬁnd signiﬁcantly diminished CSF
NPY concentrations in depressed patients, Widerlov and colleagues [170] subsequently
reported that patients with major depression do exhibit decreased CSF NPY concentrations
in comparison to sex- and age-matched controls. A recent study has also demonstrated
decreased levels of NPY in the plasma of patients who attempted suicide, and patients
who had repeatedly attempted suicide had the lowest plasma NPY levels [171]. Negative
correlations have been also observed between dimensional anxiety ratings and CSF NPY
levels in depressed patients [172]. Marked reductions in brain-tissue concentrations of
NPY have also been reported in suicide victims, with the most dramatic decreases inthose patients diagnosed with major depression [173]. Efforts toward development of NPY
receptor-speciﬁc agonists and antagonists continue, but the ﬁeld has been greatly hampered
because of the lack of availability of synthetic nonpeptide NPY receptor agonists [174].
NPY-ergic medications may have signiﬁcant beneﬁt in the treatment of affective disorders
and/or eating disorders.

244

Gutman et al.

IX. SUBSTANCE P
Mammalian members of the peptide tachykinin family are known as neurokinins [175],
including neurokinin A, neurokinin B, and substance P. The most well known and abundant of the neurokinins, the undecapeptide substance P, was discovered in 1931 by vonEuler and Gaddum, but not isolated in pure form until 1970 by Chang and Leeman. Substance P (SP) binds to the neurokinin-1 (NK-1) receptor, neurokinin A (NKA) to theneurokinin-2 (NK-2) receptor, and neurokinin B (NKB) to the neurokinin-3 (NK-3) receptor. Within the CNS, SP is localized within the limbic, hypothalamic, and brainstem areas(amygdala, hypothalamus, periaqueductal gray, locus coeruleus, and parabrachial nucleus)[176] and is colocalized within norepinephrine- and serotonin-containing cell bodies aswell [177–180]. Furthermore, substance P and other tachykinins serve as pain neurotransmitters in primary afferent neurons [181] and exert a variety of other peripheral actions,
including bronchoconstriction, vasodilatation, salivation, and smooth muscle contractionin the gut [182,183].
Preclinical studies have provided much of the impetus to continue investigation of
the potential efﬁcacy of substance P receptor antagonism in psychiatric disorders, particularly when these agents have not been effective as analgesics [184]. Substance P (or substance P agonist) administration to animals elicits behavioral and cardiovascular effects
resembling the stress response and the so-called “defense reaction” [185]. Moreover, preclinical studies documented reduction of behavioral and cardiovascular stress response byadministration of substance P receptor antagonists [186,187]. A breakthrough study had
indicated that the substance P receptor antagonist MK-869 is more effective than placedo,
and is as effective as paroxetine in patients with major depression with moderate-to-severe
symptom severity [187].
Future clinical investigations will determine whether brain and CSF substance P
concentrations are altered in patients with major depression [188] (one study showed elevated levels [189]) and whether there are signiﬁcant changes in CSF substance P concentrations after treatment [190]. Moreover, we await convincing studies that reveal whether
substance P antagonists will play a substantive therapeutic role in patients with anxiety
disorders or schizophrenia [191] or asthma, irritable bowel syndrome, and migraine.
X.

GROWTH HORMONE AND SOMATOSTATIN

A.

Biology

A great deal of evidence has accumulated demonstrating abnormalities in both growth
hormone secretion and somatostatin concentrations in CSF in depression and, to a lesser
extent, anxiety disorders. Growth hormone (GH) is synthesized and secreted from somatotrophs located in the anterior pituitary. Its release is unique in that it is controlled by
two peptide hypothalamic hypophysiotropic hormones, growth-hormone-releasing factor(GHRF), and somatostatin, and secondarily by classic neurotransmitters such as Ach, DA,
NE and 5HT that innervate the releasing factor–containing neurons. Somatostatin, also
known as growth hormone-release-inhibiting hormone (GHIH) or somatotrophin-releaseinhibiting factor (SRIF), was ﬁrst isolated from ovine hypothalamus in 1974 [192]. It isa tetradecapeptide containing a disulﬁde bridge linking the two cysteine residues. Somatostatin is released predominantly from the periventricular and paraventricular nucleus of
the hypothalamus and inhibits GH release. Somatostatin also inhibits the release of both
CRF and ACTH [193–195]. Somatostatin has a wide extrahypothalamic distribution inNeuropeptide Alterations

245

brain regions, including the median eminence [196,197], limbic system, cerebral cortex,
hippocampus, hypothalamus [198], and amygdala.
GHRF was characterized and sequenced in 1981 after considerable difﬁculty. The
long-postulated GHRF was discovered several years after the elucidation of the structureof somatostatin from extracts of an ectopic tumor associated with acromegaly. GHRF is a
44-amino-acid peptide, and has the most limited CNS distribution of all the hypothalamicreleasing hormones that have been identiﬁed. GHRF-containing neurons are concentrated
in the infundibular and arcuate nuclei of the hypothalamus and stimulate the synthesis
and release of GH. Dopamine, NE, and 5HT innervate GHRF-containing neurons thereby
modulating GH release. Both GHRF and SRIF are released from the median eminence
into the hypothalamo-hypophyseal portal system where they act on somatotrophs in theanterior pituitary to regulate GH release. Negative feedback is provided by GH, which
stimulates somatostatin release preventing further GH release. The GH axis is unique inthat it does not have a single target endocrine gland but instead growth hormone acts
directly on multiple tissue targets including bone, muscle, and liver.
Growth hormone is released in a pulsatile fashion, with its highest release occurringaround the time of sleep onset and extending into the ﬁrst non-REM period of sleep [199].
A variety of stressors, including starvation, exertion, or emotional stress, also promote
growth hormone release in humans [200]. Growth hormone is necessary for the longitudinal bone growth that occurs during the late childhood; appropriately, GH levels are highin children, reach their peak during adolescence, and decline throughout adulthood. In
addition to its effects on the long bones, growth hormone has predominantly anabolic
effects and leads to increased muscle mass and decreased body fat. GH stimulates therelease of somatomedin from the liver as well as insulin-like growth factors.
Growth hormone is released after treatment with L-dopa, a DA precursor [201],
apomorphine, a centrally active DA agonist [202,203], clonidine [204], a central α2 adrenergic receptor agonist, NE [205], and the serotonin precursors L-tryptophan [206] and 5hydroxytryptophan [207]. Serotinin receptor antagonists, methysergide and cyproheptadine, interfere with the GH response to hypoglycemia [205]. In contrast, phentolamine,a nonspeciﬁc α-adrenergic receptor antagonist, inhibits GH secretion [208] (Table 3).
B. Growth Hormone and Depression
Several ﬁndings indicate dysregulation of GH secretion in depression. A blunted nocturnal
GH surge in depression has been reported [209], whereas daylight GH secretion seems
to be exaggerated in unipolar depressed patients [210]. A number of studies have also
demonstrated a blunted GH response to noradrenergic agents (clonidine, desipramine)[211–217] and dopaminergic agonists (apomorphine) [218] in depressed patients. Siever
et al. [217] demonstrated that the blunted GH response to clonidine was not related toage or sex, and this study provided evidence that the diminished GH response to clonidine
may be secondary to decreased α2-adrenergic receptor sensitivity in depression [217].
A GHRF stimulation test has also been developed and studied in depressed patients.
Two groups observed a blunted GH response to GHRF in depressed patients [219–221].
However, Krishnan and colleagues [222,223] found minimal differences in serum GH
response to GHRH between depressed and control patients. A comprehensive review of
GHRF stimulation tests in depression, anorexia nervosa, bulimia, panic disorder, schizophrenia, and Alzheimer’s disease suggested that the results of this test are not always
consistent and in some cases contradictory [224]. Contributing factors include the variabil-

246

Gutman et al.

Table 3 Releasing and Inhibiting Factors for Growth Hormone
Growth hormone releasing factors• Growth-hormone releasing hormone (GRF of GHRH)• Dopamine• L-DOPA• Apomorphine (dopamine receptor agonist)• Norepinephrine• Clonidine (α2-adrenergic receptor agonist)• Serotonin• L-tryptophan• 5-hydroxytryptophan (5HTTP)
Factors that inhibit growth hormone release• Somatostatin (SRIF)• Phentolamine (nonspeciﬁc alpha-adrenergic receptor antagonist)• Methysergide (serotonin 5HT1,2-receptor antagonist)• Cyproheptadine (serotonin 5HT1,2a, 2c-receptor antagonist)

ity of GHRF-stimulated GH among controls, lack of standard outcome measures, andage- and gender-related effects. Further studies using GHRF will help develop a standard
stimulation test to further clarify the GH response to GHRF in depression and other psychiatric disorders. With the characterization of the genes encoding GHRF and its receptor,
alterations in the CNS of depressed patients that underlie the diminished GH response to
NE and DA agonists can now be studied in post-mortem tissue (Table 4).
Using a GHRF stimulation test, our group has demonstrated a slight exaggerationof GH response to GHRF in depressed patients compared to controls, although this groupdifference was mainly attributable to 3 of the 19 depressed patients who exhibited markedly high GH responses to GHRF [222]. Others, however, have reported a blunted GH
response to GHRF in depressed patients. Thus it is unclear whether the blunted GH response to clonidine seen in depression is because of a pituitary defect in GH secretion,
further implicating a subsensitivity of α-adrenergic receptors in depression, or to a primary
GHRF deﬁcit which leads to a secondary blunted GH response. Recently a diminishedGH response to clonidine was demonstrated in children and adolescents at high risk for
major depressive disorder. When considered with evidence demonstrating GH dysregulation in childhood depression [225], it suggests the blunted GH response seen in high-risk
adolescents may represent a trait marker for depression in children and adolescents [226].
Arguably, the blunted GH response to clonidine seen in depression may be the most reproducible and speciﬁc ﬁnding in the biology of affective disorders.
C.

Somatostatin and Depression

Several studies have demonstrated decreased SRIF concentrations in the CSF of patients
suffering with depression [143,227–231], schizophrenia [227], and dementia, including
Table 4 Growth Hormone (GH) Axis Changes in Depression↑ Circulating daily GH levels (uni- and bipolar depression)↓ Nocturnal GH in depression↓ Response of GH to noradrenergic or dopaminergic agents

Neuropeptide Alterations

247

Alzheimer’s disease [232,233]. Reduced CSF SRIF concentrations have been reported inpatients exhibiting dexamethasone nonsuppression (whether schizophrenic or depressed),
and are negatively correlated with the maximum post-dexamethasone cortisol plasma concentration in patients with major depression [234]. Although some investigators have reported normalization of CSF SRIF concentrations after recovery from depression[228,235,236], others have noted no signiﬁcant changes in CSF SRIF concentrations ofdepressed patients after clinical improvement with antidepressants [59] or ECT treatment[58]. Interestingly, administration of certain psychotropic medications is known either todecrease CSF SRIF concentrations (e.g., carbamazepine [235], diphenylhydantoin, andﬂuphenazine [237]), increase CSF SRIF concentrations (e.g., haloperidol [238]), or haveno effect (e.g., desipramine or lithium [239]). Somatostatin also inhibits the release ofboth CRF and ACTH [193–195] indicating a direct interaction between the growth hormone and HPA axes. No differences in CSF SRIF levels have been observed in patientswith generalized anxiety disorder compared to normal controls [79]. No published studies
measuring GHRH concentration and GHRH mRNA expression have been conducted in
post-mortem tissue of depressed patients and matched controls which, in light of the evidence presented here, is of interest. Similarly, CSF studies of GHRH are also lacking.
Obvious alterations of GH and SRIF concentrations and function exist in major
depression, although whether these changes represent fundamental contributors to thissyndrome or are merely epiphenomena remains to be determined. Diminished concentrations of the inhibitory neuropeptide SRIF might plausibly allow CRF hypersecretion andincreased HPA axis activity. Further elucidation of SRIF receptor function and the effects/
utility of SRIF receptor agonists and antagonists will provide important information regarding the pathophysiology of major depression and neurodegenerative disorders suchas AD.

XI. CHOLECYSTOKININ
A. Biology
Cholecystokinin (CCK) was ﬁrst identiﬁed in the gastrointestinal tract as a 33-amino-acid
peptide [240] and was later discovered in the mammalian CNS in 1975. Utilizing gastrin
antisera that avidly cross-reacts with CCK, Vanderhaeghen et al. [241] found abundant
gastrin-like material in the brain of many vertebrate species, including humans. Aminoacid sequence analysis determined this substance to be the carboxyl-terminal amidated
peptide CCK 8 [242]. In the gut, CCK exists predominantly in its larger forms of CCK,
22, 33, 39, and 58 with smaller quantities of CCK 8. In the brain, its major amidated form
is CCK 8. Although ﬁrst identiﬁed in the gastrointestinal track, CCK is found in higher
concentrations in the brain than in the gut. In the brain only neuropeptide Y exists inhigher concentrations than CCK. CCK and high densities of its receptors exist in areasof the mammalian brain associated with emotion, motivation, and sensory processing,such as the cortex, striatum, hypothalamus, hippocampus, and amygdala [243–248]. CCK
is often colocalized with DA in the ventrotegmental neurons that comprise the mesolimbic
and mesocortical DA circuits. Of the two major subtypes of CCK receptors that exist, the
CCK A subtype is primarily found in the lower gastrointestinal tract, pancreas, and gallbladder, whereas the CCKB receptor predominates in the brain.
CCK has been reported to reduce the release of DA [249–251]; conversely, therelease of CCK is modulated by DA [252,253]. Moreover, preclinical studies indicated that
DA neuronal activity may be either facilitated or inhibited by CCK [254–257]. Because of248

Gutman et al.

the interactions between DA and CCK, initial investigations had focused on a putativerole for CCK in the pathophysiology of schizophrenia with little evidence forthcoming
to support the hypothesis. Investigation of possible perturbations of CCK function in patients with mood disorders has similarly demonstrated rather disappointing ﬁndings. Thereis a single report of diminished concentrations of CSF CCK in patients with bipolar [258],
but not unipolar, depression [119,143,259,260].
B.

CCK and Panic Disorders

An impetus for the study of a role of CCK in the pathophysiology of panic disorder (PD)and other anxiety disorders was stimulated by the ﬁnding that i.v. injection of cholecystokinin tetrapeptide (CCK-4) induced panic symptoms in healthy individuals [261]. In a subsequent double-blind study, patients with PD experienced panic attacks after i.v. CCK but
not following saline challenge [262]. Furthermore, in comparison to normal controls, patients with PD exhibit an increased sensitivity to CCK-4, a preferential CCKB receptor
agonist [263–265], although both PD patients and controls experience panic attacks withincreasing doses of CCK-4 [263,264]. These ﬁndings have been extended to investigations
in which panic attacks were provoked in patients with PD, and to a lesser extent in patientswith generalized anxiety disorder [266], and normal controls with pentagastrin, another
CCKB receptor agonist [267,268]. Patients with PD have been reported to exhibit diminished CSF CCK concentrations in comparison to controls [269].
The development of CCKB receptor antagonists may lead to a potentially novel
treatment for PD and other anxiety disorders. Certain CCKA or CCKB receptor antagonists
have demonstrable anxiolytic [270–273], antidepressant [274], or memory-enhancing[275] effects in animals. Moreover, in patients with panic disorder, administration of L365,260, a benzodiazepine-derived CCKB receptor antagonist, blocks CCK-4-induced
panic [276]. In normal controls, L-365,260 did not exhibit an anxiolytic effect but did not
induce adverse changes in mood, appetite, or memory [275]. A larger placebo-controlled,
double-blind clinical trial with L-365,320 failed to ﬁnd any clinical improvements in patients with panic disorders [277]. Another compound, CI-988, has been studied in patientswith generalized anxiety disorder but was no more effective than placebo as an anxiolytic[278]. Nevertheless, efforts continue toward the development of an alternative, effective
anxiolytic that does not have the adverse sedative, dependence liability, and cognitiveeffects of benzodiazepines.
XII. CLINICAL IMPLICATIONS AND CONCLUSIONSThe last three decades of neuropsychophysiological exploration has yielded a plethora of
new ﬁndings regarding alterations of CNS circuits containing neuropeptides and hypothalamic releasing factors in certain psychiatric disorders. These studies have led to majoradvances in biological psychiatry by helping us further understand the brain circuits involved in the pathophysiology of mood and anxiety disorders. Although the balance ofevidence indicates that multiple neuropeptide systems within the CNS are altered in major
depression and anxiety disorders, determination of the activity or dysfunction of thesesystems within the brain remains relatively difﬁcult. Not only may there be differences
between hypothalamic and extrahypothalamic circuit involvement in a particular disorder,
but it remains unclear as to which compartment (or both) CSF sampling accesses. Furthermore, there is also discordance between CNS and more “peripheral” sources of several

Neuropeptide Alterations

249

neuropeptides, such as CCK. Peripheral plasma concentrations of a neuropeptide or hypothalamic releasing factor are determined not only by the rate of release, but also by local
metabolic degradation, the presence of speciﬁc binding proteins (as, for example, in thecase of CRF), and redistribution into other extravascular spaces [279]. For example,
plasma CRF concentrations can be measured, but may not truly represent CNS secretion
because of the factors noted above and the contribution by the adrenal medulla and spleen,
which also synthesize the peptide.
The importance of neuropeptides in the pathophysiology of psychiatric illness ismost evident in the large literature indicative of CRF hypersecretion in patients with major
depression. This theory is supported by evidence from a variety of disciplines and has
led to the development of a novel therapeutic approach for the treatment of anxiety anddepression, namely, CRF receptor antagonists. This is one of the few instances wherepreclinical evidence has led to a rational target for drug discovery in the hopes of treating
psychiatric disease. Furthermore, this work has provided a mechanism to explain the increase in depression seen in patients exposed to trauma early in life, ﬁrst postulated by
Freud in the early part of the twentieth century. If CRF truly is the “black bile” of depression, CRF receptor antagonists may represent a novel class of antidepressants with aunique mechanism of action distinct from other commonly used antidepressants.
Virtually all of the neuropeptide and neuroendocrine axis alterations in patients withmajor depression thus far studied are state-dependent (Table 5). However, nearly all thestudies noted in this chapter are “cross-sectional” in design (i.e., the psychiatric disorderand alterations of neuropeptide or hypothalamic releasing factor were determined at approximately the same time). Clinical investigators of the twenty-ﬁrst century will extend
understanding of whether certain neurobiological alterations provide fundamental pathophysiological contributions to the behavioral manifestation of a particular psychiatricdisorder, or are merely epiphenomena (i.e., diminished CSF concentrations of SRIF inpatients with Alzheimer’s disease). Furthermore, present efforts guided by the “neuroendocrine window strategy” and the “pharmacological bridge technique” may provide information as to whether the secretion of neuropeptides and hypothalamic-releasing factors areassociated with alterations in the activity of putative neurotransmitters, such as 5HT, DA,
and ACh, in a particular disease state. The availability of selective ligands that can beutilized with positron-emission tomography (PET) will mark the next major leap in our
understanding of the peptidergic involvement in psychiatric disorders. The ability to deter-

Table 5 Alterations of Neuropeptides and Hypothalamic
Releasing Factors in Various Psychiatric Disorders
Major Depression
Hyperactivity of the HPA axis
Dysregulation of GH secretion
Diminished SRIF activity
Diminished NPY secretion
Bipolar Disorder-Manic Phase
Hypersecretion of AVP
Anxiety Disorders
Increased sensitivity to CCK-4, a preferential CCKB-receptor agonist

250

Gutman et al.

mine peptide-receptor alterations in the brain and pituitary of patients with psychiatricdisorders will contribute immensely to our understanding of the neurobiological underpinnings of such disorders.
A clearer understanding of the neuroendocrinology of depression and anxiety may
well lead to the development of novel pharmacological agents for the treatment of thesemajor mental disorders. We await conﬁrmation of the initial report documenting the effectiveness of the substance P (NK-1) receptor antagonist, MK-869, in patients with major
depression. Early studies of novel CRF receptor antagonists suggest efﬁcacy in the treatment of depression. A selective CCKB antagonist with anxiolytic activity offers a new
psychotropic modality in the treatment of panic disorder. Progress during the last three
decades has been nothing short of remarkable and the concatenation of present ﬁndings
undoubtedly adumbrates further progress in these disorders. In conclusion, the elucidationof biochemical abnormalities in psychiatric disorders has led to an increased comprehension of the neurochemical basis of psychiatric disease, with the ultimate goal being thedevelopment of novel pharmacological and behavioral techniques to treat these devastating
disorders.

ACKNOWLEDGMENTS
The authors are supported by NIH grants MH-42088, MH-49523, MH-39415, MH-40524,
and MH-58922.

REFERENCES
1. Janowsky D, Risch SC, Neborsky R. Strategies for studying neurotransmitter hypotheses ofaffective disorders. In: Michels R et al, eds. Psychiatry. Philadelphia: Lippincott, 1993.
2. Hauger R, Dautzenberg FM. Regulation of the stress response by corticotropin releasing
factor. In Conn P, Freeman ME, eds. Neuroendocrinology in Physiology and Medicine. Totowa, NJ: Humana Press, 2000:267–293.
3. Swanson LW, Sawchenko PE, Rivier J, Vale WW. Organization of ovine corticotropinreleasing factor immunoreactive cells and ﬁbers in the rat brain: an immunohistochemical
study. Neuroendocrinology 1983; 36(3):165–186.
4. Saffran M, Schally AV, Benfey BG. Stimulation of the release of corticotropin from theadenohypophysis by a neurohypophysial factor. Endocrinology 1955; 57:439–444.
5. Vale W, Spiess J, Rivier C, Rivier J. Characterization of a 41-residue ovine hypothalamic
peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981;
213(4514):1394–1397.
6. Chalmers DT, Lovenberg TW, Grigoriadis DE, Behan DP, De Souza EB. Corticotrophinreleasing factor receptors: from molecular biology to drug design. Trends Pharmacol Sci
1996; 17(4):166–172.
7. Grigoriadis DE, Lovenberg TW, Chalmer DT, Liaw C, De Souze EB. Characterization ofcorticotropin-releasing factor receptor subtypes. Ann NY Acad Sci 1996; 780:60–80.
8. Lovenberg TW, Liaw CW, Grigoriadis DE, Clevenger W, Chalmers DT, DeSouza EB,
Oltersdorf T. Cloning and characterization of a functionally distinct corticotropin-releasing
factor receptor subtype from rat brain [published erratum appears in Proc Natl Acad Sci USA
1995; 92(12):5759]. Proc Natl Acad Sci USA 1995; 92(3):836–840.
9. Chang CP, Pearse RV, O’Connell S, Rosenfeld MG. Identiﬁcation of a seven transmembrane
helix receptor for corticotropin-releasing factor and sauvagine in mammalian brain. Neuron
1993; 11(6):1187–1195.

Neuropeptide Alterations

251

10. Chen R, Lewis KA, Perrin MH, Vale WW. Expression cloning of a human corticotropinreleasing-factor receptor. Proc Natl Acad Sci USA, 1993; 90(19):8967–8971.
11. Primus RJ, Yevich E, Baltazar C, Gallager DW. Autoradiographic localization of CRF1 andCRF2 binding sites in adult rat brain. Neuropsychopharmacology 1997; 17(5):308–316.
12. Henrichs SC, Lapsanksy J, Lovenberg TW, De Souza EB, Chalmers DT. Corticotropinreleasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior. Reg Peptides 1997; 71(1):15–21.
13. Steckler T, Holsboer F. Corticotropin-releasing hormone receptor subtypes and emotion. Biol
Psychiatry 1999; 46(11):1480–1508.
14. Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton R, Chan AV, Turnbull
D, Lovejoy C, Rivier C. Urocortin, a mammalian neuropeptide related to ﬁsh urotensin I
and to corticotropin-releasing factor [see comments]. Nature 1995; 378(6554):287–292.
15. Reyes T, Lewis K, Perrin MH, Kunitake KS, Vaugan J, Arias CA, Hogenesch JB, Gulyas
J, Rivier J, Vale WV, Sawchenko PE. Urocortin II: A member of the corticotropin-releasing
factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc
Natl Acad Sci USA 2001; 98(5):2843–2848.
16. Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, Vaughan J, Reyes TM,
Gulyas J, Fischer W, Bilezikjian L, Rivier J, Sawchenko PE, Vale WW. Identiﬁcation of
urocortin III, an additional member of the corticotropin-releasing factor (CRF) family withhigh afﬁnity for the CRF2 receptor. Proc Natl Acad Sci USA 2001; 98(13):7570–7575.
17. Dautzenberg FM, Hauger RL. The CRF peptide family and their receptors: yet more partners
discovered. Trends Pharmacol Sci 2002; 23(2):77.
18. Keck ME, Holsboer F. Hyperactivity of CRH neuronal circuits as a target for therapeuticinterventions in affective disorders. Peptides 2001; 22(5):835–844.
19. Carpenter WT Jr, Bunney WE Jr. Adrenal cortical activity in depressive illness. Am J Psychiatry 1971; 128(1):31–40.
20. Gibbons J, McHugh PR. Plasma cortical activity in depressive illness. J Psychiatr Res 1962;
1:162–171.
21. Sachar EJ, Hellman L, Fukushima DK, Gallagher TF. Cortisol production in depressive illness. A clinical and biochemical clariﬁcation. Arch Gen Psychiatry 1970; 23(4):289–298.
22. Evans DL, Nemeroff CB. The clinical use of the dexamethasone suppression test in DSMIII affective disorders: correlation with the severe depressive subtypes of melancholia andpsychosis. J Psychiatr Res 1987; 21(2):185–194.
23. Arana GW, Baldessarini RJ, Ornsteen M. The dexamethasone suppression test for diagnosis
and prognosis in psychiatry. Commentary and review. Arch Gen Psychiatry 1985; 42(12):1193—1204.
24. Evans DL, Nemeroff CB. Use of the dexamethasone suppression test using DSM-III criteria
on an inpatient psychiatric unit. Biol Psychiatry 1983; 18(4):505–511.
25. Carroll BJ, Martin FI, Davies B. Resistance to suppression by dexamethasone of plasma 11O.H.C.S. levels in severe depressive illness. Br Med J 1968; 3(613):285–287.
26. Carroll BJ, Martin FI, Davies B. Pituitary-adrenal function in depression. Lancet 1968;
1(7556):1373–1374.
27. Carroll BJ. Use of the dexamethasone suppression test in depression. J Clin Psychiatry 1982;
43(11 Pt 2):44–50.
28. Arana GW, Mossman G. The dexamethasone suppression test and depression. Approaches
to the use of a laboratory test in psychiatry. Neurol Clin 1988; 6(1):21–39.
29. Hermus AR, Pieters GF, Smals AG, Benraad TJ, Kloppenborg PW. Plasma adrenocorticotropin, cortisol, and aldosterone responses to corticotropin-releasing factor: modulatory effectof basal cortisol levels. J Clin Endocrinol Metab 1984; 58(1):187–191.
30. Amsterdam JD, Maislin G, Winokur A, Berwish N, Kling M, Gold P. The oCRH stimulation
test before and after clinical recovery from depression. J Affect Disord 1988; 14(3):213–
222.

252

Gutman et al.

31. Gold PW, Chrousos G, Kellner C, Post R, Roy A, Augerinos P, Schulte H, Oldﬁeld E,
Loriaux DL. Psychiatric implications of basic and clinical studies with corticotropin-releasing
factor. Am J Psychiatry 1984; 141(5):619–627.
32. Holsboer F, Muller OA, Doerr HG, Sippell WG, Stalla GK, Gerken A, Steiger A, Boll E,
Benkert O. ACTH and multisteroid responses to corticotropin-releasing factor in depressive
illness: relationship to multisteroid responses after ACTH stimulation and dexamethasone
suppression. Psychoneuroendocrinology 1984; 9(2):147–160.
33. Kathol RG, Jaeckle RS, Lopez JF, Meller WH. Consistent reduction of ACTH responses tostimulation with CRH, vasopressin and hypoglycaemia in patients with major depression.
Br J Psychiatry 1989; 155:468–478.
34. Young EA, Watson SJ, Kotun J, Haskett RF, Grunhaus L, Murphy-Weinberg V, Vale W,
Rivier J, Akil H. Beta-lipoprotein-beta-endorphin response to low-dose ovine corticotropin
releasing factor in endogenous depression. Preliminary studies. Arch Gen Psychiatry 1990;
47(5):449–457.
35. Krishnan KKR, Rayasam K, Reed DA, Smith M, Cliepall P, Saunders WB, Richie JC, Carroll
BJ, Nemeroff CB. The CRF corticotropin-releasing factor stimulation test in patients withmajor depression: relationship to dexamethasone suppression test results. Depression 1993;
1:133–136.
36. Aguilera G, Wynn PC, Harwood JP, Hauger RL, Millan MA, Grewe C, Catt KJ. Receptormediated actions of corticotropin-releasing factor in pituitary gland and nervous system. Neuroendocrinology 1986; 43(1):79–88.
37. Holmes MC, Catt KJ, Aguilera G. Involvement of vasopressin in the down-regulation of
pituitary corticotropin-releasing factor receptors after adrenalectomy. Endocrinology 1987;
121(6):2093–2098.
38. Wynn PC, Aguilera G, Morell J, Catt KJ. Properties and regulation of high-afﬁnity pituitary
receptors for corticotropin-releasing factor. Biochem Biophys Res Commun 1983; 110(2):602–608.
39. Wynn PC, Hauger RL, Holmes MC, Millan MA, Catt KJ, Aguilera G. Brain and pituitary
receptors for corticotropin-releasing factor: localization and differential regulation after
adrenalectomy. Peptides 1984; 5(6):1077–1084.
40. Wynn PC, Harwood JP, Catt KJ, Aguilera G. Corticotropin-releasing factor (CRF) induces
desensitization of the rat pituitary CRF receptor-adenylate cyclase complex. Endocrinology
1988; 122(1):351–358.
41. Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology
2000; 23(5):477–501.
42. Heuser I, Yassouridis A, Holsboer F. The combined dexamethasone/CRH test: a reﬁned
laboratory test for psychiatric disorders. J Psychiat Res 1994; 28(4):341–356.
43. Holsboer F, Lauer CJ, Schreiber W, Krieg JC. Altered hypothalamic-pituitary-adrenocorticalregulation in healthy subjects at high familial risk for affective disorders. Neuroendocrinology 1995; 62(4):340–347.
44. Gutman D, Owens MJ, Nemeroff CB. Corticotropin-releasing factor antagonists as novel
psychotherapeutics. Drugs Future 2000; 25(9):921–931.
45. Suda T, Tomori N, Tozawa F, Mouri T, Demura H, Shizume K. Distribution and characterization of immunoreactive corticotropin-releasing factor in human tissues. J Clin Endocrinol
Metab 1984; 59(5):861–866.
46. Sanchez MM, Young LJ, Plotsky PM, Insel TR. Autoradiographic and in situ hybridization
localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain.
J Compar Neurol 1999; 408(3):365–377.
47. Van Pett K, Viau V, Bittencourt JC, Chan RK, Li HY, Arias C, Prins GS, Perrin M, ValeW, Sawchenko PE. Distribution of mRNAs encoding CRF receptors in brain and pituitaryof rat and mouse. J Compar Neurol 2000; 428(2):191–212.

Neuropeptide Alterations

253

48. Charlton BG, Ferrier IN, Perry RH. Distribution of corticotropin-releasing factor-like immunoreactivity in human brain. Neuropeptides 1987; 10(4):329–334.
49. Arato M, Banki CM, Bissette G, Nemeroff CB. Elevated CSF CRF in suicide victims. Biol
Psychiatry 1989; 25(3):355–359.
50. Banki CM, Bissette G, Arato M, O’Connor L, Nemeroff CB. CSF corticotropin-releasing
factor-like immunoreactivity in depression and schizophrenia. Am J Psychiatry 1987; 144(7):873–877.
51. France RD, Urban B, Krishnan KRR, Bissett G, Banki CM, Nemeroff CB, Speilman FJ.
CSF corticotropin-releasing factor-like immunoreactivity in chronic pain patients with andwithout major depression. Biol Psychiatry 1988; 23:86–88.
52. Nemeroff CB. The role of corticotropin-releasing factor in the pathogenesis of major depression. Pharmacopsychiatry 1988; 21(2):76–82.
53. Risch SC, Lewine RJ, Kalin NH, Jewart RD, Risby ED, Caudle JM, Stipetic M, Turner J,
Eccard MB, Pollard WE. Limbic-hypothalamic-pituitary-adrenal axis activity and ventricular-to-brain ratio studies in affective illness and schizophrenia. Neuropsychopharmacology
1992; 6(2):95–100.
54. Roy A, Pickar D, Paul S, Doran A, Chrousos GP, Gold PW. CSF corticotropin-releasing
hormone in depressed patients and normal control subjects. Am J Psychiatry 1987; 144(5):641–645.
55. Veith RC, Lewis N, Langohr JI, Murburg MM, Ashleigh EA, Castillo S, Peskind ER,
Pascualy M, Bissette G, Nemeroff CB. Effect of desipramine on cerebrospinal ﬂuid concentrations of corticotropin-releasing factor in human subjects. Psychiatry Res 1993; 46(1):
1–8.
56. De Bellis MD, Gold PW, Geracioti TD, Listwak SJ, Kling MA. Association of ﬂuoxetine
treatment with reductions in CSF concentrations of corticotropin-releasing hormone and arginine vasopressin in patients with major depression. Am J Psychiatry 1993; 150(4):656–657.
57. Heuser I, Bissette G, Dettling M, Schweiger U, Gotthardt U, Schmider J, Lammers CH,
Nemeroff CB, Holsboer F. Cerebrospinal ﬂuid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and health controls: response toamitriptyline treatment. Depress Anxiety 1998; 8(2):71–79.
58. Nemeroff CB, Bissette G, Akil H, Fink M. Neuropeptide concentrations in the cerebrospinal
ﬂuid of depressed patients treated with electroconvulsive therapy. Corticotrophin-releasing
factor, beta-endorphin and somatostatin. Br J Psychiatry 1991; 158:59–63.
59. Banki CM, Karmasci L, Bissette G, Nemeroff CB. CSF corticotropin-releasing and somatostatin in major depression: response to antidepressant treatment and relapse. Eur Neuropsychopharmacol 1992; 2:107–113.
60. Nemeroff CB, Evans DL. Correlation between the dexamethasone suppression test in depressed patients and clinical response. Am J Psychiatry 1984; 141(2):247–249.
61. Nemeroff CB. The preeminent role of early untoward experience on vulnerability to major
psychiatric disorders: the nature-nurture controversy revisited and soon to be resolved [news;
comment]. Molec Psychiatry 1999; 4(2):106–108.
62. Holsboer F, von Bardeleben U, Wiedemann K, Muller OA, Stalla GK. Serial assessment ofcorticotropin-releasing hormone response after dexamethasone in depression. Implications
for pathophysiology of DST nonsuppression. Biol Psychiatry 1987; 22(2):228–234.
63. Coplan JD, Andrews MW, Rosenblum LA, Owens MJ, Friedman S, Gorman JM, Nemeroff
CB. Persistent elevations of cerebrospinal ﬂuid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications of pathophysiology of mood and anxiety disorders. Proc Natl Acad Sci USA 1996; 93(4):1619–1623.
64. Kirschbaum C, Pirke KM, Hellhammer DH. The ‘Trier Social Stress Test’—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology
1993; 28(1–2):76–81.

254

Gutman et al.

65. Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, Miller AH, Nemeroff CB.
Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abusein childhood. JAMA 2000; 284(5):592–597.
66. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB. The role of corticotropin-releasing
factor in depression and anxiety disorders. J Endocrinol 1999; 160(1):1–12.
67. Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, Nemeroff CB,
Charney DS. Elevated CSF corticotropin-releasing factor concentrations in posttraumaticstress disorder. Am J Psychiatry 1997; 154(5):624–629.
68. Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, Bruce AB, Orth
DN, Geracioti TD Jr. Serial CSF corticotropin-releasing hormone levels and adrenocorticalactivity in combat veterans with posttraumatic stress disorder [published erratum appears in
Am J Psychiatry 1999; 156(6):986]. Am J Psychiatry 1999; 156(4):585–588.
69. Smith MA, Davidson J, Ritchie JC, Kudler H, Chappell LSP, Nemeroff CB. The corticotropin-releasing hormone test in patients with posttraumatic stress disorder. Biol Psychiatry
1989; 26:349–355.
70. Heim C, Owens MJ, Plotsky PM, Nemeroff CB. The role of early adverse life events in the
etiology of depression and posttraumatic stress disorder. Focus on corticotropin-releasing
factor. Ann NY Acad Sci 1997; 821:194–207.
71. Stein MB, Yehuda R, Koverola C, Hanna C. Enhanced dexamethasone suppression of plasma
cortisol in adult women traumatized by childhood sexual abuse. Biol Psychiatry 1997; 42:
680–686.
72. Yehuda R, Teicher MH, Trestman RL, Levengood RA, Siever LJ. Cortisol regulation in
posttraumatic stress disorder and major depression: a chronobiological analysis. Biol Psychiatry 1996; 40(2):79–88.
73. Jolkkonen J, Lepola U, Bissette G, Nemeroff C, Riekkinen P. CSF corticotropin-releasing
factor is not affected in panic disorder. Biol Psychiatry 1993; 33(2):136–138.
74. Fossey MD, Lydiard RB, Ballenger JC, Laraia MT, Bissette G, Nemeroff CB. Cerebrospinal
ﬂuid corticotropin-releasing factor concentrations in patients with anxiety disorders and normal comparison subjects. Biol Psychiatry 1996; 39(8):703–707.
75. Roy-Byrne PP, Uhde TW, Post RM, Gallucci W, Chrousos GP, Gold PW. The corticotropinreleasing hormone stimulation test in patients with panic disorder. Am J Psychiatry 1986;
143(7):896–899.
76. Altemus M, Pigott T, Kalogeras KT, Demitrack M, Dubbert B, Murphy DL, Gold PW. Abnormalities in the regulation of vasopressin and corticotropin-releasing factor secretion inobsessive-compulsive disorder. Arch Gen Psychiatry 1992; 49(1):9–20.
77. Chappell P, Leckman J, Goodman W, Bissette G, Pauls D, Anderson G, Riddle M, Scahill
L, McDougle C, Cohen D. Elevated cerebrospinal ﬂuid corticotropin-releasing factor in
Tourette’s syndrome: comparison to obsessive compulsive disorder and normal controls. Biol
Psychiatry 1996; 39(9):776–783.
78. Altemus M, Swedo SE, Leonard HL, Richter D, Rubinow DR, Potter WZ, Rapoport JL.
Changes in cerebrospinal ﬂuid neurochemistry during treatment of obsessive-compulsive disorder with clomipramine. Arch Gen Psychiatry 1994; 51(10):794–803.
79. Banki CM, Karmacsi L, Bissette G, Nemeroff CB. Cerebrospinal ﬂuid neuropeptides in mooddisorder and dementia. J Affect Disord 1992; 25(1):39–45.
80. Hawley RJ, Nemeroff CB, Bissette G, Guidotti A, Rawlings R, Linnoila M. Neurochemicalcorrelates of sympathetic activation during severe alcohol withdrawal. Alcoholism: Clin Exper Res 1994; 18(6):1312–1316.
81. Adinoff B, Anton R, Linnoila M, Guidotti A, Nemeroff CB, Bissette G. Cerebrospinal ﬂuid
concentrations of corticotropin-releasing hormone (CRH) and diazepam-binding inhibitor(DBI) during alcohol withdrawal and abstinence. Neuropsychopharmacology 1996; 15(3):288–295.
82. Geracioti TD, Loosen PT, Ebert MH, Ekhator NN, Burns D, Nicholson WE, Orth DN. Con-

Neuropeptide Alterations

83.

84.

85.

86.

87.
88.

89.
90.

91.
92.
93.
94.

95.

96.
97.
98.
99.

100.

101.

102.

255

centrations of corticotropin-releasing hormone, norepinephrine, MHPG, 5-hydroxyindoleacetic acid, and tryptophan in the cerebrospinal ﬂuid of alcoholic patients: serial samplingstudies. Neuroendocrinology 1994; 60(6):635–642.
Roy A, DeJong J, Gold P, Rubinow D, Adinoff B, Ravitz B, Waxman R, Linnoila M. Cerebrospinal ﬂuid levels of somatostatin, corticotropin-releasing hormone and corticotropin inalcoholism. Acta Psychiatr Scand 1990; 82(1):44–48.
Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M, Holsboer F. Effects of thehigh-afﬁnity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the ﬁrst 20 patients treated. J Psychiatr Res 2000; 34(3):171–181.
Veldhuis D. The neuroendocrine control of ultradian rhythms. In: Conn P, Freeman ME,
eds. Neuroendocrinology in Physiology and Medicine. Totowa, NJ: Humana Press, 2000:
453–475.
Whybrow PC, Prange AJ Jr, Treadway CR. Mental changes accompanying thyroid gland
dysfunction. A reappraisal using objective psychological measurement. Arch Gen Psychiatry
1969; 20(1):48–63.
Jain VK. A psychiatric study of hypothyroidism. Psychiatr Clin 1972; 5(2):121–130.
Boswell E, Anﬁnson TJ, Nemeroff CB. Neuropsychiatric aspects of endocrine disorders. In:
Yudofsky S, Hales R, eds. Textbook of Neuropsychiatry, 3rd ed. Washington, DC: American
Psychiatric Association Press, Inc, 2001.
Prange AJ, Lara PP Jr, Wilson IC, Alltop LB, Breese GR. Effects of thyrotropin-releasing
hormone in depression. Lancet 1972; 2(7785):999–1002.
Kastin AJ, Ehrensing RH, Schalch DS, Anderson MS. Improvement in mental depression
with decreased thyrotropin response after administration of thyrotropin-releasing hormone.
Lancet 1972; 2(7780):740–742.
Banki CM, Bissette G, Arato M, Nemeroff CB. Elevation of immunoreactive CSF TRH in
depressed patients. Am J Psychiatry 1988; 145(12):1526–1531.
Adinoff B. Inverse relationship between CSF TRH concentrations and the TSH response to
TRH in abstinent alcohol-dependent patients. Am J Psychiatry 1991; 148(11):1586–1588.
Nemeroff CB, Simon JS, Haggerty JJ Jr, Evans DL. Antithyroid antibodies in depressed
patients. Am J Psychiatry 1985; 142(7):840–843.
Marangell LB, George MS, Callahan AM, Ketter TA, Pazzaglia PJ, L’Herrou TA, Leverich
GS, Post RM. Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory
depressed patients. Arch Gen Psychiatry 1997; 54(3):214–222.
Haggerty JJ Jr, Simon JS, Evans DL, Nemeroff CB. Relationship of serum TSH concentration
and antithyroid antibodies to diagnosis and DST response in psychiatric inpatients. Am J
Psychiatry 1987; 144(11):1491–1493.
Loosen PT, Prange AJ Jr. Serum thyrotropin response to thyrotropin-releasing hormone inpsychiatric patients: a review. Am J Psychiatry 1982; 139(4):405–416.
Bauer MS, Whybrow PC, Winokur A. Rapid cycling bipolar affective disorder. I. Association
with grade I hypothyroidism. Arch Gen Psychiatry 1990; 47(5):427–432.
Cowdry RW, Wehr TA, Zis AP, Goodwin FK. Thyroid abnormalities associated with rapidcycling bipolar illness. Arch Gen Psychiatry 1983; 40(4):414–420.
Sack DA, James SP, Rosenthal NE, Wehr TA. Deﬁcient nocturnal surge of TSH serotonin
during sleep and sleep deprivation in rapid-cycling bipolar illness. Psychiatry Res 1988;
23(2):179–191.
Souetre E, Salvati E, Wehr TA, Sack DA, Krebs B, Darcourt G. Twenty-four-hour proﬁlesof body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects. Am J Psychiatry 1988; 145(9):1133–1137.
Lazarus JH, McGregor AM, Ludgate M, Darke C, Creagh FM, Kingswood CJ. Effect oflithium carbonate therapy on thyroid immune status in manic depressive patients: a prospective study. J Affect Disord 1986; 11(2):155–160.
Myers DH, Carter RA, Burns BH, Armond A, Hussain SB, Chengapa VK. A prospective

256

103.
104.
105.
106.

107.
108.

109.

110.
111.
112.

113.
114.

115.

116.

117.

118.
119.

120.
121.

Gutman et al.
study of the effects of lithium on thyroid function and on the prevalence of antithyroid antibodies. Psychol Med 1985; 15(1):55–61.
Roy-Byrne PP, Uhde TW, Rubinow DR, Post RM. Reduced TSH and prolactin responses
to TRH in patients with panic disorder. Am J Psychiatry 1986; 143(4):503–507.
Gillette GM, Garbutt JC, Quade DE. TSH response to TRH in depression with and without
panic attacks. Am J Psychiatry 1989; 146(6):743–748.
Stein MB, Uhde TW. Thyroid indices in panic disorder. Am J Psychiatry 1988; 145(6):745–
747.
Fossey MD, Lydiard RB, Ballenger JC, Laraia MT, Bissette G, Nemeroff CB. Cerebrospinal
ﬂuid thyrotropin-releasing hormone concentrations in patients with anxiety disorders. J Neuropsychiatry Clin Neurosci 1993; 5(3):335–337.
Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview ofphysical and behavioral homeostasis. J Am Med Assoc 1992; 267:1244–1252.
Sawchenko PE, Swanson LW. Immunohistochemical identiﬁcation of neurons in the paraventricular nucleus of the hypothalamus that project to the medulla or to the spinal cord in
the rat. J Comp Neurol 1982; 205(3):260–272.
DeBold CR, Sheldon WR, DeCherney GS, Jackson RV, Alexander AN, Vale W, Rivier
J, Orth DN. Arginine vasopressin potentiates adrenocorticotropin release induced by ovine
corticotropin-releasing factor. J Clin Invest 1984; 73(2):533–538.
Plotsky P. Pathways to the secretion of adrenocorticotropin: a view from the portal. J Neuroendocrinol 1991; 3:1–9.
Insel TR. A neurobiological basis of social attachment. Am J Psychiatry 1997; 154(6):726–
735.
de Goeij DC, Jezova D, Tilders FJ. Repeated stress enhances vasopressin synthesis in corticotropin releasing factor neurons in the paraventricular nucleus. Brain Res 1992; 577(1):165–
168.
Whitnall MH. Stress selectively activates the vasopressin-containing subset of corticotropinreleasing hormone neurons. Neuroendocrinology 1989; 50(6):702–707.
Mouri T, Itoi K, Takahashi K, Suda T, Murakami O, Yoshinaga K, Andoh N, Ohtani H,
Masuda T, Sasano N. Colocalization of corticotropin-releasing factor and vasopressin in theparaventricular nucleus of the human hypothalamus. Neuroendocrinology 1993; 57(1):34–
39.
Canny BJ, Funder JW, Clarke IJ. Glucocorticoids regulate ovine hypophysial portal levelsof corticotropin-releasing factor and arginine vasopressin in a stress-speciﬁc manner. Endocrinology 1989; 125(5):2532–2539.
Caraty A, Grino M, Locatelli A, Guillaume V, Boudouresque F, Conte-Devolx B, Oliver C.
Insulin-induced hypoglycemia stimulates corticotropin-releasing factor and arginine vasopressin secretion into hypophysial portal blood of conscious, unrestrained rams. J Clin Invest
1990; 85(6):1716–1721.
Demitrack MA, Lesem MD, Brandt HA, Pigott TA, Jimerson DC, Altemus M, Gold PW.
Neurohypophyseal dysfunction: implications for the pathophysiology of eating disorders.
Psychopharmacol Bull 1989; 25(3):439–443.
Legros JJ, Ansseau M, Timsit-Berthier M. Neurohypophyseal peptides and psychiatric diseases. Reg Peptides 1993; 45(1-2):133–138.
Gjerris A, Rafaelsen OJ, Vendsborg P, Fahrenkrug J, Rehfeld JF. Vasoactive intestinal polypeptide decreased in cerebrospinal ﬂuid (CSF) in atypical depression. Vasoactive intestinal
polypeptide, cholecystokinin and gastrin in CSF in psychiatric disorders. J Affect Disord
1984; 7(3-4):325–337.
Gjerris A, Hammer M, Vendsborg P, Christensen NJ, Rafaelsen OJ. Cerebrospinal ﬂuid vasopressin-changes in depression. Br J Psychiatry 1985; 147:696–701.
Linkowski P, Geenen V, Kerkhofs M, Mendlewicz J, Legros JJ. Cerebrospinal ﬂuid neuro-Neuropeptide Alterations

122.

123.
124.

125.
126.

127.

128.
129.

130.
131.
132.
133.

134.

135.

136.
137.
138.

139.

140.

257

physins in affective illness and in schizophrenia. Eur Arch Psychiatry Neurolog Sci 1984;
234(3):162–165.
Laruelle M, Seghers A, Gofﬁnet S, Bouchez S, Legros JJ. Plasmatic vasopressin neurophysin
in depression: basic levels and relations with HPA axis. Biol Psychiatry 1990; 27(11):1249–
1263.
Gold PW, Goodwin FK, Post RM, Robertson GL. Vasopressin function in depression andmania [proceedings]. Psychopharmacol Bull 1981; 17(1):7–9.
Carroll BT, Meller WH, Kathol RG, Gehris TL, Carter JL, Samuelson SD, Pitts AF. Pituitaryadrenal axis response to arginine vasopressin in patients with major depression. Psychiatry
Res 1993; 46(2):119–126.
Meller WH, Kathol RC, Jaeckle RS, Lopez JF. Stimulation of the pituitary-adrenal axis witharginine vasopressin in patients with depression. J Psychiatric Res 1987; 21(3):269–277.
Raadsheer FC, Hoogendijk WJG, Stam FC, Tilders FJH, Swaab DF. Increased numbers ofcorticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994; 60:436–444.
Purba JS, Hoogendijk WJ, Hofman MA, Swaab DF. Increased number of vasopressin- andoxytocin-expressing neurons in the parventricular nucleus of the hypothalamus in depression.
Arch Gen Psychiatry 1996; 53(2):137–143.
Legros JJ, Ansseau M. Increased basal plasma vasopressin-neurophysin in mania. Hormone
Res 1989; 31(1-2):55–58.
Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. Identiﬁcationof two related pentapeptides from the brain with potent opiate agonist activity. Nature 1975;
258(5536):577–580.
Li CH, Chung D, Doneen BA. Isolation, characterization and opiate activity of beta-endorphin from human pituitary glands. Biochem Biophys Res Commun 1976; 72(4):1542–1547.
Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L. Dynorphin-(1-13), an extraordinarily potent opioid peptide. Proc Natl Acad Sci USA, 1979; 76(12):6666–6670.
Smith AI, Funder JW. Propiomelanocortin processing in the pituitary, central nervous system,and peripheral tissues. Endocrine Rev 1988; 9(1):159–179.
Bloom F, Battenberg E, Rossier J, Ling N, Leppaluoto J. Vargo TM, Guillemin R. Endorphinsare located in the intermediate and anterior lobes of the pituitary gland, not in the neurohypophysis. Life Sci 1977; 20(1):43–47.
Kline NS, Li CH, Lehmann HE, Lajtha A, Laski E. Cooper T. Beta-endorphin—inducedchanges in schizophrenic and depressed patients. Arch Gen Psychiatry 1977; 34(9):1111–
1113.
Gerner RH, Catlin DH, Gorelick DA, Hui KK, Li CH. Beta-endorphin. Intravenous infusioncauses behavioral change in psychiatric inpatients. Arch Gen Psychiatry 1980; 37(6):642–
647.
Catlin DH, Gorelick DA, Gerner RH, Hui KK, Li CH. Clinical effects of beta-endorphin
infusions. Adv Biochem Psychopharmacol 1980; 22:465–472.
Nemeroff CB, Bissette G. Neuropeptides in psychiatric disorders. In: Berger PA, Brodie
HKH, eds. American Handbook of Psychiatry. New York: Basic Books: 1986:64–110.
Davis GC, Bunney WE Jr, DeFraites EG, Kleinman JE, van Kammen DP, Post RM, Wyatt
RJ. Intravenous naloxone administration in schizophrenia and affective illness. Science 1977;
197(4298):74–77.
Emrich HM, Cording C, Piree S, et al. Actions of naloxone in different types of psychoses.
In: Bunney WE, Kline NS, eds. Endorphins in Mental Health Research. New York: Oxford
University Press, 1979:352–360.
Terenius L, Wahlstrom A, Agren H. Naloxone (Narcan) treatment in depression: clinicalobservations and effects on CSF endorphins and monoamine metabolites. Psychopharmacology 1977; 54(1):31–33.

258

Gutman et al.

141. Cohen MR, Cohen RM, Pickar D, Sunderland T, Mueller EA 3rd, Murphy DL. High dose
naloxone in depression. Biol Psychiatry 1984; 19(6):825–832.
142. Naber D, Pickar D, Post RM, Van Kammen DP, Waters RN, Ballenger JC, Goodwin FK,
Bunney WE Jr. Endogenous opioid activity and beta-endorphin immunoreactivity in CSF of
psychiatric patients and normal volunteers. Am J Psychiatry 1981; 138(11):1457–1462.
143. Gerner RH, Yamada T. Altered neuropeptide concentrations in cerebrospinal ﬂuid of psychiatric patients. Brain Res 1982; 238(1):298–302.
144. Inturrisi CE, Alexopoulos G, Lipman R, Foley K, Rossier J. Beta-endorphin immunoreactivity in the plasma of psychiatric patients receiving electroconvulsive treatment. Ann NY Acad
Sci 1982; 398:413–423.
145. Black PM, Ballantine HT Jr, Carr DB, Beal MF, Martin JP. Beta-endorphin and somatostatin
concentrations in the ventricular cerebrospinal ﬂuid of patients with affective disorder. Biol
Psychiatry 1986; 21(11):1077–1081.
146. Pickar D, Naber D, Post RM, van Kammen DP, Kaye W, Rubinow DR, Ballenger JC, Bunney
WE. Endorphins in the cerebrospinal ﬂuid of psychiatric patients. Ann NY Acad Sci 1982;
398:399–412.
147. Risch SC. Beta-endorphin hypersecretion in depression: possible cholinergic mechanisms.
Biol Psychiatry 1982; 17(10):1071–1079.
148. Pitkenen A, Lepola U, Ylinen A, Riekkinen PJ. Somatostatin and beta-endorphin levels in
cerebrospinal ﬂuid of nonmedicated and medicated patients with epileptic seizures. Neuropeptides 1989; 13(1):9–15.
149. Brambilla F, Bellodi L, Perna G, Battaglia M, Sciuto G, Diaferia G, Petraglia F, Panerai A,
Sacerdote P. Psychoimmunoendocrine aspects of panic disorder. Neuropsychobiology 1992;
26(1-2):12–22.
150. Guillemin R, Vargo T, Rossier J, Minick S, Ling N, Rivier C, Vale W, Bloom F. Betaendorphin and adrenocorticotropin are selected concomitantly by the pituitary gland. Science
1997; 197(4311):1367–1369.
151. Genazzani AR, Petraglia F, Facchinetti F, Monittola C, Scarone S, Brambilla F. Opioid
plasma levels in primary affective disorders. Effect of desimipramine therapy. Neuropsychobiology 1984; 12(2-3):78–85.
152. Karkkainen J, Laatikainen T, Naukkarinen H, Salminen K, Spoov J. Stenman UH, Rimon
R. Plasma endogeneous opioids and dexamethasone suppression test in depression. Psychiatry Res 1987; 21(2):151–159.
153. Cohen MR, Pickar D, Extein I, Gold MS, Sweeney DR. Plasma cortisol and beta-endorphin
immunoreactivity in nonmajor and major depression. Am J Psychiatry 1984; 141(5):628–
632.
154. Alexopoulos GS, Inturrisi CE, Lipman R, Frances R, Haycox J, Dougherty JH, Rossier J.
Plasma immunoreactive beta-endorphin levels in depression. Effect of electroconvulsive therapy. Arch Gen Psychiatry 1983; 40(2):181–183.
155. Daly RJ, Duggan PF, Bracken PJ, Doonan HJ, Kelleher NJ. Plasma levels of beta-endorphin
in depressed patients with and without pain. Br J Psychiatry 1987; 150:224–227.
156. Maes M, Jacobs MP, Suy E, Leclercq C, Christiaens F, Raus J. An augmented escape ofbeta-endorphins to suppression of dexamethasone in severely depressed patients. J Affect
Disord 1990; 18(3):149–156.
157. Meador-Woodruff JH, Haskett RF, Grunhaus L, Akil H, Watson SJ, Greden JF. Postdexamethasone plasma cortisol and beta-endorphin levels in depression: relationship to severityof illness. Biol Psychiatry 1987; 22(9):1137–1150.
158. Rupprecht R, Barocka A, Beck G, Schrell U, Pichl J. Pre- and postdexamethasone plasma
ACTH and beta-endorphin levels in endogenous and nonendogenous depression. Biol Psychiatry 1988; 23(5):531–535.
159. Brambilla F, Petraglia F, Facchinetti F, Genazzani AR. Abnormal beta-endorphin and beta-

Neuropeptide Alterations

160.
161.

162.

163.

164.

165.

166.
167.

168.

169.
170.

171.

172.

173.
174.
175.

176.
177.

259

lipotropin responses to TRH and LRH administration in primary and secondary affective
disorders. Acta Endocrinol 1986; 112(4):481–486.
Balbi D, Allen JM. Role of protein kinase C in mediating NGF effect on neuropeptide Y
expression in PC12 cells. Brain Res Molec Brain Res 1994; 23(4):310–316.
de Quidt ME, Emson PC. Distribution of neuropeptide Y-like immunoreactivity in the rat
central nervous system—I. Radioimmunoassay and chromatographic characterisation. Neuroscience 1986; 18(3):527–543.
Hendry J. Organization of neuropeptide Y neurons in the mammalian central nervous system.
In: Colmers WF, ed. The Biology of Neuropeptide Y and Related Peptides. Totowa, NJ:
Humana Press, 1993:65–156.
Sundler F, Bottcher G, Ekblad E, et al. PP PYY, and NPY—occurrence and distribution in
the periphery. In: Colmers WF, ed. The Biology of Neuropeptide Y and Related Peptides.
Totowa, NJ: Humana Press, 1993.
Liposits Z, Sievers L, Paull WK. Neuropeptide-Y and ACTH-immunoreactive innervationof corticotropin releasing factor (CSF)-synthesizing neurons in the hypothalamus of the rat.
An immunocytochemical analysis at the light and electron microscopic levels. Histochemistry 1988; 88(3-6):227–234.
Haas DA, George SR. Neuropeptide Y-induced effects on hypothalamic corticotropinreleasing factor content and release are dependent on noradrenergic/adrenergic neurotransmission. Brain Res 1989; 498(2):333–338.
Tsagarakis S, Rees LH, Besser GM, Grossman A. Neuropeptide-Y stimulates CRF-41 releasefrom rat hypothalami in vitro. Brain Res 1989; 502(1):167–170.
Inoue T, Inui A, Okita M, Sakatani N, Oya M, Morioka H, Mizuno N, Oimomi M, Baba S.
Effect of neuropeptide Y on the hypothalamic-pituitary-adrenal axis in the dog. Life Sci
1989; 44(15):1043–1051.
Thorsell A, Michalkiewicz M, Dumont Y, Quirion R, Caberlotto L, Rimondini R, MatheAA, Heilig M. Behavioral insensitivity to restraint stress, absent fear suppression of behavior
and impaired spatial learning in transgenic rats with hippocampal neuropeptide Y overexpression. Proc Nat Acad Sci USA 2000; 97(23):12852–12857.
Berrettini WH, Doran AR, Kelsoe J, Roy A, Pickar D. Cerebrospinal ﬂuid neuropeptide Y
in depression and schizophrenia. Neuropsychopharmacology 1987; 1(1):81–83.
Widerlov E, Lindstrom LH, Wahlestedt C, Ekman R. Neuropeptide Y and peptide YY as
possible cerebrospinal ﬂuid markers for major depression and schizophrenia, respectively. J
Psychiatric Res 1988; 22(1):69–79.
Westrin A, Ekman R, Traskman-Bendz L. Alterations of corticotropin releasing hormone(CRH) and neuropeptide Y (NPY) plasma levels in mood disorder patients with a recent
suicide attempt. Eur Neuropsychopharmacol 1999; 9(3):205–211.
Heilig M, Widerlov E. Neuropeptide Y: an overview of central distribution, functional aspects, and possible involvement in neuropsychiatric illnesses. Acta Psychiatr Scand 1990;
82(2):95–114.
Widdowson PS, Ordway GA, Halaris AW. Reduced neuropeptide Y concentrations in suicide
brain. J Neurochem 1992; 59(1):73–80.
Griebel G. Is there a future for neuropeptide receptor ligands in the treatment of anxiety
disorders? Pharmacol Therapeut 1999; 82(1):1–61.
Guard S, McKnight AT, Watling KJ, Watson SP. Evidence for two types of tachykinin receptors on cholinergic neurons of the guinea pig ileum myenteric plexus. Ann NY Acad Sci
1991; 632:400–403.
Ku YH, Tan L, Li LS, Ding X. Role of corticotropin-releasing factor and substance P inpressor responses of nuclei controlling emotion and stress. Peptides 1998; 19(4):677–682.
Bittencourt JC, Benoit R, Sawchenko PE. Distribution and origins of substance P-immunoreactive projections to the paraventricular and supraoptic nuclei: partial overlap with ascending
catecholaminergic projections. J Chem Neuroanat 1991; 4(1):63–78.

260

Gutman et al.

178. Magoul R, Dubourg P, Benjelloun W, Tramu G. Synaptic inputs of tachykinin-containing
nerve terminals to target tyrosine-hydroxylase-, beta-endorphin- and neuropeptide Y-producing neurons of the arcuate nucleus. Double pre-embedding immunocytochemical study inthe rat. J Chem Neuroanat 1993; 6(6):419–429.
179. Pelletier G, Steinbusch HW, Verhofstad AA. Immunoreactive substance P and serotoninpresent in the same dense-core vesicles. Nature 1981; 293(5827):71–72.
180. Helke CJ, Yang L. Interactions and coexistence of neuropeptides and serotonin in spinal
autonomic systems. Ann NY Acad Sci 1996; 780:185–192.
181. Culman J, Itoi K, Unger T. Hypothalamic tachykinins. Mediators of stress responses? Ann
NY Acad Sci 1995; 771:204–218.
182. Pernow B. Substance P. Pharmacol Rev 1983; 35(2):85–141.
183. Payan DG, Brewster DR, Goetzl EJ. Stereospeciﬁc receptors for substance P on cultured
human IM-9 lymphoblasts. J Immunol 1984; 133(6):3260–3265.
184. Nutt D. Substance-P antagonists: a new treatment for depression? Lancet 1998; 352(9141):
1644–1646.
185. Helke CJ, Krause JE, Mantyh PW, Couture R, Bannon MJ. Diversity in mammalian tachykinin peptidergic neurons: multiple peptides, receptors, and regulatory mechanisms. FASEBJ 1990; 4(6):1606–1615.
186. Culman J, Klee S, Ohlendorf C, Unger T. Effect of tachykinin receptor inhibition in thebrain on cardiovascular and behavioral responses to stress. J Pharmacol Exper Therapeut
1997; 280(1):238–246.
187. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G,
Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T, Hill
RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson
L, Smith D, Rupniak NM. Distinct mechanism for antidepressant activity by blockade ofcentral substance P receptors. [see comments]. Science 1998; 281(5383):1640–1645.
188. Rimon R, Le Greves P, Nyberg F, Heikkila L, Salmela L, Terenius L. Elevation of substanceP-like peptides in the CSF of psychiatric patients. Biol Psychiatry 1984; 19(4):509–516.
189. Berrettini WH, Rubinow DR, Nurnberger JI Jr, Simmons-Alling S, Post RM, Gershon ES.
CSF substance P immunoreactivity in affective disorders. Biol Psychiatry 1985; 20(9):965–
970.
190. Martensson B, Nyberg S, Toresson G, Brodin E, Bertilsson L. Fluoxetine treatment of depression. Clinical effects, drug concentrations and monoamine metabolites and N-terminally extended substance P in cerebrospinal ﬂuid. Acta Psychiatr Scand 1989; 79(6):586–596.
191. Takeuchi K, Uematsu M, Ofuji M, Morikiyo M, Kaiya H. Substance P involved in mental
disorders. Prog Neuro-Psychopharmacol Biol Psychiatry 1988; 12(suppl):S157–S164.
192. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R. Hypothalamic
polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science
1973; 179(68):77–79.
193. Brown MR, Rivier C, Vale W. Central nervous system regulation of adrenocorticotropin
secretion: role of somatostatins. Endocrinology 1984; 114(5):1546–1549.
194. Heisler S, Reisine TD, Hook VY, Axelrod J. Somatostatin inhibits multireceptor stimulationof cyclic AMP formation and corticotropin secretion in mouse pituitary tumor cells. Proc
Natl Acad Sci USA 1982; 79(21):6502–6506.
195. Richardson UI, Schonbrunn A. Inhibition of adrenocorticotropin secretion by somatostatinin pituitary cells in culture. Endocrinology 1981; 108(1):281–290.
196. Patel YC, Hoyte K, Martin JB. Effect of anterior hypothalamic lesions on neurohypophysial
and peripheral tissue concentrations of somatostatin in the rat. Endocrinology 1979; 105(3):712–715.
197. van Leeuwen FW, de Raay C, Swaab DF, Fisser B. The localization of oxytocin, vasopressin,
somatostatin and luteinizing hormone releasing hormone in the rat neurohypophysis. Cell
Tissue Res 1979; 202(2):189–201.

Neuropeptide Alterations

261

198. Brownstein M, Arimura A, Sato H, Schally AV, Kizer JS. The regional distribution of somatistatin in the rat brain. Endocrinology 1975; 96(6):1456–1461.
199. Finkelstein JW, Roffwarg HP, Boyar RM, Kream J, Hellman L. Age-related change in thetwenty-four-hour spontaneous secretion of growth hormone. J Clin Endocrinol Metab 1972;
35(5):665–670.
200. Nestler E, Hyman SE, Malenka RC. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. New York: McGraw Hill, 2001:280–290.
201. Boyd AF, Lebovitz HE, Pfeiffer JB. Stimulation of human-growth-hormone secretion by Ldopa. N Engl J Med 1970; 283(26):1425–1429.
202. Lal S, Martin JB, De la Vega CE, Friesen HG. Comparison of the effect of apomorphineand L-DOPA on serum growth hormone levels in normal men. Clin Endocrinol 1975; 4(3):277–285.
203. Fink G. Neuroendocrine regulation of pituitary function: general principles. In: Conn P, Freeman ME, eds. Neuroendocrinology in Physiology and Medicine. Totowa NJ: Humana Press,
2000:112–120.
204. Lal S, Tolis G, Martin SB, Brown GM, Guyda H. Effect of clonidine on growth hormone,prolactin, luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone in the serum of normal men. J Clin Endocrinol Metab 1975; 41(5):827–832.
205. Toivola PT, Gale CC. Stimulation of growth release by microinjection of norepinephrine
into hypothalamus of baboons. Endocrinology 1972; 90(4):895–902.
206. Muller EE, Brambilla F, Cavagnini F, Peracchi M, Panerai A. Slight effect of L-tryptophan
on growth hormone release in normal human subjects. J Clin Endocrinol Metab 1974; 39(1):1–5.
207. Imura H, Nakai Y, Yoshimi T. Effect of 5-hydroxytryptophan (5-HTP) on growth hormone
and ACTH release in man. J Clin Endocrinol Metab 1973; 36(1):204–206.
208. Toivola PT, Gale CC, Goodner CJ, Werrbach JH. Central-adrenergic regulation of growth
hormone and insulin. Hormones 1972; 3(4):192–213.
209. Schilkrut R, Chandra O, Osswald M, Ruther E, Baafusser B, Matussek M. Growth hormone
release during sleep and with thermal stimulation in depressed patients. Neuropsychobiology
1975; 1(2):70–79.
210. Mendlewicz J, Linkowski P, Kerkhofs M, Desmedt D, Golstein J, Copinschi G, Van Cauter
E. Diurnal hypersecretion of growth hormone in depression. J Clin Endocrinol Metab 1985;
60(3):505–512.
211. Siever LJ, Uhde TW, Silberman EK, Lake CR, Jimerson DC, Risch SC, Kalin NH, Murphy
DL. Evaluation of alpha-adrenergic responsiveness to clonidine challenge and noreadrenergic
metabolism in the affective disorders and their treatment. Psychopharmacol Bull 1982; 18(4):118–119.
212. Charney DS, Heninger GR, Sternberg DE, Hafstad KM, Giddings S, Landis DH. Adrenergic
receptor sensitivity in depression. Effects of clonidine in depressed patients and healthy subjects. Arch Gen Psychiatry 1982; 39(3):290–294.
213. Checkley SA, Slade AP, Shur E. Growth hormone and other responses to clonidine in patientswith endogenous depression. Br J Psychiatry 1981; 138:51–55.
214. Dinan TG, Barry S. Responses of growth hormone to desipramine in endogenous and nonendogenous depression. Br J Psychiatry 1990; 156:680–684.
215. Matussek N, Ackenheil M, Hippius H, Muller F, Schroder HT, Schultes H, Wasilewski B.
Effect of clonidine on growth hormone release in psychiatric patients and controls. Psychiatry
Res 1980; 25–36.
216. Siever LJ, Tamminga C, Pert A. Increased growth hormone response to clonidine in
6-hydroxydopamine-treated rats. Psychopharmacology 1987; 91(3):342–344.
217. Siever LJ, Uhde TW, Silberman EK, Jimerson DC, Aloi JA, Post RM, Murphy DL. Growth
hormone response to clonidine as a probe of noradrenergic receptor responsiveness in affective disorder patients and controls. Psychiatry Res 1982; 6(2):171–183.

262

Gutman et al.

218. Ansseau M, von Frenckell R, Legros JJ. Hormonal response to a pharmacological challenge.
Psychiatry Res 1988; 24(3):361.
219. Lesch KP, Laux G, Pfuller H, Erb A, Beckmann H. Growth hormone (GH) response to GHreleasing hormone in depression. J Clin Endocrinol Metab 1987; 65(6):1278–1281.
220. Lesch KP, Laux G, Erb A, Pfuller H, Beckmann H. Attenuated growth hormone response
to growth hormone-releasing hormone in major depressive disorder. Biol Psychiatry 1987;
22(12):1495–1499.
221. Risch S. Growth hormone-releasing factor and growth hormone. In: Nemeroff C, ed. Neuropeptides and Psychiatric Disorders. Washington, DC: American Psychiatric Press, 1991:93–
108.
222. Krishnan KR, Manepalli AN, Ritchie JC, Rayasam K, Melville ML, Thorner MO, Rivier
JE, Vale WW, Nemeroff CB. Growth hormone response to growth hormone-releasing factor
in depression. Peptides 1988; 9(suppl 1):113–116.
223. Krishnan KR, Manepalli AN, Ritchie JC, Rayasam K, Melville ML, Daughtry G, Thorner
MO, Rivier JE, Vale WW, Nemeroff CB. Growth hormone-releasing factor stimulation test
in depression. Am J Psychiatry 1988; 145(1):90–92.
224. Skare SS, Dysken MW, Billington CJ. A review of GHRH stimulation test in psychiatry.
Biol Psychiatry 1994; 36(4):249–265.
225. Ryan ND, Dahl RE, Birmaher B, Williamson DE, Iyengar S, Nelson B, Puig-Antich J, Perel
JM. Stimulatory tests of growth hormone secretion in prepubertal major depression: depressed versus normal children. J Am Acad Child Adolesc Psychiatry 1994; 33(6):824–833.
226. Birmaher B, Dahl RE, Williamson DE, Perel JM, Brent DA, Axelson DA, Kaufman J, Dorn
LD, Stull S, Rao U, Ryan ND. Growth hormone secretion in children and adolescents athigh risk for major depressive disorder. Arch Gen Psychiatry 2000; 57(9):867–872.
227. Bissette G, Widerlov E, Walleus H, Karlsson I, Eklund K, Forsman A, Nemeroff CB. Alterations in cerebrospinal ﬂuid concentrations of somatostatinlike immunoreactivity in neuropsychiatric disorders. Arch Gen Psychiatry 1986; 43(12):1148–1151.
228. Agren H, Lundqvist G. Low levels of somatostatin in human CSF mark depressive episodes.
Psychoneuroendocrinology 1984; 9(3):233–248.
229. Rubinow DR, Gold PW, Post RM, Ballenger JC, Cowdry R, Bollinger J, Reichlin S. CSF
somatostatin in affective illness. Arch Gen Psychiatry 1983; 40(4):409–412.
230. Kling MA, Rubinow DR, Doran AR, Roy A, Davis CL, Calabrese JR, Nieman LK, Post RM,
Chrousos GP, Gold PW. Cerebrospinal ﬂuid immunoreactive somatostatin concentrations inpatients with Cushing’s disease and major depression: relationship to indices of corticotropinreleasing hormone and cortisol secretion. Neuroendocrinology 1993; 57(1):79–88.
231. Rubinow D, Davis C, Post R. Somatostatin in the central nervous system. In: Bloom F,
Kupfer D, eds. Psychopharmacology: The Fourth Generation of Progress. New York: Raven
Press Ltd, 1995:553–562.
232. Molchan SE, Hill JL, Martinez RA, Lawlor BA, Mellow AM, Rubinow DR, Bissette G,
Nemeroff CB, Sunderland T. CSF somatostatin in Alzheimer’s disease and major depression:
relationship to hypothalamic-pituitary-adrenal axis and clinical measures. Psychoneuroendocrinology 1993; 18(7):509–519.
233. Bissette G, Cook L, Smith W, Dole KC, Crain B, Nemeroff CB. Regional neuropeptide
pathology in Alzheimer’s disease: corticotropin-releasing factor and somatostatin. J Alzheimer’s Dis 1998; 1:1–15.
234. Doran AR, Rubinow DR, Roy A, Pickar D. CSF somatostatin and abnormal response to
dexamethasone administration in schizophrenic and depressed patients. Arch Gen Psychiatry
1986, 43(4):365–369.
235. Rubinow DR. Cerebrospinal ﬂuid somatostatin and psychiatric illness. Biol Psychiatry 1986;
21(4):341–365.
236. Post R, Rubinow D, Gold P. Neuropeptides in manic-depressive illness. In: Nemeroff C, ed.

Neuropeptide Alterations

237.

238.
239.
240.
241.
242.
243.

244.

245.

246.
247.

248.
249.

250.

251.

252.
253.
254.
255.
256.
257.

263

Neuropeptides in Psychiatric and Neurological Disorders. Baltimore, MD: Johns Hopkins
University Press, 1998:76–115.
Doran AR, Rubinow DR, Wolkowitz OM, Roy A, Breier A, Pickar D. Fluphenazine treatment reduces CSF somatostatin in patients with schizophrenia: correlations with CSF HVA.
Biol Psychiatry 1989; 25(4)431–439.
Gattaz WF, Rissler K, Gattaz D, Cramer H. Effects of haloperidol on somatostatin-like immunoreactivity in the CSF of schizophrenic patients. Psychiatry Res 1986; 17(1):1–6.
Rubinow DR, Gold PW, Post RM, Ballenger JC. CSF somatostatin in affective illness andnormal volunteers. Progr Neuro-Psychopharmacol Biol Psychiatry 1985; 9(4):393–400.
Mutt V, Jorpes JE. Structure of porcine cholecystokinin-pancreozymin. 1. Cleavage withthrombin and with trypsin. Europ J Biochem 1968; 6(1):156–162.
Vanderhaeghen JJ, Signeau JC, Gepts W. New peptide in the vertebrate CNS reacting with
antigastrin antibodies. Nature 1975; 257(5527):604–605.
Dockray CJ. Polypeptides in brain and gut: cholecystokinin-like peptides. Adv Exp Med Biol
1978; 106:263–267.
Dietl MM, Palacios JM. The distribution of cholecystokinin receptors in the vertebrate brain:
species differences studied by receptor autoradiography. J Chem Neuroanat 1989; 2(3):149–
161.
Hokfelt T, Lundberg JM, Schultzberg M, Johansson O, Skirboll L, Anggard A, Fredholm
B, Hamberger B, Pernow B, Rehfeld J, Goldstein M. Cellular localization of peptides inneural structure. Proc R Soc London Ser B: Biol Sci 1980; 210(1178):63–77.
Innis RB, Snyder SH. Cholecystokinin receptor binding in brain and pancreas: regulation of
pancreatic binding by cyclic and acyclic guanine nucleotides. Eur J Pharmacol 1980; 65(1):123–124.
Saito A, Sankaran H, Goldﬁne ID, Williams JA. Cholecystokinin receptors in the brain:characterization and distribution. Science 1980; 208(4448):1155–1156.
Tang F, Man WS. The regional distribution of thyrotropin releasing hormone, leu-enkephalin,
met-enkephalin substance P, somatostatin and cholecystokinin in the rat brain and pituitary[erratum appears in Neuropeptides 1993; 24(1):62]. Neuropeptides 1991; 19(4):287–
292.
Roberts GW, Woodhams PL, Polak JM, Crow TJ. Distribution of neuropeptides in the limbic
system of the rat: the amygdaloid complex. Neuroscience 1982; 7(1):99–131.
Fuxe K, Andersson K, Locatelli V, Agnati LF, Hokfelt T, Skirboll L, Mutt V. Cholecystokinin peptides produce marked reduction of dopamine turnover in discrete areas in the rat brain
following intraventricular injection. Eur J Pharmacol 1980; 67(2-3):329–331.
Lane RF, Blaha CD, Phillips AG. In vivo electrochemical analysis of cholecystokinininduced inhibition of dopamine release in the nucleus accumbens. Brain Res 1986; 397(1):200–204.
Voigt M, Wang RY, Westfall TC. Cholecystokinin octapeptides alter the release of endogenous dopamine from the rat nucleus accumbens in vitro. J Pharmacol Exper Therapeut 1986;
237(1):147–153.
Meyer DK, Holland A, Conzelmann U. Dopamine D1-receptor stimulation reduces neostriatal cholecystokinin release. Eur J Pharmacol 1984; 104(3-4):387–388.
Meyer DK, Krauss J. Dopamine modulates cholecystokinin release in neostratium. Nature
1983; 301(5898):338–340.
Hommer DW, Skirboll LR. Cholecystokinin-like peptides potentiate apomorphine-induced
inhibition of dopamine neurons. Eur J Pharmacol 1983; 91(1):151–152.
Van Ree JM, Gaffori O, De Wied D. In rats, the behavioral proﬁle of CCK-8 related peptides
resembles that of antipsychotic agents. Eur J Pharmacol 1983; 93(1-2):63–78.
Crawley JN. Cholecystokinin potentiation of dopamine-mediated behaviors in the nucleus
accumbens. Ann NY Acad Sci 1985; 448:283–292.
Vaccarino FJ, Rankin J. Nucleus accumbens cholecystokinin (CCK) can either attenuate or

264

258.

259.

260.
261.
262.
263.
264.
265.

266.

267.
268.

269.

270.
271.

272.
273.
274.
275.
276.

277.

Gutman et al.
potentiate amphetamine-induced locomotor activity: evidence for rostral-caudal differencesin accumbens CCK function. Behav Neurosci 1989; 103(4):831–836.
Verbanck PM, Lotstra F, Gilles C, Linkowski P, Mendlewics J, Vanderhaeghen JJ. Reducedcholecystokinin immunoreactivity in the cerebrospinal ﬂuid of patients with psychiatric disorders. Life Sci 1984; 34(1):67–72.
Lofstra F, Verbanck PM, Gilles C, Mendlewicz, Vanderhaeghen. Reduced cholecystokinin
levels in cerebrospinal ﬂuid of parkinsonian and schizophrenic patients. Effect of ceruletidein schizophrenia. Ann NY Acad Sci 1985; 448:507–517.
Rafaelsen OJ, Gjerris A. Neuropeptides in the cerebrospinal ﬂuid (CSF) in psychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry 1985; 9(5-6):533–538.
de Montigny C. Cholecystokinin tetrapeptide induces panic-like attacks in healthy volunteers.
Preliminary ﬁndings. [see comments]. Arch Gen Psychiatry 1989; 46(6):511–517.
Bradwejn J, Koszycki D, Meterissian G. Cholecystokinin-tetrapeptide induces panic attacks
in patients with panic disorder. Can J Psychiatry—Rev Can Psychiatrie 1990; 35(1):83–85.
Bradwejn J, Koszycki D, Shriqui C. Enhanced sensitivity to cholecystokinin tetrapeptide inpanic disorder. Clinical and behavioral ﬁndings. Arch Gen Psychiatry 1991; 48(7):603–610.
Bradwejn J, Koszycki D, Bourin M. Dose ranging study of the effects of cholecystokininin healthy volunteers. J Psychiatry Neurosci 1991; 16(2):91–95.
Bradwejn J, Koszycki D, Payeur R, Bourin M, Borthwick H. Replication of action of cholecystokinin tetrapeptide in panic disorder: clinical and behavioral ﬁndings. Am J Psychiatry
1992; 149(7):962–964.
Brawman-Mintzer O, Lydiard RB, Bradwejn J, Villarreal G, Knapp R, Emmanuel N, Ware
MR, He Q, Ballenger JC. Effects of the cholecystokinin agonist pentagastrin in patients withgeneralized anxiety disorder. Am J Psychiatry 1997; 154(5):700–702.
Abelson JL, Nesse RM. Cholecystokinin-4 and panic. [letter; comment]. Arch Gen Psych
1990; 47(4):395.
van Megen HJ, Westenberg HG, den Boer JA, Haigh JR, Traub M. Pentagastrin induced
panic attacks: enhanced sensitivity in panic disorder patients. Psychopharmacology 1994;
114(3):449–455.
Lydiard RB, Ballenger JC, Laraia MT, Fossey MD, Beinfeld MC. CSF cholecystokinin concentrations in patients with panic disorder and in normal comparison subjects. Am J Psychiatry 1992; 149(5):691–693.
Hendrie C, Dourish C. Anxiolytic proﬁle of the cholecystokinin antagonist devazepide inmice. Br J Pharm 1990; 99(138).
Hughes J, Boden P, Costall B. Domeney A, Kelly E, Horwell DC. Hunter JC, Pinnock RD,
Woodruff GN. Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci USA 1990; 87(17):6728–6732.
Ravard S, Dourish CT. Cholecystokinin and anxiety. Trends Pharmacol Sci 1990; 11(7):271–273.
Ravard S, Dourish C, Iversen S. Anxiolytic-like effects of the CCK antagonists L-365,260
and devazepide in the elevated-plus maze paradigm. J Psychopharmacol 1990; 4(281).
Kelly J, Leonard B. An examination of CI-988 in 3 animal models of depression. J Psychopharmacol 1992(A14).
Lemaire M, Piot O, Roques BP, Bohme GA, Blanchard JC. Evidence for an endogenous
cholecystokininergic balance in social memory. Neuroreport 1992; 3(10):929–932.
Bradwejn J, Koszycki D, Couetoux du Tertre A, van Megan H, den Boer J, Westenberg H.
The panicogenic effects of cholecystokinin-tetrapeptide are antagonized by L-365,260, a central cholecystokinin receptor antagonist, in patients with panic disorder. Arch Gen Psychiatry
1994; 51(6):486–493.
Kramer MS, Cutler NR, Ballenger JC, Patterson WM, Mendels J, Chenault A, Shrivastava
R, Matzura-Wolfe D, Lines C, Reines S. A placebo-controlled trial of L-365,260, a CCKB
antagonist, in panic disorder. Biol Psychiatry 1995; 37(7):462–466.

Neuropeptide Alterations

265

278. Adams JB, Pyke RE, Costa J, Cutler NR, Schweizer E, Wilcox CS, Wisselink PG, Greiner
M, Pierce MW, Pande AC. A double-blind, placebo-controlled study of a CCK-B receptor
antagonist, CI-988, in patients with generalized anxiety disorder. J Clin Psychopharmacol
1995; 15(6):428–434.
279. Linares OA, Zech LA, Jacquez JA, Rosen SG, Sanﬁeld JA, Morrow LA, Supiano MA, Halter
JB. Effect of sodium-restricted diet and posture on norepinephrine kinetics in humans. Am
J Physiol 1988; 254:E222–E230.

12Immunology in Anxiety
and Depression
NORBERT MÜLLER AND MARKUS J. SCHWARZ
Hospital for Psychiatry and Psychotherapy
Ludwig Maximilian University
Munich, Germany

I.

INTRODUCTION

The objectives of psychoneuroimmunology are to elucidate the reciprocal inﬂuences of
the nervous system and the immune system and their effects on behavior and health. Thisﬁeld covers in vitro studies of tissue and lymphocytes; investigations of the inﬂuence ofstress, stress coping, and personality traits on the function of the immune system, as wellas the role of psychological factors during pathogenesis, and the course of tumor disorders
and their psychotherapeutic treatment. In addition, human behavior studies and animal
experiments, such as conditioning studies [1] or investigations into the dependency ofcoupling behavior from the human leukocyte antigen (HLA) system [2], also belong to
the category of psychoneuroimmunology.
Cytokines mediate information between cells of the peripheral immune system andthe central nervous system (CNS). In part, they are actively transported through the blood–
brain barrier, but they are also released from activated astrocytes and microglial cells.
Interleukin (IL)-1, IL-2, IL-6, and tumor necrosis factor-alpha (TNF-α) are the most relevant cytokines known to act on the CNS. Cytokines belong to a network, and they can
activate cells to produce other cytokines. Recent ﬁndings indicate the important role ofcytokines in psychiatric disorders, which may be because of their inﬂuence on neurotransmission.
From a clinical point of view, depression shows several parallels to autoimmune

267

268

Müller and Schwarz

disorders. These include early onset in many cases, genetic vulnerability, waxing andwaning course, and female preponderance.
The inﬂuence of an immune process on the pathogenesis of psychosis has been
under discussion since it was proposed that autoimmune disorders of the CNS, such as
lupus erythematosus, might lead to severe depressive states. The more it became evident
that the noradrenaline [3,4] and serotonin hypotheses [5] of depression were not sufﬁcient
to explain depressive disorders, the more other pathological agents came into the focus
of interest.
Moreover, the increasing role of psychoneuroimmunology is also due to the rapid
development of immunological methods. Thanks to the recent immunological and molecular biological investigative techniques, our knowledge of the function, mechanisms ofregulation, and interaction of the immune system is growing, as shown in Figure 1. Moreaccurate estimation of the highly differentiated and variable immune system are madepossible by recent methodological advances.
The induction of severe depressive syndromes by immune processes is shown bypsychiatric disturbances that occur during different autoimmune disorders, such as lupus
erythematosus [6], scleroderma [7], Sjögren syndrome [8], and antiphospholipid syndrome[9]. Additional evidence is given by the characteristic depressionlike side effects of interferon-α (IFN-α) treatment in patients suffering from hepatitis C or malignant melanoma[10,11].

Figure 1 Overview of important cell types and their products (cytokines) of the highly
differentiated immune system.

Immunology

269

Modern immunological methods at ﬁrst led to the investigation of lymphocyte subpopulations by monoclonal antibodies. Different cell surface markers point to different
functions of the lymphocytes. During the 1980s, several researchers studied the cellularimmune system in different psychiatric disorders [12–18]. The ﬁndings in the cellularimmune system, in particular in affective disorders, indicated that there was an immune
activation in these disorders, that in turn, raised the question as to the function of cytokines,
a key factor in the activation of the immune system.
II. THE CYTOKINE NETWORK IN THE CNS
Recent studies have revealed the close connection between the CNS, endocrine system,
and immune system [19]. Cytokines in the CNS are involved in the following different
regulatory mechanisms:
1.
2.
3.
4.

Initiation of an immune process in the CNS during an inﬂammatory disease.
Regulation of the blood–brain barrier.
Developmental and repair mechanisms after injury.
Regulation of the endocrine system in the hypothalamus–pituitary–adrenal(HPA) axis.
5. Different stimulatory and inhibitory inﬂuences on the dopaminergic, serotonergic, noradrenergic, and cholinergic neurotransmission.
Cytokines activate CNS cells in different ways. First, several cytokines such as IL-1[20], IL-2 [21], and TNF-α [22], can be transported from the blood into the CNS by
active transport mechanisms, as shown in in vitro studies. Second, glia cells secrete cytokines after activation by an antigenic challenge. Finally, it was recently reported that cytokine secretion in the CNS can be stimulated by neurotransmitters [22a]. Noradrenaline
stimulates the release of IL-6 from astrocytes in vitro in a dose-dependent manner, aneffect that can be antagonized by blocking the adrenergic receptors. Since IL-6 is closely
linked to the function of other cytokines (e.g., IL-1, IL-2, and TNF-α), this ﬁnding indicates that neurotransmitters can activate the cascade of cytokines [23]. This represents
possibly a relevant psychoneuroimmunological regulative mechanism affecting (auto-)immune disorders, susceptibility to infections, and psychiatric disorders. Noradrenaline, released during stress [24], may act as a cytokine-activating stimulus, which in turn activates
immune phenomena mediated by the cytokine cascade.
It is unclear, however, whether cytokines have different functions depending onwhether they are released from the periphery or from the CNS. Nevertheless, it is likelythat there is at least a functional synergism. The localization of interleukin receptors, inparticular IL-1 receptors in glia cells around arterioles and in the plexus choroideus, suggests that there is close communication between CNS IL-1 receptors and IL-1 invading
the CNS from the periphery [25].
III. ASTROGLIA, MICROGLIA, AND NEURONS AS CARRIERSOF THE CNS IMMUNE FUNCTION
Astrocytes form the largest cell population in the CNS, exceeding neurons by more thantenfold [26]. Astrocytes are located immediately beside neurons, often enfolding them.
This localization underlines the close relationship between astrocytes and neuronal func-

270

Müller and Schwarz

Figure 2 The relationship between the TH-1 cytokine IFN-γ and serotonin metabolism.
IDO ⫽ indoleamine 2,3-dioxygenase; KYN-Hydrox. ⫽ kynurenine hydroxylase.

tion. About 10% of the glia cells are microglia cells [26]. Both microglia cells andastrocytes can produce and release cytokines after activation, as shown schematically in
Figure 2. However, they not only do this in different ways, but also they produce different
patterns of cytokines. This indicates a functional difference in how they activate the immune process in the CNS.
Viruses and viral particles stimulate microglia to release cytokines. This mechanism
initiates an immune reaction after viral infection and expresses cellular surface structures
for recognition [27].
The existence of cytokine receptors on neurons suggests that cytokines have a direct
inﬂuence on neuronal function. IL-1–containing neurons have been found in different
areas of the CNS, including the hypothalamus and hippocampus in animal investigations[28–30]. A larger amount of messenger-RNA for IL-2 receptors (IL-2R)—the gene transcript for the protein synthesis of IL-2R—was found in neurons than in microglia or
astrocytes. Thus, IL-2 seems to directly inﬂuence neuronal functions [31], too.
Astrocytes and microglia are also able to express receptor structures of the immune
system, such as HLA molecules [32] or T-cell receptors after activation [33,34], and they
can act as antigen-presenting cells. Cytokines also play an important role during the physiological development of the CNS [35], which may be strongly altered by an over- or
underproduction of cytokines.
IV. EFFECTS OF CYTOKINES IN THE BLOOD AND IN THE CNS
IL-1, IL-2, IL-6, and TNF-α are examples for cytokine functions in the CNS, althoughmany more cytokines are known to be released in the CNS.
Psychotropic effects were ﬁrst described for IL-1. IL-1 is released by macrophages,
stimulates T-cells to proliferate, and is present everywhere in the blood. During an inﬂammation, IL-1 levels increase locally. IL-1 is actively transported into the CNS [21],but it can also move passively into the CNS via the circumventricular organs [36]. It is
produced by astrocytes or microglia cells [35].
The localization of IL-1 in neurons of the hippocampus [25] underlines its inﬂuence
on both neuronal processes and psychological phenomena. One psychotropic effect of
IL-1 is a psychomotor retardation; IL-1 also induces fever, sleep disturbance, loss ofweight, and loss of appetite, suggesting that it has an anorectic effect. IL-1 also plays apronounced role in “sickness behavior” [37].
Via hypothalamic neurons, IL-1 upregulates the hormones of the HPA axis. For

Immunology

271

example, the release of corticotropin-releasing hormone (CRH) and growth hormone releasing hormone (GHRH) is stimulated by IL-1 [38,39]. Since IL-1 release in the hypothalamus is upregulated by stress [40], one factor in the glucocorticoid stress reaction may be
IL-1, as Besedovsky et al. [38] mentioned. The central IL-1 upregulation, which leads tostimulation of CRH, the HPA axis, and the sympathetic nervous system [41,42], may cause
immunosuppression induced by CNS IL-1 effects. The upregulation of IL-1 in hypothalamic neurons was thought a conclusive link to immunosuppression during stress, historicallya focus of experimental investigations in psychoneuroimmunology [43,44]. In vivo studies
also show that the exacerbation and the course of viral disorders are inﬂuenced by stress(e.g., herpes simplex) [45,46]. In parallel, antibody titers of neurotropic viruses [47] andthe onset and course of several autoimmune disorders [48] are modulated by stress.
Like IL-1, IL-6 is known to interact strongly with the HPA axis, too. As our knowledge of the function of cytokines in the CNS grows, the concept of speciﬁcity of thecytokine action on the HPA axis needs to be revised in favor of an unspeciﬁc central
downregulating action of cytokines to the HPA axis [49]. IL-2 is produced in blood byactivated T lymphocytes; in the CNS, it is produced mainly by activated microglia cells.
Considering psychiatric disorders, IL-2 effects in the CNS are of particular interest forthree reasons: the highest concentration of IL-2 receptors is found in the hippocampus[50], psychotic phenomena occur after application of IL-2 [51], and IL-2 has an immense
effect on the dopaminergic neurotransmission [52–54].
IL-6 is a pleiotropic cytokine, which is released from different cell types in the
blood (macrophages, monocytes, T and B cells). The largest amount of IL-6 in the bloodis macrophage-derived. One function of IL-6 is to activate B cells to synthesize antibodies[55]. In the CNS, IL-6 is produced by activated astrocytes and microglia. The IL-6 production, however, differs depending on the cell type. For example, TNF-α and IL-1, as well
as norepinephrine, induced IL-6 production in astrocytes, but not in microglia [56],whereas IL-6 production in microglia is stimulated by granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), as in vitro
studies show. Astrocytes express more adrenergic receptors than neurons [57]. The strong
effect of noradrenaline on astrocytes seems to be because of this fact. Several ﬁndings
suggest that IL-6 may mediate the exacerbation of autoimmune disorders in the CNS [57](e.g., IL-6 supports the differentiation of B cells, local IgG synthesis in the CNS, andblood–brain barrier disturbance [58,59]). In the hypothalamus, IL-6 can induce the releaseof GHRH and thyroid-stimulating hormone (TSH), as does IL-1; moreover, IL-6 stimulates in vitro the secretion of prolactin, growth hormone (GH), and luteinizing hormone(LH) from pituitary cells [49].
TNF-α is a cytokine that acts synergistically with several other cytokines and hasstrong toxic effects. In the CNS, primarily astrocytes release TNF-α, but also microglia
can release TNF-α after stimulation. The release of TNF-α from activated CNS cells canbe due to several stimuli, such as neurotropic viruses [27], but also bacterial toxins. Thus,
glial-derived cytokines up- and downregulate each other, providing an endogenous feedback mechanism [35].
V.

THE CONCEPT OF INNATE AND ADAPTIVE IMMUNITYIN HUMANSThe immune system has been developed during evolution over millions of years. In orderto guarantee successful defense against numerous varying invading, life-threatening micro-

272

Müller and Schwarz

Table 1 Components of the Unspeciﬁc Innate and the More
Speciﬁc Cellular Adaptive Immune Systems in Humans
Components
Cellular

Humoral

InnateAdaptive

Monocytes
Macrophages
Granulocytes
NK cellsγ/δ cells
Complement, APP, mannosebinding lectin (MBL)

T and B cells

Antibodies

organisms like bacteria, viruses, or parasites, a highly differentiated system consisting ofdifferent lines of defense was established. A widespread heterogeneity was the consequence: two functionally different immune systems both representing different types ofbarriers and each consisting of cellular and humoral immune components. The innate
immune system is the phylogenetically older, primitive one. Its cellular arm is represented
by monocytes/macrophages, granulocytes, and natural killer (NK) cells. The humoral arm
consists of acute phase proteins and the complement system. This unspeciﬁc immune
system represents the ﬁrst line of defense.
The speciﬁc part of the immune system of higher organisms, including humans, isthe adaptive immune system, consisting of the cellular arm of the T and B cells and thehumoral arm of speciﬁc antibodies. This system includes higher functions, such as memory, and can be conditioned. In case of a reexposition to a speciﬁc antigen, this system
can specify the enemy and initiate a speciﬁc immune answer (Table 1).
The innate and adaptive immune systems are functionally balanced. Within the adaptive immune system is another balance regarding the activation of the cellular and thehumoral immune system. The cellular arm of the adaptive immune system is mainly activated by the T-helper-1 (TH-1) system—helper cells, which produce the activating
immunotransmitters IL-2, IL-12, IFN-γ, and TNF-α. The humoral arm of the adaptive
immune system is mainly activated via the TH-2 system—helper cells, which produce
mainly IL-4, IL-10, IL-13, and IL-6.
VI. MAJOR DEPRESSION: THE DISCRIMINANT POWER OF TH-1
AND TH-2 FOR SUICIDALITY
An immunological model of major depression (MD) is sickness behavior, the nonspeciﬁcreaction of the organism to infection and inﬂammation. Sickness behavior is characterized
by weakness, malaise, listlessness, inability to concentrate, lethargy, decreased interest in
surroundings, and reduced food intake—all of which are depressionlike symptoms. The
sickness-related psychopathological symptomatology during infection and inﬂammationis mediated by cytokines such as IL-1, IL-6, TNF-α, and IFN-γ. Their active pathway
from the peripheral immune system to the brain is via afferent neurons and direct targetingat the amygdala and other regions of the brain after diffusion at the circumventricularorgans and choroid plexus [60]. Undoubtedly, there is a strong relationship between thecytokine system and the neurotransmitter system, but a more differentiated analysis may
be required to understand the distinct mechanisms in the heterogeneous disease entity of

Immunology

273

major depression. Blood levels of several cytokines have already been investigated in
major depression, and their interpretation based on the TH-1/TH-2 concept may help togenerate hypotheses for discrimination between subgroups of MD.
VII. TH-1 CYTOKINES IN MAJOR DEPRESSION: THE TH-1
SEROTONIN LINK AS A BIOLOGICAL BASISFOR SUICIDALITY
Data on IL-2 in major depression are mainly reduced to some measurements of its soluble
receptor in peripheral blood. Those blood levels of sIL-2R were repeatedly described to
be increased in MD patients [61–63]. One single study dealt with CSF measurement ofsIL-2R levels and reported a highly signiﬁcant reduction in MD patients compared tohealthy control subjects [64].
Production of both IL-2 and IFN-γ is the typical marker of TH-1 cells. IFN-γ is
produced in higher amounts by lymphocytes of patients with MD than in healthy controls[65]. Higher plasma levels of IFN-γ in depressed patients, accompanied by lower plasma
tryptophan availability, were described in 1994 [66]. Mendlovic and colleagues discriminated between suicidal and nonsuicidal MD patients in a small study. They found distinct
associations between suicidality and TH-1-type immune response on the one hand and a
predominance of TH-2 parameters in nonsuicidal patients on the other hand [67]. This
combination of psychopathological symptoms and their immunological correlates may
represent a very successful strategy in immunological research of major depression. We
want to introduce a line of evidence for a relationship between the TH-1 cytokine IFN-γ,
tryptophan metabolism, and suicidality.
The essential amino acid tryptophan is the precursor of two distinct metabolic pathways, leading to the products serotonin or kynurenine (see Fig. 2). The enzyme indolamine 2,3-dioxygenase (IDO) metabolizes tryptophan to kynurenine, which is then converted to quinolinic acid by the enzyme kynurenine hydroxylase. Both IDO andkynurenine hydroxylase are induced by IFN-γ. The activity of IDO is an important regulatory component in the control of lymphocyte proliferation [68]. It induces a halt in thelymphocyte cell cycle due to the catabolism of tryptophan [69]. The TH-2 cytokines IL-4
and IL-10 inhibit the IFN-γ-induced tryptophan catabolism by IDO [70]. The enzyme
IDO is located in several cell types, including monocytes and microglial cells [71]. An
IFN-γ-induced, IDO-mediated decrease of central nervous tryptophan availability may
lead to a serotonergic deﬁciency.
One of the most consistent ﬁndings in biochemical research dealing with mental
disorders is that some patients with low 5-hydroxyindoleacetic acid (5-HIAA)—the metabolite of serotonin—in CSF are prone to commit suicide [72–74]. This gives additional
evidence for a possible link between the TH-1-like cytokine IFN-γ and the IDO-related
reduction of serotonin availability in the CNS in suicidal patients.
On the basis of epidemiological data it has been hypothesized that high IL-2 levels
are associated with suicidality [75]. Accordingly, clinical studies have observed an activation of the TH-1 system that might be related to suicidality. Increased levels of serumsIL-2R have been described in medication-free suicide attempters disregarding the psychiatric diagnosis [76]. Treatment with high-dose IL-2 has been associated with suicide
in a case report [77]. Recently, a small study showed that T cells of suicidal patients withmajor depression have TH-1 characteristics, while T cells of nonsuicidal depressed patients
showed TH-2 characteristics [67].

274

Müller and Schwarz

We believe that the possible involvement of IFN-γ-induced IDO activity in thepathophysiology of suicidality in major depression should be considered in future studies.
VIII. CYTOKINES AND THE CELLULAR IMMUNE SYSTEM IN MAJOR
DEPRESSION: FOCUS ON IL-6 AND ACUTE PHASE PROTEINSFormer studies show an increase of T-helper cells (CD4⫹ cells) and an increased CD4⫹/CD8⫹ ratio in depressive disorders [78,79]. This ﬁnding points to an immune activation
and was the starting position for a series of further studies.
Further investigations of the cellular components of the immune system focused on
monocytes and macrophages. Increased numbers of peripheral mononuclear cells havebeen described by different groups of researchers [80–82].
Neopterin is a sensitive marker of cell-mediated immunity. The main source of neopterin are monocytes/macrophages. According to the ﬁndings of increased monocytes/
macrophages, an increased secretion of neopterin has been described by several groupsof researchers [66,83–85].
As a product of monocytes and macrophages, IL-6 is one of the most frequently
investigated immune parameters in patients suffering from major depression. Most publications report a marked increase of in vitro IL-6 production [86] or serum IL-6 levels in
depressed patients [61,87–91]. Most of these studies also report elevated plasma levelsof acute phase proteins (APPs)—indicators of the unspeciﬁc (innate) immune system.
Contradictory results are very few, indicating reduced [92], or not altered serum IL-6
levels [62,92a]. An age-related increase of IL-6 serum levels was reported in patients withmajor depression [93]. From a methodological point of view, the potential inﬂuence ofpossibly interfering variables such as smoking, gender, recent infections, and medication
prior to IL-6 release and concentration must be considered [94].
IL-6 production is stimulated by prostaglandin E2 (PGE2) [95]. The central nervous
system expression of the PGE2-producing enzyme cyclooxygenase-2 (COX2) is, on theother hand, induced by IL-6 [96]. Therefore, an increased secretion of PGE2 could be
expected in depressive disorders. Indeed, several studies described increased PGE2 in the
cerebrospinal ﬂuid, serum, and saliva of depressed patients [97–99]. Moreover, in vitro
studies show an increased PGE2 secretion from lymphocytes of depressed patients compared to healthy controls [91]. Further evidence for a functional relationship between
PGE2 and depression is given by the fact that COX inhibitors are able to reduce thelipopolysaccharide-induced sickness behavior in an animal model of depression [100].
Data of IL-6 and the IL-6 system in the CSF are still rare. The only available dataon CSF IL-6 have been published by our group. Herein, we found markedly decreased
levels of IL-6 and its soluble receptor subunit IL-6Rα in elderly patients with MD compared to matched healthy controls [101].
As stated above, IL-6 is a highly important inducer of antibody production (TH-2
immune response) and, indeed, some data show increased antibody titers in MD. As in
schizophrenia, a great heterogeneity of antigen speciﬁcity of the antibodies such as antinuclear antiphospholipid, antithyroidal, or antiviral antibodies was found [86,102,103].
There is no doubt that IL-6 is involved in modulation of the HPA axis [55]. Activation of the HPA axis is one of the best-documented changes in major depression [104].
Furthermore, the relationship between psychological or physical stress and an enhanced
IL-6 secretion in the peripheral immune system seems to be well established [105–108].
An impaired ability of stress coping is often observed in depressed patients. Thus, theImmunology

275high number of data showing elevated peripheral IL-6 levels in MD patients may be related
to psychological stress. On the other hand, there is evidence for a relationship between
high peripheral IL-6 levels and elevated central nervous system serotonin availability.
Intravenous or intraperitoneal administration of IL-6 induced, not only an activation of
the HPA axis, but also an increase in brain tryptophan and serotonin metabolism, whereas
norepinephrine metabolism was unaffected in an animal model [109]. Accordingly, IL-6
seems to mediate the activation of the HPA axis and of the central nervous serotoninsystem after administration of the endotoxin lipopolysaccharide (LPS) [110]. Thus, elevated plasma levels of IL-6 do not ﬁt with the hypothesis of a serotonin deﬁciency in MD.
On the other hand, there is a report about a correlation of the increased IL-6 production in vitro with decreased tryptophan levels in depressed patients that emphasizes theinﬂuence of IL-6 on the serotonin metabolism [86]. Serotonin synthesis in the CNS is atleast partly dependent on the availability of free plasma tryptophan [110a].
It should be recognized that an inherent heterogeneity exists in the etiology of depression and different neurotransmitter systems may be disturbed. Norepinephrine is thesecond major biogenic amine that has been proposed to be causally involved in the pathophysiology of major depression [3,111] and in the mechanism of antidepressant drug
action [112]. Whether MD patients with elevated peripheral IL-6 are suffering primarily from a CNS norepinephrine deﬁciency—in contrast to the suicidal patients withmarked serotonin deﬁciency and possible TH-1-dominated immune response—needs to
be investigated.
Studies on other TH-2 cytokines are lacking and the current data on IL-6 alone areinsufﬁcient to establish any TH-2-related hypothesis on major depression. However, thequestion remains, is a TH-2 response the common immunological hallmark of both nonsuicidal depression and negative schizophrenia—two different disease concepts but showing
certain similarities in the psychopathology.
IX. DEPRESSION: A HETEROGENEOUS SYNDROME WITH
DIFFERENT IMMUNE PATHOLOGIES
Major depression is a common disorder showing a lifetime prevalence between 5% and25%, twice as frequent in women compared to men. From the standpoint of many researchers, the diagnosis of MD reﬂects different etiological and pathophysiological subgroups
as older diagnostic manuals differentiated entities such as endogenous depression, neurotic
depression, or psychoreactive depression. Moreover, different etiologies have been suggested for monopolar and bipolar depression. Therefore, it could be expected that different
immunological patterns are found in different types of depression.
Only recently, immunological investigations have been performed on different types
of MD. A group of patients suffering from MD were investigated, a part of them fulﬁllingthe criteria of melancholic-type depression. Melancholic patients had normal leukocyte,
lymphocyte, and NK-cell counts, while the nonmelancholic depressed patients showed
increased leukocytes, lymphocytes, and NK cells [82].
On the other hand, melancholic patients showed decreased production of IL-2,
IFN-γ, and IL-10, while nonmelancholic patients had cytokine production comparable tohealthy controls [82]. During antidepressive treatment, the monocyte count stayed higher
in nonmelancholic patients after 2 and 4 weeks of treatment. Accordingly, alpha-2 macroglobulin, another marker of inﬂammation, was increased in nonmelancholic patients before
therapy and after 2 and 4 weeks of treatment. There were no differences between healthy276

Müller and Schwarz

Table 2 Markers of TH-1/TH-2 Responses in Major Depression
Site of cytokine
expression
In vitro production
Peripheral

CSF
Hypothesis

TH-1
IFN-γ ↑
sIL-2R ↑↑IFN-γ ↑
IFN-γ ↑ ⇒ TRP ↓sIL-2R ↑A TH-1 serotonin link insuicidal MD?

TH-2
IL-6 ↑↑
IL-6 ↑↑

IL-6 ↓
sIL-6R ↓A TH-2 dominance or an overactivationof monocyte/macrophage system in
nonsuicidal MD?

↑↑ or ↓↓ means repeated consistent data for elevation or decrease respectively; ↑ or ↓ means less consistent
data.

controls and both melancholic and nonmelancholic depression regarding C-reactive protein, haptoglobin, and in vitro production of IL-1β [113].
These results show that different types of depression—melancholic versus nonmelancholic—are associated with different immune states. Moreover, suicidality seems toshow a further distinct immune pattern.
These results point to a methodological pitfall regarding studies of immunity anddepression: the heterogeneity of the results of immunological studies might at least be
due in part to different types of depression, including suicidality. Perhaps the ﬁnding ofincreased sIL-2R and IL-1 concentrations in depression might be due to a patient groupmore often exhibiting the melancholic type of depression.
However, regarding these ﬁndings it is doubtful that the pleiotropic cytokine IL-6
and the other components of the IL-6 system (such as the IL-6 receptor and the signaltransducing molecule gp130) are speciﬁcally altered in major depression. Moreover, increased IL-6 levels have also been observed in patients suffering from schizophrenia.
Increased levels in schizophrenia are associated with the duration of the disease and theparanoid psychopathology [114,114a].
Taken together, there might be a relationship between immunological, neurochemical, and clinical variables in MD patients: suicidality in MD may be related to a central
nervous serotonin deﬁciency, possibly induced by an IFN-γ (TH-1)-mediated IDO activation, whereas elevated levels of IL-6 (TH-2) might indicate a distinct group of MD patients
without deﬁciency of the serotonergic system. The possible predictive value of immunological parameters on antidepressant therapy regimen has to be unraveled in future studies(Table 2). However, future immunological studies of MD should emphasize the role ofclinical and neurochemical variables.

X.

CYTOKINES AND EFFECTS OF ANTIDEPRESSANTS

Only very few investigations have been carried out regarding the effects of antidepressant
medication on immune parameters [115]. However, attention has focused on the interac-Immunology

277tion of the serotonergic system and the immune system. It has been suggested that serotonin has an inhibitory action on antibody production, since an inverse relationship between
brain serotonergic concentration and antibody synthesis has been demonstrated in previous
studies [116]. The suggested role of the cytokines in depression leads one to expect that
antidepressants would have an inhibitory effect to certain activating cytokines. Studies
using modern immunological methods observed an inhibitory function of the serotoninsystem on the IFN-γ-induced MHC expression [117] and on mitogen-induced T-cell proliferation [118].
During the last years, a modulatory, mostly inhibiting, effect of serotonin reuptake–inhibiting drugs to activating immune parameters has been demonstrated in animals[119,120]. Moreover, inhibiting effects of selective serotonin reuptake inhibitors on theacute phase proteins were observed in animal investigations as well [121], and there areseveral hints that the severe side effects of zimeldine are due to immunological mechanisms of the 5HT system [122].
From an immunological point of view, some antidepressants are able to induce a
TH-1-to-TH-2 shift; Maes and colleagues demonstrated the potency of three different
antidepressants (sertraline, clomipramine, and trazodone) to signiﬁcantly reduce the IFN-γ/
IL-10 ratio in vitro. These three drugs signiﬁcantly reduced IFN-γ production, sertraline
and clomipramine and increased IL-10 production signiﬁcantly [18].
Other researchers, however, observed a decrease of IL-6 during treatment of theserotonin reuptake inhibitor ﬂuoxetine [123]. These very preliminary results point to different immune modulating effects of different antidepressants, but the immune effects ofantidepressants and especially the effect on the cytokine production has not yet been studied systematically.
An interesting study showed a relationship between IL-6 production from the lymphocytes of depressed patients and the treatment response: patients producing low levelsof IL-6 showed a better response to treatment with amitryptyline over six weeks comparedto patients showing a high IL-6 production. During treatment, however, both groups turned
to a normal IL-6 production. The production of TNF-α was high in responders to amitryptyline and turned to normal during therapy [123a].
With respect to the above-mentioned results, it can be speculated that amitryptyline
might be especially efﬁcient in patients with low IL-6 levels, which show a more TH-1related immune response (melancholic type) similar to sertraline, clomipramine, andtrazodone, while ﬂuoxetine might be more efﬁcient in patients with high IL-6 levels (nonmelancholic) with a monocyte/macrophage immune response.
Another role in immunotherapy has been suggested for the antidepressant rolipram[124]. Rolipram, a selective phosphodiesterase inhibitor, inhibits in vitro the productionof activating cytokines, especially TNF-α and IFN-γ. Moreover, rolipram is effective
in preventing, delaying, and reducing the clinical severity of EAE, the animal model ofMS [124,125]. Rolipram, not yet marketed, has been shown to be safe and effective inthe treatment of depression [126,127] and was proposed to be a potential therapy forMS [124].
The downregulating effects of antidepressants on inﬂammatory cytokines, associated with the ﬁndings of increased proinﬂammatory cytokines and cellular immune markers, which were found mainly in nonsuicidal, nonmelancholic patients suffering from MD,
point out that this immune effect might be related to the therapeutic effects of antidepressants. Further therapeutic strategies for MD should take into account those immune ﬁnd-

278

Müller and Schwarz

ings, including the different ﬁndings in the different clinical subgroups. From this pointof view, developing immunotherapeutic strategies will be a future research tool in depression.
XI. ANXIETY AND IMMUNE FUNCTION
The impact of anxiety on the immune function has widely been studied at the subclinicalmodel of stress and stress coping (i.e., the cognitive appraisal of stress stimuli). Typeand efﬁcacy of psychological defense and coping can reduce acute emotional arousal andendocrine stress responses to real-life stressors.
Several authors point out that acute stress and anxiety are associated with decreased
immune function. College students at the start of their studies exhibited signiﬁcantly lower
lymphocyte proliferative responses to the mitogen concanavalin A and lower serum levelsof IL-1. A more negative attribution style of adversive events was associated with reduced
blastogenic T-cell responses and reduced serum levels of IFN-γ [128]. Students with higher
anxiety scores during examination stress showed altered lymphocyte subsets [129]. In
other studies, high scores of anxiety have been related to decreased lymphocyte responseto mitogens [130,131]. However, lymphocyte proliferation tests are very unspeciﬁc immunological methods and the results vary widely without giving conclusive answers to thestate of the immune system. The deﬁnitions of acute or chronic stress often vary widely.
Paradigms of acute stress reach from very short-lasting stress, like bungee-jumping or
parachuting, to stress lasting over hours and days; chronic stress may last for the durationof exams or over months and years for caregivers of relatives suffering from diseases
such as Alzheimer’s, as stress models from the literature show. Cum grano salis most of
the studies point out that short-term stress is associated with an increase in immune function while long-term stress is associated with a decrease in immune function.
Anxiety is often associated with sympathetic activation. Acute psychological stresscan induce short-term catecholamine increases that may result in lymphocytosis and leukocytosis [132]. In parallel, the increase of T-lymphocyte function and natural killer cells
during acute stress might be mediated by sympathetic activation [133].
Another example are studies examining IgA concentration in the saliva. During theshort-term stress model of competition between soccer coaches during a play, an increaseof IgA concentration can be found [134] while dental students show a decrease of salivary
IgA concentration during stress periods of the academic year [135]. In addition, air-trafﬁccontrollers had a signiﬁcant increase in salivary IgA after 4 h of work [136].
Regarding the stress model of public speaking, persons who showed a high sympathetic reaction had increased NK cell number, while persons with a low sympathetic reaction showed no increase of NK cells [137]. Public speaking in particular appears to be amodel for social phobia because a marked and persistent fear of a social performance
situation in which the person is exposed to unfamiliar people is a key fear in social phobia.
It seems that the acute stress paradigm might be a suitable model for the social phobia
type of anxiety disorder.
The results of the stress paradigm studies, however, are not conclusive. This may
be due to several methodological pitfalls. Besides different deﬁnitions of acute or chronic
stress, the subjective appraisal of stress, personality traits, coping mechanisms, and cognitive function, as well as the important inﬂuence of eustress or distress, plays a role. Regarding the immunological parameters and mechanisms, older stress experiments often measured simpliﬁed immunological in vitro parameters that may not really reﬂect the inﬂuenceImmunology279

of stress on the complicated in vivo immunological state. On the other hand, those studies
had an avant-garde function during the 1960s to 1980s.
XII. ANXIETY AND IMMUNE FUNCTION IN PATIENTS WITH
GENERALIZED ANXIETY DISORDER
Patients with generalized anxiety disorder (GAD) suffer from a chronic disorder that lasts
over weeks, months, or even years. Immune changes in those patients have only beenstudied marginally. Regarding the stress model, GAD might ﬁt with the model of chronic
stress. In patients with GAD, a signiﬁcant decrease in the density of the peripheral benzodiazepine receptors on the circulating lymphocytes has been observed, which was largely
normalized by effective treatment with chronically administered diazepam.
The results of clinical and experimental studies suggest that the peripheral benzodiazepine receptors play a prominent role in the cellular and humoral immune response.
Acutely administered diazepam was without effect. These changes in the receptor density
would appear to be speciﬁc for the anxiety disorder [121]. In addition to the direct actionof benzodiazepine on peripheral benzodiazepine receptors located on immune cells, it isalso possible that the immune system is indirectly affected by the increased synthesis ofadrenal corticosteroids.
During anxiety and stress, an upregulation of the HPA axis has been widely described. On the other hand, cytokines such as IL-1, IL-6, or TNF-α also induce an upregulation of the HPA axis via stimulation of CRH in the hypothalamic region [138] (Fig. 3).

Figure 3 Diagram of changes in the endocrine and immune systems in stress and anxiety. ACh, acetylcholine; 5-HAT, 5-hydroxytryptamine; GABA, gamma-aminobutyric acid;
CRF, corticotropin-releasing factor; IL-1, interleukin-1; ⫹, stimulatory; ⫺, inhibitory.
(Adapted from Ref. 141.)

280

Müller and Schwarz

The results of clinical and experimental studies suggest that the peripheral benzodiazepine receptors play a prominent role in the cellular and humoral immune response.
Anxiolytics that act on central and/or peripheral benzodiazepine receptors can modulate
the immune system either indirectly by reducing the central secretion of CRH, the majorstress hormone, by acting on central gamma-aminobutyric acid (GABA) receptors, ordirectly by stimulating the peripheral benzodiazepine receptors on immune cells.
XIII. IMMUNE CHANGES IN PANIC DISORDER
Panic disorder with or without agoraphobia is a syndrome in which severe anxiety, often
somatic symptoms of the autonomous nervous system and a stress reaction, is the core
syndrome of the disease. Panic attacks initiate severe stressful episodes and they are also
often associated with severe depressive episodes. In panic disorder, as well as in GAD,
the results of immunological studies are somewhat controversial. A major problem isinterpreting the results, arising from the fact that several patients studied suffered fromdepression in addition to panic attacks. The heterogeneity of the clinical symptomatology
therefore might have profoundly inﬂuenced the results.
Brambilla et al. [139] found a normal mitogen stimulation of T lymphocytes but
an elevated adenocorticotrophic hormone (ACTH) concentration and a blunted cortisol
response to dexamethasone. The administration of CRH, which was associated with ahypersecretion of ACTH and cortisol, did not suppress the proliferative response of the
T lymphocytes. This lack of change in the proliferative response of T lymphocytes suggests that the secretion of IL-2, IL-6, and IFN-γ would be unchanged. However, there isevidence from other studies that female patients with panic disorders have a slight increasein the serum concentration of IL-2. A solution to this controversial ﬁnding could be thesuggestion of a relative imbalance within the group of CD4⫹ T lymphocytes. Both TH1 and TH-2 cells show the CD4⫹ surface marker, but secrete different cytokines (TH-1
cells secrete IL-2). The cytokine production of these cells is associated with immunological function.
Some studies described parallels between patients suffering from panic disorder andsevere acute psychological stress. Patients suffering from panic disorder and patients withsocial phobia had increased CD16⫹ (natural killer) cell numbers. Panic disorder patients
also had increased numbers of CD19⫹ cells (B lymphocytes), human HLA-DR-presenting
cells, and more cells with the combination of HLA-DR and CD19 surface markers (Blymphocytes with HLA-DR⫹ on their surface), an activation marker of the immune system.
These data, although preliminary, suggest that subjects with panic disorder may have alterations in circulating lymphocyte proﬁles and that, especially in panic disorder, the B-cellsystem is activated [140]. B lymphocytes produce immunoglobulin including IgA. Similar
to the ﬁndings in the acute stress model of soccer coaches, patients with “pure” panic
disorder showed a signiﬁcant increase in serum IgA concentration relative to a control
population, while concentrations of IgG, IgM, and IgE were unchanged.
Nevertheless, a major problem in interpreting the data relating to the immunechanges associated with panic disorder is the paucity of these studies, the heterogeneityof the patients studied, and the differences in the methods used to assess the immune
parameters [141].
XIV.

CONCLUSION

The current state regarding the immune system, depression, and anxiety disorders reﬂects
a controversial picture. In depression, many psychoneuroimmunological studies have been

Immunology

281

performed by several groups, especially during the last few years. The ﬁndings point todifferent immunological/inﬂammatory functions in different types of depression with respect to nonmelancholic or melancholic symptomatology and suicidality. These more conclusive results lead to preliminary therapeutic studies with immunomodulatory or antiinﬂammatory agents that are on the way.
In anxiety disorders, the results are far more inconclusive and the role of immunechanges needs to be further elucidated. Whether immunological changes are the result ofan acute or chronic accompanying stress reaction or reﬂect speciﬁc alterations of anxiety
disorders has to be the objective of further studies.
REFERENCES
1.
2.

3.
4.
5.

6.
7.

8.
9.
10.

11.

12.

13.

14.
15.

16.

Ader R, Felten DL, Cohen N, eds. Psychoneuroimmunology, 3rd ed., vol. 2. San Diego:
Academic Press, 2001.
Eggert F, Luszyk D, Westphal E, Müller-Ruchholz W, Ferstl R. Vom Gen zum Geruch zum
Verhalten; über immunogenetische Grundlagen der chemosensorischen Identität und ihre
psychobiologischen Effekte. T.W. Neurol Psychiatrie 1990; 3: 889–892.
Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting
evidence. Am J Psychiatry 1965; 122: 509–522.
Matussek N. Neurobiologie und Depression. Med Monatsschr 1966; 3: 109–112.
Coppen A, Swade C. 5-HT and depression: the present position. In: Briley M, Fillion G.
New concepts in Depression. Pierre Fabre Monograph Series. London: MacMillan, 1988:
120–136.
Krüger KW. Lupus erythematodes und Zentralnervensystem. Nervenarzt 1984; 55: 165–172.
Müller N, Gizycki-Nienhaus B, Günther W, Meurer M. Depression as a possible cerebral
manifestation of scleroderma: immunological ﬁndings in serum and CSF. Biol Psychiatry
1992; 31: 1151–1156.
Raps A, Abramovich Y, Assael M. Relation between schizophrenic-like psychosis and Sjögren Syndrome (SS). Isr J Psychiatry Relat Sci 1986; 23: 321–324.
Kurtz G, Müller N. The antiphospholipid syndrome and psychosis. Am J Psychiatry 1994;
151: 1841–1842.
Malaguarnera M, Laurino A, Di F, Pistone G, Castorina M, Guccione N, Rampello L. Neuropsychiatric effects and type of IFN-alpha in chronic hepatitis C. J Interferon Cytokine Res
2001; 21: 273–278.
Schafer M, Messer T, Wegner U, Schmid-Wendtner MH, Volkenandt M. [Psychiatric side
effects during adjuvant therapy with interferon-alpha in patients with malignant melanoma.
Clinical evaluation as well as diagnostic and therapeutic possibilities]. Hautarzt 1990; 50:
654–658.
McAllister CG, Rapaport MH, Pickar D, Podruchny TA, Christison G, Alphs LD, Paul SM.
Increased number of CD5⫹ B-lymphocytes in schizophrenic patients. Arch Gen Psychiatry
1989; 46: 890–894.
Villemain F, Chatenoud L, Galinowski A, Homo-Delarche F, Genestet D, Loo H, Zarifarain
E, Bach JF. Aberrant T-cell-mediated immunity in untreated schizophrenic patients: DeﬁcientInterleukin-2 production. Am J Psychiatry 1989; 146: 609–616.
Müller N, Ackenheil M, Hofschuster E, Mempel W, Eckstein R. Cellular immunity in schizophrenic patients before and during neuroleptic therapy. Psychiatry Res 1991; 37: 147–160.
Sperner-Unterweger B, Barnas C, Fuchs D, Kemmler G, Wachter H, Hinterhuber H, Fleischhacker WW. Neopterin production in acute schizophrenic patients: an indicator of alterationsof cell mediated immunity. Psychiatry Res 1992; 42: 121–128.
Müller N, Ackenheil M, Hofschuster E, Mempel W, Eckstein R. Cellular immunity, HLAclass I antigens, and family history of psychiatric disorder in endogenous psychoses. Psychiatry Res 1993; 48: 201–210.

282
17.

Müller and Schwarz

Müller N, Ackenheil M, Hofschuster E, Mempel W, Eckstein R. T-cells and psychopathology
in schizophrenia: relationship to the outcome of neuroleptic therapy. Acta Psychiatr Scand
1993; 87: 66–71.
18. Maes M, Song C, Lin AH, Bonaccorso S, Kenis G, De Jongh R, Bosmans E, Scharpe S.
Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma andstimulation of interleukin-10 secretion. Neuropsychopharmacology 1999; 20: 370–379.
19. Reichlin S. Neuroendocrine-immune interactions. N Engl J Med 1993; 329: 1246–1253.
20. Banks WA, Kastin AJ. The interleukins-1 alpha, -1 beta, and -2 do not acutely disrupt themurine blood–brain barrier. Int J Immunopharmacol 1992; 14: 629–636.
21. Banks WA, Kastin AJ, Gutierrez EG. Interleukin-1 alpha in blood has direct access to corticalbrain cells. Neurosci Lett 1993; 163: 41–44.
22. Gutierrez EG, Banks WA, Kastin AJ. Murine tumor necrosis factor alpha is transported fromblood to brain in the mouse. J Neuroimmunol 1993; 47: 169–176.
22a. Norris JG, Benveniste EN. Interleukin-6 production by astrocytes: induction by the neurotransmitter norepinephrine. J Neuroimmunol 1993; 45: 137–146.
23. Ransohoff RM, Benveniste EN. Cytokines in the CNS. Boca Raton: CRC, 1996.
24. Engel RR, Müller F, Münch U, Ackenheil M. Plasma catecholamine response and autonomic
function during short-time psychological stress. In: Usdin E, Kyetnansky R, Kopin J, eds.
Catecholamines and stress. Recent advances. New York: Elsevier, 1980: 461–466.
25. Licinio J, Wong ML. Localizations of Interleukin-1 and Interleukin-1 mRNA in brain: pathophysiological implications. Neuropsychopharmacol 1994; 10/1: 834.
26. Benveniste EN. Inﬂammatory cytokines within the central nervous system: sources, function,and mechanism of action. Am J Physiol 1992; 263 (Cell Physiol 32): C1–C16.
27. Lieberman AP, Pitha PM, Shin HS, Shin ML. Production of tumor necrosis factor and othercytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proc Natl
Acad Sci USA 1989; 86: 6348–6352.
28. Breder CD, Dinarello CA, Saber CB. Interleukin-1 immunoreactive innervation of the human
hypothalamus. Science 1998; 240: 321–324.
29. Lechan RM, Toni R, Clark BD, Cannon JG, Shaw AR, Dinarello CA, Reichlin S. Immunoreactive interleukin-1 beta localization in the rat forebrain. Brain Res 1990; 514: 135–140.
30. Ebbesen F, Knudsen A. The possible risk of bilirubin encephalopathy as predicted by plasma
parameters in neonates with previous severe asphyxia. Eur J Pedi 1992; 151: 910–912.
31. Shimojo M, Imay Y, Nakajiama K, Mizushima S, Uemura A, Kohsaka A. Interleukin enhances the viability of primary cultured rat neocortical neurons. Neurosci Lett 1993; 151:
170–173.
32. Hickey W, Kimura H. Perivascular microglial cells of the CNS are bone-marrow derived
and present antigen in vivo. Science 1988; 238: 290–292.
33. Budka H, Majdic O. Shared antigenic determinants between human hemopoietic cells andnervous tissues and tumors. Acta Neuropathol (Berl) 1985; 67: 58–66.
34. Maddon PI, Dalgleish AG, McDougal ES, Clapham PR, Weiss AR, Axel R. The T4 geneencodes the AIDS virus receptor and is expressed in the immune system and in the brain.
Cell 1986; 47: 333–348.
35. Merill JE. Tumor necrosis factor alpha, Interleukin 1 and related cytokines in brain development: normal and pathological. Dev Neurosci 1992; 14: 1–10.
36. Hashimoto M, Ishikawa Y, Yokota S, Goto F, Bando T, Sakakibara Y, Iriki M. Action sideof circulating interleukin-1 on the rabbit brain. Brain Res 1991; 540: 217–223.
37. Kent S, Bluthe RM, Kelley KW, Dantzer R. Sickness behavior and drug development. TIPS
1992; 13:24–28.
38. Berkenbosch F, Van Oers J, Del Ray A, Tiders F, Besedovsky HO. Corticotropin-releasing
factor-producing neurons in the rat activated by interleukin-1. Science 1987; 238: 524–526.

Immunology
39.
40.

41.

42.
43.
44.
45.

46.

47.
48.

49.
50.

51.

52.

53.
54.

55.
56.
57.
58.

59.

283

Besedovsky HO, Del Ray A, Sorkin E, Dinarello CA. Immunoregulatory feedback between
interleukin-1 and glucocorticoid hormones. Science 1986; 233: 652–654.
Minami M, Kuraishi Y, Yamaguchi T, Nakai S, Hirai Y, Satoh M. Immobilization stressinduces interleukin-1 beta mRNA in the rat hypothalamus. Neurosci Lett 1991; 123: 254–
256.
Sundar SK, Cierpial MA, Kilts C, Ritchie JC, Weiss M. Brain IL-1 induced immunosuppression occurs through activation of both pituitary-adrenal axis and sympathetic nervous system
by corticotropin-releasing factor. J Neurosci 1990; 10: 3701–3706.
Weiss JM, Quan N, Sundar SK. Immunological consequences of Interleukin-1 in the brain.
Neuropsychopharmacol 1994; 10: 833S.
Bartrop RW, Lazarus L, Luckhurst E, Kilch LG, Penny R. Depressed lymphocyte function
after bereavement. Lancet 1997; I: 834–836.
Zisook S, Shuchter SR, Irwin M, Darko DF, Sledge P, Resovsky K. Bereavement, depression,and immune function. Psychiatry Res 1994; 52: 1–10.
Kiecolt-Glaser JK, Glaser R. Psychosocial inﬂuences on herpes virus latency. In: Kurstak
E, Lipowski ZJ, Morozov PV, eds. Viruses, Immunity, and Mental Disorders. London: Plenum, 1987: 403–412.
Laudenslager ML. Psychosocial stress and susceptibility to infectious disease. In: Kurstak
E, Lipowski EJ, Morozov PV, eds. Viruses, Immunity, and Mental Disorders. London: Plenum, 1987: 391–402.
Glaser R, Kiecolt-Glaser JK, George JM, Speicher CE, Holliday JE. Stress, loneliness andchange in herpes virus latency. J Behav Med 1985; 8: 249–260.
Solomon GF. Emotional and personality factors in the onset and course of autoimmune disease, particularly rheumatoid arthritis. In: Ader R, ed. Psychoneuroimmunology. New York:
Academic Press, 1981: 159–182.
Spangelo BL, Judd AM, Isakson PC, MacLeod RM. Interleukin-6 stimulates arterior pituitaryhormone release in vitro. Endocrinology 1989; 125: 575–577.
Araujo DM, Lapchak PA, Collier B, Quirion R. Localization of interleukin-2 immunoreactivity and interleukin-2 receptors in the rat brain: interaction with the cholinergic system. Brain
Res 1989; 498: 257–266.
Denicoff KD, Rubinoff DR, Papa MZ, Simpson C, Seipp CA, Lotze MT, Chang AE,
Rosenstein D, Rosenberg SA. The neuropsychiatric effects of treatment with Interleukin-2
and lymphokine-activated killer cells. Ann Intern Med 1987; 107: 293–300.
Alonso R, Chaudieu I, Diorio J, Krishnamurthy A, Quirion R, Boksa P. Interleukin-2 modulates evoked release of [3H]dopamine in rat cultured mesencephalic cells. J Neurochem 1993;
61: 1284–1290.
Lapchak PA. A role for Interleukin-2 in the regulation of striatal dopaminergic function.
Neuroreport 1992; 3: 165–168.
Zalcman S, Green-Johnson JM, Murray L, Nance DM, Dyck D, Anisman H, Greenberg AH.
Cytokine-speciﬁc central monoamine alterations induced by interleukin-1, -2 and -6. Brain
Res 1994; 643: 40–49.
Plata-Salaman CR. Immunoregulators in the nervous system. Neurosci Biobehav Rev 1991;
15: 185–215.
Sawada M, Suzumura A, Marunouchi T. TNF-alpha induces IL-6 production by astrocytes,
but not by microglia. Brain Res 1992; 583: 296–299.
Dunn AJ. Endotoxin-induced activation of cerebral catecholamine and serotonin metabolism:
comparison with interleukin-1. J Pharmacol Exp Ther 1992; 261: 964–969.
Frei K, Malipiero UV, Leist TP, Zinkernagel RM, Schwab ME, Fontana A. On the cellularsource and function of interleukin-6 produced in the central nervous system in viral diseases.
Eur J Immunol 1989; 19: 689–694.
Muraguchi A, Hirano T, Tang B, Matsuda T, Horii Y, Nakajima K, Kishimoto T. The essen-

284

60.

61.
62.

63.

64.

65.
66.

67.
68.
69.
70.

71.

72.

73.
74.

75.
76.
77.
78.

Müller and Schwarz
tial role of B-cell stimulating factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells.
J Exp Med 1988; 167: 332–344.
Dantzer R, Bluthe R, Castanon N, Chauvet N, Capuron L, Goodall G, Kelley KW, Konsman
JP, Layé S, Parnet P, Pousset F. Cytokine effects on behavior. In: Ader R, Felten DL, CohenN, eds. Psychoneuroimmunology, 3rd ed., vol. 2. San Diego, Academic Press, 2001: 373–
382.
Sluzewska A, Rybakowski J, Bosmans E, Sobieska M, Berghmans R, Maes M, Wiktorowicz
K. Indicators of immune activation in major depression. Psychiatry Res 1996; 64: 161–167.
Maes M, Meltzer HY, Buckley P, Bosmans E. Plasma-soluble interleukin-2 and transferrin
receptor in schizophrenia and major depression. Eur Arch Psychiatry Clin Neurosci 1995;
244: 325–329.
Maes M, Meltzer HY, Buckley P, Bosmans E. Plasma-soluble interleukin-2 and transferrin
receptor in schizophrenia and major depression. Eur Arch Psychiatry Clin Neurosci 1995;
244: 325–329.
Levine J, Barak Y, Chengappa KR, Rapoport A, Antelman SM, Barak V. Low CSF solubleinterleukin-2 receptor levels in acute depression. Short communication. J Neural Transm
1999; 106: 1011–1015.
Seidel A, Arolt V, Hunstinger M, Rink L, Behnisch A, Kirchner H. Major depressive disorderis associated with increased monocyte count. Acta Psychiat Scand 1996; 94: 198–204.
Maes M, Scharpe S, Meltzer HY, Okayli G, Bosmans E, D’Hondt P, Vanden Bossche BV,
Cosyns P. Increased neopterin and interferon-gamma secretion and lower availability ofL-tryptophan in major depression: further evidence for an immune response. Psychiatry
Res 1994; 54: 143–160.
Mendlovic S, Mozes E, Eilat E, Doron A, Lereya J, Zakuth V, Spirer Z. Immune activationin non-treated suicidal major depression. Immunol Lett 1999; 67: 105–108.
Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by
starvation? Immunol Today 1999; 20: 469–473.
Munn DH, Shaﬁzadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T
cell proliferation by macrophage tryptophan catabolism. J Exp Med 1999; 189: 1363–1372.
Weiss G, Murr C, Zoller H, Haun M, Widner B, Ludescher C, Fuchs D. Modulation ofneopterin formation and tryptophan degradation by TH-1- and TH-2-derived cytokines inhuman monocytic cells. Clin Exp Immunol 1999; 116: 435–440.
Alberati GD, Ricciardi CP, Kohler C, Cesura AM. Regulation of the kynurenine metabolic
pathway by interferon-gamma in murine cloned macrophages and microglial cells. J Neurochem 1996; 66: 996–1004.
Lidberg L, Belfrage H, Bertilsson L, Evenden MM, Asberg M. Suicide attempts and impulse
control disorder are related to low cerebrospinal ﬂuid 5-HIAA in mentally disordered violent
offenders. Acta Psychiatr Scand 2000; 101: 395–402.
Mann JJ, Malone KM. Cerebrospinal ﬂuid amines and higher-lethality suicide attempts indepressed inpatients. Biol Psychiatry 1997; 41: 162–171.
Nordstrom P, Samuelsson M, Asberg M, Traskman BL, Aberg WA, Nordin C, Bertilsson
L. CSF 5-HIAA predicts suicide risk after attempted suicide. Suicide Life Threat Behav
1994; 24: 1–9.
Penttinen J. Hypothesis: Low cholesterol, suicide, and Interleukin-2. Am J Epidemiology
1995; 141: 716–718.
Nässberger L, Träksman-Bendz L. Increased soluble interleukin-2 receptor concentrations
in suicide attempters. Acta Psychiat Scand 1993; 88: 48–52.
Baron DA, Hardie T, Baron SH. Possible association of interleukin-2 with depression andsuicide. JAMA 1993; 93: 799–800.
Maes M, Stevens W, DeClerck L, Bridts C, Peeters D, Schotte C, Cosyns P. Immune disorders in depression: higher T helper/T suppressor-cytotoxic cell ratio. Acta Psychiatr Scand
1992; 86: 423–431.

Immunology
79.

285

Müller N, Ackenheil M, Hofschuster E, Mempel W, Eckstein R. Investigations of the cellularimmunity during depression and the free interval: evidence for an immune activation in affective psychosis. Prog Neuro-Psychopharmacol Biol Psychiatry 1993; 17: 713–730.
80. Herbert TB, Cohen S. Depression and immunity: A metaanalytic review. Psych Bull 1993;
113: 472–486.
81. Seidel A, Arolt V, Hunstiger M, Rink L, Behnish A, Kircher H. Major depressive disorderis associated with elevated monocyte counts. Acta-Psychiatr-Scand 1996; 94(3): 198–204.
82. Rothermundt M, Arolt V, Fenker J, Gutbrodt H, Peters M, Kirchner H. Different immune
patterns in melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin
Neurosci 2001; 251: 90–97.
83. Duch DS, Woolf JH, Nichol CA, Davidson JR, Garbutt JC. Urinary excretion of biopterin
and neopterin in psychiatric disorders. Psychiatry Res 1984; 11: 83–89.
84. Dunbar PR, Hill J, Neale TJ, Mellsop GW. Neopterin measurement provides evidence ofaltered cell-mediated immunity in patients with depression, but not with schizophrenia. Psychol Med 1992; 22: 1051–1057.
85. Bonaccorso S, Lin A, Verkerk R, Van Hunsel F, Libbrecht I, Scharpé S, DeClerck L, Biondi
M, Janca A. Maes M. Immune markers in ﬁbromyalgia: Comparison with major depressed
patients and normal volunteers. J Affect Disord 1998; 48: 75–82.
86. Maes M, Scharpe S, Meltzer HY, Bosmans E, Suy E, Calabrese J, Cosyns P. Relationships
between interleukin-6 activity, acute phase proteins, and function of the hypothalamicpituitary-adrenal axis in severe depression. Psychiatry Res 1993; 49: 11–27.
87. Maes M, Meltzer HY, Bosmans E, Bergmans R, Vandoolaeghe E, Ranjan R, Desnyder R.
Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin2 and transferrin receptor in major depression. J Affect Disord 1995; 34: 301–309.
88. Sluzewska A, Rybakowski JK, Laciak M, Mackiewicz A, Sobieska M, Wiktorowicz K. Interleukin-6 serum levels in depressed patients before and after treatment with ﬂuoxetine. Ann
NY Acad Sci 1995; 762: 474–476.
89. Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Nees H. Increased serumIL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 1997; 9: 853–858.
90. Frommberger UH, Bauer J, Haselbauer P, Fraulin A, Riemann D, Berger M. Interleukin6(IL-6)-plasma levels in depression and schizophrenia: comparison between the acute state
and after remission. Eur Arch Psychiatry Clin Neurosci 1997; 247: 228–233.
91. Song C, Lin A, Bonaccorso S, Heide C, Verkerk R, Kenis G, Bosmans E, Scharpe S, Whelan
A, Cosyns P, De Jongh R, Maes M. The inﬂammatory response system and the availabilityof plasma tryptophan in patients with primary sleep disorders and major depression. J Affect
Disord 1998; 49: 211–219.
92. Katila H, Appelberg B, Hurme M, Rimon R. Plasma levels of interleukin-1 beta and interleukin-6 in schizophrenia, other psychoses, and affective disorders. Schizophr Res 1994; 12:
29–34.
92a. Brambilla F, Bellodi L, Perna G, Battaglia M. Psychoimmunoendocrine aspects of panic
disorder. Neuropsychobiology 1992; 26: 12–22.
93. Ershler WB, Sun WH, Binkley N, Gravenstein S, Volk MJ, Kamoske G, Klopp RG, Roecker
EB, Daynes RA, Weindruch R. Interleukin-6 and aging: blood levels and mononuclear cell
production increase with advancing age and in vitro production is modiﬁable by dietary
restriction. Lymphokine Cytokine Res 1993; 12: 225–230.
94. Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kuhn M, Schuld A, Pollmacher T. Plasma
levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res 1999; 33: 407–418.
95. Hinson RM, Williams JA, Shacter E. Elevated interleukin 6 is induced by prostaglandin E2
in a murine model of inﬂammation: possible role of cyclooxygenase-2. Proc Natl Acad Sci
USA 1996; 93: 4885–4890.

286
96.

Müller and Schwarz

Cao C, Matsumura K, Shirakawa N, Maeda M, Jikihara I, Kobayashi S, Watanabe Y. Pyrogenic cytokines injected into the rat cerebral ventricle induce cyclooxygenase-2 in brain endothelial cells and also upregulate their receptors. Eur J Neurosci 2001; 13: 1781–1790.
97. Linnoila M, Whorton R, Rubinow DR, Cowdry RW, Ninan PT, Waters RN. CSF prostaglandin levels in depressed and schizophrenic patients. Arch Gen Psychiatry 1983; 40: 405–
406.
98. Calabrese JR, Skwerer AG, Barana B, Gulledge AD, Valenzuela R, Butkus A, Subichin S,
Krupp NE. Depression, immunocompetence, and prostaglandins of the E series. Psychiatry
Res 1986; 17: 41–47.
99. Ohishi K, Ueno R, Nishino S, Sakai T, Hayaishi O. Increased level of salivary prostaglandinsin patients with major depression. Biol Psychiatry 1988; 23: 326–334.
100. Linthorst AC, Reul JM. Brain neurotransmission during peripheral inﬂammation. Ann NY
Acad Sci 1998; 840: 139–152.
101. Stübner S, Schön T, Padberg F, Teipel SJ, Schwarz MJ, Haslinger A, Buch K, Dukoff R,
Lasser R, Müller N, Sunderland T, Rapoport SI, Möller HJ, Hampel H. Interleukin-6 andthe soluble IL-6 receptor are decreased in cerebrospinal ﬂuid of geriatric patients with major
depression: no alteration of soluble gp130. Neurosci Lett 1999; 259: 145–148.
102. Amsterdam JD, Hernz WJ. Serum antibodies to herpes simplex virus types I and II in depressed patients. Biol Psychiatry 1993; 34: 417–420.
103. Haggerty JJ Jr, Simon JS, Evans DL, Nemeroff CB. Relationship of serum TSH concentration
and antithyroid antibodies to diagnosis and DST response in psychiatric inpatients. Am J
Psychiatry 1987; 144(11): 1491–1493.
104. Roy A, Pickar D, Paul S, Doran A, Chrousos GP, Gold PW. CSF corticotropin-releasing
hormone in depressed patients and normal control subjects. Am J Psychiatry 1987; 144: 641–
645.
105. Salas MA, Evans SW, Levell MJ, Whicher JT. Interleukin-6 and ACTH act synergisticallyto stimulate the release of corticosterone from adrenal gland cells. Clin Exp Immunol 1990;
79: 470–473.
106. LeMay LG, Vander AJ, Kluger MJ. The effects of psychological stress on plasma interleukin6 activity in rats. Physiol Behav 1990; 47: 957–961.
107. Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS. Exposure to physical and psychological stressors elevates plasma interleukin-6: relationship to the activation of hypothalamicpituitary-adrenal axis. Endocrinology 1993; 133: 2523–2530.
108. Miyahara S, Komori T, Fujiwara R, Shizuya K, Yamamoto M, Ohmori M, Okazaki Y. Effects
of repeated stress on expression of interleukin-6 (IL-6) and IL-6 receptor mRNAs in rat
hypothalamus and midbrain. Life Sci 2000; 66: L93–L98.
109. Wang J, Dunn AJ. Mouse interleukin-6 stimulates the HPA axis and increases brain tryptophan and serotonin metabolism. Neurochem Int 1998; 33: 143–154.
110. Wang J, Dunn AJ. The role of interleukin-6 in the activation of the hypothalamo-pituitaryadrenocortical axis and brain indoleamines by endotoxin and interleukin-1 beta. Brain Res
1999; 815: 337–348.
110a. Fernstrom JD, Faller DV. Neutral amino acids in the brain: changes in response to foodingestion. J Neurochem 1977; 30: 1511–1538.
111. Bunney WE, Davis JM. Norepinephrine in depressive reactions. A review. Arch Gen Psychiatry 1965; 13: 483–494.
112. Möller HJ. Are all antidepressants the same? J Clin Psychiatry 2000; 61(Suppl 6): 24–28.
113. Rothermundt M, Arolt V, Peters M, Gutbrodt H, Fenker J, Kersting A, Kirchner H. Inﬂammatory markers in major depression and melancholia. J Affect Dis 2001; 63: 93–102.
114. Müller N, Dobmeier P, Empel M, Riedel M, Schwarz M, Ackenheil M. Soluble IL-6 Receptors in the serum and cerebrospinal ﬂuid of paranoid schizophrenic patients. Eur Psychiatry
1997; 12: 294–299.
114a. Ganguli R, Yang Z, Shurin G, Chengappa R, Brar JS, Gubbi AV, Rabin BS. Serum Interleu-

Immunology

287

kin-6 concentration in schizophrenia: elevation associated with duration of illness. Psychiatry
Res 1994; 51: 1–10.
115. Miller AH, Lackner C. Tricyclic antidepressants and immunity. In: Miller AH, ed. Depressive
Disorders and Immunity. Washington DC: American Psychiatric Press, 1989: 85–103.
116. Devoino LV, Evemina OFM, Ilyutchenok RI. The role of the hypothalamopituitary systemin the mechanism of action of reserpine and 5-hydroxytryptophan on antibody production.
Neuropharmacol 1970; 9: 67–72.
117. Sternberg FM, Wedner HJ, Leung MK. Effect of serotonin (5-HT) and other monoamineson murine macrophages: modulation of interferon-induced phagocytosis. J Immunol 1987;
138: 4360–4365.
118. Bonnet M, Lespinats G, Burtin C. Histamine and serotonin suppression of lymphocyte response to phytohemagglutinin and antigen. Cell Immunol 1984; 83: 280–291.
119. Bengtsson B-O, Zhu J, Thorell LH, Olsson T, Link H, Walinder J. Effects of zimeldine andits metabolites, clomipramine, imipramine and maprotiline in experimental allergic neuritis
in Lewis rats. J Neuroimmunol 1992; 39: 109–122.
120. Zhu J, Bengtsson BO, Mix E, Thorell LH, Olsson T, Link H. Effect of monoamine reuptake
inhibiting antidepressants on major histocompatibility complex expression on macrophages
in normal rats and rats with experimental allergic neuritis (EAN). Immunopharmacology
1994; 27: 225–244.
121. Song C, Leonard, BE. An acute phase protein response in the olfactory bulbectomised rat:
effect of sertraline treatment. Med Sci Res 1994; 22: 313–314.
122. Thomas K. Immunomodulation in mice induced by the antidepressant drug zimeldine. Thesis,
Utrecht, University of Utrecht, 1989.
123. Sluzewska A, Rybakowski JK, Laciak M, Mackiewicz A, Sobieska M, Wiktorowicz K.
Interleukin-6 serum levels in depressed patients before and after treatment with ﬂuoxetine.
Ann NY Acad Sci 1995; 762: 474–476.
123a. Lanquillon S, Krieg JC, Bening-Abu-Schach U, Vedder H. Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 2000; 22:370–379.
124. Sommer N, Löschmann P-A, Northoff GH, Weller M, Steinbrecher A, Steinbach JP, Lichtenfels R, Meyermann R, Riethmüller A, Fontana A, Dichgans J, Martin R. The antidepressantrolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat
Med 1995; 1: 244–248.
125. Raine CS. Multiple sclerosis: TNF revisited, with promise. Nat Med 1995; 1: 211–214.
126. Wachtel H, Schneider HH. Rolipram, a novel antidepressant drug, reverses the hypothermia
and hypokinesia of monoamine-depleted mice by a action beyond postsynaptic monoamine
receptors. Neuropharmacology 1986; 25: 1119–1126.
127. Scott AIF, Perini AF, Shering PA, Whalley LJ. Inpatient major depression: is rolipram aseffective as amitryptylin? Eur J Clin Pharmacol 1991; 40: 127–129.
128. Zorilla EP, Redei E, DeRubeis RJ. Reduced cytokine levels and T-cell functions in healthy
males, relation to individual differences in subclinical anxiety. Brain Behav Immunity 1994;
8: 293–312.
129. Marchesi GF, Contani P, Santone G, DiGuiseppe S, Bartocci C, Montroni M. Psychologicaland immunological relationship during acute academic stress. N Trends Exp Clin Psychiatry
1989; 5: 5–22.
130. Boyce WT, Adams S, Tschann JM, Cohen F, Wara D, Gunnar MR. Adrenocortical andbehavioral predictors of immune responses to starting school. Pediatric Res 1995; 38: 1009–
1017.
131. Gonzales-Quijano MI, Martin M, Milan S, Lopez-Calderon A. Lymphocyte response to mitogens, inﬂuence of life events and personality. Neuropsychobiology 1998; 38: 90–96.
132. Benschop RJ, Jacobs R, Sommer B, Schürmeyer TH, Schmidt RE, Schedlowski M. Propanolol and alprazolam differentially affect immunological changes induced by acute emotional
stress. FASEB J 1996; 10: 517–524.

288

Müller and Schwarz

133.

Maddon KS, Felten DL. Experimental basis for neuroimmune interactions. Physiol Rev 1995;
75: 77–106.
Kugler J, Reintjes F, Tewes V, Schedlowski M. Competition stress in soccer coaches increases salivary. Immunoglobin A and salivary cortisol concentrations. J Sports Med Phys
Fitness 1996; 36: 117–120.
Jemmot JB, Borysenko JZ, Borysenko M, McClelland DC, Chapman R, Meyer D, Benson
H. Academic stress, power motivation and decrease in salivary immunoglobulin A secretion
rate. Lancet 1983; 1400–1402.
Zeier H, Brauchli P, Joller-Jemelka HI. Stress induced enhancement of salivary IgA in air
trafﬁc controllers. Biol Psychology 1996; 42: 413–423.
Matthews KA, Caggiula AR, McAllister CG, Berga SL, Owens JF, Flory JD, Miller AL.
Sympathetic reactivity to acute stress and immune response in women. Psychosom Med
1995; 57: 564–571.
Dantzer R. Cytokine-induced sickness behavior: Where do we stand? Brain Behav Immun
2001; 15: 7–24.
Brambilla F, Maggioni M. Blood levels of cytokines in elderly patients with major depressive
disorder. Acta Psychiatr Scand 1998; 97: 309–313.
Rapaport MH. Circulating lymphocyte phenotypic surface markers in anxiety disorder patients and normal volunteers. Biol Psychiatry 1998; 43: 458–463.
Song C, Leonard, BE. Fundamentals of Psychoneuroimmunology. Chichester: J Wiley &Sons, 2000: 32ff.

134.

135.

136.
137.

138.
139.
140.
141.

13
Brain Imaging in Depression
and Anxiety
PETER S. TALBOT and SANJAY J. MATHEWNew York State Psychiatric Institute
New York, New York, U.S.A.
MARC LARUELLE
Columbia University College of Physicians and Surgeons
New York State Psychiatric Institute
New York, New York, U.S.A.

I.

INTRODUCTION

Neuroimaging research in affective and anxiety disorders has progressed considerably overthe last decade. Researchers have used ﬁndings in related ﬁelds such as neuropathology,
endocrinology, and preclinical animal work to develop high-quality hypothesis-driven
neuroimaging studies. Moreover, emphasis is now being put on the importance of such
issues as increasing the size of studies, separation of heterogeneous groups, research in
drug-free patients and the importance of interpreting functional studies in light of corresponding structural and neurochemical alterations. In the ﬁeld of radiochemistry, new andhighly selective radiotracers have increased the ability to image neurotransmitter functionin the living human brain to the point that alterations of receptor density and synaptic
neurotransmitter release are now routinely measured. In statistics, major advances havetaken place in the voxel-based analysis of images, and increases in computational processing power and memory have increased the practical feasibility of many aspects ofimage manipulation and data analysis, particularly in functional imaging.
Impressive advances have been made in the development of imaging technology,
particularly in improved scanner resolution and sensitivity. For example, brain structure
can now be imaged with a resolution of less than 1 mm. Alterations in anatomically small
regions on functional scans of relatively low resolution can now be identiﬁed with great
accuracy by delineating these regions on high-resolution coregistered structural images.
Moreover, functional neurobiological processes can now be investigated with a high degree of temporal and spatial resolution. A basic understanding of the various commonly
289

290

Talbot et al.

used imaging modalities is advantageous for interpretation of the results of many studies,and a brief overview is given below.
II. IMAGING MODALITIES: AN OVERVIEW
Brain imaging techniques reviewed here are classically divided into structural (shape andsize of brain regions and lesions), functional (ﬂow and metabolism), and molecular domains. In the current state of the art, structural imaging is performed with magnetic resonance imaging (MRI), functional imaging with functional magnetic resonance imaging(fMRI), and molecular imaging with magnetic resonance spectroscopy (MRS) or radionuclide-based techniques, including positron emission tomography (PET) and single photon emission computerized tomography (SPECT).
A.

MRIMRI provides high-resolution images of brain structure and is able to distinguish gray andwhite matter with unparalleled speciﬁcity. It has superior contrast and soft-tissue imaging
capability, and has replaced x-ray CT in most psychiatric neuroscience research applications. Newer contrast agents, such as gadolinium, have improved the ability to differentiate
certain pathological processes, such as tumors, from normal tissue.
B.

fMRI

Functional MRI produces images related to blood volume or blood ﬂow. Under physiological conditions, these measures correlate with regional metabolic activity. Local cerebral
blood ﬂow can be estimated by blood oxygenation level detection (BOLD). Regional brain
metabolic activity results in increased local blood ﬂow and the delivery of more oxygenated blood than is immediately metabolically necessary. This results in a local reductionof deoxyhemoglobin, which can be measured, because deoxyhemoglobin is paramagnetic
whereas oxygenated hemoglobin is not. Functional MRI is being increasingly used tocharacterize the brain regions associated with a wide range of psychiatric symptoms, cognitive functions, and therapeutic interventions. Although the groundwork in this ﬁeld wasmostly done using SPECT and PET, fMRI has advantages over these radionuclide techniques. The temporal and spatial resolutions are superior and no radiation exposure is
involved, permitting multiple measures per subject and the safe imaging of children.
Furthermore, the last 10 years have seen a tremendous development of MR-based
methods for producing images of brain perfusion akin to those produced by PET and
SPECT, and numerous studies have now shown that MRI measurements of regional cerebral blood volume (rCBV) and rCBF are possible (for review, see Ref. 1). However,
perfusion MRI is still in an early stage of its development and further work is necessary
to address numerous quantiﬁcation problems. At present, PET and SPECT remain superior
for the quantitative measurement of rCBF. Despite this, it can be expected that futureadvances in MR technology may reverse this balance and lead to the ability to measure
more accurately rCBF and rCBV without the need for radiation exposure.
C.

MRS

MRS is a brain imaging technique that permits the noninvasive measurement of a numberof psychiatrically relevant endogenous and exogenous brain chemicals in a given volume(voxel) of brain tissue. A standard MRI machine, with some modiﬁcations, is used. Its
technical background and use in psychiatric illness have recently been comprehensively

Brain Imaging

291

reviewed [2]. Most studies in psychiatry have used 1H or 31P MRS technology. The mostcommon is 1H MRS (proton MRS) because of its ability to detect compounds in lower
concentrations within the brain, although MRS can only observe compounds present in
at least micromolar quantities. Commonly measured compounds include those containing
myo-inositol (Ino), N-acetyl-aspartate (NAA), cytosolic choline (Cho), and creatinine(Cr). Ino is a sugar that is involved in second-messenger systems through the phosphatidylinositol cycle. NAA is a cell marker whose concentration correlates with neuronal density[3]. It is considered to be a marker of neuronal ﬁtness or viability. Increases have beeninterpreted to represent improved neuronal function, hypertrophy, or hyperplasia and decreases to represent decreased viability or neuronal loss. Cho is a precursor and metaboliteof membrane phospholipids, second-messenger compounds, and acetylcholine. Abnormalities in the Cho resonance have been linked to abnormalities in myelination, cerebral
oxidative metabolism, and alterations in intraneuronal signaling or in endocrine status. Cr
reﬂects systemic energy use and storage and is generally held to be an internal standard
in ratio analyses of neurometabolic change. It has been shown to be stable within individuals over the course of months. In addition, particular 1H MRS editing techniques permit
measurement of amino acid concentrations, including glutamate, glutamine, and gammaamino butyric acid (GABA) [4,5].
Phosphorus (31P) MRS is also frequently used to measure phosphomonoesters(PMEs) and phosphodiesters (PDEs), including sugars and phospholipid-associated metabolic and catabolic components of cell membranes, as well as energy storage metabolites
such as phosphocreatine (PCr) and nucleotide phosphates. Of further relevance to psychiatry, MRS technology can also measure brain drug concentrations using, for example, 7Li
for lithium medication and 19F to detect ﬂuorine-containing psychotropic drugs [6].
D. Radionuclide Imaging
PET imaging is based on the administration of radioisotopes that emit positrons when
they decay. When positrons encounter electrons, the two particles annihilate each other,releasing high-energy gamma rays that radiate in opposite directions. These are detectedby coincidence counters in the PET camera and the three-dimensional pattern of emissions
is reconstructed and sliced (tomographed) by computer into an image. Typically the halflives of clinically useful radioisotopes are short (e.g., 15O, 2 min; 13N, 10 min; 11C, 20
min; and 18F, 110 min) and require an on-site cyclotron, or (in the case of 18F) rapid
delivery from a cyclotron elsewhere. The radioisotope-containing compounds typicallyused to measure regional brain activity include 11C-glucose and 18F-deoxyglucose (FDG)
for regional glucose metabolism (rCMRglu) and 15O-water (H215O) for rCBF. As in BOLD
fMRI, rCBF is used as a proxy of regional metabolic activity because, under physiologicalconditions, the two measures are correlated.
SPECT is based on compounds (e.g., 123I, 99mTc) that emit a single gamma ray photon
on disintegration. These have longer half-lives than PET isotopes and do not require an onsite cyclotron. Moreover, gamma cameras are widely available in departments of nuclear
medicine and, because of its relative simplicity and lower cost, SPECT is widely used inclinical research for the measurement of rCBF. However, images have poorer spatial resolution than PET and studies are generally limited to two SPECT scans per subject. As
mentioned above, with the advent of fMRI it is foreseeable that the role of PET and
SPECT studies of ﬂow and metabolism in psychiatry research will be greatly reduced in
the future.

292

Talbot et al.

On the other hand, the ability of PET and SPECT to image speciﬁc biomolecules
is unmatched by any other method currently available to clinical investigators. Studies ofreceptors, transporters, enzymes and other processes, such as transmitter release, clearly
constitute the future of radionuclide technology, particularly PET, in psychiatric research.
Studies of synaptic neurotransmitter release are most advanced in the case of dopamine(DA). They are usually performed by stimulating DA release with pharmacological challenge and measuring the reduction in binding of the radioligand that results from competition at the receptor between the radioligand and the increased local levels of the endogenous ligand (i.e., DA). These techniques have already yielded a number of fundamental
observations.
E.

Integration of Structural and Functional Imaging

In recent years the ﬁndings from studies using different imaging modalities have started
to become informed by each other in a number of important ways. For instance, until
recently, PET and SPECT studies comparing patient groups with healthy controls havetended to report regional differences in blood ﬂow or metabolism between groups as representing enhanced or diminished function in these regions. However, as structural MRI
reveals idiopathic volumetric alterations in many brain regions in affective and anxiety
disorders, it has become evident that metabolic changes will need to be corrected fortissue volume. In some instances, this has led to important insights. For example, althoughbaseline CBF and metabolism appear abnormally decreased in subgenual anterior cingulate during major depressive episodes (MDEs), computer simulations that correct PET
data for the partial volume effect of reduced gray matter volume conclude that the “actual”
metabolic activity in the remaining tissue is increased in patients with major depressive
disorder (MDD) relative to controls [7].
This will also apply to studies in, for example, late-onset depression in which cerebrovascular disease is now believed to play an etiological role (see below). Atheroscleroticchanges reduce radiotracer delivery to affected areas and impair the interpretability ofblood ﬂow images by altering the relationship between local perfusion and local metabolic
activity. Moreover, associated tissue atrophy may lead to artifactual reductions in measured rCBF or metabolism due to the same partial volume effects as described above andreduce the apparent binding potential (BP) of neuroreceptor radioligands. Thus, images
from such subjects cannot be interpreted in the same way as images from patients withearly-onset depression or healthy controls. In this regard, MRS and PET techniques thatcan characterize the metabolic activity of ischemic tissue may prove useful. Moreover,in imaging studies of mood disorders, only unmedicated patients are likely to provide
reliable data on underlying pathophysiology, and patients with early-onset MDD must
be separated from those with late-onset MDD or MRI evidence of white matter abnormalities [8].
III. AFFECTIVE DISORDERS
A.

Major Depressive Disorder

1. MRI
Structural imaging studies have revealed a relative dichotomy between neuroanatomical
abnormalities seen in depression of early or midlife onset and depression of late onset(usually deﬁned as onset after ⬃55 years of age).

Brain Imaging

293

Late-Onset Depression. The most widely replicated ﬁnding in the whole of structural imaging of affective disorders is an increased incidence of hyperintensities on T2weighted MRI in the deep and periventricular white matter of patients with late-onset
depression [8–15]. White matter hyperintensities (WMH) are small areas where the signal
intensity is high relative to the surrounding tissue. They are extremely rare in younger,
healthy individuals and are usually associated with aging, hypertension, diabetes, cerebrovascular disorders, and a number of neurological abnormalities. Although their incidence
appears to be modestly increased in early-onset depression [16], the incidence reaches 70
to 90% in late-onset depression. Moreover, in an elderly, nondemented population, theseverity of WMH is positively correlated with both symptoms of depression and a historyof past depression [9,17].
MRI diffusion tensor imaging (DTI) shows that hyperintensities damage the structure of brain tissue [18], and postmortem neuropathological examination of these areas
reveals atherosclerosis and, when larger, infarction [19]. WMH would therefore appear
to reﬂect the MRI correlate of cerebrovascular disease. Hyperintensities in subcorticalgray matter have also been noted in the basal ganglia of patients with late-onset depression[20,21]. Hyperintensities are most common in frontal and striatal areas, and several studies
report that these are the areas in which infarctions are correlated with depression following
ischemic stroke [22,23]. However, the literature in this area is conﬂicting, and a recent
systematic review offered no support for the hypothesis that the risk of depression after
stroke is affected by the location of the brain lesion [24]. Despite this, the great majorityof evidence would suggest that the cerebrovascular disease may play a role in the pathogenesis of late-onset MDD in patients with MRI hyperintensities [8]. This has led Steffens
and Krishnan to propose the new mood disorder subtype of “vascular” depression [14].
Hyperintensities are associated with increased risk of psychotic features, cognitive
impairment, and treatment-related adverse reactions such as delirium, which are also moreprevalent in subjects with known cerebrovascular disease [8]. They are also associatedwith increased risk of suicide attempt [25], poor long-term outcome [26], as well as poor
response to pharmacotherapy [27,28] and ECT [29]. Moreover, a recent study suggests that
cerebrovascular disease (on the evidence of deep WMH) may also underlie the depressive
symptoms (especially symptoms of impaired motivation, concentration, and decision making) often found in older individuals who are not clinically depressed, particularly in thosewith the apolipoprotein E-4 (APOE-4) allele [30].
However, in addition to high-intensity lesions, it is likely that atrophy represents acomplementary pathway in late-life depression [17]. Such patients have greater cerebral
sulcal and temporal sulcal atrophy, and larger sylvian ﬁssures, lateral ventricles, thirdventricles, and temporal horns [13]. Volumetric reductions are also found in cerebellum[31], frontal lobes [17,32], orbitofrontal cortex [33], basal ganglia [34], amygdala [35],and hippocampus [35,36]. Hippocampal size is signiﬁcantly negatively correlated withtotal lifetime duration of depression, but not age, suggesting that repeated stress during
recurrent depressive episodes may result in cumulative hippocampal injury as reﬂectedin volume loss [36].
Early-Onset Depression. There is obvious overlap between the imaging ﬁndingin earlier onset (i.e., before ⬃55 years of age) and late-life depression. For example, evendepressed adolescents are found to have smaller frontal lobes and enlarged lateral ventricles [37,38]. Moreover, many imaging studies of depression have included both younger
and elderly patients. However, structural imaging ﬁndings are less consistent in younger

294

Talbot et al.

patients with MDD, and MDD in this population is likely to be heterogeneous with respect
to etiology and pathophysiology. Because of this, a number of studies have enhanced
their likelihood of ﬁnding neurobiological abnormalities by deliberately including only
unmedicated subjects who also have a history of mood disorder in a ﬁrst-degree relative(see Refs. 7, 8). Early-onset, familial mood disorders appear to be associated with a distinct
pattern of gray matter reductions in limbic or paralimbic areas of the orbital and medical
prefrontal cortex and the ventral temporal lobe [7,8,39,40]. At post-mortem examination,gray matter reduction in “subgenual” anterior cingulate (i.e., ventral to the genu of the
corpus callosum) in familial affective disorder has been found to be associated with areduction of glia, without an equivalent loss of neurons [41,42]. These structural ﬁndings
compliment an extensive, and complicated, body of literature derived from functional
imaging studies, mainly PET, in these regions. These will be addressed below.
Elevated levels of glucocorticoids in depression have been hypothesized to be associated with damage to the hippocampus, a brain area involved in learning and memory. In
this model, chronic repeated episodes of depression may lead to progressive hippocampal
atrophy over time, possibly increasing the risk for subsequent depressive relapse. The
imaging literature would currently seem to support an association between depression andhippocampal size dependent on the cumulative duration and severity of MDD. Three recent studies report normal hippocampal volume in younger populations not characterized
by severe, recurrent MDD [43–45]. However, reduced hippocampal volume has been
replicated in euthymic patients with a history of severe and repeated depressions[36,46,47], and in those with severe, treatment-resistant depression [45,48]. This atrophy
is correlated with longer cumulative duration of depression [46,49], does not appear toresolve over time [47], and a review of the subject tentatively concludes that it appears
to be irreversible [50].
Studies of neurodegenerative diseases, striatal lesions, and functional imaging suggest that the striatum may be implicated in depression. However, the majority of recent
MRI studies have failed to ﬁnd reduced striatal volume in MDD. Earlier MRI studies
found reduced caudate [51] and putamen [52] volumes, and this has seen more recent
support [53]. However, four studies have failed to ﬁnd an association [54–57]. This is incontrast to neurochemical and functional imaging studies that have found evidence forstriatal abnormalities.
2. MRS
Three early 1H and 31P MRS studies measured spectra before and after ECT in depressed
patients. However, the studies were mainly related to exploring the pathophysiology oflactate production and seizures and the results were equivocal [58–60]. Subsequent 31P
MRS studies have reported increased PDE levels in the basal ganglia and frontal lobes[61], associated with decreased levels of ATP [62], suggesting alterations of regional tissueenergetics [2].
More recently, 1H MRS has been used to investigate whether there is evidence ofhippocampal damage following ECT on the basis that neuronal damage may show up asa reduction of NAA signal [63]. No changes were detected after ECT, suggesting that
ECT is unlikely to induce hippocampal atrophy or cell death. The study also measured
Cho levels in the right and left hippocampus of the depressed patients before ECT andcompared them with a group of healthy controls and remitted depressed patients treatedwith amitriptyline. Cho levels were found to be lower bilaterally in the depressed patients

Brain Imaging

295

and increased following ECT, which corresponded with clinical response. The authors
suggest that this represents increased membrane turnover as a result of ECT treatment.
These ﬁndings are concordant with rat experiments in which repeated seizures of the
hippocampal-parahippocampal circuits can cause mossy ﬁber sprouting without cell death[64]. The authors speculate that the Cho signal increase after ECT treatment might similarly reﬂect mossy ﬁber sprouting in hippocampal subﬁelds.
These ﬁndings raise a number of issues. First, 1H MRS measurements (Cho in particular) appear to be mood-state dependent. Depressive symptoms were associated with lowered Cho in hippocampus, but the diagnosis of depression was not sufﬁcient to explain
this ﬁnding, in that remitted depressive patients successfully treated with medication displayed Cho values similar to controls. Second, this study suggests that the Cho resonancemight prove to be a more reliable marker of the severity and past number of episodes ofdepression, and a more sensitive index of the processes underlying remission and recurrence than the NAA signal. However, another study using 1H MRS reports increased Cholevels in the medial temporal lobe structures of patients with treatment-resistant MDD[48], underlining the point that the association of clinical improvement with increasing
Cho remains tentative at present and requires replication. Moreover, future studies will
also need to exclude the confounding effects of current or very recent antidepressant medication.
In other brain regions, 1H MRS has been used to investigate frontal lobes, anterior
cingulate cortex, the orbitofrontal cortex, and the basal ganglia in MDD, and most results
still require replication. In a preliminary study of the frontal lobes, mean Ino/Cr ratios
were lower in patients with MDD than in controls, but the difference was not statisticallysigniﬁcant [65]. Moreover, the depressed and control groups were not age- and sexmatched, and 15 of the 22 patients were taking a variety of antidepressant medications.
However, a subgroup of 10 patients was age- and sex-matched to controls and the Ino/
Cr was then signiﬁcantly lower in the patients.
In the anterior cingulate cortex, no signiﬁcant alterations in NAA, Cr, or Cho were
found in MDD [66], and the authors concluded that the study supported an absence ofneurodegenerative or membrane metabolic changes. However, reduced glutamate and glutamine were found, suggesting a possible role for altered glutamatergic neurotransmission
within the anterior cingulate in the pathogenesis of MDD. In the orbitofrontal cortex ofadolescents with MDD, increased Cho was found when compared to controls in the absence of structural differences [67]. In the basal ganglia, the Cho signal has been foundto be altered in depressed patients [68–70] but the direction of the changes is controversial.
However “true” response (as opposed to placebo response) to ﬂuoxetine is reported to be
associated with an increase in Cho [71].
A number of authors suggest that Cho has a key role in the integration of affective
processing within prefrontal circuitry. One author has suggested that higher Cho may
reﬂect greater myelin turnover [72], as the Cho peak includes both precursors and breakdown products of myelin. The issue of whether the Cho signal is a trait or state marker
of depression is as yet unresolved, and whether increase over time in the Cho signal incortical regions in healthy subjects is a harbinger of the onset of a depressive episode. In
interpreting the cortical 1H MRS data, regional and tissue differences of brain metabolites
must be considered [73]. The variability of both NAA and Cho has to be shown to be
dependent on region of interest, tissue differences (gray versus white matter), subtype ofaffective illness, age, and gender. Thus, in an attempt to reconcile the ﬁnding of lowered

296

Talbot et al.

Cho in hippocampus in severely depressed subjects about to embark on ECT [63] withthe ﬁndings of elevated Cho/Cr and Cho/NAA in orbitofrontal regions [67], the tissue
composition of voxels examined must be taken into account.
Several lines of evidence suggest that MDD is associated with dysfunction of
gamma-amino butyric acid (GABA) systems. Using 1H MRS, GABA levels were foundto be highly signiﬁcantly (52%) reduced in the occipital cortex of medication-free patientswith MDD when compared to healthy control subjects with no history of mental illness[74].
Overall, the current limited evidence suggests altered membrane dynamics and abnormal cellular energetics in MDD. However, more studies in tightly deﬁned, drug-freepatient samples are required before this can be ﬁrmly concluded [2].
3. Regional Blood Flow and Metabolism
The literature on functional anatomical correlates of MDD is extensive and complex. Numerous alterations of rCBF and rCMRglu have been reported in PET and SPECT studies
in regions known to be implicated in the generation or modulation of affective states.
However, many studies are difﬁcult to interpret as they have mixed patients from different
age groups, studied small numbers of patients or failed to adequately account for theconfounding effects of state-dependent differences, diagnostic heterogeneity, or current
medication. Because of this, a simple catalogue of the ﬁndings from various studies canbe unrewarding. Moreover, the interpretation of these ﬁndings requires an understandingof the normal function in these regions in various mood states as well as possible neuropathological and volumetric alterations in these regions between healthy subjects and patients with affective disorders. For many brain regions, these data are not yet known inhumans and must be inferred from the results of animal studies, or studies in humans with
regional brain lesions. Despite this, the number of high-quality functional imaging studies
has now grown to the point where their ﬁndings can be integrated with data from structural,
neuroreceptor, endocrine, lesion, and electrophysiological studies to develop hypotheses
regarding the neural substrates of MDD. A number of such integrative and comprehensive
reviews of this literature (see Refs. 7, 8, 75–78) have concluded that anatomical circuits
involving orbital and medial prefrontal cortex, striatum, pallidum, medial thalamus, amygdala and hippocampus are implicated in the pathophysiology of MDD. These ﬁndings are
summarized below, and the reader is referred to these reviews for details of individual
studies.
The ﬁnding with the most consistent replication is of decreased rCBF and metabolism in the anterior cingulate cortex ventral to the genu of the corpus callosum (subgenualAC) in unipolar and bipolar depressed patients. This would appear to be at least partly
accounted for by a corresponding left-lateralized volumetric reduction in this region and,
when correction is made for this, the “actual” metabolism in the remaining tissue is foundto be normal or increased during depression. This pattern also appears true for healthy,
nondepressed subjects, in whom ﬂow increases in the subgenual AC in experimentallyinduced sadness. It is also compatible with PET studies showing that effective antidepressant medication results in decreased metabolic activity in this region in MDD. Data forthe rest of the AC are less consistent. In the pregenual AC, most studies ﬁnd increasedrCBF and rCMRglu in a depressive episode, but relationship with treatment response
differs across studies. In the dorsal AC, rCBF is decreased in depression and its normal
cognitive activation is attenuated during a depressive relapse triggered by acute tryptophan
depletion.

Brain Imaging

297

In orbitofrontal cortex, ventrolateral prefrontal cortex and anterior insula, rCBF andmetabolism are increased during depression and decrease with remission. However, thisincrease is mainly seen in less severely ill and treatment-responsive patients. More severe
depression tends to be associated with normal or reduced activity in these regions. As
increased activity in the orbital cortex during a depressive episode may represent an endogenous attempt to attenuate the abnormal mood, the lack of this increase in more severe
depression may indicate that the orbital cortex is being prevented from exercising thiseffect, possibly by pathologically increased activity in interacting regions such as theamygdala or by abnormalities in the orbital cortex itself.
There is evidence to support both possibilities. Neuropathological abnormalities
have been found in the posterior orbital cortex, including fewer glia and smaller neurons.
In the amygdala, rCBF and metabolism are increased during depression in familial puredepressive disorder and bipolar disorder type II. These increases are positively correlatedwith the severity of depression and decrease to normal levels with successful antidepressant treatment. However, euthymic, remitted patients who are not on medication also show
increased activity in the left amygdala and this may confer a susceptibility of depressive
relapse. Electrophysiological, endocrine, and animal studies suggest that many of the behavioral, endocrine, and mood changes associated with depression could be related topathologically increased amygdalar activity through its various reciprocal connections
with other brain regions.
CBF and metabolism are also abnormally raised in the left medial thalamus, anddecreased in the caudate during depression. Reductions in caudate volume may at least
partially explain this reduction. However, following acute tryptophan depletion, those patients who experienced a depressive relapse had lower CBF in the caudate, suggestingthat alterations of caudate function may be involved in depression.
Conversely, reduced activity during depression found in dorsolateral prefrontal cortex—an area related to executive rather than affective control—may represent the relative
suppression of otherwise normal, nonessential, competing modalities.
4. Neuroreceptor Studies
Abnormalities in several neurotransmitter systems may be relevant to the pathophysiology
of depression. The serotonin [5-hydroxytryptamine (5HT)] system has been the most extensively studied, in part because of the antidepressant effect of medications that inhibit
the synaptic reuptake of serotonin, as well as a wealth of postmortem, preclinical, andclinical data suggesting that reduced serotonergic function may be implicated in depression. Theories involving subpopulations of 5HT receptors are most advanced for 5HT2A
and 5HT1A receptors, and the availability of suitable PET radioligands has allowed the invivo investigation of their putative abnormalities in depression.
Serotonin Transmission. The earliest PET study of 5HT2 receptors and depressive
symptoms used [11C]-N-methyl-spiperone to investigate binding in patients with poststroke
depression, and reported increased binding [79]. Yet, it is not clear how this ﬁnding canbe generalized to more common clinical presentations of depression. Another early study
using 2-[123I]-ketanserin and SPECT reported increased and asymmetrical cortical uptakeof the tracer in depressed patients when compared to controls [80]. However, 2-[123I]ketanserin has signiﬁcant limitations as a SPECT radiotracer because of high nonspeciﬁc
binding.
Since then, ﬁve PET studies have used newer 5HT2 PET radiotracers, [18F]-setoper-298

Talbot et al.

one [81], and [18F]-altanserin [82], to investigate cortical 5HT2A receptor binding in drugfree depressed patients. Biver et al. [83], using [18F]-altanserin, reported reduced tracer
uptake in a region of the right hemisphere including the orbitofrontal cortex and the anterior insular cortex. However, one limitation of [18F]-altanserin is that it produces radioactive lipophilic metabolites that probably cross the blood-brain barrier and contribute activity in the nondisplaceable compartment [84]. Two studies investigated midlife depression
using [18F]-setoperone and concluded that there is no major change or asymmetry in 5HT2A
receptors [85,86]. In both studies, the great majority of patients had been free of antidepressant medication for over 6 months. A fourth study supported these negative ﬁndings andreported no signiﬁcant alteration in 5HT2A receptor binding in an untreated group of patients with late-life depression without cognitive impairment [87]. Finally, the largest of
the ﬁve studies [88] found a widespread reduction in 5HT2A receptor BP and concluded
that brain 5HT2A receptors are decreased in patients with major depression. However, 40%of the patients in this study had been drug-free for only 2 weeks before scanning. Thisfactor may be signiﬁcant as the majority of antidepressants downregulate 5HT2A receptors[86,89,90].
In summary, three studies reported no signiﬁcant alteration in 5HT2A receptor binding in major depression, and two studies found reduced 5HT2A receptors. Differences between studies might stem from methodological issues, illness heterogeneity, and medication effects. None of the recent studies conﬁrmed the earlier ﬁndings of increased binding[79,80]. Similarly, the increase in 5HT2A receptors found in some, but not all, post-mortem
studies of depressed suicide victims (for review, see Ref. 91) has not been conﬁrmed byin vivo investigations. Therefore, there is currently no strong evidence supporting the
hypothesis that depression per se is associated with marked alterations of 5HT2A receptor
density.
Two lines of evidence have implicated the 5HT1A receptors in depression. The ﬁrst
is the ﬁnding that depressed patients have blunted neuroendocrine responses to 5HT1A
receptor agonists in vivo, and the second is the dense distribution of these receptors in the
hippocampus. Recent theories have implicated interactions between stress, corticosteroids,
growth factors, and hippocampal 5HT1A receptors in depression [92–94]. Postmortem studies of 5HT1A receptors in suicide and depression have been inconsistent, showing increased, decreased, and unchanged 5HT1A-receptor levels in various regions [95–99].
These discrepancies may reﬂect the possible confounding effects of suicidality, antemortem medications, differences between radioligands, and differences in the regulation of
5HT1A receptors by corticosteroids and local levels of 5HT in different brain regions. The
results of in vivo PET imaging of 5HT1A receptors in depressed patients are therefore ofinterest.
Two PET studies have investigated 5HT1A receptors in unmedicated depressed subjects using [carbonyl-11C]WAY-100635 and both have reported reductions in receptor
binding. The ﬁrst study [100] found modest (approximately 10%), but signiﬁcant, widespread reductions in BP in cortical regions including medial temporal cortex (hippocampus
and amygdala) in a group of 15 men with major depression. Subsequently, Drevets et al.
[92] reported reductions in the medial temporal cortex (27%) and raphe (41%) in a study
that limited its primary hypothesis to these two regions. This group of subjects included
both unipolar and bipolar depressed patients. All subjects had ﬁrst-degree relatives withmood disorders. Interestingly, the differences found were largely accounted for by the
subjects with bipolar disorder and those with uniplar depression who had relatives withbipolar disorder.

Brain Imaging

299

Additional studies are warranted to conﬁrm these ﬁndings of generalized decreasein 5HT1A receptors in depression. Since a major depressive episode is associated withhyperactivity of the HPA axis, and increased cortisol levels might be associated with
5HT1A-receptor downregulation [101–104], these ﬁndings might be secondary to the neuroendocrine dysregulation associated with depression.
Reductions in SERT levels in depressed patients have been reported in numerous
post-mortem studies (for review, see Ref. 91). The ﬁrst ligand used to image SERT in
vivo was the SPECT radiotracer [123I]β-CIT. β-CIT binds to both DAT and SERT withcomparable afﬁnity (Ki 1.4 and 2.4 nM for DAT and SERT, respectively) [105,106]. The
lack of DAT versus SERT selectivity is not a problem for measuring DAT in the striatum,as the density of SERT in striatum is much lower than that of DAT [106]. However, inthe midbrain, this proportion is reversed, and the β-CIT midbrain uptake mostly corresponds to SERT binding [107,108]. Studies on nonhuman primates and humans haveshown that, in the midbrain, [123I]β-CIT is selectively displaced by administration of SSRIs(but not by DAT selective drugs) [107,109]. [123I]β-CIT has been extensively used inclinical studies both for striatal DAT [110–116] and midbrain SERT evaluation [116–119].
In depression, ﬁndings from two SPECT studies using [123I]β-CIT were in agreementwith postmortem results. A reduction in SERT binding was found in the midbrain inpatients with unipolar depression [120], and in thalamus-hypothalamus in depressed patients with seasonal affective disorder [121].
A selective SERT radiotracer is required to investigate SERT density in other regions of the brain. The ﬁrst PET radiotracer available to measure SERT in humans was[11C]McN 5652 [122]. The usefulness of [11C]McN 5652 as a PET tracer for SERT was
validated in primates [123] and humans [124–126]. However, [11C]McN 5652 has limitations, which include high nonspeciﬁc binding, poor signal-to-noise ratio, nonmeasurable
free fraction in the plasma, and slow clearance from the brain [127]. Therefore, studies
using [11C]McN 5652 require long scanning time (up to 120 min), and this ligand canprovide reliable quantiﬁcation of SERT only in regions of relatively high SERT density(midbrain, thalamus, and striatum). More recently, compounds from the phenylamine
class have emerged as promising targets for both SPECT and PET tracer development.
[123I]ADAM [128] is a highly selective SPECT imaging agent for SERT. Its 11C-labeledcounterpart, [11C]ADAM, was recently reported [129]. Another compound in this series,[11C]DASB, was recently introduced and has been evaluated in rats [130] and humans[131]. Thus, it is anticipated that, in the near future, several studies will be performed toevaluate SERT density with PET in patients with major depression. If the results obtainedwith [123I]β-CIT are conﬁrmed, the reduction in SERT density might provide a usefulbiomarker for this disorder.
Dopamine Transmission. The critical role of DA in brain reward systems, the reports of low cerebrospinal ﬂuid homovanillic acid levels in depressed patients, the association of major depression with Parkinson’s disease, and the enhancement of dopaminergic
activity by several antidepressant treatments suggest that a deﬁciency of dopaminergic
function might be associated with major depression (for review, see Refs. 132–135). Fivestudies compared striatal D2 receptor availability with [123I]IBZM in patients with major
depression and control subjects. Two of the ﬁve studies reported higher [123I]IBZM speciﬁc
binding in the striatum of depressed subjects compared to controls [136,137], whereas
three studies reported no change [138–140]. Amphetamine-induced DA release was also

300

Talbot et al.

assessed in patients with major depression and found to be unchanged [140]. Two studies
examined [123I]β-CIT striatal binding in patients with major depression and yielded conﬂicting results: one study reported normal levels of striatal DAT in patients with major
depression [120], while the other one reported increased DAT levels [141]. Finally,[18F]DOPA uptake in the left caudate was observed to be signiﬁcantly lower in depressed
patients with psychomotor retardation than in depressed patients with high impulsivity
and in comparison subjects [142]. Thus, major depression per se does not appear to beconsistently associated with alteration of the dopaminergic parameters at the level of thewhole striatum. However, DA might play a role in the neurobiology underlying someclinical features of depression, such as psychomotor retardation.
B.

Bipolar Disorder

Bipolar disorder (BPD) has been extensively investigated by imaging, particularly by
structural MRI and MRS, and this literature has recently been reviewed by a number ofauthors [143,144].
1. MRIThe most consistent ﬁnding in MRI studies is a higher than expected incidence of whitematter hyperintensities (WMH), particularly in periventricular regions, and there are several comprehensive reviews and meta-analyses of these structural studies in BPD [15,145–
147]. The nature of WMH is discussed in the section of MRI ﬁndings in late-life MDD.
In BPD, they appear to be present early in the course of the illness [148,149] and arefound more frequently in patients of all ages, even children and adolescents [150,151].
Their exact etiology and relevance in BPD is currently uncertain, most patients do nothave them, and they do not appear to be associated with cognitive deﬁcits [152]. However,some (but not all) studies have reported that they are associated with a worse clinicalcourse and outcome [15,146,153]. Moreover, a recent study has reported that birth season,
illness outcome, and deep subcortical white matter lesions appear to be closely linked,
raising the hypothesis that these lesions may be a marker of a toxic or infective insult inutero [154]. There is no clear association between WMHs and medications, such as lithium, which can alter lipid metabolism and lead to MR signal changes [145,155].
A number of studies have reported increased ventricular volume in BPD, particularly
in lateral ventricles [156] or temporal horn [157]. One study found that the degree ofenlargement was indistinguishable from that in schizophrenia [157]. However, most ﬁnd
no change [15,145], and there does not appear to be a consistent decrease in volume of
temporal lobes [156] or gray matter in the brain regions surrounding the lateral and thirdventricles [158].
Studies in most other regions have been inconsistent or require replication. Prefrontal cortical volumes were found to be smaller, and this reduction was correlated withattentional dysfunction in a group of patients hospitalized for a manic episode [159]. Hippocampal volume has been found to be both smaller [160,161] and normal [156,162]. The
amygdala has been reported to be both smaller [163] and larger [162], and the thalamus
has been found to be smaller [164]. Perhaps the most consistent volumetric ﬁnding isdecreased cerebellar size, particularly in older patients and those who have had multiple
affective episodes [15,165]. However, reduced cerebellar size is also found in other psychotic disorders including schizophrenia, and other factors may also contribute to alteredcerebellar size, such as alcohol and lithium medication.

Brain Imaging

301

Studies have also found that the volume of the subgenual anterior cingulate is decreased in patients with familial affective disorder, including MDD and BPD [40,41,166].
Signiﬁcantly decreased volume was not found in patients without a family history of affective disorder, nor in schizophrenics [40]. This region has been implicated in the controlof affective state. This ﬁnding is consistent with abnormalities found in MRS [167,168],functional imaging [166], and postmortem studies [41] of the anterior cingulate region in
BPD.
Several other recent studies are of interest, although they will require replication.
Brambilla et al. report ﬁndings consistent with an exaggerated age-related gray matter
decline in bipolar patients [169], and Sassi et al. ﬁnd smaller pituitary volumes in BPD[170]. The authors suggest that this latter ﬁnding may reﬂect a dysfunctional HPA axis.
2. MRSA recent meta-analysis of the 31P MRS literature [171] concluded that phosphomonoester(PME) values are lower in euthymic bipolar patients than in healthy controls, and thatbipolar patients have signiﬁcantly higher PME values when depressed compared to wheneuthymic. The PME resonance by 31P MRS is often taken to be a measure of precursors
for membrane lipids, and this would support the idea of abnormalities of membrane phospholipid metabolism in BPD, which may reﬂect a dysregulation in brain-signal transduction systems.
Studies using 1H MRS report various patterns of altered chemicals in the basal ganglia [172–175], thalamus [176], frontal lobes [177], dorsolateral prefrontal cortex(DLPFC) [178], and anterior cingulate [167,168]. Increased thalamic NAA was interpreted
possibly to represent neuronal hypertrophy or hyperplasia, reduced glial cell density, or
abnormal synaptic and dendritic pruning. Increased thalamic creatine may represent altered cellular energy metabolism [176]. Increased choline in the anterior cingulate wasinterpreted as consistent with impaired intraneuronal signaling mechanisms [167].
Moreover, acute lithium treatment is associated with a signiﬁcant reduction of myoinositol levels, and this action may underlie (or perhaps only trigger) its therapeutic effect[168,179]. Decreased NAA in the DLPFC may represent decreased neuronal density orneuronal dysfunction. Interestingly, lithium therapy recently has also been shown to increase brain NAA levels [180]. As NAA is considered to be a marker of neuronal viability
or function, the authors suggest that some of lithium’s long-term beneﬁcial effects may
be mediated by neurotrophic or neuroprotective processes. This hypothesis is supportedby the ﬁnding that chronic lithium signiﬁcantly increases total gray matter volume [181].
Also of interest is the recent ﬁnding that in a drug-free group of children with BPD, allsubjects had elevated levels of glutamate/glutamine in both frontal lobes and basal ganglia
relative to a control group [182]. This is in line with increasing evidence for an association
between alterations of brain glutamatergic neurotransmission and the pathophysiology ofaffective disorders. It may also be consistent with a recent 1H MRS study that reports
signiﬁcantly higher CSF glutamine concentrations in depressed patients [183]. The authors
suggest that this may reﬂect an abnormality of the brain glial-neuronal glutamine/glutamate cycle associated with NMDA receptor systems in patients with depression.
3. fMRI
In line with the structural data related to the cerebellum (above), and current theories that
support a role for the cerebellum in both cognitive and affective processes, Loeber et al.
used dynamic susceptibility contrast MRI (DSC MRI) to measure cerebellar rCBV in three

302

Talbot et al.

study groups: schizophrenic patients, bipolar patients, and psychiatrically healthy controls[184]. In this technique, which uses MRI technology coupled with a contrast agent, blood
volume is taken as a measure of the amount of active tissue in a region [1]. Bipolar patientswere found to have mean values that were lower than controls and schizophrenic patients
had mean values that were higher than controls. This difference was most signiﬁcant in thetonsillar region and, importantly, this ﬁnding did not appear to be because of differences intissue volume.
In another study, adults with BPD showed a reduction in DLPFC activation and anincrease in amygdalar activation in response to viewing a fearful facial affect. No changes
were found in these regions in a group of healthy controls. In addition, bipolar patients
had an impaired ability to correctly identify fearful facial affect but not happy facial affect.
The authors concluded that, in some patients with BPD, there may be a reduction of frontal
cortical function that may be associated with affective, as well as attentional, processing
deﬁcits [185].
4. Blood Flow and Glucose Metabolism Studies
Most rCBF and CMRglu studies including bipolar depressed patients have also included
subjects with unipolar depression. As mentioned in the section on MDD above, there isstrong evidence for altered rCBF and CMRglu in patients with MDD. At present, resultsof studies comparing bipolar and unipolar patients show no clear consensus and are relatively few in number. Moreover, confounding effects of methodological differences, illness heterogeneity, state-trait differences, and treatment effects remain to be fully elucidated. During a depressive episode, unipolar depressed patients had relatively increasedrCBF in the left frontal lobes, but no differences were found between controls and bipolar
depressives [186]. Conversely, signiﬁcant decreases in rCBF have been reported in prefrontal cortices, limbic system, and paralimbic areas in both depression groups [187].
Another study has reported increased metabolism in basal ganglia and thalamus during
bipolar depression [188].
In mania, there are reports of increased CMRglu in the left amygdala [189], increased rCBF in superior anterior cingulate [190], increased rCBF in subgenual prefrontal
cortex [166], and decreased rCBF in the orbitofrontal cortex during rest along with impaired activation in rostral and orbital prefrontal cortex during word generation [191]. A
recent study has also reported posterior hypermetabolism in a group of rapid cycling,treatment-resistant patients [192].
5. Radioligand Studies
In comparison with major depressive disorder, only limited radioligand PET studies havebeen reported in patients with bipolar disorders. As discussed above, it may be signiﬁcantthat the ﬁndings of reduced 5HT1A receptor binding in the medial temporal cortex andraphe of depressed patients [92] were largely accounted for by the subjects with bipolar
disorder and those with unipolar depression who had relatives with bipolar disorder.
Because of the relationship between mania and psychosis, a number of PET studies
have investigated the DA system in bipolar disorders. D1 receptor binding in the frontal
cortex was reported to be decreased in a study of 10 symptomatically heterogeneous, drugfree bipolar patients [193]. Increases in D2-like (i.e., D2, D3, and D4) receptor density inthe striatum were found in seven psychotic patients with bipolar disorder when comparedto 7 nonpsychotic patients with bipolar disorder and 24 control subjects. The authors
concluded that an increase in D2-like receptors is associated with the state of psychosis

Brain Imaging

303

rather than with a diagnosis of bipolar disorder [194]. As part of the same studies, Gjedde
and Wong also reported ﬁndings consistent with an elevated concentration of synaptic
DA in bipolar patients with psychosis, but not in nonpsychotic bipolar patients [195]. On
the other hand, amphetamine-induced DA release was reported to be normal in euthymic
patients with bipolar disorders [196].
In conclusion, few investigations have been reported using PET molecular imaging
techniques in patients with bipolar disorders, and the ﬁndings reported so far might berelated to clinical states (depression, mania with psychosis) rather than to the bipolar
condition per se.

IV. ANXIETY DISORDERS
A. Imaging Studies of Anxiety in Healthy Human Subjects
A number of studies have investigated putative neurobiological differences between
healthy subjects with differing levels of trait anxiety. A signiﬁcant negative correlation
was found betwen trait anxiety and cortical 5HT1A receptor binding [197]. The authors
report that this is consistent both with animal models that have shown higher anxiety inmice lacking 5HT1A receptors and with clinical trials demonstrating anxiolytic properties ofpartial 5HT1A agonists [198]. MRS studies have shown a high positive correlation between
anxiety and chemical concentrations, particularly NAA levels, in orbitofrontal cortex[199,200].
Functional studies using H215O PET have also investigated rCBF changes associatedwith induced anxiety in healthy volunteers. However, there is no current uniformity of
protocol and methods used to provoke anxiety have included intravenous cholecystokinin[201,202], anticipation of electric shock [203,204] and memory induction [205,206].
While there is considerable variability in the ﬁndings, a number of paralimbic-corticalregions are consistently identiﬁed, including medial prefrontal cortex, anterior cingulate
cortex, orbitofrontal cortex, anterior temporal cortex, parahippocampal gyrus, and theclaustrum-insular-amygdala region. On the basis of these regions it has been suggested thatsadness and anxiety are represented by segregated, but partially overlapping, corticolimbic
pathways [206,207]. A major role has been proposed for selective dorsal cortical deactivations during sadness, and ventral cortical deactivations in anxiety [206].
This partial overlap of the pathways may have relevance to the clinical observationof high comorbidity of sadness and anxiety symptoms in depressive disorder and someanxiety disorders. Neuroimaging studies of patients with anxiety disorders will therefore
be important to determine the relevance of the normal volunteer studies to the pathophysiology of clinical conditions. Initial studies suggest that thalamic and medial prefrontal
regions may participate in aspects of normal emotion unrelated to its type, and that differing clinical anxiety disorders may share underlying neural mechanisms involving anterior cingulate, inferior and orbital prefrontal cortex, insular cortex, and midbrain [208,209].
B. Generalized Anxiety Disorder
In comparison with other anxiety disorders, relatively few imaging studies have beenreported in generalized anxiety disorder (GAD). A preliminary MRI study in child andadolescent subjects with GAD found that right and total amygdala volumes were signiﬁcantly larger. Other measures did not differ, including intracranial, cerebral gray and white

304

Talbot et al.

matter, temporal lobe, hippocampal, and basal ganglia volumes and measures of the midsagittal area of the corpus callosum [210].
One PET study reported lower absolute metabolic rates in basal ganglia and whitematter in patients with GAD [211]. Relative metabolism was increased in the occipital
lobe, right posterior temporal lobe, and the right precentral gyrus. Benzodiazepine (BZD)
therapy resulted in decreased absolute metabolic rates for cortical surface, limbic system,
and basal ganglia but was not associated with normalization of patterns of glucose metabolism.
Because of the anxiolytic and anxiogenic effects of agonists and inverse agonists
at the central BZD receptor on the GABAA complex, abnormalities of BZD receptor function have been hypothesized in anxiety disorders. An initial SPECT study of GAD in
drug-free female patients using [123I]NNC13-8241 reported reduced binding in the left
temporal lobe, and decreased heterogeneity of distribution [212]. However, this was not
conﬁrmed in a PET study using [ 11C]-ﬂumazenil, which found no differences in drug-freepatients [213].
C.

Panic Disorder

By comparison, patients with panic disorder have been more extensively studied. Structural MRI studies have found an increased incidence of focal atrophy or abnormal signal
intensity in temporal lobes [214,215], particularly in the septo-hippocampal region [216].
A recent volumetric study found smaller temporal lobes bilaterally despite normal-sizedhippocampi [217].
Early PET studies showed abnormal hemispheric asymmetries of parahippocampal
rCBF, blood volume, oxygen metabolism, and abnormally high whole-brain metabolism inlactate-sensitive patients with panic disorder, but not in those who were lactate-insensitive[218,219]. Since then, a fairly consistent pattern has been reported in unmedicated patientsof asymmetrically reduced rCBF or rCMRglu in hippocampal, parahippocampal and inferior frontal regions [220–223] that do not normalize with imipramine treatment [221].
Abnormalities in these regions in panic disorder are broadly supported by the resultsof receptor imaging studies of the BZD receptor. Three studies using [123I]iomazenil
SPECT have reported that binding is decreased in the lateral temporal region [224], decreased in the right prefrontal cortex [225], and increased in the right orbitofrontal cortex
in BZD-naı̈ve patients [226]. However, there were differences in methodology and control
groups in these studies. A fourth [ 123I]iomazenil SPECT, using a quantitative measurementof regional binding potential (BP), reported decreased binding in the left hippocampus
and precuneus in panic disorder patients relative to controls. Interestingly, patients who
had a panic attack at the time of the scan had a relative decrease in binding in the prefrontal
cortex, suggesting that BZD receptor function in the prefrontal cortex may be involvedin changes in state-related panic [227]. In support of these SPECT studies, a fully quantitative PET study using [11C]ﬂumazenil in medication-free patients found a global reduction
in benzodiazepine receptor binding throughout the brain in patients with panic disordercompared with controls. The largest regional decreases were in the right orbitofrontal
cortex and right insula [228].
These ﬁndings have been complimented by the results of 1H MRS studies that show
reduced total occipital cortex GABA concentration [229], as well as an exaggerated risein brain lactate levels in response to lactate infusion [230–232] and hyperventilation [233]in patients compared to controls.

Brain Imaging

305

D. Phobias
1. Speciﬁc Phobias
Functional imaging studies in phobic anxiety have investigated alterations in rCBF orrCMRglu associated with the anxiety of being exposed to phobia-relevant material insubjects with speciﬁc phobias. However, there is great variability in the results of studies
using PET, and no clear consensus can be derived. Several report increased rCBF in thesecondary visual cortex and reduced rCBF in the hippocampus, orbitofrontal cortex, prefrontal cortex, posterior cingulate cortex, and temporal lobe [234,235]. Others report increases in rCBF in the anterior cingulate cortex, the insular cortex, the anterior temporal
cortex, the somatosensory cortex, the posterior medial orbitofrontal cortex, and the thalamus [236]. Still others implicate the thalamus [237,238] or distinct neuronal pathways
that also involve the amygdala and striatum [238]. However, the involvement of theseareas does not appear to be exclusive to phobic anxiety and they may be involved in
uncontrolled emotions in other conditions like post-traumatic stress disorder, panic disorder, and schizophrenia [238]. One study found reduced rCBF only in the primary visualcortex [239] and another study found no clear association between phobic anxiety andrCBF using SPECT [240].
2. Social Phobia (Social Anxiety Disorder)
Neurobiological mechanisms underlying social phobia, including neuroimaging ﬁndings,
have recently been critically reviewed [241,242]. A consensus is that the ﬁeld of social
phobia research has until recently had a number of weaknesses, including lack of guiding
theories, static comparisons between subject groups, analysis oblivious to individual variations [241], and neglect of neurodevelopmental processes and the functional interactions
between neurotransmitters [242]. Both reviews provide theoretical frameworks and recommendations to guide future research in the ﬁeld, including neuroimaging studies. There
are few replicated neuroimaging studies to date in social phobia, but the data so far implicate basal ganglia structures, the amygdala, and a number of cortical regions.
A volumetric MRI study has found no statistically signiﬁant differences in total
cerebral, caudate, putamen, and thalamic volumes between social phobia patients and normal control subjects. However, it did reveal an age-related reduction in putamen volumes
in the social phobics that was greater than seen in controls [243].
The results of MRS studies have so far been inconsistent. A preliminary study reported decreased levels of Cho, Cr, and NAA in a number of cortical and subcorticalregions including thalamus and caudate [244]. These changes were attributed to an alteration in the activty of the 5HT and/or DA systems in these brain areas. However, the useof signal-to-noise ratios and relatively poor resolution are limitations in this study. A
repeat MRS study reported signiﬁcantly lower NAA and higher Cho and Ino in corticalgray matter. Higher Ino levels were also observed in subcortical gray matter. These differences were not observed following clonazepam treatment [245]. These ﬁndings were interpreted as showing an alteration in phospholipase C activity. Phospholipase C is a secondmessenger pathway associated with a number of different neurotransmitters, including
noradrenaline, dopamine, and serotonin. While these data might point to altered neurotransmitter function in social phobia, there are other possible explanations [241].
A preliminary blood ﬂow SPECT study found normal rCBF in subjects with social
phobia who were not experiencing social anxiety at the time of tracer injection [246]. In
another SPECT study, treatment with the SSRI citalopram led to signiﬁcantly reduced

306

Talbot et al.

activity in the left temporal and frontal cortices and the left cingulate cortex [247]. However, changes in these regions are not exclusive to socially induced anxiety.
Two H215O PET studies of symptom provocation have been reported. In one, thechanges speciﬁc to social phobia included increased rCBF in the right DLPFC and leftparietal cortex [248]. In the other, rCBF was found to decrease in the social phobics andincrease in the comparison subjects in the orbitofrontal and insular cortices and in thetemporal lobe during public speaking [249]. The study concluded that the functional neuroanatomy of social phobia involves the activation of a phylogenetically older danger recognition system. Moreover, increased anxiety was accompanied by enhanced rCBF in the
amygdaloid complex in social phobics relative to control subjects [249]. Functional abnormalities in the amygdala and hippocampus have also been found in two fMRI studies. In
the ﬁrst, the amygdala was selectively activated in social phobics during presentation ofpotentially fear-relevant stimuli, which in this case were neutral face stimuli [250]. Second,in a study of conditioned aversive stimuli, signal decreases were found in the amygdala
and hippocampus in normal subjects, but an opposite increased activation was found inboth regions in social phobics [251].
Radioligand studies give some support to the hypothesis that dopaminergic neurotransmission may be altered in social phobia, although they are not currently conclusive.
Tiihonen et al., using SPECT and [123I]β-CIT to label DAT in the striatum, reported thatdensities were markedly lower in patients with social phobia than in age- and gendermatched controls [252]. The authors suggested that the lowered DAT density might reﬂect
an overall smaller number of dopaminergic synapses and neurons in the striatum. Anotherstudy using [123I]IBZM reported a signiﬁcant decrease in D2 receptor BP in patients withsocial phobia compared to controls [253]. However, the interpretation of this report is
difﬁcult to reconcile with the report by Tiihonen et al. of decreased DAT binding, as
decreased [123I]IBZM binding potentials could also reﬂect increased levels of synaptic DA
in the vicinity of D2 receptors, altered afﬁnity of D2 receptors for DA, or some combinationof these factors.
Of possible relevance to social phobia is the association between dopaminergic abnormalities and the personality trait of personal detachment. Studies using [11C]raclopridereport that personal detachment is related to low D2 receptor density in the striatum [254].
However, the relationship is not evident on all measures of detachment [254,255]. Detachment was also found to be associated with low DAT binding in the putamen [256]. Inview of the association between social phobia and low DAT and D2 receptors [252,253], it
has been argued that these neurobiological ﬁndings might underlie a commonality between
detachment and social phobia [257].
Imaging ﬁndings in other neurotransmitter systems are relatively less advanced atpresent. In the 5HT system, a recent study using [11C]McN 5652 failed to ﬁnd marked
alterations in SERT in patients with social phobia, despite an excellent response to SSRI
treatment [258].
E.

Obsessive-Compulsive Disorder

Imaging studies have been important in the development of current hypotheses regarding
the pathophysiology of obsessive-compulsive disorder (OCD). These studies have recently
been comprehensively reviewed and integrated with the basic science literature on thefunctional neuroanatomy of cortico-basal ganglia-thalamo-cortical circuits to present atheoretical model of brain mediation of OCD symptoms and response to treatment

Brain Imaging

307[259,260]. This model suggests that OCD symptoms are mediated by hyperactivity inorbitofrontal-subcortical circuits, which may be due to an imbalance of tone between direct
and indirect striato-pallidal pathways. Serotonergic drugs may improve OCD symptoms
by changing the relative balance of tone through the indirect versus direct orbitofrontalsubcortical pathways, thereby decreasing activity in the overall circuit that exists in thesymptomatic state.
Functional imaging studies show a highly consistent pattern in these circuits, particularly those involving the orbitofrontal and anterior cingulate cortices. Hyperactivity isfound during neutral states [261–265], becomes accentuated during symptom provocation[266–269] or cognitive challenge [270], and attenuates with successful treatment[261,271–274]. Moreover, lower pretreatment metabolism in the orbitofrontal cortex has
been found to predict greater improvement on SSRI medication [275]. However, different
treatment modalities may have different predictive levels of pretreatment metabolism[276]. Functional abnormalities have also been replicated in lateral frontal cortex[266,268,277], medial temporal lobe structures including amygdala [268,278] and hippocampus [267,279], and in lateral temporal cortex [266].
OCD has been widely studied by volumetric MRI in an attempt to ﬁnd structural
correlations with the above functional abnormalities. Studies have shown signiﬁcantly lesstotal white matter and greater total neocortical volume [280–282] or increased gray matter
density [283]. Reduced orbitofrontal and amygdala volumes have been found in somestudies [284] but not in others [280]. A recent study in drug-naive children with OCD
found increased thalamic volume, which declined signiﬁcantly after paroxetine treatment
to levels comparable with those of controls. Moreover, the decrease in thalamic volume
was associated with reduction in OCD symptom severity [285]. The corpus striatum has
been the most extensively studied region but, despite the large number of studies, theﬁndings remain inconsistent. Some studies have found reduced caudate size [281,286,287],
another found increased caudate size [288], and most found no difference [281,289–292].
This variability may possibly be explained by clinical heterogeneity (e.g., pediatric oradult subjects, the presence or absence of tics in the populations studied, age at onset,
illness duration, gender, treatment status, and issues related to data analysis).
In contrast to the structural data, the results of MRS studies of NAA currently appear
to be more consistent. As mentioned earlier in this chapter, NAA is considered to be aputative marker of neuronal viability and decreased levels suggest decreased neuronaldensity or viability. In studies of drug-free and drug-naive patients with OCD, decreased
levels of NAA have been reported in corpus striatum [290,293], anterior cingulate [293],
and thalamus [294], even in the absence of measurable volumetric reduction [290]. Interestingly, one study failed to ﬁnd a difference in NAA in the caudate-putamen in a groupof 12 patients, 10 of whom were taking clomipramine or haloperidol treatment [295]. The
suggestion has therefore been made that MRS may provide a more sensitive measure ofneuronal loss than volumetric MRI [290]. Moreover, MRS studies have demonstrated
increased glutamate concentration in the caudate of treatment-naive children with OCD[296,297]. This declined signiﬁcantly after paroxetine treatment to levels comparable withthose of controls, and the decrease was associated with a decrease in OCD symptom
severity [296]. Excessive glutamate levels are known to be neurotoxic, and the authors
suggest that paroxetine treatment may be mediated by a serotonergically modulated reduction in caudate glutamate concentration.
Abnormalities of serotonergic neurotransmission have long been hypothesized in
the pathophysiology of OCD on the basis of the therapeutic efﬁcacy of medications that

308

Talbot et al.

selectively increase synaptic 5HT levels (including SSRIs and clomipramine) in nondepressed OCD patients, and the high level of comorbid depression in OCD. No neuroreceptor PET studies have so far been reported in OCD, but studies of the regional binding of
5HT1A and 5HT2A receptors and the SERT will be of great interest.
F.

Post-Traumatic Stress Disorder

Imaging studies in post-traumatic stress disorder (PTSD) have recently been comprehensively reviewed by a number of authors [50,298–300]. Such studies are leading to rapid
advances in our understanding of the pathogenesis and pathophysiology of this disorder.
Reduced hippocampal volume has been consistently demonstrated in adults withchronic PTSD, although the time course of this volume reduction and its relation to trauma
remain to be elucidated. Radionuclide and fMRI studies have implicated functional abnormalities in a number of regions, including the anterior cingulate and amygdala. As a resultof such studies, it has been hypothesized that symptoms of PTSD are mediated by a dysfunction of the anterior cingulate, along with a failure to inhibit amygdala activation and/or an intrinsic lower threshold of amygdala response to fearful stimuli. The model further
proposes that hippocampal atrophy found in volumetric MRI studies may be a result ofchronic hyperarousal symptoms mediated by amygdala activation [299]. There is a large
body of literature on the damaging effects of chronically or repeatedly raised levels of
glucocorticoids on the hippocampus. However, the role of glucocorticoids in PTSD—
which often follows a single overwhelmingly stressful event—remains controversial [50].
Indeed there are no imaging data published at present to support the idea that hippocampal
atrophy occurs in PTSD arising from a single trauma. These ﬁndings, and their relevanceto the pathophysiology of PTSD, are discussed below.
Using MRI, children and adolescents with PTSD have been reported to have smaller
intracranial and cerebral volumes [301,302], attenuation of frontal lobe asymmetry [302],
and larger lateral ventricles [301] than matched controls. Brain volume was positively
correlated with age of onset of trauma and negatively correlated with duration of abuse[301]. In this population, hippocampal volume appears to be normal [301,302]. However,well-controlled studies have consistently reported smaller hippocampal volumes in adultsubjects with chronic PTSD following Vietnam combat experiences as adults [303,304]
or following sexual or physical abuse in childhood [305,306]. It has been suggested [307]that left atrophy predominates in PTSD arising from childhood [305,306] and that righthippocampal atrophy predominates in PTSD arising from adulthood [303]. However, sucha lateralized effect in adulthood is not consistent [304].
These ﬁndings have given rise to a number of important questions, particularly as
to whether atrophy occurs prior to trauma, as a result of trauma, or as a result of the PTSD
following trauma. The idea that small hippocampi may be present prior to PTSD has beensigniﬁcantly weakened by the results of two more recent longitudinal MRI studies, whichshow that hippocampal atrophy is not demonstrable in the ﬁrst 6 months after trauma in
adult subjects with PTSD following a single traumatic event [308] or in peripubertal children with maltreatment-related PTSD followed up for at least 2 years [309]. This leaves
the question of whether atrophy is related to the trauma itself, or to the subsequent PTSD.
However, the answer to this remains unclear. On the one hand, the recent longitudinal
MRI ﬁndings would tend to argue against the idea that hippocampal atrophy arises fromthe trauma itself, leaving the suggestion that atrophy may arise as a consequence of the
PTSD. On the other hand, however, the data of these studies will only become pertinent

Brain Imaging

309

if those with PTSD ultimately do demonstrate atrophy. Moreover, it has been pointed out[50] that in two of the studies cited above [304,305], atrophy may be related more totrauma itself than to a diagnosis of PTSD. Furthermore, in adults with PTSD related toabuse in childhood, hippocampal atrophy does not appear to correlate with time since
trauma [306,310]. Distinguishing among those possibilities will require more data indicating when atrophy is ﬁrst demonstrable (with respect to the trauma), whether it worsens
with time after trauma, and the extent to which atrophy is a correlate of trauma itself, as
opposed to PTSD [50].
Neurochemical studies using MRS have shown that hippocampal volume reduction
is associated with reduced levels of NAA in PTSD [311]. However, a more recent study
suggests that reduced NAA can be independent of hippocampal volume [312]. In thisstudy, 18 male subjects with combat-related PTSD showed bilateral reductions of 23%
in NAA in the hippocampus. Importantly, comorbid alcohol-related disorders were excluded if they occurred within the previous 5 years, as these have been associated withdecrements in hippocampal volume on MRI. However, 10 of the 18 subjects had a lifetime
history of major depression, and this may be of relevance as depression is itself known
to be associated with hippocampal volume and chemistry, as discussed in the MDD sectionof this chapter. Unfortunately, no post hoc analyses of these subjects were reported. The
authors interpret the ﬁnding of decreased NAA in the absence of volume loss to reﬂect
their neuronal loss in the presence of gliosis and/or neuronal metabolic impairments. There
were no alterations reported in the Cho resonance in this study. An earlier 1H MRS study
in PTSD examining hippocampal regions speciﬁcally reported that patients with PTSD
had lower NAA in the right medial temporal lobe and lower Cho in the left medial temporal
lobe compared to controls [313]. Because NAA is regarded as an indicator of neuronaldensity, this ﬁnding was interpreted (in line with structural MRI ﬁndings) to suggest thatneuronal density of right-sided medial temporal structures in patients with combat-related
PTSD may be decreased. Abnormalities in the region of the anterior cingulate have been
consistently found in PTSD using radionuclide imaging (see below). This region wasinvestigated by 1H MRS [314] in 11 children and adolescents with PTSD secondary tomaltreatment. NAA was signiﬁcantly reduced suggesting (in line with the radionuclide
studies) that anterior cingulate neuronal metabolism may be altered in childhood PTSD.
Functional imaging studies have implicated a number of regions in the symptomatology of PTSD. In a controlled study using fMRI, Rauch et al. studied combat veteranswith PTSD and demonstrated exaggerated amygdala responses to masked-fearful versus
masked-happy faces in these patients. The authors conclude that this represents evidence
for exaggerated amygdala responses to general negative stimuli in PTSD [315]. A numberof controlled SPECT and PET studies have investigated the alterations in rCBF orrCMRglu associated with experimentally provoked intrusive imagery and enhanced anxiety. The main groups studied have been Vietnam combat veterans [316–319], adults witha history of childhood sexual abuse [320,321], and victims of torture [322]. A particularly
consistent ﬁnding in the PET studies is a relative failure to activate the anterior cingulate[317,320,321] during provoked PTSD symptoms. This is supported by the results of a
recent fMRI study showing diminished response in rostral anterior cingulate cortex in thepresence of emotionally relevant stimuli in Vietnam combat veterans with PTSD [323].
Other areas associated with symptom exposure include medial prefrontal cortex,
posterior cingulate, visual association cortex and hippocampus, as well as middle andsuperior temporal, middle frontal, right orbitofrontal, occipital, parahippocampal, anterior
temporal, and inferior frontal cortices. These have shown either increases or decreases in310

Talbot et al.

perfusion depending on the study conditions and sample population. The severity of provoked imagery in chronic PTSD was recently found to be correlated with rCBF in a widelydistributed group of regions including brainstem and areas associated with motor control,
complex visual/spatial cues, and memory [324].
Any alterations of regional receptor populations in PTSD are currently unknown.
However, PET quantiﬁcation of 5HT and benzodiazepine receptor binding potential inanterior cingulate and medial temporal areas will be of particular interest.
V.

CONCLUSION

Neuroimaging research has provided a number of insights into underlying pathophysiological processes in affective and anxiety disorders. However, only in late-onset MDD can
it so far be said to have provided convincing evidence of etiological factors. It would
appear that cerebrovascular disease may play a role in the pathogenesis of late-onset MDD
in patients with MRI evidence of hyperintensities, and the new mood disorder subtype ofvascular depression has been proposed. In depression of earlier onset, amygdalar activity
appears to be pathologically increased, and abnormalities have been replicated in corticostriatal-pallidal-thalamic circuits particularly implicating the orbital and medial prefrontal
cortex. There also seems to be an association between depression and hippocampal size
dependent on the cumulative duration and severity of MDD. In the 5HT system, reduced
densities of 5HT1A receptors and SERT have been replicated.
In other disorders, the integration of structural, neurochemical, and functional imaging ﬁndings is not so far advanced. However, this should not obscure the number ofwell-replicated and highly consistent patterns found in these disorders that are providing
clues to underlying pathophysiological processes. In BPD, the most consistent ﬁndings
are of a higher than expected incidence of white matter hyperintensities and abnormalitiesof membrane phospholipid metabolism. Dopaminergic neurotransmission is also dysregulated during psychosis, but this ﬁnding does not appear to be speciﬁc to BPD. In panic
disorder, a fairly consistent pattern has been reported of reduced activity in hippocampal,
parahippocampal and inferior frontal regions, along with reductions of BZD receptor binding. In OCD, there is a highly consistent pattern of increased activity in cortico-striatalthalamic-cortical circuits involving the orbitofrontal and anterior cingulate cortices, which
attenuates with successful treatment. Moreover, replicated MRS ﬁndings suggest reduced
neuronal density in the striatum in OCD. Finally, in PTSD, reduced hippocampal volume
has been consistently demonstrated in adults with chronic PTSD, along with relative failure to activate the anterior cingulate gyrus and relatively increased amygdalar activity.
Beyond these relatively well-replicated ﬁndings, it is interesting to note that a number of forebrain regions (orbitoprefrontal cortex, anterior cingulate, amygdala, hippocampus, and striatum) have been frequently implicated by imaging studies in the pathophysiology of anxiety and mood disorders. This anatomical overlap mirrors the frequentcomorbidity of anxiety and mood disorders, but also illustrates the limitations of brainimaging techniques. While these techniques might point toward regional alterations inshape, volume, metabolism, or concentration of speciﬁc biomolecules, the precise neuronalbasis of these abnormalities remains to be described. So far, brain imaging has not contributed signiﬁcantly to the elucidation of the etiology of these afﬂictions nor to the development of new medications.
To move beyond phenomenological descriptions is the challenge facing the studyof these disorders by brain imaging. In the next decade, development of more speciﬁc

Brain Imaging

311

and dynamic biomolecular imaging probes, realistic and testable models for imaging regional and neuronal connectivity, and close collaboration with other ﬁelds of neuropsychiatric research (molecular biology, genetics and epidemiology, animal models, post-mortem
studies, neurocognitive sciences) will be important factors contributing to the growth ofbrain-imaging techniques.
ACKNOWLEDGMENTS
Supported by the National Alliance for Research on Schizophrenia and Depression (NARSAD and Lieber Center), and the National Institute of Mental Health (K02 MH0160301).
REFERENCES
1. Barbier EL, Lamalle L, Decorps M. Methodology of brain perfusion imaging. J Magn Res
Imaging 2001; 13(4):496–520.
2. Henry ME, Frederick BB, Moore CM, Stoddard E, Renshaw PF. Magnetic resonance spectroscopy in psychiatric Illness. In: Rauch SL, ed. Psychiatric Neuroimaging Research: Contemporary Strategies. Washington, DC: American Psychiatric Publishing, 2001:291–333.
3. Barker PB. N-acetyl aspartate—a neuronal marker? [letter; comment]. Ann Neurol 2001;
49(4):423–424.
4. Pan JW, Mason GF, Vaughan JT, Chu WJ, Zhang Y, Hetherington HP. 13C editing of glutamate in human brain using J-refocused coherence transfer spectroscopy at 4.1 T. Magn Res
Med 1997; 37(3):355–358.
5. Hetherington HP, Newcomer BR, Pan JW. Measurement of human cerebral GABA at 4.1
T using numerically optimized editing pulses. Magn Reson Med 1998; 39(1):6–10.
6. Gonzalez RG, Guimaraes AR, Sachs GS, Rosenbaum JF, Garwood M, Renshaw PF. Measurement of human brain lithium in vivo by MR spectroscopy. Am J Neuroradiol 1993;
14(5):1027–1037.
7. Drevets WC. Neuroimaging studies of mood disorders. Biol Psychiatry 2000; 48:813–829.
8. Drevets WC. Integration of structural and functional imaging: examples in depression research. In: Rauch SL, ed. Psychiatric Neuroimaging Research: Contemporary Strategies.
Washington, DC: American Psychiatric Publishing, 2001:249–290.
9. de Groot JC, de Leeuw FE, Oudkerk M, Hofman A, Jolles, J, Bretelker MM. Cerebral whitematter lesions and depressive symptoms in elderly adults. Arch Gen Psychiatry 2000; 57(11):1071–1076.
10. Coffey CE, Figiel GS, Djang WT, Weiner RD. Subcortical hyperintensity on magnetic resonance imaging: a comparison of normal and depressed elderly subjects. Am J Psychiatry
1990; 147(2):187–189.
11. Howard RJ, Beats B, Forstl H, Graves P, Bingham J, Levy R. White matter changes in late
onset depression: A magnetic resonance imaging study. Int J Geriatr Psychiatry 1993; 8:
183–185.
12. Krishnan KR. Neuroanatomic substrates of depression in the elderly. J Geriatr Psychiatry
Neurol 1993; 6(1):39–58.
13. Rabins PV, Pearlson GD, Aylward E, Kumar AJ, Dowell K. Cortical magnetic resonanceimaging changes in elderly inpatients with major depression. Am J Psychiatry 1991; 148(5):617–20.
14. Steffens DC, Krishnan KR. Structural neuroimaging and mood disorders: recent ﬁndings,
implications for classiﬁcation, and future directions. Biol Psychiatry 1998; 43(10):705–712.
15. Soares JC, Mann JJ. The anatomy of mood disorders—review of structural neuroimaging
studies. Biol Psychiatry 1997; 41(1):86–106.

312

Talbot et al.

16. Coffey CE, Wilkinson WE, Weiner RD, Parashos IA, Djang WT, Webb MC, Figiel GS,
Spritzer CE. Quantitative cerebral anatomy in depression. A controlled magnetic resonanceimaging study. Arch Gen Psychiatry 1993; 50(1):7–16.
17. Kumar A, Bilker W, Jin Z, Udupa J. Atrophy and high intensity lesions: complementary
neurobiological mechanisms in late-life major depression. Neuropsychopharmacology 2000;
22(3):264–274.
18. Taylor WD, Payne ME, Krishnan KR, Wagner HR, Provenzale JM, Steffens DC, MacFall
JR. Evidence of white matter tract disruption in MRI hyperintensities. Biol Psychiatry 2001;
50(3):179–83.
19. Chimowitz MI, Estes ML, Furlan AJ. Further observations on the pathology of subcorticallesions identiﬁed on magnetic resonance imaging. Arch Neurol 1992; 49:747–752.
20. Iidaka T, Nakajima T, Kawamoto K, Fukuda H, Suzuki Y, Maehara T, Shiraishi H. Signal
hyperintensities on brain magnetic resonance imaging in elderly depressed patients. Euro
Neurol 1996; 36(5):293–299.
21. Steffens DC, Helms MJ, Krishnan KR, Burke GL. Cerebrovascular disease and depression
symptoms in the Cardiovascular Health Study. Stroke 1999; 30(10):2159–2166.
22. Vataja R, Pohjasvaara T, Leppavuori A, Mantyla R, Aronen HJ, Salonen O, Kaste M, Erkinjuntti T. Magnetic resonance imaging correlates of depression after ischemic stroke. ArchGen Psychiatry 2001; 58(10):925–931.
23. Kim JS, Choi-Kwon S. Poststoke depression and emotional incontinence: correlation withlesion location. Neurology 2000; 54(9):1805–1810.
24. Carson AJ, MacHale S, Allen K, Lawrie SM, Dennis M, House A, Sharpe M. Depression
after stroke and lesion location: a systematic review. Lancet 2000; 356(9224):122–126.
25. Ahearn EP, Jamison KR, Steffens DC, Cassidy F, Provenzale JM, Lehman A, Weisler RH,
Carroll BJ, Krishnan KR. MRI correlates of suicide attempt history in unipolar depression.
Biol Psychiatry 2001; 50(4):266–270.
26. O’Brien J, Ames D, Chiu E, Schweitzer I, Desmond P, Tress B. Severe deep white matterlesions and outcome in elderly patients with major depressive disorder: follow up study. Br
Med J 1998; 317(7164):982–984.
27. Simpson SW, Jackson A, Baldwin RC, Burns A. 1997 IPA/Bayer Research Awards in Psychogeriatrics. Subcortical hyperintensities in late-life depression: acute response to treatment
and neuropsychological impairment. Int Psychogeriatr 1997; 9(3):257–275.
28. Simpson S, Baldwin RC, Jackson A, Burns AS. Is subcortical disease associated with apoor response to antidepressants? Neurological, neuropsychological and neuroradiologicalﬁndings in late-life depression. Psychol Med 1998; 28(5):1015–1026.
29. Steffens DC, Conway CR, Dombeck CB, Wagner HR, Tupler LA, Weiner RD. Severity of
subcortical gray matter hyperintensity predicts ECT response in geriatric depression. J ECT
2001; 17(1):45–49.
30. Nebes RD, Vora IJ, Meltzer CC, Fukui MB, Williams RL, Kamboh MI, Saxton J, Houck
PR, DeKosky ST, Reynolds CF 3rd. Relationship of deep white hyperintensities and apolipoprotein E genotype to depressive symptoms in older adults without clinical depression. Am
J Psychiatry 2001; 158(6):878–884.
31. Shah SA, Doraiswamy PM, Husain MM, Escalona PR, Na C, Figiel GS, Patterson LJ, Ellinwood EH, Jr., McDonald WM, Boyko OB. Posterior fossa abnormalities in major depression:a controlled magnetic resonance imaging study. Acta Psychiatr Scand 1992; 85(6):474–479.
32. Kumar A, Bilker W, Lavretsky H, Gottlieb G. Volumetric asymmetries in late-onset mooddisorders: an attenuation of frontal asymmetry with depression severity. Psychiatry Res 2000;
100(1):41–47.
33. Lai T, Payne ME, Byrum CE, Steffens DC, Krishnan KR. Reduction of orbital frontal cortex
volume in geriatric depression. Biol Psychiatry 2000; 48(10):971–975.
34. Steffens DC, Tupler LA, Ranga K, Krishnan R. Magnetic resonance imaging signal hypointensity and iron content of putamen nuclei in elderly depressed patients. Psychiatry Res 1998;
83(2):95–103.

Brain Imaging

313

35. von Gunten A, Fox NC, Cipolotti L, Ron MA. A volumetric study of hippocampus andamygdala in depressed patients with subjective memory problems. J Neuropsychiatry Clin
Neurosci 2000; 12(4):493–498.
36. Sheline YI, Shaghavi M, Mintun MA, Gado MH. Depression duration but not age predicts
hippocampal volume loss in medically healthy women with recurrent major depression. J
Neurosci 1999; 19(12):5034–5043.
37. Steingard RJ, Renshaw PF, Yurgelun-Todd D, Appelmans KE, Lyoo IK, Shorrock KL, Bucci
JP, Cesena M, Abebe D, Zurakowski D, Poussaint TY, Barnes P. Structural abnormalities
in brain magnetic resonance images of depressed children. J Am Acad Child Adolesc Psychiatry 1996; 35(3):307–311.
38. Steingard RJ. The neuroscience of depression in adolescence. J Affect Disord 2000; 61(suppl
1):15–21.
39. Botteron KN, Raichle ME, Drevets WC, Heath AC, Todd RD. Volumetric reduction in left
subgenual prefrontal cortex in early onset depression. Biol Psychiatry 2002; 51(4):342–
344.
40. Hirayasu Y, Shenton ME, Salisbury DF, Kwon JS, Wible CG, Fischer IA, Yurgelun-Todd
D, Zarate C, Kikinis R, Jolesz FA, McCarley RW. Subgenual cingulate cortex volume inﬁrst-episode psychosis. Am J Psychiatry 1999; 156(7):1091–1093.
41. Drevets WC, Ongur D, Price JL. Neuroimaging abnormalities in the subgenual prefrontal
cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry
1998; 3(3):190–1, 220–6.
42. Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mooddisorders. Proc Nat Acad Sci USA 1998; 95:13290–13295.
43. Rusch BD, Abercrombie HC, Oakes TR, Schaefer SM, Davidson RJ. Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms. Biol
Psychiatry 2001; 50(12):960–964.
44. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, Yurgelun-Todd
DA. Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry 2000; 47(12):1087–1090.
45. Shah PJ, Ebmeier KP, Glabus MF, Goodwin GM. Cortical grey matter reductions associatedwith treatment-resistant chronic unipolar depression. Controlled magnetic resonance imaging
study. Br J Psychiatry 1998; 172:527–532.
46. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy inrecurrent major depression. Proc Natl Acad Sci USA 1996; 93(9):3908–3913.
47. Bremmer JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal
volume reduction in major depression. Am J Psychiatry 2000; 157(1):115–118.
48. Mervaala E, Fohr J, Kononen M, Valkonen-Korhonen M, Vainio P, Partanen K, Partanen
J, Tiihonen J, Viinamaki H, Karjalainen AK, Lehtonen J. Quantitative MRI of the hippocampus and amygdala in severe depression Psychol Med 2000: 30(1):117–125.
49. Axelson DA, Doraiswamy PM, McDonald WM, Boyko OB, Tupler LA, Patterson LJ, Nemeroff CB, Ellinwood EH, Jr., Krishnan KR. Hypercortisolemia and hippocampal changes in
depression. Psychiatry Res 1993; 47(2):163–173.
50. Sapolsky RM: Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. ArchGen Psychiatry 2000; 57(10):925–935.
51. Krishnan KR, McDonald WM, Escalona PR, Doraiswamy PM, Na C, Husain MM, Figiel
GS, Boyko OB, Ellinwood EH, Nemeroff CB. Magnetic resonance imaging of the caudate
nuclei in depression. Preliminary observations. Arch Gen Psychiatry 1992; 49(7):553–557.
52. Husain MM, McDonald WM, Doraiswamy PM, Figiel GS, Na C, Escalona PR, Boyko OB,
Nemeroff CB, Krishnan KR. A magnetic resonance imaging study of putamen nuclei inmajor depression. Psychiatry Res 1991; 40(2):95–99.
53. Parashos IA, Tupler LA, Blitchington T, Krishnan KR. Magnetic-resonance morphometry
in patients with major depression. Psychiatry Res 1998; 84(1):7–15.
54. Dupont RM, Jernigan TL, Heindel W, Butters N, Shafer K, Wilson T, Hesselink J, Gillin

314

55.

56.

57.

58.
59.

60.

61.

62.

63.

64.
65.

66.

67.

68.
69.

70.

Talbot et al.
JC: Magnetic resonance imaging and mood disorders. Localization of white matter and othersubcortical abnormalities. Arch Gen Psychiatry 1995; 52(9):747–755.
Greenwald BS, Kramer-Ginsberg E, Bogerts B, Ashtari M, Aupperle P, Wu H, Allen L,
Zeman D, Patel M. Qualitative magnetic resonance imaging ﬁndings in geriatric depression.
Possible link between later-onset depression and Alzheimer’s disease? Psychol Med 1997;
27(2):421–431.
Pillay SS, Renshaw PF, Bonello CM, Later B, Fava M, Yurgelun-Todd D. A quantitative
magnetic resonance imaging study of caudate and lenticular nucleus gray matter volume inprimary unipolar depression: relationship to treatment response and clinical severity. Psychiatry Res 1998; 84:61–74.
Lenze EJ, Sheline YI: Absence of striatal volume differences between depressed subjects
with no comorbid medical illness and matched comparison subjects. Am J Psychiatry 1999;
156(12):1989–1991.
Woods BT, Chiu TM. In vivo 1H spectroscopy of the human brain following electroconvulsive therapy. Ann Neurol 1990; 28:745–749.
Woods BT, Chiu TM. Induced and spontaneous seizures in man produce increases in regional
brain lipid detected by in vivo proton magnetic resonance spectroscopy. Adv Experi Med
Biol 1992; 318:267–274.
Felber SR, Pycha R, Hummer M, Aichner FT, Fleischhacker WW. Localized proton andphosphorous magnetic resonance spectroscopy following electroconvulsive therapy. Biol
Psychiatry 1993; 33(8–9):651–654.
Volz HP, Rzanny R, Riehemann S, May S, Hegewald H, Preussler B, Hubner G, Kaiser
WA, Sauer H. 31P magnetic resonance spectroscopy in the frontal lobe of major depressed
patients. Eur Arch Psychiatry Clin Neurosci 1998; 248(6):289–295.
Moore CM, Christensen JD, Lafer B, Fava M, Renshaw PF. Lower levels of nucleoside
triphosphate in the basal ganglia of depressed subjects: a phosphorous-31 magnetic resonancespectroscopy study. Am J Psychiatry 1997; 154(1):116–118.
Ende G, Braus DF, Walter S, Weber-Fahr W, Henn FA. The hippocampus in patients treatedwith electroconvulsive therapy: A proton magnetic resonance spectroscopic imaging study.
Arch Gen Psychiatry 2000; 57(10):937–943.
Stringer JL, Agarwal KS, Dure LS. Is cell death necessary for hippocampal mossy ﬁber
sprouting? Epilepsy Res 1997; 27(1):67–76.
Frey R, Metzler D, Fischer P, Heiden A, Scharfetter J, Moser E, Kasper S. Myo-inositol in
depressive and healthy subjects determined by frontal 1H-magnetic resonance spectroscopy
at 1.5 tesla. J Psychiatric Res 1998; 32(6):411–420.
Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F. Reduced glutamate in the anterior
cingulate cortex in depression: an in vivo proton magnetic spectroscopy study. Biol Psychiatry 2000, 47(4):305–313.
Steingard RJ, Yurgelun-Todd DA, Hennen J, Moore JC, Moore CM, Vakili K, Young AD,
Katic A, Beardslee WR, Renshaw PF. Increased orbitofrontal cortex levels of choline indepressed adolescents as detected by in vivo proton magnetic resonance spectroscopy. Biol
Psychiatry 2000; 48(11):1053–1061.
Soares JC, Krishnan KR, Keshavan MS. Nuclear magnetic resonance spectroscopy: new
insights into the pathophysiology of mood disorders. Depression 1996; 4(1):14–30.
Renshaw PF, Lafer B, Babb SM, Fava M, Stoll AL, Christensen JD, Moore CM, YurgelunTodd DA, Bonello CM, Pillay SS, Rothschild AJ, Nierenberg AA, Rosenbaum JF, Cohen
BM. Basal ganglia choline levels in depression and response to ﬂuoxetine treatment: an invivo proton magnetic resonance spectroscopy study. Biol Psychiatry 1997; 41(8):837–843.
Chalres HC, Lazeyras F, Krishnan KR, Boyko OB, Payne M, Moore D: Brain choline indepression: in vivo detection of potential pharmacodynamic effects of antidepressant therapy
using hydrogen localized spectroscopy. Progr Neuro-Psychopharmacol Biol Psychiatry 1994;
18(7):1121–1127.

Brain Imaging

315

71. Sonawalla SB, Renshaw PF, Moore CM, Alpert JE, Nierenberg AA, Rosenbaum JF, Fava M.
Compounds containing cytosolic choline in the basal banglia: a potential biological marker oftrue drug response to ﬂuoxetine. Am J Psychiatry 1999; 156(10):1638–1640.
72. Jung RE, Brooks WM, Yeo RA, Chiulli SJ, Weers DC, Sibbitt WL, Jr. Biochemical markers
of intelligence: a proton MR spectroscopy study of normal human brain. Proc R Soc London
Ser B 1999; 266(1426):1375–1379.
73. Schuff N, Ezekiel F, Gamst AC, Amend DL, Capizzano AA, Maudsley AA, Weiner MW.
Region and tissue differences of metabolites in normally aged brain using multislice 1H
magnetic resonance spectroscopic imaging. Magn Res Med 2001; 45(5):899–907.
74. Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OA, Berman RM, Charney
DS, Krystal JH. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1999; 56(11):1043–1047.
75. Drevets WC. Prefrontal cortical-amygdalar metabolism in major depression. Ann NY Acad
Sci 1999; 877:614–637.
76. Drevets WC. Functional neuroimaging studies of depression: the anatomy of melancholia.
Ann Rev Med 1998; 49:341–361.
77. Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci 1997; 9(3):471–481.
78. Liotti M, Mayberg HS. The role of functional neuroimaging in the neuropsychology of depression. J Clin Exp Neuropsychol 2001; 23(1):121–136.
79. Mayberg H, Robinson R, Wong D, Parikh R, Boulduc P, Starkstein S, Price T, Dannals R,
Links J, Wilson A, Ravert H. PET imaging of cortical S2 serotonin receptors after stroke:
lateralized changes and relationship to depression. Am J Psychiatry 1988; 145(8):937–943.
80. D’haenen H, Bossuyt A, Mertens J, Bossuyt-Piron C, Gijesmans M, Kaufman. SPECT imaging of serotonin2 receptors in depression. Psychiatry Res Neuroimag 1992; 45(4):227–
237.
81. Blin J, Pappata S, Kijosawa M, Crouzel JC. [18F]setoperone: a new high-afﬁnity ligand for
positron emission tomography study of the serotonin-2 receptors in baboon brain in vivo.
Eur J Pharmacol 1988; 147:73–82.
82. Lemaire C, Cantineau R, Guillaume M, Plenevaux A, Christiaens L. Fluorine-18-altanserin:a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic
behavior in rats. J Nucl Med 1991; 32(12):2266–2272.
83. Biver F, Wikler D, Lotstra F, Damhaut P, Goldman S, Mendlewicz J. Serotonin 5-HT2 receptor imaging in major depression: Focal changes in orbito-insular cortex. Br J Psychiatry 1997;
171:444–448.
84. Tan PZ, Baldwin RM, Van Dyck CH, Al-Tikriti M, Roth B, Khan N, Charney DS, Innis
RB. Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent. Nucl Med Biol 1999; 26(6):601–608.
85. Meyer JH, Kapur S, Houle S, DaSilva J, Owczarek B, Brown GM, Wilson AA, Kennedy
SH. Prefrontal cortex 5-HT2 receptors in depression: An [18F]setoperone PET imaging
study. Am J Psychiatry 1999; 156(7):1029–1034.
86. Attar-Levy D, Martinot J-L, Blin J, Dao-Castellana M-H, Crouzel C, Mazoyer B, Poirier
M-F, Bourdel M-C, Aymard N, Syrota A, Feline A. The cortical serotonin2 receptors studied
with positron-emission tomograpy and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine. Biol Psychiatry 1999; 45(2):180–186.
87. Meltzer CC, Price JC, Mathias CA, Greer PJ, Cantwell MN, Houck PR, Mulsant BH, BenEliezer D, Lopresti B, DeKosky ST, Reynolds III: PET imaging of serotonin type 2A receptors in late-life neuropsychiatric disorders. Am J Psychiatry 1999; 156(12):1871–1878.
88. Yatham LN, Liddle PF, Shiah I-S, Scarrow G, Lam RW, Adam MJ, Zis AP, Ruth TJ. Brain
serotonin2 receptors in major depression: A positron emission tomography study. Arch Gen
Psychiatry 2000; 57(9):850–858.

316

Talbot et al.

89. Meyer JH, Kapur S, Eisfeld B, Brown GM, Houle S, DaSilva J, Wilson AA, Raﬁ-Tari S,
Mayberg HS, Kennedy SH. The effect of paroxetine on 5-HT2A receptors in depression:
An [18F]setoperone PET imaging study. Am J Psychiatry 2001; 158(1):78–85.
90. Yatham LN, Liddle PF, Dennie J, Shiah I-S, Adam MJ, Lane CJ, Lain RW, Ruth TJ. Decreasein brain serotonin 2 receptor binding in patients with major depression following desipramine
treatment: A positron emission tomography study with ﬂuorine-18-labeled setoperone. ArchGen Psychiatry 1999; 56(8):705–711.
91. Mann JJ. Role of the serotonergic system in the pathogenesis of major depression and suicidal
behavior. Neuropsychopharmacology 1999; 21(2 Suppl):99S–105S.
92. Drevets WC, Frank E, Price JC, Kupfer DJ, Holt D, Greer PJ, Yuang Y, Gautier C, Mathis
C. PET imaging of serotonin 1A receptor binding in depression. Biol Psychiatry 1999;
46(10):1375–1387.
93. Fujita M, Charney DS, Innis RB. Imaging serotonergic neurotransmission in depression:
Hippocampal pathophysiology may mirror global brain alterations. Biol Psychiatry 2000;
48(8):801–812.
94. Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. ArchGen Psychiatry 1997; 54(7):597–606.
95. Lowther S, DePaermentier F, Cheetham SC, Crompton MR, Katona CLE, Horton RW. 5HT1A receptor binding sites in post-morten brain samples from depressed suicides and controls. J Affective Disord 1997; 42(2–3):199–207.
96. Dillon KA, Gross-Isseroff R, Israeli M, Biegon A. Autoradiographic analysis of serotonin
5-HT1A receptor binding in the human brain postmortem: effects of age and alcohol. Brain
Res 1991; 554(1–2):56–64.
97. Matsubara S, Arora RC, Meltzer HY. Serotonergic measures in suicide brain: 5-HT1A binding sites in frontal cortex of suicide victims. J Neural Transm Gen Sec 1991; 85(3):181–
194.
98. Arranz B, Eriksson A, Mellerup E, Plenge P, Marcusson J. Brain 5-HT1A, 5-HT1D, and 5HT2 receptors in suicide victims. Biol Psychiatry 1994; 35(7):457–463.
99. Arango V, Underwood MD, Gubbi AV, Mann JJ. Localized alterations in pre-and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res
1995; 688(1–2):121–133.
100. Sargent PA, Kjaer KH, Bench CJ, Rabiner EA, Messa C, Meyer J, Gunn RN, Grasby PM,
Cowen PJ. Brain serotonin(1A) receptor binding measured by positron emission tomography
with [11C]WAY-100635: Effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000; 57(2):174 -180.
101. Porter RJ, McAllister-Williams RH, Jones S, Young AH. Effects of dexamethasone on neuroendocrine and psychological responses to L-tryptophan infusion. Psychopharmacol (Berl)
1999; 143(1):64–71.
102. Lopez JF, Liberzon I, Vazquez DM, Young EA, Watson SJ. Serotonin 1A receptor messenger
RNA regulation in the hippocampus after acute stress. Biol Psychiatry 1999; 45(7):934–
937.
103. Lopez JF, Vazquez DM, Chalmers DT, Watson SJ. Regulation of 5-HT receptors and the
hypothalamic-pituitary-adrenal axis. Implications for the neurobiology of suicide. Ann NY
Acad Sci 1997; 836:106–134.
104. Chaouloff F. Regulation of 5-HT receptors by corticosteroids: where do we stand? Fundam
Clin Pharmacol 1995; 9(3):219–233.
105. Wang S, Gao Y, Laruelle M, Baldwin RM, Scanley BE, Innis RB, Neumeyer JL. Enantioselectivity of cocaine recognition sites: binding of (1S)- and (1R)-2 beta-cargomethoxy-3 beta(4-iodophenyl)tropane (beta-CIT) to monoamine transporters. J Med Chem 1993; 36(13):1914–1917.
106. Laruelle M, Giddings SS, Zea-Ponce Y, Charney DS, Neumeyer JL, Baldwin RM, Innis RB.
Methyl 3 beta-(4-[125I]iodophenyl)tropane-2 beta-carboxylate in vitro binding to dopamine

Brain Imaging

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

317

and serotonin transporters under “physiological” conditions. J Neurochem 1994; 62(3):978–986.
Laruelle M, Baldwin RM, Malison RT, Zea-Ponce Y, Zoghbi SS, al-Tikriti MS, Sybirska
EH, Zimmerman RC, Wisniewski G, Neumeyer JL, et al. SPECT imaging of dopamine andserotonin transporters with [123I]beta- CIT: pharmacological characterization of brain uptake
in nonhuman primates. Synapse 1993; 13(4):295–309.
Brücke T, Kornhuber J, Angelberger P, Asenbaum S, Frassine H, Podreka I. SPECT imaging
of dopamine and serotonin transporters with [123I]β-CIT. Binding kinetics in the human brain.
J Neural Transm Gen Sect 1993; 94(2):137–146.
Pirker W, Asenbaum S, Kasper S, Walter H, Angelberger P, Koch G, Pozzera A, Deecke
L, Podreka I, Brucke T. Beta-CIT SPECT demonstrates blockade of 5HT-uptake sites bycitalopram in the human brain in vivo. J Neural Transm Gen Sect 1995; 100(3):247–256.
Seibyl JP, Marek KL, Quinlan D, Sheff K, Zoghbi S, Zea-Ponce Y, Baldwin RM, Fussell
B, Smith EO, Charney DS, et al. Decreased single-photon emission computed tomographic[123I]beta-CIT striatal uptake correlates with symptom severity in Parkinson’s disease. Ann
Neurol 1995; 38(4):589–598.
Marek KL, Seibyl JP, Zoghbi SS, Zea-Ponce Y, Baldwin RM, Fussel B, Charney DS, van
Dyck C, Hoffer PB, Innis RP. [123I] beta-CIT/SPECT imaging demonstrates bilateral lossof dopamine transporters in hemi-Parkinson’s disease. Neurology 1996; 46(1):231–237.
Eising EG, Muller TT, Zander C, Kuhn W, Farahati J, Reiners C, Coenen HH. SPECTevaluation of the monoamine uptake site ligand [I-123](1R)-2-beta-carbomethoxy-3-beta(4-iodophenyl)-tropane ([I-123]beta-CIT) in untreated patients with suspicion of Parkinson
disease. J Invest Med 1997; 45(8):448–452.
Seibyl JP, Marek K, Sheff K, Zoghbi S, Baldwin RM, Charney DS, van Dyck CH, Innis
RB. Iodine-123-beta-CIT and iodine-123-FPCIT SPECT measurement of dopamnine transporters in healthy subjects and Parkinson’s patients. J Nucl Med 1998; 39(9):1500–1508.
Muller U, Wachter T, Barthel H, Reuter M, von Cramon DY. Striatal [123I]beta-CIT SPECTand prefrontal cognitive functions in Parkinson’s disease. J Neural Transm 2000; 107(3):303–319.
Malison RT, Best SE, van Dyck CH, McCance EF, Wallace EA, Laruelle M, Baldwin RM,
Seibyl JP, Price LH, Kosten TR, Innis RB. Elevated striatal dopamine transporters during
acute cocaine abstinence as measured by [123I]beta-CIT SPECT. Am J Psychiatry 1998;
155(6):832–834.
Laruelle M, Abi-Dargham A, van Dyck C, Gil R, D’Souza DC, Krystal J, Seibyl J, Baldwin
R, Innis R. Dopamine and serotonin transporters in patients with schizophrenia: an imaging
study with [(123)I]beta-CIT. Biol Psychiatry 2000; 47(5):371–379.
Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L, Sanacora G,
Owens MJ, Nemeroff CB, Rajeevan N, Baldwin RM, Seibyl JP, Innis RB, Charney DS.
Reduced brain serotonin transporter availability in major depression as measured by [123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed
tomography. Biol Psychiatry 1998; 44(11):1090–1098.
Heinz A, Ragan P, Jones DW, Hommer D, Williams W, Knable MB, Gorey JG, Doty L.
Geyer C, Lee KS, Coppola R, Weinberger DR, Linnoila M: Reduced central serotonin transporters in alcoholism. Am J Psychiatry 1998; 155(11):1544–1549.
Heinz A, Knable MB, Wolf SS, Jones DW, Gorey JG, Hyde TM, Weinberger DR: Tourette’s
syndrome: [I-123]beta-CIT SPECT correlates of vocal tic severity. Neurology 1998; 51(4):1069–1074.
Malison RT, Price LH, Berman R, van Dyck CH, Pelton GH, Carpenter L, Sanacora G,
Owens MJ, Nemeroff CB, Rajeevan N, Baldwin RM, Seibyl JP, Innis RB, Charney DS.
Reduced brain serotonin transporter availability in major depression as measured by [123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed
tomography. Biol Psychiatry 1998; 44(11):1090–1098.

318

Talbot et al.

121. Willeit M, Praschak-Reider N, Neumeister A, Pirker W, Asenbaum S, Vitouch O, Tauscher
J, Hilger E, Stastny J, Brucke T, Kasper S. [123I]-beta-CIT SPECT imaging shows reduced
brain serotonin transporter availability in drug-free depressed patients with seasonal affective
disorder. Biol Psychiatry 2000; 47(6):482–489.
122. Suehiro M, Scheffel U, Ravert HT, Dannals RF, Wagner H, Jr. [11C](⫹)McN5652 as aradiotracer for imaging serotonin uptake sites with PET. Life Sci 1993; 53(11):883–892.
123. Szabo Z, Scheffel U, Suehiro M, Dannals RF, Kim SE, Ravert HT, Ricaurte Ga, Wagner
HN, Jr. Positron emission tomography of 5-HT transporter sites in the baboon brain with
[11C]McN5652. J Cereb Blood Flow Metab 1995; 15(5):798–805.
124. Szabo Z, Scheffel U, Mathews WB, Ravert HT, Szabo, Kraut M, Palmon S, Ricaurte GA,
Dannals RF. Kinetic analysis of [11C]McN5652: a serotonin transporter radioligand. J Cereb
Blood Flow Metab 1999; 19(9):967–981.
125. Parsey RV, Kegeles LS, Hwang DR, Simpson N, Abi-Dargham A, Mawlawi O, Slifstein
M, Van Heertum RL, Mann JJ, Laruelle M. In vivo quantiﬁcation of brain serotonin transporters in humans using [11C]McN 5652. J Nucl Med 2000; 41(9):1465–1477.
126. Buck A, Gucker PM, Schonbachler RD, Arigoni M, Kneifel S, Vollenweider FX, Ametamey
SM, Burger C. Evaluation of serotonergic transporters using PET and [11C](⫹)McN-5652:
assessment of methods. J Cereb Blood Flow Metab 2000; 20(2):253–262.
127. Parsey RV, Kegeles LS, Hwang DR, Simpson N, Abi-Dargham A, Mawlawi O, Slifstein
M, Van Heertum RL, Mann JJ, Laruelle M. In vivo quantiﬁcation of brain serotonin transporters in humans using [11C]McN 5652. J Nucl Med 2000: 41(9):1465–1477.
128. Oya S, Choi SR, Hou C, Mu M, Kung MP, Acton PD, Siciliano M, Kung HF. 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM): an improved serotonin transporter ligand. Nucl Med Biol 2000; 27(3)249–254.
129. Vercouillie J, Tarkiainen J, Halldin C, Edmond P, Chalon S, Sandell J, Langer O, Guilloteau
D. Precursor synthesis and radiolabeling of [11C]ADAM: a potent radioligand for the serotonin transporter exploration by PET. J Labelled Cpd Radiopharm 2001; 44:113–120.
130. Wilson AA, Ginovart N, Schmidt M, Meyer JH, Threlkeld PG, Houle S. Novel radiotracers
for imaging the serotonin transporter by positron emission tomography: synthesis, radiosynthesis, and in vitro and ex vivo evaluation of (11)C-labeled 2-(Phenylthio)araalkylamines.
J Med Chem 2000; 43(16):3103–3110.
131. Houle S, Ginovart N, Hussey D, Meyer JH, Wilson AA. Imaging the serotonin transporter
with positron emission tomography: initial human studies with [11C]DAPP and [11C]DASB[In Process Citation]. Eur J Nucl Med 2000; 27(11):1719–1722.
132. Kapur S, Mann JJ. Role of the dopaminergic system in depression. Biol psychiatry 1992;
32(1):1–17.
133. Brown AS, Gershon S. Dopamine and depression. J Neural Transm Gen Sec 1993; 91(2–3):75–109.
134. Diehl DJ, Gershon S. The role of dopamine in mood disorders. Comprehens Psychiatry 1992;
33(2):115–120.
135. Willner P, Muscat R, Papp M. Chronic mild stress-induced anhedonia: a realistic animalmodel of depression. Neurosci Biobehav Rev 1992; 16(4):525–534.
136. D’Haenen H A, Bossuyt A. Dopamine D2 receptors in depression measured with single
photon emission computed tomography. Biol Psychiatry 1994; 35(2):128–132.
137. Shah PJ, Ogilvie AD, Goodwin GM, Ebmeier KP. Clinical and psychometric correlates of
dopamine D2 binding in depression. Psychol Med 1997; 27(6):1247–1256.
138. Ebert D, Feistel H, Loew T, Pirner A. Dopamine and depression—strial dopamine D2 receptor SPECT before and after antidepressant therapy. Psychopharmacology 1996; 126(1):91–
94.
139. Klimbe A, Larisch R, Janz A, Vosberg H, Muller-Gartner HW, Gaebel W. Dopamine D2
receptor binding before and after treatment of major depression measured by [123I]IBZM
SPECT. Psychiatry Res 1999; 90(2):91–101.

Brain Imaging

319

140. Parsey RV, Oquendo MA, Zea-Ponce Y, Rodenhiser J, Kegeles LS, Pratap M, Cooper
TB, Van Heertum R, Mann JJ, Laruelle M. Dopamine D(2) receptor availability andamphetamine-induced dopamine release in unipolar depression. Biol Psychiatry 2001;
50(5):313–322.
141. Laasonen-Balk T, Kuikka J, Viinamaki H, Husso-Saastamoinen M, Lehtonen J, Tiihonen J.
Striatal dopamine transporter density in major depression. Psychopharmacologia 1999;
144(3):282–285.
142. Martinot M, Bragulat V, Artiges E, Dolle F, Hinnen F, Jouvent R, Martinot J. Decreased
presynaptic dopamine function in the left caudate of depressed patients with affective ﬂattening and psychomotor retardation. Am J Psychiatry 2001; 158(2):314–316.
143. Strakowski SM, DelBello MP, Adler C, Cecil DM, Sax KW. Neuroimaging in biopolar disorder. Bipolar Disord 2000; 2(3 Pt 1):148–164.
144. Stoll AL, Renshaw PF, Yurgelun-Todd DA, Cohen BM. Neuroimaging in bipolar disorder:
what have we learned? Biol Psychiatry 2000; 48(6):505–517.
145. Norris SD, Krishnan KR, Ahearn E. Structural changes in the brain of patients with bipolar
affective disorder by MRI: a review of the literature. Progr Neuro-Psychopharmacol Biol
Psychiatry 1997; 21(8):1323–1337.
146. Altshuler LL, Curran JG, Hauser P, Mintz J, Denicoff K, Post R. T2 hyperintensities inbioplar disorder: magnetic resonance imaging comparison and literature meta-analysis. Am
J Psychiatry 1995; 152(8):1139–1144.
147. Videbech P. MRI ﬁndings in patients with affective disorder: a meta-analysis. Acta Psychiatr
Scand 1997; 96(3):157–168.
148. Strakowski SM, Wilson DR, Tohen M, Woods BT, Douglass AW, Stoll AL. Structural brain
abnormalities in ﬁrst-episode mania. Biol Psychiatry 1993; 33(8–9):602–609.
149. Strakowski SM, Woods BT, Tohen M, Wilson DR, Douglass AW, Stoll AJ. MRI subcorticalsignal hyperintensities in mania at ﬁrst hospitalization. Biol Psychiatry 1993; 33(3):204–206.
150. Botteron KN, Vannier MW, Geller B, Todd RD, Lee BC. Preliminary study of magnetic
resonance imaging characteristics in 8- to 16-year-olds with mania. J Am Acad Child Adolesc
Psychiatry 1995; 34(6):742–749.
151. Botteron KN, Figiel GS, Wetzel MW, Hudziak J, VanEerdewegh M. MRI abnormalities inadolescent bipolar affective disorder. J Am Acad Child Adolesc Psychiatry 1992; 31(2):258–
261.
152. Krabbendam L, Honig A, Wiersma J, Vuurman EF, Hofman PA, Derix MM, Nolen WA,
Jolles J. Cognitive dysfunctions and white matter lesions in patients with bioplar disorderin remission. Acta Psychiatr Scand 2000: 101(4):274–280.
153. Moore PB, Shepherd DJ, Eccleston D, Macmillan IC, Goswami U, McAllister VL, Ferrier
IN. Cerebral white matter lesions in bipolar affective disorder: relationship to outcome. Br
J Psychiatry 2001; 178:172–176.
154. Moore PB, El-Badri SM, Cousins D, Shepherd DJ, Young AH, McAllister VL, Ferrier IN.
White matter lesions and season of birth of patients with bipolar affective disorder. Am J
Psychiatry 2001; 158(9):1521–1524.
155. Figiel GS, Krishnan KR, Rao VP, Doraiswamy M, Ellinwood EH, Jr., Nemeroff CB, Evans
D, Boyko O. Subcortical hyperintensities on brain magnetic resonance imaging: a comparisonof normal and bipolar subjects. J Neuropsych Clin Neurosci 1991; 3(1):18–22.
156. Hauser P, Matochik J, Altshuler LL, Denicoff KD, Conrad A, Li X, Post RM. MRI-based
measurements of temporal lobe and ventricular structures in patients with bioplar I and bipolar II disorders. J Affect Disord 2000; 60(1):25–32.
157. Roy PD, Zipursky RB, Saint-Cyr JA, Bury A, Langevin R, Seeman MV. Temporal hornenlargement is present in schizophrenia and bipolar disorder. Biol Psychiatry 1998; 44(6):418–422.
158. Zipursky RB, Seeman MV, Bury A, Langevin R, Wortzman G, Katz R. Deﬁcits in gray

320

159.

160.

161.
162.

163.

164.

165.

166.
167.

168.

169.

170.

171.
172.

173.

174.
175.
176.

Talbot et al.
matter volume are present in schizophrenia but not bipolar disorder. Schiz Res 1997; 26(2–3):85–92.
Sax KW, Strakowski SM, Zimmerman ME, DelBello MP, Keck PE, Jr., Hawkins JM. Frontosubcortical neuroanatomy and the continuous performance test in mania. Am J Psychiatry
1999; 156(1):139–141.
Swayze VW, 2nd, Andreasen NC, Alliger RJ, Yuh WT, Ehrhardt JC. Subcortical and temporal structures in affective disorder and schizophrenia: a magnetic resonance imaging study.
Biol Psychiatry 1992; 31(3):221–240.
Noga JT, Vladar K, Torrey EF. A volumetric magnetic resonance imaging study of monozygotic twins discordant for bipolar disorder. Psychiatry Res 2001; 106(1):25–34.
Altshuler LL, Bartzokis G, Grieder T, Jimenez T, Leigh K, Wilkins J, Gerner R, Mintz J.
An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia.
Biol Psychiatry 2000; 48(2):147–162.
Pearlson GD, Barta PE, Powers RE, Menon FIR, Richards SS, Aylward EH, Federman EB,
Chase GA, Petty FIG, Tien AY. Medial and superior temporal gyral volumes and cerebral
asymmetry in schizophrenia versus bipolar disorder. Biol Psychiatry 1997; 41:1–14.
Dasari M, Friedman L, Jesberger J, Stuve TA, Findling RL, Swales TP, Schulz SC. A magnetic resonance imaging study of thalamic area in adolescent patients with either schizophrenia or bipolar disorder as compared to healthy controls. Psychiatry Res 1999; 91(3):155–
162.
DelBello MP, Strakowski SM, Zimmerman ME, Hawkins JM, Sax KW. MRI analysis of
the cerebellum in bipolar disorder: a pilot study. Neuropsychopharmacology 1999; 21(1):63–68.
Drevets WC, Price JL, Simpson JR, Jr., Todd RD, Reich T, Vannier M, Raichle ME. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997; 386(6627):824–827.
Moore CM, Breeze JL, Gruber SA, Babb SM, Frederick BB, Villafuerte RA, Stoll AL, Hennen J, Yurgelun-Todd DA, Cohen BM, Renshaw PF. Choline, myo-inositol and mood in
bipolar disorder: a proton magnetic resonance spectroscopic study of the anterior cingulate
cortex. Bipolar Disord 2000; 2(3 Pt 2):207–216.
Davanzo P, Thomas MA, Yue K, Oshiro T, Belin T, Strober M, McCracken J. Decreased
anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment inchildren with bipolar disorder. Neuropsychopharmacology 2001; 24(4):359–369.
Brambilla P, Harenski K, Nicoletti M, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS,
Soares JC. Differential effects of age on brain gray matter in bipolar patients and healthy
individuals. Neuropsychobiology 2001; 43(4):242–247.
Sassi RB, Nicoletti M, Brambilla P, Harenski K, Mallinger AG, Frank E, Kupfer DJ, Keshavan MS, Soares JC. Decreased pituitary volume in patients with bipolar disorder. Biol Psychiatry 2001; 50(4)271–280.
Yildiz A, Sachs GS, Dorer DJ, Renshaw PF. 31P Nuclear Magnetic resonance spectroscopyﬁndings in biopolar illness: a meta-analysis. Psychiatry Res 2001; 106(3):181–191.
Kato T, Hamakawa H, Shioiri T, Murashita J, Takahashi Y, Takahashi S, Inubushi T. Choline-containing compounds detected by proton magnetic resonance spectroscopy in the basal
ganglia in bipolar disorder. J Psychiatry Neurosci 1996; 21(4):248–254.
Hamakawa H, Kato T, Murashita J, Kato N. Quantitative proton magnetic resonance spectroscopy of the basal ganglia in patients with affective disorders. Eur Arch Psychiatry Clin Neurosci 1998; 248(1):53–58.
Kato T, Inubushi T, Kato N. Magnetic resonance spectroscopy in affective disorders. J Neuropsychiatry Clin Neurosci 1998; 10(2):133–147.
Sharma R, Venkatasubramanian PN, Barany M, Davis JM. Proton magnetic resonance spectroscopy of the brain in schizophrenic and affective patients. Schiz Res 1992; 8(1):43–49.
Deicken RF, Eliaz Y, Feiwell R, Schuff N. Increased thalamic N-acetylaspartate in malepatients with familial bipolar I disorder. Psychiatry Res 2001; 106(1):35–45.

Brain Imaging

321

177. Hamakawa H, Kato T, Shioiri T, Inubushi T, Kato N. Quantitative proton magnetic resonancespectroscopy of the bilateral frontal lobes with bipolar disorder. Psychol Med 1999; 29(3):639–644.
178. Winsberg ME, Sachs N, Tate DL, Adalsteinsson E, Spielman D, Ketter TA. Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder. Biol Psychiatry 2000; 47(6):475–
481.
179. Moore GJ, Bebchuk JM, Parrish JK, Faulk MW, Arfken CL, Strahl-Bevacqua J, Manji HK.
Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol andclinical response in manic-depressive illness. Am J Psychiatry 1999; 156(12):1902–1908.
180. Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW,
Koch S, Glitz DA, Jolkovsky L, Manji HK. Lithium increased N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2’s neurotrophic effects? Biol Psychiatry 2000;
48(1):1–8.
181. Manji HK, Moore GJ, Chen G. Clinical and preclinical evidence for the neurotrophic effects
of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive
illness. Biol Psychiatry 2000; 48(8):740–754.
182. Castillo M, Kwock L, Courvoisie H, Hooper SR. Proton MR spectroscopy in children withbipolar affective disorder: preliminary observations. Ajnr: Am J Neuroradiol 2000; 21(5):832–838.
183. Levine J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW. Increased
cerebrospinal ﬂuid glutamine levels in depressed patients. Biol Psychiatry 2000; 47(7):586–
593.
184. Loeber RT, Sherwood AR, Renshaw PF, Cohen BM, Yurgelun-Todd DA. Differences incerebellar blood volume in schizophrenia and bipolar disorder. Schiz Res 1999; 37(1):81–89.
185. Yurgelun-Todd DA, Gruber SA, Kanayama G, Killgore WD, Baird AA, Young AD. fMRI
during affect discrimination in bipolar affective disorder. Bipolar Disord 2000; 2(3 Pt 2):
237–248.
186. Tutus A, Simsek A, Sofuoglu S, Nardali M, Kugu N, Karaaslan F, Gonul AS. Changes inregional cerebral blood ﬂow demonstrated by single photon emission computed tomography
in depressive disorders: comparison of unipolar vs. bipolar subtypes. Psychiatry Res 1998;
83(3):169–177.
187. Shimizu E, Kodama K, Sakamoto T, Komatsu N, Yamanouchi N, Okada S, Sato T. Recovery
from neuroendocrinological abnormalities and frontal hypoperfusion after remission in a casewith rapid cycling bipolar disorder. Psychiary Clin Neurosci 1997; 51(4):207–212.
188. Baxter LR Jr., Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, Gerner RH,
Sumida RM. Reduction of prefrontal cortex glucose metabolism common to three types ofdepression. Arch Gen Psychiatry 1989; 46(3):243–250.
189. al-Mousawi AH, Evans N, Ebmeier KP, Roeda D, Chaloner F, Ashcroft GW. Limbic dysfunction in schizophrenia and mania. A study using 18F-labelled ﬂuorodeoxyglucose andpositron emission tomography. Br J Psychiatry 1996; 169(4):509–516.
190. Goodwin GM, Cavanagh JT, Glabus MF, Kehoe RF, O’Carroll RE, Ebmeier KP. Uptake of
99mTc-exametazime shown by single photon emission computed tomography before andafter lithium withdrawal in bipolar patients: associations with mania. Br J Psychiatry 1997;
170:426–430.
191. Blumberg HP, Stern E, Ricketts S, Martinez D, de Asis J, White T, Epstein J, Isenberg N,
McBride PA, Kemperman I, Emmerich S, Dhawan V, Eidelberg D, Kocsis JH, Silbersweig
DA. Rostral and oribital prefrontal cortex dysfunction in the manic state of bipolar disorder.
Am J Psychiatry 1999; 156(12):1986–1988.
192. Ketter TA, Kimbrell TA, George MS, Dunn RT, Speer AM, Benson BE, Willis MW, Danielson A, Frye MA, Herscovitch P, Post RM. Effects of mood and subtype on cerebral glucose
metabolism in treatment-resistant bipolar disorder. Biol Psychiatry 2001; 49(2):97–109.

322

Talbot et al.

193. Suhara T, Nakayama K, Inoue O, Fukuda H, Shimizu M, Mori A, Tateno Y. D1 dopamine
receptor binding in mood disorders measured by positron emission tomography. Psychopharmacology 1992; 106(1):14–18.
194. Wong WF, Pearlson GD, Tune LE, Young LT, Meltzer CC, Dannals RF, Ravert HT, Reith
J, Kuhar MJ, Gjedde A. Quantiﬁcation of neuroreceptors in the living human brain: IV. Effectof aging and elevations of D2-like receptors in schizophrenia and bipolar illness. J Cereb
Blood Flow Metab 1997; 17(3):331–342.
195. Gjedde A, Wong DF. Quantiﬁcation of neuroreceptors in living human brain. V. Endogenous
neurotransmitter inhibition of haloperidol binding in psychosis. J Cereb Blood Flow Metab
2001; 21(8):982–994.
196. Anand A, Verhoeff P, Seneca N, Zoghbi SS, Seibyl JP, Charney DS, Innis RB. Brain SPECT
imaging of amphetamine-induced dopamine release in euthymic bipolar disorder patients.
Am J Psychiatry 2000; 157(7):1108–1114.
197. Tauscher J, Bagby RM, Javanmard M, Christensen BK, Kasper S, Kapur S. Inverse relationship between serotonin 5-HT1A receptor binding and anxiety: A [11C]WAY-100635 PET
investigation in healthy volunteers. Am J Psychiatry 2001; 158(8):1326–1328.
198. Zhuang X, Gross C, Santarelli L, Compan V, Trillat AC, Hen R. Altered emotional statesin knockout mice lacking 5-HT1A or 5-HT1B receptors. Neuropsychopharmacology 1999;
21(2 Suppl):52S–60S.
199. Grachev ID, Apkarian AV. Anxiety in healthy humans is associated with orbital frontal chemistry. Mol Psychiatry 2000; 5(5):482–488.
200. Grachev ID, Apkarian AV. Chemical mapping of anxiety in the brain of healthy humans:
an in vivo 1H-MRS study on the effects of sex, age, and brain region. Hum Brain Mapping
2000; 11(4):261–272.
201. Benkelfat C, Bradwejn J, Meyer E, Ellenbogen M, Milot S, Gjedde A, Evans A. Functional
neuroanatomy of CCK-4-induced anxiety in normal healthy volunteers. [see comments]. Am
J Psychiatry 1995; 152(8):1180–1184.
202. Javanmard M, Shlik J, Kennedy SH, Vaccarino FJ, Houle S, Bradwejn J. Neuroanatomic
correlates of CCK-4-induced panic attacks in healthy humans: a comparison of two time
points. Biol Psychiatry 1999; 45(7):872–882.
203. Chua P, Krams M, Toni I, Passingham R, Dolan R. A functional anatomy of anticipatory
anxiety. Neuroimage 1999; 9(6 Pt 1):563–571.
204. Simpson JR, Jr, Drevets WC, Snyder AZ, Gusnard DA, Raichle ME. Emotion-inducedchanges in human medial prefrontal cortex: II. During anticipatory anxiety. Proc Natl Acad
Sci USA 2001; 98(2):688–693.
205. Kimbrell TA, George MS, Parekh PI, Ketter TA, Podell DM, Danielson AL, Repella JD,
Benson BE, Willis MW, Herscovitch P, Post, RM. Regional brain activity during transient
self-induced anxiety and anger in healthy adults. Biol Psychiatry 1999; 46(4):454–465.
206. Liotti M, Mayberg HS, Brannan SK, McGinnis S, Jerabek P, Fox PT. Differential limbic—
cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders. Biol Psychiatry 2000; 48(1):30–42.
207. Osuch EA, Ketter TA, Kimbrell TA, George MS, Benson BE, Willis MW, Herscovitch P,
Post RM. Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients. Biol Psychiatry 2000; 48(10):1020–1023.
208. Reiman EM. The application of positron emission tomography to the study of normal andpathologic emotions. J Clin Psychiatry 1997; 58(Suppl 16):4–12.
209. Rauch SL, Savage CR, Alpert NM, Fischman AJ, Jenike MA. The functional neuroanatomyof anxiety: a study of three disorders using positron emission tomography and symptom
provocation. Biol Psychiatry 1997; 42(6):446–452.
210. De Bellis MD, Casey BJ, Dahl RE, Birmaher B, Williamson DE, Thomas KM, Axelson DA,
Frustaci K, Boring AM, Hall J, Ryan ND. A pilot study of amygdala volumes in pediatricgeneralized anxiety disorder. Biol Psychiatry 2000; 48(1):51–57.

Brain Imaging

323

211. Wu JC, Buchsbaum MS, Hershey TG, Hazlett E, Sicotte N, Johnson JC. PET in generalized
anxiety disorder. Biol Psychiatry 1991; 29(12):1181–1199.
212. Tiihonen J, Kuikka J, Rasanen P, Lepola U, Koponen H, Liuska A, Lehmusvaara A, Vainio P,
Kononen M, Bergstrom K, Yu M, Kinnunen I, Akerman K, Karhu J. Cerebral benzodiazepine
receptor binding and distribution in generalized anxiety disorder: a fractal analysis. Mol Psychiatry 1997; 2(6):463–471.
213. Abadie P, Boulenger JP, Benali K, Barre L, Zariﬁan E, Baron JC. Relationships between
trait and state anxiety and the central benzodiazepine receptor: a PET study. Eur J Neurosci
1999; 11(4):1470–1478.
214. Ontiveros A, Fontaine R, Breton G, Elie R, Fontaine S, Dery R. Correlation of severity ofpanic disorder and neuroanatomical changes on magnetic resonance imaging. J Neuropsychiatry Clin Neurosci 1989; 1(4):404–408.
215. Fontaine R, Breton G, Dery R, Fontaine S, Elie R. Temporal lobe abnormalities in panic
disorder: an MRI study. Biol Psychiatry 1990; 27(3):304–310.
216. Dantendorfer K, Prayer D, Kramer J, Amering M, Baischer W, Berger P, Schoder M, Steinberger K, Windhaber J, Imhof H, Katsching H. High frequency of EEG and MRI brain
abnormalities in panic disorder. Psychiatry Res 1996; 68(1):41–53.
217. Vythilingam M, Anderson ER, Goddard A, Woods SW, Staib LH, Charney DS, Bremner
JD. Temporal lobe volume in panic disorder—a quantitative magnetic resonance imaging
study. Psychiatry Res Neuroimag 2000; 99(2):75–82.
218. Reiman EM, Raichle ME, Butler FK, Herscovitch P, Robins E. A focal brain abnormality
in panic disorder, a severe form of anxiety. Nature 1984; 310(5979):683–685.
219. Reiman EM, Raichle ME, Robins E, Butler FK, Herscovitch P, Fox P, Perlmutter J. The
application of positron emission tomography to the study of panic disorder. Am J Psychiatry
1986; 143(4):469–477.
220. Bisaga A, Katz J, Antonini A, Wright E, Margouleff C, Gorman J, Eidelberg D. Cerebral
glucose metabolism in women with panic disorder. Am J Psychiatry 1998; 155:1178–
1183.
221. Nordahl TE, Stein MB, Benkelfat C, Semple WE, Andreason P, Zametkin A, Uhde TW,
Cohen RM. Regional cerebral metabolic asymmetries replicated in an independent group ofpatients with panic disorders. Biol Psychiatry 1998; 44(10):998–1006.
222. Nordahl TE, Semple WE, Gross M, Mellman TA, Stein MB, Goyer P, King AC, Uhde TW,
Cohen RM. Cerebral glucose metabolic differences in patients with panic disorder. Neuropsychopharmacology 1990; 3(4):261–272.
223. De Cristofaro MT, Sessarego A, Pupi A, Biondi F, Faravelli C. Brain perfusion abnormalities
in drug-naive, lactate-sensitive panic patients: a SPECT study. Biol Psychiatry 1993;33(7):505–512.
224. Kaschka W, Feistel H, Ebert D. Reduced benzodiazepine receptor binding in panic disorders
measured by iomazenil SPECT. J Psychiatric Res 1995; 29(5):427–434.
225. Kuikka J, Pitkanen A, Lepola U, Partanen K, Vainio P, Bergstrom K, Wieler H, Kaiser K,
Mittelbach L, Koponen H. Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder. Nucl Med Commun 1995; 16:273–280.
226. Brandt CA, Meller J, Keweloh L, Hoschel K, Staedt J, Munz D, Stoppe G. Increased benzodiazepine receptor density in the prefrontal cortex in patients with panic disorder. J Neur
Transm (Budapest) 1998; 105(12–12):1325–1333.
227. Bremner JD, Innis RB, White T, Fujita M, Silbersweig D, Goddard AW, Staib L, Stern E,
Cappiello A, Woods S, Baldwin R, Charney DS. SPECT [I-123]iomazenil measurement of
the benzodiazepine receptor in panic disorder. Biol Psychiatry 2000; 47(2):96–106.
228. Malizia AL, Cunningham VJ, Bell CJ, Liddle PF, Jones T, Nutt DJ. Decreased brain
GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from aquantitative PET study. Arch Gen Psychiatry 1998; 55(8):715–720.
229. Goddard AW, Mason GF, Almai A, Rothman DL, Behar KL, Petroff OA, Charney DS,

324

230.

231.
232.

233.

234.
235.

236.

237.

238.
239.
240.

241.
242.
243.
244.

245.

246.
247.

Talbot et al.
Krystal JH. Reductions in occipital cortex GABA levels in panic disorder detected with 1hmagnetic resonance spectroscopy. Arch Gen Psychiatry 2001; 58(6):556–561.
Dager SR, Friedman SD, Heide A, Layton ME, Richards T, Artru A, Strauss W, Hayes
C, Posse S. Two-dimensional proton echo-planar spectroscopic imaging of brain metabolicchanges during lactate-induced panic. Arch Gen Psychiatry 1999; 56(1):70–77.
Dager SR, Richards T, Strauss W, Artru A. Single-voxel 1H-MRS investigation of brain
metabolic changes during lactate-induced panic. Psychiatry Res 1997; 76(2–3):89–99.
Dager SR, Marro KI, Richards TL, Metzger GD. Preliminary application of magnetic resonance spectroscopy to investigate lactate-induced panic. Am J Psychiatry 1994; 151(10:57–
63.
Dager SR, Strauss WL, Marro KI, Richards TL, Metzger GD, Artru AA. Proton magnetic
resonance spectroscopy investigation of hyperventilation in subjects with panic disorder andcomparison subjects. Am J Psychiatry 1995; 152(5):666–672.
Wik G, Fredrikson M, Ericson K, Eriksson L, Stone-Elander S, Greitz T. A functional cerebral response to frightening visual stimulation. Psychiatry Res 1993; 50(1):15–24.
Fredrikson M, Wik G, Annas P, Ericson K, Stone-Elander S. Functional neuroanatomy ofvisually elicited simple phobic fear: additional data and theoretical analysis. Psychophysiology 1995; 32(1):43–48.
Rauch SL, Savage CR, Alpert NM, Miguel EC, Baer L, Breiter HC, Fischman, AJ, Manzo
PA, Moretti C, Jenike MA. A positron emission tomographic study of simple phobic symptom provocation. Arch Gen Psychiatry 1995; 52(1):20–28.
Fredrikson M, Wik G, Greitz T, Eriksson L, Stone-Elander S, Ericson K, Sedvall G. Regional
cerebral blood ﬂow during experimental phobic fear. Psychophysiology 1993; 30(1):126–
130.
Wik G, Fredrikson M, Fischer H. Evidence of altered cerebral blood-ﬂow relationships inacute phobia. Int J Neurosci 1997; 91(3–4):253–263.
Wik G, Fredrikson M, Fischer H. Cerebral correlates of anticipated fear: a PET study of
speciﬁc phobia. Int J Neurosci 1996; 87(3–4):267–276.
O’Carroll RE, Moffoot AP, Van Beck M, Dougall N, Murray C, Ebmeier KP, Goodwin GM.
The effect of anxiety induction on the regional uptake of 99mTc-exametazime in simple
phobia is shown by single photon emission tomography (SPET). J Affect Disord 1993; 28(3):203–210.
Dewar KM, Stravynski A. The quest for biological correlates of social phobia: an interim
assessment. Acta Psychiatr Scand 2001; 103(4):244–251.
Mathew SJ, Coplan JD, Gorman JM. Neurobiological mechanisms of social anxiety disorder.
Am J Psychiatry 2001; 158(10):1558–1567.
Potts NL, Davidson JR, Krishnan KR, Doraiswamy PM. Magnetic resonance imaging insocial phobia. Psychiatry Res 1994; 52(1):35–42.
Davidson JR, Krishnan KR, Charles HC, Boyko O, Potts NL, Ford SM, Patterson L. Magnetic
resonance spectroscopy in social phobia: preliminary ﬁndings. J Clin Psychiatry 1993;
54(Suppl):19–25.
Tupler LA, Davidson JR, Smith RD, Lazeyras F, Charles HC, Kirshnan KR. A repeat proton
magnetic resonance spectroscopy study in social phobia. Biol Psychiatry 1997; 42(6):419–
424.
Stein MB, Leslie WD. A brain single photon-emission computed tomography (SPECT) studyof generalized social phobia. Biol Psychiatry 1996; 39(9):825–828.
Van der Linden G, van Heerden B, Warwick J, Wessels C, van Kradenburg J, Zungu-Dirwayi
N, Stein DJ. Functional brain imaging and pharmacotherapy in social phobia: single photon
emission computed tomography before and after treatment with the selective serotonin reuptake inhibitor citalopram. Progr Neuro-Psychopharmacol Biol Psychiatry 2000; 24(3):419–
438.

Brain Imaging

325

248. Bell CJ, Malizia AL, Nutt DJ. The neurobiology of social phobia. [Review]. Eur Arch Psychiatry Clin Neurosci 1999; 249(Suppl):S11–S18.
249. Tillfors M, Furmark T, Marteinsdottir I, Fischer H, Pissiota A, Langstrom B, Fredrikson M.
Cerebral blood ﬂow in subjects with social phobia during stressful speaking tasks: A PET
study. Am J Psychiatry 2001; 158(8):1220–1226.
250. Birbaumer N, Grodd W, Diedrich O, Klose U, Erb M, Lotze M, Schneider F, Weiss U, Flor
H. fMRI amygdala activation to human faces in social phobics. Neuroreport 1998; 9(6):1223–1226.
251. Schneider F, Weiss U, Kessler C, Muller-Gartner HW, Posse S, Salloum JB, Grodd W,
Himmelmann F, Graebel W, Birbaumer N. Subcortical correlates of differential classicalconditioning of aversive emotional reactions in social phobia. Biol Psychiatry 1999; 45(7):863–871.
252. Tiihonen J, Kuikka J, Bergstrom K, Lepola U, Koponen H, Leinonen E. Dopamine reuptake
site densities in patients with social phobia. Am J Psychiatry 1997; 154(2):239–242.
253. Schneier FR, Leibowitz MR, Abi-Dargham A, Zea-Ponce Y, Lin SH, Laruelle M. Dopamine
reuptake site densities in patients with social phobia. Am J Psychiatry 2000; 157(3):457–
459.
254. Breier A, Kestler L, Adler C, Elman I, Wiesenfeld N, Malhotra A, Pickar D. Dopamine D2
receptor density and personal detachment in healthy subjects. Am J Psychiatry 1998; 155(10):1440–1442.
255. Kestler LP, Malhotra AK, Finch C, Adler C, Breier A. The relation between dopamine D2
receptor density and personality: Preliminary evidence from the NEO Personality InventoryRevised. Neuropsychiatry Neuropsychol Behav Neurol 2000; 13(1):48–52.
256. Laakso A, Vilkman H, Kajander J, Bergman J, Haaparanta M, Solin O, Hietala J. Predictionof detached personality in healthy subjects by low dopamine transporter binding. Am J Psychiatry 2000; 157(2):290–292.
257. Schneier FR, Leibowitz MR, Laruelle M. Detachment and generalized social phobia. Am J
Psychiatry 2001; 158(2):327.
258. Kent J, Coplan JD, Lombardo I, Parsey RV, Hwang DR, Simpson N, Mawlawi O, Anderson
A, Mann JJ, Van Heertum R, Gorman JM, Laruelle M. Imaging the serotonin transporter insocial phobia with (⫹)[C-11]McN5652. J Nucl Med 2000; 41:200P.
259. Saxena S, Bota RG, Brody AL. Brain-behavior relationships in obsessive-compulsive disorder. Sem Clin Neuropsychiatry 2001; 6(2):82–101.
260. Saxena S, Rauch SL. Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder. Psychiatric Clin North Am 2000; 23(3):563–586.
261. Perani D, Colombo C, Bressi S, Bonfanti A, Grassi F, Scarone S, Bellodi, Smeraldi E, Fazio
F. [18F]FDG PET study in obsessive-compulsive disorder. A clinical/metabolic correlation
study after treatment. Br J Psychiatry 1995; 166(2):244–250.
262. Nordahl TE, Benkelfat C, Semple WE, Gross M, King AC, Cohen RM. Cerebral glucose
metabolic rates in obsessive compulsive disorder. Neuropsychopharmacology 1989; 2(1):
23–28.
263. Swedo SE, Schapiro MB, Grady CL, Cheslow DL, Leonard HL, Kumar A, Friedland R,
Rapoport SI, Rapoport JL. Cerebral glucose metabolism in childhood-onset obsessivecompulsive disorder. Arch Gen Psychiatry 1989; 46(6):518–523.
264. Baxter LR, Jr, Phelps ME, Mazziotta JC, Guze BH, Schwartz JHM, Selin CE. Local cerebral
glucose metabolic rates in obsessive-compulsive disorder. A comparison with rates in unipolar metabolic rates in obsessive-compulsive disorder. A comparison with rates in unipolar
depression and in normal controls. [see comments]. [erratum appears in Arch Gen Psychiatry
1987 Sep;44(9):800]. Arch Gen Psychiatry 1987; 44(3):211–218.
265. Baxter LR, Jr, Schwartz JM, Mazziotta JC, Phelps ME, Pahl JJ, Guze BH, Fairbanks L.
Cerebral glucose metabolic rates in nondepressed patients with obsessive-compulsive disorder. Am J Psychiatry 1988; 145(12):1560–1563.

326

Talbot et al.

266. Adler CM, McDonough-Ryan P, Sax KW, Holland SK, Arndt S, Strakowski SM. fMRI
of neuronal activation with symptom provocation in unmedicated patients with obsessive
compulsive disorder. J Psychiatric Res 2000: 34(4–5):317–324.
267. McGuire PK, Bench CJ, Frith CD, Marks IM, Frackowiak RS, Dolan RJ. Functional anatomyof obsessive-compulsive phenomena. Br J Psychiatry 1994; 164(4):459–468.
268. Breiter HC, Rauch SL, Kwong KK, Baker JR, Weisskoff RM, Kennedy DN, Kendrick AD,
Davis TL, Jiang A, Cohen MS, Stern CE, Belliveau JW, Baer L, O’Sullivan RL, Savage
CR, Jenike JA, Rosen BR. Functional magnetic resonance imaging of symptom provocationin obsessive-compulsive disorder. Arch Gen Psychiatry 1996; 53(7):595–606.
269. Rauch SL, Jenike MA, Alpert NM, Baer L, Breiter HC, Savage CR, Fischman AJ. Regional
cerebral blood ﬂow measured during symptom provocation in obsessive-compulsive disorderusing oxygen 15-labeled carbon dioxide and positron emission tomography [see comments].
Arch Gen Psychiatry 1994; 51(1):62–70.
270. Pujol J, Torres L, Deus J, Cardoner N, Pifarre J, Capdevila A, Vallejo J. Functional magnetic
resonance imaging study of frontal lobe activation during word generation in obsessivecompulsive disorder. Biol Psychiatry 1999; 45(7):891–897.
271. Schwartz JM, Stoessel PW, Baxter LR, Jr, Martin KM, Phelps ME. Systematic changes incerebral glucose metabolic rate after successful behavior modiﬁcation treatment of obsessivecompulsive disorder. Arch Gen Psychiatry 1996; 53(2):109–113.
272. Swedo SE, Pietrini P, Leonard HL, Schapiro MB, Rettew DC, Goldberger EL, Rapoport SI,
Rapoport JL, Grady CL. Cerebral glucose metabolism in childhood-onset obsessivecompulsive disorder. Revisualization during pharmacotherapy. Arch Gen Psychiatry 1992;
49(9):690–694.
273. Benkelfat C, Nordahl TE, Semple WE, King AC, Murphy DL, Cohen RM. Local cerebral
glucose metabolic rates in obsessive-compulsive disorder. Patients treated with clomipramine. Arch Gen Psychiatry 1990; 47(9):840–848.
274. Biver F, Goldman S, Francois A, De La Porte C, Luxen A, Gribomont B, Lotstra F. Changes
in metabolism of cerebral glucose after stereotactic leukotomy for refractory obsessivecompulsive disorder: a case report. J Neurol Neurosurg Psychiatry 1995; 58(4):502–
505.
275. Saxena S, Brody AL, Maidment KM, Dunkin JJ, Colgan M, Alborzian S, Phelps ME, Baxter
LR, Jr. Localized orbitofrontal and subcortical metabolic changes and predictors of response
to paroxetine treatment in obsessive-compulsive disorder. Neuropsychopharmacology 1999;
21(6):683–693.
276. Brody AL, Saxena S, Schwartz JM, Stoessel PW, Maidment K, Phelps ME, Baxter LR, Jr.
FDG-PET predictors of response to behavioral therapy and pharmacotherapy in obsessive
compulsive disorder. Psychiatry Res 1998; 84(1):1–6.
277. Mallet L, Mazoyer B, Martinot JL. Functional connectivity in depressive, obsessive-compulsive, and schizophrenic disorders: an explorative correlational analysis of regional cerebral
metabolism. Psychiatry Res 1998; 82(2):83–93.
278. Horwitz B, Swedo SE, Grady CL, Pietrini P, Schapiro MB, Rapoport JL, Rapoport SI. Cerebral metabolic pattern in obsessive-compulsive disorder: altered intercorrelations between
regional rates of glucose utilization. Psychiatry Res 1991; 40(4):221–237.
279. Rauch SL, Savage CR, Alpert NM, Dougherty D, Kendrick A, Curran T, Brown HD, Manzo
P, Fischman AJ, Jenike MA. Probing striatal function in obsessive-compulsive disorder: a
PET study of implicit sequence learning. J Neuropsychiatry Clin Neurosci 1997; 9(4):568–
573.
280. Grachev ID, Breiter HC, Rauch SL, Savage CR, Baer L, Shera DM, Kennedy DN, Makris
N, Caviness VS. Structural abnormalities of frontal neocortex in obsessive-compulsive disorder. Arch Gen Psychiatry 1998; 55(5):181–182.
281. Jenike MA, Breiter HC, Baer L, Kennedy DN, Savage CR, Olivares MJ, O’Sullivan RL,
Shera DM, Rauch SL, Keuthen N, Rosen BR, Caviness VS, Filipek PA. Cerebral structural

Brain Imaging

282.

283.

284.

285.

286.

287.

288.

289.

290.

291.

292.
293.

294.

295.

296.

297.

298.

327

abnormalities in obsessive-compulsive disorder. A quantitative morphometric magnetic resonance imaging study. Arch Gen Psychiatry 1996; 53(7):625–632.
Breiter HC, Filipek PA, Kennedy DN, Baer L, Pitcher DA, Olivares MJ, Renshaw PF, Caviness FS, Jr. Retrocallosal white matter abnormalities in patients with obsessive-compulsive
disorder. Arch Gen Psychiatry 1994; 51(8):663–664.
Kim JJ, Lee MC, Kim J, Kim IY, Kim SI, Han MH, Chang KH, Kwon JS. Grey matter
abnormalities in obsessive-compulsive disorder: statistical parametric mapping of segmented
magnetic resonance images. Br J Psychiatry 2001; 179:330–334.
Szeszko PR, Robinson D, Alvir JM, Bilder RM, Lencz T, Ashtari M, Wu H, Bogerts B.
Orbital frontal and amygdala volume reductions in obsessive-compulsive disorder. Arch Gen
Psychiatry 1999; 56(10):913–919.
Gilbert AR, Moore GJ, Keshaven MS, Paulson LA, Narula V, Mac Master FP, Stewart CM,
Rosenberg DR. Decrease in thalamic volumes of pediatric patients with obsessive-compulsive disorder who are taking paroxetine. Arch Gen Psychiatry 2000; 57(5):449–556.
Rosenberg DR, Keshavan MS, O’Hearn KM, Dick EL, Bagwell WW, Seymour AB, Montrose DM, Pierri JN, Birmaher B. Frontostriatal measurement in treatment-naive children
with obsessive-compulsive disorder. Arch Gen Psychiatry 1997; 54(9):824–830.
Robinson D, Wu H, Munne RA, Ashtari M, Alvir JM, Lerner G, Koreen A, Cole K, Bogerts
B. Reduced caudate nucleus volume in obsessive-compulsive disorder. Arch Gen Psychiatry
1995; 52(5):393–398.
Scarone S, Colombo C, Livian S, Abbruzzese M, Ronchi P, Locatelli M, Scotti G, Smeraldi
E. Increased right caudate nucleus size in obsessive-compulsive disorder: detection with magnetic resonance imaging. Psychiatry Res 1992; 45(2):115–121.
Aylward EH, Harris GJ, Hoehn-Saric R, Barta PE, Machlin SR, Pearlson GD. Normal caudate nucleus in obsessive-compulsive disorder assessed by quantitative neuroimaging. ArchGen Psychiatry 1996; 53(7):577–584.
Bartha R, Stein MB, Williamson PC, Drost DJ, Neufeld RW, Carr TJ, Canaran G, Densmore
M, Anderson G, Siddiqui AR. A short echo 1H spectroscopy and volumetric MRI study ofthe corpus striatum in patients with obsessive-compulsive disorder and comparison subjects.
Am J Psychiatry 1998; 155(11):1584–1591.
Stein DJ, Coetzer R, Lee M, Davids B, Bouwer C. Magnetic resonance brain imaging in
women with obsessive-compulsive disorder and trichotillomania. Psychiatry Res 1997; 74(3):177–182.
Kellner CH, Jolley RR, Holgate RC, Austin L. Lydiard RB, Laraia M, Ballenger JC. Brain
MRI in obsessive-compulsive disorder. Psychiatry Res 1991; 36(1):45–49.
Ebert D, Speck O, Konig A, Berger M, Henning J, Hohagen F. 1H-magnetic resonance spectroscopy in obsessive-compulsive disorder: evidence for neuronal loss in the cingulate gyrus
and the right striatum. Psychiatry Res 1997; 74(3):173–176.
Fitzgerald KD, Moore GJ, Paulson LA, Stewart CM, Rosenberg DR. Proton spectroscopic
imaging of the thalamus in treatment-naive pediatric obsessive-compulsive disorder. Biol
Psychiatry 2000; 47(3):174–182.
Ohara K, Isoda H, Suzuki Y, Takehara Y, Ochiai M, Takeda H, Igarashi Y. Proton magnetic
resonance spectroscopy of lenticular nuclei in obsessive-compulsive disorder. Psychiatry Res.
Neuroimag 1999; 92(2–3):83–91.
Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart CM, Moore GJ. Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorderpatients taking paroxetine. J Am Child Adolesc Psychiatry 2000; 39(9):1096–1103.
Moore GJ, MacMaster FP, Stewart C, Rosenberg DR. Case study: caudate glutamatergicchanges with paroxetine therapy for pediatric obsessive-compulsive disorder. J Am Acad
Child Adolesc Psychiatry 1998; 37(6):663–667.
Newport DJ, Nemeroff CB: Neurobiology of posttraumatic stress disorder. Curr Opin Neurobiol 2000; 10(2):211–218.

328

Talbot et al.

299. Villarreal G, King CY. Brain imaging in posttraumatic stress disorder. Sem Clin Neuropsychiatry 2001; 6(2):131–145.
300. Pitman RK, Shin LM, Rauch SL. Investigating the pathogenesis of posttraumatic stress disorder with neuroimaging. J Clin Psychiatry 2001; 62(Suppl 17):47–54.
301. De Bellis MD, Keshavan MS, Clark DB, Casey BJ, Giedd JN, Boring AM, Frustaci K, Ryan
ND. A.E. Bennett Research Award. Developmental traumatology. Part II: Brain development. Biol Psychiatry 1999; 45(10):1271–1284.
302. Carrion VG, Weems CF, Eliez S, Patwardhan A, Brown W, Ray RD, Reiss AL. Attenuationof frontal asymmetry in pediatric posttraumatic stress disorder. Biol Psychiatry 2001; 50(12):943–951.
303. Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM, Delaney RC,
McCarthy G, Charney DS, Innis RB. MRI-based measurement of hippocampal volume inpatients with combat-related posttraumatic stress disorder. Am J Psychiatry 1995; 152(7):973–981.
304. Gurvits TV, Shenton ME, Hokama H, Ohta H, Lasko NB, Gilbertson MW, Orr SP, Kikinis
R, Jolesz FA, McCarley RW, Pitmann RK. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry 1996;
40(11):1091–1099.
305. Stein MB, Koverola C, Hanna C, Torchia MG, McClarty B. Hippocampal volume in women
victimized by childhood sexual abuse. Psychol Med 1997; 27(4):951–959.
306. Bremner JD, Randall P, Vermetten E, Staib L, Bronen RA, Mazure C, Capelli S, McCarthy
G, Innis RB, Charney DS. Magnetic resonance imaging-based measurement of hippocampal
volume in posttraumatic stress disorder related to childhood psychic and sexual abuse—apreliminary report. Biol Psychiatry 1997; 41(1):23–32.
307. Bremner JD. Does stress damage the brain? Biol Psychiatry 1999; 45(7):797–805.
308. Bonne O, Brandes D, Gilboa A, Gomori JM, Shenton ME, Pitman RK, Shalev AY. Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am J Psychiatry
2001; 158(8):1248–1251.
309. De Bellis MD, Hall J, Boring AM, Frustaci K, Moritz G. A pilot longitudinal study of hippocampal volumes in pediatric maltreatment-related posttraumatic stress disorder. Biol Psychiatry 2001; 50(4):305–309.
310. Bremner J, Scott T, Delaney R, Southwick S, Mason J, Johnson D, Innis R, McCarthy G,
Charney D. Deﬁcits in short-term memory in post-traumatic stress disorder. Am J Psychiatry
1993; 150:1015–1023.
311. Schuff N, Marmar CR, Weiss DS, Neylan TC, Schoenfeld F, Fein G, Weiner MW. Reduced
hippocampal volume and N-acetyl aspartate in posttraumatic stress disorder. Ann NY Acad
Sci 1997; 821:516–520.
312. Schuff N, Neylan TC, Lenoci MA, Du AT, Weiss DS, Marmar CR, Weiner MW. Decreased
hippocampal N-acetylaspartate in the absence of atrophy in posttraumatic stress disorder.
Biol Psychiatry 2001; 50(12):952–959.
313. Freeman TW, Cardwell D, Karson CN, Komoroski RA. In vivo proton magnetic resonancespectroscopy of the medial temporal lobes of subjects with combat-related posttraumaticstress disorder. Magn Reson Med 1998; 40(1):66–71.
314. De Bellis MD, Keshavan MS, Spencer S, Hall J. N-acetylaspartate concentration in the anterior cingulate of maltreated children and adolescents with PTSD. Am J Psychiatry 2000;
157(7):1175–1177.
315. Rauch SL, Whalen PJ, Shin KM, McInerney SC, Macklin ML, Lasko NB, Orr SP, Pitman
RK. Exaggerated amygdala response to masked facial stimuli in posttraumatic stress diorder:
a functional MRI study. Biol Psychiatry 2000; 47(9):769–776.
316. Liberzon I, Taylor SF, Amdur R, Jung TD, Chamberlain KR, Minoshima S, Koeppe RA,
Fig LM. Brain activation in PTSD in response to trauma-related stimuli. Biol Psychiatry
1999; 45(7):817–826.

Brain Imaging

329

317. Bremner JD, Staib LH, Kaloupek D, Southwick SM, Soufer R, Charney DS. Neural correlatesof exposure to traumatic pictures and sound in Vietnam combat veterans with and without
posttraumatic stress disorder: a positron emission tomography study. Biol Psychiatry 1999;
45(7):806–816.
318. Bremner JD, Innis RB, Ng CK, Staib LH, Salomon RM, Bronen RA, Duncan J, Southwick
SM, Krystal JH, Rich D, Zubal G, Dey H, Soufer R, Charney DS. Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combatrelated posttraumatic stress disorder. Arch Gen Psychiatry 1997; 54(3):246–254.
319. Zubieta J, Chinitz JA, Lombardi U, Fig LM, Cameron OG, Liberzon I. Medial frontal cortex
involvement in PTSD symptoms: A SPECT study. J Psychiatric Res 1999; 33:259–264.
320. Shin LM, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL, Alpert NM, Metzger LJ,
Lasko NB, Orr SP, Pitman RK. Regional cerebral blood ﬂow during script-driven imagery
in childhood sexual abuse-related PTSD: A PET investigation. Am J Psychiatry 1999; 156(4):575–584.
321. Bremner JD, Narayan M, Staib LH, Southwick SM, McGlashan T, Charney DS. Neuralcorrelates of memories of childhood sexual abuse in women with and without posttraumaticstress disorder. Am J Psychiatry 1999; 156(1):1787–1795.
322. Mirzaei S, Knoll P, Keck A, Preitler B, Gutierrez E, Umek H, Kohn H, Pecherstorfer M.
Regional cerebral blood ﬂow in patients suffering from post-traumatic stress disorder. Neuropsychobiology 2001; 43(4):260–264.
323. Shin LM, Whalen PJ, Pitman RK, Bush G, Macklin ML, Lasko NB, Orr SP, McInerney SC,
Rauch SL. An fMRI study of anterior cingulate function in posttraumatic stress disorder.
Biol Psychiatry 2001; 50(12):932–942.
324. Osuch EA, Benson BE, Geraci M, Podell DM, Herscovitch P, McCann UD, Post RM. Regional cerebral blood ﬂow correlated with ﬂashback intensity in patients with posttraumaticstress disorder. Biol Psychiatry 2001; 50(4):246–253.

14
Neurobiology of Anxiety
and Depression
PHILIP T. NINAN and THOMAS K CUMMINS
Emory University School of Medicine
Atlanta, Georgia, U.S.A.

I.

INTRODUCTION

The current diagnostic nomenclature in psychiatry is based on phenomenology. Signs andsymptoms, with deﬁned time periods, are the predominant criteria for diagnoses, with theadditional requirement of a threshold of distress/dysfunction. Anxiety and mood disorders
are carved into several categories with precise criteria. This allows for diagnostic reliability. However, reliability does not necessarily equate with validity. Core components ofan illness may not get the appropriate emphasis if they cannot be reliably measured. In
addition, diagnostic labels are categorical, to the uninitiated, implying clear boundaries
without overlap and coincidental comorbidity. Brain function and pathology do not fall
into such simple categories. The reality is that clinical diagnoses have overlapping presentations and are heterogeneous with multiple etiopathological pathways. This heterogeneity
may also be the basis of signiﬁcant variance in treatment response as well as overlap inresults from studies in neurobiology. Failure to recognize such limitations are potential
impediments to the development of novel pharmacological as well as psychotherapeutic
treatments. Starting from an understanding of brain functions may allow a new view of theneurobiology underlying anxiety and depressive disorders and, in a “reverse engineering”
approach may guide us in improving the classiﬁcation of anxiety and depressive disorders.
II. THE DIAGNOSTIC CONUNDRUM
There are several dimensions of symptoms subsumed under anxiety and depressive disorders. The disorders are largely a collection of symptoms that clinical medicine would
331

332

Ninan and Cummins

consider as syndromes. In major depressive disorder (MDD), these dimensions are emotional (sadness, anhedonia, anxiety), cognitive (impaired concentration and memory, speciﬁc cognitions such as guilt, worthlessness, and suicidal thoughts), endocrine manifestations (change in sleep and appetite, diurnal variation), somatic expressions (preoccupation
with physical symptoms and health), as well as behavioral manifestations (motor retardation, inertia). Similarly, generalized anxiety disorder (GAD) has domains that are emotional (anxiety), cognitive (uncontrollable worry, poor concentration), somatic (muscle
tension, autonomic symptoms, somatic preoccupation), and behavioral (irritability, restlessness).
Symptomatic overlap is present to a prominent degree among diagnostic categories
in the anxiety and depressive syndromes. Thus anxiety as symptoms are the norm rather
than the exception in mood disorders like MDD. Thus, the majority of patients with MDD
experience anxiety at an emotional, cognitive, and somatic level, including paroxysmal
anxiety as in panic attacks [1]. Similarly, anxiety disorders have dysphoria as a common
symptom. It is hard for individuals preoccupied with intense anxiety to focus much on
the experience of pleasure.
Part of the confusion might be that several overlapping terms are used to denotethe key states of anxiety and dysphoria. Thus words like nervousness, fear, worry, apprehension, tension, irritability, agitation, and restlessness all capture some component of
the rubric of anxiety. Similarly, dysphoria also includes sadness, anguish, dissatisfaction,
rumination, and somatic preoccupation. As is evident, many of these terms can be usedinterchangeably in anxiety and depressive disorders. The difﬁculty is partly the result of
the subjective component of these experiences, which do not have a linear relationshipwith the underlying biological processes that mediate their entry into conscious awareness.
An example of the diagnostic confusion is the criteria for GAD and dysthymia. Bothrequire long-term symptoms (6 months for GAD and 2 years for dysthymia). GAD requires
anxiety and cognitive worry as its core symptoms, associated with restlessness, fatigue,poor concentration, irritability, muscle tension, and sleep disturbance. These associatedsymptoms are also part of the criteria for dysthymia, which requires sadness and anhedonia
as its core symptoms. However, many patients are unable to report whether anxiety orsadness at an emotional level are their core experiences and clinicians may have difﬁculty
distinguishing the worry of GAD from depressive ruminations; this raises questions about
the reliability of such distinctions. Such conceptual confusion has implications. Thus, recent genetic studies suggest that the genetic vulnerability for GAD and MDD is the same[2]. That may be so, or the unity of genetic factors may be the result of an inability toclinically separate the two conditions with validity.
Comorbidity of disorders may occur historically or concurrently. Anxiety disorders
have high comorbidity with depressive disorders [3]. In a study of 109 patients with a
primary diagnosis of GAD, 42% met current or past criteria for MDD [4]. In the Epidemiological Catchment Area study, 16.6% of subjects with social anxiety disorder had a historyof MDD and 12.5% had dysthymia. Rasmussen and Eisen [5] reported that among 100
subjects with primary obsessive-compulsive disorder (OCD), 67% met lifetime and 31%
met current criteria for MDD.
Among patients with MDD, there is a similar high representation of comorbidity
with anxiety disorders. Schatzberg et al. [6] reported that 58% of their patients with acurrent diagnosis of MDD had a history of an anxiety disorder and 49% met current
criteria for anxiety disorder. Similarly, the National Co-Morbidity Survey reported 58%
of individuals with a lifetime episode of major depression also met criteria for an anxiety

Neurobiology of Anxiety and Depression

333

disorder [7]. The anxiety disorder developed ﬁrst in 68% of individuals, with major depression developing, on average, 11 years later. This period was shorter for GAD and panic
disorder (average 1.5 years) and over a decade each for post-traumatic stress disorder(PTSD), simple, social, and agoraphobia [7]. This is consistent with data from the Epidemiological Catchment Area study, which found 47.2% of patients with lifetime MDD also
had an anxiety disorder [8]. The anxiety disorder came ﬁrst in 55% of individuals, and
MDD in 18%. The average number of years between the phobic disorders and the onset
of MDD was around a decade, but around a year for panic disorder and OCD. Thus,
anxiety and depressive disorders are highly comorbid syndromes.
The distinction between those patients who have full syndromal comorbid anxiety
disorder and MDD from those with only a single disorder has not been adequately addressed in the literature. A large proportion of studies performed by the pharmaceuticalindustry for regulatory purposes did not use structured interviews to examine comorbidity
even though they were diagnostic categories in the exclusion criteria. Thus many of thepivotal and other studies performed without a stringent diagnostic emphasis are of little
value in examining these issues.

III. NEUROCHEMISTRY OF ANXIETY AND DEPRESSION
A brief review of the studies that examined neurochemical aspects of individual anxiety
and depressive disorders is provided below.
A. Generalized Anxiety Disorder
The diagnostic criteria for GAD have evolved with iterations of the DSM over the past
two decades. Thus, the current knowledge of the neurobiology of GAD rests largely on
studies that have used previous deﬁnitions. In addition, the overall number of studies islimited.
The study of noradrenergic receptor function has been implicated in GAD although
not universally [9]. The blunting of the growth hormone response to clonidine challenge
and yohimbine has been noted to evoke an attenuated MHPG response in GAD patients
as compared to controls [10]. Peripheral platelet α2 binding sites have also been reported
to be reduced [11,12].
The function of the serotonin system has also been studied to a limited extent in
GAD. In one study, the 5HT agonist meta-chlorophenylpiperazine (mCPP) has beenshown to produce increased anxiety and hostility in GAD [13]. Reduced cerebrospinal
ﬂuid levels of 5HT [14] and reduced platelet paroxetine binding [15] have also been observed in GAD. Limited studies have also been done on the GABA/benzodiazepine receptor system. A lower number of peripheral benzodiazepine binding sites have been noted onplatelets [16] and lymphocytes[17]. In two studies, treatment with benzodiazepine drugs
produced an increase in the number of peripheral binding sites [16,18]. Reduced sensitivityof central benzodiazepine receptors has also been found in one study [19].
Lactate and CO2 challenge studies have also been performed in GAD. Both lactate
and CO2 challenge produced higher rates of anxiety in GAD patients as compared tononanxious controls, but rates of panic attacks were lower than those found in panic patients [20–23]. The function of the hypothalamic-pituitary-adrenal (HPA) axis was also
assessed utilizing the dexamethasone suppression test in two studies. Both studies reported

334

Ninan and Cummins

elevated rates of dexamethasone nonsuppression [24,25]. A third study, however, did notreveal any evidence for increased baseline urinary cortisol in GAD [26].
B.

Panic Disorder

There is evidence suggesting noradrenergic, serotonergic, respiratory, and peptidergic abnormalities in panic disorder. Panic patients have an increased sensitivity to β-adrenergic
stimulation. Isoproterenol, a β-adrenergic receptor agonist, induces panic attacks in patients with panic disorder compared to nonanxious controls [27,28]. Central α2-adrenergic
receptor function is altered in panic disorder as growth hormone release by clonidine, an
α2-adrenergic receptor antagonist, is blunted in panic patients in the majority of studies[29–34]. Clonidine also disproportionately reduces serum levels of the noradrenergic metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with panic disorder [29–31]. In addition, the α2-adrenergic receptor antagonist yohimbine has produced signiﬁcantly greater rises in plasma MHPG, elevations in systolic blood pressure, and elevatedratings of anxiety symptoms in patients with panic disorder as compared to controls [35–37].
Evidence suggests the involvement of the serotonin system in panic disorder. The
serotonin reuptake inhibitors are effective in the treatment of panic disorder. Meta-chlorophenylpiperazine, a 5HT2C agonist, produced signiﬁcantly greater rates of panic and anxiety symptoms in patients with panic disorder compared to controls [38], although this was
not replicated [39]. Different doses and routes of administration used in these two studies
may explain the discrepancy. Studies using other direct serotonin agonists including
ipsapirone, fenﬂuramine, and clomipramine have generally found evidence of abnormal
serotonin receptor responses [40–43] although not universally [44]. Serotonergic stimulation may induce a state of high anticipatory anxiety that predisposes to a panic attack
rather than directly triggering one [45,46]. Differences in the outcome of studies may also
result from the impact of other variables like sex, seasonal factors, and age, all of which
impact upon serotonergic function [47,48].
The prominence of respiratory symptoms like dyspnea in panic attacks has led to
examination of the chemoreceptor function in panic disorder. Two techniques have beenused—lactate infusion and carbon dioxide inhalation. Lactate infusion has triggered panic
symptoms in a signiﬁcantly greater number of patients with panic disorder than controls
in several studies [21,49,50]. The lactate-infusion-induced panic attacks are similar to
those experienced during naturally occurring panic [51] and are blocked by pharmacological agents effective in the treatment of panic disorder [19,52–55]. Inhalation of various
concentrations (5–35%) of a carbon dioxide mixture have also induced panic attacks ina large proportion of patients with panic disorder compared to controls [22,56–63]. Carbon
dioxide–induced panic is also subjectively similar to naturally occurring panic attacks[64] and is blocked by pharmacological agents effective in the treatment of panic disorder[65,66]. The precise mechanism by which these challenges induce panic attacks remains
to be elucidated.
Neuropeptides also appear to play a role in the biology of anxiety, particularly panic
attacks. The neuropeptides cholecystokinin (CCK) and neuropeptide Y have been demonstrated to modulate anxiety in animal models of anxiety [67,68]. CCK-related peptides
have consistently elicited panic-like symptoms under a challenge paradigm in panic disorder patients and have done so in a dose-dependent fashion [69,70].

Neurobiology of Anxiety and Depression

335

C. Obsessive-Compulsive Disorder
The efﬁcacy of serotonergic drugs in OCD and the failure of noradrenergic medications
have resulted in a focus on serotonin in neurochemical studies. The direct serotonin receptor agonist mCPP has been used in challenge studies to assess the function of serotoninsystems in OCD. The results of these studies have been mixed, as some studies haveshown mCPP to increase anxiety and obsessions in OCD patients as compared to normal
controls [71,72], whereas other studies have failed to replicate these ﬁndings [73]. The
discrepancy may be related to the differing doses and routes of administration used in thevarious studies.
Noradrenergic function has also been studied. Clonidine challenge has been shown
to result in blunted GH release in some studies of OCD patients [74,75] but not in others[76].
D. Social Anxiety Disorder (Social Phobia)
Social anxiety disorder (SAD) is relatively poorly understood from a neurochemical perspective. This limited understanding may be further complicated by the fact that the generalized and discrete subtypes of this disorder may be signiﬁcantly distinct and may require
separate study [77].
Studies of SAD involve challenge studies designed to study the functioning of speciﬁc neurotransmitter systems. In studies of noradrenergic function, an abnormal bluntingof growth hormone response to intravenous clonidine challenge was found in one studyof SAD patients as compared to controls. The degree of blunting was found to be lessthan that seen in panic patients in the same study [78]. A follow-up study using oral
clonidine challenge, however, failed to demonstrate any abnormality in growth hormone
response [78]. A role for serotonin in the pathophysiology of SAD has been supportedby the clinical effectiveness of SRI medications in the treatment of SAD. In studies investigating serotonergic function, SAD patients have shown increased anxiety relative to controls upon exposure to mCPP [79] and fenﬂuramine, with augmented cortisol responses
also noted upon exposure to fenﬂuramine [78,80,81]. Dopamine receptor functioning has
also recently been studied using SPECT functional neuroimaging scans. One study revealed a 20% reduction in striatal dopamine transporter sites. A study by Tiihonen et al.
[82] as well as a second study revealed a similar magnitude of reduction in dopamine-2
receptor binding [4].
Challenge studies assessing chemoreceptor function have also been used to study
the neurobiology of SAD. Three studies using 35% CO2 have shown increased rates of
CO2-induced panic in SAD patients as compared to controls. Two studies showed panic
induction rates lower than those seen in panic disorder patients [59,83], but the third
study revealed similar rates to panic patients [84]. A single lactate challenge test has been
performed and revealed similar responses in SAD patients and controls [85].
E.

Post-Traumatic Stress Disorder

There have been signiﬁcant recent advances in the study of the neurochemistry posttraumatic stress disorder in adults. Alterations in catecholamine function have been notedin adult PTSD patients. Peripheral catecholamine levels are increased in PTSD patients
under basal [86] and stimulated conditions [87]. Administration of yohimbine produces

336

Ninan and Cummins

both an increase in PTSD symptoms and serum levels of MHPG in trauma survivors with
PTSD [88].
The function of the HPA axis in PTSD has also been the subject of a number ofstudies. Lower plasma cortisol levels and/or 24-h urinary cortisol levels have been foundin combat veterans with PTSD [89], Holocaust survivors with PTSD [90], and in the highrisk group of adult children of Holocaust survivors [91] (rather than the intuitively expected elevation of cortisol levels in the face of stress). Another study did, however, ﬁnd
elevated 24-h urinary cortisol levels in female survivors of childhood sexual abuse with
PTSD [92]. Initially, these ﬁndings of low cortisol levels were explained as reﬂecting achronic adaptation to stress [93]. More recent ﬁndings, however, have called that explanation into question. One study has shown cerebrospinal ﬂuid levels of corticotropin-releasing factor (CRF) to be elevated in PTSD patients as compared to controls [94]. This raises
the possibility of a disconnection between CRF and cortisol release in PTSD. A recent
longitudinal study has shown that motor vehicle accident victims who went on to develop
PTSD had a signiﬁcantly lower cortisol response immediately following the trauma than
did patients who went on to develop major depression. The response of those who did
not develop a psychiatric disorder was found to be between the other two groups [86]. A
second study demonstrated that women with a prior history of rape or assault had relatively
lower cortisol levels immediately after rape than did women without such a history [95].
Combat veterans with PTSD also have greater cortisol suppression following dexamethasone administration than do controls [90,96,97]. This ﬁnding has more recently been
demonstrated in adult women survivors of childhood sexual abuse [98] and in adolescents
who developed PTSD following an earthquake [99]. This ﬁnding appears to be related toenhanced sensitivity of glucocorticoid receptor [100].
F.

Major Depressive Disorder

The neurochemical explorations in clinical depression have focused largely on major depressive disorder. The studies were initially based on the fortuitous ﬁndings of therapeutic
beneﬁts of pharmacological agents subsequently labeled as antidepressants. These were
initially monoamine oxidase inhibitors and tricyclic antidepressants and subsequently the
new generation of serotonergic medications, particularly the inhibitors of the serotonintransporter. Using a reverse engineering method, the mechanism of action of antidepressants was thought to be related to the pathophysiology of the disorder.
Functional measures of presynaptic activity were performed by measuring neurotransmitters and their metabolites in the CSF and other body ﬂuids. Peripheral measures
included platelet studies. Reactivity of these systems was also measured by pharmacological challenge paradigms. Neurotransmitter depletion methods that reversed the antidepressant effects of antidepressants using dietary or pharmacological manipulations were also
performed.
The antihypertensive medication reserpine was observed clinically to induce a stateof depression indistinguishable from idiopathic MDD. Reserpine depleted monoaminesand so the catcholamine hypothesis of MDD postulated that a reduction in activity of
the norepinephrine system was the basis of depression and the therapeutic efﬁcacy ofantidepressants was based on its reversal. MHPG is a metabolite of NE and a measureof NE levels. Roughly 20% is derived from the CNS pool [101], but no consistent patternis recognized in studies of unipolar patients. Clonidine challenges measure α2-adrenergic
stimulation, resulting in secretion of growth hormone (GH) from the pituitary throughNeurobiology of Anxiety and Depression

337

postsynaptic effects. Studies have generally reported blunting of this response in MDD,
both during the depressive episode as well as following successful treatment, suggesting
it is a trait marker for MDD. Alpha-methyl-para-tyrosine (AMPT) inhibits tyrosine hydroxylase, the rate-limiting enzyme for the production of norepinephrine. AMPT-induced
depletion of NE in MDD resulted in a relapse of depressive symptoms in those on anoradrenergic antidepressant but not a serotonergic one.
The serotonergic hypothesis was based initially on the beneﬁt of trazadone and subsequently the serotonin reuptake inhibitors (SSRIs). Several studies, though not all, havereported CSF levels of 5HIAA decreased in MDD, particularly in those who were signiﬁcantly suicidal and impulsive. Intravenous tryptophan increases serotonin and serum prolactin and this has been reported to be blunted in MDD. Fenﬂuramine also increases prolactin through its presynaptic effects, with blunting reported in MDD. Depleting tryptophan,
the amino acid precursor of serotonin, induces relapse of depressive symptoms in thoseon a serotonergic antidepressant, but not untreated MDD patients.
IV. FUNCTIONAL ANATOMY OF ANXIETY AND DEPRESSION
Preclinical studies in the neurosciences provide insights into neural circuits that underlie
motivational systems from which emotional and behavioral responses are derived[102,103]. The neural circuitry associated with emotional processing is complex but overlaps signiﬁcantly with the classical limbic system as described by Papez. Thus, there isa signiﬁcant overlap between the anatomical structures that are correlated with the depressive and anxiety disorders, and the symptomatic overlap may be a function of theoverlap of neurocircuits.
Structures in the basal forebrain are critical hubs for the emotional experiences atthe core of anxiety and pleasure. Neuroanatomical models of fear and anxiety have focusedon the central role played by the extended amygdala. Pleasurable or hedonic responses
have been associated with the so-called reward pathways in the brain, including structures
like the ventral tegmental area (VTA) and the nucleus accumbens. These motivational
systems are closely and reciprocally connected to the executive systems mediated by theprefrontal cortex. Under typical conditions, there is a ﬂexible shift in the activity of thesesystems with the potential for willful choice of affective or cognitive responses driving
behavioral output. In pathological states such as anxiety and depressive disorders, theinterrelationships between these systems are altered such that there is diminished executive
control, which is easily overridden by more automatic, noncognitively driven responses
programmed through the more phylogenetically primitive structures.
Systems mediating positive emotions like pleasure may be awry in depressive disorders. These have been best mapped primarily in studies examining substance use disorders,
but their relevance in depression is increasingly being recognized. The clinical diagnosis
of major depression requires sadness and the reduced ability to experience pleasure, also
termed anhedonia. Pleasurable or hedonic responses have been associated with structures
like the VTA, nucleus accumbens, and medial prefrontal cortex [104,105]. The rewarding(hedonic) system is a preservative one and responds to appetitive stimulation. In particular,
the VTA/nucleus accumbens circuit is implicated in reward-driven behavior (e.g., operant
conditioning). Neurochemical studies most strongly link dopamine to this circuit, but otherneurotransmitters are associated with reward, with mounting evidence for both serotonin
and norepinephrine. Evidence for state-dependent dysregulation of these circuits in MDD
has been reported and may predict treatment responsiveness [106].

338

Ninan and Cummins

Fear and anxiety are often used interchangeably, although fear focuses on physicalthreat while anxiety response may be seen as predicting the threat. The amygdala is analmond-shaped structure consisting of several cell groups, part of the limbic system, critical for processing emotional experiences. Highly processed sensory information from various areas of the cortex reaches the amygdala through its lateral and basolateral nuclei.
These nuclei then project to the central nucleus of the amygdala, which then projects tohypothalamic and brainstem target areas, which mediate the speciﬁc signs and symptomsof fear and anxiety.
Considerable evidence supports the hypothesis that the amygdala and its efferent
projections represent a central fear/anxiety system involved in both the expression andthe acquisition of conditioned fear. Different parts of the amygdala and closely related
structures may be involved in different types of fear and anxiety. Three such forms ofanxiety can be distinguished. An unconditioned threat results in the fear response. If thisis paired with a neutral stimulus, that becomes a cued trigger for the fear response, called
conditioned fear. Such unconditioned and conditioned fear elicited by explicit cues appears
to be processed through the central nucleus of the amygdala.
Contextual fear refers to the fear noted when there is exposure to the environment(or context) where the fear conditioning occurred. Contextual fear may be closer to theconcept of anxiety because the context is associated with the threat, although this association may or may not be consciously connected. Such anxiety appears to be processed via
circuitry that involves not only the amygdala but also the hippocampus and the bed nucleusof the stria terminalis. The role of the hippocampus in processing spatial information anddeclarative (conscious) memory may aid in its role in contextual fear/anxiety.
Avoidance of aversive experiences like the triggering of the fear response is anadditional component of the anxiety response. Such avoidant conditioning may be inﬂuenced by the medial prefrontal cortex, which is reciprocally connected to the amygdala.
The extinction of conditioned avoidance is prolonged by damage to the medial prefrontal
cortex. The prefrontal cortex may in fact allow for “cognitive” control of conditioned fearand provide the circuitry critical for the beneﬁt in cognitive-behavioral therapies.
V.

NEUROIMAGING STUDIESThe different anxiety disorders may share a common functional anatomy, but may also
have additional and unique circuits involved in their expression.
The functional anatomy of panic disorder has been explored using neuroimaging
techniques. PET studies have revealed that panic patients susceptible to lactate-induced
panic have increased right parahippocampal blood ﬂow and oxygen metabolism and abnormally high whole-brain oxygen metabolism in the nonpanic state [107,108]. A SPECT
imaging study utilizing a substantially different methodology revealed decreased hippocampal blood ﬂow in lactate-sensitive panic patients [109]. Another SPECT study revealed
reduced regional cerebral blood ﬂow in the frontal lobes of panic patients after yohimbine
administration as compared to controls [110].
Neuroimaging and EEG studies have also been conducted in SAD. A PET study
revealed changes in regional cerebral blood ﬂow, including increased blood ﬂow in theright dorsolateral prefrontal cortex and the left parietal cortex when SAD subjects were
provoked with a script of fear-evoking autobiographical material [111] when comparedto ﬁndings in controls under the same conditions noted in an earlier study [112]. Twostudies using magnetic resonance spectroscopy (MRS) have found abnormal choline me-Neurobiology of Anxiety and Depression

339

tabolite levels in SAD patients [113,114]. An additional SPECT study in generalized SAD
failed to reveal evidence of a focal abnormality in cerebral blood ﬂow [115]. A recent
EEG study comparing SAD patients and controls showed SAD patients to have marked
selective activation of right frontal alpha power in anticipation of and immediately after
a public speaking task [116].
Neuroimaging studies have also demonstrated signiﬁcant changes in brain morphology in PTSD patients as compared to controls. The primary ﬁnding based on MRI studies
has been reduced hippocampal volume in combat veterans and adult sexual abuse survivors
with PTSD [94,98,117,118]. The laterality of ﬁndings has varied between studies. A recent
functional neuroimaging study using PET demonstrated that recollection and imagery of
traumatic events was accompanied by increased regional cerebral blood ﬂow in anterior
paralimbic regions. These changes were demonstrated in trauma-exposed individuals bothwith and without PTSD, but the patterns of changes were signiﬁcantly different between
the two groups [119]. One MRI study comparing maltreated but medically healthy children
and adolescents with PTSD and matched controls has been reported. This study demonstrated signiﬁcantly smaller intracranial and cerebral volumes in the PTSD group as compared to controls. However, contrary to adult studies, hippocampal volumes were notdecreased in the PTSD group [120].
Obsessive compulsive disorder, appears to involve basal ganglia structures basedon imaging studies. Abnormalities in basal ganglia–frontal cortex circuits, speciﬁcally theventral prefrontal cortex–striatal circuits, have been implicated in the pathophysiology of
OCD. Neuroimaging studies have demonstrated changes in adult OCD patients compared
to controls. Functional neuroimaging studies have demonstrated increased metabolic rates
in the ventral prefrontal cortex [121–125]. Functional imaging studies of adults with childhood-onset OCD have also shown that metabolic activity in the ventral prefrontal cortex
and striatum correlate with OCD symptom severity and response to treatment [125,126].
Structural neuroimaging studies have in general yielded mixed results [127]. One recent
study, however, showed several signiﬁcant differences between OCD patients and controls
including signiﬁcantly smaller orbital frontal and amygdala volumes, as well as a lack of
the normal hemispheric asymmetry of the hippocampus–amygdala complex in OCD patients [128].
Other studies have sought to identify speciﬁc brain circuits involved in OCD. Thesestudies have focused on the prefrontal cortex which, based on animal models and clinicalneuropsychological studies, appears to be primarily responsible for the inhibition of therepetitive, ritualistic thoughts and behaviors that characterize OCD [129–135]. A recent
study utilized oculomotor tests to assess prefrontal cortex functioning in 18 children andadolescents with OCD and 18 matched controls. The OCD patients were not depressed
and were medication naive. The OCD patients showed a signiﬁcantly higher number of
failures in the prefrontal cortex function of response suppression. The difference between
the patient and control groups was particularly high among the younger patients and controls [136]. This ﬁnding replicated a similar study of medicated adult OCD patients [137].
An earlier study showed an increase in a number of neurological soft-sign abnormalities
in pediatric OCD patients as compared to controls [138].
Neuroimaging technologies have also been used in the study of childhood OCD.
An MRI study of treatment naive 7 to 17-year-old OCD patients did not reveal any differences in total prefrontal cortical gray or white matter volumes as compared to controls.
This study also studied the morphology of the striatum speciﬁcally. The examination of
the striatum was motivated by previous adult functional brain-imaging studies showing

340

Ninan and Cummins

differences in OCD patients in this brain region. Pediatric OCD patients had signiﬁcantly
smaller striatal volumes than controls and these ﬁndings correlated inversely with obsessive, but not compulsive, symptom severity. The putamen and caudate subcomponents ofthe striatum were also speciﬁcally measured and the putamen, but not the caudate, volumes
were signiﬁcantly smaller [139]. A follow-up study of 21 pediatric OCD patients andmatched controls showed signiﬁcantly larger ventral prefrontal cortical (VPFC) anterior
cingulate volumes in OCD patients as compared to controls, but no signiﬁcant differencesin the posterior cingulate cortex or the dorsolateral prefrontal cortex [127]. It is noteworthy
that a previous PET study demonstrated that the VPFC and its target ﬁelds in the striatum
play key roles in inhibiting context-inappropriate responses to sensory stimuli in healthy
human subjects [140]. An additional recent study examined the effect of SRI treatment
on a speciﬁc brain region implicated in the pathophysiology of OCD. Magnetic resonancespectroscopy examinations of the left caudate in 11 psychotropic-naive children and 11
controls showed signiﬁcantly greater caudate glutamatergic concentrations in the OCD
patients, which declined to levels comparable to controls after 12 weeks of treatment withparoxetine [141].
VI. ETIOPATHOGENIC STUDIES IN OCD
Recent ﬁndings in the neurobiology of pediatric OCD may usher in a major paradigm
shift in the study of the etiopathogenesis of a number of psychiatric diseases. A series ofstudies have explored the apparent link between the immune reaction to certain infectious
agents and the development of OCD and tic disorders in children. Pediatric autoimmune
neuropsychiatric disorders associated with streptococcal infections (PANDAS) is a relatively new diagnostic construct that refers to children and adolescents who develop andhave repeated exacerbations of obsessive-compulsive disorder and/or tic disorders following group A beta hemolytic streptococcal infections. The proposed pathophysiology involves group A beta-hemolytic streptococcal bacteria triggering the production of antibodies that cross-react with the basal ganglia of genetically susceptible hosts, leading to thedevelopment of OCD and/or tics [142].
Several recent studies have supported this proposed link. Two MRI studies foundsigniﬁcantly larger basal ganglia volumes in subjects meeting working diagnostic criteria
for PANDAS as compared to matched controls [143,144]. IgG antibodies have also been
noted in blood samples of a subgroup of children with PANDAS similar to the antibodies
found in patients with Sydenham’s chorea [145]. Also, the nonhuman lymphocyte antigen
DR-positive cell surface marker D8/17, found in over 90% of patients with Sydenham’schorea [146] has also been detected in 85% of a group of patients with PANDAS [147].
Evidence hinting at the possibility that immunological mechanisms may be involvedin other pediatric anxiety disorders has been noted in other studies. A retrospective review
of childhood risk factors for psychiatric disorders in adolescence and early adulthoodfound a speciﬁc link between illness in the ﬁrst year of life, particularly with high fever,
and adolescent anxiety disorders [148]. An earlier study also noted an association between
allergic symptoms, particularly hay fever, and inhibited temperament in young children[149].
VII. MOLECULAR STUDIESThe serotonin transporter in humans is coded in a single gene on the 17th human chromosome. A promoter region is genetically polymorphic with a long allele and a short allele

Neurobiology of Anxiety and Depression

341

version. The majority of individuals appear to have the short allele version, which resultsin the reduced expression and function of the serotonin transporter. These individuals havea slightly greater propensity toward anxiety measured on personality tests [150]. An fMRI
study reported that individuals with one or two copies of the short allele also demonstrated
an increase in the amygdala response to fearful faces compared to individuals with thelong allele [151]. The majority of studies in MDD report a decrease in serotonin transporter
binding compared to normal controls and this normalizes with successful antidepressanttreatment [152]. Pharmacogenomic studies will allow the classiﬁcation of individuals with
anxiety and depressive disorders into biologically homogeneous groups, which may produce greater precision in predicting side effects and response to treatment.

VIII. CONCLUSION
Given the high prevalence of anxiety and depressive disorders, their chronicity and societal
burden, it is critical to elucidate the multiple neurobiological underpinnings of pathologicalanxiety and depression. Such knowledge will provide the foundation for the next generation of advances in pharmacological as well as other treatments.

REFERENCES
1. Fawcett J, Kravitz HM. Anxiety syndromes and their relationship to depressive illness. J
Clin Psychiatry 1983; 44:8–11.
2. Kendler KS. Major depression and generalised anxiety disorder. Same genes, (partly) different environments—revisited. Br J Psychiatry 1996; 168:(suppl 30), 68–75.
3. Brawman-Mintzer O, Lydiard RB, Emmanuel N, Payeur R, Johnson M, Roberts J, Jarrell
MP, Ballenger JC. Psychiatric comorbidity in patients with generalized anxiety disorder. Am
J Psychiatry 1983; 150:1216–1218.
4. Schneier FR, Johnson J, Hornig CD, Liebowitz MR, Weissman MM. Social phobia. Comorbidity and morbidity in an epidemiologic sample. Arch Gen Psychiatry 1992; 49:282–288.
5. Rasmussen SA, Eisen JL. The epidemiology and differential diagnosis of obsessive compulsive disorder. J Clin Psychiatry 1992; 53:4–10.
6. Schatzberg AF, Samson JA, Rothschild AJ, et al. Depression secondary to anxiety: Findings
from the McLean Hospital Research Facilities. Psychiatr Clin North Am 1990; 13:633–649.
7. Kessler RC, Nelson CB, Mcgonagle KA, Liu J, Swartz M, Blazer DG. Comorbidity of DSM
III-R major depressive disorder in the general population: Results from the US National
Comorbidity Survey. Br J Psychiatry 1996;168:(suppl 30), 17–30.
8. Regier DA, Rae DS, Narrow WE, Kaelber CT, Schatzberg AF. Prevalence of anxiety disorders and their comorbidity with mood and addictive disorders. Br J Psychiatry 1998; 173:
(suppl 34), 24–28.
9. Munjack DJ, et al. Generalized anxiety disorder: Some biological aspects. Psychiatry Res
1990; 32:35–43.
10. Charney DS, Woods SW, Heninger GB. Noradrenergic function in generalized anxiety disorder: Effects of yohimbine in healthy subjects and patients with generalized anxiety disorder.
Psychiatry Res 1989; 27:173–182.
11. Cameron OG, et al. Adrenergic status in anxiety disorders: platelet alpha two-adrenergic
receptor binding, blood pressure, pulse and plasma catecholamines in panic and generalized
anxiety disorder patients and in normal subjects. Biol Psychiatry 1990; 28:3–20.
12. Sevy S, et al. Noradrenergic function in generalized anxiety disorder, major depressive disorder, and healthy subjects. Biol Psychiatry 1989; 25:141–152.

342

Ninan and Cummins

13. Germine M, et al. Anger and anxiety responses to m-chlorophenylpiperazine in generalized
anxiety disorder. Biol Psychiatry 1992; 32:457–467.
14. Brewerton TD, et al. CSF serotonin: Diagnostic and seasonal differences. 148th Meetingof the American Psychiatric Association. Washington, D.C.: American Psychiatric Press,
1995.
15. Iny LJ, et al. Studies of a neurochemical link between depression, anxiety and stress from
3H-imipramine and 3H-paroxetine binding on human platelets. Biol Psychiatry 1994; 36:
281–291.
16. Weizman R, et al. Peripheral benzodiazepine binding sites on platelet membranes are increased during diazepam treatment of anxious patients. Eur J Pharmacol 1987; 138:289–
292.
17. Ferrarese C, et al. Decreased density of benzodiazepine receptors in lymphocytes of anxious
patients: Reversal after chronic diazepam treatment. Acta Psychiatr Scand 1990; 82:169–
173.
18. Rocca P, et al. Peripheral-type benzodiazepine receptors in anxiety disorders. Acta Psychiatr
Scand 1991; 84:537–544.
19. Cowley D, et al. Lactate vulnerability after alprazolam versus placebo treatment of panic
disorder. Biol Psychiatry 1991; 30:49–56.
20. Cowley D, et al. Response to lactate infusion in generalized anxiety disorder. Biol Psychiatry
1988; 24:409–414.
21. Cowley D, Arana, G. The diagnostic utility of lactate sensitivity in panic disorder. Arch Gen
Psychiatry 1990; 47:277–284.
22. Gorman J, et al. Ventilatory physiology of patients with panic disorder. Arch Gen Psychiatry
1988; 45:31–39.
23. Holt PE, Andrews G. Hyperventilation and anxiety in panic disorder, social phobia, GAD
and normal controls. Behav Res Ther 1989; 27:453–460.
24. Avery DH, et al. The DST in psychiatric outpatients with generalized anxiety disorder, panic
disorder or primary affective disorder. Am J Psychiatry 1985; 142:844–848.
25. Tiller JG, et al. The dexamethasone suppression test and plasma dexamethasone in generalized anxiety disorder. Biol Psychiatry 1988; 23:261–270.
26. Rosenbaum AH, Schatzberg AF, Jost FA. Urinary free cortisol levels in anxiety. Psychosomatics 1983; 24:835–837.
27. Balon R, et al. Lactate and isoproterenol induced panic attacks in panic disorder patientsand controls. Psychiatry Res 1988; 23:153–160.
28. Pohl R, et al. Isoproterenol induced panic attacks. Biol Psychiatry 1988; 24:891–902.
29. Charney DS, Heninger GB. Abnormal regulation of noradrenergic function in panic disorders. Arch Gen Psychiatry 1986; 43:1042–1054.
30. Nutt DJ. Altered central alpha-2 sensitivity in panic disorder. Arch Gen Psychiatry 1989;
46:165–169.
31. Uhde TW, et al. Behavioral and physiological effects of short-term and long-term administration of clonidine in panic disorder. Arch Gen Psychiatry 1989; 46:170–177.
32. Abelson JL, et al. Endocrine, cardiovascular and behavioral responses to clonidine in patientswith panic disorder. Biol Psychiatry 1992; 32:18–25.
33. Coplan JD, et al. Persistence of blunted human growth hormone response to clonidine inpanic disorder following ﬂuoxetine treatment. Am J Psychiatry 1995; 152:619–622.
34. Brambilla F, et al. Alpha-2-adrenergic receptor sensitivity in panic disorder: I. GH response
to GHRH and clonidine stimulation in panic disorder. Psychoneuroendocrinology 1995; 20:
1–9.
35. Charney DS, Heninger GB, Breier A. Noradrenergic function in panic anxiety: effects ofyohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen
Psychiatry 1984; 41:751–763.

Neurobiology of Anxiety and Depression

343

36. Charney DS, et al. Neurobiological mechanisms of panic anxiety: biochemical and behavioral
correlates of yohimbine induced panic attacks. Am J Psychiatry 1987; 144:1030–1036.
37. Charney DS, Woods SW, Krystal JH. Noradrenergic neuronal dysregulation in panic disorder: The effects of intravenous yohimbine and clonidine in panic disorder patients. Acta
Psych Scand 1992; 86:273–282.
38. Kahn RJ, McNair DM, Lipman RS, Covi L, Rickels K, Downing R, Fisher S, Frankenthaler
LM. Imipramine and chlordiazepoxide in depressive and anxiety disorders. II. Efﬁcacy inanxious outpatients. Arch Gen Psychiatry 1986; 43(1):79–85.
39. Charney DS, et al. Serotonin function in anxiety: II. Effects of the serotonin agonist MCPP
in panic disorder patients and healthy subjects. Psychopharmacology 1987; 92:14–24.
40. Lesch KP, et al. 5-HT1A receptor-effector system responsivity in panic disorder. Psychopharmacology 1992; 106:111–117.
41. Targum SD, Marshall LE. Fenﬂuramine provocation of anxiety in patients with panic disorder. Psychiatry Res 1989; 28:295–306.
42. Targum SD. Differential responses to anxiogenic challenge studies in patients with major
depressive disorder and panic disorder. Biol Psychiatry 1990; 28:21–34.
43. Apostalopoulus M, Judd FK, Burrows GD. Prolactin response to dlfenﬂuramine in panic
disorder. Psychoneuroendocrinology 1993; 18:337–342.
44. Judd FK, Apostalopoulus M, Burrows GD. Serotonergic function in panic disorder: Endocrine responses to d-fenﬂuramine. Prog Neuropsychopharmacol Biol Psychiatry 1994; 18:
329–337.
45. Hollander E, et al. Fenﬂuramine, cortisol and anxiety (letter; comment). Psychiatry Res 1990;
31:211–213.
46. Targum SD. Cortisol response during different anxiogenic challenges in panic disorder patients. Psychoneuroendocrinology 1992; 17:453–458.
47. McBride P, et al. Effects of age and gender on CNS serotonergic responsivity in normal
adults. Biol Psychiatry 1990; 27:1143–1155.
48. Brewerton T. Seasonal variation of serotonin function. Ann Clin Psychiatry 1989; 1:153–
164.
49. Aronson T, et al. Biological correlates of lactate sensitivity in panic disorder. Biol Psychiatry
1989; 26:463–477.
50. Lapierre Y, Knott V, Gray R. Psychophysiological correlates of sodium lactate. Psychopharmacol Bull 1984; 20:50–57.
51. Dillon D, Gorman J, Liebowitz MR. Measurement of lactate induced panic and anxiety.
Psychiatry Res 1987; 20:97–105.
52. Carr DB, et al. Neuroendocrine correlates of lactate induced anxiety and their response tochronic alprazolam therapy. Am J Psychiatry 1986; 143:483–494.
53. Fyer A, et al. Lactate vulnerability of remitted panic patients. Psychiatry Res 1985; 14:143–
148.
54. Rifkin A, et al. Blockade by imipramine or desipramine of panic induced by sodium lactate.
Am J Psychiatry 1981; 138:676–677.
55. Yeragani VK, et al. Sodium lactate infusions after treatments with tricyclic antidepressants:
Behavioral and physiological ﬁndings. Biol Psychiatry 1988; 24:767–774.
56. Gorman J, et al. Anxiogenic effects of carbon dioxide and hyperventilation in patients withpanic disorder. Am J Psychiatry 1994; 151:547–553.
57. Griez E, et al. Speciﬁc sensitivity of patients with panic attacks to carbon dioxide inhalation.
Psychiatry Res 1990; 31: 193–199.
58. Holt PE, Andrews, G. Provocation of panic: Three elements of the panic reaction in fouranxiety disorders. Behav Res Ther 1989; 27:253–261.
59. Papp LA, et al. Diagnostic and substance speciﬁcity of carbon dioxide induced panic. Am
J Psychiatry 1993; 150:250–257.

344

Ninan and Cummins

60. Perna G, et al. Carbon dioxide/oxygen challenge test in panic disorder. Psychiatry Res 1993;
52:159–171.
61. Perna G, et al. Laboratory responses of patients with panic and obsessive compulsive disorders to 35% CO2 challenges. Am J Psychiatry 1995; 152:85–89.
62. Rapee RM, et al. Response to hyperventilation and inhalation of 5.5% carbon dioxide enriched air across the DSM-III-R anxiety disorders. J Abnorm Psychol 1992; 101:538–552.
63. Woods S, et al. Carbon dioxide induced anxiety. Arch Gen Psychiatry 1988; 45:43–52.
64. Sanderson M, Wetzler S. Five percent carbon dioxide challenge: valid analogue and marker
of panic disorder? Biol Psychiatry 1990; 27:689–701.
65. Woods S, et al. The effects of long term imipramine treatment on carbon dioxide induced
anxiety in panic disorder patients. J Clin Psychiatry 1990; 51:505–507.
66. Woods S, Charney DS, Loke J. Carbon dioxide sensitivity in panic anxiety. Ventilatory andanxiogenic response to carbon dioxide in healthy subjects and patients with panic anxiety
before and after alprazolam treatment. Arch Gen Psychiatry 1986; 43:900–909.
67. Wahlestedt C, Pich E, Koob GF. Modulation of anxiety and neuropeptide Y-Y1 receptors
by antisense oligodeoxynucleotides. Science 1993; 259:528–531.
68. Palmour R, et al. The anxiogenic and cardiovascular effects of CCK-4 are blocked by CCKB antagonists LY 262, 691. Neuroscience 1991; 17:1602.
69. Bradwejn J, et al. A dose ranging study of the behavioral and cardiovascular effects of CCKtetrapeptide in panic disorder. Biol Psychiatry 1992; 32:903–912.
70. Abelson JL, Neese RM. Cholecystokinen-4 and panic. Arch Gen Psychiatry 1990; 47:395.
71. Zohar J, Insel T. Obsessive compulsive disorder: psychobiological approaches to diagnosis,
treatment and pathophysiology. Biol Psychiatry 1987; 22:667–687.
72. Pigott TA, et al. A comparison of the behavioral effects of oral versus intravenous mCPP
administration in OCD patients and the effect of metergoline prior to IV mCPP. Biol Psychiatry 1993; 33:3–14.
73. Charney DS, et al. Serotonin function in obsesssive compulsive disorder: a comparison of
the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects. ArchGen Psychiatry 1988; 45:177–185.
74. Brambilla F, et al. Noradrenergic receptor sensitivity in obsessive-compulsive disorders, I:
growth hormone response to clonidine stimulation. Psychiatry Res 1997; 69:155–162.
75. Siever LJ. Growth hormone response to clonidine in obsessive-compulsive patients. Br J
Psychiatry 1983; 142:184–187.
76. Lee MA, et al. Alpha-2-adrenoreceptor status in obsessive-compulsive disorder. Biol Psychiatry 1990; 27:1083–1093.
77. Stein MB. Neurobiological perspectives on social phobia: from afﬁliation to zoology. Biol
Psychiatry 1998; 44:1277–1285.
78. Tancer ME. Neurobiology of social phobia. J Clin Psychiatry 1993; 54(suppl 12):26–30.
79. Hollander E, et al. 5-HT function and neurology of social phobia. In 144th Annual Meetingof the American Psychiatric Association, New Orleans, 1991.
80. Tancer ME, et al. Neuroendocrine responsivity to monoaminergic system probes in generalized social phobia. Anxiety 1994/1995; 1:216–223.
81. Tancer ME, et al. Neuroendocrine responsivity to monoaminergic system probes in generalized social phobia. Anxiety 1994/1995; 1:216–223.
82. Tiihonen J, et al. Dopamine reuptake site densities in patients with social phobia. Am J
Psychiatry 1997; 154:239–242.
83. Gorman JM, et al. High dose carbon dioxide challenge test in anxiety disorder patients. Biol
Psychiatry 1990; 28:743–757.
84. Caldirola D, et al. The 35% CO2 challenge test in patients with social phobia. Psychiatry
Res 1997; 71:41–48.
85. Liebowitz MR, et al. Speciﬁcity of lactate infusions in social phobia versus panic disorder.
Am J Psychiatry 1985; 142:947–950.

Neurobiology of Anxiety and Depression

345

86. Yehuda RJ, et al. Plasma norepinephrine and MHPG concentrations and severity of depression in combat PTSD and major depressive disorder. Biol Psychiatry 1998; 44:56–63.
87. McFall M, et al. Autonomic response to stress in Vietnam combat veterans with posttraumaticstress disorder. Biol Psychiatry 1990; 27:1165–1175.
88. Southwick SM, et al. Abnormal noradrenergic function in posttraumatic stress disorder. ArchGen Psychiatry 1993; 50:266–274.
89. Yehuda R, et al. Low urinary cortisol excretion in PTSD. J Nerv Ment Dis 1990; 178:366–
369.
90. Yehuda R, et al. Low urinary cortisol excretion in Holocaust survivors with posttraumaticstress disorder. Am J Psychiatry 1995; 152:982–986.
91. Yehuda R. Parental PTSD as a risk factor for PTSD. In: Yehuda R, ed. Progress in Psychiatry
Series. Washington DC: American Psychiatric Association, 1999.
92. Lemieux AM, Coe CL. Abuse-related posttraumatic stress disorder: evidence for chronic
neuroendocrine activation in women. Psychosom Med 1995; 57:105–115.
93. Selye H. The Stress of Life. New York: McGraw-Hill, 1976.
94. Bremner J, et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumaticstress disorder. Am J Psychiatry 1997; 154:624–629.
95. Resnick HS, et al. Effect of prior trauma on acute hormonal response to rape. Am J Psychiatry
1995; 152:1675–1677.
96. Yehuda R, et al. Enhanced suppression of cortisol following dexamethasone administrationin combat veterans with posttraumatic stress disorder and major depressive disorder. Am J
Psychiatry 1993; 150:83–86.
97. Kellner M, Baker D, Yehuda R. Salivary cortisol in Operation Desert Storm returnees. Biol
Psychiatry 1997; 41:849–850.
98. Stein MB, et al. Enhanced dexamethasone suppression of plasma cortisol in adult womentraumatized by childhood sexual abuse. Biol Psychiatry 1997; 42:680–686.
99. Goenjian AK, Yehuda R, Pynoos RS. Basal cortisol and dexamethasone suppression of cortisol among adolescents after the 1988 earthquake in Armenia. Am J Psychiatry 1996; 153:
929–934.
100. Yehuda R. Biology of posttraumatic stress disorder. J Clin Psychiatry 2000; 61(suppl 7):
14–21.
101. Potter WZ, Karoum F, et al. “Common mechanisms of action of biochemically “speciﬁc”
antidepressants.” Prog Neuropsychopharmacol Biol Psychiatry 1984; 8:153–161.
102. Davidson RJ, Irwin W. The functional neuroanatomy of emotion and affective style. Trends
Cogn Sci 1999; 3:11–21.
103. Ninan PT. The functional anatomy, neurochemistry and pharmacology of anxiety. J Clin
Psychiatry 1999; 60:12–17.
104. Scheel-Kruger J, Willner P. The mesolimbic system. In: Scheel-Kruger J, Willner P, eds.
Principles of Operation. The Mesolimbic Dopamine System: From Motivation to Action.
Chicester: Wiley, 1991:559–597.
105. Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science
1997; 275:1593–1599.
106. Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry 1997; 9:471–481.
107. George MS, Ballenger JC. The neuroanatomy of panic disorder: the emerging role of theright parahippocampal region. J Anxiety Disord 1992; 6:181–188.
108. Reiman EM, et al. Neuroanatomical correlates of a lactate-induced anxiety attack. Arch Gen
Psychiatry 1989; 46:469–477.
109. DeCristoforo M, et al. Brain perfusion abnormalities in drug-naive, lactate-sensitive panic
patients: A SPECT study. Biol Psychiatry 1993; 33:505–512.
110. Woods SW. Regional cerebral blood ﬂow imaging with SPECT in psychiatric disease: focus on
schizophrenia, anxiety disorders, and substance abuse. J Clin Psychiatry 1992; 53:20–25.

346

Ninan and Cummins

111. Bell CJ, Malizzia AL, Nutt DJ. The neurobiology of social phobia. Eur Arch Psychiatry Clin
Neurosci 1999; 249(suppl 1):S11–S18.
112. Malizzia AL. PET studies in experimental and pathological anxiety. J Psychopharmacol
1997; 11:A88.
113. Davidson R, et al. While a phobic waits: regional brain electrical and autonomic activity insocial phobics during anticipation of public speaking. Biol Psychiatry 2000; 47:85–95.
114. Tupler LA, et al. A repeat magnetic resonance spectroscopy study in social phobia. Biol
Psychiatry 1997; 42:419–424.
115. Stein MB, Leslie WD. A brain single photon emission computed tomography study of generalized social phobia. Biol Psychiatry 1996; 39:825–828.
116. Davidson R, et al. While a phobic waits: regional brain electrical and autonomic activity insocial phobics during anticipation of public speaking. Biol Psychiatry 2000; 47:85–95.
117. Bremner JD, et al. MRI based measurement of hippocampal volume in patients with combat
related posttraumatic stress disorder. Am J Psychiatry 1995; 152:973–981.
118. Gurvits TG, et al. Magnetic resonance imaging study of hippocampal volume in chronic,
combat-related PTSD. Biol Psychiatry 1996; 40:1091–1099.
119. Shin LM, et al. Regional cerebral blood ﬂow during script-driven imagery in childhood sexual
abuse-related PTSD: a PET investigation. Am J Psychiatry 1999; 156:575–584.
120. DeBellis MD, et al. Developmental traumatology part II: brain development. Biol Psychiatry
1999; 45:1271–1284.
121. Baxter LR, Schwartz JM, Mazziota JC. Cerebral glucose metabolic rates in non-depressed
patients with obsessive compulsive disorder. Am J Psychiatry 1988; 145:1560–1563.
122. Baxter LR, Schwartz JM, Bergman KS, Szuba MP, Buze BH, Mazziotta JC, Alazraki A,
Selin CE, Ferng HK, Munford P, Phelps ME. Caudate glucose metabolic rate changes withboth drug and behavior therapy for obsessive-compulsive disorder. Arch Gen Psychiatry
1992; 49:681–689.
123. Benkelfat C, et al. Local cerebral glucose metabolic activity in obsessive-compulsive disorder: patients treated with clomipramine. Arch Gen Psychiatry 1990; 141:840–848.
124. Hoehn-Saric R, Pearlson G, Harris G. Effects of ﬂuoxetine on regional cerebral blood ﬂow
in obsessive-compulsive patients. Am J Psychiatry 1991; 148:1243–1245.
125. Swedo SE, et al. Cerebral glucose metabolism in childhood-onset obsessive compulsive disorder: Revisualization during pharmacotherapy. Arch Gen Psychiatry 1992; 49:690–694.
126. Rauch SL, et al. Regional cerebral blood ﬂow measured during symptom provocation inobsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography. Arch Gen Psychiatry 1994; 51:62–70.
127. Rosenberg DR, Keshavan MS. Toward a neurodevelopmental model of obsessive-compulsive disorder. Biol Psychiatry 1998; 43: 623-640.
128. Szeszko PR, et al. Orbital frontal and amygdala volume reductions in obsessive-compulsive
disorder. Arch Gen Psychiatry 1999; 56:913–919.
129. Diamond A, Goldman-Rakic PS. Comparison of human infants and rhesus monkeys on
Piaget’s AB task: evidence for dependence on dorsolateral prefrontal cortex. Exp Brain
Res 1989; 74:24–40.
130. Goodglass H, Kaplan E. An assessment of aphasia and related disorders. Philadelphia: Lea &Febiger, 1972; 54–72.
131. Luria AR. Higher Cortical Function in Man. New York: Basic Books, 1996: 246.
132. Stuss DT, Benson DF. Frontal lobe lesions and behavior. In: Kertesz A, ed. Localization in
Neuropsychology, New York: Academic Press, 1983: 429–449.
133. Passingham RE. Visual discrimination learning after selective prefrontal ablations in monkeys. Neuropsychologia 1972; 10:27–39.
134. Rosvold HE, Mishkin M. Non-sensory effects of frontal lesions on discrimination learningand performance. In: Delafresnaye JF, ed. Brain Mechanisms and Learning. Oxford: Blackwell, 1961: 555–576.

Neurobiology of Anxiety and Depression

347

135. Stuss DT, Benson DF. Frontal lobe lesions and behavior. In: Kertesz A, ed. Localization in
Neuropsychology. New York: Academic Press, 1983: 429–449.
136. Rosenberg DR, et al. Oculomotor response inhibition abnormalities in pediatric obsessivecompulsive disorder. Arch Gen Psychiatry 1997; 54:831–838.
137. Tien AY, et al. Oculomotor performance in obsessive-compulsive disorder. Am J Psychiatry
1992; 149:641–646.
138. Pierri JN, et al. Neurological soft signs: OCD and offspring at risk for schizophrenia. In: 43rd
Annual Meeting of the American Academy of Child and Adolescent Psychiatry. Philadelphia:
Lippincott, 1996.
139. Rosenberg DR, et al. Fronto-striatal morphology of treatment-naive pediatric obsessivecompulsive disorder. Arch Gen Psychiatry 1997; 54: 824-830.
140. Sweeney JA, et al. A positron emission tomography study of voluntary saccadic eye movements and spatial working memory. J Neurophysiol 1996; 75:454–468.
141. Rosenberg DR, et al. Decrease in caudate glutamatergic concentrations in pediatric obsessive
compulsive disorder patients taking paroxetine. J Am Acad Child Adolesc Psychiatry 2000;
39:1096–1103.
142. Garvey MA, Giedd J, Swedo SE, PANDAS: the search for environmental triggers of pediatricneuropsychiatric disorders. Lessons from rheumatic fever. J Child Neurol 1998; 13:413–
423.
143. Garvey MA, Giedd J, Swedo SE, PANDAS: the search for environmental triggers of pediatricneuropsychiatric disorders. Lessons from rheumatic fever. J Child Neurol 1998; 13:413–
423.
144. Giedd JN, Rapoport JL, Garvey MA. MRI assessment of children with obsessive compulsive
disorder or tics associated with streptococcal infection. Am J Psychiatry 2000; 157:281–283.
145. Swedo SE, Kilpatrick K, Shapiro MB. Antineuronal antibodies in Sydenham’s chorea andobsessive compulsive disorder. Pediatr Res 1991; 29:364A.
146. Patarroyo ME, et al. Association of a B-cell alloantigen with susceptibility to rheumatic fever.
Nature 1979; 278:173–174.
147. Swedo SE, Leonard HL, Mittleman BB. Identiﬁcation of children with pediatric autoimmune
neuropsychiatric disorders associated with streptococcal infections by a marker associatedwith rheumatic fever. Am J Psychiatry 1997; 154:110–112.
148. Allen NB, Lewinsohn PM, Seeley JR. Prenatal and postnatal inﬂuences on risk for psychopathology in childhood and adolescence. Dev Psychopathol 1998; 10:513–529.
149. Kagan J, Reznick J, Clarke C. Behavioral inhibition to the unfamiliar. Child Dev 1984; 55:
2212–2225.
150. Lesch KP, Bengel D, et al. Association of anxiety-related traits with a polymorphism in theserotonin transporter gene regulatory region. Science 1996; 274:1257–1231.
151. Hariri AR, Mattay VS, Tessitore A, Kolanchana B, Fera F, Goldman D, Egan MF, Weinberger DR. Serotonin transporter genetic variation and the response of the human amygdala.
Science 2002; 297:400–403.
152. Ellis PM, Salmond C. Is platelet imipramine binding reduced in depression? A meta-analysis.
Biol Psychiatry 1994; 36:292–299.

15Intracellular Signaling Transduction
Dysregulation in Depression
and Possible Future Targets
for Antidepressant Therapy:
Beyond the Serotonin Hypothesis
ANDREA TRENTANI, S. KUIPERS, G. J. TER HORST,
and JOHAN A. DEN BOER
Academic Hospital Groningen
Groningen, The Netherlands

I.

THE MONOAMINE HYPOTHESIS OF DEPRESSION

The monoamine hypothesis of depression was coined over 30 years ago [1,2]. This hypothesis proposes that there is an underlying biological basis for depression, namely a deﬁciency of the monoamine neurotransmitters norepinephrine, serotonin, and/or dopaminein the central nervous system [3]. With this theory in mind, various classes of antidepressants have been developed that act to increase levels of monoamines within the synaptic
cleft, either by inhibition of their degradation or by blockade of their reuptake. Newer
antidepressants that elevate serotonin, norepinephrine, and/or dopamine levels in the brain
have been shown to effectively alleviate the symptoms of depression. Although substantial
evidence exists to support a role of monoamine systems in the mechanism of action ofantidepressants, intensive investigation has failed to ﬁnd conclusive afﬁrmation of a primary dysfunction of a speciﬁc monoamine system in patients with major depressive disorders [4–6].

349

350

A.

Trentani et al.

Problems with the Monoamine Hypothesis and with
Antidepressant Action on the Monoaminergic System

There are several major issues that have not been addressed by the monoamine hypothesis.
These problems mainly concern the action of medication acting on serotonergic and noradrenergic systems.
1. Efﬁcacy
Antidepressive medication, especially the newest generations of drugs including selective
serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NRIs) and selective serotonin/norepinephrine reuptake inhibitors (sSNRIs), appear to be effective inapproximately 60% of the patients suffering from major depression [7]. However, eventhough the ﬁrst tricyclic agent (TCA) was introduced more than 30 years ago, the newest
selective SRIs or NRIs fail to demonstrate an enhanced efﬁcacy compared to the older
TCAs [8,9], despite the fact that they are better tolerated and do not show the serious
cognitive, cardiac, and other somatic side effects commonly observed after long-term treatment with TCAs [10–17].
2. Selectivity
Although it is clear that SSRIs, NRIs, or NaSRIs act through the stimulation of serotonergic and noradrenergic systems, there is still confusion regarding the speciﬁc cellular or
molecular targets responsible for their therapeutic action, which appears to include neurotransmitter transporters, speciﬁc receptors, intracellular proteins, several enzymes, andtranscription factors [18–22]. Moreover, various lines of evidence indicate that during
chronic administration of these agents, the selectivity of the therapy dissipates. In fact,
after several weeks of continuous administration, highly selective drugs such as SSRIs or
NRIs, which stimulate speciﬁc neurotransmitter systems, may even inﬂuence the activityof other neural systems not directly associated with the initial therapeutic target [23–27].
An intriguing possibility is that it might be their aspeciﬁcity (modulation of the activityof a broader range of brain areas), rather than their selectivity, which is mainly responsible
for their antidepressant effects.
3. Mode of Action
Another important question to be addressed concerns the mechanisms by which antidepressants cause therapeutic effects. In contrast to antidepressants acting through the potentiation of monoaminergic transmission (TCAs, SSRIs, NRIs, and NaSRIs), other effective
antidepressants act by enhancing serotonin reuptake (an opposite mechanism compared
to SSRIs, e.g., tianeptine) [28,29] or by the inhibition and/or stimulation of selective
enzymes and transcription factors that are not directly linked to serotonin or norepinephrine metabolism or signaling transduction pathways (such as lithium and valproate)[30,31].
4. Delayed Onset of the Therapeutic Effect
While the adverse effects of antidepressants are manifested within hours or days following
the beginning of the administration, the therapeutic action is delayed and can take several
weeks or even months to appear, causing considerable problems with the compliance ofthe patients [32–34].

Beyond the Serotonin Hypothesis

351

5. Monoamine Depletion
Experimental monoamine depletion exacerbates depressive symptoms only in depressed
patients that have previously responded successfully to treatment while monoamine depletion fails to induce the same effects in medication-free symptomatic patients or in healthy
subjects. The failure to precipitate depressive symptoms implies that a serotonergic and/or noradrenergic dysfunction is unlikely to be the cause of depression, although it can beused to explain the mechanism by which antidepressants act [5,6,35,36].
While the monoaminergic systems appear to be crucial in the therapeutic effects ofantidepressants, only fragmentary evidence seems to support a primary role of monoaminedeﬁciencies in the etiology of depression. Several factors might be involved in the development of depression, but the dysfunction of the monoaminergic system may represent only
one of the possible consequences of this disease. The biogenic amine neurotransmitter
systems are extensively distributed within the limbic–cortical system, the neural network
involved in the modulation of cognition and emotions but also implicated in the regulationof other functions as sleep, appetite, arousal, cardiovascular regulation, sexual, and endocrine activity [37–40]. It is not surprising that clinical research strategies over the years
have identiﬁed dysregulation of noradrenergic, dopaminergic, serotonergic, and cholinergic systems as well as the hypothalamic–pituitary–adrenal axis (HPA) in depressed patients [41–46]. The behavioral and physiological manifestations of the illness are complex
and undoubtedly mediated by a network of interconnected neurotransmitter pathways.
Possibly the abnormal activity of one or more key components of this complex neuralnetwork may disrupt its ability to respond to incoming sensory stimuli with appropriate
emotional responses. Depression appears to be a syndrome that originates from a heterogeneous pathology with several different etiological causes and, possibly, one consequence,that is an abnormal modulation of the limbic–cortical function leading to mood and cognitive impairments [46,47]. A breakthrough in the understanding of this heterogeneous disease and its treatment calls for a clear comprehension of the factors and mechanisms that
could lead to limbic–cortical functional dysregulation. The discovery of novel antidepressants does not represent an easy task, however, primarily because of our poor understanding of the pathophysiology of this illness. Nevertheless, alternative but more speculative
mechanisms may prove to be more successful in the long run.

II. STRESS AND BRAIN (DYS)FUNCTIONS
Depression is a complex disease in which several different etiological causes, including
environmental risk factors such as stressful life events (SLEs), and genetic risk factors(vulnerability or predisposition), interact in various, complex manners [48]. Clinical studies have conﬁrmed the importance of SLEs in the development of mood disorders: astrong and signiﬁcant correlation has repeatedly been demonstrated between SLEs andthe precipitation of depression, especially in women [49–51]. In addition, Kendler andcolleagues have calculated that the association between SLEs and major depression thatis causal is approximately 75% [51]. Although it is difﬁcult to attribute a numerical value
to the effect that SLEs play in the occurrence of depression, it appears that environmental
factors may override genetic inﬂuences and induce the onset of depression in subjects
independent of their genetic background, that is, with low or without vulnerability andpredisposition [49,51].
The brain appears to respond to stress in a complex but orchestrated manner. Most

352

Trentani et al.

likely, it is the loss of the organized response that plays a crucial role in the developmentof psychiatric disorders. Preclinical studies suggest that stress can promote long-termchanges in multiple neurotransmitter systems and brain structures implicated in the etiology of depression [52–54]. It has also been hypothesized that neurobiological changes
associated with SLEs may confer vulnerability for the development of affective and otherpsychiatric disorders. A leading hypothesis to explain the inﬂuence of SLEs in the development of depression is that psychological stressors play a greater role in the initial stage
than in the subsequent episode of depressive disorders: the strength of the relationshipbetween SLEs and major depression progressively declines with an increasing number ofprevious depressive episodes (this hypothesis is also known as kindling hypothesis) [55–57]. SLEs have been found to be strongly associated with subsequent episodes of depression and their effect appears to be greater than other etiological factors including genetic
vulnerabilities. Furthermore, the depressogenic effects of SLEs seem to be concentrated
in the period immediately after event occurrence. However, although environmental risk
factors play a major role in the occurrence of major depression, several other investigations
have found that genetic inﬂuences cannot be forgotten. Two possible models might explain
the relationship between these two main risk factors: the additive and the genetic control
of sensitivity to the environment model. In the additive model, the increase in risk associated with the exposure to SLEs is similar for individuals with low-risk and high-risk
genotypes; this model predicts that the impact of SLEs and genetic factors on liability tomajor depression are independent. In the genetic control of sensitivity to the environment
model, the increase in risk of depression associated with the exposure to SLEs is greaterfor those with a high genetic risk than for those with a low genetic risk; genes have an
impact on the risk of depression in part by altering the individual’s sensitivity to thedepression-inducing effect of SLEs [49]. Clinical data appear to be consistent with thegenetic control of sensitivity to the environment model [50].
Another important question related to the relationship between SLEs and depressionis the impact of multiple SLEs [58]. Also in this case, three plausible hypotheses can bearticulated to explain that relationship. The simplest or additive model proposes that the
impact of SLEs is independent of the occurrence of other events. Multiple SLEs might
be positively interactive if the depressogenic effect of a SLE increases when it co-occurs
with other SLEs. A positively interactive model suggests a reservoir of “coping ability”
that might withstand the impact of one event but could be overwhelmed by multiple events.
A negatively interactive model suggests a threshold for stress that, if exceeded, has no
additional impact on depressive risk. Harris and Brown concluded that their work, which
focuses on severe SLEs, tends to best support the negatively interactive model. Given one
severe SLE, they found little or no increased risk for depression given additional severe
SLEs [59]. Kendler and associates, who examined multiple SLEs occurring together inthe same month, support the positively interactive model: the impact of increasing numbersof SLEs on risk for a depressive onset is signiﬁcantly more than predicted under an additivemodel [58].
Although the association between stressful events, brain abnormalities, and the occurrence of depression appears to be consistent, much less is known about the mechanisms
by which stress can induce changes in the CNS and lead to limbic–cortical defects. Stress,
especially when prolonged, appears to affect brain activity and structure, and induce alterations at cellular and molecular levels. Changes at the molecular level include stressinduced modiﬁcations of protein expression and activity leading to alteration of the expres-Beyond the Serotonin Hypothesis

353

sion of speciﬁc genes, while changes at the cellular level include stress-induced dendritic
remodeling and/or atrophy, reduction of neurogenesis, and neuronal death.
A. Stress-Induced Modiﬁcation of Protein Expression
Advances in molecular biology have enhanced our insights in the mechanisms that are
responsible for the deleterious effects of stress on cellular activity and the relationships
between intracellular defects and the development of depression. In the last few years,
several studies have begun to characterize the effect of stress and antidepressant treatments
beyond the neurotransmitter and receptor level. This work has demonstrated that there
are many intracellular pathways that could mediate the action of antidepressant treatments[18,60]. One such pathway, which appears to be a common target for medication that
stimulates serotonergic and noradrenergic systems, is the cAMP signal transduction cascade [61,62]. Long-term use of antidepressants results in a sustained activation of thecAMP system in speciﬁc brain regions, including increased function and expression of
the transcription factor cAMP/calcium response element-binding protein (CREB) in the
hippocampus and neocortex [63,64]. Moreover, the time course for CREB induction isconsistent with that for the therapeutic actions of antidepressant treatments (10–21 days)[63,65]. Importantly, the cAMP system and CREB are involved in the modulation of theexpression of selective genes that play an important role in neural plasticity and emotional
modulation, including tyrosine hydroxylase (the rate-limiting enzyme in biosynthesis ofcatecholamine neurotransmitters), brain-derived neurotrophic factor (BDNF), and TrkB
receptor genes [66–68]. An intriguing possibility is that stress could possibly precipitate
depression mainly through dysregulation of BDNF synthesis and release. Several preclinical studies have reported that chronic stress can induce a strong decrease of BDNF expression in several brain regions including the hippocampus [69,70]. Stress-induced glucocorticoid expression may augment this effect [71]. In our laboratory, we have investigatedthe effect of prolonged stress on phospho-CREB activity. Interestingly, 3 weeks of unpredictable and uncontrollable stress signiﬁcantly downregulated phospho-CREB in several
limbic and cortical regions of the rat brain. This effect was particularly signiﬁcant in thefrontal cortex (prefrontal cortex and anterior cingulate) and in the thalamus (paraventricular thalamic nucleus), two regions characterized by a dense serotonergic innervation (Fig.
1a,b). Thus, our data appear to substantiate previous observations about the effect of sustained stress on BDNF expression and may provide information about the way in whichchronic stress may inﬂuence the activity of the serotonergic system and induce selective
dysfunctions in limbic–cortical regions involved in the modulation of emotional responses
and in the pathogenesis of depression, through its effects on phospho-CREB and/or BDNF
expression.
B. Stress-Induced Modiﬁcation of Brain Structure and Function
The adult brain appears to possess a high degree of plasticity and ﬂexibility. Remodelingof synaptic contacts, growth, and branching of dendrites are only a few examples of suchplasticity necessary for adaptation to the continuously changing environment. The dynamic process is based on the capability of neuronal systems, brain nuclei, single neurons,
synapses, and receptors to adapt to alterations in the internal and/or external environmentby modifying speciﬁc structure and functions [72]. In the past few years, neurogenesis
has been reported in the adult brain of rats, tree shrews, macaques, and humans demonstrat-

354

Trentani et al.

Figure 1 Phospho-CREB expression in cortical (a) and subcortical regions (b) following
chronic stressful stimulation in male rats. Phospho-CREB expression was quantiﬁed in several cortical (PFC, cingulate, somatosensory and perirhinal cortex) and subcortical regions(dentate gyrus, paraventricular thalamus and paraventricular hypothalamus) in rats killed 2
h following the last stimulation. The greater decrease of phospho-CREB expression was
detected in the PFC and in the thalamus (p ⬍ 1e-7 and p ⬍ 1e-5).

ing that adult-generated neurons are a feature common to the mammalian brain [73,74].
The newly generated neurons protrude axons and appear to establish functional connections with surrounding neurons, indicating that they are capable of integration into existingneuronal circuitry in the hippocampus and cerebral cortex. These brain regions have been
extensively studied for several reasons, including involvement in stress-induced neuraldefects and the etiology of depression. The hippocampus is an especially plastic and vulnerable area that controls the HPA activity and, in turn, is affected by stress hormones[52]. It also responds to gonadal, thyroid, and adrenal hormones, which modulate changes
in synapse formation and dendritic structure and regulate dentate gyrus volume during
development and in adult life [75,76].

Beyond the Serotonin Hypothesis

355

The structural plasticity of the brain is affected by stress [77,78]. Repeated stresscauses atrophy and, in severe cases, death of hippocampal neurons. Moreover, chronic
stress strongly reduces dendrite growth and branching [53]. Both acute and chronic stresshas been shown to suppress neurogenesis, especially in the adult brain [73]. These formsof hippocampal structural plasticity are relevant for normal functioning of the hippocampus and subsequent mental health as a number of psychiatric disorders are characterized
by selective hippocampal defects. Atrophy of the hippocampus has also been observed inpatients suffering from recurrent major depression [79–81]. Thus, although mood disorders have traditionally been conceptualized as neurochemical disorders, there is now considerable literature demonstrating that these psychiatric disorders are also associated withsigniﬁcant reductions in regional central nervous system (CNS) volume and cell numbers.
The structural changes observed in depression, however, do not appear to be limited tothe hippocampus. Several recent postmortem studies of the prefrontal cortex have also
demonstrated a reduction in volume and cell number in depressed patients [82–84]. In
addition, unexpected reductions in the glial cell number and density were also observed[84–86]. Furthermore, in the prefrontal cortex (PFC), a histological study of area sg24
located in the subgenual PFC found striking reductions in glial cell number in patientswith familial major depression (24% reduction) and manic depressive illness (41% reduction), as compared with control subjects [46]. Together, these ﬁndings provide convincing
evidence that decreased regional CNS volume, caused by reduction in cell numbers andneurogenesis, and structural changes may be involved in the development of depression,at least in a subset of depressed patients.
Depression, therefore, seems to be a multifactorial disorder, for which the risk ofdevelopment is inﬂuenced by several factors, including genetic as well as environmental
elements. In the absence of assessed SLEs, the risk of the onset of depression is inﬂuenced
by genetic factors, but even in the absence of high genetic risk, SLEs continue to besigniﬁcant predictors of the onset of major depression. Clinical evidence suggests that therole of environmental factors may even overcome the effects of genetic factors in theonset of depression. Nevertheless, even though it is clear that several factors are involvedin the precipitation of depression, less is known about the manner and mechanisms inwhich these factors, individually or combined, interact to induce changes in brain structureand function that eventually contribute to increased vulnerability for the development ofaffective disorders. Deﬁning the pathway by which stressful stimuli interact with genetic
predisposition in order to induce brain defects appears to be fundamental for both theprevention and the treatment of depression.
C. Regulation of Gene Expression: Coupling Extracellular Signals
with Selective Gene Expression
Alterations of the internal or external environments cause rapid changes in gene expression
in the brain. Extracellular stimuli that trigger long-term phenotypic changes in neurons,
such as differentiation of a precursor cell or synaptic strengthening, elicit changes in gene
expression. These stimuli cause changes in gene expression by activating intracellularpathways that propagate the initial signal from the plasma membrane to the nucleus. Thesepathways are composed of protein kinase cascades that culminate in the phosphorylation
and activation of critical transcription factors, including CREB and FOS [87,88] (Fig. 2).
FOS was one of the ﬁrst transcriptional factors to be identiﬁed. It is codiﬁed by the
proto-oncogene c-fos and belongs to the family of immediate early genes (IEGs). IEGs

356

Trentani et al.

Figure 2 Transcription factor regulation (CREB and c-Fos). The transcription factor
CREB binds to the cAMP response element (CRE) and activates gene transcription in response to a wide variety of extracellular signals (including growth factors, hormones, andneurotransmitters). Transcriptional activation of CREB is controlled through phosphorylation
at Ser133 by ERK1 and ERK2. The transcriptional activity of the proto-oncogene c-Fos has
been implicated in cell growth, differentiation, and development. Fos is induced by many
stimuli, ranging from mitogens to pharmacological agents. c-Fos has been shown to be
associated with another proto-oncogene, c-Jun, and together they bind to the AP-1 bindingsite to regulate gene transcription. (Reprinted with permission from Sigma-Aldrich Chimie
B.V., The Netherlands.)

are transcribed in a very rapid phase immediately after individual cells perceive extracellular stimuli and play important roles in signal transduction and transcriptional regulation innormal cells [89]. Importantly, FOS has long been used as a marker of neuronal activation
following various stimuli in living animals. In fact, when animals are subjected to stressors, the c-fos gene is immediately expressed in discrete brain areas, especially in thelimbic and HPA axis systems. Although FOS is constitutively expressed in many brain
areas, its levels rapidly and transiently rise in those regions activated by new stimuli,Beyond the Serotonin Hypothesis

357

peaking after 2 h before returning to the normal expression levels. This provides detailed
maps of the activation patterns of selective neural circuits in response to speciﬁc extracellular stimuli [90,91]. IEGs code for transcription factors that bind to regulatory regionsof target genes to regulate their transcription. FOS, in particular, forms heterodimers withmembers of the Jun family of IEGs and its activity is dependent on new protein synthesis.
This FOS-Jun complex is referred to as AP-1 and binds to AP-1 binding sites of target
genes modulating their expression [92].
CREB is perhaps the best characterized, stimulus-induced transcription factor. It
was originally identiﬁed as a target of the cAMP signaling pathway, but recent studies
have revealed that this transcription factor is also a target of other signaling cascades
activated by a diverse array of stimuli. Contrary to FOS, CREB-mediated gene expression
is not directly dependent on new protein synthesis but on its phosphorylation instead. In
fact, only the phosphorylated CREB (phospho-CREB) is able to induce gene expression.
Thus, all signaling pathways that activate CREB lead to the phosphorylation of a particular
residue, the serine 133 (Ser133). CREB phosphorylation at residue 133 appears to havemultiple roles. Since non-phosphorylated-CREB has also been found in the cytoplasm,
phosphorylation at Ser133 might induce translocation of the cytoplasmatic CREB to the
nucleus. In the nucleus, phosphorylation at Ser133 might affect the ability of CREB todimerize and might promote its binding to the cAMP-responsive element (CRE). Finally,
phosphorylation at Ser133 might lead to transcriptional activation by promoting interaction
with components of the transcription machinery [93]. Phospho-CREB is involved in theregulation of the expression of several genes including somatostatin, tyrosine hydroxylase,and BDNF. Interestingly, CREB phosphorylation also appears to trigger the transcriptionof c-fos [94].

III. A MOLECULAR AND CELLULAR THEORY OF DEPRESSION:
THE STRESS-BDNF HYPOTHESIS
A. The Neurotrophin Transduction Pathways
Neurotrophins mediate a broad range of neuronal functions, including synaptic plasticity,
survival, differentiation, growth, and apoptosis. The biological activities of neurotrophinsare mediated by two structurally distinct classes of cell surface receptors, the Trk tyrosine
kinase receptors (TrkA, TrkB, and TrkC receptor types), and the p75 neurotrophin receptor(p75NTR) [95,96]. In particular, nerve growth factor (NGF) binds TrkA; BDNF andneurotrophin-4/5 bind to TrkB; neurotrophin-3 binds primarily TrkC: the p75NTR binds
all neurotrophins at least with low afﬁnity. While Trk receptors transmit positive signals
such as enhanced survival, p75NTR transmits both positive and negative signals. The
signals generated by these two neurotrophin receptors can either augment or oppose eachother. Trk and p75NTR receptors thus exist in a paradoxical relationship, each acting tosuppress or enhance the other’s actions [97].
The activation of neurotrophin receptors by their extracellular ligands triggers acomplex sequence of intracellular events that begin with receptor autophosphorylation,
followed by the activation of several downstream phosphorylation cascades that ﬁnallylead to the stimulation and/or inhibition of the expression of selective genes (Fig. 3). The
ﬁrst intracellular neurotrophin-activated signaling protein shown to mediate survival inneurons was the small GTP-binding protein Ras. This protein is responsible for the 40 to
60% of neurotrophin-mediated neuronal/cellular survival even though it does not act di-

358

Trentani et al.

Figure 3 Trk signaling pathways regulating survival and neurite growth in neuronal cells.
Neurotrophin binding to Trks stimulates receptor transphosphorylation, resulting in the recruitment of a series of signaling proteins to docking sites on the receptor. These proteins
include Ras and Raf, which participate in activating MAPK. Trks also activate PI-3K throughRas. PI-3K activity stimulates the activities of Akt. The targets of PI-3K/Akt antiapoptotic
activity, including BAD, GSK-3, Bcl-2, and the p53 cell death pathway. (Reprinted from
Ref. xx.)
rectly to promote this. Rather, Ras functions by translating and directing neurotrophininitiated signals into multiple signal transduction pathways. Recent data indicate that twoof these signaling cascades, phosphatidylinositol-3-kinase/protein kinase B (PI-3K/Akt)and mitogen-activated extracellular kinase/mitogen-activated protein kinase (MEK1/
ERKs), are the major effectors of neurotrophin-activated survival [97].
The PI-3 kinase enzymes are present in all cell types, and their activities have beenshown to be necessary for many different regulatory cell pathways. The array of different
functional roles attributed to these enzymes includes a role in mitogenesis as well as interminally differentiated cells, suggesting that there are many complexities both in theregulation of the enzymes and in their downstream targets. In neurons, the Ras/PI-3K/
Akt route is recognized as the main mediator of the neurotrophin-mediated protective
effect. A pivotal role in this survival pathway is played by the protein kinase B (or Akt1) [98,99]. Several studies have reported the involvement of this enzyme in neurotrophinrelated protective activity. Its effects may involve a direct inhibition of the activity of
p53, Bad (an inhibitor of the Bcl-2 anti-apoptotic protein), an indirect suppression of GSK-

Beyond the Serotonin Hypothesis359

3 apoptotic activity, or the blockade of the function of the primary neuronal apoptotic
pathway [99–101]. Most likely, Akt-1 mediates cell survival at a number of levels, depending upon the cell type, target availability, and requirements for transcriptional or posttranscriptional events to suppress apoptosis.
The second main intracellular cascade involved in the transduction of neurotrophin
signals is the MEK1/ERKs pathway [102,103]. Recent data suggest that this cascade mightplay a critical role in suppressing neuronal apoptosis triggered by cellular damage and its
main function may be to protect neurons from death due to injury or toxicity [104]. MEK1/
ERKs induce survival by stimulating the activity or expression of antiapoptotic proteins,
including Bcl-2 and CREB. Nerve growth factor (NGF), through this cascade, potently
increases Bcl-2 levels in sympathetic neurons, which in turn protect these and other neurons from apoptotic cell death [105]. CREB activity is also required for Bcl-2 expression
and survival by NGF, suggesting a MEK1/ERKs-CREB-Bcl-2 survival pathway [106].
The activation of CREB by survival factors is likely to be due to phosphorylation at Ser133
by multiple kinases, including MAP kinases and Akt-1 [107] (Table 1).
Thus, neurotrophins regulate neuronal survival and apoptosis at several levels, which
requires the orchestrated activity of different receptors, enzymes, and transcription factors.
The functional cross-talk between all of these effectors appears to be crucial in determining
the ﬁnal result of their activity.
B. The Neurotrophin Hypothesis of Synaptic Plasticity
The neurotrophin (NT) family of molecules is a set of gene products that have multiple
functions at different stages of development and at different locations in the CNS. They
play a fundamental role in neuronal differentiation and survival, axon pathﬁnding, andsynaptic plasticity [108,109]. Repetitive neuronal activity enhances the expression, secretion, and/or actions of the synapse to modify synaptic transmission and connectivity,
thereby providing a connection between neuronal activity and synaptic plasticity. The
expression of these proteins is linked to activity-dependent plasticity: neurotrophin genes
are regulated by neuronal activity. BDNF is one of the members of the NT family. Its
expression and secretion is upregulated by electrical activity, but other NTs may remainin the cytoplasm under resting conditions to be released in response to depolarization[110]. BDNF has been shown to increase the length and complexity of the dendritic trees
in cortical neurons, morphological changes requiring neuronal activity. Neuronal activity
appears to enhance BDNF-induced potentiation of synaptic activity. It seems that presynaptic depolarization elevates the activity of the cAMP system, which in turn facilitates thetransduction of BDNF signaling. Both BDNF and synaptic plasticity have been reported toactivate the calcium-calmodulin-dependent pathway that leads to CREB phosphorylation[111].
C. Neurotrophin Signaling Pathway Members, Survival,and Antidepressants
Additional evidence about the role of the neurotrophin signaling pathway in the etiology
and treatment of depression is provided by the large number of studies reporting alterationsin the expression of one or more of the members of this cascade as a consequence ofantidepressant therapies. The neurotrophin intracellular cascade appears, in fact, to be acommon target of antidepressants independent of their pharmacological proﬁle.

360

Trentani et al.

Table 1 Enzymes and Protein Involved in the Transduction of Neurotrophic Signals
and in Their Cellular Actions
Protein/enzyme
Ras
MEK1
ERK1 and 2

PI-3-Ks

protein kinase B(Akt-1)

P53

Bcl-2

GSK-3

Function

Refs.

MAPK kinase kinase kinase
MAPK kinase 1: it is responsible for the dual phosphorylationthat activates ERK1 and 2
MAP kinases: they are involved in the transduction of neurotrophin signals and play important roles in the adult brain
modulating synaptic plasticity and neuronal survival. They
are activated by MEK1: phospho-ERKs can phosphorylate abroad variety of proteins and transcription factors including
microtubule-associated proteins, CREB and FOS.
The PI 3-kinase activities have been shown to be necessary formany different cell regulatory pathways. Their functions are
crucial during mitogenesis but also in terminally differentiated cells. In neurons, they have a fundamental role in theneurotrophin-mediated survival.
Serine/threonine kinase downstream from PI-3K. This enzyme
plays a pivotal role in the modulation of survival in neurons
regulating the activity and expression of several pro- andanti-apoptotic proteins, including bcl-2, p-53 and GSK-3-β.
p53-protein functions include maintenance of DNA stability,
control of mitochondria integrity and regulation of apoptosis.
p53-mediated apoptosis may involve multiple mechanisms,
including the interference with the growth factor–mediatedsurvival signals. The inhibition of p53 functions and expression appears to prevent apoptosis.
bcl-2 proteins are involved in the regulation of cell death.
Many of these proteins show widespread expression and arealso expressed in the nervous system in developing and adultorganisms. A physiological role for bcl-2 in neuron survival
has been shown: these proteins have been shown to protect
neurons from a wide array of toxic insults.
Glycogen synthase kinase-3-β (GSK-3-β) is a serine/threonine
protein kinase ubiquitously expressed and involved in several
neuronal functions including cytoskeleton stability andapoptosis. GSK-3-β has been shown to be the target of several intracellular cascades. PKA and Akt have been reported
to phosphorylate GSK-3-β inhibiting its proapoptotic activity.

221
221
221

98,222

98,99,222

223

113

224,225

1. Mood-Stabilizing Drug: Lithium
For almost half a century, lithium has been the most widely used treatment for bipolar
depressive disorder, but the mechanisms by which this cation exerts its long-term beneﬁcial effects are not yet clear. Lithium has a variety of beneﬁts in the treatment ofmood disorders, including acute antimanic and antidepressant effects, antidepressantpotentiating effects, and long-term prophylactic effects. It is unlikely that any single biochemical action can mediate all of lithium’s clinical effects [31]. It has recently been

Beyond the Serotonin Hypothesis

361

demonstrated that lithium-mediated stabilizing effects on bipolar depression might be mediated by key enzymes and transcription factors of the neurotrophin intracellular signalingcascade, including GSK-3-β, ERKs and bcl-2 [112]. The latter is an inhibitor of both
apoptotic and necrotic cell death and an enhancer of neurite outgrowth, axonal growthrate, and regeneration in the mammalian CNS [113]. Several cellular mechanisms are
involved in the protective effects of bcl-2, including inhibition of caspase activation andenhancement of antioxidant effects, mitochondrial calcium reuptake, and release of calcium and cytochrome C from mitochondria [114–116]. Lithium appears to robustly increase the level of bcl-2 both in vitro and in vivo and recent studies have shown that both
phosphatidylinositol-3-kinase and MAPK pathways are involved in this action. MAPK
cascade activation, in particular, does so through CREB involvement. In this manner,
lithium might enhance hippocampal neurogenesis and exert the neuroprotective effects
reported to be fundamental for antidepressant activity [117]. Other targets of lithium are
GSK-3-β and p53/capsase cascades. Lithium, at therapeutic concentrations, is a potent
inhibitor of the GSK-3-β [118] enzyme involved in the maintenance of cytoskeletal integrity via tau and synapsin I, as well as phosphorylation of c-jun and β-catenin that mediate
long-term effects via alteration of gene transcription [119,120]. In addition, lithium has
been shown to increase basal transcription factor binding to AP-1 and CRE sites [121].
These lithium-induced changes in transcription factor binding activity may be an effectof the inhibition of GSK-3-β, which, in turn, phosphorylates transcription factors such as
c-Jun, inhibiting its DNA binding capacity [122]. Moreover, lithium affects the expressionof p53, another protein involved in the regulation of apoptosis [123]. It is well establishedthat p53 positively regulates Bax but negatively regulates bcl-2 expression [124,125].
Since accumulation of p53 in the nucleus is a critical intermediate step for many signaling
processes that culminate in cell death, attenuation of p53 activation by lithium may be amechanism by which this cation supports neuronal survival. To date, lithium is the only
medication that produces robust increases in the level of bcl-2 in the frontal cortex andhippocampus in vivo. Evidence of lithium’s neuroprotective effects, as well as the growing
appreciation that mood disorders are associated with cell loss and/or atrophy, suggeststhat these effects on neuroplasticity may be critical aspects for long-term treatment ofmood disorders [126].
2. Serotonin and/or Norepinephrine Reuptake InhibitorscAMP-mediated regulation of gene transcription has been implicated in the activity ofantidepressant drugs acting on serotonin and/or norepinephrine neurotransmitter systems
in which CREB appears to be the main effector in the cascade. Chronic antidepressant
administration increases CRE-mediated gene expression and CREB phosphorylation in aregion- and drug-speciﬁc manner [63,65]. The most consistent effects were observed in
the amygdala, hippocampus, and cerebral cortex [64]. More importantly, induction of
CRE-mediated gene expression and CREB phosphorylation were not observed in responseto acute antidepressant treatment, which is consistent with the time course of the therapeutic action of these drugs [63]. Thus, antidepressant induction of CREB phosphorylation
has been found in brain regions that are thought to play a role in the regulation of emotion
and responses to stress. Previous studies have demonstrated that the amygdala mediates
some of the behavioral actions of antidepressants and that neurochemical adaptations toantidepressants are observed in this limbic area [64]. The amygdala plays a signiﬁcantrole in fear conditioning and conditioned avoidance behavior [127,128]. The possibility
that CREB inﬂuences the function of this limbic area is supported by recent observations

362

Trentani et al.

that illustrate that overexpression of CREB in the amygdala alters long-term memory of
fearful conditions [129,130]. It is also possible that neurochemical alterations in the amygdala could contribute to the displaced emotion often observed in depressed patients.
Chronic antidepressant treatment also results in neurochemical and cellular adaptationsin the cerebral cortex and hippocampus [63,131]. Importantly, CREB’s involvement in themode of action of antidepressant drugs is supported by the fact that chronic antidepressanttreatment increases the expression and function of CREB in these aforementioned brain
regions. In addition, it has been found that SSRIs and NRIs increase the expression of
BDNF in the hippocampus [131]. The possibility that BDNF induction involves CREB
is supported by recent reports that show that the promoter of the BDNF gene contains a
CRE. Thus, upregulation of CREB and BDNF, induced by antidepressant treatment, could
act to oppose the damaging effects of stress on hippocampal neurons or facilitate therecovery from previous insults. A role for CREB in the pathophysiology of depression
and in the antidepressants’ mechanism of action is supported by a recent study demonstrating that CREB levels are decreased in the cerebral cortex of depressed patients and increased in patients receiving antidepressant medication prior to death [18].
3. Serotonin Reuptake Enhancer: Tianeptine
Tianeptine is a novel antidepressant agent, both structurally (modiﬁed tricyclic) and interms of its pharmacodynamic proﬁle. Unlike other antidepressant agents, tianeptine stimulates the uptake of serotonin [132]. In patients with major depression without melancholia
or psychotic features or with depressed bipolar disorder or dysthymic disorder, the antidepressant efﬁcacy of short-term (4 weeks to 3 months) tianeptine therapy appears to be
similar to that of amitriptyline, imipramine, and ﬂuoxetine [28,133]. The hippocampus,
most likely, is an important target for tianeptine’s therapeutic action. The human hippocampus undergoes atrophy in the aftermath of traumatic stress, recurrent depression, andCushing’s syndrome [79,134–136]. Prolonged psychological stress in monkeys is associated with loss of hippocampal neurons [137], whereas repeated psychological stress inprimitive primates and in rats causes hippocampal CA3 pyramidal neurons to undergo
dendritic atrophy [138,139]. The atrophy is only seen in the apical dendritic tree andcomprises a reduction in length and branching and must involve alterations in the apicaldendritic cytoskeleton [140]. Three factors play a role in hippocampal damage. These
include glucocorticoid hormones, which potentiate damage produced by other insults,
endogenous excitatory amino acids, and serotonin [141,142]. Serotonin is released bystressors and plays a role in the actions of stress on nerve cells. It appears that stressors
activate the release of excitatory amino acids from mossy ﬁber synapses and promote
serotonin release and adrenal steroid secretion that concur to enhance the effect of stressful events in the hippocampus. Interestingly, tianeptine treatment prevents stress-induced
atrophy of CA3 pyramidal neurons, whereas neither ﬂuoxetine nor desipramine has such
effects. Tianeptine treatment also prevents the stress-induced learning impairment. The
molecular mechanisms by which tianeptine prevents stress-mediated dendritic atrophy is
not yet fully understood, however [29].
4. Electroconvulsive Therapy
Although electroconvulsive therapy (ECT) has been used for the treatment of depression
for several decades, the neurobiological effect of this antidepressant treatment has notbeen determined. The majority of studies investigating the effects of ECT have focusedon the monoamine neurotransmitter systems. However, alterations of the synaptic levels

Beyond the Serotonin Hypothesis363

of serotonin and norepinephrine, or adaptations of the receptors for these neurotransmitters, cannot account for the delayed action of antidepressants [66]. These results havegenerated a novel hypothesis stating that the pathophysiology and treatment of depression
and the mechanisms of ECT action may result from alterations in the expression andfunction of neurotrophin factors [19]. The expression of BDNF and TrkB are affected byshort- and long-term electroconvulsive shock (ECS) treatment as ECS treatment results
in a rapid and dramatic induction of BDNF mRNA expression in cortical and limbic brain
regions. This increase in BDNF mRNA is most pronounced in the hippocampal dentate
gyrus and cerebral cortex, areas frequently implicated in the etiology of depression. The
expression of TrkB mRNA is also increased in the same brain regions in response to asingle ECS treatment [131,143]. Long-term ECS treatment results in a larger and longerlasting (⬎18 h) induction of BDNF mRNA [131]. The induction of BDNF in response
to ECS treatment most likely involves the activation of multiple neurotransmitter systems
and intracellular signal transduction pathways. A prominent role appears to be played by
the cAMP/calcium system and by the transcription factor CREB [19]. CREB-mediatedinduction of BDNF expression is supported by the ﬁnding that ECS, as well as antidepressant drugs, increase CREB function and expression. Moreover, the time course of expression and cellular distribution of CREB is similar for antidepressant and ECS-induced
expression of BDNF and TrkB. Furthermore, upregulation of BDNF expression suggests
an involvement of synaptic plasticity and alterations of neuronal structure in the mode ofaction of long-term ECS treatment [131]. These structural alterations could occur at several
levels, including changes in length and complexity of the presynaptic processes and subtle
alterations of the synapse architecture. Repeated, in contrast to single, ECS treatment
signiﬁcantly increases hippocampal granule cell sprouting. This effect is long lasting andcan be observed up to 6 months following the last ECS treatment. Sprouting of granulecells could result in an altered functioning of these neurons leading to an enhanced responsiveness to stimuli. It is also possible that the neuronal sprouting and enhanced responsiveness represent adaptations to reverse the atrophy of hippocampal neurons or to protectthese neurons from further stress-induced damage [19].
IV. STRESS-INDUCED BRAIN OVERLOAD
Preclinical studies suggest that stress can promote long-term changes in multiple neurotransmitter systems and brain structures implicated in the etiology of depression. It has
also been well established that both anxiety disorders and depression are diseases that arecharacterized by a higher prevalence in women than in men. In our laboratory, we haveinvestigated the response of several limbic regions to chronic stress in male and female
rats using the IEG c-fos protein as a marker of neuronal activation (Fig. 4). Prolonged,
but not acute, stress induced pronounced sex-related differences in the pattern of activationin several “higher” limbic regions, including the frontal cortex (Fig. 4a), the amygdala(Fig. 4b), the hippocampus (Fig. 4c), and the thalamus. In particular, chronically stressed
females showed a decreased limbic activation while an increased regional activity was
found in male rats. The pattern of limbic activity found in chronically conditioned females
may demonstrate a different female susceptibility to the effects of stress as well as atransition from a physiological adaptation to an emotional circuitry malfunction. Important
indications for understanding the differential response to prolonged stress came from theobservation of a signiﬁcant difference in limbic activity in basal conditions. Nonstressed
females showed an overall higher limbic FOS expression and, consequently, a higher

364

Trentani et al.

Figure 4 Effect of a chronic stressful challenge on FOS density in the (a) frontal cortex,(b) amygdala, (c) hippocampus and hypothalamus. The symbol * expresses the comparisonof FOS density between control and stressed rats (* ⫽ p ⬍ 0.05; ** ⫽ p ⬍ 0.01; *** ⫽p ⬍ 0.001), killed 2 h following the last stimulation. The symbol # expresses the comparisonof the basal c-fos expression between control male and control female rats, both cyclic andovariectomized (# ⫽ p ⬍ 0.05; ## ⫽ p ⬍ 0.01; ### ⫽ p ⬍ 0.001). The symbol @ expresses
the comparison of the basal FOS expression between control cyclic and ovariectomized
female rat (@ ⫽ p ⬍ 0.05; @@ ⫽ p ⬍ 0.01).

limbic activity than males (5–7 times higher), especially in the frontal regions. Interestingly, these differences are not limited to experimental animals, since several clinicalstudies also reported gender-related diversities in brain activity, with women exhibiting
higher values than men [144–146]. Functional brain imaging techniques have illustrated
sex-related differences in global as well as in the regional brain activity and reports ofdifferential activation in the frontal lobes have been particularly prevalent [147]. Esposito
and coworkers [148] reported substantial gender-related differences in the frontal loberCBF during performance of a variety of cognitive tasks as women demonstrated a signiﬁcantly higher activation [148]. This higher level of neural activity in female rats may
reﬂect larger cognitive abilities in basal conditions but reduced abilities following achronic stressful challenge, as demonstrated by the decreased limbic activation and behavioral changes. No gender-related differences were found after acute conditioning, however.
Of interest is the fact that these sex-related differences were particularly evident in theBeyond the Serotonin Hypothesis

365

frontal cortex (PFC and AC). Therefore, our results appear to be in line with those of
Esposito, who reported a higher level of regional activity especially in frontal areas andduring activation paradigms in women [148]. It has been well established that gender
determines cognitive and learning abilities [149–151]. Therefore, these results appear to
be in accordance with our data, as nonstressed male rats showed a lower FOS density
than females but an increased FOS expression after chronic stress. Conversely, the basal
neural activity in female rats was higher in nonstressed animals and decreased after chronic
stress conditioning. This differential FOS response together with the abnormal behavioral
response could be an illustration of distinctive susceptibilities between sexes for enduring
effects of stress on brain activity [152]. Male rats appear better able to cope with stressful
situations, whereas females suffer more from the effects of stress especially when it becomes prolonged. Thus, the decreased FOS expression after chronic stress training infemale rats could represent the histological evidence of selective impairment of cognitive
functions caused by reduction of limbic regional activity, particularly evident in the frontal
cortical regions. Hypothetically, the brain may support only a limited level of activity.
Women do show a higher vulnerability to mood disorders and this could be related totheir higher basal limbic activity. This “overload threshold” hypothesis is supported by
George and coworkers [146], who investigated neural activation during the induction ofsadness. They found that men and women deemed themselves equally sad during theexperiment, while the left prefrontal cortex of both sexes was equally activated. Nevertheless, women showed an eight times greater blood ﬂow in the anterior limbic regions thanmen. George speculated that hyperactivity of the anterior limbic system in women experiencing sadness could, in time, exhaust that particular region and lead to the hypoactivity
seen there during clinical depression [146]. Stress-induced limbic hyperactivity, subsequent overload, and a prolonged hypoactivity may not be enough to induce brain dysfunctions. As stated before, the brain responds to stress in a complex yet orchestrated mannerthat requires a high grade of plasticity and consequently a large availability of BDNF.
BDNF release, however, is activity-dependent. Stress initially induces an increase in limbic activity: during this phase there is a massive release of BDNF that allows the brain
to respond to stress with dynamic structural changes.
At this point there are two possibilities.
1. Prolonged and persistent stress is a cause of neuronal hyperactivity associatedwith massive release, and eventually exhaustion of BDNF supplies. This leads
to a stress-induced deﬁciency of BDNF and reduction of neuronal plasticity.
2. Sustained stress gradually increases the activity of speciﬁc limbic areas andleads to their hyperactivity (earlier in females because of the higher basal activity closer to the overload threshold). Prolonged neuronal hyperactivity causes
the exhaustion of the brain region and, consequently, hypoactivity (overload).
At this point, the brain region, because of the reduction of BDNF synthesis andrelease (BDNF release is reported to be activity-dependent), is unable to facethe effects of stress with the plastic changes that it needs. Thus, reduction of
BDNF availability might increase the vulnerability of the brain to subsequent
insults and may be the prelude to selective limbic defects because of the brain’s
inability to deal with the effects of stress with an adequate structural plasticity.
This second possibility is supported by our results regarding the effects of chronic
stress on phospho-ERK1/2 (Fig. 5a,b) and phospho-CREB expression in male rats (Fig.
1a,b). After 3 weeks of exposure to a chronic unpredictable and uncontrollable stressor,

366

Trentani et al.

Figure 5 Phospho-ERK1/2-positive cortical dendrites after chronic stress in male rats(a). Phospho-ERK1/2-positive dendrites were counted in four cortical regions including
PFC, cingulate, somatosensory, and perirhinal cortex. The number of p-ERK1/2-stained
dendrites was quantiﬁed as the number of horizontal and vertical intersections between
positive dendrites and the imaginary detection grid present in the quantiﬁcation ﬁeld, using
a computerized image analysis system (Leica). The resulting data were reported as thenumber of positive H ⫹ V intersections/0.1mm2. Phospho-ERK1/2 accumulation was selectively restricted to the PFC (p ⬍ 0.005). No other cortical regions showed an increase ofactivated MAPKs. Phospho-ERK1/2-positive prefrontocortical dendrites of male rats exposed to acute (3 days), subchronic (10 days), and chronic stressful conditioning (21 days)
and killed 2 h following the last stimulation (b). A signiﬁcant “accumulation” of phosphoERK1/2 in the PFC was found only after chronic ( p ⬍ 0.005) but not after acute or subchronic stress.

Beyond the Serotonin Hypothesis

367

rats showed an accumulation of phospho-ERK1/2 in the dendrites of the higher layers (IIand III) of the PFC (prelimbic and infralimbic regions) (Fig. 5a,b). This accumulation
was signiﬁcant only after chronic ( p ⬍ 0.005) not acute (3 days) or subchronic (10 days)
conditioning (Fig. 5b). Chronically stressed rats also demonstrated a global reduction ofcortical phospho-CREB expression that was particularly signiﬁcant in the PFC ( p ⬍⬍0.001) (Fig. 1a). CREB is an important nuclear transcription factor of the BDNF/MAPK
signaling cascade and ERKs play a fundamental role in its phosphorylation. In turn,
phospho-CREB is involved in the regulation of the BDNF gene expression. Thus, this
uncoordinated response (increased presence of phospho-ERKs and decreased phosphoCREB expression) might be interpreted as a paradox.
The BDNF/MAPK cascade, in order to operate properly, requires a balanced activity
between the members of the kinase and phosphatase systems and that, most likely, isassured by the availability of BDNF. MAPK phosphorylation states must be carefully
regulated, as a perturbed ERK signaling has been related to neuronal dysfunctions anddeath [153]. ERK cascade, as seen above, plays a pivotal role in the transduction of neurotrophin signals but recent studies have also identiﬁed it as an important pathway involvedin the regulation of cytoskeletal organization in neurons [154,155]. ERKs, through thephosphorylation of several key components of the cytoskeletal apparatus including neuroﬁlaments and microtubule-associated proteins, control several important neuronal functions such as axonal transport, microtubule stability, complexity of the dendritic tree, number of synaptic contacts, and neurotransmitter release [156]. A balanced activity of thisintracellular pathway appears to be crucial for proper neuronal activity and maintenanceof cell structure. Stress inﬂuences neuronal activity; acute stress increases neuronal activation and enhances learning and memory, possibly to the stimulation of BDNF release andsynaptic plasticity. Indirect evidence of this action is represented by the improvement oflearning shown by animals facing acute stress situations [157]. The increased release of
BDNF in response to acute stress might be related to the enhancement of neuronal activity.
The synthesis and release of these proteins is activity-dependent and acute stress appears
to enhance neural activity [111]. On the other hand, persistent stress shows deleterious
effects on learning and memory, probably because of its negative effects on brain plasticity[53,138,158,159]. BDNF mediates synaptic plasticity and chronic stress has been reported
to reduce its expression and, consequently, neural plasticity [69,160]. Therefore, it is possible that during acute and subchronic stress conditioning the brain is still able to cope withstress because of the availability of neurotrophins that assure sufﬁcient plasticity. However, when stress becomes chronic, the reduction of BDNF availability and the consequentloss of neural plasticity reduce the ability of the brain to face the deleterious effects ofstress.
During the acute stress phase, increased neuronal activity and BDNF release leadto the persistent activation of the MAPK/ERK cascade. BDNF not only increases theactivity of the kinase system, but also modulates the phosphatase system since only abalanced activity of both systems guarantees the proper transduction of neurotrophin signals. As a consequence of persistent stress conditions and exhaustion of BDNF supplies,
the release of neurotrophin ceases. The subsequent BDNF deﬁciency might particularly
inﬂuence the activity and synthesis of new phosphatases and this defect in the phosphatasesystem leads to a permanent activation of ERKs [154,161]. ERK hyperactivity and accumulation may involve selective and vulnerable neuronal subpopulations. In turn, this situation might have nuclear and cytoplasmic consequences including defects in the phosphorylation of transcription factors and alteration of cytoskeletal stability (dendritic atrophy and368

Trentani et al.

altered neurotransmitter release). Chronically stressed rats showed an abnormal reductionof cortical phospho-CREB expression indicating that, even if overexpressed, ERKs are notable to phosphorylate CREB. This consequence is particularly important because CREB is
involved in the regulation of the expression of several genes, including the one codingfor BDNF. Thus, the defect in CREB phosphorylation might lead to the reduced synthesisof this neurotrophin. In addition, several studies have reported that the reduction of phosphatase activity due to an unbalanced kinase/phosphatase system leads to dysregulationof the pattern of synapsin and synaptophysin expression [155,162]. A consequence ofsuch dysregulation is a decrease in the complexity and extent of neurite arborization, lossof synapses, and neurotransmitter release [162]. Both nuclear and cytoplasmic abnormalities could act together and lead to a reduction in BDNF release (because of decreased
synthesis, through a CREB-mediated mechanism, and decreased release, through a synapsin-mediated mechanism). It is less important which mechanism plays the main role inthe chronic stress-mediated dysfunction: the ﬁnal consequence remains the same, that is
a reduction of synaptic and brain plasticity that reduces the ability of the brain to deal
with the effects of stress with plastic changes as it requires. In turn, this inability could
represent the prelude to the development of limbic defects.
V.

FUTURE OPPORTUNITIES IN THE TREATMENT OF DEPRESSION

Whether or not chronic stress, through its action on neurotrophin expression, is one of
the main pathological factors involved in the etiology of depression, this hypothesis provides new targets to improve the efﬁcacy and/or reduce the delay and side effects typicalof antidepressants today. These alternative approaches are summarized below, followedby an in-depth discussion of each perspective.
1.

2.
3.

4.
A.

Removal or reduction of stress. Reduction of stress refers not only to the reduction of external stressors (psychological or physical stressors), but also to thephysiological and/or pathological changes induced by their acute or prolonged
exposition (such as increased blood pressure and cortisol levels, changes inreleasing factors and/or releasing hormones). The normalization of the physiological parameters and restoration of body homeostasis might enhance the efﬁcacy of antidepressant treatments.
BDNF replacement therapy.
Direct stimulation or inhibition of selective kinases or phosphatases involvedin the neurotrophin transduction system (ﬂuoxetine stimulates the expressionof a gene that codiﬁes for a MAPK-phosphatase).
Estrogen replacement therapy. Prevention of stress-induced limbic overload.

Removal or Reduction of the Stressor or Its Effects
on Body Homeostasis

Stress plays a crucial role in the precipitation of depression but it might also be involved
in determining the therapeutic effects of antidepressants by reducing or delaying theiractivity. The persistence of stressors may thwart, reduce, or slow down the onset of theantidepressant action. Therefore, an important measure to enhance the efﬁcacy of antidepressant therapies may consist of removing the psychological or physical stressors andrestoring the internal homeostasis. The alteration of several physiological parameters isreported in response to persistent stress and depression, as follows.

Beyond the Serotonin Hypothesis369

1. Cardiovascular Abnormalities
Stress and depression have been reported to induce important cardiovascular events that
may reduce the therapeutic effects of antidepressant therapies. Several studies have investigated the effects of acute and chronic stress on cardiovascular function, ﬁnding a strongcausal relation between stress and atherosclerosis, elevation of arterial blood pressure andheart rate, neurohormonal arousal, coagulation abnormalities, and impairment of coronary
endothelial integrity. Interestingly, mental stress induces coronary vasoconstriction that
leads to a reduction of blood ﬂow and, consequently, oxygen supply [163]. Thus, a normalization of cardiovascular parameters might be necessary before beginning antidepressanttherapy in order to assure improved therapeutic efﬁcacy.
2. Neuroendocrine Abnormalities
Hypothalamic–Pituitary–Thyroid (HPT) Axis. Several abnormalities in the HPT
axis have been reported in depressed patients [164]. Changes in thyroid status are involvedin many cases of clinical depression. Virtually 100% of patients with severe hypothyroidism also suffer from depression [165]. A hallmark of depression is the ﬁnding of elevatedserum T4 or free T4 without changes in T3. Reductions in T4 levels accompany a beneﬁcial
response to antidepressant medication. Moreover, thyroid status strongly inﬂuences both
noradrenergic and serotonergic neurotransmission [166]. The changes seen in the HPT
axis might explain or might be explained by a central monoamine deﬁciency. The normalization of the HPT axis in conjunction with the antidepressant therapy may improve its
efﬁcacy and/or reduce the subsequent relapse of depression.
Hypothalamic–Pituitary–Adrenal Axis. Hypercortisolemia, resulting from an increased release of glucocorticoid, is perhaps the main and most investigated effect ofstress, represented by the increased release of glucocorticoids. The secretion of corticosteroid hormones (predominantly cortisol in humans) is the most important component of
the response to stress. A common feature observed in depression is the increased secretionof this hormone throughout the day. This change is seen in approximately 50% of patientswith major depression [167–169]. Glucocorticoids can have a broad range of effects inthe brain, particularly in the hippocampus [78]. A permanent hypercortisolemia is thought
to trigger neuronal and dendritic atrophy, neuronal death, and increase the vulnerabilityof this limbic region to subsequent insults [170]. High glucocorticoid levels might also
reduce the effects of antidepressant treatment. In fact, it appears that glucocorticoids suppress BDNF expression at the mRNA and protein level. Activated mineralocorticoid andglucocorticoid receptors seem, in fact, to repress transcriptional activity of the BDNF
promoter site speciﬁcally via interaction with other transcription factors [171]. As mentioned earlier, neurogenesis continues postnatally and into adulthood in the brains of many
animals, including humans. This is particularly prominent in the dentate gyrus of the hippocampal formation. One factor that potently suppresses adult neurogenesis is stress, probably through the increased glucocorticoid levels [74]. Thus, high plasma levels of glucocorticoids through their effect on neurogenesis and/or BDNF synthesis may not only be
an important factor in precipitating episodes of depression but also may be a crucial factor
involved in determining the success of antidepressant treatment. Hypercortisolemia may
thwart, reduce, or slow down the onset of the antidepressant action. Several options to
reduce stress-induced hypercortisolemia are now available, including selective corticocotropin-releasing hormone (CRH) receptor 1 antagonists (R121919) [172], cortisol biosynthesis inhibitors (ketoconazole) [173,174], and selective glucocorticoid receptor antago-

370

Trentani et al.

nists (spironolactone) [175,176]. Clinical studies have demonstrated that these treatments
effectively reduce plasma cortisol levels and improve several signs of anxiety and depression.
Restoration of internal body homeostasis by suppressing the physiological/pathological alterations induced by stress may denote the ﬁrst fundamental step toward a more
effective treatment of depression and a reduction in the number of treatment-resistantpatients. In fact, disrupted body homeostasis may constitute the major destabilizing factor
leading to an alteration of brain homeostasis and subsequently to a limbic defect.
B.

BDNF Therapy

Neurotrophins play a crucial role in the maintenance, survival, and selective vulnerabilityof various neuronal populations within the normal and diseased brain. Recent evidence
suggests that neurotrophic factors may protect mature neurons from neuronal atrophy inthe degenerating human brain. Furthermore, it has been proposed that the pathogenesisof several human disorders, including Alzheimer’s and Huntington’s disease, as well as
depression, may be due to an alteration in neurotrophic factors and/or Trk receptor levels.
Thus, the use of neurotrophic factors as therapeutic agents designates a novel approach
aimed at restoring and maintaining neuronal function in the central nervous system.
A promising treatment to remedy these psychiatric and neurological diseases is offered by BDNF replacement therapy. The potential of BDNF replacement therapy, however, is limited by the fact that it is impossible to administer the BDNF protein peripherally, because of the very high rate of removal of this neurotrophic factor from thecirculation and the absence of transport through the brain capillary wall, which makes up
the blood-brain barrier (BBB). These limitations have made invasive application strategies
necessary. Several options to administer BDNF directly to the brain are now available,
including intracerebroventricular administration [177], adenovirus-mediated transfer ofthe BDNF gene [178], and BDNF-secreting neural stem cell lines [179]. A promising andnoninvasive alternative that allows the administration of BDNF peripherally consists of amolecular reformulation of BDNF that incorporates polyethylene glycol (PEG) to optimize
plasma pharmacokinetics and links pegylated BDNF to the OX26 mAb, which undergoes
receptor-mediated transport through the BBB in vivo [180]. In the absence of pegylation
modiﬁcation, BDNF is rapidly removed from the blood stream with a half-life of approximately 5 min. This chimeric peptide shows two very important advantages compared tonative BDNF: a higher stability in the blood stream and the ability to cross the BBB andreach the brain compartment in a therapeutic concentration. Thus, this might provide a
useful alternative for noninvasive neurotrophin delivery to the brain. Since more than 90%of the total body TrkB receptor is located in the central nervous system and less than 10%
in peripheral tissue, peripheral administration of BDNF may be accompanied by a minimal
number of side effects [180].
C.

Direct Kinase Activity Targeting

BDNF therapy may represent a promising and efﬁcient way to modulate brain activity,
improve neuronal functions, and enhance plasticity and survival of neural cells throughstimulation and/or inhibition of several enzymes of the neurotrophin signal transduction
pathways. A possible alternative approach would be the selective modulation of the activity of individual proteins involved in the transduction of neurotrophin signals including
ERK1 and 2, Akt-1, GSK-3-β, p53, and bcl-2.

Beyond the Serotonin Hypothesis

371

Although numerous studies have associated ERK activation with neuronal plasticity
and survival [102], ERK members do not appear to act universally to promote these fundamental functions. Recently, several reports have shown that prolonged ERK activation
can contribute to neuronal death [153]. It is possible that the precise kinetics of ERK
activation will ultimately dictate whether the activated kinases participate in a cell-deathpromoting or cell-survival pathway. The selective “accumulation” of phospho-ERK1/2
that we found in prefrontocortical dendrites might illustrate a stress-induced defect in ERK
signaling regulation in speciﬁc neuronal subpopulations. This increased number of cortical
ERK-positive dendrites was not accompanied by a corresponding increase of ERK-positive cell nuclei (data not shown), however, supporting a persistent, and possibly uncontrolled, ERK phosphorylation. Several studies have reported a prolonged ERK cascade
activation in cortical neurons after glutamate exposure that appeared to lead to excitotoxic
degeneration or apoptosis [153]. A defect in the system involved in the modulation of
ERK activity might lead to their excessive and persistent activation, which, in turn, leads
to the hyperphosphorylation of cytoskeletal proteins, including microtubule-associatedproteins and neuroﬁlaments [156] and, consequently, to the weakening of the dendritic
structure, especially in the synaptic terminals where these proteins are particularly abundant. If dysregulation of ERK activity represents a possible mechanism by which chronic
stress induces prefrontal dysfunctions, the reduction of ERK hyperphosphorylation,
through the activity of speciﬁc protein phosphatases involved in their dephosphorylationor through the administration of inhibitors of selective downstream kinases responsible
for both phosphorylation and activation, might prevent the development of stress-related
neuronal defects and/or facilitate the recovery. The inhibition of ERK phosphorylation,by using selective MEK1 and 2 (the kinases responsible for the activation of ERK1 and
2) inhibitors PD98059 and U0126, has been reported to reduce microtubule-associatedprotein hyperphosphorylation (and consequently disorganization of the cytoskeleton), neuronal degeneration, and apoptosis in neurons [153,181].
A second important neurotrophin signal transduction pathway that appears to playa crucial role in the modulation of neuronal function while providing important targets
for an antidepressant therapy is the PI-3-K/Akt cascade. This cascade actually includes
several members that play a crucial role in modulating neuronal functions involved in thetherapeutic action of antidepressants, including Akt-1, GSK-3-β, and bcl-2. The importance of this cascade in neuronal survival has been conﬁrmed by recent data regarding
the effects of lithium on the brain. Chronic treatment with this bivalent cation has beenreported to enhance neurogenesis and survival mainly through the activation of the serine/
threonine Akt-1 [99,182], increased expression of the cytoprotective bcl-2 [112,117,123],
and inhibition of the GSK-3-β [183]. Activation of Akt-1 seems to protect neurons against
a wide range of insults including glutamate excitotoxicity, and its activity appears to be
performed through different mechanisms. In fact, it has been reported that enhanced Akt1 activation leads to the inactivation of several key proteins including BAD (a proapoptotic
member of the bcl-2 family), p53, or GSK-3-β [99–101]. Akt-1, in fact, has been shownto phosphorylate and inactivate GSK-3-β and the inhibition of this serine/threonine kinasehas been proposed as a mechanism by which neurons become resistant to apoptotic stimuli[98,184]. However, in spite of the large number of studies concerning the crucial role
played by members of neurotrophin signaling transduction pathways in neuronal survival
and their importance in the therapeutic effects of antidepressants, no drugs that selectively
stimulate it have yet been developed. These drugs might offer a valid alternative to traditional antidepressants because of their selective intracellular targets, which allow therapeu-

372

Trentani et al.

tic action focused on speciﬁc brain regions, to reduce the latency period preceding theonset of therapeutic effects, and to limit the side effects associated with traditional antidepressant treatments. In addition, targeting selective intracellular proteins may also offer
an effective prophylactic tool to prevent stress-induced brain overload or neuronal defects.
In fact, whether prolonged stress can lead to neuronal dysfunction through the alterationof the activity of vulnerable enzymes, the administration of selective drugs able to modulate their activity and restore their original functions may reduce the depressogenic effectof SLEs and prevent the development of depression. These “second-messenger controllers” might be administered for a short interval immediately after serious SLEs andthis may help subjects to overcome the series of events responsible for the deleterious
consequences of chronic stress on brain function and prevent the precipitation of depression.
D.

Estrogen and Neural Plasticity

For decades estrogen has been referred to only as a “sex” or “female” hormone. In recent
years, however, estrogen has been shown to exert effects on the structure and function of
the brain during development as well as in adulthood. Numerous studies from human andanimal models suggest that estrogen has many positive effects on neural tissue, including
stimulation of dendritogenesis, axon growth, and neurotransmitter synthesis [185–189].
It may also be beneﬁcial in preserving cognitive function, preventing or retarding postmenopausal depression, and Alzheimer’s disease and in facilitating recovery from brain
injuries [190–192].
The classic estrogen receptors were considered ligand-induced transcription enhancers. This means that the regulation of gene expression by steroid hormones is mediated through receptor proteins that bind DNA sequence and then interact with the transcriptional machinery to initiate transcription [193]. To date, two estrogen receptor (ER) types
have been characterized: ER-α and ER-β [194,195]. However, the classic mechanism of
estrogen action, which is mediated by intracellular ER-α and ER-β, inadequately explains
the extensive range of estrogen’s actions. Recent studies suggest the presence of a new
type of estrogen receptor that appears to be associated with the cell membrane [196,197].
Increasing evidence documents that this putative membrane-associated estrogen receptor
can mediate extracellular signals in both an estrogen-dependent and -independent manner,
through growth factor signaling pathways [198]. Neurons in the forebrain regions of both
sexes coexpress estrogen and neurotrophin receptors and are also the sites of estrogen andneurotrophin synthesis [199,200]. Thus, estrogen and neurotrophins may inﬂuence eachother’s action by regulating receptor and/or ligand availability through reciprocal regulation at gene transcription level. Another possible consequence of this coexpression is thesharing of similar, if not overlapping, sequences of intracellular biochemical events
through convergence or cross-coupling of their signaling pathways [201]. Cross-couplingof converging estrogen and neurotrophin signaling pathways may lead to similar nuclear
endpoints, which result in the regulation of the same broad array of genes involved
in dendritogenesis and neurite growth, including β-tubulin, MAP-2, tau-microtubuleassociated protein, and GAP-43 [202–205]. A strong candidate for the transduction of
estrogen signals is the MEK-ERK pathway, also involved in the transduction of neurotrophin signals. Estrogen has been shown to induce ERK activation in various cell models.
In explants of the cerebral cortex, estrogen elicited a rapid and sustained activation of
ERK1 and ERK2, an effect that requires MEK activation [206]. However, whether theBeyond the Serotonin Hypothesis373

ERK pathway is the major intracellular cascade involved in the transduction of estrogensignals remains unclear. Other signaling substrates that could act either in parallel or by
converging with the MAPK cascade might be activated by estrogen as well, including thecAMP, Ca2⫹ channels, and protein kinase A and C in neuronal cells [207–209]. In addition,
immunohistochemical studies have shown that estrogen treatment in ovariectomized rats
can induce a long-lasting increase of phospho-CREB; more importantly, this effect was
post-transcriptional and did not arise from de novo RNA protein synthesis [210].
Thus, the effects of estrogen can no longer be restricted to those related to reproductive function. Cross-coupling of estrogen and neutrophin signaling pathways may be required for estrogen and the neurotrophins to elicit their neuroprotective effects, especiallyduring development. Mediation of estrogen’s actions through interaction with locally synthesized growth factors, their receptors, and their signaling cascades in the brain may
represent the mechanism by which estrogen exerts its effects. Estrogen and neurotrophins,
acting in concert, may not only have important developmental roles but may also decrease
the vulnerability of target neurons to the consequences of neurodegenerative disease processes and enhance the compensatory response [211].
E.

Estrogen-Replacement Therapy

Although depression is classiﬁed as an affective disorder, modulation of mood and emotion is one of the higher functions that is affected during the course of the disease. Anothercommon alteration that can be observed in depressed patients is the impairment of cognitive functions, such as decreased concentration and memory loss. In addition, recent studies suggest that mild cognitive impairment might serve as an early marker of Alzheimer
disease. Thus, the abnormalities observed in depression may predict the subsequent development of other serious illnesses.
The central nervous system is an important target for the steroid hormones. During
the climacteric period the rapid decline of gonadal steroids causes neuroendocrine changes
in different areas of the brain. The failure of gonadal hormone production causes speciﬁc
symptoms due to the central nervous system derangement. Physical and psychologicalchanges occur, the latter of which include anxiety, irritability, and depression [212]. Regional cerebral blood ﬂow (rCBF) is diminished in hypoestrogen, with a pattern resembling that of depression and Alzheimer patients. Interestingly, menopausal women areoften subjected to progressive cognitive decline while depression has been described ashigh as 35% during perimenopause [213]. In addition, some investigators have postulated
that if decreasing estrogen levels have short-term effects on cognition during the perimenopausal period, then long-term estrogen deﬁciency may play a role in more signiﬁcantcognitive impairments such as the development of dementia in some women. Therefore,
it has been proposed that exogenous replacement of estrogen may prevent the cognitive
decline in postmenopausal women [214–216], as well as the development of postmenopausal depression, while the onset of Alzheimer’s disease may also be delayed [217,218].
Considerable evidence has been accumulated that suggests that estrogen modulates
CNS function. These include increases in dendritic spine density and synaptic excitability,
enhancement of cholinergic neurotransmission, and effects on other neurotransmitter systems including serotonin, norepinephrine, and dopamine [75,185–189]. In addition, estrogen also affects cerebrovasculature by increasing cardiac and cerebral blow ﬂow[214,219]. Importantly, a decreased cerebral blood ﬂow in speciﬁc limbic-cortical regions
has been reported in depression and its normalization after antidepressant therapy is con-

374

Trentani et al.

sidered an important predictor for clinical recovery. Interestingly, brain perfusion abnormalities might not be responsible only for the emotional dysfunctions associated withdepression but also for the cognitive impairment frequently observed to accompany depression. Estrogen-replacement therapy has been shown to reverse the detrimental blood
ﬂow changes following menopause and increase the relative rCBF in several limbic-cortical regions including hippocampus, parahippocampal gyrus, and middle temporal lobe
[220]. There are also several reports of improved attention, reaction time, enhanced memory, and overall cognitive abilities associated with ERT in postmenopausal women [214–216]. The neurobiological mechanism through which ERT improves cognitive abilities
is not completely understood. It may indirectly affect rCBF through its effects on the
cerebrovasculature enhancing the perfusion of selective regions involved in attention andmemory processes or directly by affecting intracellular pathways that modulate hippocampal function and in turn memory performance [220].
Although ERT alone cannot be considered as an antidepressant therapy, it might
represent a useful augmentation treatment in combination with traditional antidepressanttherapy. Estrogen is a potent trophic factor for the CNS and it may help the brain to oppose
age-related plasticity reduction. Furthermore, ERT may help to prevent postmenopausal
depression and age-related cognitive impairments, while also constituting an effective
measure in the prevention of Alzheimer’s disease in women.
VI. CONCLUSION
Depression appears to be a heterogeneous disorder in which several different etiologicalcauses interact leading to an abnormal modulation of the limbic-cortical activity. A breakthrough in the understanding of this disease and its treatment calls for clear comprehensionof the factors and mechanisms that could induce the functional dysregulation that characterizes it. Although the monoamine hypothesis of depression was introduced and accepted
for more than 30 years as a valid explanation for the etiology of depression, intensive
investigation has failed to ﬁnd conclusive afﬁrmation of a primary dysfunction of a speciﬁcmonoamine system in depressed patients. A crucial role in the development of depression
appears to be played by chronic stressful events. The brain responds to stress in a complex
but orchestrated manner and it is most likely the loss of this organized response that plays
a crucial role in the development of psychiatric disorders. Thus, the prevention of thedeleterious effects of stress might represent a valid instrument to avoid the onset of thedisease. Stress can promote long-term changes in the body and brain homeostasis thatmight constitute the major destabilizing factor that leads to an alteration of brain function
and subsequently creates the basis for limbic-cortical defects and development of depression. The treatment of depression is mainly based on the use of serotonin and/or noradrenaline reuptake inhibitors. However, they offer a limited efﬁcacy, delayed therapeutic action,and several side effects. New options in the treatment of depression are beginning to beavailable that may prove to be more successful in the long run, including BDNF replacement therapy to enhance brain plasticity and second-messenger controllers to prevent the
detrimental effects of stress. Intracellular signal transduction cascades appear to offer abroad variety of interesting targets for future antidepressant therapy. The only doubts
concern the selectivity of this intracellular approach. However, several clinical investigations have shown that intracellular alterations responsible for abnormal neural activity are
limited to speciﬁc regions and not to the total brain. Thus, even the systemic administrationof second-messenger controllers may modulate and target only the activity of those areas

Beyond the Serotonin Hypothesis

375

showing a speciﬁc defect, making intracellular targeting a very effective and selective
therapy. Another important advantage of intracellular targeting is the possibility of using
second-messenger controllers as a prophylactic measure, which would not only help treat
the disease but also prevent that sequence of intracellular events that leads to the development of depression. Finally, additional help for women comes from the neuroprotective
effects of estrogen replacement therapy that may enhance the therapeutic action of antidepressants.
REFERENCES
1. Bunney WE, Davis JM. Norepinephrine in depressive reactions. A review. Arch Gen Psychiatry 1965; 13(6):483–494.
2. Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting
evidence. Am J Psychiatry 1965; 122(5):509–522.
3. Hirschfeld RM. History and evolution of the monoamine hypothesis of depression. J Clin
Psychiatry 2000; 61(suppl 6):4–6.
4. Heninger GR, Delgado PL, Charney DS. The revised monoamine theory of depression: amodulatory role for monoamines, based on new ﬁndings from monoamine depletion experiments in humans. Pharmacopsychiatry 1996; 29(1):2–11.
5. Salomon RM, Miller HL, Krystal JH, Heninger GR, Charney DS. Lack of behavioral effects
of monoamine depletion in healthy subjects. Biol Psychiatry 1997; 41(1):58–64.
6. Delgado P, Moreno F. Antidepressants and the brain. Int Clin Psychopharmacol 1999; 14(suppl 1):S9–16.
7. Nelson JC. A review of the efﬁcacy of serotonergic and noradrenergic reuptake inhibitors
for treatment of major depression. Biol Psychiatry 1999; 46(9):1301–1308.
8. Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a metaanalysis of efﬁcacy and tolerability. J Affect Disord 2000; 58(1):19–36.
9. Geddes JR, Freemantle N, Mason J, Eccles MP, Boynton J. SSRIs versus other antidepressants for depressive disorder. Cochrane Database Syst Rev 2000;(2):CD001851.
10. Claghorn JL, Earl CQ, Walczak DD, Stoner KA, Wong LF, Kanter D et al. Fluvoxamine
maleate in the treatment of depression: a single-center, double-blind, placebo-controlled comparison with imipramine in outpatients. J Clin Psychopharmacol 1996; 16(2):113–120.
11. Berzewski H, Van Moffaert M, Gagiano CA. Efﬁcacy and tolerability of reboxetine compared with imipramine in a double-blind study in patients suffering from major depressive
offsodes. Eur Neuropsychopharmacol 1997; (Suppl 1):S37–S47.
12. Leinonen E, Lepola U, Koponen H, Mehtonen OP, Rimon R. Long-term efﬁcacy and safetyof milnacipran compared to clomipramine in patients with major depression. Acta Psychiatr
Scand 1997; 96(6):497–504.
13. Keller MB, Gelenberg AJ, Hirschfeld RM, Rush AJ, Thase ME, Kocsis JH et al. The treatment of chronic depression, part 2: a double-blind, randomized trial of sertraline and imipramine. J Clin Psychiatry 1998; 59(11):598–607.
14. Schweizer E, Rickels K, Hassman H, Garcia-Espana F. Buspirone and imipramine for thetreatment of major depression in the elderly. J Clin Psychiatry 1998; 59(4):175–183.
15. Tignol J, Pujol-Domenech J, Chartres JP, Leger JM, Pletan Y, Tonelli I et al. Double-blind
study of the efﬁcacy and safety of milnacipran and imipramine in elderly patients with major
depressive episode. Acta Psychiatr Scand 1998; 97(2):157–165.
16. Benedictis E. Double-blind comparison of venlafaxine and amitriptyline in outpatients withmajor depression with or without melancholia. J Psychopharmacol 2000; 14(1):61–66.
17. McGrath PJ, Stewart JW, Janal MN, Petkova E, Quitkin FM, Klein DF. A placebo-controlled
study of ﬂuoxetine versus imipramine in the acute treatment of atypical depression. Am J
Psychiatry 2000; 157(3):344–350.

376

Trentani et al.

18. Duman RS. Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry
1998; 44(5):324–335.
19. Duman RS, Vaidya VA. Molecular and cellular actions of chronic electroconvulsive seizures.
J ECT 1998; 14(3):181–193.
20. Shelton RC. Intracellular mechanisms of antidepressant drug action. Harv Rev Psychiatry
2000; 8(4):161–174.
21. Hebert C, Habimana A, Elie R, Reader TA. Effects of chronic antidepressant treatments on
5-HT and NA transporters in rat brain: an autoradiographic study. Neurochem Int 2001;
38(1):63–74.
22. Zanardi R, Artigas F, Moresco R, Colombo C, Messa C, Gobbo C et al. Increased 5-hydroxytryptamine-2 receptor binding in the frontal cortex of depressed patients responding toparoxetine treatment: a positron emission tomography scan study. J Clin Psychopharmacol
2001; 21(1):53–58.
23. Rogoz R, Dziedzicka-Wasylewska M. Effects of antidepressant drugs on the dopamine D2/
D3 receptors in the rat brain differentiated by agonist and antagonist binding—an autoradiographic analysis. Naunyn Schmiedebergs Arch Pharmacol 1999; 359(3):178–186.
24. Kameda K, Kusumi I, Suzuki K, Miura J, Sasaki Y, Koyama T. Effects of citalopram on
dopamine D2 receptor expression in the rat brain striatum. J Mol Neurosci 2000; 14(1-2):
77–86.
25. Hajos-Korcsok E, McTavish SF, Sharp T. Effect of a selective 5-hydroxytryptamine reuptake
inhibitor on brain extracellular noradrenaline: microdialysis studies using paroxetine. Eur J
Pharmacol 2000; 407(1-2):101–107.
26. Mateo Y, Ruiz-Ortega JA, Pineda J, Ugedo L, Meana JJ. Inhibition of 5-hydroxytryptamine
reuptake by the antidepressant citalopram in the locus coeruleus modulates the rat brain noradrenergic transmission in vivo. Neuropharmacology 2000; 39(11):2036–2043.
27. Lammers CH, Diaz J, Schwartz JC, Sokoloff P. Selective increase of dopamine D3 receptor
gene expression as a common effect of chronic antidepressant treatments. Mol Psychiatry
2000; 5(4):378–388.
28. Ginestet D. Efﬁcacy of tianeptine in major depressive disorders with or without melancholia.
Eur Neuropsychopharmacol 1997; 7(suppl 3):S341–S345.
29. McEwen BS, Conrad CD, Kuroda Y, Frankfurt M, Magarinos AM, McKittrick C. Preventionof stress-induced morphological and cognitive consequences. Eur Neuropsychopharmacol
1997; 7(suppl 3):S323–S328.
30. Johannessen CU. Mechanisms of action of valproate: a commentary. Neurochem Int 2003;
37(2-3):103–110.
31. Lenox RH, Hahn CG. Overview of the mechanism of action of lithium in the brain: ﬁftyyear update. J Clin Psychiatry 2000; 61(suppl 9):5–15.
32. Gelenberg AJ, Chesen CL. How fast are antidepressants? J Clin Psychiatry 2000; 61(10):712–721.
33. Gumnick JF, Nemeroff CB. Problems with currently available antidepressants. J Clin Psychiatry 2000; 61(suppl 10):5–15.
34. Culpepper L. Early onset of antidepressant action: impact on primary care. J Clin Psychiatry
2001; 62(suppl 4):4–6.
35. Moreno FA, Gelenberg AJ, Heninger GR, Potter RL, McKnight KM, Allen J et al. Tryptophan depletion and depressive vulnerability. Biol Psychiatry 1999; 46(4):498–505.
36. Delgado PL, Moreno FA. Role of norepinephrine in depression. J Clin Psychiatry 2000; 61(suppl 1):5–12.
37. Verberne AJ, Owens NC. Cortical modulation of the cardiovascular system. Prog Neurobiol
1998; 54(2):149–168.
38. Born J, Fehm HL. Hypothalamus-pituitary-adrenal activity during human sleep: a coordinating role for the limbic hippocampal system. Exp Clin Endocrinol Diabetes 1998; 106(3):153–163.

Beyond the Serotonin Hypothesis

377

39. Pfaus JG. Neurobiology of sexual behavior. Curr Opin Neurobiol 1999; 9(6):751–758.
40. Price JL. Prefrontal cortical networks related to visceral function and mood. Ann NY Acad
Sci 1999; 877:383–396.
41. Plotsky PM, Owens MJ, Nemeroff CB. Psychoneuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis. Psychiatr Clin North Am 1998; 21(2):293–307.
42. Staley JK, Malison RT, Innis RB. Imaging of the serotonergic system: interactions of neuroanatomical and functional abnormalities of depression. Biol Psychiatry 1998; 44(7):534–
549.
43. Mann JJ. Role of the serotonergic system in the pathogenesis of major depression and suicidal
behavior. Neuropsychopharmacology 1999; 21(2 suppl):99S–105S.
44. Steckler T, Holsboer F, Reul JM. Glucocorticoids and depression. Baillieres Best Pract Res
Clin Endocrinol Metab 1999; 13(4):597–614.
45. Anand A, Charney DS. Norepinephrine dysfunction in depression. J Clin Psychiatry 2000;
61(suppl 10):16–24.
46. Drevets WC. Functional anatomical abnormalities in limbic and prefrontal cortical structuresin major depression. Prog Brain Res 2000; 126:413–431.
47. Drevets WC. Neuroimaging and neuropathological studies of depression: implications forthe cognitive-emotional features of mood disorders. Curr Opin Neurobiol 2001; 11(2):240–
249.
48. Kendler KS, Eaves LJ. Models for the joint effect of genotype and environment on liability
to psychiatric illness. Am J Psychiatry 1986; 143(3):279–289.
49. Kendler KS, Kessler RC, Walters EE, MacLean C, Neale MC, Heath AC et al. Stressful life
events, genetic liability, and onset of an episode of major depression in women. Am J Psychiatry 1995; 152(6):833–842.
50. Kendler KS, Karkowski-Shuman L. Stressful life events and genetic liability to major depression: genetic control of exposure to the environment? Psychol Med 1997; 27(3):539–
547.
51. Kendler KS, Karkowski LM, Prescott CA. Causal relationship between stressful life eventsand the onset of major depression. Am J Psychiatry 1999; 156(6):837–841.
52. Bremner JD. Does stress damage the brain? Biol Psychiatry 1999; 45(7):797–805.
53. McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci 1999; 22:105–122.
54. Pani L, Porcella A, Gessa GL. The role of stress in the pathophysiology of the dopaminergic
system. Mol Psychiatry 2000; 5(1):14–21.
55. Post RM, Weiss SR. Sensitization and kindling phenomena in mood, anxiety, and obsessivecompulsive disorders: the role of serotonergic mechanisms in illness progression. Biol Psychiatry 1998; 44(3):193–206.
56. Ghaemi SN, Boiman EE, Goodwin FK. Kindling and second messengers: an approachto the neurobiology of recurrence in bipolar disorder. Biol Psychiatry 1999; 45(2):137–
144.
57. Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the
etiology of major depression in women: an evaluation of the “kindling” hypothesis. Am J
Psychiatry 2000; 157(8):1243–1251.
58. Kendler KS, Karkowski LM, Prescott CA. Stressful life events and major depression: risk
period, long-term contextual threat, and diagnostic speciﬁcity. J Nerv Ment Dis 1998;
186(11):661–669.
59. Harris TO, Brown GW. The LEDS ﬁndings in the context of other research: An overview.
In: Brown GW, Harris TO, eds. Life Events and Illness. New York: Guilford Press, 1989:
385–437.
60. Popoli M, Brunello N, Perez J, Racagni G. Second messenger-regulated protein kinases inthe brain: their functional role and the action of antidepressant drugs. J Neurochem 2000;
74(1):21–33.
61. Mori S, Garbini S, Caivano M, Perez J, Racagni G. Time-course changes in rat cerebral

378

62.

63.

64.

65.

66.
67.

68.

69.
70.

71.
72.
73.
74.
75.
76.

77.
78.
79.
80.
81.

Trentani et al.
cortex subcellular distribution of the cyclic-AMP binding after treatment with selective serotonin reuptake inhibitors. Int J Neuropsychopharmacol 1998; 1(1):3–10.
Popoli M, Mori S, Brunello N, Perez J, Gennarelli M, Racagni G. Serine/threonine kinases
as molecular targets of antidepressants: implications for pharmacological treatment andpathophysiology of affective disorders. Pharmacol Ther 2001; 89(2):149–170.
Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci
1996; 16(7):2365–2372.
Thome J, Sakai N, Shin K, Steffen C, Zhang YJ, Impey S et al. cAMP response elementmediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci
2000; 20(11):4030–4036.
Frechilla D, Otano A, Del Rio J. Effect of chronic antidepressant treatment on transcription
factor binding activity in rat hippocampus and frontal cortex. Prog Neuropsychopharmacol
Biol Psychiatry 1998; 22(5):787–802.
Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. ArchGen Psychiatry 1997; 54(7):597–606.
Nagamoto-Combs K, Piech KM, Best JA, Sun B, Tank AW. Tyrosine hydroxylase genepromoter activity is regulated by both cyclic AMP-responsive element and AP1 sites following calcium inﬂux. Evidence for cyclic amp-responsive element binding protein-independent
regulation. J Biol Chem 1997; 272(9):6051–6058.
Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME. Ca2⫹ inﬂux regulates BDNF
transcription by a CREB family transcription factor-dependent mechanism. Neuron 1998;
20(4):709–726.
Smith MA, Makino S, Kvetnansky R, Post RM. Effects of stress on neurotrophic factor
expression in the rat brain. Ann NY Acad Sci 1995; 771:234–239.
Ueyama T, Kawai Y, Nemoto K, Sekimoto M, Tone S, Senba E. Immobilization stress reduced the expression of neurotrophins and their receptors in the rat brain. Neurosci Res 1997;
28(2):103–110.
Smith MA. Hippocampal vulnerability to stress and aging: possible role of neurotrophic
factors. Behav Brain Res 1996; 78(1):25–36.
Zilles K. Neuronal plasticity as an adaptive property of the central nervous system. Anat
Anz 1992; 174(5):383–391.
Gould E, Tanapat P. Stress and hippocampal neurogenesis. Biol Psychiatry 1999; 46(11):1472–1479.
Jacobs BL, Praag H, Gage FH. Adult brain neurogenesis and psychiatry: a novel theory ofdepression. Mol Psychiatry 2000; 5(3):262–269.
McEwen BS. Multiple ovarian hormone effects on brain structure and function. J Gend Specif
Med 1998; 1(1):33–41.
Shughrue PJ, Merchenthaler I. Estrogen is more than just a “sex hormone”: novel sites for
estrogen action in the hippocampus and cerebral cortex. Front Neuroendocrinol 2000; 21(1):95–101.
Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment.
Biol Psychiatry 1999; 46(9):1181–1191.
McEwen BS. The neurobiology of stress: from serendipity to clinical relevance. Brain Res
2000; 886(1-2):172–189.
Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy inrecurrent major depression. Proc Natl Acad Sci USA 1996; 93(9):3908–3913.
Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal
volume reduction in major depression. Am J Psychiatry 2000; 157(1):115–118.
Mervaala E, Fohr J, Kononen M, Valkonen-Korhonen M, Vainio P, Partanen K et al. Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med 2000; 30(1):117–125.

Beyond the Serotonin Hypothesis

379

82. Drevets WC, Price JL, Simpson JR, Todd RD, Reich T, Vannier M et al. Subgenual prefrontal
cortex abnormalities in mood disorders. Nature 1997; 386(6627):824–827.
83. Lai T, Payne ME, Byrum CE, Steffens DC, Krishnan KR. Reduction of orbital frontal cortex
volume in geriatric depression. Biol Psychiatry 2000; 48(10):971–975.
84. Rajkowska G. Postmortem studies in mood disorders indicate altered numbers of neurons
and glial cells. Biol Psychiatry 2000; 48(8):766–777.
85. Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY et al. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol
Psychiatry 1999; 45(9):1085–1098.
86. Rajkowska G, Halaris A, Selemon LD. Reductions in neuronal and glial density characterize
the dorsolateral prefrontal cortex in bipolar disorder. Biol Psychiatry 2001; 49(9):741–752.
87. Curtis J, Finkbeiner S. Sending signals from the synapse to the nucleus: possible roles for
CaMK, Ras/ERK, and SAPK pathways in the regulation of synaptic plasticity and neuronal
growth. J Neurosci Res 1999; 58(1):88–95.
88. Whitmarsh AJ, Davis RJ. Regulation of transcription factor function by phosphorylation.
Cell Mol Life Sci 2000; 57(8-9):1172–1183.
89. Curran T, Morgan JI. Fos: an immediate-early transcription factor in neurons. J Neurobiol
1995; 26(3):403–412.
90. Chaudhuri A. Neural activity mapping with inducible transcription factors. Neuroreport 1997;
8(13):iii–vii.
91. Kovacs KJ. c-Fos as a transcription factor: a stressful (re)view from a functional map. Neurochem Int 1998; 33(4):287–297.
92. Kaminska B, Pyrzynska B, Ciechomska I, Wisniewska M. Modulation of the compositionof AP-1 complex and its impact on transcriptional activity. Acta Neurobiol Exp (Warsz)
2000; 60(3):395–402.
93. Shaywitz AJ, Greenberg ME. CREB: a stimulus-induced transcription factor activated by adiverse array of extracellular signals. Annu Rev Biochem 1999; 68:821–861.
94. Liu FC, Graybiel AM. Spatiotemporal dynamics of CREB phosphorylation: transient versus
sustained phosphorylation in the developing striatum. Neuron 1996; 17(6):1133–1144.
95. Rafﬁoni S, Bradshaw RA, Buxser SE. The receptors for nerve growth factor and other neurotrophins. Annu Rev Biochem 1993; 62:823–850.
96. Chao MV, Hempstead BL. p75 and Trk: a two-receptor system. Trends Neurosci 1995; 18(7):321–326.
97. Kaplan DR, Miller FD. Neurotrophin signal transduction in the nervous system. Curr Opin
Neurobiol 2000; 10(3):381–391.
98. Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM et al. Regulation ofneuronal survival by the serine-threonine protein kinase Akt. Science 1997; 275(5300):661–
665.
99. Yamaguchi A, Tamatani M, Matsuzaki H, Namikawa K, Kiyama H, Vitek MP et al. Akt
activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activityof p53. J Biol Chem 2001; 267(7):5256–5264.
100. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y et al. Akt phosphorylation of BAD
couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91(2):231–241.
101. Pap M, Cooper GM. Role of glycogen synthase kinase-3 in the phosphatidylinositol 3Kinase/Akt cell survival pathway. J Biol Chem 1998; 273(32):19929–19932.
102. Grewal SS, York RD, Stork PJ. Extracellular-signal-regulated kinase signalling in neurons.
Curr Opin Neurobiol 1999; 9(5):544–553.
103. Gottschalk WA, Jiang H, Tartaglia N, Feng L, Figurov A, Lu B. Signaling mechanisms
mediating BDNF modulation of synaptic plasticity in the hippocampus. Learn Mem 1999;
6(3):243–256.
104. Hetman M, Xia Z. Signaling pathways mediating anti-apoptotic action of neurotrophins. Acta
Neurobiol Exp (Warsz) 2000; 60(4):531–545.

380

Trentani et al.

105. Roberts ML, Virdee K, Sampson CP, Gordon I, Tolkovsky AM. The combination of bcl-2
expression and NGF-deprivation facilitates the selective destruction of BAD protein in living
sympathetic neurons. Mol Cell Neurosci 2000; 16(2):97–110.
106. Riccio A, Ahn S, Davenport CM, Blendy JA, Ginty DD. Mediation by a CREB familytranscription factor of NGF-dependent survival of sympathetic neurons. Science 1999;
286(5448):2358–2361.
107. Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 2000; 275(15):10761–10766.
108. Thoenen H. Neurotrophins and neuronal plasticity. Science 1995; 270(5236):593–598.
109. Song HJ, Poo MM. Signal transduction underlying growth cone guidance by diffusible factors. Curr Opin Neurobiol 1999; 9(3):355–363.
110. Mowla SJ, Pareek S, Farhadi HF, Petrecca K, Fawcett JP, Seidah NG et al. Differential
sorting of nerve growth factor and brain-derived neurotrophic factor in hippocampal neurons.
J Neurosci 1999; 19(6):2069–2080.
111. Schinder AF, Poo M. The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci
2000; 23(12):639–645.
112. Manji HK, Moore GJ, Chen G. Lithium up-regulates the cytoprotective protein Bcl-2 in the
CNS in vivo: a role for neurotrophic and neuroprotective effects in manic depressive illness.
J Clin Psychiatry 2000; 61 (Suppl 9):82–96.
113. Merry DE, Korsmeyer SJ. Bcl-2 gene family in the nervous system. Annu Rev Neurosci
1997; 20:245–267.
114. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998;
281(5381):1322–1326.
115. Bruckheimer EM, Cho SH, Sarkiss M, Herrmann J, McDonnell TJ. The Bcl-2 gene family
and apoptosis. Adv Biochem Eng Biotechnol 1998; 62:75–105.
116. Li H, Yuan J. Deciphering the pathways of life and death. Curr Opin Cell Biol 1999; 11(2):261–266.
117. Chen G, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK. Enhancement of hippocampal
neurogenesis by lithium. J Neurochem 2000; 75(4):1729–1734.
118. Klein PS, Melton DA. A molecular mechanism for the effect of lithium on development.
Proc Natl Acad Sci USA 1996; 93(16):8455–8459.
119. Willert K, Nusse R. Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev
1998; 8(1):95–102.
120. Salinas PC, Hall AC. Lithium and synaptic plasticity. Bipolar Disord 1999; 1(2):87–90.
121. Chen G, Yuan PX, Jiang YM, Huang LD, Manji HK. Lithium increases tyrosine hydroxylase
levels both in vivo and in vitro. J Neurochem 1998; 70(4):1768–1771.
122. Manji HK, McNamara R, Chen G, Lenox RH. Signalling pathways in the brain: cellulartransduction of mood stabilisation in the treatment of manic-depressive illness. Aust NZ J
Psychiatry 1999; 33(suppl):S65–S83.
123. Chen RW, Chuang DM. Long term lithium treatment suppresses p53 and Bax expression
but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity.
J Biol Chem 1999; 274(10):6039–6042.
124. Xiang H, Kinoshita Y, Knudson CM, Korsmeyer SJ, Schwartzkroin PA, Morrison RS. Bax
involvement in p53-mediated neuronal cell death. J Neurosci 1998; 18(4):1363–1373.
125. Budhram-Mahadeo V, Morris PJ, Smith MD, Midgley CA, Boxer LM, Latchman DS. p53
suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor. J Biol Chem 1999; 274(21):15237–15244.
126. Manji HK, Moore GJ, Rajkowska G, Chen G. Neuroplasticity and cellular resilience in mooddisorders. Mol Psychiatry 2000; 5(6):578–593.
127. Maren S. Long-term potentiation in the amygdala: a mechanism for emotional learning andmemory. Trends Neurosci 1999; 22(12):561–567.

Beyond the Serotonin Hypothesis

381

128. Buchel C, Dolan RJ. Classical fear conditioning in functional neuroimaging. Curr Opin Neurobiol 2000; 10(2):219–223.
129. Hall J, Thomas KL, Everitt BJ. Fear memory retrieval induces CREB phosphorylation and
Fos expression within the amygdala. Eur J Neurosci 2001; 13(7):1453–1458.
130. Josselyn SA, Shi C, Carlezon WA, Neve RL, Nestler EJ, Davis M. Long-term memory isfacilitated by cAMP response element-binding protein overexpression in the amygdala. J
Neurosci 2001; 21(7):2404–2412.
131. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain bychronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995;
15(11):7539–7547.
132. Wilde MI, Benﬁeld P. Tianeptine. A review of its pharmacodynamic and pharmacokinetic
properties, and therapeutic efﬁcacy in depression and coexisting anxiety and depression.
Drugs 1995; 49(3):411–439.
133. Loo H, Saiz-Ruiz J, Silva JACE, Ansseau M, Herrington R, Vaz-Serra A et al. Efﬁcacy andsafety of tianeptine in the treatment of depressive disorders in comparison with ﬂuoxetine.
J Affect Disord 1999; 56(2-3):109–118.
134. Starkman MN, Gebarski SS, Berent S, Schteingart DE. Hippocampal formation volume,
memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry 1992; 32(9):756–765.
135. Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM et al. MRI-based
measurement of hippocampal volume in patients with combat-related posttraumatic stressdisorder. Am J Psychiatry 1995; 152(7):973–981.
136. Gurvits TV, Shenton ME, Hokama H, Ohta H, Lasko NB, Gilbertson MW et al. Magnetic
resonance imaging study of hippocampal volume in chronic, combat-related posttraumaticstress disorder. Biol Psychiatry 1996; 40(11):1091–1099.
137. Uno H, Tarara R, Else JG, Suleman MA, Sapolsky RM. Hippocampal damage associatedwith prolonged and fatal stress in primates. J Neurosci 1989; 9(5):1705–1711.
138. Magarinos AM, Verdugo JM, McEwen BS. Chronic stress alters synaptic terminal structure
in hippocampus. Proc Natl Acad Sci USA 1997; 94(25):14002–14008.
139. McKittrick CR, Magarinos AM, Blanchard DC, Blanchard RJ, McEwen BS, Sakai RR.
Chronic social stress reduces dendritic arbors in CA3 of hippocampus and decreases binding
to serotonin transporter sites. Synapse 2000; 36(2):85–94.
140. Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 1992; 588(2):341–345.
141. Magarinos AM, McEwen BS. Stress-induced atrophy of apical dendrites of hippocampal
CA3c neurons: comparison of stressors. Neuroscience 1995; 69(1):83–88.
142. Watanabe Y, Gould E, Daniels DC, Cameron H, McEwen BS. Tianeptine attenuates stressinduced morphological changes in the hippocampus. Eur J Pharmacol 1992; 222(1):157–
162.
143. Lindefors N, Brodin E, Metsis M. Spatiotemporal selective effects on brain-derived neurotrophic factor and trkB messenger RNA in rat hippocampus by electroconvulsive shock.
Neuroscience 1995; 65(3):661–670.
144. Devous MD, Stokely EM, Chehabi HH, Bonte FJ. Normal distribution of regional cerebral
blood ﬂow measured by dynamic single-photon emission tomography. J Cereb Blood Flow
Metab 1986; 6(1):95–104.
145. Baxter LR, Mazziotta JC, Phelps ME, Selin CE, Guze BH, Fairbanks L. Cerebral glucose
metabolic rates in normal human females versus normal males. Psychiatry Res 1987; 21(3):237–245.
146. George MS, Ketter TA, Parekh PI, Herscovitch P, Post RM. Gender differences in regional
cerebral blood ﬂow during transient self-induced sadness or happiness. Biol Psychiatry 1996;
40(9):859–871.
147. Andreason PJ, Zametkin AJ, Guo AC, Baldwin P, Cohen RM. Gender-related differences

382

148.
149.

150.

151.
152.

153.

154.

155.

156.

157.
158.
159.

160.
161.

162.
163.
164.
165.
166.
167.

Trentani et al.
in regional cerebral glucose metabolism in normal volunteers. Psychiatry Res 1994; 51(2):175–183.
Esposito G, Van Horn JD, Weinberger DR, Berman KF. Gender differences in cerebral blood
ﬂow as a function of cognitive state with PET. J Nucl Med 1996; 37(4):559–564.
Steenbergen HL, Heinsbroek RP, Van Hest A, Van de Poll NE. Sex-dependent effects ofinescapable shock administration on shuttlebox-escape performance and elevated plus-mazebehavior. Physiol Behav 1990; 48(4):571–576.
Steenbergen HL, Heinsbroek RP, Van Haaren F, Van de Poll NE. Sex-dependent effects ofinescapable shock administration on behavior and subsequent escape performance in rats.
Physiol Behav 1989; 45(4):781–787.
Kimura D. Sex, sexual orientation and sex hormones inﬂuence human cognitive function.
Curr Opin Neurobiol 1996; 6(2):259–263.
Wood GE, Shors TJ. Stress facilitates classical conditioning in males, but impairs classicalconditioning in females through activational effects of ovarian hormones. Proc Natl Acad
Sci USA 1998; 95(7):4066–4071.
Stanciu M, Wang Y, Kentor R, Burke N, Watkins S, Kress G et al. Persistent activation of
ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primarycortical neuron cultures. J Biol Chem 2000; 275:12200–12206.
Baum L, Seger R, Woodgett JR, Kawabata S, Maruyama K, Koyama M et al. Overexpressed
tau protein in cultured cells is phosphorylated without formation of PHF: implication ofphosphoprotein phosphatase involvement. Brain Res Mol Brain Res 1995; 34(1):1–17.
Veeranna GJ, Shetty KT, Takahashi M, Grant P, Pant HC. Cdk5 and MAPK are associatedwith complexes of cytoskeletal proteins in rat brain. Brain Res Mol Brain Res 2000; 76:
229–236.
Reynolds C, Betts JC, Blackstock WP, Nebreda AR, Anderton BH. Phosphorylation sites
on tau identiﬁed by nanoelectrospray mass spectrometry: differences in vitro between the
mitogen-activated protein kinases ERK2, c-Jun N-terminal kinase and P38, and glycogensynthase kinase-3beta. J Neurochem 2000; 74:1557–1595.
Shors TJ. Acute stress rapidly and persistently enhances memory formation in the male rat.
Neurobiol Learn Mem 2001; 75(1):10–29.
Nishimura J, Endo Y, Kimura F. A long-term stress exposure impairs maze learning performance in rats. Neurosci Lett 1999; 273(2):125–128.
Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Chui DH, Tabira T. Chronic stress induces
impairment of spatial working memory because of prefrontal dopaminergic dysfunction. J
Neurosci 2000; 20(4):1568–1574.
Nibuya M, Takahashi M, Russell DS, Duman RS. Repeated stress increases catalytic TrkB
mRNA in rat hippocampus. Neurosci Lett 1999; 267(2):81–84.
Runden E, Seglen PO, Haug FM, Ottersen OP, Wieloch T, Shamloo M et al. Regional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures:
evidence for a MAP kinase-dependent mechanism. J Neurosci 1998; 18(18):7296–7305.
Jovanovic JN, Czernik AJ, Fienberg AA, Greengard P, Sihra TS. Synapsins as mediators of
BDNF-enhanced neurotransmitter release. Nat Neurosci 2000; 3(4):323–329.
Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesisof cardiovascular disease and implications for therapy. Circulation 1999; 99(16):2192–2217.
Kirkegaard C, Faber J. The role of thyroid hormones in depression. Eur J Endocrinol 1998;
138(1):1–9.
Haggerty JJ, Prange AJ. Borderline hypothyroidism and depression. Annu Rev Med 1995;
46:37–46.
Henley WN, Koehnle TJ. Thyroid hormones and the treatment of depression: an examinationof basic hormonal actions in the mature mammalian brain. Synapse 1997; 27(1):36–44.
Halbreich U, Asnis GM, Shindledecker R, Zumoff B, Nathan RS. Cortisol secretion in endogenous depression. I. Basal plasma levels. Arch Gen Psychiatry 1985; 42(9):904–908.

Beyond the Serotonin Hypothesis

383

168. Halbreich U, Asnis GM, Shindledecker R, Zumoff B, Nathan RS. Cortisol secretion in
endogenous depression. II. Time-related functions. Arch Gen Psychiatry 1985; 42(9):909–
914.
169. Rubin RT, Poland RE, Lesser IM, Winston RA, Blodgett AL. Neuroendocrine aspects ofprimary endogenous depression. I. Cortisol secretory dynamics in patients and matched controls. Arch Gen Psychiatry 1987; 44(4):328–336.
170. Sheline YI. 3D MRI studies of neuroanatomic changes in unipolar major depression: therole of stress and medical comorbidity. Biol Psychiatry 2000; 48(8):791–800.
171. Schaaf MJ, De Kloet ER, Vreugdenhil E. Corticosterone effects on BDNF expression in the
hippocampus. Implications for memory formation. Stress 2000; 3(3):201–208.
172. Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A, Ising M et al. Effects of the highafﬁnity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression:
the ﬁrst 20 patients treated. J Psychiatr Res 2000; 34(3):171–181.
173. Thakore JH, Dinan TG. Cortisol synthesis inhibition: a new treatment strategy for the clinicaland endocrine manifestations of depression. Biol Psychiatry 1995; 37(6):364–368.
174. Wolkowitz OM, Reus VI, Chan T, Manfredi F, Raum W, Johnson R et al. Antiglucocorticoid
treatment of depression: double-blind ketoconazole. Biol Psychiatry 1999; 45(8):1070–1074.
175. Young EA, Lopez JF, Murphy-Weinberg V, Watson SJ, Akil H. The role of mineralocorticoid receptors in hypothalamic-pituitary-adrenal axis regulation in humans. J Clin Endocrinol
Metab 1998; 83(9):3339–3345.
176. Heuser I, Deuschle M, Weber B, Stalla GK, Holsboer F. Increased activity of the hypothalamus-pituitary-adrenal system after treatment with the mineralocorticoid receptor antagonist
spironolactone. Psychoneuroendocrinology 2000; 25(5):513–518.
177. Kiprianova I, Freiman TM, Desiderato S, Schwab S, Galmbacher R, Gillardon F et al. Brainderived neurotrophic factor prevents neuronal death and glial activation after global ischemia
in the rat. J Neurosci Res 1999; 56(1):21–27.
178. Isenmann S, Klocker N, Gravel C, Bahr M. Short communication: protection of axotomized
retinal ganglion cells by adenovirally delivered BDNF in vivo. Eur J Neurosci 1998; 10(8):2751–2756.
179. Rubio F, Kokaia Z, Arco A, Garcia-Simon M, Snyder E, Lindvall O et al. BDNF gene transfer
to the mammalian brain using CNS-derived neural precursors. Gene Ther 1999; 6(11):1851–1866.
180. Wu D, Pardridge WM. Neuroprotection with noninvasive neurotrophin delivery to the brain.
Proc Natl Acad Sci USA 1999; 96(1):254–259.
181. Guise S, Braguer D, Carles G, Delacourte A, Briand C. Hyperphosphorylation of tau is mediated by ERK activation during anticancer drug-induced apoptosis in neuroblastoma cells. J
Neurosci Res 2001; 63(3):257–267.
182. Chalecka-Franaszek E, Chuang DM. Lithium activates the serine/threonine kinase Akt-1 andsuppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci
USA 1999; 96(15):8745–8750.
183. Williams RS, Harwood AJ. Lithium therapy and signal transduction. Trends Pharmacol Sci
2000; 21(2):61–64.
184. Franke TF, Kaplan DR, Cantley LC, Toker A. Direct regulation of the Akt proto-oncogene
product by phosphatidylinositol-3,4-bisphosphate. Science 1997; 275(5300):665–668.
185. Kendall DA, Stancel GM, Enna SJ. Imipramine: effect of ovarian steroids on modiﬁcations
in serotonin receptor binding. Science 1981; 211(4487):1183–1185.
186. Gould E, Woolley CS, Frankfurt M, McEwen BS. Gonadal steroids regulate dendritic spine
density in hippocampal pyramidal cells in adulthood. J Neurosci 1990; 10(4):1286–1291.
187. Honjo H, Tamura T, Matsumoto Y, Kawata M, Ogino Y, Tanaka K et al. Estrogen asa growth factor to central nervous cells. Estrogen treatment promotes development ofacetylcholinesterase-positive basal forebrain neurons transplanted in the anterior eye chamber. J Steroid Biochem Mol Biol 1992; 41(3-8):633–635.

384

Trentani et al.

188. Woolley CS. Estrogen-mediated structural and functional synaptic plasticity in the female
rat hippocampus. Horm Behav 1998; 34(2):140–148.
189. Gibbs RB. Effects of gonadal hormone replacement on measures of basal forebrain cholinergic function. Neuroscience 2000; 101(4):931–938.
190. Inestrosa NC, Marzolo MP, Bonnefont AB. Cellular and molecular basis of estrogen’s neuroprotection. Potential relevance for Alzheimer’s disease. Mol Neurobiol 1998; 17(1-3):73–86.
191. Wise PM. Estradiol: a protective factor in the adult brain. J Pediatr Endocrinol Metab 2000;
13(suppl 6):1425–1429.
192. Garcia-Segura LM, Azcoitia I, DonCarlos LL. Neuroprotection by estradiol. Prog Neurobiol
2001; 63(1):29–60.
193. Landers JP, Spelsberg TC. New concepts in steroid hormone action: transcription factors,
proto-oncogenes, and the cascade model for steroid regulation of gene expression. Crit Rev
Eukaryot Gene Expr 1992; 2:19–63.
194. Mosselman S, Polman J, Dijkema R. ER beta: identiﬁcation and characterization of a novel
human estrogen receptor. FEBS Lett 1996; 392(1):49–53.
195. Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, Hosoi T et al. The complete primarystructure of human estrogen receptor beta (hER beta) and its heterodimerization with ER
alpha in vivo and in vitro. Biochem Biophys Res Commun 1998; 243(1):122–126.
196. Pappas TC, Gametchu B, Watson CS. Membrane estrogen receptors identiﬁed by multiple
antibody labeling and impeded-ligand binding. FASEB J 1995; 9(5):404–410.
197. Watson CS, Pappas TC, Gametchu B. The other estrogen receptor in the plasma membrane:
implications for the actions of environmental estrogens. Environ Health Perspect 1995; 103(suppl 7):41–50.
198. O’Malley C, Hautamaki RD, Kelley M, Meyer EM. An alternative ligand-independent pathway for activation of steroid receptors. Recent Prog Horm Res 1995; 50:333–347.
199. Toran-Allerand CD, Miranda RC, Bentham WD, Sohrabji F, Brown TJ, Hochberg RB et al.
Estrogen receptors colocalize with low-afﬁnity nerve growth factor receptors in cholinergic
neurons of the basal forebrain. Proc Natl Acad Sci USA 1992; 89(10):4668–4672.
200. Miranda RC, Sohrabji F, Toran-Allerand CD. Neuronal colocalization of mRNAs for neurotrophins and their receptors in the developing central nervous system suggests a potential
for autocrine interactions. Proc Natl Acad Sci USA 1993; 90(14):6439–6443.
201. Schule R, Evans RM. Cross-coupling of signal transduction pathways: zinc ﬁnger meetsleucine zipper. Trends Genet 1991; 7(11-12):377–381.
202. Guo JZ, Gorski J. Estrogen effects on histone messenger ribonucleic acid levels in the rat
uterus. Mol Endocrinol 1988; 2(8):693–700.
203. Ferreira A, Caceres A. Estrogen-enhanced neurite growth: evidence for a selective inductionof Tau and stable microtubules. J Neurosci 1991; 11(2):392–400.
204. Lustig RH, Sudol M, Pfaff DW, Federoff HJ. Estrogenic regulation and sex dimorphism ofgrowth-associated protein 43 kDa (GAP-43) messenger RNA in the rat. Brain Res Mol Brain
Res 1991; 11(2):125–132.
205. Lorenzo A, Diaz H, Carrer H, Caceres A. Amygdala neurons in vitro: neurite growth andeffects of estradiol. J Neurosci Res 1992; 33(3):418–435.
206. Singh M, Setalo G, Guan X, Warren M, Toran-Allerand CD. Estrogen-induced activationof mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogenand neurotrophin signaling pathways. J Neurosci 1999; 19(4):1179–1188.
207. Zhou Y, Watters JJ, Dorsa DM. Estrogen rapidly induces the phosphorylation of the cAMP
response element binding protein in rat brain. Endocrinology 1996; 137(5):2163–2166.
208. Murphy DD, Segal M. Morphological plasticity of dendritic spines in central neurons ismediated by activation of cAMP response element binding protein. Proc Natl Acad Sci USA
1997; 94(4):1482–1487.

Beyond the Serotonin Hypothesis

385

209. Ansonoff MA, Etgen AM. Estradiol elevates protein kinase C catalytic activity in the preoptic
area of female rats. Endocrinology 1998; 139(7):3050–3056.
210. Panickar KS, Guan G, King MA, Rajakumar G, Simpkins JW. 17beta-estradiol attenuates
CREB decline in the rat hippocampus following seizure. J Neurobiol 1997; 33(7):961–967.
211. Toran-Allerand CD, Singh M, Setalo G. Novel mechanisms of estrogen action in the brain:
new players in an old story. Front Neuroendocrinol 1999; 20(2):97–121.
212. Carranza-Lira S, Valentino-Figueroa ML. Estrogen therapy for depression in postmenopausal
women. Int J Gynaecol Obstet 1999; 65(1):35–38.
213. Hay AG, Bancroft J, Johnstone EC. Affective symptoms in women attending a menopause
clinic. Br J Psychiatry 1994; 164(4):513–516.
214. Ohkura T, Isse K, Akazawa K, Hamamoto M, Yaoi Y, Hagino N. Evaluation of estrogen
treatment in female patients with dementia of the Alzheimer type. Endocr J 1994; 41(4):361–371.
215. Schmidt R, Fazekas F, Reinhart B, Kapeller P, Fazekas G, Offenbacher H et al. Estrogen
replacement therapy in older women: a neuropsychological and brain MRI study. J Am Geriatr Soc 1996; 44(11):1307–1313.
216. Resnick SM, Maki PM, Golski S, Kraut MA, Zonderman AB. Effects of estrogen replacement therapy on PET cerebral blood ﬂow and neuropsychological performance. Horm Behav
1998; 34(2):171–182.
217. Tang MX, Jacobs D, Stern Y, Marder K, Schoﬁeld P, Gurland B et al. Effect of oestrogen
during menopause on risk and age at onset of Alzheimer’s disease. Lancet 1996; 348(9025):
429–432.
218. Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer’s disease:
the Baltimore Longitudinal Study of Aging. Neurology 1997; 48(6):1517–1521.
219. Prelevic GM, Beljic T. The effect of oestrogen and progestogen replacement therapy on
systolic ﬂow velocity in healthy postmenopausal women. Maturitas 1994; 20(1):37–44.
220. Maki PM, Resnick SM. Longitudinal effects of estrogen replacement therapy on PET cerebral
blood ﬂow and cognition. Neurobiol Aging 2000; 21(2):373–383.
221. Garrington TP, Johnson GL. Organization and regulation of mitogen-activated protein kinasesignaling pathways. Curr Opin Cell Biol 1999; 11(2):211–218.
222. Yao R, Cooper GM. Requirement for phosphatidylinositol-3 kinase in the prevention of
apoptosis by nerve growth factor. Science 1995; 267(5206):2003–2006.
223. Sheikh MS, Fornace AJ. Role of p53 family members in apoptosis. J Cell Physiol 2000;
182(2):171–181.
224. Li M, Wang X, Meintzer MK, Laessig T, Birnbaum MJ, Heidenreich KA. Cyclic AMP
promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta. Mol Cell
Biol 2000; 20(24):9356–9363.
225. Cross DA, Culbert AA, Chalmers KA, Facci L, Skaper SD, Reith AD. Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurons from death.
J Neurochem 2001; 77(1):94–102.

16
Norepinephrine in Depression
and Anxiety
PEDRO L. DELGADO
University Hospitals of Cleveland
Case Western Reserve University School of Medicine
Cleveland, Ohio, U.S.A.

I.

INTRODUCTION

Interest in the role of noradrenaline (NA) function in affective and anxiety disorders begana short time after it was discovered that antidepressant drugs potently interacted withNA neurons and receptors. In the shadow of the momentous discovery that basal ganglia
dopamine (DA) dysfunction was associated with Parkinson’s disease [1,2], early theorists
hypothesized that similar relationships would be found for NA in depression and/or anxiety states [3,4]. It was proposed that diminished NA content [3,4] or function [5,6] caused
depression and that increased NA content or function caused either mania [3] or severe
anxiety or panic attacks [7].
In the 30 years that followed the development of these early hypotheses, researchers
enthusiastically and systematically searched for the hypothesized deﬁciency or excess of
NA or NA function in a variety of psychiatric patients. Initial studies of NA and its metabolites in blood, cerebrospinal ﬂuid (CSF), and urine were followed by neuroendocrine challenge studies, autopsy studies, and studies of NA receptors on platelets and leukocytes[8]. However, in spite of the accumulation of a massive database on NA measures inhumans, evidence of global NA dysfunction in patients with major depression, anxiety
disorders, or mania has not been consistently identiﬁed.
The work of the past 30 years was not without beneﬁt. Much has been learned about
the NA system. Our understanding of the neuroanatomy, neurophysiology, neuropharmacology, and molecular biology of the NA system has grown tremendously. This knowledge
387

388

Delgadosuggests a complex role for NA in a variety of cognitive and behavioral functions involved
in mood and anxiety disorders, as well as several other major mental disorders, degenerative disorders, and normal states.
Much of the confusion about the role of NA function in mental disorders arises
because of our relatively limited understanding of brain function and the relative easewith which large modulatory neurotransmitter systems like NA could be altered with relatively safe drugs. This led investigators to focus on these systems rather than attempting
to understand the regulation and function of NA’s target brain structures. For example,
we have numerous drugs capable of increasing or decreasing brain NA, but few, if any,
capable of selectively activating or deactivating speciﬁc target brain areas such as theprefrontal cortex, amygdala, or hippocampus. This has sometimes led to the erroneous
conclusion that behaviors mediated by these terminal brain structures and nuclei are “NAbehaviors.”
This chapter will review the current state of knowledge about the function of theNA system and its possible role in mood and anxiety disorders and the therapeutic effectsof certain medications.

II. THE NA SYSTEM
A.

AnatomyNA neurons are deﬁned by the intracellular presence of NA and NA synthetic enzymes.
They are localized in both the peripheral nervous system (PNS) as well as the central
nervous system (CNS). In the PNS, NA is the major neurotransmitter in postganglionic
neurons. Peripheral sympathetic neurons innervate the adrenal medulla, regulating therelease of NA and epinephrine directly into the bloodstream as part of the “ﬁght-or-ﬂight”
response to severe stress. NA neurons in the CNS form several distinct nuclei locatedprimarily in the brainstem that project rostrally to almost all areas of the mid and forebrain,
dorsoventrally to the cerebellum, and caudally to the lumbar segments of the spinal cordin a monosynaptic fashion (9). About half of all CNS NA cell bodies originate from thelocus coeruleus (LC) in the dorsal pons [10,11]. It was ﬁrst thought that LC axons branched
to innervate all areas of cortex. Recent data suggest that LC neurons are not uniform anddemonstrate a laminar distribution and at least four distinct cell types [12]. Additionally,
there is evidence suggesting topographic innervation of target brain areas. The signiﬁcanceof this is not fully understood. The vast majority of rostrally projecting NA ﬁbers do not
cross over to the other hemisphere.
The axons of the LC form ﬁve major bundles. The dorsal bundle contains the majority of ﬁbers projecting to the cortex [13]. Within the cortex, NA neurons primarily innervate layers I, IV, and V. While there is considerable heterogeneity, layer I tends to containa dense plexus of ﬁbers while layers IV and V have moderately dense, short oblique ﬁbers,
and layer VI tends to exhibit long ﬁbers that are oriented anterior to posterior. Few NA
ﬁbers are found in white matter.
Not all NA-containing nerve terminals in the cortex make synaptic contact with thelocal cortical neurons; rather some of these neurons release NA in a manner similar tothat through which hormones are secreted and thus have generalized effects on other CNS
regions [14]. There is a natural loss of LC neurons with aging [15]; recent studies suggesting that this loss can range from 30 to 40% of cell bodies [12].

Norepinephrine

389

B. Biochemistry
NA was one of the ﬁrst neurotransmitters to be discovered. A brief review of this history
is of interest because it highlights how relatively young the ﬁeld of neuroscience actuallyis. Prior to 1900, neurons were thought to communicate exclusively by passive current
ﬂow. In 1901, Langley noted that extracts from the adrenal gland had similar effects as
stimulation of sympathetic nerves [16]. Elliot subsequently hypothesized that an adrenalinlike substance might be secreted by sympathetic nerve terminals and this substance chemically stimulated the effector organ [17]. The theory of chemical neurotransmission gained
signiﬁcant ground when Otto Loewi (1921) [18] showed that when the superfusion of one
heart whose rate had been decreased by electrical stimulation was transferred to a second,
unstimulated heart, its rate also decreased. Subsequently, Cannon and coworkers established the existence of an epinephrine-like substance (“sympathin”) that they claimed was
the chemical transmitter released by sympathetic nerves [19]. Nine years later, von Euler(1946) [20] established that the sympathetic neurotransmitter was demethylated epinephrine (norepinephrine).
The synthesis of NA and DA are dependent on availability of the precursor aminoacid tyrosine. Tyrosine, one of eight large neutral amino acids (LNAA), is competitivelytransported across the blood-brain barrier from the serum to the cerebrospinal ﬂuid by a
LNAA carrier. In NA neurons, tyrosine is converted to L-dihydroxy-phenylalanine (LDOPA) by the rate-limiting enzyme tyrosine hydroxylase. L-DOPA is then rapidly decarboxylated to DA and DA is metabolized to NA by the enzyme dopamine beta-hydroxylase.
Vesicular NA is transported to nerve terminals, where release into the synaptic cleft
occurs during neuronal ﬁring in a calcium-dependent process. Synaptic NA is rapidly takenback up into presynaptic terminals by the NA transporter (NAT) or into DA terminals by
the DA transporter (DAT). Vesicular NA is then either transported back into vesicles or
metabolized intraneuronally by monoamine oxidase A, producing 3,4-dihydroxyphenylglycol (DHPG) or 3,4-dihydroxymandelic acid (DHMA). These compounds are thenmetabolized further into the primary NA metabolites 3-methoxy-4-hydroxyphenylglycol(MHPG) or 3-methoxy-4-hydroxy-mandelic acid (VMA).

C. Physiology and Pharmacology
NA neurons, particularly those making up the LC, are activated in a variety of stressful
and aversive conditions and novel environments [21–23]. The activity of LC neurons ismodulated by several different neurotransmitter systems. The LC receives inhibitory input
from the serotonin (5HT), endogenous opioid, gama-amino-butyric-acid (GABA), DA,
and glycine systems and excitatory input from the corticotropin releasing factor (CRF),
methylxanthine, glutamate, substance P, and muscarinic cholinergic systems [11,24]. LC
neurons may utilize electrotonic coupling, a process that could explain the coordinatedﬁring characteristic of these cells. Another well-characterized regulatory mechanism isthrough an autoinhibitory presynaptic α2-adrenoreceptor that decreases the ﬁring rate of
LC neurons.
NA mediates its effects on target neurons via receptors traditionally classiﬁed as
being either of the α- or β-adrenergic subtype. Recent pharmacological, radioligand binding, and molecular biology data have led to a classiﬁcation of adrenergic receptors into
three groups based on the G-protein coupling. The three groups are the β-adrenergic sub-

390

Delgadotype (Gs coupled; β1, β2), the α2-adrenergic subtype (Gi coupled; α2a, α2b, α2c), and the
α1-adrenergic subtype (Gx coupled; α1a, α1b) [25].
Studies of the NA system have implicated alterations in β-, α1-, and α2-adrenoreceptor binding after long-term antidepressant treatment. Long-term treatment with tricyclic
antidepressants, monoamine oxidase inhibitors (MAOIs), trazodone, iprindole, and ECT(but not with some selective 5HT reuptake inhibitors, or bupropion, mianserin, and nomifensine) decrease β-adrenoreceptor binding in laboratory animals [26]. Increases in α1adrenoreceptor binding have also been reported for many antidepressants, and decreases
in α2-adrenoreceptor binding have been reported for some antidepressants. These ﬁndings
have been much less consistent than for β-adrenoreceptors [5,27].
Electrophysiological studies in laboratory animals ﬁnd that MAOIs produce an immediate decrease in the ﬁring rate of the LC and this decrease persists with long-term
treatment [28]. This suggests that the changes in LC ﬁring rate are not sufﬁcient for anantidepressant response to MAOIs. Sustained administration of citalopram or paroxetine
gradually decreased (14–21 days) while sustained administration of desipramine rapidly(2 days) decreased LC ﬁring [29]. Unlike the gradual return of ﬁring rate of 5HT neurons
during long-term antidepressant treatment, both 5HT and NA drugs caused a sustained
reduction of LC ﬁring, highlighting an important temporal and qualitative difference inhow 5HT and NA neurons differ in their long-term response to antidepressant drugs [29].
D.

NA and Neuroplasticity

NA and other monoamine neurotransmitters have both short- and long-term effects on
postsynaptic neurons. The long-term effects have increasingly become the focus of attention. It is now well established that NA causes changes in the long-term expression of avariety of gene products [30]. Changes in synaptic levels of NA or 5HT have been hypothesized to result in adaptive changes in neurons that may underlie the behavioral effectsof stress and the therapeutic effects of antidepressant drugs [31,32].
Studies have shown that a variety of antidepressants increase signal transduction
through second-messenger systems. Long-term antidepressant treatment increased the coupling of the second-messenger adenylyl cyclase to the stimulatory G-protein Gs [33],increased levels of cAMP-dependent protein kinase in limbic brain regions [34,35], andincreased the expression of the cAMP response element binding protein (CREB) [36].
While the precise mechanism by which NA increases signal transduction is not fully understood, one important result is to increase intracellular pathways leading to modiﬁcationof the rate of gene expression, including the production of brain-derived neurotrophic
factor (BDNF) [32]. Increased BDNF has been hypothesized to be a possible ﬁnal common
pathway for how NA- and 5HT-enhancing drugs mediate their therapeutic effects in depression [31]. The increase in BDNF and signal transduction mediated by NA could be
explained by effects of NA on either β1- or α1-adrenergic receptors [32].
E.

Function of LC

NA plays a critical role in modulation of the function of the prefrontal cortex (PFC). Both
NA and DA systems densely innervate the PFC and these neurotransmitters have thecapacity to modulate PFC function. The PFC is thought to be involved in the processof using working memory to regulate behavior and attention, allowing for inhibition of
inappropriate responses [37]. For example, depletion of NA and DA markedly impair

Norepinephrine

391

working memory [38,39]. Lesions of the NA system also impair several other functionsof the PFC, including maintenance of sustained [40] and shifting attention [41]. Deﬁcits
induced by depletion or lesions of the PFC can be reversed by administration of drugs
that stimulate NA receptors, especially the α2-adrenergic receptors on PFC neurons [42].
Physiologically the locus coeruleus is exquisitely sensitive to novel stimuli. It appears to modulate levels of arousal and has been postulated to be involved in opiate andalcohol withdrawal states, as well as anxiety disorders and depression [7,11]. Recent worksuggests that the LC is primarily involved in the process of selective attention, especiallyin regard to novel stimuli [43,11]. NA decreases spontaneous neuronal activity while augmenting activity evoked by afferent stimulation, increasing the signal-to-noise ratio intarget areas [43].
The NA system also has an effect on the acquisition of new memories [44]. Recall
for details of a vignette that includes emotionally arousing material is signiﬁcantly greaterthan for an emotionally neutral vignette [44]. This effect can be blocked by propranolol[45], a β-adrenergic antagonist that crosses the blood-brain barrier, but not by nadolol[46], a β-adrenergic antagonist that does not enter the CNS. These and other data have
led to the hypothesis that NA modulates the amygdala in such a way as to strengthen
memory consolidation and fear conditioning, playing an essential role in conveying emotional signiﬁcance to prior experience [44,47].
III. ASSESSMENT OF THE NA SYSTEM IN HUMANS: ROLE IN
DEPRESSION AND ANXIETY
Direct assessment of the role of NA in emotion, behavior, and mental illness has sufferedbecause methods do not exist that allow direct measurement of CNS NA function in living
humans. Many strategies have been used over the past 40 years to try to determine CNS
NA function. These include measurement of NA and/or NA metabolites in urine, blood,and CSF, challenge studies, and neuroimaging studies. Several of these strategies havebeen suggested to be a reliable measure of central NA function; however, none has provento be adequate.
While research into the role of NA in depression and anxiety dates back to the
1960s, several factors led to a relative reduction in interest in NA during the late 1980s
and 1990s. These included the introduction of selective 5HT reuptake inhibitors (SSRIs);
the failure to ﬁnd evidence of a NA deﬁciency in depressed or anxious patients; and thedisappointing results of studies of NA receptor agonists and antagonists as treatment foranxiety disorders and major depression.
The reawakening of interest in the role of NA in depression and antidepressanteffects and the clinical development of selective NA reuptake inhibitors (NRI)s was fueledin part by results from neurotransmitter depletion studies [24,48–52]. These studies
showed that the therapeutic effects of SSRls could be transiently reversed by rapid depletion of 5HT but not by depletion of NA [24,50,53]. Conversely, the therapeutic effectsof the NRI (desipramine) could be transiently reversed by depletion of NA but not bydepletion of 5HT [50,53].
In spite of the growing conﬁdence in the therapeutic effects of selective NRIs fortreatment of depression and some anxiety disorders, the precise role of NA in the pathophysiology of depression and anxiety remains unclear. The following sections will review
data from human studies aimed at addressing these questions.

392

A.

DelgadoUrine, Plasma, and CSF NA and NA Metabolites

As the metabolic pathways for NA were delineated, it was logical to measure urine, plasma
or CSF levels of NA or its primary metabolite, MHPG [54]. Studies did show that there
were moderate correlations between CSF, plasma, and urine measures of NA [55]. Additionally, manic patients and depressed patients with “high” anxiety had elevated CSF NA
compared with “low” anxiety depressed patients and neurological controls [56]. However,there is more variability in NA than in MHPG in the CSF and the origin of NA is more
likely to derive from spinal neurons than from cells originating in the locus coeruleus andother rostral projecting NA neurons [54,56]. Movement or exercise also affects NA and
MHPG, making potentially small methodological differences very important when assessing these markers [57].
Concentrations of MHPG have been measured in the urine, plasma, and CSF ofpatients with depression, but no consensus has been reached as to whether there is acorrelation between levels and depressive symptoms. For example, increased, decreased,
and unchanged urinary concentrations of MHPG have been reported in patients with depression [58–62].
While it is clear that NA and MHPG in CSF, blood, and urine derive from NA
neurons, it remains unclear to what extent and under which circumstances they may provide useful information about the status of brain NA systems of interest in regard to moodand anxiety disorders.
B.

Platelets and Lymphocytes

Many studies have investigated NA receptors on platelets and lymphocytes, hoping that
abnormalities inherent to the NA system might be similarly expressed in these peripheral
systems. As in the CNS, presynaptic α2-adrenoceptors on peripheral NA neurons also play
an important physiological role in the regulation of NA release [63]. Some differences in
NA measures between depressed patients and controls have been described. In addition,
an increase in the afﬁnity and density of α2-adrenoceptors on isolated human platelets
from depressed patients has also been reported [64].
Peripheral α2-adrenergic receptors located on blood platelets have been extensively
investigated with a variety of radiolabeled α2-adrenergic receptor agonist and antagonist
probes. Platelet α2-adrenergic receptor number as measured by 3H-clonidine [65], 3Hdihydroergocryptine [66], 3H-epinephrine, and 3H-para-aminoclonidine [64] have beenreported to be increased compared to healthy subjects. However, other studies utilizing
3
H-clonidine [67], 3H-dihydroergocryptine [68], 3H-yohimbine, and 3H-rauwolscine [69]have revealed no signiﬁcant difference between healthy subjects and depressed patients.
Studies of peripheral α2-adrenergic receptor responsiveness have been used to assess
the above conﬂicting results in receptor number. However, these studies have also been
contradictory, with some studies noting no difference between patients and controls andother studies noting a blunted cyclic adenosine monophosphate (cAMP) response [69,70].
Antidepressant drug treatment and electroconvulsive therapy are associated with a decrease in the density of α2-adrenoceptors and in the afﬁnity of ligands at these receptors
in platelets from depressed patients [71].
β-Adrenergic receptors are present on blood lymphocytes. Measurement of thesereceptors has also yielded mixed results with some authors reporting decreased numbers[72] and others reporting no difference [73,74] between depressed patients and healthy
subjects. On the other hand, the cyclic adenosine monophosphate (cAMP) response toNorepinephrine

393

stimulation of β-adrenergic receptors by β-adrenergic agonists has led to consistent reports
of a blunted response in depressed patients when compared to healthy subjects [72,74,
75–77].
C. Postmortem Studies
A variety of studies have assessed the LC and markers for NA function in the postmortem
brains of patients with depression or those having committed suicide. These studies havemeasured neuron density, NA receptor binding, as well as levels of NA synthetic enzymes.
While allowing for direct measurement, autopsy studies are inherently limited because of
the difﬁculty in obtaining reliable information relevant to diagnosis (including comorbid
diagnoses), use of medications, levels of stress or distress prior to or during death, anduse of alcohol or illicit drugs. In particular, many studies of suicide victims have included
patients with a wide variety of known axis I diagnoses (including schizophrenia) as wellas individuals with no known psychiatric diagnosis [78].
Some studies using postmortem tissue indicate that the density and afﬁnity of the
α2-adrenoceptors (autoreceptors) are increased in the frontal cortex [79–81], and LC [82]of suicide victims. However, this ﬁnding has not been replicated in other studies [83]. A
recent study assessing cerebral blood ﬂow during performance of cognitive testing with
[15O]H2O positron emission tomography (PET) before and after intravenous clonidine infusion in six depressed women compared with six matched controls [84]. While the study
failed to identify differences in plasma growth hormone response to clonidine, the depressed patients showed an increase in blood ﬂow in the right superior prefrontal cortex
during clonidine, while the controls showed a decrease [84]. The authors interpreted thisﬁnding as consistent with the prior studies showing greater density and afﬁnity of α2receptors in this region.
A variety of other measures also suggest differences in the LC of patients withdepression or suicide. Direct assessment of the LC shows that some individuals with depression or suicide have decreased neuronal density compared with controls [12,85,86].
Tyrosine hydroxylase activity has been reported as increased [78], although another study
reported a decrease in activity [87]. Reduced binding of radiolabeled nisoxetine, a ligand
for the NA reuptake transporter, has been reported in the postmortem locus coeruleus
tissue from suicide victims and patients with depression, compared with control subjects[88].
D. Challenge Studies
1. Neuroendocrine Challenges
As detailed knowledge of the regulation pituitary hormones by CNS monoamine neurotransmitter systems emerged, it was logical to attempt to gain an understanding of thefunction of CNS monoamine systems by measuring changes in plasma levels of pituitaryhormones. Because measurement of static levels of most compounds is inherently associated with greater variability within as well as between subjects, neuroendocrine challenge
strategies evolved as a method by which dynamic changes could be assessed.
While there was considerable optimism in the 1980s that the neuroendocrine challenge strategy might uncover the biological origin of mood and anxiety disorders, as thedecade wore on, the optimism faded. In part, this was because of the lack of speciﬁcity
that emerged as neuroendocrine tests were studied in increasingly broad patient groups.

394

DelgadoAdditionally, as the multitude of environmental, clinical, and demographic variables that
could affect the results of these tests became known, the complexity of controlling for somany variables increased, requiring either prohibitively large samples or patient samples
that had been so highly selected that the ﬁndings were of questionable generalizability.
Rather than attempt an exhaustive review of this literature, this chapter will highlightthe strengths and weaknesses of this approach by focusing on one of the most rigorously
studied neuroendocrine challenges in psychiatry: the growth hormone response to clonidine. Clonidine is an α2-adrenergic receptor agonist that causes an increase in the secretionof growth hormone by the anterior pituitary as well as a decrease in the plasma MHPG,
blood pressure, and sedation [89]. The release of growth hormone by α2-adrenergic receptor agonists is mediated by the activation of postsynaptic α2-adrenergic receptors within
the hypothalamus exerting a stimulatory effect on the secretion of growth hormone releasing hormone (GHRH) [90]. However, regulation of growth hormone secretion includes
many other neurotransmitters, including 5HT and DA. For example, depletion of both
5HT and NA in rats leads to a weaker growth hormone response to clonidine than does
depletion of NA alone [91].
One of the most consistent ﬁndings from research investigating the growth hormone
response to clonidine in humans is that this response is blunted in drug-free depressed
patients [92–94]. Acute administration of desipramine also causes an increase in the release of growth hormone. Depressed patients also show a blunted growth hormone response to desipramine, supporting the hypothesis that aspects of NA function may bedifferent in depressed individuals [95–97].
Importantly, a blunted growth hormone response to clonidine is not speciﬁc to depression, as it is also reported in patients with panic disorder [98], generalized anxiety
disorder [99], social phobia [100], obsessive-compulsive disorder [101], alcohol dependence [102], Gilles de la Tourette syndrome [103], and schizoaffective disorder [104]. In
alcoholic subjects with concurrent major depression, the blunted growth hormone response
to clonidine was present during retesting, even though depression and anxiety symptoms
had remitted [105]. By contrast, one study in 24 children (aged 7–14) with anxiety
disorders and 15 age-matched control children did not ﬁnd evidence of blunting, rather
clonidine-stimulated growth hormone secretion was increased in the anxious children
relative to the controls [106].
In a study of patients with OCD, the growth hormone response to GHRH was normal, while the response to clonidine was blunted compared with healthy controls [101].
This suggests that the blunted response is not simply because of a deﬁcit at the pituitarylevel. There is a high correlation between the release of growth hormone by GHRH andthat caused by clonidine [107].
A variety of factors have been shown to affect the growth hormone response toclonidine. Some antidepressants appear to cause a diminution of the response [108,109].
These effects have been observed to last as long as 6 months after the exposure to desipramine in healthy subjects [110]. Weight loss increases [111] the GH response to clonidine
and menstruation and recent alcohol use reduce the response [112,109].
2. Neurotransmitter Depletion Challenges
As the synthetic pathways for monoamines were discovered, it became possible to speciﬁcally enhance or block a particular step. Experimentation with various substrates for the
newly discovered synthetic enzymes revealed that chemical modiﬁcation of some precur-

Norepinephrine

395

Figure 1 Neurotransmitter depletion.

sors caused them to act as reversible inhibitors of key rate-limiting enzymes. One exampleof this was alpha methyl para tyrosine (AMPT). AMPT reversibly inhibits tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of NA and DA synthesis (Fig. 1).
AMPT treatment in humans (600–4000 mg/day) decreases urinary excretion of catecholamine metabolites by up to 75% [113]. A 3g/day dose of AMPT reliably reduces
urinary MHPG by 70% and reduces CSF levels of the DA metabolite, homovanillic acid
(HVA), by 61% with no change in the 5HT metabolite, 5HIAA (114). Maximum reductionof catecholamine metabolites during AMPT treatment occurs within 2 to 3 days of initiation of treatment and returns to normal within 3 to 4 days after withdrawal of the drug
[113,114].
Initial studies with AMPT were poorly controlled and difﬁcult to interpret. Even
after administration over several months to patients with general medical illnesses, AMPT
did not seem to cause signiﬁcant changes in mood [113]. Most nonpsychiatric patients andhealthy subjects demonstrate little behavioral change other than sedation during AMPT
treatment, with rebound insomnia frequently seen for 1 to 2 days after AMPT discontinuation [113–115]. AMPT was reported to decrease craving for opiates and amphetamines
in a small case series [116], decrease tic movements in Tourette’s syndrome [117], reduceoral tardive dyskinesia [118], and potentiate antipsychotic efﬁcacy in schizophrenia [119].
In an open-treatment trial of AMPT in patients with essential hypertension, 6 of 20 hypertensive patients had a history of a previous depressive episode. Three of these six became
agitated on AMPT, requiring drug discontinuation [113]. In a double-blind trial, AMPT
reduced manic symptoms in ﬁve of seven bipolar patients in the manic phase, but two
had an increase in manic symptoms [114,120]. In the same study, three of four psychotic
depressed patients became more depressed during AMPT treatment [114,120]. In threedepressed patients having had a therapeutic response to imipramine, AMPT had no signiﬁcant effect on the antidepressant response [121]. In one of these patients, AMPT wasstarted prior to initiation of antidepressant treatment and that patient went on to have atherapeutic response to imipramine [121].
The ﬁrst carefully controlled behavioral studies with AMPT suggest that the mostprominent effects are in NRI-treated depressed patients [49–51]. Patients who achieved
and maintained a treatment response to desipramine were more likely to have a temporary
return of depressive symptoms during exposure to AMPT 3 g/day than those successfully
treated with ﬂuoxetine or sertraline [49,50]. These ﬁndings are the mirror image of theresults with the use of rapid plasma tryptophan (TRP) depletion, a method for reducing

396

Delgadobrain 5HT synthesis [24]. In those studies, TRP depletion was more likely to cause atemporary return of depressive symptoms in depressed patients successfully treated withand taking ﬂuoxetine than those treated with and taking desipramine [53].
Unexpectedly, unmedicated, currently depressed patients did not worsen during exposure to either AMPT 3 g/day [51] or TRP depletion [122]. Severity of depression did
not alter the behavioral response to either type of depletion: patients did not become moredepressed, whether mildly ill or severely ill. These results suggest that the pathophysiology
of depression is unlikely to be understood by focusing on monoamine neurotransmission
alone [123].
A recent meta-analysis of previously published data with TRP and catecholamine
depletion revealed differences in the symptoms that emerge during each type of depletion[124]. Data from 123 depressed patients on and off antidepressants (44 catecholamine
depletion and 79 TRP depletion) who participated in one of several prior studies [50–53,125] including a subset of 11 patients who had both TPR and catecholamine depletion[126], were pooled for analysis. Change from baseline during depletion was calculatedfor Hamilton Depression (Ham-D) scale scores. Both TRP and catecholamine depletion
led to statistically signiﬁcant increases in total HAM-D score, signiﬁcantly increasingscores on the following items: depressed mood, loss of interest, retardation, agitation,
psychic and somatic anxiety, loss of energy, loss of sexual interest, decreased appetite,
decreased concentration, and helplessness, hopelessness, and worthlessness. The magnitude of increase in item score for “impaired concentration,” “loss of interest,” and “retardation” was signiﬁcantly greater for catecholamine than TRP depletion. The magnitude ofincrease in somatic anxiety was greater for TRP than catecholamine depletion. Figure 2graphically shows these changes. One can infer that the symptoms evoked by NA depletion
were more similar than different to those evoked by 5HT depletion. As might have been
expected, NA depletion impaired cognitive symptoms more than 5HT depletion, while
5HT depletion led to more somatic anxiety. The similarities and differences in symptoms
suggest that NA and 5HT share considerable overlap in modulating brain areas mediating
the symptoms of depression but have less of an overlap with some symptoms of anxiety

Figure 2 AMPT versus tryptophan depletion.

Norepinephrine397

and cognition. This may have relevance to putative differences between 5HT-selective,
NA-selective, and dual-action antidepressants.
Studies in healthy volunteers with no personal or family history of depression
showed that depletion alone could not bring about depressive syndrome [127–129], although healthy women report more negative mood states and irritability during NA depletion [130]. However, in patients who had recovered from recurrent episodes of major
depression and who were medication-free, it was observed that the majority of the patients
experienced a transient return of depressive symptoms in response to TRP depletion[131,127]. Similar ﬁndings have recently been reported with catecholamine depletion [52].
E.

Treatment Studies

Theories about the neurobiology of mood and anxiety disorders have been important tothe ﬁeld, but unless the predictions from these theories are borne out in treatment research,
the theories must be questioned. Therefore, clinical efﬁcacy trials serve both to advancetreatment and to test biological theories. However, it is important also to keep in mind that
evidence for efﬁcacy does not necessarily inform about pathophysiology. For example, thefact that topical corticosteroids alleviate rashes does not show that rashes are due to a
corticosteroid deﬁciency.
Since the early 1950s, when MAOIs and imipramine were coincidently discovered
to have therapeutic effects in the treatment of depression [132], and imipramine was foundto be effective for panic attacks in patients with agoraphobia [133], a steady stream of
new medications for depression and anxiety became available for clinical use. The ﬁrst
of these drugs were simple modiﬁcations of the original tricyclic or MAOI compounds.
However, as our understanding of the pharmacology of these compounds evolved, newer
drugs were tailored to have speciﬁc neurochemical effects. The vast majority of newer
compounds have been designed to potently enhance NA and/or 5HT neurotransmission
without anticholinergic, antihistaminergic, or antiadrenergic properties. It was hoped that
this would lead to drugs with fewer side effects and/or greater efﬁcacy and faster onsetof action.
The drugs we call antidepressants appear to have a broad efﬁcacy proﬁle, treating
most mood and anxiety disorders. However, as NA and 5HT selective reuptake inhibitors
have emerged, there is a growing body of literature suggesting that differences in thetherapeutic proﬁle exist. NA- and 5HT-selective drugs appear to have comparable efﬁcacy
for treatment of major depression, but 5HT-selective drugs and dual-action drugs may be
more effective in a broader range of anxiety disorders than selective NA reuptake inhibitors. The full implications of this for the underlying biological differences between moodand anxiety disorders remain to be elucidated.
The following sections provide a selected review of data from clinical studies investigating the efﬁcacy of several drugs with potent effects of NA and/or 5HT for treatment of major depression and several anxiety disorders. Figure 3 shows the relative potency at inhibition of NA and 5HT reuptake for common antidepressants.
1. NA Reuptake Inhibitors (NRIs)
Desipramine is one of the classical NRIs and there are extensive data available regarding
its clinical efﬁcacy proﬁle. It is well established as effective in the acute treatment ofmajor depressive episodes in 45 to 63% of outpatients and 48 to 63% in inpatients [134].

398

DelgadoFigure 3 Comparative inhibition of reuptake.
Like other tricyclic antidepressants, it has a host of pharmacological properties that contribute to its side-effect burden. These include anticholinergic, antihistaminergic, and antiadrenergic effects [134]. Desipramine has been reported to be effective in the treatment ofpanic disorder [l35–138], although clomipramine was even more effective [138]. Desipramine is not efﬁcacious in treatment of OCD [139–141], or post-traumatic stress disorder(PTSD) [142,143]. Bupropion is a very weak DA reuptake blockade inhibitor; its behavioral proﬁle in laboratory animals and humans is that of a central nervous system (CNS)
stimulant and indirect DA agonist [144]. It increases locomotor activity and causes stereotyped behaviors in laboratory animals. In humans, it can cause restlessness, insomnia,anorexia, and psychosis. Bupropion is structurally related to phenylethylamines and unrelated to the TCAs, SSRIs, or MAOIs. It has no signiﬁcant potency at binding to any known
neurotransmitter receptors. It has no signiﬁcant effects at blocking reuptake of 5HT orNA, although its primary metabolite (hydroxybupropion) is a potent NA reuptake inhibitor[145]. Hydroxybupropion is produced rapidly in humans, with peak plasma levels of up
to 3 times those of bupropion and a half-life of 24. Clinical studies have demonstrated
that bupropion is effective in the treatment of major depressive episodes [134]. While
early studies suggested that bupropion might be less likely to cause hypomania or mania
in bipolar patients, subsequent studies suggested that it can cause mania and psychosis inbipolar patients, especially those with high pretreatment levels of the DA metabolite HVA[146,147]. In a recent open-label study, bupropion was not effective for treatment of PTSD
[148]. However, contrary to commonly held clinical impressions, bupropion was reported
to have therapeutic effects in a patient with social phobia [149]. Additionally, a recent
review contrasting the relative efﬁcacy of bupropion and sertraline in treatment of anxiety
symptoms in patients with major depression showed that baseline Hamilton Anxiety Scale(Ham-A) scores did not predict response to either drug [150] and both drugs equally
reduced Ham-A total score [151].
Reboxetine was approved for use as an antidepressant in much of western Europe,
South America, and Mexico in 1998. Reboxetine is the only truly selective NRI. It potently
inhibits the reuptake of NA without having signiﬁcant effects on the reuptake of 5HT or
DA. It does not inhibit MAO, nor does it bind to 5HT1A or 5HT2A, DA1 or DA2, α- or βadrenergic, muscarinic cholinergic, gamma aminobutyric acid (GABA), benzodiazepine,or histamine H1-receptors. Reboxetine has primarily been studied in European studies

Norepinephrine399

involving about 665 nonelderly and 56 elderly (age ⬎ 65 years) depressed patients [152].
It is administered twice per day at doses ranging from 4 to 12 mg/day. The European
data show that reboxetine is more effective than placebo and comparable to imipramine,
desipramine, and ﬂuoxetine for the treatment of major depression. Reboxetine has also
been found to be equally effective as imipramine in severely ill depressed patients andmelancholic depressed patients (see Ref. 48 for review). One study found that while reboxetine restored normal function as measured on a social adjustment scale, ﬂuoxetine did
not [153]. The ﬁnding of improved social adjustment was interpreted to support the speciﬁc
involvement of the NA system in “sustaining drive” [153]. A recent study showed reboxetine to be highly effective in the treatment of panic disorder [154].
2. SSRIs
The ﬁve drugs in this class are ﬂuoxetine, sertraline, paroxetine, ﬂuvoxamine, and citalopram. All are relatively new and were developed because they are potent and selective
5HT reuptake inhibitors [155]. They share similar side effects and therapeutic spectrumof action, being effective in the treatment of MDE, OCD, and panic disorder. Early clinicalexperience suggests that while these drugs are more similar than different, there are differences in side-effect proﬁles between the ﬁve that are unexplained by current knowledge.
These include sedation/asthenia versus activation and propensity to cause nausea. In general, ﬂuvoxamine and paroxetine are more frequently associated with a sedation-like“blah” feeling referred to as “asthenia” and nausea, whereas ﬂuoxetine and sertraline are
more “activating.” Citalopram is intermediate in most side effects compared to other
SSRIs, probably accounting for its popularity in Europe and the U.S. Another interesting
difference is the potency of sertraline in blocking DA reuptake [144] and in binding tosigma receptors [156] and of paroxetine for inhibition of NA reuptake [157]. These datasuggest that sertraline may be problematic in psychotic depression and that in high doses
paroxetine may be a dual NA/5HT reuptake inhibitor. Paroxetine is also an inhibitor of
the enzyme nitric oxide synthetase [158], possibly contributing to a slightly higher rateof sexual dysfunction compared with other SSRIs [159].
3. Clinical Differences Between SSRIs and NRIs in Depression Studies
Nelson [160] recently published a comprehensive review of prior studies comparing an
NRI to an SSRI in patients with major depression. Sixteen studies were reviewed [160].
The NA selective agents included desipramine, nortriptyline, reboxetine, lofepramine, andmaprotiline and SSRIs included ﬂuoxetine, paroxetine, sertraline, ﬂuvoxamine, zimelidine, and citalopram. A total of 1563 patients were included in these studies. Response
rates were similar, 65% and 60%, for the SSRIs and NRIs. When baseline symptoms thatpredict response were examined, there were no consistent ﬁndings across studies, althoughsome studies have found baseline anxiety to predict preferential response to SSRIs versus
NRIs [161,162]. The topic of whether NRIs are as effective for anxiety symptoms/disorders as SSRIs continues to be an important focus of debate. In part, this debate is fueledby the lack of efﬁcacy of NRIs for OCD [139–141] and PTSD [142,143,148], as well asa generally held perception that SSRIs are more effective in depressed patients with moderate-to-severe anxiety symptoms [163]. Arguing against a signiﬁcant class difference inefﬁcacy in patients with comorbid major depression and anxiety symptoms are the studies
showing NRIs to be effective in panic disorder [135–137,154] as well as a recent study
showing that baseline Ham-A score did not predict response to either sertraline or bupropion during treatment of depression [150].

400

Delgado

4. Dual NA/5HT Reuptake Inhibitors
Approved by the FDA for the treatment of major depression in 1994, venlafaxine is theoldest of the newer antidepressants and stands out from most of the others in having
minimal effects on blocking neurotransmitter receptors. It is as potent at blocking 5HT
reuptake as imipramine, but is weaker at blocking NA reuptake, making it slightly more
selective for 5HT than NA, especially at lower doses. It does not inhibit MAO and does
not signiﬁcantly bind to 5HT, NA, DA, muscarinic cholinergic, α1-, α2-adrenergic, orhistamine H1-receptors [164].
Venlafaxine has fared well in placebo-controlled studies and has shown efﬁcacy ininpatients and outpatients with major depression and in patients with major depression
with melancholia [165,166]. In contrast to SSRIs, there is evidence for a dose-response
relationship, with higher doses being more likely to lead to successful antidepressant responses than lower doses. This has been hypothesized to be due to the likelihood that at
lower doses (less than 150 mg/day) venlafaxine is predominantly an SSRI and at higher
doses the NA reuptake inhibition begins to contribute to its action [167,168].
Several studies suggest that venlafaxine may lead to higher rates of response anda more “robust” proﬁle of response (when more stringent response criteria are used) whencompared to ﬂuoxetine, imipramine, or paroxetine. This is especially true in severely ill
or melancholic depressed patients [169–172].
Venlafaxine has been suggested to have a faster onset than imipramine [168] andﬂuoxetine [169]. Early onset has also been reported in placebo-controlled trials [173].
While early onset is more likely to be seen with aggressive dose escalation, it is thought
to result from the dual action of venlafaxine on 5HT and NA systems [174].
Venlafaxine may have as broad an efﬁcacy proﬁle as SSRIs. Small open-label studies have suggested efﬁcacy in OCD [175–178]. Venlafaxine has also been found effective
for the treatment of panic disorder [179,180], attention deﬁcit hyperactivity disorder[181,182], and social phobia [183].
5. NA Receptor Agonists and Antagonists
Mirtazapine. FDA-approved for the treatment of depression in the summer of
1998, mirtazapine is unique among antidepressants by virtue of the fact that it does notinhibit the reuptake 5HT, NA, or DA. Its primary mechanism of action relates to its potent
antagonism of α2-adrenergic receptors and 5HT2 receptors. It is also a potent antagonistof 5HT3 and histamine H1-receptors, effects that inﬂuence its side-effect proﬁle. Mirtazapine has no effects on DA, cholinergic, or α1-adrenergic receptors [184]. By blocking α2but not the α1-adrenergic receptors, mirtazapine leads to an increase in ﬁring rate andrelease of both NA and 5HT. This is because α2-adrenergic receptors are localized on both
NA and 5HT neurons. On NA neurons, presynaptic α2-receptors function as autoreceptors,
inhibiting the release of NA. Blocking these receptors leads to an increased ﬁring rate
and release of NA in most brain regions. NA released near the cell bodies of 5HT neurons
activate α1-adrenergic receptors located on 5HT cell bodies, and since these receptors act
in an excitatory fashion, the ﬁring rate of 5HT neurons is increased. 5HT neurons also
have α2-adrenergic receptors but, in this case, the receptors are localized on 5HT terminals
and function to inhibit the release of 5HT. Blocking these α2-adrenergic receptors enhances
the amount of 5HT released each time the neurons ﬁre [184].
Mirtazapine has been shown to be more effective than placebo in both hospitalized
patients and outpatients, and patients with “severe” depression (17-item Hamilton Depres-Norepinephrine

401sion Scale score ⬎ 25). It has comparable efﬁcacy with amitriptyline [185], doxepin [186],
and clorimipramine [187], and has been shown to be more efﬁcacious than trazodone[188] and ﬂuoxetine [189] in severely ill depressed patients.
Most studies have documented improvement in both depression and anxiety andmany studies have shown efﬁcacy in anxious depressed patients [190]. However, there
are no published reports of mirtazapine treatment for anxiety disorders, although several
studies are currently in progress.
Other Adrenergic Antagonists and Agonists. Comprehensive review of the literature on the use of NA receptor antagonists and agonists is beyond the scope of this chapter,but given the theoretical importance, a brief overview is called for. In general, the studies
conducted support the interpretation that drugs that reduce NA activity decrease anxiety
and cause fatigue and sedation and drugs that increase NA release (yohimbine) increase
anxiety, especially (but not exclusively) in individuals with anxiety disorders. There aremany published studies on the use of β-adrenergic receptor antagonists (most often propranolol, atenolol, or metropolol), α2-adrenergic agonists (mostly clonidine), and α2-adrenergic antagonists (mostly yohimbine) in a variety of anxiety disorders, mixed depression
and anxiety states, and anxiety-inducing situations. Many open-label and controlled trials
have been conducted and, in general, the results for all anxiety disorders have been mixed
with comparable numbers of positive and negative studies (for reviews of these data, see
Refs. 191–194). While sometimes effective, treatment with these drugs is most often limited by cardiovascular side effects, sedation, fatigue, and asthma [191–193]. Recent workwith the α1-adrenergic antagonist prazosin in patients with PTSD found it to have evidenceof efﬁcacy, improving sleep and decreasing nightmares [195] (Table 1).
IV. OVERVIEW OF NA IN MOOD AND ANXIETY DISORDERS
There has been substantial progress in elucidating many of the normal functions of NA
in the brain. The LC appears to be a critical component in the brain’s attention system[43]. NA modulation of the PFC explains one aspect of how we modulate our focus on
rapidly changing external events [40–42]. In the periphery, NA serves to ready the bodyfor a potential challenge in the classic ﬂight-or-ﬁght paradigm. CNS NA also serves tomodify the storage of emotion-laden memory, perhaps conveying aspects of emotionalsigniﬁcance to memory of events [44,45]. Chronic activation of NA causes adaptivechanges in NA neurons and postsynaptic brain areas, possibly contributing to the symptoms of stress [30–32]. Increasing NA release in healthy people results in mild anxiety[7] and decreasing it results in mild decreases in attention, fatigue, and irritability (49–52, 115–118, 121, 130, 196). More marked differences have been observed in various
patient groups, but the fact that such differences exist suggests that NA dysfunction may
not be the central pathophysiological component in most patients with affective and/or
anxiety disorders.
The assumptions underlying early models for the neurobiology of depression weregreatly inﬂuenced by the discovery of the CNS DA deﬁciency in patients suffering from
Parkinson’s disease [1] and by the remarkable therapeutic effects of the DA precursor,
L-DOPA [197]. It was in this historical context that the therapeutic and pharmacologicaleffects of antidepressant drugs were discovered and the ﬁrst neurobiological theories ofdepression and anxiety disorders were proposed. The research of the past 30 years suggeststhat new, more complex models are in order.

402

Table 1

Clinical Proﬁle of Action of Selected Drugs with Potent NA and/or 5HT Effects

Drug
a

Major
depression

SSRI
Venlafaxine
Reboxetine
Desipramine
Bupropion
Mirtazapine

⫹⫹⫹⫹
⫹⫹⫹⫹
⫹⫹⫹⫹
⫹⫹⫹⫹
⫹⫹⫹⫹
⫹⫹⫹⫹

β-Antagonistsb
Clonidine

NA
NA

Socialanxietydisorder

GAD

Panic
disorder

⫹⫹⫹⫹
⫹⫹⫹⫹
NA
NA
⫹
NA
⫹⫹/
(⫺)(⫺)(⫺)
NA

⫹⫹⫹⫹
⫹⫹⫹
NA
NA
NA
NA
⫹⫹⫹/
(⫺)(⫺)(⫺)⫹/(⫺)(⫺)

⫹⫹⫹⫹
⫹⫹⫹⫹
⫹⫹⫹
⫹⫹
⫹⫹
⫹
⫹⫹⫹/
(⫺)(⫺)(⫺)⫹/(⫺)(⫺)

PTSD

OCD

⫹⫹⫹⫹
⫹⫹⫹
NA
⫹/(⫺)(⫺)(⫺)(⫺)
⫹⫹

⫹⫹⫹⫹
⫹⫹⫹⫹
NA
(⫺)(⫺)(⫺)
NA
⫹

⫹c
⫹⫹

(⫺)(⫺)(⫺)⫹⫹⫹⫹, Randomized placebo-controlled trials with comparison drug showing greater efﬁcacy than both placebo and comparator; ⫹⫹⫹, at least one placebocontrolled trial or more than one open-label trial in a total of 50 or more patients showing efﬁcacy; ⫹⫹, two or more case reports with a total of 10 ormore patients reporting efﬁcacy in over half of the patients; ⫹, at least one case suggesting efﬁcacy; NA, no data available; (⫺), at least one case suggestinglack of efﬁcacy; (⫺)(⫺), two or more case reports with a total of 10 or more patients failing to show evidence of efﬁcacy in over half of the patients;(⫺)(⫺)(⫺), at least one placebo-controlled trial or more than one open-label trial in a total of 50 or more patients failing to show efﬁcacy.
aSSRI (selective serotonin reuptake inhibitors) includes citalopram, ﬂuoxetine, ﬂuvoxamine, paroxetine, and sertraline.
b
Includes propranolol and atenolol.
c
Propranolol blocked some of the symptoms of acute stress in persons recently traumatized (Ref. 42).

DelgadoNorepinephrine

403

Many studies have identiﬁed differences in measures of NA between patients withmajor depression or anxiety disorders and healthy controls. Of the prior research, one of
the most consistent ﬁndings has been the blunted growth hormone response to clonidine in
drug-free depressed patients. The major problem with prior interpretations of this ﬁnding isthat it is highly nonspeciﬁc, being present in a wide variety of psychiatric conditions. Fewof the other markers have been comparably researched in multiple patient populations,but the ones that have suggest considerable overlap between diagnostic groups exists.
It is likely that many of the differences identiﬁed in prior studies of NA function
in clinical samples are a consequence of the differences in levels of stress between thegroups. One of the most serious limitations of prior work investigating NA function inpatients with affective and anxiety disorders is the fact that healthy controls were usuallyused as a comparison. It is well established that the NA system is highly stress responsive
and that adaptive changes to chronic stress include many of the same abnormalities identiﬁed in patient populations [14,23,30–32]. Therefore, rather than using healthy controls,studies investigating the NA system in clinical samples should ideally be using “stressed”
healthy controls. This would help to disentangle whether differences in NA measures
reﬂect a nonspeciﬁc effect of stress or the pathophysiological underpinnings of a psychiatric disorder.
Some of the most important studies addressing the role of NA in clinical syndromes
are those that have utilized NA depletion. The fact that NA depletion does not lead todepressive symptoms in healthy controls, nonantidepressant-treated clinical samples, orin depressed patients taking SSRIs (49–52, 115–118, 121, 130, 197) suggests that NA
dysfunction may contribute to the symptoms of affective and anxiety disorders, but ishighly unlikely to be causal. On the other hand, the results of NA depletion studies conﬁrm
the importance of NA to the antidepressant response of NRIs relative to SSRIs [49–52].
Similar studies in patients suffering from anxiety disorders have not been conducted todate.
It is likely that biological vulnerability to affective and anxiety disorders is heterogeneous, with many factors converging to cause a common brain dysregulation. While the
etiology of these conditions may be heterogeneous, the brain systems involved in determining speciﬁc emotions, cognitions, and somatic processes are likely to be similar
across patients. In spite of the sometimes dramatic differences in individual symptoms
between patients with major depression, most antidepressant drugs are comparably effective across patients. This suggests that the drugs are causing widespread effects in many
brain regions rather than simply reversing a common neurochemical abnormality. Considerable evidence supports the idea that speciﬁc brain networks and the neuroanatomical
circuits that join them underlie emotional experience, cognition, and somatic function[198]. While our current understanding of the role and function of these circuits and networks remains primitive, a rough outline is beginning to emerge [199].
If this view is correct, then patients suffering with similar symptoms most likely
have similar dysfunction of the same networks and circuits. Recent data support this andsuggest that depression may be associated with localized reductions in brain morphology
in the frontal cortex [200]. The etiology of the dysfunction may differ between patients,
but the net functional impact may be similar. An analogous situation would be a cardiac
arrhythmia leading to an increase in heart rate. In some situations, this could be causedby an electrolyte imbalance, but in many others it will arise from dysfunction of speciﬁc
conduction pathways in the heart. The same symptom arises from different pathologicalprocesses, but the symptom arises from dysfunction of a speciﬁc circuit. These types of404

Delgadointegrative models begin to account for the diversity of clinical presentations and offer
explanations of how neurotransmitter systems, brain circuits, and life experiences that
affect the development of these systems could interact to produce vulnerabilities to depression and anxiety disorders.
None of the data reviewed provide insights into the how the biology of affective
and anxiety disorders might differ. It is unlikely that any differences that exist reside indifferences in NA function. Until we fully understand the brain networks involved inmodulating discrete emotions, it is unlikely that we will have sufﬁcient understanding of
the brain to distinguish between these conditions or to even know if anxiety and affective
disorders are part of a related spectrum. The treatment data (Table 1) suggest that there
will be signiﬁcant overlap between most anxiety and affective disorders. OCD and PTSD
may turn out to be important exceptions to this.
In particular, with the clinical conditions in which most antidepressants seem towork equally, currently available drugs may be acting to cause an alteration in the functionof postsynaptic neurons residing in critical brain circuits, an effect that would account forthe delay [31,201]. Only after this had occurred would behavioral improvement follow.
Abnormalities in the functioning of the postsynaptic receptors may be subcellular, forexample, in the G-protein coupling, second- or third-messenger systems, or at the levelof gene transcription. Some evidence already exists to suggest that the monoamines sharecommon pathways at this level (31,202,203).
While it is well established that there are considerable interactions between NA and5HT neurons in the brain, it is also clear that there can be independent effects of changing
neurotransmission in either system [31,48–53]. This would explain why the pharmacological proﬁle of the antidepressant drug that the patient is taking is so important to the effects
of monoamine depletion. While both neurotransmitter systems generally innervate mostbrain regions, the pattern of innervation sometimes involves different layers of the cortex;
there can be selective innervation of some brain regions; and both common and dissimilareffects can be observed in intracellular responses in postsynaptic neurons (31,204,205).
In considering the possible role of NA in mood and anxiety disorders, it is clearthat much more work is needed to further elucidate the role of NA in normal brain function
and mental disorders. Future work will beneﬁt from a broader perspective, incorporating
research from the cognitive neurosciences, systems neuroscience, molecular and cellularresearch, as well as neuropsychopharmacology.

REFERENCES
1. Ehringer H, Hornykiewicz O. Verteilung von Noradrenalin and Dopamin (3-Hydroxytyramin) im Gehirn des Menschen und ihr Verhalten bei Erkrankungen des estrapyramidalen
Systems. Klin Wschr 1960; 38:1236–1239.
2. Hornykeivicz O. Pharmacol Rev 1966; 18:925–964.
3. Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting
evidence. Am J Psychiatry 122:509–522, 1965.
4. Bunney WE Jr., Davis JM. Norepinephrine in depressive reactions: a review. Arch Gen Psychiatry 1965;13: 483–494.
5. Charney DS, Menekes DB, Heninger GR. Receptor sensitivity and the mechanism of actionof antidepressant treatment. Arch Gen Psychiatry 1981; 38: 1160–1180.
6. Siever LJ, Davis KL. Overview: Toward a dysregulation hypothesis of depression. Am J
Psychiatry 1985; 142:1017–1031.

Norepinephrine

405

7. Charney DS, Redmond DE. Neurobiological mechanisms in human anxiety: evidence supporting central noradrenergic hyperactivity. Neuropharmacol 1983; 22(12B):1531–1536.
8. Delgado PL, Charney DS, Price LH, et al. Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma
tryptophan. Arch Gen Psychiatry 1990; 47:411–418.
9. Carpenter MB, Sutin J. Human Neuroanatomy. Baltimore: Williams and Wilkins, 1983.
10. Swanson LW. The locus coeruleus: A cytoarchitectronic, Golgi and immunohistochemical
study in the albino rat. Brain Res 1976; 110:39–56.
11. Redmond DE. Studies of the nucleus locus coeruleus in monkeys and hypotheses for neuropsychopharmacology. In: Meltzer HY, ed. Psychopharmacology: The Third Generation of
Progress. New York: Raven Press, 1987:967–975.
12. Chan-Palay V, Asan E. Quantitation of catecholamine neurons in the locus coeruleus inhuman brains of normal young and older adults and in depression. J Comp Neurol 1989;
287:357–372.
13. Ungerstedt U. Stereotaxic mapping of the monoamine pathways of the rat brain. Acta Physiol
Scand 1971;367:1–49.
14. Woodward DJ, Moises HC, Waterhouse BD, Hoffer BJ, Freedman R. Modulating actionsof norepinephrine in the central nervous system. Fed Proc 1979; 38: 2109–2116.
15. Bartus RT, Flemming D, Johnson HR. Aging in the rhesus monkey: debilitating effects on
short-term memory. J Gerontol 1978; 33:858–871.
16. Langley JN. Observations on the physiological action of extracts of the supra-renal bodies.
J Physiol 1901; 27:237–256.
17. Elliot TR. On the action of adrenalin. J Physiol Proc 1904; 31:20–21.
18. von Loewi O. Uber humerale uvertragbarkeit der herznervenwirkung. Pﬂugers Arch Physiol
1921; 189:239–242.
19. Cannon WB, Rosenbleuth A. The Supersensitivity of Denervated Structures. New York:
Macmillan, 1937.
20. Von Euler US. The presence of a substance with sympathin E properties in spleen extracts.
Acta Physiol Scand 1946; 11:168–186.
21. Korf J, Aghajanian GK, Roth R. Increased turnover of norepinephrine in the rat cerebral
cortex during stress: Role of the locus coeruleus. Neuropharmacol 1973; 12:933–938.
22. Abercrombie ED, Keller RW, Zigmond MJ. Characterization of hippocampal norepinephrine
release as measured by microdialysis perfusion: pharmacological and behavioral studies.
Neurosci 1988; 27:897–904.
23. Valentino RJ, Foote SL, Page ME. The locus coeruleus as a site for integrating corticotropinreleasing factor and noradrenergic mediation of stress responses. In: Tache Y, ed. Corticotropin-Releasing Factor and Cytokines: The Role in the Stress Response. City: Publisher, 1993:
173–188.
24. Charney DS, Southwick SM, Delgado PL, Krystal JH. Current status of the receptor sensitivity hypothesis of antidepressant action: implications for the treatment of severe depression.
In: Amsterdam JD, ed. Pharmacotherapy of Depression. New York: Marcel Dekker, Inc.,
1990:13–34.
25. Bylund DB. Subtypes of α2-adrenoreceptors: pharmacological and molecular biological evidence converge. TIPS 1988; 9:356–361.
26. Heninger GR, Charney DS, Delgado PL. Neurobiology of treatments for refractory depression. In: Tasman A, Goldﬁnger SM, Kaufman CA, eds. Review of Psychiatry. Washington,
D.C.: American Psychiatric Press, Vol. 9, 1990:33–58.
27. Heninger GR, Charney DS. Mechanism of action of antidepressant treatments: Implications
for the etiology and treatment of depressive disorders. In: Meltzer HY, ed. Psychopharmacology: The Third Generation of Progress. New York: Raven Press, 1987:535–544.
28. Blier P, de Montigny C. Current advances and trends in the treatment of depression. Trends
Pharmacol Sci 1994; 15:220–226.

406

Delgado29. Szabo ST, de Montigny C, Blier P. Progressive attenuation of the ﬁring activity of locus
coeruleus noradrenergic neurons by sustained administration of selective serotonin reuptake
inhibitors. Int J Neuropsychopharmacol 2000; 3:1–22.
30. Hyman SE, Nestler EJ. Initiation and adaptation: a paradigm for understanding psychotropic
drug action. Am J Psychiatry 1996; 153:151-162.
31. Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. ArchGen Psychiatry 1997; 54:597–606.
32. Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment.
Biol Psychiatry 1999; 46:1181–1191.
33. Ozawa H, Raesnick MM. Chronic electroconvulsive treatment augments coupling of the
GTP-binding protein Gs to the catalytic moiety of adenylyl cyclase in a manner similar tothat seen with chronic antidepressant drugs. J Neurochem 1991; 56:330–338.
34. Nestler EJ, Terwilliger RZ, Duman RS. Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem 1989; 53:1644–1647.
35. Perez J, Tinelli D, Brunello N, Racagni G. CAMP-dependent phosphorylation of soluble
and crude microtubule fractions of rat cerebral cortex after prolonged desmethylimipramine
treatment. Eur J Pharmacol 1989; 172:305–316.
36. Nibuya M, Nestler EJ, Duman RS. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci
1996; 16:2365–2372.
37. Birnbaum S, Gobeske KT, Aurbach J, Taylor JR, AFT Arnsten. A role for norepinephrine
in stress-induced cognitive deﬁcits: α-1-adrenoreceptor mediation in the prefrontal cortex.
Biol Psychiatry 1999; 46:1266–1274.
38. Anlezark GM, Crow TJ Greenway AP. Impaired learning and decreased cortical norepinephrine after bilateral locus coeruleus lesions. Science 1973; 181:682–684.
39. Brozoski T, Brown RM, Rosvold HE, Goldman PS. Cognitive deﬁcit caused by regional
depletion of dopamine in prefrontal cortex of rhesus monkey. Science 1979; 205:929–931.
40. Carli M, Robbins TW, Evenden JL, Everitt BJ. Effects of lesions to ascending noradrenergic
neurons on performance of a 5-choice serial reaction task in rats. Implications for theories
of dorsal noradrenergic bundle functions based on selective attention and arousal. Behav
Brain Res 1983; 9:361–380.
41. Devauges V, Sara SJ. Activation of the noradrenergic system facilitates an attention shift in
the rat. Behav Grain Res 1990; 39:19–29.
42. Friedman JI, Adler DN, Davis KL The role of norepinephrine in the pathophysiology ofcognitive disorders: potential applications to the treatment of cognitive dysfunction in schizophrenia and Alzheimer’s Disease. Biol Psychiatry 1999; 46:1243–1252.
43. Aston-Jones G, Rajkowski J, Cohen J. Role of locus coeruleus in attention and behavioral
ﬂexibility. Biol Psychiatry 1999; 46:1309–1320.
44. Cahill L, Prins B, Weber M, McGaugh JL. β-Adrenergic activation and memory for emotional events. Nature 1994; 371:702–704.
45. Cahill L, Pham CA, Setlow B. Impaired memory consolidation in rats produced with βadrenergic blockade. Neurobiol Learning Memory 2000; 74:259-266.
46. van Stegeren AH, Everaerd W, Cahil L, McGaugh JL, Gooren LJ. Memory for emotional
events: Differential effects of centrally versus peripherally acting beta-blocking agents. Psychopharmacology (Berl) 1998; 138:305–310.
47. Pittman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, Lasko NB, Cahill L, Orr SP.
Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol
Psychiatry 2002; 51:189–142.
48. Delgado PL, Price LH, Miller HM, Salomon RM, Licinio J, Krystal JH, Heninger GR, Charney DS. Rapid serotonin depletion as a provocative challenge test for patients with major

Norepinephrine

49.

50.

51.

52.

53.

54.
55.
56.
57.

58.

59.
60.
61.

62.
63.
64.

65.

66.

407

depression: relevance to antidepressant action and the neurobiology of depression. Psychopharmacol Bull 1991; 27(3):321–330.
Delgado PL, Miller HL, Salomon RM, et al. Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants. Psychopharmacol Bull 1993; 29:389–396.
Miller HL, Delgado PL, Salomon RM, et al. Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry
1996; 53:117–128.
Miller HL, Delgado PL, Salomon RM, Heninger GR, Charney DS. Effects of alpha-methylpara-tyrosine (AMPT) in drug-free depressed patients. Neuropsychopharmacol 1996; 14:
151–157.
Berman RM, Narasimhan M, Miller HL, Anand A, Cappiello A, Oren DA, Heninger GR,
Charney DS. Transient depressive relapse induced by catecholamine depletion: potential phenotypic vulnerability marker? Arch Gen Psychiatry 1999; 56:395–403.
Delgado PL, Miller HM, Salomon RM, Licinio J, Krystal JH, Heninger GR, Charney DS.
Tryptophan depletion challenge in depressed patients treated with desipramine or ﬂuoxetine:
implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry 1999; 46:212–220.
Ziegler MG, Wood JH, Lake R, Kopin IJ. Norepinephrine and 3-methoxy-4-hydroxyphenyl
glycol gradients in human cerebrospinal ﬂuid. Am J Psychiatry 1977; 134(5):565–568.
Roy A, Pickar D, De Jong J, Karoum F, Linnoila M. Norepinephrine and its metabolites incerebrospinal ﬂuid, plasma, and urine. Arch Gen Psychiatry 1988; 45:849–857.
Post RM, Lake CR, Jimerson DC, Bunney WE, Wood JH, Ziegler MG, Goodwin FK. Cerebrospinal ﬂuid norepinephrine in affective illness. Am J Psychiatry 1978; 135(8):907–12.
Schatzberg AF, Schildkraut JJ. Recent studies on norepinephrine systems in mood disorders.
In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress.
New York: Raven Press, 1995: 911–920.
Potter WZ, Muscettola G, Goodwin FK. Sources of variance in clinical studies in MHPG.
In: Maas JW, ed. MHPG: Basic Mechanisms and Basic Psychopathology. New York: Academic Press, 1983:l45–165.
Maas JW, Fawcett JA, Dekirmenjiam H. Catecholamine metabolism, depressive illness anddrug response. Arch Gen Psychiatry 1972; 26: 252–262.
Schatzberg AF, Rothschild AJ. Psychotic major depression: should it be included as a distinct
syndrome in DSM-IV? Am J Psychiatry 1992; 149:733–745.
Schildkraut JJ, Orsulak PJ, Schatzberg AF et al. Toward a biochemical classiﬁcation of depressive disorders. I. Differences in urinary excretion of MHPG and other catecholamine
metabolites in clinically deﬁned subtypes of depressions. Arch Gen Psychiatry 1978; 35:
1427–1433.
Muscettola G, Potter WZ, Pickar D, et al. Urinary 3-methoxy-4-hydroxyphenyl-glycol andmajor affective disorders. Arch Gen Psychiatry 1984; 41: 337–342.
Langer SZ. Presynaptic regulation of the release of catecholamines. Pharmacol Rev 1981;
32:337–362.
Piletz JE, Halaris A, Saran A, Marler M. Elevated 3H-para-aminoclonidine binding to platelet
puriﬁed plasma membranes from depressed patients. Neuropsychopharmacology 1990; 3:
201–210.
Garcia-Sevilla JA, Zis AP, Hollingsworth PJ, et al. Platelet alpha 2-adrenergic receptors inmajor depressive disorder. Binding of tritiated clonidine before and after tricyclic antidepressant drug treatment. Arch Gen Psychiatry 1981; 38:1327–1333.
Siever LJ, Kafka MS, Insel TR, Lake CR, Murphy DL. Effect of clorgyline administration
on human platelet alpha-adrenergic receptor binding and platelet cyclic AMP responses. Psychiatry Res 1984; 9:37–44.

408

Delgado

67. Georgotas A, Schweitzer J, McCue RE, et al. Clinical and treatment effects on 3H-clonidine
and 3H-imipramine binding in elderly depressed patients. Life Sci 1987; 40:2137–2143.
68. Wood K, Coppen A. Alpha2 adrenergic receptors in depression. Lancet 1982; 1:1121–1122.
69. Siever LJ. Role of noradrenergic mechanisms in the etiology of the affective disorders. In:
Meltzer HT, ed. Psychopharmacology: The Third Generation of Progress. New York: Raven
Press, 1987: 493–504.
70. Kindler S, Lerer B. Norepinephrine and depression: a reappraisal. In: Pohl R, Gershon S,
eds. The Biologic Basis of Psychiatric Treatment. Progress in Basic and Clinical Pharmacology. Basel: Karger, 1990: 120–141.
71. Garcı́a-Sevilla JA, Padró D, Giralt T, Guimón J, Areso P. a2-Adrenoreceptor mediated inhibition of platelet adenylate cyclase and induction of aggregation in major depression: effectof long-term cyclic antidepressant drug treatment. Arch Gen Psychiatry 1990; 47:125–132.
72. Extein I, Tallman J, Smith CC, Goodwin FK. Changes in lymphocyte beta-adrenergic receptors in depression and mania. Psychiatry Res 1971; 1:191–197.
73. Cooper SJ, Kelly JG, King DJ. Adrenergic receptors in depression: effects of electroconvulsive therapy. Br J Psychiatry 1985; 147:23–29.
74. Mann JJ, Brown RP, Halper JP et al. Reduced sensitivity of lymphocyte beta adrenergic
receptors in patients with endogenous depression and psychomotor agitation. N Engl J Med
1985; 313:715–720.
75. Pandey GN, Dysken MW, Garver DL, Davis JM. Beta-adrenergic receptor function in affective illness. Am J Psychiatry 1979; 136:675–678.
76. Pandey GN, Sudershan P, Davis JM. Beta adrenergic receptor functon in depression and theeffect of antidepressant drugs. Acta Pharmacol Toxicol 1985; 56(Suppl 1):66–79.
77. Ebstein RP, Lerer B, Shapira B, Shemesh Z, Moscovich EDG, Kindler S. Cyclic AMP second
messenger ampliﬁcation in depression. Br J Psychiatry 1988; 152:665–669.
78. Zhu M-Y, Klimek V, Dilley GE, Haycock JW, Stockmeier C, Overholser JC, Meltzer HY,
Ordway GA. Elevated levels of tyrosine hydroxylase in the locus coeruleus in major depression. Biol Psychiatry 1999; 46(9):1275–1286.
79. Meana JJ, Garcia-Sevilla JA. Increased alpha2 adrenoreceptor density in the frontal cortex
of depressed suicide victims. J Neural Trans 1987; 70:377–381.
80. Callado LF, Meana JJ, Grijalba B, et al. Selective increase of alpha2A-adrenoceptor agonist
binding sites in brains of depressed suicide victims. J Neurochem 1998; 70:1114–1123.
81. Garcia-Sevilla JA, Scriba PV, Ozaita A, La Harpe R, Walzer C, Eytan A, et al. Up-regulationof immunolabeled α2a-adrenoreceptors, Gi coupling proteins, and regulatory receptor kinasesin the prefrontal cortex of depressed suicides. J Neurochem 1999; 72:282–291.
82. Ordway GA, Widowson PS, Smith KS, Halaris AE. Agonist binding to α2-adrenoreceptors
is elevated in the locus coeruleus from victims of suicide. J Neurochem 1994; 63:617–624.
83. Klimek V, Rajkowska G, Luker S, Dilley G, Meltzer HY, Overholser J, et al. Brain noradrenergic receptors in major depression and schizophrenia. Neuropsychopharmacology 1999; 21:
69–81.
84. Fu CHY, Reed LJ, Meyer JH, Kennedy S, Houle S, Eisfeld BS, Brown GM. Noradrenergic
dysfunction in the prefrontal cortex in depression: An [15O]H2O PET study of the neuromodulatory effects of clonidine. Biol Psychiatry 2001; 49:317–325.
85. Bronisch T. The relationship between suicidality and depression. Arch Suicide Res 1996; 2:
235–254.
86. Arango V, Underwood MD, Mann JJ. Fewer pigmented locus coeruleus neurons in suicide
victims: preliminary results. Biol Psychiatry 1996; 39:112–120.
87. Biegon A, Fieldust S. Reduced tyrosine hydroxylase immunoreactivity in locus coeruleus ofsuicide victims. Synapse 1992; 10:79–82.
88. Klimek V, Stockmeier C, Overholser J, Meltzer HY, Kalka S, Dilley G, Ordway G. Reduced
levels of norepinephrine transporters in the locus coeruleus in major depression. J Neurosci
1997; 17(21):8451–8458.

Norepinephrine

409

89. Lal S, Tolis G, Martin JB, Brown GM, Guyda H. Effect of clonidine on growth hormone,prolactin, leutinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone in the serum of normal men. J Clin Endocrinol Met 1975; 41: 827–832.
90. Frohman LA, Jansson JO. Growth hormone releasing hormone. Endocrine Rev 1986; 7:223–
253.
91. Soderpalm B, Andersson L, Carlsson M, Modigh K, Eriksson E. Serotonergic inﬂuence on
the growth hormone response to clonidine in the rat. J Neur Transm 1987; 69: 105–114.
92. Matussek N, Ackenheil M, Hippius H, et al. Effects of clonidine on growth hormone releasein psychiatric patients and controls. Psychiatry Res 1980; 2:25–36.
93. Charney DS, Heninger GR, Sternberg DE, Hafstead KM, Giddings S, Landis H. Adrenergic
receptor sensitivity in depression: effects of clonidine in depressed patients and healthy subjects. Arch Gen Psychiatry 1982; 39:290–294.
94. Ansseau M, Von Frenckell, Cerfontaine R, et al. Blunted response of growth hormone toclonidine and apomorphine in endogenous depression. Br J Psychiatry 1988; 153:65–71.
95. Meesters P, Kerkhofs M, Charles G, Decoster C, Vanderelst M, Mendlewicz J. Growth hormone response after desipramine in depressive illness. Eur Arch Psychiatry Neurol Sci 1985;
235:140–142.
96. Laakmann G, Zygan K, Schoen HW, et al. Effects of receptor blockers (methysergide, propranolol, phentolamine, yohimbine, and prazosin) on the desimipramine-induced pituitaryhormone stimulation in humans. Part I: growth hormone. Psychoneuroendocrinol 1986; 11:447–461.
97. Asnis GM, Lemus CZ, Halbreich U. The desipramine cortisol test— a selective noradrenergic challenge (relationship to other cortisol tests in depressives and normals). Psychopharmacol Bull 1986; 22:571–578.
98. Coplan JD, Pine DS, Papp LA, Gorman JM. A view on noradrenergic, hypothalamicpituitary-adrenal axis and extrahypothalamic corticotropin-releasing factor function inanxiety and affective disorders: the reduced growth hormone response to clonidine. Psychopharmacol Bull 1997; 33:193–204.
99. Abelson JL, Glitz D, Cameron OG, et al. Blunted growth hormone response to clonidine inpatients with generalized anxiety disorder. Arch Gen Psychiatry 1991; 48:157–162.
100. Tancer ME, Stein MD, Uhde TW. Growth hormone response to intravenous clonidine insocial phobia: Comparison to patients with panic disorder and healthy controls. Biol Psychiatry 1993; 34:591–595.
101. Brambilla F, Perma G, Bellodi L, Arancio C, et al. Noradrenergic receptor sensitivity inobsessive-compulsive disorders: I. Growth hormone response to clonidine stimulation. Psychiatry Res 1997; 69:155–162.
102. Berggren U, Fahlke C, Norrby A, Zachrisson O, Balldin J. Subsensitive alpha2-adrenoceptor
function in male alcohol-dependent individuals during 6 months of abstinence. Drug Alcohol
Dependence 2000; 57(3):255–260.
103. Mueller N, Putz A, Klages U, Hofschuster E, et al. Blunted growth hormone response toclonidine in Gilles de la Tourette syndrome. Psychoneuroendocrinology 1994; 19:335–341.
104. Mokrani M-C, Duval F, Diep TS, Bailey PE, Macher JP. Multihormonal response to clonidine in patients with affective and psychotic symptoms. Psychoneuroendocrinology 2000;
25(7):741–752.
105. C Fahlke, U Berggren, C Lundborg, J Balldin. Psychopathology in alcohol withdrawal:Relationship to alpha2 –adrenoceptor function. Alcohol Alcoholism 1999; 34(5):750–759.
106. Sallee FR, Richman H, Ethurman G, Dougherty D, Sine L, Altman-Hamamdzic S. Clonidine
challenge in childhood anxiety disorder. J Am Acad Child Adol Psychiatry 1998; 37:655–
662.
107. Eriksson E, Balldin J, Lindstedt G, Modigh K. Growth hormone response to the alpha2adrenoreceptor agonist guanfacine and to growth hormone releasing hormone in depressed
patients and controls. Psychiatry Res 1988; 26:59–67.

410

Delgado108. Schittecatte M, Charles G, Machowski R, Wilmotte J. Tricyclic wash-out and growth hormone response to clonidine. Br Psychiatry 1989; 154:858–863.
109. Seiver LJ, Trestman RL, Coccaro EF, Bernstein D, Gabriel SM, Owen K, et al. The growth
hormone response to clonidine in acute and remitted depressed male patients. Neuropsychopharmacology 1992; 6:165–177.
110. Schittecatte M, Charles G, Nefve C, Valentin JG, et al. Long-term downregulatoin of central
adrenoreceptor function by desipramine treatment: a clonidine study in normal subjects. Biol
Psychiatry 1992; 31:856–858.
111. Goodwin GM, Fairburn CG, Cowen P. The effects of dieting and weight loss on neuroendocrine responses to tryptophan, clonidine, and apomorphine in volunteers: Implications forneuroendocrine investigations in depression. Arch Gen Psychiatry 1987; 44:952–957.
112. Matussek N, Ackenheil M, Herz M. The dependence of the clonidine growth hormone teston alcohol drinking habits and the menstrual cycle. Psychoneuroendocrinology 1984; 9:173–
177.
113. Engelman K, Horwitz D, Jequier E, Sjoerdsma A. Biochemical and pharmacologic effectsof α-methyltyrosine in man. J Clin Invest 1968; 47:577–594.
114. Bunney WE, Brodie HKH, Murphy DL, Goodwin FK. Studies of alpha-methyl-para-tyrosine,
L-dopa, and L-tryptophan in depression and mania. Am J Psychiatry 1971; 127:872–
881.
115. McCann UD, Thorne D, Hall M, Popp K, et al. The effects of L-dihydroxyphenylalanineon alertness and mood in α-methyl-para-tyrosine-treated healthy humans: Further evidence
for the role of catecholamines in arousal and anxiety. Neuropsychopharmacol 1995; 13(1):41-52.
116. Pozuelo J. Suppression of craving and withdrawal in humans addicted to narcotics or amphetamines by administration of alpha-methyl-para-tyrosine (AMPT) and 5-butylpicolinic acid(fusaric acid) Cleve Clin Q 1976; 43:89–94.
117. Sweet RD, Bruun R, Shapiro E, Shapiro AK. Presynaptic catecholamine antagonists as treatment for Tourette syndrome. Arch Gen Psychiatry 1974; 31:857–861.
118. Gerlach J, Thorsen K. The movement pattern of oral tardive dyskinesia in relation to anticholinergic and antidopaminergic treatment. Int Pharmacopsychiatry 1976; 11:1–7.
119. Carlsson A, Persoon T, Roose B–E, Walinder J. Potentiation of phenothiazines by α-methyltyrosine in treatment of chronic schizophrenia. J Neural Transm 1972; 33:83–90.
120. Brodie HKH, Murphy DL, Goodwin FK, Bunney WE. Catecholamines and mania: the effectof alpha-methyl-para-tyrosine on manic behavior and catecholamine metabolism. Clin Pharmacol Therapeutics 1970; 12:218–224.
121. Shopsin B, Gershon S, Goldstein M, Friedman E, Wilk S. Use of synthesis inhibitors indeﬁning a role for biogenic amines during imipramine treatment in depressed patients. Psychopharmacol Commun 1975; 1:239–249.
122. Delgado PL, Price LH, Aghajanian GK, Miller HM, Salomon RM, Heninger GR, Charney
DS. Serotonin and the neurobiology of depression: effects of tryptophan depletion in drugfree depressed patients. Arch Gen Psychiatry 1994; 51:865–874.
123. Delgado PL. Are there differences between the role of monoamine systems in the pathophysiology of depression and the mechanisms of antidepressant drug action: evidence from neurotransmitter depletion studies. Eur Neuropsychopharmacol 1997; 7(suppl 2):S77.
124. Delgado PL, Moreno FA. “Noradrenaline Dysfunction in Depression: Implications for Treatment.” Presented at symposium titled, Noradrenaline in Depression, 22nd Annual Meetingof the CINP, Brussels, Belgium, July 10, 2000.
125. Moreno FA, McKnight K, Gelenberg AJ, R Potter, Heninger GR, Delgado PL. Tryptophan
depletion and depressive vulnerability. Biol Psychiatry 1999; 46:498–505.
126. Delgado PL, Moreno FA, Onate L, Gelenberg AJ. Sequential catecholamine and serotonin
depletion in mirtazapine-treated depressed patients. Int J Neuropsychopharmacol 2002; 5:
63–66.

Norepinephrine

411127. Delgado PL, Gelenberg AJ, Moreno F, Laukes C, Strayer L. Tryptophan and 5-HT in psychiatric illness. Adv Exper Med Biol 1996; 398:73.
128. Benkelfat C, Seletti E, Mark A, Dean P, Palmour RM et al. Mood-lowering effects of tryptophan depletion: enhanced susceptibility in young men at risk for major affective disorders.
Arch Gen Psychiatry 1994; 51:687–697.
129. Delgado PL, Moreno FA, Potter R, Gelenberg AJ. Norepinephrine and serotonin in antidepressant action: evidence from neurotransmitter depletion studies. In Briley M, ed. Antidepressant Therapy at the Dawn of the Third Millennium. London: Martin Dunitz Ltd, 1997:
141–163.
130. Leyton M, Young SN, Pihl RO, Etezadi S, Lauze C, Blier P, Baker GB, Benkelfat C. Effects
on mood of acute phenylalanine/tyrosine depletion in healthy women. Neuropsychopharmacol 2000; 22:52–63.
131. Smith KA, Fairburn CG, Cowen PJ. Relapse of depression after rapid depletion of tryptophan.
Lancet 1997; 349:915–919.
132. Loomer HP, Saunders JC, Kline NS. A clinical and pharmacodynamic evaluation of iproniazid as a psychic energizer. Psychiatric Res Rep 1957; 8:129–141.
133. Klein DF, Fink M. Psychiatric reaction patterns of imipramine. Am J Psychiatry 1962; 119:
432–438.
134. Depression Guideline Panel. Depression in primary care: Volume 2: Treatment of major
depression. Technical Report Number 5. Rockville, MD: US Department of Health and Human Resources, Public Health Service, 1993.
135. Kalus, Asnis GM, Rubinson E, Kahn R, et al. Desipramine treatment in panic disorder. J
Affect Disord 1991; 21:239–244.
136. Lydiard RB, Morton WA, Emmanuel NP, Zealberg JJ, et al. Preliminary report: Placebocontrolled, double-blind study of the clinical and metabolic effects of desipramine in panic
disorder. Psychopharmacol Bull 1993; 29(2):183–188.
137. Villarreal G. Desipramine plasma levels and treatment response in panic disorder. Can J
Psychiatry 1995; 40(2):110–111.
138.
139. Goodman WK, Price LH, Delgado PL, Palumbo J, et al. Speciﬁcity of serotonin reuptake
inhibitors in the treatment of obsessive-compulsive disorder: comparison of ﬂuvoxamine anddesipramine. Arch Gen Psychiatry 1990; 47(6):577–585.
140. Leonard HL, Swedo SE, Lenane MC, Rettew DC, et al. A double-blind desipramine substitution during long-term clomipramine treatment in children and adolescents with obsessivecompulsive disorder. Arch Gen Psychiatry 1991; 48(10):922–927.
141. Lelliott PT, Montiero WO. Drug treatment of obsessive compulsive disorder. Drugs 1986;
31:75-80.
142. Reist C, Kauffmann CD, Haier RJ, Sangdahl C, et al. A controlled trial of desipramine in
18 men with posttraumatic stress disorder. Am J Psychiatry 1989; 146:513–516.
143. Dow B, Kline N. Antidepressant treatment of posttraumatic stress disorder and major depression in veterans. Ann Clin Psychiatry 1997; 9:1–5.
144. Bolden-Watson C, Richelson E. Blockade by newly-developed antidepressants of biogenic
amine uptake into rat brain synaptosomes. Life Sci 1993; 52:1023–1029.
145. Ferris RM, Cooper BR. Mechanism of antidepressant activity of bupropion. J Clin Psychiatry
Monogr 1993; 11(1):2–14.
146. Golden RN, James SP, Sherer MA, Rudorfer MV, Sack DA, Potter WZ. Psychoses associatedwith bupropion treatment. Am J Psychiatry 1985; 142:1459–1462.
147. Golden RN, Rudorfer MV, Sherer MA, Linnoila M, Potter WZ. Bupropion in depression.
Arch Gen Psychiatry 1988; 45:139–149.
148. Canive JM, Clark RD, Calais LA, Qualls C, Tuason VB. Bupropion treatment in veteranswith posttraumatic stress disorder: An open study. J Clin Psychopharmacol 1998; 18:379–
383.

412

Delgado149. Emmanuel NP, Lydiard BR, Ballenger JC. Treatment of social phobia with bupropion. J Clin
Psychopharmacol 1991; 11:276–277.
150. Rush AJ, Batey SR, Donahue RMJ, Asher JA, Carmody TJ, Metz A. Does pretreatment
anxiety predict response to either bupropion SR or sertraline? J Affect Disord 2001; 64:81–
87.
151. Trivedi MH, Rush AJ, Carmody TJ, Donahue RMJ, Bolden-Watson C, Houser TL, Metz A.
Do bupropion SR and sertraline differ in their effects on anxiety in depressed patients? J
Clin Psychiatry 2001; 62:776–781.
152. Burrows GD, Maguire KP, Norman TR. Antidepressant efﬁcacy and tolerability of the selective norepinephrine reuptake inhibitor reboxetine: a review. J Clin Psychiatry 1998:59(suppl
14):4–7.
153. Dubini A, Bosc M, Polin V. Do noradrenaline and serotonin differentially affect social motivation and behavior? Eur Neuropsychopharmacol 1997; (7 suppl)1:S49–S55.
154. Versiani M, Cassano G, Perugi G, Benedetti A, Mastalli L, Nardi A, Savino M. Reboxetine,
a selective norepinephrine reuptake inhibitor, is an effective and well-tolerated treatment forpanic disorder. J Clin Psychiatry 2002; 63:31–37.
155. Leonard BE. The comparative pharmacology of new antidepressants. J Clin Psychiatry 1992;
54(suppl 8):3–15.
156. Tulloch IF, Johnson AM. The pharmacologic proﬁle of paroxetine, a new selective serotonin
reuptake inhibitor. J Clin Psychiatry 1992; 53(2 suppl):7–12.
157. Owens MJ, Knight DL, Nemeroff CB. Paroxetine binding to the rat norepinephrine transporter in vivo. Biol Psychiatry 2000; 47:842–845.
158. Finkel MS, Laghrissi-Thode F, Pollock BG, Rong J. Paroxetine is a novel nitric oxide synthase inhibitor. Psychopharmacol Bull 1996; 32:653–658.
159. Montejo AL, Llorca G, Izquierdo JA, Rico-Villademoros F. Incidence or sexual dysfunction
associated with antidepressant agents: a prospective multicenter study of 1022 outpatients.
J Clin Psychiatry 2001; 62(Suppl3):10–21.
160. Nelson JC. A review of the efﬁcacy of serotonergic and noradrenergic reuptake inhibitors
for treatment of major depression. Biol Psychiatry 1999; 46:2301–1308.
161. Tyrer PJ, Lee I, Edwards JG, Steinberg B, Elliot EJ, Nightingale JH. Prognostic factors
determining response to antidepressant drugs in psychiatric out-patients and general practice.
J Affect Disord 1980; 2:149–156.
162. Aberg-Wistedt A. A double-blind study of zimelidine, a selective serotonin uptake inhibitor,and desipramine, a noradrenaline uptake inhibitor, in endogenous depression: I. Clinical ﬁndings. Acta Psychiatr Scand 1982; 66:50–65.
163. Blackwell B. Side effects of antidepressant drugs. In: Hales RE, Frances AJ, eds. Psychiatry
Update: The American Psychiatric Association Annual Review. Washington, DC: American
Psychiatric Press, 1987: 724–745.
164. Muth EA, Moyer JA, Haskins JT, Andree TH, Husbands GEM. Biochemical, neurophysiological, and behavioral effects of Wy-45,233 and other identiﬁed metabolites of the antidepressant venlafaxine. Drug Dev Res 1991; 23:191–199.
165. Feighner J. The efﬁcacy of venlafaxine in major depression and preliminary ﬁndings in thetreatment of refractory depression. J Clin Psychiatry 1993; 54:123–124.
166. Rudolph R, Entsuah R, Aguiar L, Derivan A. Early onset of antidepressant activity of venlafaxine compared with placebo and ﬂuoxetine in outpatients in a double-blind study. Eur
Neuropsychopharmacol 1998;8(suppl 2):S142.
167. Nirenberg AA, Feighner JP, Rudolph R, Cole JO, Sullivan J. Venlafaxine for treatmentresistant unipolar depression. J Clin Psychopharmacol 1994; 14:419–423.
168. Benkert O, Gründer G, Wetzel H, et al. A randomised double-blind comparison of a rapidly
escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia. J Psychiatr Res 1996; 30:441–451.
169. Clerk GE, Ruimy P, Verdeau-Pailles J. A double-blind comparison of a venlafaxine andNorepinephrine

170.

171.

172.
173.

174.
175.
176.
177.
178.
179.
180.
181.
182.
183.
184.
185.
186.

187.

188.

189.

190.

413

ﬂuoxetine in patients hospitalized for major depression and melancholia. Int Clin Psychopharmacol 1994; 9:138–143.
Dierick M, Ravizza L, Realini R, Martin A. A double-blind comparison of venlafaxine andﬂuoxetine for treatment of major depression in outpatients. Prog Neuro-Psychopharmacol
Biol Psychiatry 1996; 20:51–57.
Rudolph RL, Feiger AD. A double-blind, randomized, placebo-controlled trial of once-daily
venlafaxine extended release (XR) and ﬂuoxetine for the treatment of major depression. J
Affect Disord 1998.
Poirier M-F, Boyer P. Double-blind, randomized comparison of venlafaxine and paroxetine
for treatment of resistant depression. Br J Psychiatry 1998.
Rudolph RL, Fabre LF, Feighner JP, Rickels K, Entsuah R, AT Derivan. A randomized,
placebo-controlled, dose-response trial of venlafaxine hydrochloride in the treatment of major
depression. J Clin Psychiatry 1998; 59:116–122.
Derivan A, Entsuah RA, Kikta D. Venlafaxine: measuring the onset of antidepressant action.
Psychopharmacol Bull 1995; 31:439–447.
Zajecka JM, Fawcett J, Guy C. Coexisting major depression and obsessive-compulsive disorder treated with venlafaxine. J Clin Psychopharmacol 1990; 10:152–153.
Rauch SL, O’Sullivan RL, Jenike MA. Open treatment of obsessive-compulsive disorderwith venlafaxine: a series of ten cases. J Clin Psychopharmacol 1996; 16:81-84.
Taryura-Tobias JA, Neziroglu FA. Venlafaxine in obsessive-compulsive disorder. Arch Gen
Psychiatry 1996; 53:653–654.
Grossman R, Hollander E. Treatment of obsessive-compulsive disorder with venlafaxine.
Am J Psychiatry 1996; 153:576–577.
Geracioti TD. Venlafaxine treatment of panic disorder: a case series. J Clin Psychiatry 1995;
56:408–410.
Papp LA, Sinha SS, Martinez JM, Coplan JD, Amchin J, Gorman J. Low-dose venlafaxine
treatment of panic disorder. Psychopharmacol Bull 1998; 34:207–209.
Wilens TE, Biederman J, Spencer TJ. Venlafaxine for adult ADHD. Am J Psychiatry 1995;
152:1099–1100.
Pleak RR, Gormly LJ. Effects of venlafaxine treatment for ADHD in a child. Am J Psychiatry
1995; 152:1099.
Kelsey JE. Venlafaxine in social phobia. Psychopharmacol Bull 1995; 31:767–771.
De Boer TH. The pharmacologic proﬁle of mirtazapine. J Clin Psychiatry 1996; 57(suppl4):
19–25.
Bremner JD. A double-blind comparison of Org 3770, amitriptyline, and placebo in major
depression. J Clin Psychiatry 1995; 56:519–525.
Marttila M, Jaaskelainen J, Jarvi R, Romanov M, Miettinen E, Sorri P, Ahlfors U. A doubleblind study comparing the efﬁcacy and tolerability of mirtazapine and doxepin in patientswith major depression. Eur Neuropsychopharmacol 1995; 5:441–446.
Richou H, Ruimy P, Charbaut J, Delisle JP, Brunner H, Patris M, Zivkov M. A multicentere,
double-blind, clomipramine-controlled efﬁcacy and safety study of Org 3770. Human Psychopharmacol 1995; 10:263–271.
Van Moffaert M, de Wilde J, Vereecken A, Dierick M, Evrard JL, Wilmotte J, Mendelwicz J.
Mirtazapine is more effective than trazodone: a double-blind controlled study in hospitalized
patients with major depression. Int Clin Psychopharmacol 1995; 5:441–446.
Wheatley DP, van Moffaert M, Timmerman L, Kremer CME, and the Mirtazapine-Fluoxetine Study Group. Mirtazapine: efﬁcacy and tolerability in comparison with ﬂuoxetine inpatients with moderate to severe major depressive disorder. J Clin Psychiatry 1998; 59:306–
312.
Fawcett J, Barkin RL. A meta-analysis of eight randomized, double-blind, controlled clinical
trials of mirtazapine for the treatment of patients with major depression and symptoms ofanxiety. J Clin Psychiatry 1998; 59:123–127.

414

Delgado191. Lader M. β-Adrenoreceptor antagonists in neuropsychiatry: an update. J Clin Psychiatry
1988; 49:213–223.
192. Tyrer P. Anxiolytics not acting at the benzodiazapine receptor: Beta blockers. Prog NeuroPsychopharmacol Biol Psychiatry 1992; 16:17–26.
193. Noyes Jr. R. Treatments of choice for anxiety disorders. In: Coryell W, Winokur G, Eds.
The Clinical Management of Anxiety Disorders. New York: Oxford University Press, 1991:
140–153.
194. Price LH, Goddard AW, Barr LC, Goodman WK. Pharmacological challenges in anxiety
disorders. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of
Progress. New York: Raven Press, Ltd., 1995; 1311–1323.
195. Taylor F, Raskind MA. The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder. J Clin Psychopharmacol 2002; 22:
82–85.
196. Carpenter WT. Serotonin now: clinical implications of inhibiting its synthesis with parachlorophenylalanine. Ann Intern Med 1970; 73: 607–629.
197. Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modiﬁcation of Parkinsonism. N Engl J Med 1967; 276(7):374–379.
198. Panksepp J. Towards a general psychobiological theory of emotions. Behav Brain Sci 1982;
5:407–467.
199. Halgren E, Marinkovic K. Neurophysiological networks integrating human emotions. In:
Gazzaniga MS, ed. The Cognitive Neurosciences. Cambridge: MIT Press, 1995: 1137–1151.
200. Rajkowska G. Postmortem studies in mood disorders indicate altered numbers of neurons
and glial cells. Biol Psychiatry 2000; 48:766–777.
201. Stahl SM. Are two antidepressant mechanisms better than one? J Clin Psychiatry 1997; 58:
339–340.
202. Manji HK. G proteins: Implications for psychiatry. Am J Psychiatry 1992; 149:746–760.
203. Racagni G, Tinelli D, Bianchi E, Brunello N, Perez J, cAMP-dependent binding proteinsand endogenous phosphorylation after antidepressant treatment. In: Sandler X, Merton X,
Coppen X, Alec X. 5-Hydroxytryptamine in Psychiatry: A Spectrum of Ideas. New York:
Oxford University Press, 1991: 116–123.
204. Van Bockstaele EJ, Peoples J, Valentino RJ. Anatomic basis for differential regulation of
the rostrolateral peri-locus coeruleus region by limbic afferents. Biol Psychiatry 1999; 46:
1352–1363.
205. Azmitia EC. Serotonin neurons, neuroplasticity, and homeostasis of neural tissue. Neuropsychopharmacol 1999; 21(Suppl2):33S–45S.

17
Benzodiazepines, Benzodiazepine
Receptors, and Endogenous Ligands
WERNER SIEGHART
University of Vienna
Vienna, Austria

I.

PHARMACOLOGICAL AND CLINICAL ACTIONSOF BENZODIAZEPINESThe term “benzodiazepines,” as used in this chapter, includes two properties, namely achemical structure and a certain mechanism of action leading to a characteristic pharmacological proﬁle. Thus it also includes structurally unrelated compounds that have a mechanism of action similar to that of the classic benzodiazepines.
Structurally, benzodiazepines are best considered as derivatives of the prototype
diazepam (Fig. 1A, B). Over the years, more than 3000 benzodiazepine derivatives havebeen synthesized and pharmacologically investigated [1,2]. Approximately 50 benzodiazepines and compounds with a similar mechanism of action have been, or still are, available
as therapeutics worldwide.
The classic benzodiazepines have a characteristic proﬁle of activity by which theycan easily be distinguished from other neuropsychotropic drugs, such as antipsychotics
or antidepressants. They differ in their relative potencies and by the relative prominenceof single components of the proﬁle. Typically, benzodiazepines generally have a low toxicity and there is a wide separation between the lowest pharmacologically active doses andthose producing marked undesired or even fatal effects [3]; they are virtually devoid of
direct actions on cells outside the central nervous system and produce a wide variety ofcentrally mediated effects that can be grouped conveniently into anticonvulsant activity,
behavioral effects related to their clinical antianxiety effect, sedative effects (reduction ofarousal state and attention level, facilitation of sleep, potentiation of effects of other centrally depressant agents, depression of consciousness and production of anterograde amne415

416

Sieghart(A)

Figure 1A

Commercially available benzodiazepines. (From Ref. 1.)

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands(B)

Figure 1B Commercially available benzodiazepines (continued).

417

418

Sieghartsia), modulation of the central control of vegetative functions (autonomic nervous andendocrine systems), reduction of skeletal muscle tone, and impairment of motor coordination [3].
Because of these pharmacological actions, beneﬁcial as well as adverse effects areassociated with the use of benzodiazepines, especially at higher doses. Adverse effects
include amnesia, ataxia, sedation, increase of the effects of ethanol, development of tolerance and physiological dependence, and occurrence of withdrawal symptoms on discontinuation of the drugs. Furthermore, it is precisely because of their positive attributes—
safety, tolerability, and rapid onset of action—that the benzodiazepines may be misusedor abused. While the vast majority of patients are treated correctly, benzodiazepines may
be prescribed inappropriately, for the wrong patients, and/or for the wrong time period.
There is also a small, but deﬁnite, problem of the illegal abuse of benzodiazepines by
those for whom they were not prescribed. Such abuse, however, is usually by those who
already abuse other drugs [4,5].
The reactions to these problems by regulatory authorities in different countries has
led to major variations in the use of benzodiazepines. According to their particular concerns, countries will impose strict or less strict controls on who should receive benzodiazepines and when. The actions they take are related to their culture, their attitudes to psychological problems, their methods of drug prescription and distribution, and so on [5].
Furthermore, in the absence of hard evidence on the beneﬁts and the risks of benzodiazepines in the clinical setting, decisions are often based on the opinions of experts, themedia, and politicians who are either strongly in favor or strongly against their use. Whatis required is ﬁrm evidence of the real scenario regarding benzodiazepines in society,examining both the data on the beneﬁts to the millions of anxiety sufferers and the true
extent of misuse and abuse—and the costs of that to society [5].
A.

Anticonvulsive Actions

Benzodiazepines are the most potent known anticonvulsants. They are effective in virtually
all forms of spontaneous (genetic), chemically, or electrically induced forms of epileptiform activity [6]. It is assumed that benzodiazepines predominantly act by inhibiting the
spread of paroxysmal activities, but stabilization of overexcited neurons in the epileptic
focus might also be of importance. Benzodiazepines are especially potent in model systems
where seizures, are elicited by a suppression of GABAergic inhibition, such as the pentylenetetrazole-induced seizures or seizures elicited by inhibitors of GABA synthesis (thiosemicarbazide). In these models, the activity of benzodiazepines correlates very well with
their afﬁnity for the benzodiazepine receptor (see below) and their potency in humanpatients.
They are much less potent in inhibiting strychnine-induced seizures or seizures elicited by supramaximal electroshock. The potency of benzodiazepines in the latter model
does not correlate at all with their afﬁnity for the benzodiazepine receptors and the anticonvulsive effects in this model might thus not be produced by these receptors [7]. Benzodiazepines are also potent anticonvulsants in a variety of human epilepsies. They are the drugs
of ﬁrst choice for status epilepticus and convulsions due to drug poisoning, and are effective in 80% of cases [8]. Unfortunately, however, the anticonvulsant action of the benzodiazepines in humans as well as in animal experiments is reduced over time because oftolerance development, and thus their long-term therapeutic application against epilepsy
is limited.

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

419

B. Anxiolytic Actions
The anxiolytic action of benzodiazepines usually is investigated in anticonﬂict tests inanimal experiments. There are a variety of different anticonﬂict tests and these tests areusually based on measuring reactions to punished spontaneous or learned behavior. Benzodiazepines over a wide dose range enhance the number of punished responses of the animals without inﬂuencing unpunished behavior [3,7]. This speciﬁc action of benzodiazepines can also be observed with barbiturates in a small-dose range and with thetranquilizers meprobamate and metaqualone, but not with neuroleptics and antidepressants. Benzodiazepines are also active in other test procedures such as the “social interaction test” and positively enhance exploratory behavior in an unfamiliar surrounding (testfor neophobia, see Ref. 3).
The relatively selective effect on anxiety is probably related to the fact that benzodiazepines suppress activity in many limbic and other brain areas involved in anxiogenesis,
including the septal area, amygdala, hippocampus, hypothalamus, locus coeruleus, andraphé nuclei. They also decrease the turnover of acetylcholine, noradrenaline, serotonin,and dopamine in these areas. Suppression of noradrenergic and/or serotonergic pathways
appears to be of particular importance in relation to anxiolytic effects [8].
In addition to the anxiolytic action of benzodiazepines these drugs might also be
involved in the reduction of the hyperactivity of the vegetative nervous system [9]. Benzodiazepines reduce the secretion of peripheral stress parameters such as catecholamines or
cortison and reduce stress-induced stomach ulcera. Thus, these drugs might also be beneﬁcial in the treatment of cardiovascular and gastrointestinal disturbances caused by psychosomatic disorders. It is not clear, however, whether these drugs modulate stress andanxiety only, or in addition have beneﬁcial effects on the accompanying somatic diseases.
The anxiolytic and stress-reducing action of the benzodiazepines is the pharmacological basis for the widespread therapeutic use of these drugs in treatment of anxiety, stress,
tension, and excitation. Anxiolytic effects are exerted in doses that cause minimal sedation,although the hypnotic, muscle relaxant, and perhaps amnesic actions may all contributeto relief of associated tension and insomnia [8]. The major clinical advantage of benzodiazepines as anxiolytics is the rapid onset of action, usually apparent after a single dose. This
immediate effect contrasts with the delayed anxiolytic effects of antidepressants, buspirone, and psychological treatments. In addition, benzodiazepines are relatively nontoxic
and safer than most of the alternative drugs [8]. Unpleasant side effects such as indifference, distance from reality, or reduced effects, which are sometimes observed, might be
explained by an overreduction of anxiety, but the sedative component of the benzodiazepine action might also be involved [7].
The anxiolytic action of benzodiazepines might also be responsible for the antiaggressive activity of these drugs in various animal models. It is assumed that benzodiazepines do not reduce aggression per se but are only active when aggression is caused byanxiety [7]. Under certain conditions, however, when aggression is suppressed by anxiety
or social subordination, benzodiazepines can also induce aggression. Such mechanisms
might explain the relatively rarely observed paradoxical induction of aggressive behavior
in humans by benzodiazepines [7,8].
C. Sedative-Hypnotic Actions
The sedative-hypnotic activities of the benzodiazepines can be studied in animal experiments by investigating the exploratory behavior or the prolongation of sleep time caused

420

Sieghartby these drugs. In addition, benzodiazepines improve the quality of disturbed sleep inanimals and humans. Benzodiazepines, in general, hasten sleep onset, decrease nocturnal
awakenings, increase total sleeping time, and often impart a sense of deep, refreshing sleep[8]. They do, however, alter the normal sleep pattern: stage 2 (light sleep) is prolonged andmainly accounts for the increased sleeping time, while the duration of slow-wave sleep
and rapid eye movement (REM) sleep may be considerably reduced. The onset of the ﬁrst
REM sleep episode is delayed and dreaming is diminished [8]. The suppression of the
REM sleep may initially be helpful in decreasing nightmares, but may also be an importantfactor in determining rebound insomnia in drug withdrawal.
The typical changes in sleep stages occur with most benzodiazepines in most patients, but individual variations in response are considerable and are inﬂuenced by dosage,
duration of treatment, type of benzodiazepine, age and clinical state. The increase in total
sleeping time appears to be greatest in patients who complain of insomnia and in thosewith short baseline sleep duration [8].
The sedative-hypnotic activities of the benzodiazepines are also responsible for theunwanted side effects of these drugs, such as sedation during the day, somnolence, andreduced attention and reactivity. In contrast, even high doses of benzodiazepines do not
produce narcosis. Thus, benzodiazepines alone in contrast to barbiturates, cannot be usedas narcotics.
D.

Amnesic Actions

Although benzodiazepines cannot directly cause narcosis, they are frequently used as apremedication for anesthesia to sedate the patients. Especially with intravenous application
anterograde amnesia often can be observed [7,8]. This effect might be beneﬁcial, for instance, when applied as premedication for endoscopy, where the patients, although having
been awake, cannot remember the unpleasant procedure. Amnestic effects can also be
observed in animal experiments. However, in these animal experiments as well as in patients, a reduction in cognitive abilities rather than true amnesia is probably produced.
These effects can be used to test for compounds that might possibly improve cognitive
abilities.
E.

Central Muscle Relaxation

It is not easy to verify the central muscle relaxant activities of the benzodiazepines because
the simultaneous reduction in vigilance caused by these drugs also can elicit changes inmuscle tonus. Nevertheless, a variety of experimental tests have conﬁrmed the central
muscle relaxant activities of benzodiazepines [6]. These effects seem to be produced bydampening of supraspinal activatory inﬂuences on motor neurons and by inhibition ofpolysynaptic reﬂexes or enhancement of presynaptic inhibition at the spinal level. Ataxia
caused by high doses of benzodiazepines might also be caused by a direct inﬂuence of
these drugs on cerebellar circuits.
The muscle relaxant activity of the benzodiazepines can sometimes be used in avariety of motor disorders. These include a range of dystonias and involuntary movements,
myoclonus, akithesia, restless legs syndrome, and muscle spasm associated with pain.
However, tolerance develops with long-term use and the drugs are not always effective
and may give rise to withdrawal problems [8].
But the muscle relaxant activity of the benzodiazepines is also the cause of severeside effects, such as muscle weakness and disturbed walking, and therefore should not beBenzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

421

used in patients with myasthenia or ataxia. Disturbance of walking and subsequent falls
with risk of bone fractures can be caused by overdosage of benzodiazepines and are especially dangerous in old patients [7]. Muscle relaxation by benzodiazepines might also
cause a disturbance of breathing [8]. A direct inﬂuence of benzodiazepines on breathingis usually only observed with very high, nontherapeutic doses of these drugs. Like otherdrugs that depress respiration, they should be avoided in patients with severe chronic
obstructive airways disease [8].
F.

Toxic Actions

Benzodiazepines exhibit an extremely low toxicity. Lethal doses of benzodiazepines forlaboratory animals are extremely high with ED50 values in the range of many 100 mg/kg[6]. Clinical experiences over the last 30 years also indicate that lethal benzodiazepine
intoxication is extremely rare and in most cases occurs because of secondary factors, suchas undercooling, or because of a combined treatment with other centrally active drugs or
ethanol [4]. Some toxicological effects of benzodiazepines in laboratory animals, such as
their lethal actions, are not correlated with their afﬁnity for the benzodiazepine receptors
and might thus be due to toxic effects at very high doses caused by mechanisms presently
not known [6].
G.

Plasma Levels and the Pharmacokinetic–Pharmacodynamic
RelationshipThe relationship between plasma levels of benzodiazepines, free benzodiazepine concentration, and receptor occupation in the brain has been extensively investigated [10–12].
These investigations clearly demonstrated that the free plasma concentration, which is inequilibrium with the benzodiazepine concentration in the brain, determines the extent ofbenzodiazepine receptor occupation. And the extent of receptor occupation determines
the pharmacodynamic action of the benzodiazepines. Although different doses are neededfor different benzodiazepines to elicit speciﬁc actions, these doses are in a clear relationship to the doses necessary for half-maximal occupation of the receptors. In case of thepentylenetetrazole test, for instance, it was demonstrated that for all compounds investigated in the range of their pharmacological ED50 values, receptor occupation is about
25%. In addition, it was also demonstrated that a different extent of occupation of the
benzodiazepine receptors is required for different pharmacological actions. These data
indicate that there is a clear correlation between the receptor occupation and the pharmacological effect and that the classic benzodiazepines exhibit quite similar pharmacologicalinteractions with their receptors [7].
Although in certain tests there is a good correlation between the pharmacokinetic
elimination velocity and the length of the pharmacodynamic action of the benzodiazepines,
this does not hold true for all benzodiazepine effects observed. In many cases, distributionof the drug between brain and peripheral tissues is an important factor that determines
the length of action of benzodiazepines. Thus, it has been demonstrated that the lengthof the hypnotic effect of benzodiazepines does not depend on the pharmacokinetic elimination velocity but is strongly determined by the distribution of the drugs from the brain
into peripheral tissues [11]. These considerations are valid, however, only for the hypnotic
action of benzodiazepines that requires a high concentration of these drugs in the brain.
Hangover effects of benzodiazepines, such as difﬁculties in concentration and fatigue in422

Sieghart

the morning after the use of the drugs, for instance, are inﬂuenced by the elimination halflife of the drug.
H.

Tolerance Development

A variety of studies has demonstrated the development of functional tolerance in animals[13] and humans [4,8] after chronic treatment with benzodiazepines. Development of tolerance is more prominent for the sedative-hypnotic and anticonvulsant properties of the
benzodiazepines than for their anxiolytic actions. Tolerance to the hypnotic effects develops rapidly, sometimes after only a few days of regular use [8]. Although developmentof tolerance against the sedative-hypnotic properties is desirable when benzodiazepines
are used as anxiolytics, the development of tolerance against the anticonvulsive properties
signiﬁcantly limits the use of benzodiazepines in the treatment of epilepsy. The mechanismof tolerance development is not yet well understood, partially because the effects observedin animals not only depend on the drugs used but also on the intensity and duration ofchronic treatment, the time of analysis post-treatment, and the brain area evaluated [14].
But it is generally assumed that tolerance is caused by a downregulation of receptor density
or function.
I.

Addiction, Dependence, Withdrawal

Animal experiments have indicated a weak tendency for self-application of benzodiazepines when these drugs were added to the drinking water. Although self-administrationof these drugs was increased on parenteral injections of the benzodiazepines, it was stillmuch less frequent than self-administration of cocaine, codeine, or barbiturates [15]. Similar results were obtained in double-blind placebo-controlled experiments with probands
for a variety of classic benzodiazepines. Although there was a slight preference for benzodiazepines over placebo, this preference was much less than that of barbiturates [4,15].
Since there were only small differences in preference between different benzodiazepines,
it can be concluded that all benzodiazepines have a low potential for inducing addiction.
Clinical experiences indicate that patients taking benzodiazepines stay with the same doseover years and there is no tendency to increase the dosage.
But, of course, a certain form of physical dependence develops on long-term useof benzodiazepines that is indicated by withdrawal symptoms on abrupt discontinuationof the drug. In animals, this can lead to increased motor activity, tremor, increased muscle
tonus, and seizure susceptibility [4,15]. In humans, rebound anxiety and insomnia, someperceptual and motor disturbances, and sometimes even seizures can occur [4,8]. Chronic
benzodiazepine doses needed to elicit such effects, however, are higher than the relevant
pharmacological ED50 values in the animal species investigated. Potent benzodiazepines
with relatively short elimination half-lives (triazolam, alprazolam, lorazepam) appear tocarry the highest risk of causing problems with dependence [8]. In contrast to classicalbenzodiazepines that presumably exhibit similar potential to cause addiction and dependence, partial benzodiazepine receptor agonists (see below) seem to be less prone to eliciting these effects. It is not yet clear, however, whether this also holds true for patients.
II. BENZODIAZEPINE RECEPTORS
After the discovery of speciﬁc high afﬁnity binding sites for benzodiazepines on brain
membranes [6,17], a wealth of experimental data have accumulated indicating that thesebinding sites are heterogeneous. Most of the benzodiazepine binding sites have been identiﬁed to represent allosteric modulatory sites on γ-aminobutyric acidA (GABAA) receptors.

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

423

Figure 2 Model of the GABA A receptor.
Since there is an excellent correlation between the clinical potency of benzodiazepinesand related compounds and their ability to displace radiolabeled diazepam or ﬂunitrazepam
from these GABAA-receptor-associated binding sites, it is now clear that most, if not all,of the clinically relevant effects of benzodiazepines are mediated by modulating the function of GABAA receptors [1,3,7,14].
In addition to these “central” benzodiazepine receptors (that actually are no receptors, but modulatory binding sites, see Ref. 18), other benzodiazepine binding sites havebeen identiﬁed in several peripheral tissues as well as in the central nervous system[17,19]. These “peripheral” benzodiazepine receptors, although exhibiting high afﬁnity
for some benzodiazepines, are not associated with GABAA receptors. They appear to represent a heteromeric complex of at least three different proteins [20] and there is no signiﬁcant correlation between the clinical potency of benzodiazepines and their afﬁnity for the“peripheral” binding sites. The physiological functions of these sites are not known, butthey might be involved in steroidogenesis, in the regulation of cell proliferation, and in
the adaptation of the organism to stress and brain damage (for review, see Ref. 20).
Finally, “micromolar” benzodiazepine binding sites have been identiﬁed [21] thatdiffer from the central and peripheral benzodiazepine binding sites not only in their much
lower afﬁnity for benzodiazepines but also in their binding properties and kinetic andpharmacological characteristics. Evidence has accumulated that these binding sites areable to modulate Ca2⫹ channel processes [22,23], but probably are not involved in mostof the clinical actions of benzodiazepines.
III. BENZODIAZEPINE MODULATION OF GABAA RECEPTORSGABA is the major inhibitory transmitter in the central nervous system. It is estimatedthat about 30% of all synapses of the brain use GABA as a transmitter [14]. Most of thephysiological actions of GABA are mediated by GABAA receptors. These receptors arecomposed of ﬁve protein subunits forming a central chloride ion channel that can be
opened by GABA (Fig. 2). So far, at least 6α, 3β, 3γ, 1δ, 1ε, 1π, 1θ, and 3ρ subunits havebeen identiﬁed in the mammalian nervous system [18] and, depending on their subunit
composition, receptors exhibit distinct pharmacological and electrophysiological properties [14]. Recent immunocytochemical studies have indicated that individual subunits exhibit a distinct and often widespread distribution throughout the nervous system [24,25].
The resulting expression of multiple subunits in the same neurons suggest the existenceof a large variety of GABAA-receptor subtypes in the brain.
Evidence has accumulated that the majority of the GABAA receptors are composed424

Sieghart

Figure 3 Stoichiometry and subunit arrangement of GABA A receptors. A mirror arrangement is equally possible. BZ or GABA ⫽ site of interaction of benzodiazepines or GABA
with GABA A receptors, respectively.
of 2α, 2β, and 1γ subunit [26]. Minor receptors appear to be pentamers composed of αβδ,
αβε, αβπ, αβ, or homo- and hetero-oligomeric ρ subunits. Because two different α and/or two different β subunits can be present in the same receptor, probably more than 500
distinct GABAA-receptor subtypes do exist in the brain. Their subunit composition andregional and cellular distribution, however, presently are not known. Only recently, methods have been developed that allow the identiﬁcation of the composition and quantitative
importance of receptor subtypes in different brain regions [27]. Because of the widespread
distribution and quantitative importance of the GABA system, even minor GABAA-receptor subtypes probably exhibit an abundance that is comparable to that of some monoamine,
serotonin, or peptide receptors.
A.

Action of GABA on GABAA Receptors

Evidence has accumulated that the GABA binding site of GABAA receptors is located at
the interface between α and β subunits (Fig. 3) [28]. Since there are two α/β interfaces
on GABAA receptors, these receptors contain two more or less equivalent GABA bindingsites. Binding of GABA to both of these sites seems to be necessary to induce the conformational change that leads to the opening of the chloride ion channel integrated into the
GABAA receptor [29]. The direction and strength of the chloride ﬂux depends on themembrane potential and the chloride concentrations on both sides of the membrane. In
most cases, GABA induces an inﬂux of chloride ions and thus a hyperpolarization andan inhibition of the electrical activity of the cell. So far, no GABA binding site ligands
are available that could signiﬁcantly differentiate between different GABAA-receptor subtypes.
B.

Action of Benzodiazepines and Related Ligands on GABAA
Receptors

Benzodiazepines do not bind to the GABA binding site. They bind to a separate site on
GABAA receptors that is present only on receptors containing a γ subunit (Fig. 3). Thisbenzodiazepine binding site is located at the interface between the α and γ subunit of
GABAA receptors [30] and the exact type of the α and γ subunit forming this site strongly
inﬂuences its pharmacological properties [14]. Since there are six different α and threedifferent γ subunits, up to 18 different GABAA-receptor-associated benzodiazepine binding sites do exist in the brain. By binding to these sites, benzodiazepines cause a conforma-Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

425

Figure 4 Partially selective benzodiazepine site ligands. β-CCM: β-carboline-3-carboxylate methylester.

tional change in the receptor that usually enhances GABA-induced chloride ﬂux. These
drugs, however, cannot directly activate the chloride ion ﬂux of GABAA receptors in theabsence of GABA. They are just only modulating ongoing GABAergic activity. This
explains the extremely low toxicity [1,4] of benzodiazepines.
The classic benzodiazepines all have a similar action. This is not surprising because
all these compounds exhibit comparable afﬁnities for the benzodiazepine binding sites ofmost of the benzodiazepine-sensitive GABAA-receptor subtypes in the brain [14]. Theyenhance GABA-induced chloride ﬂux and at relatively low concentrations exhibit anticonvulsant and anxiolytic actions. At higher concentrations they exhibit sedative-hypnotic
and muscle-relaxing effects.
In a search for compounds with a more selective action, many ligands with a benzodiazepine or nonbenzodiazepine structure were identiﬁed that exhibited a high afﬁnity
for the GABAA-receptor-associated benzodiazepine binding site [1,2,18]. Some of thesecompounds exhibited a certain selectivity for GABAA-receptor subtypes (Fig. 4). Thus,
the benzodiazepines quazepam and oxoquazepam, several β-carboline-3-carboxylates, imidazopyridines such as zolpidem or alpidem, or the triazolopyridazine Cl-218872 exhibiteda high afﬁnity for the benzodiazepine binding site of GABAA receptors composed of α1,β, and γ 2 subunits (old nomenclature: type I receptors, BZ1 receptors, ω1 receptors), anda 10 to 15 times lower afﬁnity for the benzodiazepine binding sites of other GABAA
receptors (old nomenclature: type II receptors, BZ2 receptors, ω2 receptors) (see Ref. 18).
It is now clear that the latter type of receptors represents a mixture of many different
receptors. This small selectivity in the binding properties of these compounds, of course,
is not sufﬁcient to avoid coactivation of all the other receptors, and it thus was no surprisethat most of these compounds exhibited properties that were only marginally different
from those of classic benzodiazepines [31,32].

426

Sieghart

Figure 5 Schematic presentation of the various classes of ligands for the benzodiazepine
binding site of GABA A receptors. (Modiﬁed from Ref. 128.)Interestingly, the β-carboline-3-carboxylates exhibited actions opposite to that ofbenzodiazepines although interacting with the benzodiazepine binding site of GABAA receptors. This discrepancy was solved when the efﬁcacy of various benzodiazepine bindingsite ligands for modulating GABAA receptors was systematically investigated. It was demonstrated that some of these ligands, the “benzodiazepine binding site agonists” like theclassic benzodiazepines, cause a conformational change in GABAA receptors that enhances
GABA-induced chloride ion ﬂux (positive intrinsic efﬁcacy). These compounds exhibit
anxiolytic, anticonvulsant, muscle relaxant, and sedative hypnotic properties. Other ligands, the “benzodiazepine binding site inverse agonists” cause a conformational changethat reduces GABA-induced chloride ion ﬂux (negative intrinsic efﬁcacy). These compounds have an action opposite to that of agonists: they produce convulsant, stimulant,
and anxiogenic effects [33,34]. The agonist as well as the inverse agonist actions areproduced via the same (benzodiazepine) binding site, because there is also a third groupof ligands, the benzodiazepine binding site antagonists, that bind with high afﬁnity to the
benzodiazepine binding site of GABAA receptors but have either no or only weak intrinsic
efﬁcacy for changing GABAergic transmission. These compounds, therefore, have no or
only weak intrinsic effects when given to animals or humans, but are able to inhibit theeffects of both benzodiazepine site agonists or benzodiazepine site inverse agonists. Between these extreme actions, compounds were identiﬁed (partial agonists or partial inverse
agonists) with intermediate actions (Fig. 5). Such compounds have less positive or negative
intrinsic efﬁcacy than full agonists or inverse agonists [1,34].

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

427

Figure 6 Partial agonists at the benzodiazepine site.
Partial agonists recently have become quite interesting clinically, because it wasdemonstrated that a different extent of receptor occupation is necessary to elicit the anxiolytic, anticonvulsant, muscle relaxant, and sedative-hypnotic effects of benzodiazepines[35,36]. Thus, full agonists are able to elicit their anxiolytic and anticonvulsant effects at a
relatively low receptor occupancy. Since partial agonists only weakly enhance GABAergictransmission, they need a higher receptor occupancy to elicit comparable effects. To elicit
muscle relaxant and sedative effects, however, full agonists require a higher receptor occupancy. Because of their weaker enhancement of GABAergic transmission, partial agonists
no longer can elicit muscle relaxant and sedative effects with comparable strength andthus exhibit less side effects than full agonists [35,36].
Some partial agonists, such as bretazenil (Fig. 5) or abecarnil (Fig. 6), raised highhopes because in animal experiments they acted as potent anxiolytics and anticonvulsantswithout tolerance development and sedation and little potentiation of alcohol intoxication.
In clinical experiments, however, these compounds were disappointing because of side
effects, particularly sedation [32]. Imidazenil (Fig. 6), a compound related to bretazenil
but not yet clinically tested, produced a preclinical proﬁle similar to bretazenil but unlike
diazepam, did not produce amnesia at dosage levels with maximal anticonvulsant efﬁcacy[31]. It is unclear at present why the pharmacological proﬁle of these compounds should
be unfavorable in humans.
Some newer benzodiazepine site ligands, L-838.417 [37] or SL-651.498 (Fig. 6)[38], exhibit an even more restricted action on various GABAA-receptor subtypes and inanimal experiments again exhibit predominantly anxiolytic, but no sedative actions. The
investigation of their clinical effects is eagerly awaited.
Benzodiazepine binding-site agonists, inverse agonist, or antagonists were identiﬁed428

Sieghartin each class of compounds interacting with the benzodiazepine binding site of GABAA
receptors. In addition, it was demonstrated that the efﬁcacy of compounds for activating or
inhibiting the function of GABAA receptors differs for different GABAA-receptor subtypes.
Thus, a compound can be a full agonist for a certain receptor and a partial agonist or evenantagonist for other receptor subtypes. The degree of partial agonism also can vary between different receptor subtypes [31,39], although the compound might exhibit a similar
afﬁnity for all of them! The often observed slightly different spectrum of action of different
benzodiazepines can thus be explained by a difference in their ability to activate various
GABAA-receptor subtypes.
C.

Action of Other Compounds on GABAA Receptors

In addition to benzodiazepines, a variety of pharmacologically and clinically important
drugs such as barbiturates (phenobarbital, pentobarbital), neuroactive steroids (progesterone and deoxycorticosterone metabolites), anesthetics (propofol, halothane, isoﬂurane,
chloralhydrate), and convulsants have been demonstrated to produce at least part of theirclinically relevant effects by interacting with allosteric binding sites on GABAA receptors[14]. In addition, other compounds such as avermectin, γ-butyrolactones, etazolate, etomidate, chlormethiazole, Zn2⫹, La3⫹, antidepressant drugs such as amoxapine and mianserine[40,41], or antipsychotic drugs such as clozapine and olanzapine [42] are acting on thesereceptors [14,43]. The exact number of different allosteric modulatory sites present on
GABAA receptors and their location currently is not known. Binding of any of these drugs
again causes a conformational change in the structure of GABAA receptors and, by this,enhances or reduces GABA-induced chloride ion ﬂux. This comparable mode of action
explains the synergistic effects of all these centrally depressant drugs with benzodiazepines
as observed in clinical studies.
In addition to their GABAA-receptor modulatory activity and in contrast to benzodiazepines, barbiturates, neuroactive steroids, anesthetics, etazolate, etomidate, or chlormethiazole at higher concentrations are also able to directly activate the chloride ion channel of GABAA receptors in the absence of GABA. These drugs, therefore, exhibit a muchhigher toxicity than benzodiazepines [14].
Ethanol shares some properties with barbiturates and benzodiazepines, because it
exhibits anxiolytic, anticonvulsant, and sedative-hypnotic activity. A development ofcross-tolerance among these compounds has also been observed [44]. Other evidence indicates that ethanol is able to potentiate GABAergic transmission in at least some neuronalsystems (for review, see Refs. 14, 45) and might thus mediate part of its pharmacologicaland toxicological effects via GABAA receptors. The exact mode of action of ethanol on
GABAA receptors, however, so far could not be determined.
IV. ENDOGENOUS LIGANDSA.

Endogenous Ligands Acting via the Benzodiazepine Binding Site

A variety of evidence indicates that benzodiazepine binding site antagonists, previously
described as intrinsically inactive, are able to induce effects in animals and humans underparticular circumstances [46]. Although these effects, for instance, also could be explainedby a possible dependence of the antagonist efﬁcacy on the previous activity of GABAA
receptors or its state of phosphorylation [47], alternatively, endogenous agonists or inverse

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

429

agonists might exist and modulate the function of these receptors. A variety of brain
disorders, such as anxiety, insomnia, epilepsy, spasticity, alcoholism, coma, or dementia
may then be associated with a disequilibrium of opposing endogenous benzodiazepinesite ligands changing the excitability of neurons implicated in these diseases [46].
Over the years, several endogenous ligands [48] acting at the benzodiazepine binding site of GABAA receptors (endozepines) have been discovered, although a possible
physiological function of none of these compounds so far has been deﬁnitely established.
Thus, the purines inosine and hypoxanthine inhibit diazepam binding with IC50 values 400
to 1300 µM and 700 to 3700 µM, respectively [49]. Similarly, adenosine [50] and Sadenosylhomocysteine [51] can inhibit benzodiazepine binding. Concentrations needed
for these effects, however, seem to be high compared to the endogenous concentrationsof these compounds [52].
The following three groups of substances are currently thought to be the most likely
endozepine candiates: diazepam binding inhibitor (DBI) and/or its processing products
being the only peptides among them [53]; n-butyl-β-carboline-carboxylic acid ester [54];and benzodiazepine-like compounds [55,56]. Experimental evidence suggests that DBI
and n-butyl-β-carboline esters are inverse agonists, whereas benzodiazepine-like substances are agonists at the benzodiazepine binding site of GABAA receptors. All theseagents were isolated from the brain of various mammals including humans, but they havebeen shown to fulﬁll the criteria for modulators of GABAergic inhibition to various degrees [46].
To date, only DBI and its smaller fragment, octadecaneuropeptide, were found colocalized and coreleased with GABA from neurons [57]. Both DBI and n-butyl-β-carbolinecarboxylic acid ester induced anxiogenic and proconvulsant effects that were antagonizedby the benzodiazepine binding-site antagonist ﬂumazenil (Fig. 5) [53,54]. Whereas nbutyl-β-carboline-carboxylic acid ester binds to the benzodiazepine binding site of GABAA
receptors with high afﬁnity, DBI is a ligand with intermediate afﬁnity. DBI is, however,
sufﬁciently concentrated in the brain to activate GABAA receptors. Interestingly, DBI andsome of its processing products bind also to the “peripheral” benzodiazepine binding sites
in the brain and in endocrine tissues, where they promote the synthesis of neurosteroids
and thereby indirectly affect GABAA receptors [46].
In the case of benzodiazepine-like substances, some of which are indeed benzodiazepines (diazepam, desmethyldiazepam), their endogenous source has still not been provensince both plants and gut microorganisms synthesize them [56], perhaps contributing toan environmental-based relaxed behavior. Some experimental data nevertheless suggestthat mammalian cells may synthesize similar, not yet identiﬁed substances, which arereleased from neurons, block convulsions elicited by the GABA antagonist bicuculline,
and enhance GABA-mediated currents in neurons [46].
B. Increase of Endogenous Ligands in Neuropsychiatric Diseases
Several lines of evidence indicate that endogenous benzodiazepine binding site ligands
can be found enriched in neuropsychiatric diseases. For instance, hepatic encephalopathy
is clearly associated with increased levels of endogenous benzodiazepines such as diazepam, desmethyldiazepam, and other benzodiazepine-like substances in plasma, urine, CSF,
and brain of patients [58], and these compounds play a role in the pathophysiology ofthis syndrome by potentiating the GABA-induced CNS depression. Flumazenil, the only

430

Sieghartbenzodiazepine site antagonist studied in detail, rapidly alleviates the symptomatology ofhepatic encephalopathy, induces arousal from coma, responding to stimuli, and awarenessof the environment without leading to noticeable adverse effects [58].
Coma from other origin was also reported to respond favorably to ﬂumazenil. For
example, ﬂumazenil transiently reversed comatose states due to alcohol, carbamazepine,
baclofen, halothane, chloralhydrate, and cannabis intoxication [59–62]. Since ﬂumazenil
is a selective benzodiazepine site antagonist, the most parsimonious explanation of these
unexpected therapeutic effects would be antagonism of a coma-related activation of endogenous benzodiazepine agonists.
In addition, it has been demonstrated that another brain disorder, the idiopathic recurrent stupor, is associated with a large increase of endogenous benzodiazepine bindingsite agonists [63]. In a case of idiopathic recurrent stupor, both the prompt abolition by
ﬂumazenil of the stupor episodes and a dramatic increase of endogenous benzodiazepineagonists during these attacks in CSF and plasma of the patient indicated an involvementof endogenous benzodiazepine agonists in the pathogenesis of this rare disorder [64].
In some other neuropsychiatric diseases apparently inverse agonists predominate.
For instance, DBI was elevated in the CSF of depressed patients with pronounced anxiety[65]. This anxiety might have been directly induced by DBI because it is known that
inverse agonists can induce anxiety [66]. Similarly, late-onset alcoholic patients with anxious personality had increased CSF levels of DBI when compared to early-onset alcoholics
demonstrating antisocial personality and a genetic predisposition [67]. Release of an endogenous benzodiazepine inverse agonist during withdrawal from ethanol was also suggested by the ﬁnding that ﬂumazenil was able to diminish alcohol withdrawal symptoms,
such as tremor, sweating, nausea, anxiety, depression, and restlessness [68].
A recent demonstration of increased levels of a less well-characterized endogenous
benzodiazepine site ligand in the plasma of anxious and depressed patients, as well as instressed healthy volunteers, suggests its involvement in processes related to stress and/or
anxiety [59,69,70]. If elevated, DBI in CSF produces a reduced GABAergic function, thendepression as well as alcoholism coupled to anxiety might possibly be associated with adownregulated GABAA-receptor function, in certain brain areas.
All these results would be consistent with the proposal [46] that endogenous benzodiazepine binding-site ligands are at least partially colocalized with GABA in neurons
and coreleased with it in response to deﬁned stimuli according to the spatiotemporal organization of particular neuronal circuits. Endogenous benzodiazepine agonists would thenincrease and inverse agonists decrease the effect of GABA upon GABAA receptors, leading
to enhanced or reduced inhibition of postsynaptic neurons, respectively. Depending on
arrangements of GABAergic neurons in various CNS regions and their roles in integrating
behavioral patterns, a disequilibrium of endogenous benzodiazepine ligands with a preponderance of either agonists or inverse agonists would ultimately contribute to different
levels of excitability of GABA-receptive neurons that may be critically implicated in theexpression of CNS disorders [46].
Since it was shown that the release of a peptidergic cotransmitter is increased uponhigher frequency stimulation of presynaptic neurons while that of the principal transmitterremains the same through a range of stimulation frequencies [71], at least in the case of
DBI and its metabolites it may be assumed that enhanced neuronal ﬁring of GABAergic
neurons would release higher amounts of the peptides, thus reducing the inhibitory effectof coreleased GABA and further increasing neuronal excitability. Such a mechanism mightalso contribute to the genesis of epilepsy. Flumazenil exhibits a moderate antiepileptic

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

431

activity [72–74], which may have been underestimated because of short half-life and low
bioavailability of this drug.
C. Endogenous Ligands Acting via Other Sites of GABAA Receptors
As mentioned above, a variety of endogenous neuroactive steroids (progesterone anddesoxycorticosterone metabolites) can allosterically modulate the function of GABA on
GABAA receptors [14,75]. There are regional differences in the sensitivity of GABAA
receptors to modulation by neuroactive steroids [76], and the effects of neuroactive steroids are dependent on the subunit composition of the GABAA receptor [77]. The locationof these sites on GABAA receptors currently is not known. Since steroids at higher concentrations can directly activate the GABAA-receptor-associated chloride channel, presumably
more than one speciﬁc steroid binding site is present on these receptors. In addition tosteroids that can enhance the actions of GABA on GABAA receptors, other steroids, suchas pregnenolone sulfate, allosterically reduce the actions of GABA on these receptors[14,75].
Some steroids, such as the progesterone metabolites pregnanolone (3α-hydroxy-5βpregnan-20-one) and allopregnanolone (3α-hydroxy-5α-pregnan-20-one), are synthesizedin the brain and their concentration varies depending on the hormonal situation (estrous
cycle) of the individual [78]. From animal studies, it is known that these metabolites
exhibit anxiolytic, hypnotic, and anticonvulsant effects. Their withdrawal during the estrous cycle might contribute to the symptoms of premenstrual syndrome, such as anxiety
and seizure susceptibility [79]. Reduced concentrations of these steroids might also contribute to postpartum or postmenopausal dysphoria [80].
In addition to these direct effects of steroids on GABAA receptors, indirect effects
via genomic receptors also seem to occur. Thus, estrogens regulate GABAA-receptor subunit mRNA expression in regions of the female rat brain known to contain estrogen receptors [81].
Since allopregnanolone has a poor oral availability, a new synthetic neuroactive
steroid ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) has been developed andis currently under clinical trials. It is a potent and efﬁcacious anticonvulsant agent for the
management of generalized absence and partial seizures [82] as well as for convulsions
due to cocaine poisoning [83]. Recently, it was reported that ganaxolone is superior tovalproate, ethosuximide, clonazepam, diazepam, and phenobarbital in preventing the pentylenetetrazole-induced convulsions and the behavioral effects of pentylenetetrazole including its depressant effects on locomotor activity and rearing in mice, thereby suggestingthat ganaxolone may provide additional beneﬁts in the treatment of epilepsy by controlling
anxiety, mood changes, and other behavioral alterations associated with preseizure activity[84].
Other steroids such as allotetrahydrodeoxycorticosterone (5α-THDOC) are synthesized in the adrenal gland, although this compound is found in the brain where its concentration is increased during stress [85]. 5α-THDOC is one of the most potent known steroid
modulators of GABAA receptors and, thus, can directly modulate the function of thesereceptors via the steroid binding site. In addition, steroids produced in the adrenals directly
or indirectly inﬂuence the expression of GABAA-receptor subunits in the brain, as shownby adrenalectomy [86]. This indicates that GABAA-receptor function is under constantregulation by such steroids.
Other hormones, such as the thyroid hormones, also directly [87–89] or indirectly432

Sieghart[90,91] modulate the function of GABAA receptors. Although somatostatin-14, a biologically active tetradecapeptide, is known to mediate its biological actions through the Gprotein-coupled membrane receptors [92]; its direct interaction with the GABAA-receptor
complex has also been reported [93,94]. Similarly, melatonin has been reported to interact
directly with GABAA receptors [95,96]. Because this effect was observed already at nanomolar concentrations of melatonin, an interaction of melatonin with GABAA receptors
might have some physiological signiﬁcance.
In addition, neuronal growth factors such as neurotrophin-3 [97] or platelet-derived
growth factor [98] seem to be able to directly or indirectly inhibit the function of GABAA
receptors. A low-molecular-weigth factor released from astrocytes is also able to negatively modulate the function of GABAA receptors [99]. This factor seems not to act via
the benzodiazepine binding site because its effect could not be blocked by ﬂumazenil.
In addition, polyamines, such as spermine, spermidine, and putrescine, or arachidonic acid and fatty acids are able to modulate the function of GABAA receptors [14].
Cis-9,10-octadecenoamide, a fatty acid primary amide that accumulates in the CSF of
sleep-deprived cats and may represent a novel signaling molecule, has also been demonstrated to modulate the function of GABAA receptors. This compound might be involvedin the regulation of arousal and has been implicated in the circadian control of physiological sleep [100].
Imidazoleacetic acid is normally present in the brains of rats and humans as wellas in human CSF. This compound is a full agonist at the GABA binding site of GABAA
receptors and can be synthesized from minute quantities of histamine in the brain. Its
central administration induces a host of centrally mediated effects, including sedation andhypnosis (for review, see Ref. 101). This compound might be involved in a novel mechanism for interactions between histamine and the GABAergic system.
Normal human urine contains inhibitory activity for the enzyme monoamine oxidase(MAO). It has been tentatively termed tribulin and it has been speculated that tribulin
might be related to an endogenous anxiety factor acting via the benzodiazepine receptor
and bearing structural similarities to β-carbolines [102]. Subsequently, it has been established that tribulin consists of several low-molecular-mass fractions that exhibit four
known bioactivities: monoamine oxidase A and B inhibitory activities and peripheral andcentral benzodiazepine receptor-binding-inhibitory activities [103]. The compounds involved in these activities seem to be differentially distributed in the brain of rats and theirlevel is increased in both human urine and rat tissues by stress or anxiety, and by anxiogenic drugs [104]. Further studies have to be performed to clarify the function of thecompounds contributing to tribulin.
The intracellular loops of several subunits of the GABAA receptor contain consensus
sequences for phosphorylation by various protein kinases [14]. Such phosphorylation directly modulates the function of GABAA receptors and the detailed effects probably depend on the subunit composition of the individual receptor subtypes. Several different
kinases have been identiﬁed to modulate the function of GABAA receptors and the effectsof phosphorylation are the subject of intensive investigation [14,105–107]. The identityof the corresponding phosphatases so far has been much less investigated. Because thevarious enzymes involved in phosphorylation and dephosphorylation of GABAA receptors
could be activated by many different transmitter and second-messenger systems, this offers
the possibility of short- and long-term modulation of GABAA-receptor function by othertransmitter systems, hormones, or growth factors. Furthermore, it should be stressed that

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

433

Table 1 Endogenous Ligands Acting on GABAA Receptors
Refs.
Ligands acting at the benzodiazepine site:
DBI
β-carbolines
benzodiazepines
Ligands acting at other sites:
neuroactive steroids
thyroid hormones
somatostatin
melatonin
neurotrophin-3
platelet-derived growth factor
polyamines, arachidonic acid, fatty acids
imidazoleacetic acid
tribulin
Ligands indirectly modulating GABAA receptors via
protein phosphorylation
various transmitters and modulators

53
54
55, 5614, 75
87–89
93, 9495, 9697
98
14, 100
101
102–104

105–107

drugs interfering with these regulatory mechanisms could inﬂuence the GABAergic system and could lead to speciﬁc GABAergic effects.
Endogenous ligands modulating GABAA receptors are summarized in Table 1. The
accumulated data indicate that the function of GABAA receptors is highly regulated by avariety of ligands and signals and can thus be immediately adjusted to the physiologicalrequirements of the individual.

V.

FUNCTION OF GABAA-RECEPTOR SUBTYPES

Although a large variety of allosteric binding sites have been identiﬁed on GABAA receptors, only a few compounds have been discovered so far that exhibit a certain receptor
subtype selectivity (see Sec. III). Their selectivity, however, is not sufﬁcient to allow aselective modulation of a single receptor subtype and, thus, to determine its function in
the brain.
Several attempts have been made to identify the function of receptor subtypes bygenerating mouse lines in which the gene encoding for a certain GABAA-receptor subunit
was inactivated. A knockout of γ 2-subunits was lethal [108], possibly at least in part because the γ 2-subunit is required for synaptic clustering of GABAA receptors [109]. By
contrast, mice heterozygous for the γ 2-subunit knockout developed and behaved normally.
The synaptic clustering of GABAA receptors was only partly reduced (about 15–30%,
depending on the brain region); the unclustered receptors consisted of α- and β-subunits.
When exposed to certain fear-inducing stimuli, these animals showed a striking diseasephenotype with a high anxiety response to natural and learned aversive stimuli, as wellas cognitive bias for threat cues [110]. This indicates that a reduction in the number of
GABAA receptors containing γ2-subunits might cause a predisposition for anxiety and is434Sieghart

consistent with the fact that benzodiazepines produce their anxiolytic action by interactingwith GABAA receptors containing a γ-subunit [14].
A knockout of the α 6-subunit, which is expressed more or less exclusively in the
cerebellar granule cells, did not result in an overt phenotype [111]. However, the α 6 knockout mice were more sensitive to the motor-impairing action of diazepam in an acceleratingrotarod test than their wild-type counterparts [112]. Although disruption of the gene encoding the β 3 or δ-subunit produced mice with an epileptic phenotype [113] or an attenuatedsensitivity to neuroactive steroids [114], respectively, a possible change in the development and function of the brain, as well as changes in the expression of other receptors
or ion channels caused by the lack of these receptors could not be excluded.
In a more subtle attempt to identify the function of receptors that contain speciﬁc
α-subunits, a new genetic approach was recently developed [115]. This approach was
based on introducing a point mutation (His101Arg) into the α 1-subunit of GABA A receptors, rendering α 1-containing receptors insensitive to allosteric modulation by diazepam
without altering their GABA sensitivity. In the absence of any change in signal intensity
produced by the mutated receptors, animals possessing this mutation developed normallyand the cellular and subcellular location of receptors was unchanged. In these animals,
therefore, diazepam mediated its effects through only the α 2-, α 3-, and α 5-subunit-containing receptors, because receptors containing α 4- or α 6-subunits are insensitive to diazepam [14]. A comparison of drug-induced behavioral responses in α 1(His101Arg) mutant
and wild-type mice then allowed the identiﬁcation of diazepam effects that are missing
in mutant mice and, thus, to determine the contribution of α 1-containing receptors to theeffects of diazepam. It was demonstrated that α 1(His101Arg) mutant mice failed to show
the sedative, amnesic, and, in part, anticonvulsant actions of diazepam. By contrast, theanxiolytic-like, myorelaxant, and ethanol-potentiating effects were fully retained, whichindicates that these effects are produced via the nonmutated GABA A receptors that contain
α 2-, α 3-, or α 5-subunits [115]. Using a similar approach, most of these ﬁndings wereconﬁrmed by a different group [37]. The small discrepancies between these studies could
be explained by differences in the test procedures applied [38].
In subsequent studies, the function of α 2- or α 3-subunit containing receptors inthe brain was investigated. For this, point mutations were introduced into α 2- or α 3subunits at positions homologous to that of α1His101 [116]. However, in α 3(His126Arg)
mice the anxiolytic activity of diazepam, as tested by the light-dark choice test and theelevated plusmaze test, was not impaired compared with wild-type mice. By contrast, in
α 2(His101Arg) mice, the anxiolytic activity of diazepam was absent [116]. Thus, the anxiolytic activity of diazepam seems to be mediated by neurons expressing α 2-containing
receptors. This ﬁnding is consistent with the expression of α 2-subunits in brain areas thatare associated with emotional stimulus processing [24,25]. Thus, α 2-containing receptors
are abundant in the central nucleus of the amygdala. In addition, these receptors aredensely packed on the axon initial segment of principal cells of the cerebral cortex andthe hippocampus bringing their output activity under GABA-mediated control [117,118].
Given that α 2-containing receptors constitute only about 15% of diazepam-sensitive
GABA A receptors, ligands selective for α 2-containing GABA A receptors would be expected to show a much reduced side-effect proﬁle. Such agents would be highly selective
drugs compared with the nonselective benzodiazepines in clinical use.
To identify the GABA A-receptor subtypes mediating the action of diazepam on muscle tone, in a subsequent study, the myorelaxant properties of diazepam were investigatedin these α 2 or α 3-point mutated mice [119]. Whereas in α 2(His101Arg) mice the myorelax-

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

435

ant action of diazepam was almost completely abolished at doses up to 10 mg/kg, thesame dose induced myorelaxation in both wild-type and α 3(His126Arg) mice. It was only
at a very high dose (30 mg/kg diazepam) that α 2(His101Arg) mice showed partial myorelaxation and α 3(His 126Arg) mice were partially protected from myorelaxation comparedwith wild-type mice. From this it was concluded that the myorelaxant activity of diazepam
seems to be mediated primarily by α 2-subunit-containing GABA A receptors and at highconcentrations also by α 3-containing receptors [119].
Thus, α 2-containing receptors apparently mediate the anxiolytic as well as muscle
relaxant action of diazepam. But these actions presumably are elicited by receptors in
different brain regions and there seems to be a difference in the dose necessary to exhibit
these effects. From this it can be predicted that a partial agonist selective at α 2-containing
GABA A receptors will exhibit anxiolytic but no sedative and muscle relaxant properties. A
compound coming close to these properties might be L-838.417 (Fig. 6). This compound,although binding with high afﬁnity to α 1-, α 2-, α 3-, and α 5-subunit-containing receptors,
does not enhance GABA-response on α 1-receptors but acts as a partial agonist on α 2,
α 3-, and α 5-containing receptors [37]. Studies on the clinical effects of this compoundare eagerly awaited.
Interestingly, a recent report has indicated that α 5-subunit deﬁcient mice seem toexhibit increased abilities in learning and memory tasks [120], possibly indicating that
α 5-subunit-containing GABA A receptors mediate the memory-impairing effect of diazepam. This conclusion is supported by the abundant location of α 5-subunits in the hippocampus [24,25], a brain region in which GABA A receptors are involved in memory encoding and retrieval [121]. Selective partial inverse agonists of GABA A receptors containing
α 5-subunits might thus represent excellent candidates for the generation of memoryenhancing drugs.
In conclusion, recent studies have indicated that the different effects of benzodiazepines not only are produced in different brain regions but are also mediated by partiallydifferent GABA A-receptor subtypes. These results should cause a revival of GABA A-receptor research and strongly stimulate the development of drugs with a higher α 2-, α 3-,or α 5-receptor subtype selectivity. Since GABA A receptors not only are involved in controlling the excitability of the brain [122] and the modulation of anxiety [123,124], butalso in the modulation of feeding and drinking behavior [125], circadian rhythms [126],
cognition, vigilance, memory, and learning [121,127], a selective modulation of individual
receptor subtypes will generate quite selective clinical effects.

REFERENCES
1. Haefely W, Kyburz E, Gerecke M, Möhler H. Recent advances in the molecular pharmacology of benzodiazepine receptors and in the structure-activity relationships of their agonists
and antagonists. In: Testa B, ed. Advances in Drug Research, Vol. 14. London: Academic
Press, 1985:165–322.
2. Gardner CR, Tully WR, Hedgecock CJR. The rapidly expanding range of neuronal benzodiazepine receptor ligands. Progr Neurobiol 1993; 40:1–61.
3. Haefely W. Tranquillizers. In: Grahame-Smith DG, Cowen PJ, ed. Psychopharmacology 1,
Part 1: Preclinical psychopharmacology. Amsterdam: Excerpta Medica, Elsevier Science
Publishing Co., 1983:107–151.
4. Woods JH, Katz JL, Winger G. Benzodiazepines: use, abuse, and consequences. Pharmacol
Rev 1992; 44:151–347.

436

Sieghart

5. Costa e Silva JA. A review of the place of the benzodiazepines. Introduction: the implications
for public health of controls on the benzodiazepines. Eur Neuropsychopharmacol 1999; 9:
6:S391–392.
6. Haefely W, Pieri L, Polc P, Schaffner R. General pharmacology and neuropharmacology
of benzodiazepine derivatives. In: Hoffmeister F, Stille G, eds. Handbook of Experimental
Pharmacology, Vol 55/II. Berlin: Springer, 1981:13–262.
7. Müller WE. Benzodiazepin-Tranquilizer. Experimentelle und klinische Pharmakologie. In:
Riederer P, Laux G, Pöldinger W, eds. Neuropsychopharmaka, Ein Therapie-Handbuch. vol.
2, Tranquilizer und Hypnotika. Vienna: Springer-Verlag, 1995:23–41.
8. Ashton H. Guidelines for the rational use of benzodiazepines. When and What to use. Drugs
1994; 48:25–40.
9. Drugan RC, Holmes PV. Central and peripheral benzodiazepine receptors: involvement inan organism’s response to physical and psychological stress. Neurosci Behav Rev 1991; 15:
277–298.
10. Mennini T, Garattini S. Benzodiazepine receptor binding in vivo: pharmacokinetic and pharmacological signiﬁcance. In: Biggio G, Costa E, eds. Benzodiazepine Recognition Site Ligands: Biochemistry and Pharmacology. New York: Raven Press, 1983:189–199.
11. Arendt RM, Greenblatt DJ, DeJong RH, Bonin JD, Abernethy DR, Ehrenberg BL, Giles HG,
Sellers EM, Shader RI. In vitro correlates of benzodiazepine cerebrospinal ﬂuid uptake, pharmacodynamic action and peripheral distribution. J Pharmacol Exp Ther 1983; 227:98–106.
12. Laurijssens BE, Greenblatt DJ. Pharmacokinetic-pharmacodynamic relationships for benzodiazepines. Clin Pharmacokinet 1996; 30:52–76.
13. File SE. Behavioural pharmacology of benzodiazepines. Prog Neuropsychopharmacol Biol
Psychiat 1984; 8:19–31.
14. Sieghart W. Structure and pharmacology of γ-aminobutyric acid A receptor subtypes. Pharmacol Rev 1995; 47:181–234.
15. Woods JH, Katz JL, Winger GD. Abuse liability of benzodiazepines. Pharmacol Rev 1987;
39:251–419.
16. Möhler H, Okada T. Benzodiazepine receptors—demonstration in the central nervous system. Science 1977; 198:849–851.
17. Braestrup C, Squires R. Speciﬁc benzodiazepine receptors in rat brain characterized by highafﬁnity [3H]diazepam binding. Proc Natl Acad Sci USA 1977; 74:3804–3809.
18. Barnard EA, Skolnick P, Olsen RW, Möhler H, Sieghart W, Biggio G, Braestrup C, Bateson
AN, Langer SZ. International Union of Pharmacology. XV. Subtypes of γ-aminobutyric acid A
receptors: classiﬁcation on the basis of subunit structure and receptor function. Pharmacol
Rev 1998; 50:291–313.
19. Verma A, Snyder SH. Peripheral type benzodiazepine receptors. Annu Rev Pharmacol Toxicol 1989; 29:307–322.
20. Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L, Weisinger G, Weitzman A. Enigma
of the peripheral benzodiazepine receptor. Pharmacol Rev 1999; 51: 629–650.
21. Bowling AC, DeLorenzo RJ. Micromolar afﬁnity benzodiazepine receptors: identiﬁcationand characterization in central nervous system. Science 1982; 216:1247–1250.
22. Johansen J, Taft WC, Yang J, Kleinhaus AL, DeLorenzo RJ. Inhibition of Ca2⫹ conductancein identiﬁed leech neurons by benzodiazepines. Proc Natl Acad Sci USA 1985; 82:3935–3939.
23. Rampe D, Triggle DJ. Benzodiazepines and calcium channel function. Trends Pharmacol
Sci 1986; 7:461–464.
24. Fritschy JM, Benke D, Mertens S, Oertel WH, Bachi T, Möhler H. Five subtypes of typeA γ-aminobutyric acid receptors identiﬁed in neurons by double and triple immunoﬂuorescence staining with subunit-speciﬁc antibodies. Proc Natl Acad Sci USA 1992; 89:6726–
6730.
25. Pirker S, Schwarzer C, Wieselthaler A, Sieghart W, Sperk G. GABA A receptors: immunocytochemical distribution of 13 subunits in the adult rat brain. Neurosci 2000; 101:815–850.

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

437

26. Sieghart W, Fuchs K, Tretter V, Ebert V, Jechlinger M, Höger H, Adamiker D. Structureand subunit composition of GABA A receptors. Neurochem Int 1999; 34:379–385.
27. Jechlinger M, Pelz R, Tretter V, Klausberger T, Sieghart W. Subunit composition and quantitative importance of heterooligomeric receptors: GABA A receptors containing α6 subunits.
J Neurosci 1998; 18:2449–2457.
28. Smith GB, Olsen RW. Functional domains of GABA A receptors. Trends Pharmacol Sci 1995;
16:162–168.
29. Macdonald RL, Olsen RW. GABA A receptor channels. Ann Rev Neurosci 1994; 17:569–
602.
30. Sigel E, Buhr A. The benzodiazepine binding site of GABA A receptors. Trends Pharmacol
Sci 1997; 18:425–429.
31. Costa E, Guidotti A. Benzodiazepines on trial: a research strategy for their rehabilitation.
Trends Pharmacol Sci 1996; 17: 192–200.
32. Korpi ER, Mattila MJ, Wisden W, Lüddens H. GABA A-receptor subtypes: clinical efﬁcacy
and selectivity of benzodiazepine site ligands. Ann Med 1997; 29: 275–282.
33. Polc P, Bonetti EO, Schaffner R, Haefely W. A three state model of the benzodiazepine
receptor explains the interactions between the benzodiazepine antagonist Ro15-1788, benzodiazepine tranquillizers, β-carbolines and phenobarbitone. Naunyn Schmiedeberg’s Arch
Pharmacol 1982; 321:260–264.
34. Braestrup C, Honore T, Nielsen M, Petersen EN, Jensen LH. Ligands for benzodiazepine
receptors with positive and negative efﬁcacy. Biochem Pharmacol 1984; 33:859–862.
35. Facklam M, Schoch P, Haefely WE. Relationship between benzodiazepine receptor occupancy and potentiation of γ-aminobutyric acid-stimulated chloride ﬂux in vitro of four ligandsof differing intrinsic efﬁcacies. J Pharmacol Exp Ther 1992; 261:1106–1112.
36. Facklam M, Schoch P, Bonetti EP, Jenck F, Martin JR, Moreau J-L, Haefely WE. Relationship between benzodiazepine receptor occupancy and functional effects in vivo of four ligands of differing intrinsic efﬁcacies. J Pharmacol Exp Ther 1992; 261:1113–1121.
37. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers
J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O,
Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ. Sedative
but not anxiolytic properties of benzodiazepines are mediated by the GABA A receptor α1
subtype. Nature Neurosci 2000; 3:587–592.
38. Rudolph U, Crestani F, Möhler H. GABA A receptor subtypes: dissecting their pharmacological functions. Trends Pharmacol Sci 2001; 22:188–194.
39. Hevers W, Lüddens H. The diversity of GABA A receptors. Pharmacological and electrophysiological properties of GABA A channel subtypes. Mol Neurobiol 1998; 18:35–86.
40. Squires RF, Saederup E. Antidepressants and metabolites that block GABA A receptors coupled to 35S-t-butylbicyclophosphorothionate binding sites in rat brain. Brain Res 1988; 441:
15–22.
41. Malatynska E, Crites G, Yochum A, Kopp R, Giroux ML, Dilsaver SC. Schild regression
analysis of antidepressant and bicuculline antagonist effects at the GABA A receptor. Pharmacol 1998; 57:117–123.
42. Squires RF, Saederup E. Clozapine and several other antipsychotic/antidepressant drugs preferentially block the same “core” fraction of GABA A receptors. Neurochem Res 1998; 23:
1283–1290.
43. Mehta AK, Ticku MK. An update on GABA A receptors. Brain Res Rev 1999; 29:196–217.
44. Nakahiro M, Arakawa O, Narahashi T. Modulation of γ-aminobutyric acid receptor-channel
complex by alcohols. J Pharmacol Exp Ther 1991; 259:235–240.
45. Mihic SJ. Acute effects of ethanol on GABA A and glycine receptor function. A review.
Neurochem Int 1999; 35:115–123.
46. Polc P. Involvement of endogenous benzodiazepine receptor ligands in brain disorders: therapeutic potential for benzodiazepine antagonists? Med Hypotheses 1995; 44:439–446.

438

Sieghart

47. Nutt D, Smith CF, Bennett R, Jackson HC. Investigations on the set point theory of benzodiazepine receptor function. In: Biggio G, Concas A, Costa E, eds. GABAergic Synaptic Transmission. New York: Raven Press, 1992:419–429.
48. Rothstein JD, Garland W, Puia G, Guidotti A, Weber RJ, Costa E. Puriﬁcation and characterization of naturally occurring benzodiazepine receptor ligands in rat and human brain. J Neurochem 1992; 58:2102–2115.
49. Asano T, Spector S. Identiﬁcation of inosine and hypoxanthine as endogenous ligands forthe brain benzodiazepine-binding sites. Proc Natl Acad Sci USA 1979; 76:977–981.
50. Phillis JW, Wu PH. Interaction between the benzodiazepines, methylxanthines and adenosine. Can J Neurol Sci 1980; 7:247–249.
51. Tsvetnitsky V, Campbell IC, Gibbons WA. S-Adenosyl-L-homocysteine and 5′-methylthioadenosine inhibit binding of [3H]ﬂunitrazepam to rat brain membranes. Eur J Pharmacol
1995; 282:255–258.
52. Braestrup C, Nielsen M. Benzodiazepine receptors. In: Iversen L, Iversen SD, Snyder SH,
eds. Handbook of Psychopharmacology, Vol 17, New York: Plenum Press, 1983:285–384.
53. Costa E, Guidotti A. Diazepam binding inhibitor (DBI): a peptide with multiple biologicalactions. Life Sci 1991; 49:325–344.
54. De Robertis E, Pena C, Paladini AC, Medina JH. New developments on the search for theendogenous ligand(s) of central benzodiazepine receptors. Neurochem Int 1988; 13:1–11.
55. De Blas AL, Park D, Friedrich P. Endogenous benzodiazepine like molecules in the human,
rat and bovine brains studied with a monoclonal antibody to benzodiazepines. Brain Res
1987; 413:275–284.
56. Medina JH, Pena C, Piva M, Wolfman C, de Stein ML, Wasowski C, Da Cunha C, Izquierdo
I, Paladini AC. Benzodiazepines in the brain. Their origin and possible biological roles. Mol
Neurobiol 1993; 6:377–386.
57. Rothstein JD, Guidotti A, Costa E. Release of endogenous benzodiazepine receptor ligands(endozepines) from cultured neurons. Neurosci Lett 1992; 143:210–214.
58. Basile AS , Jones EA , Skolnick P. The pathogenesis and treatment of hepatic encephalopathy: evidence for the involvement of benzodiazepine receptor ligands. Pharmacol Rev 1991;
43:27–71.
59. Marazziti D, Michelini S, Giannaccini G, Martini C, Castrogiovanni P, Cassano GB, Luccachini A. Stress-related changes of benzodiazepine binding inhibitory activity (B.B.I.A) in
humans. Life Sci 1990; 46:1833–1836.
60. Scollo-Lavizzari G, Matthis H. Benzodiazepine antagonist (Ro15-1788) in ethanol intoxication: a pilot study. Eur Neurol 1985; 24:352–354.
61. Geller E, Weinbrum A, Schiff B, Speiser Z, Nevo Y, Halpern P, Cohen S. The effects of
ﬂumazenil on the process of recovery from halothane anaesthesia. Eur J Anaesth 1998; (suppl
2):151–153.
62. Rubio F, Quintero S, Hernandez A, Fernandez S, Cozar L, Lobato IM, Pantoja S. Flumazenil
for coma reversal in children after cannabis. Lancet 1993; 341:1028–1029.
63. Rothstein JD, Guidotti A, Tinuper P, Cortelli P, Avoni P, Plazzi G, Lugaresi E, Schoch P,
Montagna P. Endogenous benzodiazepine receptor ligands in idiopathic recurrent stupor.
Lancet 1992; 340:1002–1004.
64. Tinuper P, Montagna P, Cortelli P, Avoni P, Lugaresi A, Schoch P, Bonetti EP, Galassi R,
Sforza E, Lugaresi E. Idiopathic recurring stupor: a case with possible involvement of the
gamma-aminobutyric acid (GABA)ergic system. Ann Neurol 1992; 31:503–506.
65. Barbaccia ML, Costa E, Ferrero P, Guidotti A, Roy A, Sunderland T, Pickar D, Paul SM,
Goodwin FK. Diazepam binding inhibitor. A brain neuropeptide present in human spinal
ﬂuid: studies in depression, schizophrenia and Alzheimer’s disease. Arch Gen Psychiat 1986;
43:1143–1147.
66. Dorow R, Horowski R, Paschelke G, Amin M, Braestrup C. Severe anxiety induced by FG
7142, a β-carboline ligand for benzodiazepine receptors. Lancet 1983; 9:98–99.

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

439

67. Roy A, DeJong J, Lamparski D, Adinoff B, George T, Moore V, Garnett D, Kerich M,
Linnoila M. Mental disorders among alcoholics. Relationship to age of onset and cerebrospinal ﬂuid neuropeptides. Arch Gen Psychiat 1991; 48:423–427.
68. Gerra G, Caccavari R, Volpi R, Maninetti L, Delsignore R, Coiro V. Effectiveness of ﬂumazenil in the treatment of ethanol withdrawal. Curr Ther Res 1991; 50:62–66.
69. Marazziti D, Michelini S, Martini C, Giannaccini G, Lucacchini A, Cassano GB. Further
investigation on benzodiazepine binding inhibitory activity in patients with major depression
or panic disorder and in healthy volunteers. Neuropsychobiol 1989; 21:14–16.
70. Kapczinski F, Curran HV, Gray J, Lader M. Flumazenil has an anxiolytic effect in simulated
stress. Psychopharmacol 1994; 114:187–189.
71. Iverfeldt K, Serfözö P, Arnesto LD, Bartfai T. Differential release of coexisting neurotransmitters: frequency dependence of the efﬂux of substance P, thyrotropin releasing hormoneand [3H]serotonin from tissue slices of rat ventral spinal cord. Acta Physiol Scand 1989; 137:
63–71.
72. Scollo-Lavizzari G. The clinical anti-convulsant effects of ﬂumazenil, a benzodiazepine antagonist. Eur J Anaesth 1988; 2:129–138.
73. Hart YM, Meinardi H, Sander JWAS, Nutt DJ, Shorvon SD. The effect of intravenous ﬂumazenil on interictal electroencephalographic epileptic activity: results of a placebocontrolled study. J Neurol Neurosurg Psychiatry 1991; 54:305–309.
74. Sharief MK, Sander JWAS, Shorvon SD. The effect of oral ﬂumazenil on interictal epileptic activity: results of a double-blind, placebo-controlled study. Epilepsy Res 1993; 15:
53–60.
75. Majewska MD. Neurosteroids: endogenous bimodal modulators of the GABA A receptor.
Mechanism of action and physiological signiﬁcance. Prog Neurobiol 1992; 38:379–395.
76. Jussoﬁe A. Brain region-speciﬁc effects of neuroactive steroids on the afﬁnity and densityof the GABA-binding site. Biol Chem Hoppe-Seyler 1993; 374:265–270.
77. Puia G, Ducic I, Vicini S, Costa E. Does neurosteroid modulatory efﬁcacy depend on GABA A
receptor subunit composition? Recept Channels 1993; 1:135–142.
78. Sundström I, Ashbrook D, Bäckström T. Reduced benzodiazepine sensitivity in patients withpremenstrual syndrome: a pilot study. Psychoneuroendocrinol 1997; 22:25–38.
79. Smith SS, Gong QH, Hsu FC, Markowitz RS, Ffrench-Mullen JMH, Li X. GABA A receptor
α4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature
1998; 392:926–930.
80. Smith SS, Gong QH, Li X, Moran MH, Bitran D, Frye CA, Hsu FC. Withdrawal from 3αOH-5α-pregnan-20-one using a pseudopregnancy model alters the kinetics of hippocampal
GABA A-gated current and increases the GABA A receptor α4 subunit in association with increased anxiety. J Neurosci 1998; 18:5275–5284.
81. Herbison AE, Fenelon VS. Estrogen regulation of GABA A receptor subunit mRNA expression in preoptic area and bed nucleus of the stria terminalis of female rat brain. J Neurosci
1995; 15:2328–2337.
82. Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, White HS, Wolf
HH, Mirsadeghi S, Tahir SH, Bolger MB, Lan NC, Gee KW. Characterization of the anticonvulsant properties of ganaxolone (CCD 1024; 3-hydroxy-3β-methyl-5α-pregnan-20-one) a
selective, high afﬁnity, steroid modulator of the γ-aminobutyric acid A receptor. J Pharmacol
Exp Ther 1997; 280:1284–1295.
83. Gasior M, Carter RB, Goldberg SR, Witkin JM. Anticonvulsant and behavioral effects ofneuroactive steroids alone and in conjunction with diazepam. J Pharmacol Exp Ther 1997;
282:543–553.
84. Beekman M, Ungard JT, Gasior M, Carter RB, Dijkstra D, Goldberg SR, Witkin JM. Reversalof behavioral effects of pentylenetetrazole by the neuroactive steroid ganaxolone. J Pharmacol Exp Ther 1998; 284:868–877.
85. Purdy RH, Morrow AL, Moore PH, Paul SM. Stress-induced elevations of γ-aminobutyric

440

86.
87.
88.

89.

90.
91.

92.

93.
94.
95.
96.
97.

98.

99.

100.

101.
102.
103.
104.
105.

106.

Sieghart
acid type A receptor-active steroids in the rat brain. Proc Natl Acad Sci USA 1991; 88:4553–
4557.
Orchinik M, Weiland NG, McEwen BS. Adrenalectomy selectively regulates GABA A receptor subunit expression in the hippocampus. Mol Cell Neurosci 1994; 5:451–458.
Nagy A, Lajtha A. Thyroid hormones and derivatives inhibit ﬂunitrazepam binding. J Neurochem 1983; 40:414–417.
Martin JV, Williams DB, Fitzgerald RM, Im HK, von-Voigtlander PF. Thyroid hormonal
modulation of the binding and activity of the GABA A receptor complex of brain. Neuroscience 1996; 73:705–713.
Chapel R, Martin J, Machu TK, Leidenheimer NJ. Direct channel-gating and modulatory
effects of triidothyronine on recombinant GABA A receptors. Eur J Pharmacol 1998; 349:
115–121.
Medina JH, De Robertis E. Benzodiazepine receptor and thyroid hormones: in vivo and invitro modulation. J Neurochem 1985; 44:1340–1344.
Gavish M, Weizman A, Okun F, Youdim MBH. Modulatory effects of thyroxine treatment
on central and peripheral benzodiazepine receptors in the rat. J Neurochem 1986; 47:1106–
1110.
Viollet C, Bodenant C, Prunotto C, Roosterman D, Schaefer J, Meyerhof W, Epelbaum J,
Vaudry H, Leroux P. Differential expression of multiple somatostatin receptors in the rat
cerebellum during development. J Neurochem 1997; 68:2263–2272.
Epelbaum H, Doumaud P, Fodor M, Viollet C. The neurobiology of somatostatin. Crit Rev
Neurobiol 1994; 8:25–44.
Vincens M, Mauvais-Jarvis F, Behar S. A novel recognition site for somatostatin-14 on the
GABA A receptor complex. Eur J Pharmacol 1998; 344:R1–R2.
Coloma FM, Niles LP. Melatonin enhancement of [3H]GABA and [3H]muscimol binding in
rat brain. Biochem Pharmacol 1988; 37:1271–1274.
Niles LP, Peace Ch. Allosteric modulation of t-[35S]butylbicyclophosphorothionate bindingin rat brain by melatonin. Brain Res Bull 1990; 24:635–638.
Kim HG, Wang T, Olafsson P, Lu B. Neurotrophin 3 potentiates neuronal activity and inhibits
γ-aminobutyric acid synaptic transmission in cortical neurons. Proc Natl Acad Sci USA 1994;
91:12341–12345.
Valenzuela CF, Kazlauskas A, Brozowski SJ, Weiner JL, Demali KA, Mcdonald BJ, Moss
SJ, Dunwiddie TV, Harris RA. Platelet-derived growth factor receptor is a novel modulatorof type A γ-aminobutyric acid-gated ion channels. Mol Pharmacol 1995; 48:1099–1107.
Rigo JM, Belachew S, Coucke P, Leprince P, Malgrange B, Rogister B, Moonen G.
Astroglia-released factor with negative allosteric modulatory properties at the GABA A receptor. Evidence from binding studies. Biochem Pharmacol 1996; 52:465–473.
Lees G, Edwards MD, Hassoni AA, Ganellin CR, Galanakis D. Modulation of GABA A receptors and inhibitory synaptic currents by the endogenous CNS sleep regulator cis-9,10octadecenoamide. Br J Pharmacol 1998; 124:873–882.
Thomas B, Prell GD. Imidazoleacetic acid, a γ-aminobutyric acid receptor agonist, can beformed in rat brain by oxidation of histamine. J Neurochem 1995; 65:818–826.
Sandler M. The emergence of Tribulin. Trends Pharmacol Sci 1982; 3:471–472.
Hucklebridge F, Doyle A, Pang FY, Adlard M, Evans P, Clow A. Regional and molecularseparation of the four bioactivities of “tribulin.” Neurosci Lett 1998; 240:29–32.
Glover V. Function of endogenous monoamine oxidase inhibitors (tribulin). J Neural Transm
Suppl 1998; 52:307–313.
Brandon NJ, Uren JM, Kittler JT, Wang H, Olsen R, Parker PJ, Moss SJ. Subunit-speciﬁc
association of protein kinase C and the receptor for activated C kinase with GABA type A
receptors. J Neurosci 1999; 19:9228–9234.
Poisbeau P, Cheney MC, Browning MD, Mody I. Modulation of synaptic GABA A receptor
function by PKA and PKC in adult hippocampal neurons. J Neurosci 1999; 19:674–683.

Benzodiazepines, Benzodiazepine Receptors, and Endogenous Ligands

441

107. Hodge CW, Mehmert KK, Kelley SP, McMahon T, Haywood A, Foster Olive M, Wang D,
Sanchez-Perez AM, Messing RO. Supersensitivity to allosteric GABA A receptor modulators
and alcohol in mice lacking PKC ε. Nature Neurosci 1999; 2:997–1002.
108. Günther U, Benson J, Benke D, Fritschy J-M, Reyes G, Knoﬂach F, Crestani F, Aguzzi A,
Arigoni M, Lang Y, Bluethmann H, Möhler H, Lüscher B. Benzodiazepine-insensitive mice
generated by targeted disruption of the γ 2 subunit gene of γ-aminobutyric acid type A receptors. Proc Natl Acad Sci USA 1995; 92:7749–7753.
109. Essrich C, Lorez M, Benson JA, Fritschy J-M, Lüscher B. Postsynaptic clustering of major
GABA A receptor subtypes requires the γ 2 subunit and gephyrin. Nature Neurosci 1998; 1:
563–571.
110. Crestani F, Lorez M, Baer K, Essrich C, Benke D, Laurent JP, Belzung C, Fritschy J-M,
Lüscher B, Möhler H. Decreased GABA A receptor clustering results in enhanced anxiety
and a bias for threat cues. Nature Neurosci 1999; 2:833–839.
111. Jones A, Korpi ER, McKernan RM, Pelz R, Nusser Z, Mäkelä R, Mellor JR, Pollard S, Bahn
S, Stephenson FA, Randall AD, Sieghart W, Somogyi P, Smith AJH, Wisden W. Ligandgated ion channel subunit partnerships: GABA A receptor α6 subunit gene inactivation inhibits
δ subunit expression. J Neurosci 1997; 17:1350–1362.
112. Korpi ER, Koikkalainen P, Vekovischeva OY, Mäkelä R, Kleinz R, Uusi-Oukari M, Wisden
W. Cerebellar granule-cell-speciﬁc GABA A receptors attenuate benzodiazepine-induced
ataxia: evidence from α6-subunit-deﬁcient mice. Eur J Neurosci 1999; 11:233–240.
113. DeLorey TM, Handforth A, Anagnostaras SG, Homanics GE, Minassian BA, Asatourian A,
Fanselow MS, Delgado-Escueta A, Ellison GD, Olsen RW. Mice lacking the β3 subunit of
the GABA A receptor have the epilepsy phenotype and many of the behavioural characteristics
of Angelman syndrome. J Neurosci 1998; 18:8505–8514.
114. Mihalek RM, Banerjee PK, Korpi ER, Quinlan JJ, Firestone LL, Mi Z-P, Lagenaur C, Tretter
V, Sieghart W, Anagnostaras SG, Sage JR, Fanselow MS, Guidotti A, Spigelman I, Li Z,
DeLorey TM, Olsen RW, Homanics GE. Attenuated sensitivity to neuroactive steroids in γaminobutyrate type A receptor δ subunit knockout mice. Proc Natl Acad Sci USA 1999; 96:12905–12910.
115. Rudolph U, Crestani F, Benke D, Brünig I, Benson JA, Fritschy JM, Martin JR, Bluethmann
H, Möhler H. Benzodiazepine actions mediated by speciﬁc γ-aminobutyric acid A receptor
subtypes. Nature 1999; 401:796–800.
116. Löw K, Crestani F, Keist R, Benke D, Brünig I, Benson JA, Fritschy JM, Rülicke T,
Bluethmann H, Möhler H, Rudolph U. Molecular and neuronal substrate for the selective
attenuation of anxiety. Science 2000; 290:131–134.
117. Nusser Z, Sieghart W, Benke D, Fritschy J-M, Somogyi P. Differential synaptic localizationof two major γ-aminobutyric acid type A receptor α subunits on hippocampal pyramidalcells. Proc Natl Acad Sci USA 1996; 93:11939–11944.
118. Fritschy J-M, Weinmann O, Wenzel A, Benke D. Synapse-speciﬁc localization of NMDA
and GABA A receptor subunits revealed by antigen-retrieval immunohistochemistry. J Comp
Neurol 1998; 390:194–210.
119. Crestani F, Löw K, Keist R, Mandelli MJ, Möhler H, Rudolph U. Molecular targets for the
myorelaxant action of diazepam. Mol Pharmacol 2001; 59:442–445.
120. Collinson N, Cothliff R, Rosahl TW, Sur C, Kuenzi F, Howell O, Seabrook GR, Atack JR,
McKernan RM, Dawson GR, Whiting PJ. Role of the α5 subunit of the GABA A receptor inlearning and memory. Eur J Neurosci 2000; 12 (suppl 11):171.
121. Paulsen O, Moser EI. A model of hippocampal memory encoding and retrieval: GABAergic
control of synaptic plasticity. Trends Neurosci 1998; 21:273–278.
122. Olsen RW, Avoli M. GABA and epileptogenesis. Epilepsia 1997; 38:399–407.
123. Nutt DJ, Glue P, Lawson C. The neurochemistry of anxiety: an update. Prog Neuro-Psychopharmacol Biol Psychiat 1990; 14:737–752.
124. Pratt JA. The neuroanatomical basis of anxiety. Pharmacol Ther 1992; 55:149–181.

442

Sieghart

125. Cooper SJ. Benzodiazepines and appetite: recent preclinical advances and their clinical implications. Human Psychopharmacol 1989; 4:81–89.
126. Turek FW, Van Reeth O. Altering the mammalian circadian clock with the short-acting benzodiazepine triazolam. Trends Neurosci 1988; 11:535–541.
127. Sarter M, Schneider HH, Stephens DN. Treatment strategies for senile dementia: antagonist
β-carbolines. Trends Neurosci 1988; 1:13–16.
128. Haefely WE. Structure and function of the benzodiazepine receptor. Chimia 1987; 41:389–
396.

18
Antidepressants for the Treatmentof Depression and Anxiety Disorders:
Same Mechanism of Action?
R. HAMISH McALLISTER-WILLIAMS and STEPHEN P. TYRER
University of Newcastle upon Tyne
Newcastle upon Tyne, England

I.

INTRODUCTION

Comorbidity of depression and anxiety is common. Approximately 45% of patients witha current anxiety disorder also have a depressive disorder, and about 40% of patients withdepression have been found to have an anxiety disorder [1]. Antidepressants are effective
for the treatment of depressive illnesses in the majority of patients, regardless of the degreeof anxiety symptoms present. They are also an effective treatment for several primaryanxiety disorders, which has led to the hypothesis of “affective spectrum disorders,” deﬁned by their response to antidepressants and speculation that similar pathophysiologicalprocesses underlie these conditions [2]. However, this is predicated on the assumptionthat antidepressants have the same or similar mechanisms of action in anxiety disorders
as in depression. This chapter will brieﬂy review the evidence for the effectiveness ofantidepressants in depression and a number of anxiety disorders. Several issues will be
explored including: (1) how far are the effects of antidepressants in anxiety disorders due
to a nonspeciﬁc effect on mood and (2) to what extent do these agents have speciﬁc effects
on the core psychopathology of anxiety disorders?
If antidepressants work through the same mechanism to alleviate depression andanxiety, then it would be expected that the clinical response to antidepressants would be
similar in time course, that similar classes of antidepressants would have similar efﬁcacy,
and that similar doses of drug would be required. The clinical response to antidepressants

443

444

McAllister-Williams and Tyrer

will be examined in depression and three anxiety disorders—obsessive-compulsive disorder (OCD), panic disorder, and post-traumatic stress disorder (PTSD). Clinical observations suggest that antidepressants work by different mechanisms in at least some anxiety
disorders when compared with depression; various possible explanations of these observations will be explored.

II. CLINICAL RESPONSE TO ANTIDEPRESSANTS
A.

Depression

The discovery of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors(MAOIs) in the 1950s and 1960s led to the monoamine hypothesis of the pathophysiology
of depressive illnesses, implicating both norepinephrine (NE) and serotonin (5HT). The
ﬁrst randomized controlled trial of the effectiveness of these drugs in depression was
conducted by the Medical Research Council of the United Kingdom in 1965 [3]. This
demonstrated the superiority of imipramine over placebo and, incidentally, the ineffectiveness of phenelzine in the severely depressed group of patients in this study. The adventof the selective serotonin reuptake inhibitors (SSRIs) in the 1980s led to much debate as
to whether drugs that acted solely on the 5HT system could be as effective as those that
acted on NE system as well. Accordingly, large numbers of comparative studies comparing
TCAs and SSRIs have been conducted in patients with varying degrees of severity ofdepression. Several meta-analyses of these studies have demonstrated that both classes ofdrugs are equally effective in general [4–6]. Of interest is the conclusion that drugs thatare relatively selective at blocking NE reuptake, such as desipramine, produce similar
response rates as SSRIs. However, analysis of those studies investigating the treatmentof hospitalized patients with severe depressive illnesses suggests that the older TCAs may
be superior to SSRIs in this population, with this superiority residing almost entirely withamitriptyline [6,7]. More recently, meta-analysis of studies comparing the NE and 5HT
reuptake inhibitor venlafaxine with SSRIs has also demonstrated a superiority of venlafaxine at doses of 150 mg/day and above in moderate to severely ill patients with major
depression [8,9]. The reason for the superior clinical potency of amitriptyline and venlafaxine in major depression is unknown, although both drugs are potent in the blockade ofboth the NE and 5HT uptake mechanism. Further support for the notion that dual action
leads to improved clinical outcome comes from studies examining the effect of combining
an SSRI with a relatively NE-selective TCA [10], which show increased efﬁcacy in thiscombination over an SSRI alone. Although the interpretation of these studies is complicated by the potential pharmacokinetic interaction that can occur between SSRIs and TCAs
due to the metabolism of the latter by the cytochrome P450 isoenzyme 2D6 being inhibitedby the former [11], these results support the notion that blockade of the reuptake of boththese amines is more effective than that of 5HT alone. Thus, it can be concluded that in
the management of major depression, SSRIs are as effective as selective NE reuptake
inhibitors and that drugs that potently block both uptake mechanisms are probably superior
in the treatment of the severely ill.
Clinical observations of depressed patients treated with antidepressants demonstratethat response is not immediate. Improvements in mood, cognitive functioning, and somatic
symptoms are ﬁrst observable in patients who eventually respond to tricyclic antidepressants after 1 to 2 weeks [12], with a similar temporal proﬁle seen also in the elderly treatedwith ﬂuoxetine [13]. However, there is little information in the literature regarding theAntidepressant Treatment445

total length of time patients take to recover when treated with antidepressants. The Foodand Drug Administration (FDA) in the United States recommends that acute treatment
studies in depressed patients should be conducted for a period of 6 weeks (http://www.
fda.gov/cder/guidance/old050fn.pdf ), although there appears to be little basis for thisopinion. Analysis of a large number of patients treated in placebo-controlled studies suggests that only a few patients who have not shown any signs of improvement after 4 weeks
of treatment show some response at 6 weeks [14]. This ﬁnding is independent of the natureof the depressive illness or antidepressant used [14], although the elderly may take longer
to respond [15]. This has led to clinical guidelines for the management of depression in
adults, recommending changes in antidepressant treatment in patients who have either
failed to show any response at 4 weeks, or only minimal response at 6 weeks, once thediagnosis has been reviewed and compliance checked [16].
B. Obsessive-Compulsive Disorder
The Epidemiological Catchment Area survey in the United States reported a lifetime prevalence of OCD of 2.5% [17]. Two-thirds of OCD patients have a lifetime history of major
depression and one-third satisfy criteria for major depression at the time of ﬁrst evaluation[18]. Conversely, over 20% of bipolar and 10% of unipolar affective disorder patients,
respectively, have comorbid OCD [19]. Despite the high rates of co-occurrence of bothdepressive and obsessive-compulsive symptomatology in patients, it is possible to selectively investigate effects of treatment on core OCD symptoms using well-validated scales
such as the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) [20,21]. This is an important issue because it allows the possibility of examining the speciﬁc effects of antidepressants in OCD.
A meta-analysis of randomized controlled trials demonstrates a superiority of clomipramine and SSRIs over placebo in OCD patients as assessed using speciﬁc scales
such as the Y-BOCS [22]. However, neither nortriptyline [23] nor imipramine [24] show
evidence of superiority over placebo. The difference between clomipramine and other
TCAs that are less 5HT selective is supported by a meta-analysis of eight direct comparison studies, which reveal clomipramine to demonstrate superior efﬁcacy in alleviating thecore symptoms of OCD [22]. Similarly, ﬂuvoxamine has been shown to be superior todesipramine [25]. While it appears that the effect size seen with clomipramine comparedto placebo is bigger than that with SSRIs [22], in direct head-to-head comparisons, SSRIs
appear to be equally effective as clomipramine in OCD [26]. In addition, the hypothesisthat the efﬁcacy of clomipramine in OCD resides entirely in its ability to block 5HT uptake
is supported by the ﬁnding that the addition of an NE uptake inhibitor (desipramine) toan SSRI in treatment-resistant OCD patients has no effect [27]. Although clomipramine
is metabolized to desmethylclomipramine, which is largely an NE uptake blocker, theassumption is that clomipramine acts independently in this condition.
Given the high rates of comorbid depressive symptomatology, an important questionis whether antidepressants are effective in OCD simply by ameliorating these symptoms,
rather than the core psychopathology of the disorder. As described above, both clomipramine and SSRIs appear to have signiﬁcant effects compared to placebo on OCD symptoms
as assessed using speciﬁc rating scales. However, this question has been further investigated by comparing the relative efﬁcacy of clomipramine versus placebo according to thelevels of depression of patients at the outset of the trial. Piccinelli and colleagues [22]compared trials in which patients were excluded if they had a primary affective disorder

446

McAllister-Williams and Tyrer

and/or patients had a baseline Hamilton Depression Rating Scale score lower than 17 withtrials in which OCD patients had concomitant depression. Interestingly, clomipramine wassuperior to placebo in both sets of trials, but the effect was greatest in those trials where
patients had little or no concomitant depression.
Not only is there a difference in the range of antidepressants that is effective in thetreatment of OCD compared to depression, but the doses needed and the time to response
also appear to be different. Many of the randomized controlled studies conducted to datehave compared treatments over periods of 8 to 12 weeks. These have often revealed adelayed response to treatment, leading expert consensus to suggest therapeutic trials fora minimum of 8 weeks [28,29], twice the duration recommended for depression [16]. In
addition, the dose of antidepressant needed to treat OCD tends to be higher than thatneeded to treat depression. In a ﬁxed-dose comparison of placebo, 20 mg, 40 mg, and 60
mg of ﬂuoxetine in OCD, a dose-response relationship is apparent with 20 mg being no
better than placebo [30]. This is somewhat different from the situation in depression, where
20 mg of ﬂuoxetine is clearly effective and there is little evidence of a dose-response
relationship for higher doses [31,32]. These differences may simply be due to OCD beinga more severe form of illness than depression. However, such a situation cannot explain
the different range of effective treatments in the two conditions.
C.

Panic Disorder

Around two-thirds of patients with panic disorder have experienced a major depressive
episode at some time [33]. Such comorbidity is associated with a more severe illness andis reﬂected by a suicide rate twice that seen in depressed patients without comorbid panic
disorder [1]. While some studies have suggested that such comorbidity has no effect on
response to treatment [34,35], the majority of studies show that comorbid depression leads
to a poorer treatment response in panic disorder patients [36]. This suggests a complex
interaction between the expression of depressive and panic symptoms in patients and is
to a certain extent consistent with the notion that there may be a shared pathophysiology
between these conditions. This matter is further confounded as there are differences in
the response to treatment between the conditions.
The assessment of the effect of treatments in panic disorder is complicated by thehigh frequency of occurrence of comorbid conditions. Many studies comparing different
treatments have assessed global anxiety, depression ratings, or overall clinical improvement [37]. This makes it difﬁcult to be certain that the treatments are having an effect oncore panic disorder symptoms rather than associated or comorbid symptomatology. The
clearest, but far from perfect, way of assessing the effect of treatments in panic disorderis simply to measure panic attack frequency. Using such measures, it can be seen that insome patients panic disorder responds to treatment with TCAs such as imipramine [34].
The response to imipramine appears to correlate with the plasma concentration of imipramine itself rather than its active metabolite desmethyl-imipramine [38]. Since imipramine
is predominantly a 5HT uptake inhibitor, while its metabolite is an NE uptake inhibitor,
this ﬁnding suggests that blockade of 5HT uptake is the mechanism by which imipramine
acts in panic disorder. This supposition is supported by ﬁndings that the tetracyclic antidepressant maprotiline [39], which selectively inhibits NE uptake, and the TCA lofepramine[40], which is relatively NE selective, are ineffective in panic disorder. Conversely, SSRIs
appear to be highly effective in the treatment of panic disorder [37,41]. Despite the 5HT
uptake blockade potency of the parent compound, imipramine does not appear to be asAntidepressant Treatment447

effective as clomipramine [42], which is more potent at blocking 5HT uptake. In addition,
in a meta-analysis SSRIs have been shown to be more clinically effective in panic disorderthan imipramine [41]. These data suggest that 5HT uptake blockade is more important intreating panic disorder than NE uptake blockade, and are reﬂected in expert consensus
statements on the management of panic disorder [43]. However, the picture is not as clear
as in OCD [28], because TCAs (i.e., imipramine) other than clomipramine appear to beeffective. This may relate to the complex presentation of panic disorder and the problemsof assessment of response to treatment.
D. Post-Traumatic Stress Disorder
Post-traumatic stress disorder is characterized by a triad of psychopathology, including
reexperiencing a traumatic event, such as recurrent and intrusive ﬂashbacks; avoidanceof any situation or activity that directly or indirectly reminds the patient of the trauma;
and increased arousal. However, in addition, a high proportion (up to 80%) of patients
also suffer from comorbid anxiety disorders and depression [44]. Therefore, it is not surprising that there has been interest for some years in the use of antidepressants for thetreatment of PTSD. A recent systematic review of methodologically sound, randomized
controlled trials suggests that antidepressants are effective in the treatment of PTSD [45].
Of particular interest is that improvement in the core symptoms of PTSD is seen, rather
than just comorbid depression. This would tend to suggest that antidepressants are effective in treating, or at least ameliorating the effect of, the underlying pathophysiology of
PTSD.
Most recent interest in the treatment of PTSD has centered on the use of SSRIs.
These have been shown clearly to be effective [46]. It has been suggested that the effectsize seen with antidepressants in PTSD correlates with their serotonergic speciﬁcity [47].
This is supported by a small and short duration study that found desipramine, a relatively
NE-selective TCA, to be ineffective [48]. The evidence for the speciﬁcity of the SSRIs
in this condition is not clear-cut and it is not surprising that expert consensus guidelines
recommend the use of SSRIs, nefazodone, or venlafaxine as ﬁrst-line treatments of PTSD
[49], although the inclusion of the latter two drugs does not have great evidence-based
support [50].
In addition to possible differences in the range of antidepressants that have efﬁcacy
in PTSD compared to depression, there is also a suggestion of a difference in the timecourse of response. No FDA recommendations exist regarding the duration of controlled
studies of medication in PTSD patients, although generally studies range in duration from4 to 12 weeks. Expert consensus suggests that the time to response is longer than indepressive illness and a duration of 8 weeks is recommended in therapeutic trials [49,50].
However, even this length of treatment may not be sufﬁcient as inspection of several of
the longer controlled trials suggests that a signiﬁcant proportion of nonresponders at 8
weeks may well become responders by week 12 [46,51,52]. This is clearly well beyond
the normal response time seen in depressive illness.
III. MECHANISM OF ACTION OF ANTIDEPRESSANTS
A. Depression
Little is known about the mechanism of action of antidepressants in ameliorating the symptoms of depressive illness in humans. Not surprisingly, most hypotheses regarding poten-

448

McAllister-Williams and Tyrer

tial mechanisms center on effects on monoaminergic systems. Because the clinical response to antidepressants is delayed, any hypothesis needs to explain why this occurs
despite inhibition of monoamine uptake or metabolism, or receptor blockade occurring
as soon as a single oral dose of an antidepressant is absorbed. Such explanations usually
postulate neuroadaptive changes occurring in response to raised monoamine concentrations, based on experimental work in animals.
Postmortem binding studies in suicide victims have led to hypotheses that depression
is associated with a supersensitivity of beta-adrenoceptors [53]. Data from animal studies
demonstrate that repeated administration of TCAs, MAOIs, and electroconvulsive shocks
decrease beta-adrenoceptor numbers in rats [54,55]. This has led to the suggestion that
this is the potential mechanism of action of antidepressants [56]. Of note is that changes
in the number of beta-adrenoceptors are seen after 7 to 21 days of treatment, but not after
a single dose of an antidepressant [55], in line with the time course of response of depressed patients to pharmacological treatment. However, the effect of SSRIs on betaadrenoceptors appears to be inconsistent, with sertraline [57] reported to cause a similar
reduction as TCAs, but no effect of the most selective of the SSRIs, citalopram [58,59].
Other monoamine hypotheses of the mechanism of action of antidepressants haveincluded those connected with 5HT receptors. Rapidly lowering brain tryptophan levels(and hence 5HT) can lead to signiﬁcant lowering of mood in subjects with a vulnerability
to depression, such as patients with a strong family history of depression [60,61] andeuthymic subjects with a history of recurrent depression [62,63]. The consequences of
rapid lowering of 5HT on the functional activity of the serotonergic system remain to be
determined. Deakin and Graeff [64] have suggested that 5HT neurons in the median raphéthat project onto postsynaptic 5HT1A receptors in the hippocampus maintain adaptive behaviors in the face of aversive stimuli. They further hyphothesize that a failure of thissystem leads to helplessness in animals and depression in humans [64]. This model would
predict a mood-lowering effect of tryptophan depletion in humans as a result of reduced
transmission through postsynaptic 5HT1A receptors. Several studies have reported ablunted growth hormone response to L-tryptophan in depressed patients compared to controls [65], a neuroendocrine test believed to be an indicator of 5HT1A function [66].
There is further evidence that 5HT1A receptors are involved in the mechanism ofantidepressant action. Antidepressant treatments may lead to a neuroadaptive change thatcounteracts an impairment of postsynaptic 5HT1A receptors. In vivo studies in rodents
have demonstrated that a range of antidepressants and electroconvulsive shocks, when
given chronically over 14 days, but not single doses, attenuate the function of somatodendritic 5HT1A receptors located on raphé neurons [67,68]. Single doses have no effect.
Attenuation of these autoreceptors enhances serotonergic transmission generally, including transmission mediated through postsynaptic 5HT1A receptors. An overall effect of antidepressants enhancing 5HT transmission through postsynaptic hippocampal 5HT1A receptors has also been argued by Blier and de Montigny [69] using in vivo electrophysiological
techniques in rats, although they argue for differing mechanisms between antidepressants.
For example, repeated TCAs are claimed to lead to a supersensitivity of postsynaptic
5HT1A receptors, while SSRIs are said to cause a downregulation of somatodendritic 5HT1A
receptors [69]. In either case, these effects are seen after 14 days of treatment with antidepressants, but not after single doses.
More recently, there have been hypotheses explaining that antidepressants are effective in depression through mechanisms independent of monoaminergic systems, such asalterations in the expression of glucocorticoid receptors [70] and pathways involved inAntidepressant Treatment449

neuronal plasticity and cell survival [71]. These hypotheses, particularly the former, relate
to the hypercortisolemia seen in depression [72,73] that may be of pathophysiologicalimportance [74]. In common with proposed monoaminergic mechanisms of action, theseeffects of antidepressants are likely only to become apparent after at least several daysof treatment. As such, they are also able to explain the clinical delay in response seen in
depressed patients.
B. Obsessive-Compulsive Disorder
The pathophysiology of OCD is far from clear. However, PET imaging studies have suggested that the disorder is associated with increased activity in orbitofrontal-subcorticalcircuitry [75,76], which appears to normalize upon successful treatment of the disorder[77]. How this might relate to possible 5HT abnormalities is unclear, but given the weightof clinical data regarding the efﬁcacy of serotonergic antidepressants described above,
5HT systems seem to be closely involved at least in the successful pharmacological treatment of the condition.
One of the cornerstones of the proposed mechanism of action of antidepressants indepression is that animal investigations demonstrate adaptive changes to occur over 1 or
2 weeks; this is similar to the time course seen in the clinical response in depression.
However, as discussed above, the clinical response in OCD tends to take a much longer
period of time, and this is at odds with the earlier animal data published in investigations
concerned with depression. However, recent investigations have shown that administrationof an SSRI desensitizes 5HT autoreceptors and increases 5HT release in the orbitofrontal
cortex after 8 weeks of treatment, but this effect is not seen after 3 weeks [2]. This is ofparticular interest given the ﬁndings suggesting the importance of this region in OCD[75]. In addition, this effect also appears to require larger doses of SSRIs that are effectivein the treatment of depression [78]. Therefore, it may well be the case that some antidepressants are clinically effective in OCD at high doses because of their ability to desensitize
5HT autoreceptors in the orbitofrontal cortex, as opposed to effects seen at lower doses
on other 5HT pathways that are important in the relief of depression.
C. Panic Disorder
Many systems have been hypothesized as involved in the pathophysiology of panic disorder [79]. However, given the evidence illustrating a preferential effect of serotonergic
versus norepinephrinergic antidepressants, the 5HT system is likely to play a major role.
Two possibly conﬂicting hypotheses have been proposed.
The ﬁrst posits that panic disorder results from an excess of 5HT and/or a supersensitivity of postsynaptic 5HT receptors. This is supported by ﬁndings that fenﬂuramine,
which induces neuronal release of 5HT, increases the level of anxiety in panic disorderpatients [80]. In addition, the nonselective 5HT2 agonist mCPP increases anxiety in healthy
subjects as well as in patients with panic disorder [81]. The second 5HT hypothesis of
panic disorder is the complete reverse, postulating that the disorder arises because of a
5HT deﬁcit. Deakin and Graeff [64] have proposed that the serotonergic input to theperiaqueductal gray matter (PAG) is particularly involved in the mediation of panic. The
PAG receives its 5HT input from the dorsal raphé and it is hypothesized that increased
5HT activity to the PAG reduces panic-like response. It is important to note that this
proposed pathway (dorsal raphé to PAG) is different from that hypothesized by the sameauthors as being involved in depression (median raphé to hippocampus) [64]. This 5HT

450

McAllister-Williams and Tyrer

deﬁcit hypothesis is supported by ﬁndings that an infusion of tryptophan appears to decrease anxiety in panic disorder patients [82]. Further, while tryptophan depletion does
not lead to panic attacks directly, it does make patients more sensitive to panicogenic
challenges [83].
On theoretical grounds, the action of SSRIs in alleviating panic disorder is explicableon the basis of either a 5HT excess or a deﬁcit hypothesis. In the former case, SSRIs may
initially increase anxiety [84] because of increased postsynaptic availability. However,the delayed therapeutic response may result from a downregulation of postsynaptic 5HT
receptors, compensating for their pathological supersensitivity and/or an excess of 5HT.
Conversely, if panic disorder results from a 5HT deﬁcit, then SSRIs may act by repeatedadministration, leading to a downregulation of somatodendritic 5HT1A autoreceptors in theraphé, reducing feedback inhibition of the 5HT system and so increased 5HT availability in
PAG. This is a similar explanation as that for the action of antidepressants on the 5HT
system in depression, except that it is an action on somatodendritic 5HT1A autoreceptors
in dorsal, rather than median, raphé nuclei that is important for the treatment in panic
disorder.
D.

Post-Traumatic Stress Disorder

One of the most prominent areas of research into the pathophysiology of PTSD is inrelation to abnormalities in the hypothalamic–pituitary–adrenal (HPA) axis. These studies
have revealed striking differences compared with depression. Severe depressive illness is
associated with hypercortisolemia [72,73] and cortisol nonsuppression in the dexamethasone suppression test (DST) [85]. The hypercortisolemia may arise because of a hypothalamic overdrive because raised corticotrophin-releasing hormone (CRH) is also found in
the CSF of depressed patients [86]. Alternatively (or additionally), raised cortisol and anabnormal DST may arise because of abnormal or reduced glucocorticoid receptors, which
are involved in the feedback control of the HPA axis, because these are found to be reduced
in lymphocytes [87] and in the brains of suicide victims [88]. The situation in PTSD israther different. Patients with this condition have been found to have increased CRH in
CSF, as in depression, but this is associated with normal or even low cortisol levels [89].
In addition, the DST in PTSD patients is either normal [90] or even enhanced [91], regardless of comorbid depression. These ﬁndings have been suggested to result from an increasein glucocorticoid receptors, which has been demonstrated in lymphocytes [92].
Given these differences in pathophysiology between depression and PTSD, it seems
unlikely that antidepressants act in identical ways in the two conditions. Speciﬁcally, thehypothesis that antidepressants act in depression by increasing the expression of glucocorticoid receptors [70] seems to be an unlikely mechanism of action in PTSD, where thesereceptors may already be overexpressed.
With regard to 5HT systems in PTSD, it has been demonstrated that there is areduction in 5HT uptake sites on platelets in patients, regardless of comorbid depression[93]. Investigations in depressed patients show a similar change [94,95]. In both cases,
there appears to be a normalization of 5HT uptake sites upon successful treatment withan SSRI. This argues for a possible similar mechanism of action of antidepressants in
PTSD and depression. However, there is also evidence of an abnormal sensitivity of postsynaptic 5HT2 receptors in PTSD similar to that seen in panic disorder, in that mCPP
provokes symptoms of PTSD in patients [96]. Therefore, it may be the case that the therapeutic effect of antidepressants in PTSD may involve similar 5HT pathways as are relevant

Antidepressant Treatment451

in panic disorder—that is, an effect on dorsal raphé projections to PAG rather than medianraphé projections to the temporal lobe.

IV. SUMMARY
Because antidepressants are effective in the treatment of depression and a number of anxiety disorders, it has been postulated that similar pathophysiological mechanisms may underlie both conditions [97]. This seems unlikely to be the case. As described here, there
are differences in the spectrum of drugs that are effective in treating depression and anumber of anxiety disorders. Furthermore, the clinical response varies according to thediagnosis of the patient, with differing time courses and core symptoms of the anxiety
disorders being differentially affected relative to comorbid depressive symptoms. In addition, there is evidence for several anxiety disorders of a distinct psychopathology that is
separate from that found in depression. Most of the systems postulated to be involved in
the pathophysiology of these conditions, for example, the 5HT system, are extremelycomplex with multiple pathways. It seems likely that the differences in clinical response
may reﬂect differential effects of antidepressants on different systems and/or pathways.
Given the frequent comorbidity of depression and many of the anxiety disorders, together
with the nosological difﬁculty in deﬁning such disorders as generalized anxiety, panic,
and social phobia, it is sometimes hard to draw deﬁnitive conclusions. Nonetheless, there
is no reason to suppose that, because a particular patient responds to an antidepressant,this agent is acting in one speciﬁc way in every case. Beneﬁts may result from the actionof the drug on several distinct neurochemical pathways.
It is unfortunate that the group of drugs that we know as antidepressants was termedin this way. Their efﬁcacy in several conditions other than depression, probably by acting
in a way that is distinct from the way they act in this disorder, clamor for a change inname. It is difﬁcult to characterize these agents simply from the description of a simple
pharmacological action (e.g., speciﬁc serotonin reuptake inhibition) because their efﬁcacy
in some/all conditions may or may not reside in this action. All involved in this rapidly
developing ﬁeld should be aware of the many-faceted actions of the antidepressant drugs
and beware of attributing their actions to alleviation of depression alone.

REFERENCES
1. Lecrubier Y, Ustun TB. Panic and depression: a worldwide primary care perspective. Int Clin
Psychopharmacol 1998; 13(suppl 4):S7–11.
2. Bergqvist PB, Bouchard C, Blier P. Effect of long-term administration of antidepressant treatments on serotonin release in brain regions involved in obsessive-compulsive disorder. Biol
Psychiatry 1999; 45:164–174.
3. Report to the Medical Research Council by its Clinical Psychiatry Committee. Clinical trialof the treatment of depressive illness. Br Med J 1965; 1:881–886.
4. Song F, Freemantle N, Sheldon TA, House A, Watson P, Long A, Mason J. Selective serotonin
reuptake inhibitors: meta-analysis of efﬁcacy and acceptability. Br Med J 1993; 306:683–687.
5. Anderson IM, Tomenson BM. The efﬁcacy of selective serotonin re-uptake inhibitors in depression: a meta-analysis of studies against tricyclic antidepressants. J Psychopharm 1994; 8:
238–249.
6. Anderson IM. Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a metaanalysis of efﬁcacy and tolerability. J Affect Disord 2000; 58:19–36.

452

McAllister-Williams and Tyrer

7. Barbui C, Hotopf M. Amitriptyline v. the rest: still the leading antidepressant after 40 yearsof randomised controlled trials. Br J Psychiatry 2001; 178:129–144.
8. Einarson TR, Arikian SR, Casciano J, Doyle JJ. Comparison of extended-release venlafaxine,
selective serotonin reuptake inhibitors, and tricyclic antidepressants in the treatment of depression: a meta-analysis of randomized controlled trials. Clin Ther 1999; 21:296–308.
9. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or
selective serotonin reuptake inhibitors. Br J Psychiatry 2001; 178:234–241.
10. Seth R, Jennings AL, Bindman J, Phillips J, Bergmann K. Combination treatment with noradrenalin and serotonin reuptake inhibitors in resistant depression. Br J Psychiatry 1992; 161:
562–565.
11. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An
overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin
Pharmacokin 1997; 32(suppl 1):1–21.
12. Katz MM, Koslow SH, Maas JW, Frazer A, Bowden CL, Casper R, Croughan J, Kocsis J,
Redmond, E Jr. The timing, speciﬁcity and clinical prediction of tricyclic drug effects in depression. Psychol Med 1987; 17:297–309.
13. Koran LM, Hamilton SH, Hertzman M, Meyers BS, Halaris AE, Tollefson GD, Downs JM,
Folks DG, Jeste DV, Lazarus LW. Predicting response to ﬂuoxetine in geriatric patients withmajor depression. J Clin Psychopharmacol 1995; 15:421–427.
14. Quitkin FM, McGrath PJ, Stewart JW, Ocepek-Welikson K, Taylor BP, Nunes E, Deliyannides
D, Agosti V, Donovan SJ, Petkova E, Klein DF. Chronological milestones to guide drugchange. When should clinicians switch antidepressants? Arch Gen Psychiatry 1996; 53:785–
792.
15. Georgotas A, McCue RE, Cooper TB, Nagachandran N, Friedhoff A. Factors affecting thedelay of antidepressant effect in responders to nortriptyline and phenelzine. Psychiatry Res
1989; 28:1–9.
16. Anderson IM, Nutt DJ, Deakin JF. Evidence-based guidelines for treating depressive disorders
with antidepressants: a revision of the 1993 British Association for Psychopharmacology
guidelines. J Psychopharmacol 2000; 14:3–20.
17. Hollander E, Greenwald S, Neville D, Johnson J, Hornig CD, Weissman MM. Uncomplicatedand comorbid obsessive-compulsive disorder in an epidemiologic sample. Depression Anxiety
1996; 4:111–119.
18. Rasmussen SA, Eisen JL. The epidemiology and differential diagnosis of obsessive compulsive disorder. J Clin Psychiatry 1992; 53(suppl):4–10.
19. Chen YW, Dilsaver SC. Comorbidity for obsessive-compulsive disorder in bipolar and unipolar disorders. Psychiatry Res 1995; 59:57–64.
20. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger
GR, Charney DS. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, andreliability. Arch Gen Psychiatry 1989; 46:1006–1011.
21. Goodman WK, Price LH, Rasmussen SA, Mazure C, Delgado P, Heninger GR, Charney DS.
The Yale-Brown Obsessive Compulsive Scale. II. Validity. Arch Gen Psychiatry 1989; 46:
1012–1016.
22. Piccinelli M, Pini S, Bellantuono C, Wilkinson G. Efﬁcacy of drug treatment in obsessivecompulsive disorder. A meta-analytic review. Br J Psychiatry 1995; 166:424–443.
23. Thoren P, Asberg M, Cronholm B, Jornestedt L, Träskman L. Clomipramine treatment ofobsessive-compulsive disorder. I. A controlled clinical trial. Arch Gen Psychiatry 1980; 37:
1281–1285.
24. Foa EB, Steketee G, Kozak MJ, Dugger D. Imipramine and placebo in the treatment of obsessive-compulsives: their effect on depression and on obsessional symptoms. Psychopharmacol
Bull 1987; 23:8–11.
25. Goodman WK, Price LH, Delgado PL, Palumbo J, Krystal JH, Nagy LM, Rasmussen SA,
Heninger GR, Charney DS. Speciﬁcity of serotonin reuptake inhibitors in the treatment of

Antidepressant Treatment

26.
27.

28.
29.
30.

31.

32.

33.
34.

35.

36.
37.
38.
39.

40.

41.
42.
43.

44.
45.
46.

453

obsessive-compulsive disorder. Comparison of ﬂuvoxamine and desipramine. Arch Gen Psychiatry 1990; 47:577–585.
Zohar J, Judge R. Paroxetine versus clomipramine in the treatment of obsessive-compulsive
disorder. OCD Paroxetine Study Investigators. Br J Psychiatry 1996; 169:468–474.
Barr LC, Goodman WK, Anand A, McDougle CJ, Price LH. Addition of desipramine to serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder. Am J Psychiatry
1997; 154:1293–1295.
Anonymous. Treatment of obsessive-compulsive disorder. The Expert Consensus Panel forobsessive-compulsive disorder. J Clin Psychiatry 1997; 58(suppl 4):2–72.
Greist JH, Jefferson JW. Pharmacotherapy for obsessive-compulsive disorder. Br J Psychiatry
1998; 175(suppl 35):64–70.
Tollefson GD, Rampey AH Jr, Potvin JH, Jenike MA, Rush AJ, Kominguez RA, Koran LM,
Shear MK, Goodman W, Genduso LA. A multicenter investigation of ﬁxed-dose ﬂuoxetinein the treatment of obsessive-compulsive disorder. Arch Gen Psychiatry 1994; 51:559–567.
Beasley CM Jr, Bosomworth JC, Wernicke JF. Fluoxetine: relationships among dose, response,
adverse events, and plasma concentrations in the treatment of depression. Psychopharmacol
Bull 1990; 26:18–24.
Tyrer SP, Marshall EF, Grifﬁths HW. The relationship between response to ﬂuoxetine, plasma
drug levels, imipramine binding to platelet membranes and whole-blood 5-HT. Prog Neuropsychopharmacol Biol Psychiatry 1990; 14:797–805.
Cowley DS, Flick SN, Roy-Byrne PP. Long-term course and outcome in panic disorder: anaturalistic follow-up study. Anxiety 1996; 2:13–21.
Keller MB, Lavori PW, Goldenberg IM, Baker LA, Pollack MH, Sachs GS, Rosenbaum JF,
Deltito JA, Leon A, Shear K. Inﬂuence of depression on the treatment of panic disorder withimipramine, alprazolam and placebo. J Affect Disord 1993; 28:27–38.
Black DW, Wesner R, Bowers W, Monahan P, Gabel J. Acute treatment response in outpatients with panic disorder: high versus low depressive symptoms. Ann Clin Psychiatry 1995;
7:181–188.
Lecrubier Y. The impact of comorbidity on the treatment of panic disorder. J Clin Psychiatry
1998; 59(suppl 8):11–14.
den Boer JA. Pharmacotherapy of panic disorder: differential efﬁcacy from a clinical viewpoint. J Clin Psychiatry 1998; 59(suppl 8):30–36.
Mavissakalian MR, Perel JM. Imipramine dose-response relationship in panic disorder withagoraphobia. Preliminary ﬁndings. Arch Gen Psychiatry 1989; 46:127–131.
den Boer JA, Westenberg HG. Effect of a serotonin and noradrenaline uptake inhibitor inpanic disorder; a double-blind comparative study with ﬂuvoxamine and maprotiline. Int Clin
Psychopharmacol 1988; 3:59–74.
Fahy TJ, O’Rourke D, Brophy J, Schazmann W, Sciascia S. The Galway Study of Panic
Disorder. I: Clomipramine and lofepramine in DSM III-R panic disorder: a placebo controlled
trial. J Affect Disord 1992; 25:63–75.
Boyer W. Serotonin uptake inhibitors are superior to imipramine and alprazolam in alleviating
panic attacks: a meta-analysis. Int Clin Psychopharmacol 1995; 10:45–49.
Modigh K, Westberg P, Eriksson E. Superiority of clomipramine over imipramine in the treatment of panic disorder: a placebo-controlled trial. J Clin Psychopharmacol 1992; 12:251–261.
Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Baldwin DS, den Boer JA, Kasper S, Shear
MK. Consensus statement on panic disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry 1998; 59(suppl 8):47–54.
Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in
the National Comorbidity Survey. Arch Gen Psychiatry 1995; 52:1048–1060.
Stein DJ, Zungu-Dirwayi N, Der Linden GJ, Seedat S. Pharmacotherapy for PosttraumaticStress Disorder. Cochrane Database Syst Rev CD002795, 2000.
Stein DJ, Seedat S, van der Linden GJ, Zungu-Dirwayi N. Selective serotonin reuptake inhibi-

454

47.
48.

49.

50.

51.
52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.
63.

64.

McAllister-Williams and Tyrer
tors in the treatment of post-traumatic stress disorder: a meta-analysis of randomized controlled
trials. Int Clin Psychopharmacol 2000; 15(suppl 2):S31–S39.
Penava SJ, Otto MW, Pollack MH, Rosenbaum JF. Current status of pharmacotherapy for
PTSD: an effect size analysis of controlled studies. Depress Anxiety 1996; 4:240–242.
Reist C, Kauffmann CD, Haier RJ, Sangdahl C, DeMet EM, Chicz-DeMet A, Nelson JN. A
controlled trial of desipramine in 18 men with posttraumatic stress disorder. Am J Psychiatry
1989; 146:513–516.
Foa EB, Davidson JRT, Frances A. The expert consensus guideline series. Treatment of Posttraumatic Stress Disorder. The Expert Consensus Panels for PTSD. J Clin Psychiatry 1999;
60(suppl 16):3–76.
Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Foa EB, Kessler RC, McFarlane AC, Shalev
AY. Consensus statement on posttraumatic stress disorder from the International Consensus
Group on Depression and Anxiety. J Clin Psychiatry 2000; 61(suppl 5):60–66.
Connor KM, Sutherland SM, Tupler LA, Malik ML, Davidson JR. Fluoxetine in post-traumaticstress disorder. Randomised, double-blind study. Br J Psychiatry 1999; 175:17–22.
Brady K, Pearlstein T, Asnis GM, Baker D, Rothbaum B, Sikes CR, Farfel GM. Efﬁcacy andsafety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial.
JAMA 2000; 283:1837–1844.
Mann JJ, Stanley M, McBride PA, McEwen BS. Increased serotonin-2 and beta-adrenergic
receptor binding in the frontal cortices of suicide victims. Arch Gen Psychiatry 1986; 43:954–
959.
Vetulani J, Stawarz RJ, Dingell JV, Sulser F. A possible common mechanism of action ofantidepressant treatments: reduction in the sensitivity of the noradrenergic cyclic AMP generating system in the rat limbic forebrain. Naunyn Schmiedebergs Arch Pharmacol 1976; 293:
109–114.
Wolfe BB, Harden TK, Sporn JR, Molinoff PB. Presynaptic modulation of beta adrenergic
receptors in rat cerebral cortex after treatment with antidepressants. J Pharmacol Exp Ther
1978; 207:446–457.
Ventulani J, Stawarz RJ, Sulser F. Adaptive mechanisms of the noradrenergic cyclic AMP
generating system in the limbic forebrain of the rat: adaptation to persistent changes in theavailability of norepinephrine (NE). J Neurochem 1976; 27:661–666.
Byerley WF, McCornell EJ, McCabe RT, Dawson TM, Grosser BI, Wamsley JK. Chronic
administration of sertraline, a selective serotonin uptake inhibitor, decreased the density ofbeta-adrenergic receptors in rat frontoparietal cortex. Brain Res 1987; 421:377–381.
Hyttel J, Overo KF, Arnt J. Biochemical effects and drug levels in rats after long-term treatment with the speciﬁc 5-HT-uptake inhibitor, citalopram. Psychopharmacology (Berl) 1984;
83:20–27.
Garcha G, Smokcum RW, Stephenson JD, Weeramanthri TB. Effects of some atypical antidepressants on beta-adrenoceptor binding and adenylate cyclase activity in the rat forebrain.
Eur J Pharmacol 1985; 108:1–7.
Benkelfat C, Ellenbogen MA, Dean P, Palmour RM, Young SN. Mood lowering effect oftryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective
disorders. Arch Gen Psychiatry 1994; 51:687–697.
Klaassen T, Riedel WJ, van Someren A, Deutz NE, Honig A, van Praag HM. Mood effectsof 24-hour tryptophan depletion in healthy ﬁrst-degree relatives of patients with affective disorders. Biol Psychiatry 1999; 46:489–497.
Smith KA, Fairburn CG, Cowen PJ. Relapse of depression after rapid depletion of tryptophan.
Lancet 1997; 349:915–919.
Moreno FA, Gelenberg AJ, Heninger GR, Potter RL, McKnight KM, Allen J, Phillips AP,
Delgado PL. Tryptophan depletion and depressive vulnerability. Biol Psychiatry 1999; 46:
498–505.
Deakin JFW, Graeff FG. 5-HT and mechanisms of defence. J Psychopharm 1991; 5:305–315.

Antidepressant Treatment455

65. Power AC, Cowen PJ. Neuroendocrine challenge tests: assessment of 5-HT function in anxiety
and depression. Molec Aspects Med 1992; 13:205–220.
66. Smith CE, Ware CJ, Cowen PJ. Pindolol decreases prolactin and growth hormone responses
to intravenous L-tryptophan. Psychopharm 1991; 103:140–142.
67. Goodwin GM, de Souza RJ, Green AR. Presynaptic serotonin receptor-mediated response inmice attenuated by antidepressant drugs and electroconvulsive shock. Nature 1985; 317:531–
533.
68. Maj J, Moryl E. Effects of sertraline and citalopram given repeatedly on the responsivenessof 5-HT receptor subpopulations. J Neural Trans Gen Sect 1992; 88:143–156.
69. Blier P, de Montigny C. Current advances in the treatment of depression. Trends Pharmacol
1994; 15:220–226.
70. Barden N, Reul JMHM, Holsboer F. Do antidepressants stabilize mood through actions on
the hypothalamic-pituitary-adrenocortical system? Trends Neurosci 1995; 18:6–11.
71. Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression. Nat Med 2001;
7:541–547.
72. Sachar EJ, Hellman L, Roffwarg HP, Halpern FS, Fukushima DK, Gallagher TF. Disrupted
24-hour patterns of cortisol secretion in psychotic depression. Arch Gen Psychiatry 1973; 28:
19–24.
73. Murphy BPE. General review: steroids and depression. J Steroid Biochem Mol Biol 1991;
38:537–559.
74. McAllister-Williams RH, Ferrier IN, Young AH. Mood and neuropsychological function in
depression: the role of corticosteroids and serotonin. Psychol Med 1998; 28:573–584.
75. Baxter LR Jr, Phelps ME, Mazziotta JC, Guze BH, Schwartz JM, Selin CE. Local cerebral
glucose metabolic rates in obsessive-compulsive disorder. A comparison with rates in unipolar
depression and in normal controls. Arch Gen Psychiatry 1987; 44:211–218.
76. Saxena S, Rauch SL. Functional neuroimaging and the neuroanatomy of obsessive-compulsive
disorder. Psychiatr Clin North Am 2000; 23:563–586.
77. Baxter LR Jr, Schwartz JM, Bergman KS, Szuba MP, Guze BH, Mazziotta JC, Alazraki A,
Selin CE, Ferng HK, Munford P. Caudate glucose metabolic rate changes with both drug andbehavior therapy for obsessive-compulsive disorder. Arch Gen Psychiatry 1992; 49:681–689.
78. el Mansari M, Bouchard C, Blier P. Alteration of serotonin release in the guinea pig orbitofrontal cortex by selective serotonin reuptake inhibitors. Relevance to treatment of obsessivecompulsive disorder. Neuropsychopharm 1995; 13:117–127.
79. Nutt DJ. Antidepressants in panic disorder: clinical and preclinical mechanisms. J Clin Psychiatry 1998; 59(suppl 8):24–28.
80. Targum SD. Differential responses to anxiogenic challenge studies in patients with major
depressive disorder and panic disorder. Biol Psychiatry 1990; 28:21–34.
81. Charney DS, Woods SW, Goodman WK, Heninger GR. Serotonin function in anxiety. II.
Effects of the serotonin agonist MCPP in panic disorder patients and healthy subjects. Psychopharmacology (Berl) 1987; 92:14–24.
82. Charney DS, Heninger GR. Serotonin function in panic disorders. The effect of intravenous
tryptophan in healthy subjects and patients with panic disorder before and during alprazolam
treatment. Arch Gen Psychiatry 1986; 43:1059–1065.
83. Miller HE, Deakin JF, Anderson IM. Effect of acute tryptophan depletion on CO2-induced
anxiety in patients with panic disorder and normal volunteers. Br J Psychiatry 2000; 176:182–
188.
84. Boyer WF, Feighner JP. Side effects of the selective serotonin re-uptake inhibitors. In: Feighner JP, Boyer WF, eds. Selective Serotonin Re-uptake Inhibitors. Chichester: John Wiley &Sons Ltd, 1991:133–152.
85. Carroll BJ, Feinberg M, Greden JF, Tarika J, Albala AA, Haskett RF, James NM, Kronfol
Z, Lohr N, Steiner M, de Vigne JP, Young E. A speciﬁc laboratory test for the diagnosis ofmelancholia. Arch Gen Psychiatry 1981; 38:15–22.

456

McAllister-Williams and Tyrer

86. Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, Kilts CD, Loosen
PT, Vale W. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984; 226:1342–1344.
87. Gormley GJ, Lowy MT, Reder AT, Hospelhorn VD, Antel JP, Meltzer HY. Glucocorticoid
receptors in depression: relationship to the dexamethasone suppression test. Am J Psychiatry
1985; 142:1278–1284.
88. Lopez JF, Chalmers DT, Little KY, Watson SJ. A.E. Bennett Research Award. Regulation ofserotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus:
implications for the neurobiology of depression. Biol Psychiatry 1998; 43:547–573.
89. Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, Bruce AB, Orth
DN, Geracioti TD Jr. Serial CSF corticotropin-releasing hormone levels and adrenocorticalactivity in combat veterans with posttraumatic stress disorder. Am J Psychiatry 1999; 156:
585–588.
90. Kosten TR, Wahby V, Giller E Jr, Mason J. The dexamethasone suppression test and thyrotropin-releasing hormone stimulation test in posttraumatic stress disorder. Biol Psychiatry 1990;
28:657–664.
91. Stein MB, Yehuda R, Koverola C, Hanna C. Enhanced dexamethasone suppression of plasma
cortisol in adult women traumatized by childhood sexual abuse. Biol Psychiatry 1997; 42:
680–686.
92. Yehuda R, Boisoneau D, Lowy MT, Giller EL Jr. Dose-response changes in plasma cortisol
and lymphocyte glucocorticoid receptors following dexamethasone administration in combat
veterans with and without posttraumatic stress disorder. Arch Gen Psychiatry 1995; 52:583–
593.
93. Arora RC, Fichtner CG, O’Connor F, Crayton JW. Paroxetine binding in the blood plateletsof post-traumatic stress disorder patients. Life Sci 1993; 53:919–928.
94. Aberg-Wistedt A, Jostell KG, Ross SB, Westerlund D. Effects of zimelidine and desipramine
on serotonin and noradrenaline uptake mechanisms in relation to plasma concentrations andto therapeutic effects during treatment of depression. Psychopharmacology (Berl) 1981; 74:
297–305.
95. Stain-Malmgren R, Khoury AE, Aberg-Wistedt A, Tham A. Serotonergic function in major
depression and effect of sertraline and paroxetine treatment. Int Clin Psychopharmacol 2001;
16:93–101.
96. Southwick SM, Paige S, Morgan CA III, Bremner JD, Krystal JH, Charney DS. Neurotransmitter alterations in PTSD: catecholamines and serotonin. Semin Clin Neuropsychiatry 1999; 4:
242–248.
97. Hudson JI, Pope HG Jr. Affective spectrum disorder: does antidepressant response identify afamily of disorders with a common pathophysiology? Am J Psychiatry 1990; 147:552–564.

19Studies on the Neurobiology
of Depression
CARLOS A. ZARATE, Jr. and DENNIS S. CHARNEY
National Institute of Mental HealthNational Institutes of Health
Bethesda, Maryland, U.S.A.

I.

INTRODUCTION

Major depressive disorders are common, severe, chronic and often life-threatening illnesses. It is estimated that more than 15% of all adults will experience a major depressive
episode at some point in their lives [155,280]. Suicide is estimated to be the cause ofdeath in up to ⬃15% of individuals with major depressive disorders and, in addition tosuicide, many other deleterious health-related effects are increasingly being recognized[231,309]. Indeed, there is a growing appreciation that, far from being diseases with purely
psychological manifestations, major depressive disorders are systemic diseases with deleterious effects on multiple organ systems [231,309]. For example, major depressive disorders represent a major risk factor for both the development of cardiovascular disease, as
well as for death after an index myocardial infarction [231,309]. Furthermore, a recent
study, which controlled for physical illness, smoking, and alcohol consumption found thatthe magnitude of the increased mortality risk conferred by the presence of high depressive
symptoms was similar to that of stroke and congestive heart failure [309]. The cumulative
effects of recurring bouts of affective episodes lead to an increased rate of marital andfamily breakdown, unemployment, impaired career progress, and consequent ﬁnancial
difﬁculties. The costs associated with disability and premature death from major mooddisorders represent an economic burden of tens of billions of dollars annually in the UnitedStates alone [126,378].
Despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30 to 40% of depressed patients fail to respond to ﬁrst-line antidepressant treat457

458

Zarate and Charney

ment despite adequate dosage, duration, and compliance [344]. There is mounting evidence that recurrent mood disorders—once considered “good prognosis diseases”—are,in fact, often very severe and life-threatening illnesses. For many patients, the long-term
outcome is often much less favorable than previously thought, with incomplete interepisode recovery, and a progressive decline in overall functioning observed [347]. While
there is often a complete remission of symptoms, and general functioning returns to premorbid level in some patients, in a large proportion of cases, some symptoms of theepisode persist for long periods of time and functioning may be severely impaired. Indeed,according to the Global Burden of Disease Study, mood disorders are among the leading
causes of disability worldwide and are likely to represent an increasingly greater health,societal, and economic problem in the coming years [230]. Despite the devastating impactthat these diseases have on the lives of millions worldwide, there is still a dearth of knowledge concerning their underlying etiology and pathophysiology. This dearth of knowledge
regarding the cellular underpinnings of depression has undoubtedly contributed to the lackof development of new treatments for depression. Studies on pathophysiology of mooddisorders involve genetics, neurotransmitter systems, intracellular signal transduction
pathways, neurotrophic factors, neuroimaging, endocrine abnormalities, neurodegeneration, vascular disease and increased platelet aggregability, pineal function and circadianrhythm, and immunological function. This chapter will review studies on the pathophysiology of major depression.
II. GENETICS OF MOOD DISORDERS
Genetics undoubtedly plays a major role in the etiology of mood disorders. By determining
the rates of illness in different types of relatives, genetic epidemiological studies can provide information about the familial and genetic nature of a disorder (e.g., depression).
The probability that a person will develop a mood disorder is inﬂuenced by a number offactors, including premature death of a parent, a history of traumatic event, inadequate
rearing by parents, poverty, malnutrition, medical illness (e.g., diabetes), personal or family history of affective episodes, extent of psychosocial support, and recent stressful life
events [152]. In terms of the genetic component of major depression, such studies havebeen conducted and provide much information about the genetic transmission of mooddisorders. Three types of studies have been used to determine the role of genetic factors
in mood disorders: (1) family studies; (2) twin studies; (3) adoption studies.
A.

Family Studies

Family studies address the question of whether a disorder is familial. These types of studies
determine whether the rate of depression in the family members of the probands with thedisorder is greater than that of the general population. The studies conducted on the families of probands with unipolar depression reveal morbid risks for depressive disorders
among ﬁrst-degree relatives, which are two to three times those of the general population.
These data argue strongly for a genetic component of mood disorders. Depressive disorders have also been reported to occur at a higher rate in the families of probands withbipolar disorders, and the rate of bipolar disorder is also elevated in the families of probands with depressive disorders. The morbid risk of bipolar disorder in ﬁrst-degree relatives of bipolar disorder probands is reported to range between 3 and 8%. This rate contrasts markedly with the 1% rate in the general population. Weissman and colleagues

Neurobiology of Depression

459[364] reported that the ﬁrst-degree relatives of patients with bipolar disorder were at least
24 times more likely to develop bipolar disorder than relatives of control subjects. A recent
meta-analysis found that, across ﬁve family studies, there was strong evidence for an
association between major depression in the probands and major depression in ﬁrst-degree
relatives [336]. However, family studies cannot establish that a disorder is hereditary, asfamilial aggregation of a disorder (e.g., major depression) may reﬂect a shared environment [255]. Other types of genetic studies address some of the limitations of family
studies.
B. Twin Studies
The family study data clearly indicate that affective disorders are familial. However, suchstudies cannot distinguish whether genetic or environmental factors are responsible forfamilial transmission. Families might share a variety of different environmental factorsthat could transmit the illness. Such factors might be common exposure to a particular
culture, diet, behavior, virus, toxin, or other brain insult. Twin studies provide a powerfulapproach to teasing out genetic from environmental factors. Twin studies compare theconcordance rate for illness in pairs of monozygotic (identical) twins with the rate of
dizygotic (nonidentical) twins. The rationale is that monozygotic twins share identicalgenes, whereas dizygotic twins share only half their genes. Typically, twin pairs are selected who have been raised together, so that environmental factors are shared equally.
Thus, if monozygotic twins show a greater concordance rate for a particular psychiatricdisorder than do dizygotic twins, this is believed to be evidence for a genetic contribution
to development of the disorder. The marked difference in concordance rates between monozygotic and dizygotic twins strongly supports the hypothesis of a major genetic contribution to the development of unipolar depression [151,152,213,214]. These studies ﬁnd thatthe concordance rate for mood disorder in monozygotic twins is two to four times thatin dizygotic twins. Since the concordance rate for monozygotic twins is not 100%, othernonheritable environmental factors are at work and also play a signiﬁcant role in mooddisorders.
C. Adoption Studies
Adoption studies provide an attempt to tease out the genetic and environmental factors
in familial transmission. Mendlewicz and Rainer [220] found a threefold increase in therate of bipolar disorders in biological relatives of probands with bipolar disorders. They
also found a twofold increase in the rate of depressive disorders in biological relatives[220]. Similarly, Wender and colleagues [362] found evidence for a genetic effect on thetransmission of major depression. The authors reported a threefold increase in the rate of
unipolar disorder and a sixfold increase in the rate of completed suicide in the biologicalrelatives of mood disorder probands. Using offspring of psychiatrically disturbed and normal biological parents, adopted at birth, Cadoret found that the incidence of depression
was signiﬁcantly higher in the affective-parented adoptees (3 depressed of 8 adoptees)
than in the remaining adoptees whose biological parents had other psychiatric conditions
or were apparently psychiatrically well (8 depressed of 118). The results suggest a genetic
factor in affective disorders. In contrast, the study by von Knorring et al. [358] did not ﬁndan increase in mood disorders in the biological parents of adoptees with mood disorders.
Unfortunately, this method of study has not been pursued much in the last two decades,
thus limiting the amount of data with which to make any ﬁrm conclusions.

460

Zarate and Charney

III. MODE OF TRANSMISSION
Although the genetic basis for affective disorders has been recognized, the exact modeof transmission remains unknown. An initial report in the Amish community found thatthe gene responsible for manic-depressive illness was found to be positioned on chromosome 11 and was inherited by autosomal dominant transmission [107]. Unfortunately,subsequent analysis on an expanded data set of the same population was unable to conﬁrm
the investigators’ original ﬁndings [149]. Other investigators have reported linkage between bipolar disorder and the X chromosome [45], chromosome 4 [44], chromosome 5[71], chromosome 6 [348], chromosome 11 [107], chromosome 12 [80], chromosome 16[112], chromosome 18 [36], chromosome 18q for bipolar II [217], and chromosome 21[335]. Recently, Souery and colleagues [328] failed to detect an association between the
A2186C polymorphism of the trytophan hydroxylase gene and bipolar and unipolar affective disorders.
While the study of the mode of transmission in mood disorders has certainly advanced in the past decade, the exact mode of transmission still remains unknown.
A.

Neurotransmitter Hypothesis

1. Norepinephrine and Adrenergic Receptors
The noradrenergic system was one of the ﬁrst neurotransmitter systems studied in thepathophysiology of depression. Early theories of depression postulated that an imbalancein the metabolism of norepinephrine was responsible for affective disorders [56,305]. The
hypothesis that the noradrenergic system was responsible for the pathophysiology of affective disorders was referred to as the “catecholamine hypothesis” of affective disorders.
The noradrenergic dysfunction in the pathophysiology of depression has been reported tooccur at many different levels, including problems with precursor availability, neurotransmitter synthesis, storage, release, presynaptic autoreceptor function, neurotransmitter reuptake, metabolism, and postsynaptic neurotransmitter receptors.
Norepinephrine, epinephrine, and dopamine are all catecholamines, and the principal
metabolite of norepinephrine, 3-methoxy-4-hydroxyphenylglycol (MHPG), is generally
considered to reﬂect presynaptic activity of noradrenergic neurons. This metabolite canbe measured in cerebrospinal ﬂuid (CSF), plasma, and urine. In these earlier studies,
MHPG was found to be elevated in CSF in patients with depression, mania, and schizoaffective disorder [305]. The predictive value of CSF levels of the norepinephrine metabolites and response to antidepressant treatment has received much attention. The CSF
level of norepinephrine metabolites has been studied in patients receiving treatment withtricyclic antidepressants (desipramine, nortriptyline, amitriptyline), maprotiline, bupropion, ﬂouxetine, and ﬂuvoxamine. Asberg and colleagues [13] reported that treatment withclomipramine in 14 depressed patients resulted in signiﬁcant decreases in the levels of 4hydroxy-3-methoxyphenyl glycol MHPG. Aberg-Wistedt and colleagues [1] reported thathigh levels of MHPG in CSF in depressed patients at baseline predicted a better response
to desipramine than those with low levels of this norepinephrine metabolite. Dahl andcolleagues [81] reported that in spite of a signiﬁcant improvement in depressive symptoms
in depressed outpatients treated with desipramine 150 mg/day for 6 weeks, there were no
consistent changes in MHPG in CSF. In addition, the pretreatment level of CSF MHPG
had no predictive value for the outcome of desipramine treatment. Mendlewicz and col-

Neurobiology of Depression

461

leagues [221] reported that treatment with 150 mg/day amitriptyline for 14 days in depressed inpatients with moderate-to-severe illness resulted in a signiﬁcant decrease in CSF
levels of MHPG. However, they did not ﬁnd a relationship between therapeutic response,
plasma antidepressant levels, or pretreatment CSF MHPG levels in this small group ofpatients. Nordin et al. [246] reported that treatment with nortriptyline in depressed patientsfor 3 weeks was associated with a 31% mean decrease in the MHPG in CSF. The samegroup [247] later reported an 18% mean decrease in MHPG in CSF in ﬁve depressed
patients treated with E-10-hydroxynortriptyline (the major metabolite of nortriptyline).
Timmerman and colleagues [346] found no correlation in clinical response and CSF
MHPG in depressed patients treated with maprotiline for 3 weeks. Golden and colleagues[123] reported that there was a trend toward a reduction in CSF MHPG following successful bupropion treatment in depressed patients, although this change did not achieve statistical signiﬁcance. Recent studies have documented that ﬂuvoxamine or ﬂuoxetine treatment
of depression is associated with signiﬁcant reductions of CSF MHPG concentrations, conﬁrming the notion that even selective serotonergic antidepressants may ultimately affectthe noradrenergic system [317]. Martensson et al. [200] reported that CSF MHPG concentrations decreased signiﬁcantly in depressed patients treated with the serotonergic antidepressant ﬂuoxetine. Similarly, DeBellis et al. [86] reported that CSF MHPG levels fornine depressed patients, although no different from those of control subjects, decreased
signiﬁcantly after treatment with ﬂuoxetine.
Some authors [315] have suggested that caution should be exercised when interpreting CSF MHPG levels in depressed patients without correction for the diffusion of MHPG
across the blood–brain barrier. Kopin and colleagues [162] reported that concentrationsof free MHPG in the plasma and CSF are highly correlated, but that concentrations in
the CSF are always higher than those in plasma, even when large amounts of the catecholamine metabolite are derived from a tumor of the adrenal medulla. MHPG that is synthesized, but not catabolized, in the CNS maintains CSF ﬂuid levels at an increment overthose in plasma.
Elevated plasma norepinephrine and norepinephrine metabolite concentrations[180,289,354], and elevated urinary concentrations of norepinephrine and its metabolites,
have been reported in patients with unipolar depression. Rudorfer and colleagues [292]reported that supine plasma norepinephrine levels were signiﬁcantly lower in bipolar patients than in either unipolar depressives or normal volunteers. Following the orthostaticchallenge, the fractional norepinephrine increase in both patient groups exceeded that in
the controls. Siever and colleagues [321] reported that plasma MHPG responses to clonidine were reduced in depressed patients compared to controls, suggesting a reduced responsiveness of α2-adrenergic receptors in depression. While depressed patients have highbasal plasma concentrations of norepinephrine, those with melancholia are reported tohave even greater elevations in plasma norepinephrine levels when subjected to orthostaticchallenge than do either nondepressed control subjects or depressed patients without melancholia [288]. Furthermore, depressed patients who are dexamethasone (DST) nonsuppressors have signiﬁcantly higher basal and cold-stimulated levels of norepinephrine than
do depressed patients who are DST suppressors [288]. Following treatment with tricyclic
antidepressants (TCA), urinary excretion of norepinephrine and its metabolites diminisheswith plasma norepinephrine concentrations [65,123].
The association between CSF and plasma norepinephrine metabolites and suicide
has not been thoroughly examined. Secunda and colleagues [302] reported that in de-462

Zarate and Charneypressed inpatients who participated in the NIMH Collaborative Study on the Psychobiology of Depression that the CSF and plasma MHPG did differentiate between suicide attempters and nonattempters.
Initial research examining urinary MHPG levels attempted to stratify patients withunipolar depression based on MHPG values. Patients with unipolar depression have beenclassiﬁed as having low, intermediate, or high urinary MHPG values [307]. Those patientsin the low category are considered to have diminished activity of the noradrenergic system
and are reported to respond to treatment with tricyclic and tetracyclic antidepressants andﬂuoxetine [137,185]. Patients with unipolar depression and high MHPG values are believed to have increased activity of presynaptic noradrenergic neurons. These groups ofpatients are also reported to have high plasma cortisol levels, to be nonsuppressors on the
DST tests, and to be resistant to treatment with conventional antidepressants. The utilityof intermediate MHPG values in unipolar patients remains unknown.
Aberg-Wistedt et al. [1] reported that in depressed patients urinary excretion of
MHPG decreased signiﬁcantly during desipramine treatment. Bipolar patients are reported
to have signiﬁcantly elevated plasma norepinephrine and epinephrine concentrations during manic episodes than during depression or euthymia [191]. Manic patients also exhibit
signiﬁcantly increased urinary concentrations of norepinephrine in comparison to depressed patients or control subjects [338]. In a later study, Swann and colleagues [339]
noted that an individual’s “environmental sensitivity” had a signiﬁcant effect on urinary
norepinephrine excretion. Manic patients whose episodes were environmentally sensitive
demonstrated elevated norepinephrine excretion, compared with patients with manic episodes that were unrelated to external stressors.
Much research has emphasized the quantitation of catecholamine metabolites to obtain more homogeneous subtypes of depressed patients. With regard to urinary excretionof MHPG, unipolar depressed patients are more heterogeneous than are bipolar I patients[184]. Plasma and urinary concentrations of MHPG were signiﬁcantly elevated in bipolar
patients when they were manic compared with MHPG concentrations when these patientswere depressed [130]. Furthermore, depressed bipolar patients were found to have signiﬁcantly diminished urinary MHPG concentrations than unipolar depressed patients orhealthy control subjects [306].
More recent studies suggest that reduced urinary MHPG concentrations are characteristic of bipolar I depressed patients but not bipolar II depressed patients, with MHPG
levels similar to those of patients with unipolar depression [303]. Patients with unipolar
depression generally have greater urinary MHPG concentrations than bipolar I patients.
Kopin and colleagues [163] argue that the measurement of urinary MHPG may have little
value in assessing the noradrenergic system because less than 20% of MHPG is derived
from brain norepinephrine metabolism. Furthermore, because unconjugated MHPG isreadily diffusible, there is a free exchange of this metabolite among plasma, CSF, andnerve tissues (including brain and spinal cord). The CSF MHPG levels, after correction
for the plasma contribution of the metabolite, more accurately reﬂect its rate of formationin the CNS. Hollister and colleagues [137] have also emphasized early on that collecting
urine for MHPG determination in depressed patients is not easy, that the variability of
excretion within patients is considerable, and the range of MHPG excretion closely parallels that in normal persons. Tsuji et al. [349] found correlations among the CSF concentrations of MHPG and 3,4-dihydroxyphenylglycol (DHPG) in CSF and plasma, but no signiﬁcant correlations were found between the urinary levels and either plasma or CSF levelsof these metabolites. Furthermore, neither the MHPG nor DHPG levels in the urine ofNeurobiology of Depression

463

depressed patients revealed any signiﬁcant correlation with their clinical assessments using
the Hamilton rating scale score.
The relationship between sympathoadrenal and hypothalamic–pituitary–adrenal(HPA) axis activity has also been an active area of investigation in patients with major
depression. Several [303], but not all [186], investigators have reported signiﬁcant positive
correlations between urinary cortisol and urinary MHPG concentrations in depressed patients. A similar positive correlation has been reported for plasma cortisol and epinephrine
concentrations [334]. Previous studies regarding the levels of CSF norepinephrine and
CSF corticotropin-releasing hormone (CRH) receptor have reported normal, reduced, andincreased levels [118,234,270,288]. Recently, Wong and colleagues [376] reported that,around the clock, patients with melancholic depression have elevated levels of CSF norepinephrine and plasma cortisol, but not CSF CRH or plasma adrenocorticotropic hormone(ACTH).
In summary, the data suggest that plasma or CSF noradrenergic metabolites (MHPGand DHPG) provide more important information than those in the urine. However, thesetypes of studies have fallen into disuse over recent years and have not been replicated.
Over the last several years, there has been a steady shift in utilizing less invasive, invivo, high-resolution methods (functional magnetic resonance imaging, positron emission
tomography, and single-photon-emission computed tomography) to study the catecholamine function in the CNS of depressed patients instead of peripheral measures of catecholamine function.
Additional evidence of noradrenergic dysfunction in the pathophysiology of depression comes from studies that use α-methylparatyrosine (AMPT) to deplete central norepinephrine stores [225]. In these studies, administration of AMPT to depressed patients who
had been successfully treated with desipramine or mazindol (both are NE uptake inhibitors) resulted in a rapid return of depressive symptoms. Interestingly, administration of
AMPT to depressed patients did not worsen the core symptoms of depression but didcause worsening of some neurovegetative symptoms, in particular, anergy and tiredness[225].
Neurotransmission in the noradrenergic system is mediated by a number of different
neurotransmitter receptors whose function has been implicated in either the pathophysiology of depression or in the mechanism of action of antidepressants. The α2-adrenergic
receptors and β-adrenergic receptors have been the focus of considerable research on theirrole in the pathophysiology of depression. Increased α2-receptor density is seen in thebrains of suicide victims [218]. Treatment with antidepressants has been associated withdecreases in the density and sensitivity of these receptors on platelets. Several methods
have been used to investigate the role of the α2-receptor in depression. An indirect method
for studying α2-receptors is to challenge subjects with the α2-receptor agonist clonidine.
Administration of clonidine induces growth hormone secretion, primarily through postsynaptic α2-receptors. Several abnormalities in growth hormone release in patients withmajor depression have been reported. Growth hormone response to clonidine is blunted
in unipolar depressed patients [202,321,322], supporting the concept of decreased responsiveness of postsynaptic α2-adrenergic receptors in depressed patients.
Charney and colleagues [66] reported that long-term desipramine treatment signiﬁcantly attenuated the effects of clonidine on plasma MHPG level and blood pressure,indicating that during desipramine treatment α2-adrenergic receptors had become subsensitive. In addition, they reported that plasma MHPG levels were signiﬁcantly reduced duringlong-term desipramine treatment. Neuroendocrine tests have also been used in an attempt

464

Zarate and Charney

to better subtype depression. Price et al. [273] reported that the cortisol response to yohimbine (an α2-adrenergic antagonist) was signiﬁcantly greater in depressed patients than incontrols, despite similar MHPG responses between groups.
Maes and colleagues [189] reported that major depression is accompanied by decreased platelet α2-adrenoreceptor density, and that subchronic treatment with TCAs, but
not ﬂuoxetine, resulted in a decreased afﬁnity of rauwolscine (a selective α2-adrenergic
antagonist) for platelet α2-adrenoceptor. Another method of examining the function of α2receptors is to measure intracellular response following α2-receptor activation. GarciaSevilla and colleagues [116] measured the functional status of α2-receptors in depressed
patients by assessing both inhibition of adenylate cyclase activity and induction of platelet
aggregation. They concluded that the latter measure was a better marker to assess changes
in the α2-receptor in depressed patients.
The β1- and β2-adrenergic receptor subtypes are found postsynaptically and also
stimulate the intracellular adenylate cyclase system. Preclinical studies have shown thatchronic antidepressant administration produces desensitization of the β-adrenergic receptor. The β-adrenergic receptor downregulation hypothesis posits that the mode of actionof clinically effective antidepressants is by decreasing the number of β-adrenergic receptor
sites. Initial measurements of these β-adrenergic receptors in depressed patients haveyielded mixed results. Biegon et al. [37] reported a signiﬁcant, 50% increase in β-adrenergic receptor density found in prefrontal cortical homogenates in the postmortem brain
tissue of suicide victims. They reported that the increased binding is selective, appearing
in some cortical regions but not in basal ganglia or white matter areas. Mann and colleagues [197] also reported increased β-adrenergic receptor density in post-mortem brain
tissue of suicide victims. However, Crow and colleagues [79] demonstrated decreased
density of hippocampal β-adrenergic receptors in the postmortem brain tissue of depressed
patients who had been hospitalized. In this latter group, previous antidepressant treatment
may have induced β-adrenergic receptor downregulation. Similarly, contradictory results
have been reported from studies determining the Bmax (number of binding sites) for βreceptors on leukocytes. Some investigators have reported reduced Bmax for peripheral βreceptors in depressed patients, but others have documented no difference between depressed patients and healthy control subjects [132]. Monoamine oxidase (MAO)-A is an
important target of a number of antidepressant drugs that inhibit its activity. Based on
this pharmacological action and other evidence, a number of researchers reasoned that
depression may have its biological basis in disruption of central monoamine systems. A
number of investigators have measured MAO activity in brains from suicide victims andnonsuicide control subjects. Mann and Stanley [197], Sherif et al. [319], and Galva et al.
[115] demonstrated no change in MAO-A activity in the frontal cortex of suicide victims
compared to that of control subjects. Ordway and colleagues [253] also failed to ﬁnd any
differences in MAO-A distribution at any level of the locus ceruleus or raphe nuclei between subjects with major depression or psychiatrically normal controls.
Lecrubier et al. [172] supported the noradrenergic hypothesis of depressive states,
especially the involvement of β-adrenergic receptors in depression. They reported that theuse of salbutamol, a β-adrenergic stimulant, depressed patients had in some cases led toa clear and rapid antidepressant effect.
2. Serotonin
The serotonergic system has also received much study in the pathophysiology of depression. The hypothesis that the serotonin is responsible for the pathophysiology for affectiveNeurobiology of Depression

465

disorders has been referred to as the “serotonin hypothesis” of affective disorders [219].
There is considerable evidence of abnormalities in the serotonergic neurotransmitter system in patients suffering from depression [219]. The serotonergic dysfunction in the pathophysiology of depression has been reported to occur at many different levels, including
problems with precursor availability, neurotransmitter synthesis, storage, release, presynaptic autoreceptor function, neurotransmitter reuptake, metabolism, and postsynaptic
neurotransmitters receptors.
Serotonin is synthesized from the amino acid tryptophan, which is derived from thediet. The rating-limiting step in serotonin synthesis is the hydroxylation of tryptophan by
the enzyme tryptophan hydroxylase to form 5-hydroxytryptophan. Under normal circumstances, this rating-limiting enzyme is not saturated by substrate, so tryptophan concentration can impact the rate of synthesis. Tryptophan is then taken up into brain via a saturable
carrier mechanism. Tryptophan actively competes with other large neutral amino acids
for transport; brain uptake of tryptophan is determined both by the amount of circulating
tryptophan and by the ratio of tryptophan to the other large neutral amino acids. This ratio
may be affected (elevated) by carbohydrate intake, which induces the release of insulin
and the uptake of many large neutral amino acids into peripheral tissues. High-protein
foods tend to be relatively low in tryptophan, thus lowering this ratio. The administrationof specialized low-tryptophan diets has been found to produce signiﬁcant declines in thebrain serotonin levels.
Pretreatment plasma tryptophan has been reported to be lower in depressed patients
than in healthy controls and to differentiate certain subgroups of depression [187,219].
Depressed patients exhibit reduced plasma concentrations of 5-hydroxytryptophan afteringestion of test doses of oral L-tryptophan [82]. Other studies report that, in normal
control subjects, lowering of plasma tryptophan via dietary manipulation produces a depressed mood [89]. The occurrence of depression following acute tryptophan depletionhas been reported to occur more commonly in healthy subjects with ﬁrst-degree relatives
with affective disorders than in healthy subjects with no family history of a mood disorder[33,109]. Lower pretreatment plasma tryptophan has been reported to predict antidepressant treatment [181,227]. The depletion of dietary L-tryptophan has also been reported toinduce relapse in recently remitted depressed patients [89,239]. In contrast to these ﬁndings, several studies have recently found that the effect may be less consistent than previously reported. Moore and colleagues [228] observed no effect on mood in fully remitted
patients medicated with selective serotonin reuptake inhibitors (SSRIs). Leyton and colleagues [177] also reported that acute tryptophan depletion did not induce relapse orchange in mood in fully remitted, medication-free, former patients with major depression.
In another study [1] of patients who had responded to treatment with citalopram, only 5of 12 patients relapsed, and the effect seemed to be clinically signiﬁcant in only 1 patient.
While depletion of dietary L-tryptophan has been reported to induce relapse in recently
remitted depressed patients, Cassidy and colleagues [63] did not ﬁnd that depletion of Ltryptophan results in relapse in patients who had successful treatment with ECT. Theseprevious studies suggest that acute tryptophan depletion reﬂects a reversal of mechanisms
involved in the therapeutic effects of antidepressants but not of ECT. Depletion of plasma
tryptophan has been reported to cause dysphoria in the ﬁrst-degree relatives of patientswith depression.
A series of neuroendocrine challenge paradigms have been conducted to moreclosely examine the presynaptic serotonergic neurons in patients with depression. In normal subjects, the intravenous infusion of tryptophan increases prolactin plasma levels

466

Zarate and Charney[274]. However, in depressed patients, this release of prolactin to intravenous tryptophan
is blunted compared to healthy controls [62,274]. The neuroendocrine challenge with theappetite suppressant fenﬂuramine also produces similar results to the intravenous infusionof tryptophan. The administration of fenﬂuramine causes a rapid increase in the plasma
levels of prolactin in normal healthy subjects. However, when fenﬂuramine is administeredin depressed patients, the prolactin release is blunted [226,314]. The blunted prolactin
response has been reported to normalize with successful treatment and has been proposed
as a test for predicting response to antidepressant treatment [195,314].
Recent neuroendocrine challenge studies have incorporated the use of PET technology. Instead of measuring prolactin, PET scans measure the blood ﬂows in response to
fenﬂuramine challenge [198]. In this study, similar to the results obtained with serum
prolactin levels, depressed subjects who were challenged with fenﬂuramine had a signiﬁcant decrease in cerebral glucose utilization compared to normal controls. Another neuroendocrine challenge test that has been used is m-chlorophenylpiperazine (m-CPP) [8].
m-CPP has mixed pharmacological actions at the postsynaptic serotonin receptors. Twostudies did not ﬁnd differences in neuroendocrine measures between depressed and healthy
controls following a challenge with m-CPP [8,274].
The utility of directly measuring 5-hydroxyindolacetic acid (5-HIAA), the principal
metabolite of serotonin, in CSF in patients with depression remains unclear. Several studies have detected reduced CSF concentrations of 5HIAA in some depressed patients, inpatients who committed suicide, particularly by violent means, independent of their psychiatric diagnosis, and in patients who had poor impulse control [353,356].
Another method for evaluating presynaptic serotoninergic function is by the measurement of serotonin transporter (SERT) binding. SERT’s role is to pump serotonin fromthe synaptic space back to the presynaptic neuron. Since SERT is transcribed from a single
copy gene, both the platelet and CNS SERT are identical. Thus, abnormalities in platelet
SERT most likely reﬂect problems with CNS SERT. The SERT has been studied both inplatelets and in post-mortem tissue of patients who were depressed at the time of death.
A number of studies on the concentration of the SERT on platelets have been measured with [3H]-imipramine binding and [3H]-paroxetine binding. The results of these studies have been mixed, with some studies reporting no differences in the Bmax for the platelet
SERT between depressed and healthy control subjects [50,51]. However, a large metaanalysis reported that the Bmax value for platelets was signiﬁcantly lower in depressedcompared to healthy control subjects [110].
A number of studies investigating SERT in projection regions of serotonergic cellbodies in suicide victims with depressive disorder have been conducted on post-mortem
brain tissue. The results of these studies are mixed. Early studies primarily focused on
suicide victims and used [3H] imipramine, a less than optimum radioligand, for measuringserotonin transporter. The earlier studies reported increases, decreases, or no change in[3H] imipramine binding to frontal cortex in suicide victims [12,79,330]. More recently,
other radioligands including [3H] paroxetine, [3H] citalopram, and [125I] cyanoimipramine
have been identiﬁed as superior ligands for measuring serotonin transporters [129]. Unfortunately, the results with these newer ligands in subjects with depression are also mixed.
Some studies reveal either signiﬁcant decreases [10,145] or no changes [40,197].
Several different serotonin receptor subtypes have been identiﬁed in recent years.
Subtyping is based in part on the characteristics of binding to serotonin, other agonists,
or antagonists. Three main classes—5HT1, 5HT2, and 5HT3 receptors—are further subdivided into subtypes 5HT1A, 5HT1B, 5HT1D, 5HT1E, 5HT1F. The 5HT2 receptor appears toNeurobiology of Depression

467

be virtually identical to the 5HT1C receptor; this class may be divided into 5HT2A and 5HT2B
subtypes. The 5HT1A receptor, in particular, has been implicated in the pathophysiology
of mood disorders through evidence that major depressives have blunted physiologicalresponses to 5HT1A-receptor agonists in vivo and abnormal 5HT1A-receptor binding postmortem [46,178,333]. During 5HT1A-receptor agonists challenge, the physiological increases of plasma concentrations of ACTH and cortisol are attenuated in unmedicatedsubjects with major depressive disorder [77]. Postmortem studies of cerebral 5HT1Areceptor binding and mRNA expression in major depressive disorders and bipolar disorder suggest 5HT1A-receptor dysfunction in mood disorders, but these data are limited
to two studies involving small sample sizes [46,178]. Lopez and colleagues [178] showed
5HT1A-receptor mRNA levels were abnormally reduced in the hippocampus in six subjects
with major depressive disorder who died by suicide, and Bowden et al. [46] found reduced
5HT1A-receptor binding to [3H]8-OH-DPAT in the temporal polar and posterior ventrolateral prefrontal cortex in seven medication depressives with major depressive disorder orbipolar disorder dying of natural causes. Supporting the postmortem ﬁndings, Drevets andcolleagues [98] reported that the regional 5HT1A-receptor binding of depressed subjects
with primary, recurrent, familial mood disorders determined by using positron emission
tomography was signiﬁcantly reduced compared to healthy controls. The investigators
found that the mean 5HT1A-receptor binding potential was reduced by 42% in the midbrain
raphe and 25 to 33% in limbic and neocortical areas in the mesiotemporal, occipital, andparietal cortex.
Cowen and colleagues [76] have suggested that major depression may be associatedwith impaired sensitivity of 5HT1A autoreceptors and that the decrement in serotonin neurotransmission at postsynaptic 5HT1A receptors in depression is due to decreased serotoninrelease rather than impaired responsivity of postsynaptic 5HT1A receptors.
Mann and colleagues [197] reported an increased number of postsynaptic 5HT2 receptors in the brains of depressed patients. Mattsubara and colleagues [203] documented
an increase in the number of 5HT1 and 5HT2 receptors in the prefrontal cortex of suicide
victims, although other investigators have not replicated this ﬁnding [332].
ECT has been reported to enhance central serotonergic responsivity [313]. Chronic
administration of effective antidepressant therapy, including ECT, induces an upregulationin the number of 5HT1A postsynaptic receptors [131]. Even antidepressants such as desipramine, which act primarily on norepinephrine neurons, appear to exert potent effects on
5HT1A receptors [182]. Conversely, most antidepressants—including MAOIs, TCAs,
SSRIs, nefazodone, and trazodone—induce downregulation of postsynaptic 5HT2 receptors [75,124]. One notable exception is ECT, which results in upregulation of 5HT2 receptors [174].
5HT2-receptor binding to platelet membranes and serotonin-induced shape change
and aggregation have been used to study 5HT2 receptors in patients with mood disorders.
Biegon and colleagues [38] suggested that the increase in number of 5HT2 receptors onplatelets may be viewed as a state-dependent marker in major depression. In their studyof 15 depressed patients, 3 weeks of treatment with maprotiline were associated withsigniﬁcant decreases in 5HT2-receptor binding in responders; in contrast, receptor binding
increased or remained the same in the nonresponders.
The human platelet concentrates serotonin from plasma via the serotonin transporterin a fashion similar to that seen in the brain, and therefore it has been posited as a modelof central serotonin neurons. [3H] Imipramine binds to the serotonin transporter on thepresynaptic nerve terminal and on the platelet. A reduction in the number of the platelet

468

Zarate and Charney[3H] imipramine binding sites in depressed patients has been reported by several groups[50,235]. Perry et al. [260] reported decreased density of [3H] imipramine binding sites
in the hippocampus and occipital cortex of depressed patients, conﬁrming the original
studies by Stanley and colleagues [330].
Recently, Malison and colleagues [194], observed decreased serotonin transporter
binding in the midbrain of depressed patients compared to control subjects using [123I] βcarbomethoxy-3 β-(4-iodo-phenyl) tropane [123I] β-CIT) and SPECT imaging.
In recent years, [3H] imipramine has been found to have less speciﬁcity than [3H]
paroxetine [236]. Nemeroff and colleagues [237] reported that [3H] paroxetine-bindingsites are reduced in the platelets of drug-free depressed patients. This may ultimately provea more useful tool than [3H] imipramine.
Brain 5HT2 receptors have also been examined in living depressed patients that usedeither single-photon-emission computed tomography or PET. Agren and colleagues [2]reported that a signiﬁcantly lower uptake of [11C] 5HTP across the blood–brain barrier
in depressed patients, regardless of phase of illness compared to healthy volunteers. The
authors suggest that the transport of 5HTP across the blood–brain barrier is compromisedin major depression. In the only study that used single-photon-emission computed tomography, D’Haenen and colleagues [90] reported an increase in uptake of 2-ketanserin labeled with iodine 123 [123I] in parietal cortex bilaterally and right greater than left asymmetry in the inferofrontal region of depressed patients compared with control subjects. A
PET study [43] reported a decrease in uptake of altanserin labeled with ﬂuorine [18F] inthe right anterior part of insular cortex and right posterolateral orbitofrontal cortex ofdepressed patients compared with controls. PET studies suggest mixed results, two[16,379] reported a decrease in [18F] setoperone binding in the frontal cortex of depressed
patients compared with control subjects, while the other [224] found no difference between
the two groups.
The cortisol response to 5-hydroxytryptophan administration has been found to beenhanced in unmedicated depressed patients and to decrease following treatment withantidepressants [164]. Noting a signiﬁcant negative correlation between baseline plasma
cortisol levels and the cortisol response to 5-hydroxytryptophan in nondepressed control
subjects, Koyama and Meltzer [164] postulated that serotonin may play an important rolein the simulation of basal plasma cortisol secretion.
Because serotonin activates the HPA axis, increased serotonin activity could playa role in the increased HPA axis activity and pathogenesis of psychotic depression. In areview of the literature, Schatzberg and Rothschild [304] noted that increased serotonin
uptake into platelets and increased CSF levels of 5HIAA have both been reported in patients with psychotic depression.
3. Dopamine
A relevant preclinical model derives from the crucial role of mesoaccumbens dopamine(DA) in the neural circuitry of reward and/or incentive motivational behavior [371]. Lossof motivation is one of the central features of depression, and indeed anhedonia is oneof the deﬁning characteristics of melancholia. Thus, a deﬁciency of DA systems stands
out as a prime candidate for involvement in the pathophysiology of depression [368]. The
strongest ﬁnding from clinical studies implicating DA in depression is reduced homovanillic acid (HVA), the major DA metabolite in the CSF of depressed patients. Indeed, thisis one of the most consistent biochemical ﬁndings in depression [269]. There is also evidence of a decreased rate of CSF HVA accumulation in subgroups of depressed patients,

Neurobiology of Depression

469

including those with marked psychomotor retardation versus agitation [366]. Furthermore,
low levels of HVA may be associated with cognitive impairment, both in depressed patients and patients suffering from Parkinson’s disease [372].
Preclinical studies show that chronic administration of antidepressants and electroconvulsive shock (ECS) enhances mesolimbic DA functioning [367]. Thus, in someanimal models of depression, the efﬁcacy of antidepressants involves increased transmission through DA synapses, particularly in the mesolimbic system [367]. Similarly, damphetamine-induced locomotor activity, a behavior dependent on the integrity of themesoaccumbens DA neurons, is enhanced following chronic use of antidepressants.
Since the responses to either DA or apomorphine (direct acting agonists) are also enhanced following chronic antidepressants use, they appear to be due, at least in part, toincreased postsynaptic DA receptor sensitivity [192].
The mechanisms by which antidepressants enhance postsynaptic DA function in theaccumbens remain unknown, and binding studies have failed to reveal consistent alterations in the density of either D1 or D2 receptors. However, recent studies on chronicallystressed animals suggest that the effect may involve both D1 and D2 receptors or an interaction between them. Despite the opposite effects of D1 and D2 receptors on adenylyl cyclase
activity, these receptors also couple to multiple G proteins and effectors such that D1
stimulation can facilitate a variety of D2 responses [196]. Furthermore, D1- and D2-receptor
stimulation may be required for maximal production of vigilance, alertness, and moresensitive control of reactivity [251].
The preclinical study of ECS on dopaminergic function is especially relevant because ECT is especially effective in those psychiatric syndromes which likely involve
impaired dopaminergic transmission: depression with psychotic features or marked psychomotor retardation, mania, and catatonia. Indeed, ECT is remarkably efﬁcacious in the
prototypic “dopamine deﬁciency” condition, Parkinson’s disease [15]. A dramatic improvement in motor symptoms occurs with maintenance of a therapeutic regime of direct
and indirect DA agonists, suggesting that ECT exerts some effects via postsynaptic mechanisms. Although many behavioral studies suggest enhancement of postsynaptic DA receptor sensitivity after ECS, there are conﬂicting reports about changes in presynaptic DA
receptor sensitivity. Studies of D2-receptor density have consistently failed to reveal any
alterations following chronic ECS. Newman and Lerer [240] showed enhancement of D1
stimulated adenylyl cyclase activity in the caudate following chronic ECS. In humans,
ECT appears to increase DA receptor responsiveness, as indexed by apomorphine’s effecton plasma prolactin [23]. Moreover, chronic ECT increases both CSF HVA and 5hydroxy-indoleacetic acid (5HIAA), suggesting increased DA and serotonin (5HT) turnover [293].
Interestingly, monoamine oxidase inhibitors (MAOIs) constitute the only pharmacological monotherapy, which is reported to be effective in 50% or more of patients who
fail to respond to the full range of tricyclic antidepressants. Nolen et al. [245] reported
a controlled trial pointing to the superior efﬁcacy of tranylcypromine (average dose of
approximately 80 mg/day) in those patients. Tranylcypromine is superior to imipramine
in chronic, mild unipolar patients [212] and in “anergic” bipolar depression [135,343],
and phenelzine is superior in unipolar patients refractory to imipramine [210]. An openlabel study of high-dose tranylcypromine (average 120 mg/day) in 14 unipolar patients
who “had a clear history of nonresponse to at least two prior medication treatments”
yielded an impressive 50% “complete” (21-item Hamilton depression rating scale score⬍ 10) response rate [6]. It was speculated that “at higher plasma concentrations of tranyl-

470

Zarate and Charney

cypromine, the inherent sympathomimetic (amphetamine-like) activity of the drug
emerges.” Studies with dopamine reuptake inhibitors such as nomifensine have shown
clear antidepressant effects in major depression. Similarly, bromocriptine, a postsynaptic
dopamine receptor agonist, has been reported to have efﬁcacy comparable with standard
tricyclic antidepressants [323] and to be useful in antidepressant-resistant depression[142], and in relapses that occur with SSRI treatment [211]. Other dopaminergic treatments, such as stimulants [243] and ECT [93], have also been reported to be useful forthe treatment of depression in patients with Parkinson’s disease.
Neuroimaging studies have been conducted to directly assess the in vivo availabilityof dopamine D2 receptors in patients with major depression. Four studies compared thebinding of the SPECT radiotracer [123I]IBZM, a selective D2 /D3 antagonist [169] in patientswith major depression and control subjects. The results of these studies are mixed. Twoof the four studies reported higher [123I]IBZM speciﬁc binding in the striatum of depressedsubjects compared to control subjects [91,311], whereas two studies reported no changes[106,161].
The in vivo binding of [123I]IBZM is affected by competition with endogenous dopamine [170], and it has been proposed that increased [123I]IBZM binding in depression
might be due to decreased synaptic dopamine concentration and subsequent upregulationof D2 receptors [91]. Thus, in vivo neuroreceptor binding techniques can be used to measure acute changes in the concentration of endogenous transmitters in the vicinity of receptors [171]. Psychostimulant-induced dopamine release was recently examined in patientswith unipolar depression [256]. The authors did not ﬁnd alterations in striatal D2-receptor
density in depressed patients and concluded that stimulant-induced dopamine release is
not altered in major depression.
4. Acetylcholine
Janowsky and colleagues [146] postulated than an increased ratio of cholinergic to adrenergic activity may underlie the pathophysiology of depression, whereas the reverse occurs
in mania. Although the adrenergic–cholinergic balance hypothesis appears incompletein the face of increasing data on the preeminent role of alterations in serotonergic andnoradrenergic neurotransmission in major depression, the importance of cholinergic mechanisms in some forms of depression is supported by both preclinical and clinical data.
Animal models of depression (e.g., the forced swim test) are exacerbated by theadministration of cholinesterase inhibitors such as physostigmine [216], whereas muscarinic receptor antagonists reverse the effects of these agents. Additional evidence concerning the importance of acetylcholine in the maintenance of mood is the induction of depressed mood following administration of physostigmine or cholinergic agonists (e.g.,
arecoline) in euthymic control subjects [111], unipolar depressed patients [147], and bipolar manic patients [147]. Another neuroendocrine test that has been conducted to examine
the acetylcholine system in depression is the enhanced growth hormone release in response
to pyridostigmine challenge in depressed subjects relative to healthy comparison subjects.
The investigators found that the mean delta growth hormone (the difference between basal
and maximal growth hormone following pyridostigmine) was signiﬁcantly greater thancomparison subjects in patients with major depression. The responses observed in patientswith schizophrenia and alcohol dependence syndrome did not differ from the comparisongroup. The sensitivity of the pyridostigmine/growth hormone test was 63% for major
depression. These authors suggest that the pyridostigmine/growth hormone test may help

Neurobiology of Depression

471

distinguish depression from schizophrenia, alcohol-dependence syndrome, or panic disorder [72].
Depressive symptoms, including psychomotor retardation and depressed mood, areoften a complication of acetylcholinesterase inhibitor treatment of Alzheimer’s disease.
Such sensitivity to the mood-lowering effects of cholinergic drugs appears dependent on
the presence of an underlying psychiatric disorder. If cholinergic mechanisms contributein some manner to the pathophysiology of major depression, then anticholinergic drugs
should be effective antidepressants. Although physostigmine-induced dysphoria may bereversed with atropine [111], little evidence indicates that anticholinergic medications
have signiﬁcant antidepressant properties [147]. Moreover, the newer antidepressants, including the SSRIs, have little afﬁnity for muscarinic cholinergic receptors, yet remain
effective antidepressants. Sitaram and colleagues [324] proposed that primary affective
illness (speciﬁcally bipolar disorder) may be characterized by a state-independent cholinergic hypersensitivity in conjunction with a state-dependent noradrenergic supersensitivity(during late depression and early mania), which return to normal during remission.
5. γ-Aminobutyric Acid
γ-Aminobutyric acid (GABA) is the principal mediator of inhibitory synaptic transmission
in the mammalian brain and, therefore, is likely to participate in wide-ranging aspects ofboth normal and abnormal CNS function. GABA regulates many CNS functions, such as
seizure threshold, and it also has inhibitory input into other neurotransmitter systems suchas norepinephrine and dopamine. Clinical and pharmacological data suggest that GABA
metabolism may be altered in affective disorders.
Several lines of clinical investigation suggest that the GABA system may contributeto the pathophysiology of depression. Several clinical trials have demonstrated potent
antidepressant and mood-stabilizing properties of several compounds with GABAmimetic activity [46,259,264]. The anticonvulsants valproic acid and carbamazepine wereserendipitously noted to have a mood-stabilizing effect, decreasing the intensity and frequency of manic and perhaps depressive phases of bipolar disorder. All antimanic agents(including lithium) have been suggested to stabilize mood in part by increasing GABAergic transmission, leading to the hypothesis that a relative GABA deﬁciency plays a rolein mania.
Several investigators have reported that CSF and plasma GABA concentrations in
depressed patients are signiﬁcantly lower than in nondepressed control subjects; this ﬁnding has been replicated in several studies [261,262]. Low levels of GABA are not speciﬁc
to cases of depression or mania but are also seen in alcoholism [263].
Recently, Sanacora and colleagues [297] measured in vivo brain GABA levels with
proton magnetic resonance spectroscopy and found that the depressed patients demonstrated a highly signiﬁcant (52%) reduction in occipital cortex GABA levels comparedwith the group of healthy subjects.
6. Glutamate
Excitatory amino acid receptors are the principal mediators of excitatory synaptic transmission in the mammalian brain and, therefore, are likely to participate in wide-ranging
aspects of both normal and abnormal CNS function. Glutamate-mediated excitotoxicity
has been implicated in certain neurodegenerative diseases, including amyotrophic lateralsclerosis, Alzheimer’s disease, and Huntington’s disease [67]. Glutamatergic neurotrans-

472

Zarate and Charney

mission dysfunction has also been implicated in the pathogenesis of schizophrenia andobsessive-compulsive disorder, and is now being explored as a potentially novel mechanism of action for antipsychotic drugs [254,284]. Given the potential role of glutamatein CNS injury and neurodegenerative diseases, several treatment strategies have been implemented to reduce glutamate-mediated excitotoxicity. There is evidence suggesting that
there may also be glutamatergic neurotransmission dysfunction in depressed patients. Glutamine plasma levels were found to be high in depressed patients compared with a population control group [156,201]. Altamura et al. [5], studying platelets and plasma in 15
patients with unipolar and bipolar depression and comparison subjects, found lower plasma
glutamine levels in the depressed patient group compared with a neurological control
group (10 subjects). Mauri et al. [204] found elevated plasma and platelet levels of glutamate in depressed patients compared to controls. Recently, Berk and colleagues [34] reported that the platelet glutamate receptors may be supersensitive in schizophrenia anddepression with psychotic features, but not in mania with psychotic features compared tonormal controls.
Functional imaging also suggests that the glutamatergic system may be involved in
the pathophysiology of depression. Ongur et al. [252] reported a reduction of glial-cellmass in the subgenual frontal cortex of mood-disorder patients. This, and the absence ofreports indicating an increase of glial cell mass in brain areas of affective patients, suggeststhat neuronal metabolic rather than glial processes are responsible for the high glutaminelevels. A temporary reduction in a number of neurobiochemicals including myo-inositol(mI) and glutamate was noted in two patients with secondary depression during tamoxifen/
Neupogen chemotherapy for breast cancer [74]. Auer et al. [17] found a signiﬁcant decrease of glutamate in severely depressed patients in the anterior cingulate cortex. Levine
et al. [176], using a proton magnetic resonance spectroscopy (MRS) technique found that,compared with the control group, the depressed patient group had signiﬁcantly higher
CSF glutamine concentrations. Disturbances in glutamatergic neurotransmission appear
to be present early in life in patients with mood disorder. In one study, 10 children withbipolar affective disorder, aged 6 to 12 years, compared to a control group using proton
MRS were found to have elevated levels of glutamate/glutamine in both frontal lobes andbasal ganglia [64].
In postmortem studies, Nowak et al. [249] reported that the proportion of highafﬁnity, glycine-displaceable [3H] CGP-39653 binding to glutamate receptors was reducedin suicide patients compared with control subjects.
In the 1950s, D-cycloserine (a partial agonist at the N-methyl-D-aspartate (NMDA)receptor glycine site used as a part of multidrug antituberculosis treatment) was reported
to have a mood-elevating effect [133]. Since then, there is increasing evidence for an
association between alterations of brain glutamatergic neurotransmission and the pathophysiology of mood disorders. A growing body of preclinical research suggests that the
NMDA class of glutamate receptors may be involved in the pathophysiology of major
depression and the mechanism of action of antidepressants [325]. NMDA-receptor antagonists such as MK-801 and AP-7 have demonstrated antidepressant effects in animal models
of depression, including the application of inescapable stressors, forced-swim, and tailsuspension-induced immobility tests in learned helplessness models of depression andin animals exposed to a chronic mild stress procedure [258]. Conversely, antidepressant
administration has been shown to affect NMDA-receptor function [248,249] and receptorbinding proﬁles [257]. Furthermore, the role of glutamatergic dysfunction in depression

Neurobiology of Depression

473

is further supported by the fact that repeated antidepressant administration regionally alters
expression of mRNA that encodes multiple NMDA-receptor subunits [325] and radioligand binding to these receptors within circumscribed areas of the CNS [325].
Recently, Berman et al. [35] reported the ﬁrst placebo-controlled, double-blind trial
assessing the treatment effects of a single dose of an NMDA-receptor antagonist, ketamine,in seven patients with depression. The authors reported that subjects with depression evidenced signiﬁcant improvement in depressive symptoms within a short period of time(72) after taking ketamine but not placebo. In this study, treatment with ketamine wasassociated with transient cognitive deﬁcits, euphoria, and greater scores on the Brief Psychiatric Rating Scale, especially the positive symptoms. Similarly, another antiglutamatergic agent, lamotrigine, was found to be effective in acute bipolar depression [61].
B. Intracellular Signal Transduction Pathways and Depression
1. Stress and Depression
Preclinical and clinical studies demonstrate that neuronal atrophy and cell death occur in
response to stress and in the brains of depressed patients. Although major depressive
disorders undoubtedly have a strong genetic basis, recent evidence has shown that severe
stressors are associated with a substantial increase in risk for the onset of major depressive
disorder in susceptible individuals. In rodents, certain stressors are capable of producing
dendritic atrophy, death, or endangerment of hippocampal CA3 pyramidal neurons [209].
Activation of the HPA axis appears to play a critical role in mediating these effects, sincestress-induced neuronal atrophy is prevented by adrenalectomy, and increased by exposure
to high concentrations of glucocorticoids [209]. These observations are noteworthy withrespect to the pathophysiology of major depressive disorders, because a signiﬁcant proportion of patients with major depressive disorder display an excessive activation of the HPA
axis, and the subtypes of depression most frequently associated with HPA activation arethose most likely to be associated with hippocampal volume reductions. The mechanisms
by which glucocorticoids exert these deleterious effects on the hippocampus need to be
fully elucidated, but likely involve the facilitation of glutamatergic signaling and inhibitionof glucose transport [209]. The reduction in the resilience of hippocampal neurons may
also reﬂect the propensity for various stressors to decrease the expression of brain-derived
neurotrophic factor (BDNF) in this region [209].
In addition to the accumulating neuroimaging evidence, several postmortem brain
studies are now providing direct evidence for reductions in regional CNS volume, cellnumber, and cell body size. Baumann and associates [27] reported reduced volumes ofthe left nucleus accumbens, the right putamen, and bilateral pallidum externum in postmortem brain samples obtained from patients with unipolar depression or bipolar disorder.
Several recent postmortem stereological studies of the prefrontal cortex also havedemonstrated reduced regional volume, cell numbers, and/or sizes. Morphometric analysisof the density and size of cortical neurons in the dorsolateral prefrontal cortex and orbitofrontal cortices has revealed signiﬁcant reductions in mood-disorder patients as compared
to control subjects [276,277]. Marked reductions in the density of large neurons (corresponding to pyramidal glutamatergic excitatory neurons) were found in layers III and Vof the dorsolateral prefrontal cortex in bipolar disorder and major depressive disorder. In
other prefrontal regions such as rostral orbitofrontal cortex, the most prominent neuronal
reductions in major derpressive disorder are conﬁned to layer II cells. Reductions in the474

Zarate and Charneydensity of speciﬁc populations of layer II nonpyramidal neurons containing the calcium
binding protein, calretinin, also have been reported in the anterior cingulate cortex insubjects with a history of mood disorders.
Additional morphometric studies also have reported layer-speciﬁc reductions ininterneurons in the anterior cingulate cortex, and reductions in nonpyramidal neurons(⬃40% lower) in CA2 of the hippocampal formation in bipolar disorder subjects compared
to controls [32]. Overall, the layer-speciﬁc cellular changes observed in several distinct
brain regions, including the prefrontal cortex, anterior cingulate cortex, and hippocampus
suggest that multiple neuronal circuits underlie the neuropathology of mood disorders.
This is not altogether surprising since the behavioral and physiological manifestations of
the illnesses are complex and include cognitive, affective, motor, and neurovegetative
symptomatology, as well as alterations of circadian rhythms and neuroendocrine systems,
and are thus undoubtedly mediated by networks of interconnected neurotransmitter systems and neural circuits [276].
In addition to neuronal pathology, unexpected reductions in glial cell number anddensity also have recently been found in postmortem brains of both major depressive
disorder and bipolar disorder patients. Thus, a histological study of area sg24 located in
the subgenual prefrontal cortex found striking reductions in glial cell numbers in patientswith familial major depressive disorder (24% reduction) and bipolar disorder (41% reduction) as compared to controls [252]. This observation is consistent with this group’s neuroimaging report on reductions in cortical gray matter volume found in the same brain region
in a similar diagnostic group. Marked decreases in overall and laminar (layers III-IV) glial
cell packing densities also were found in subjects with major depressive disorder compared
to nonpsychiatric control subjects [277]. Comparable reductions in glial densities werealso detected in the dorsolateral prefrontal cortex from subjects with bipolar disorderacross all cortical layers (except layer IV) [276]. In view of the growing appreciation of
the critical roles of glia in regulating synaptic glutamate levels, CNS energy homeostasis,
liberation of trophic factors, and, indeed, the very existence of synaptic networks of neurons and glia [78,179] all suggest that the prominent glial loss observed in major depressive
disorder and bipolar disorder may be integral to the pathophysiology of the disorders andworthy of further study.
Recent morphometric neuroimaging studies have demonstrated that patients withboth bipolar disorder and major depressive disorder display morphometric changes thatsuggest cell loss and/or atrophy [316,318]. The preponderance of evidence from recent
volumetric neuroimaging studies suggests an enlargement of third and lateral ventricles,
as well as reduced gray matter volumes in the orbital and medial prefrontal cortex, theventral striatum, and the mesiotemporal cortex in patients with mood disorders[316,318,331]. Reductions in frontal lobe volumes, and striking ⬃40% reductions in themean gray matter volume in the region located ventral to the genu of the corpus callosum
have recently been demonstrated in bipolar disorder depressives and familial unipolar
depressives [95]. Additional studies suggest that these subgenual prefrontal cortex graymatter volume reductions may be particularly evident in “enriched” patient populations,
namely those with positive family histories of mood disorders [136]. Reductions in thevolume of the hippocampus have also been observed in subjects with a history of major
depressive disorder, ﬁndings that may persist for decades after the depressive episodes
have resolved [316,318]. Interestingly, the loss of hippocampal volume appears to becorrelated with the total lifetime duration of major depressive disorder but not with theNeurobiology of Depression475

age of the patients [318], leading to the suggestion that these changes may represent thesequelae of repeated and/or prolonged episodes of depression [53,300].
2. Neurotrophic Factors and Depression
In recent years, the cellular and molecular model basis for the effects of antidepressantsand stress on the survival of hippocampal neurons in the pathophysiology of depression
has received much attention [100]. They proposed that a decrease in serotonin and norepinephrine transmission may lead to decreased levels of brain-derived neurotrophic factor(BDNF), which may be decreased even further by glucocorticoids, eventually leading toneuronal cell death. Their model suggests that antidepressants may prevent the downregulation of BDNF in response to stress. In addition, the genetic expression of some factors
involved in neuronal atrophy and survival is inﬂuenced by antidepressant drug treatments[102]. Further evidence supporting their model is that chronic, but not acute, administration of various classes of antidepressants upregulates the cAMP-CREB cascade and theexpression of BDNF in the rodent hippocampus and the number of new cells apparent in
the dentate gyrus granule cell layer [66,101]. Recently, Chen and colleagues [66] reported
that in the learned helplessness model rats that received bilateral microinjection of herpes
simplex virus-CREB into the dentate gyrus showed signiﬁcantly fewer escape failures inthe subsequent conditioned avoidance test than those injected with control vector, suggesting that overexpression of CREB in the hippocampus results in an antidepressanteffect. Further research is underway to determine whether hippocampal neurogenesis plays
any direct role in the therapeutic actions of antidepressants and whether antidepressants
exert major effects on neurotrophic factors and the signaling cascades.
C. Neuroimaging Studies
Neuroimaging studies have also been used to better understand the pathophysiology ofmood disorders. In this section, we review the controlled structural (CT and MRI) andfunctional (PET [positron emission tomography] and SPECT [single photon emission
computed tomography]) imaging studies of patients with affective disorder.
1. CT and MRI Studies
Many CT and MRI studies have demonstrated increased ventricle size in patients withunipolar and bipolar disorders. However, these studies are confounded by numerous methodological problems. For example, most of these studies estimate lateral ventricle size byusing a ventricular brain ratio. Unfortunately, few conclusions can be drawn from the CT
literature on ventricular enlargement in affective disorder. More consistent, however, are
the CT and MRI studies of increased ventricular size in depression in geriatric patients(individuals ages 65 and older). Some investigators believe that ventricular enlargement
is a nonspeciﬁc structural brain alteration [108].
The hippocampus, a structure of paramount importance to learning and memory,
and which has high concentrations of glucocorticoid receptors, appears particularly vulnerable to the effects of stress on the brain [299]. Several groups have examined volumetricchanges in the hippocampus of those with major depression. Some have found no difference between the hippocampal volume of nonpsychiatric control subjects and that of patients with major depression [22]. In contrast, Sheline and colleagues [316] reported
smaller left and right hippocampal volumes in patients with major depression. In addition,

476

Zarate and Charney

the authors reported that the extent of hippocampal atrophy was signiﬁcantly correlated
to the duration of depression; there was no difference in whole-brain volume between
these groups [316]. In one study, the depressed group was divided into two subtypes basedon the individual’s response to treatment. They analyzed volumetric changes in cerebral
and cerebellar regions. Although they did not ﬁnd signiﬁcant differences when comparing
depressed patients as a whole with control subjects, they did ﬁnd signiﬁcant results when
depressed subjects were divided into groups of responders and nonresponders. Recently,
Vakili and colleagues [350] reported that there were no signiﬁcant differences observed
between the hippocampal volumes of patients with major depression and control subjects;
however, the authors found a signiﬁcant correlation between the left hippocampal volume
of men and their depression scores at baseline.
The abnormal presence of hyperintensities of gray and white matter has been reported in multiple MRI studies of geriatric patients with affective disorder, particularly
those with late-onset depression (i.e., elderly depressed patients who experience their ﬁrst
depression after age 60). Subcortical hyperintensities in the elderly are age-dependent andmay reﬂect a variety of life-long insults and/or from pathophysiological processes related
to cerebrovascular disease, including arteriosclerosis of the small lacunar arterioles that
supply the basal ganglia and subcortical white matter [127,175]. Hypertension is associated with white matter hyperintensity in both depressed and nondepressed control individuals [175]. Study of nondepressed control subjects has also revealed that increasing age
is associated with reduction of the size of the putamen [141] and caudate nuclei [166],
as well as of the size of the midbrain [310] and pituitary gland [167]. A recent study
reported that elderly adults (⬎60 years old) with severe white matter lesions are 3 to 5
times more likely to have depressive symptoms as compared to persons with only mild
or no white matter lesions [84]. Elderly adults with severe subcortical but not periventricular white matter lesions were more likely to have a history of depression with an onset
after 60 years compared with persons with only mild or no white matter lesions. Severityof white matter hyperintensity predicts poorer response to antidepressant therapy [134].
Ahearn and colleagues [3] in a post hoc analysis reported that unipolar patients witha history of attempted suicide demonstrated signiﬁcantly more subcortical gray matter
hyperintensities compared with patients without such history.
To assess whether abnormal brain structure is associated with abnormal brain function, investigators used CT and MRI studies in association with depression rating scores,
neuroendocrine stimulation tests, neuropsychological testing, monitoring of patients’ clinical course, and response to treatment. For example, postdexamethasone cortisol levels
are signiﬁcantly correlated with ventricular brain ratio [278] and pituitary volume [21].
Furthermore, in depressed elderly patients, caudate hyperintensities are associated withan increased risk for the development of TCA- and ECT-induced delirium [113,114], as
well as neuroleptic-induced Parkinsonism [114].
2. PET and SPECT
Compared with nondepressed individuals, patients with unipolar depression have had alateralized decrease in activity in the left lateral prefrontal cortex repeatedly documented
by PET investigations [28,140]. Similar reduction in activity of the left frontal cortex has
been observed in depression secondary to other CNS disorders, including epilepsy, humanimmunodeﬁciency virus, Huntington’s chorea, and Parkinson’s disease [359].
Of particular interest is the decreased neuronal activity of the caudate and putamen,
and globus pallidus. The basal ganglia can be visualized as the motor behavioral effector

Neurobiology of Depression

477

mechanism that underlies the cognitive expression of emotion. Vulnerability to affective
dysfunction might derive from disruption of connections between the basal ganglia orfrom interruption of pathways connecting the basal ganglia to other parts of the brain,
speciﬁcally the limbic system and prefrontal cortex [167]. Recent PET neuroimaging studies support a distinction between the neural substrates of normal sad mood states and major
depression (e.g., left amygdala); such physiological states do not mimic the inﬂuence ofmajor depression on frontal cortical function. Using PET images, Drevets and colleagues[95] localized abnormally decreased activity in the left prefrontal cortex ventral to the
corpus callosum genu in both familial bipolar and unipolar depressed patients (patientswith a family history of bipolar and unipolar depression, respectively). This diminishedactivity was explained in part by a corresponding reduction in volume in this same area
as demonstrated by MRI. Resting neuroimaging studies of adult depressed patients haveshown left-sided or bilateral hypoactivity in the dorsolateral, inferior, and medial frontal
regions as well as the temporal limbic regions, particularly the amygdala [94,95,205].
Functional neuroimaging studies during resting and activation have also been conducted. Resting-state hypoactivity in the medial prefrontal cortex has been correlated withcognitive impairment [31]. Blunted left cingulate activation has been observed in younger
depressed patients performing a response interference task [117]. de Asis and colleagues[83] reported bilateral activation deﬁcits in the dorsal anterior cingulate gyrus and hippocampus of depressed geriatric patients. The depressed patients also had memory deﬁcits
that correlated with lower hippocampal activity during both rest and activation.
Furthermore, PET studies of depressed patients often reveal signiﬁcant correlation
between the severity of depressive symptoms and the reduction in left frontal cortical
function. Clinical response of depressed patients to antidepressant treatment may be associated with increased blood ﬂow or metabolism within the basal ganglia, cingulate, or
prefrontal cortex [94,140]. However, one group has documented reductions in cerebral
blood ﬂow, both global and in anterior cortical regions, in manic patients and depressedindividuals who have shown clinical remission of their symptoms following ECT [244] ortreatment with oral antidepressants [244]. Mayberg et al. [206] reported that the metabolic
response of depressed patients’ rostral anterior cingulate metabolism differentiated antidepressant treatment responders from nonresponders.
Functional neuroimaging studies may have future potential in identifying effective
treatment strategies tailored to the individual depressed patient or to those with certain
symptom complexes [31]. Recent PET and SPECT studies of depressed patients havefound differences in regional brain activity evident in pre- and post-treatment scans that
distinguish treatment responders from nonresponders. Hyperactivity in the cingulate region of the frontal cortex prior to overnight sleep deprivation was associated with a positive clinical response of depressive symptoms to sleep deprivation. Nonresponders exhibited normal cingulate gyrus activity before and after sleep deprivation [377]. Mayberg andcolleagues [207] found that patients with unipolar depression who responded to ﬂuoxetine
treatment after 6 weeks showed higher pretreatment glucose metabolism in a rostral regionof the anterior cingulate cortex (Brodmann’s area 24a/b) than nonresponders and nonpsychiatric comparison subjects. Pizzagalli and colleagues [266] reported that, in a group ofindividuals treated for major depression, baseline theta activity within a rostral region of
the anterior cingulate cortex involving areas 24 and 32 predicted degree of response 4 to
6 months later. Depressed patients showing a better response had higher theta activity
than those responding less well, and they also tended to have higher activity than comparison subjects. This study replicates the ﬁndings by Mayberg and colleagues [206].

478

Zarate and Charney

Brody and colleagues [52] reported that at baseline subjects with major depressive
disorder had higher normalized metabolism than controls in the prefrontal cortex and lower
metabolism in the temporal lobe. With treatment, subjects with major depressive disorder had metabolic changes in the direction of normalization in these regions and thatparoxetine-treated patients had a greater mean decrease in Hamilton Depression Rating
Scale score than did subjects treated with interpersonal psychotherapy. Kennedy and colleagues [153] reported that successful paroxetine therapy was associated with signiﬁcant
increases in metabolic activity in dorsolateral, ventrolateral, and medial aspects of theprefrontal cortex (left greater than right), parietal cortex, and dorsal anterior cingulate.
Sackeim [296] points out that in contrast to the general agreement about baseline
imaging deﬁcits in major depressive episode, changes following treatment are uncertain,
with reports of normalization of baseline deﬁcits, increased abnormal activities, and nochange [296]. He identiﬁes many factors as possibly responsible for the inconsistency inﬁndings including small sample sizes in the initial and retest studies, technical difﬁculties
in obtaining images across two time points, and studies that are semiquantitative.
3. Anatomical Circuits Implicated in Major Depressive Disorderand Bipolar Disorder
These data implicate two interconnected circuits in familial major depressive disorder andbipolar disorder: a limbic-thalamo-cortical circuit involving the amygdala, the mediodorsal
nucleus of the thalamus (in the medial thalamus), and the ventrolateral and medial prefrontal cortex; and a limbic-striatal-pallidal-thalamic circuit involving related parts of the striatum and ventral pallidum as well as the components of the other circuit [94]. The limbicstriatal-pallidal-thalamic circuit constitutes a disinhibitory side loop between the amygdalaor prefrontal cortex and mediodorsal nucleus. The amygdala and the prefrontal cortex
send excitatory projections to overlapping parts of the ventromedial striatum [94]. Because
the major depressive disorder criteria likely encompass a group of conditions that areheterogeneous with respect to etiology, neuroimaging measures may differ across pathophysiologically distinct depressive subtypes. For example, lesions involving the parts ofthe prefrontal cortex that participate in the limbic-thalamo-cortical circuit and diseases ofthe basal ganglia (e.g., Parkinson’s disease and Huntington’s disease) are associated withhigher rates of major depression than other similarly debilitating conditions [97], suggesting that dysfunction at multiple points within this system may give rise to the depressive syndrome. Because these conditions affect this system in different ways, imbalances within these circuits rather than overall increased or decreased synaptic activity
within a particular structure may be associated with the depressive syndrome [94].
4. Speciﬁcity of Elevated Limbic-Thalamo-Cortical (LTC) Activity
Other studies identiﬁed clinical distinctions that may also identify elevated limbic thalamiccortical activity in major depressive disorder. Wu et al. [377] and Ebert et al. [105] foundmetabolism in the amygdala and anterior cingulate abnormally elevated in major depressive disorder subgroups who were responsive to sleep deprivation, and Bremner et
al. [48] reported that medicated, remitted major depressive disorder subjects who relapsed
during serotonin depletion had higher baseline amygdala and orbital cortex metabolism
than those who did not. Other studies of unmedicated depressives with major depressive
disorder have also reported increased cerebral blood ﬂow and metabolism in the orbital
cortex relative to healthy controls, and longitudinal studies in which depressives are imaged before and during treatment consistently show that orbital cortex cerebral blood ﬂow

Neurobiology of Depression

479

and metabolism decrease following effective antidepressant drug therapy, ECT, phototherapy, repeated transcranial magnetic stimulation, and sleep deprivation (reviewed in Ref.
96). In contrast, studies reporting data acquired from subjects receiving psychotropic drugs
at the time of scanning or which included subjects with depression secondary to neurological disorders have not found elevated activity in these structures (reviewed in Ref. 96).
D. Endocrine Studies
1. HPA Axis in Affective Disorder
Numerous studies suggest hypercortisolemia in depression [24,26]. The HPA axis has
been well established in the physiological response to stress and the hippocampus has
been suggested as a regulator involved in the negative-feedback control of cortisol [144].
Hypercortisolemia may induce neuronal damage in the hippocampus [298] because of thehigh levels of glucocorticoid receptors in the hippocampus [281]. Hippocampal atrophy
may then result from a long-term exposure to higher levels of glucocorticoids.
HPA axis hyperactivity occurs in depression [267] and its magnitude can be similar
to that seen in mild Cushing’s disease, and is linked to suicidal ideation [57] and risk ofsuicide [73]. It is also associated with severity of depressive illness [58,69], endogeneity[69], psychotic symptoms [286], and inpatient status [188] or symptoms associated with
the need for hospitalization [268]. Adrenal gland hypertrophy, an index of centrally mediated hyperstimulation of the adrenal cortex, occurs in up to 70% of depressed subjects
and resolves upon treatment [290]. HPA dysfunction precedes the resolution of affective
illness, whereas unresolved or recurrence of HPA dysregulation may be prognosticallyominous in both unipolar and bipolar disorders [139,282,308]. Even modest chronic exposure to excess glucocorticoids can also have medical consequences such as accelerated
bone loss [143].
The rates of DST nonsuppression in depression vary widely according to study.
Nelson and Davis performed a meta-analysis of studies comparing DST suppression test
results and found an overall nonsuppression rate of 36% among inpatient melancholicpatients but only 22% among outpatients and, when inpatient status was controlled for,melancholia did not predict nonsuppression [232]. However, Rush et al. reported nonsuppression rates of 62% among Research Diagnostic Criteria (RDC) endogenous inpatients,
with similar rates for unipolar and bipolar patients subgroups [295]. Inpatient status andseverity of illness may predict HPA axis abnormality. Patients with high spontaneous
cortisol levels or cognitive impairment have a poorer response to treatment with antidepressants [68,70] and some, but not other, studies suggest that DST nonsuppression isassociated with poor response to TCAs [7]. Frequent recurrent episodes of mood disorder[340,341] or long duration of episodes may increase treatment resistance [30,327] andlimbic neuroendangerment; all of which could be hypothesized as related to elevated HPA
activity. It should be noted that given the likely day-to-day oscillations in HPA axis activity
in patients with major depression some patients may be hypercortisolemic overall eventhough they may suppress in response to DST on a given day.
Corticotropin-releasing factor (CRF) is both a direct regulator of secretion of ACTH
from the corticotrophs in the anterior pituitary and is a neurotransmitter that is abundantly
located in extrahypothalamic brain areas. It has been hypothesized that a major role of
CRH is to regulate stress responses throughout the CNS, coordinating the endocrine, immune, autonomic, and behavioral responses to stress. In this capacity and as the principal
regulator of ACTH secretion, the CRF system is believed to be involved in the pathophysi-

480

Zarate and Charney

ology of depression [238]. Hypercortisolinemia, DST nonsuppression, and the stress intolerance displayed by depressed patients all suggest dysregulation of the CRF system inthese patients.
The CSF CRF concentration in untreated depressed patients is increased comparedto healthy controls [234]. Other research groups have also replicated this ﬁnding. An
increased CSF CRH concentration is also elevated in suicide victims [11].
Among the biological abnormalities tentatively associated with risk for suicide,those involving the HPA axis have shown particular promise. In postmortem studies, persons who died by suicide, in comparison to matched subjects who died by other violentmeans, had greater adrenal weights [92,342], fewer binding sites for CRF in the frontal
cortex, and higher levels of CRF in CSF. Each of these ﬁndings associates suicide with
HPA axis hyperactivity. Studies examining whether abnormal DST results are associatedwith suicide have been mixed, some studies ﬁnding an association between abnormal DST
results and suicide and other studies not ﬁnding this association. More recently, Coryell
and Schlesser [73] reported on the predictive validity of abnormal DST and suicide in
78 inpatients with major depressive disorder or schizoaffective disorder, depressed type,followed for up to 15 years. Survival analyses showed that the estimated risk for eventual
suicide in patients with abnormal DST was 27% compared to only 3% among patients
who had normal DST results.
More than a dozen studies have examined patients’ ACTH responses to administration of exogenous CRH in mood disorder and the majority of studies included both unipolar and bipolar subjects [121,122,283,357]. Subjects were generally inpatients with melancholic features. Gold et al. found that bipolar depressed subjects had only half the peakand net integrated ACTH response to CRH, whereas there was no signiﬁcant difference
from placebo in mania or recovered patients [120]. Despite methodological differences,
11 of 13 studies found that, compared to normal controls, the depressed subjects had
blunted plasma ACTH and normal cortisol responses that were disproportional to the
ACTH responses, occurring in the context of CRH stimulation, indicative of adrenal hyperresponsiveness [42]. A blunted plasma ACTH response in association with nonblunted
cortisol responses is indicative of centrally mediated hypercortisolism. In euthymic bipolar
patients maintained on lithium, a blunted ACTH response to CRH predicted subsequent
relapse into depression [355]. Drug effects of lithium and tricyclics do not signiﬁcantlyinterfere with detecting group differences if they fail to treat the depression [42,355].
Depression-related disruptions of cognitive function have been observed in multiple
domains [125]. Depression-related deﬁcits in cognitive function include alterations inmemory, attention, and executive functioning in areas including working memory and set
shifting that may correlate with psychosis [18,233], endogenous features [294], or narrowly deﬁned melancholia using the CORE and Newcastle scales [19,20,222].
Moreover, hypercortisolemia found in severe depression in association with neurotoxicity and atrophy of the hippocampus and other limbic-related structures and selective
atrophy of the hippocampus occurs in Cushing’s disease [300]. Hippocampal dysfunction
may be in part the etiological mechanism in cognitive disturbances involving memory insevere depression [29]. Cumulative cognitive effects of recurrent [154] or lengthy depressive episodes may result in dysfunction of frontostriatal and mesiotemporal/hippocampal circuits [125]. Animal stress model implicate the hippocampus in glucocorticoidinduced abnormalities. Rubinow et al. [291] observed a signiﬁcant positive relationshipbetween mean urinary free cortisol levels of depressed patients and errors on the Halstead
Category Test. Other studies have reported DST nonsuppressors have greater cognitiveNeurobiology of Depression

481

deﬁcits than those with normal receptor sensitivity [55,369]. Newcomer et al. [241] foundexogenous glucocorticoids impair declarative memory and Wolkowitz et al. [373] foundthat DST nonsuppression or exogenous glucocorticoids predicted errors of commission
on the Wallach Memory Recognition Test. Hippocampal volume loss in depression correlates with declarative memory impairment and the duration of past depression, and plausibly is glucocorticoid-mediated [49]. As well, impairment of working memory after glucocorticoids suggests prefrontal cortex involvement [183]. Prefrontal cortex dysfuntion is
reﬂected in executive dysfunction in severe depression and may predict nonresponse to
SSRIs or other standard treatments [103,206]. Thus treatment of hypercortisolism or otherfactors resulting in cognitive dysfunction in depression may facilitate treatment response.
In 11 studies of antiglucocorticoid agents reviewed by Wolkowitz and Reus, 67%of the treated patients had a clinically meaningful antidepressant response. Earlier studies
used ketoconazole, metyrapone, or aminoglutethimide [374]. Interestingly, an early indicator of response may be improved cognitive function [374]. Subjects tended to have sustained improvement even after drug discontinuation [374] and it is suggested that antiglucocorticoid treatment may be “resetting” the HPA axis. Some studies have suggested no
relationship to baseline cortisol and response to antiglucocorticoid treatment [119],
whereas others have noted considerable relationship. In a double-blind case study, Anandet al. [9] noted a close relationship between decrease in cortisol and Hamilton depression
rating scale scores. Wolkowitz also reported signiﬁcantly reduced 4 PM cortisol in an
open study of ketoconazole and a correlation between treatment response and baseline
cortisol in a double-blind controlled trial [374,375]. Ravaris et al. treated a bipolar typeII patient with ketoconazole that was added to lithium and phenelzine. Improvement correlated in this case with a decrease in urinary free cortisol levels [279]. Brown et al. report
improvement in 3 of 6 treatment-resistant bipolar depressed patients. Response occurredin inpatients receiving ketoconazole 400 to 800 mg, although they did not detect a change
in serum cortisol levels [54]. Recently, DeBattista and colleagues [85] reported that intravenous administration of a moderate dose of hydrocortisone produced a robust and rapid
improvement in Hamilton depression scale scores in depressed patients. Mifepristone(MifeprexTM) is FDA indicated for the medical termination of intrauterine pregnancy andhas potential antineoplastic properties [160]. Soon after its synthesis in 1980, the steroid
compound mifepristone or RU38486 (17-hydroxy-11b (4-dimethylaminophenyl)-17(1propynyl) oestra-4,9-dien-3-one) was found to act as a competitive, speciﬁc, high-afﬁnity
antagonist of progesterone and glucocorticoid receptor-2 and has weak antiandrogenic
activity (product labeling). The antiglucocorticoid effect of RU486 is dose dependent andbecomes apparent for single doses of 4 mg/kg [59]. It has been demonstrated that after
8 days of treatment with 200 mg of mif per day, the adrenocortical and pituitary reserves
are preserved. Mifepristone also attenuates retention of immobility response in the forced
swim test, a paradigm sometimes associated with antidepressant activity [88]. Murphy et
al. reported that four treatment-refractory patients with chronic severe depression were
given RU486 (200 mg/day) for periods up to 8 weeks. One of the patients was diagnosed
as bipolar and she improved signiﬁcantly after 9 days of therapy with mifepristone (3.9mg/kg): her Hamilton depression rating scale score fell from pretreatment average of 31
to 6 [229]. A number of studies indicate that mifepristone acts quickly on psychotic depressive symptoms and can be effective in treatment periods of 7 days or less. In an earlyreport, the psychiatric symptoms of a patient with co-morbid Cushing’s syndrome andpsychotic depression were resolved within 2 weeks of treatment with doses as high as
140 mg per day [242]. Lower doses of 400 to 800 mg per day rapidly reversed psychotic

482

Zarate and Charneydepression in two patients with Cushing’s syndrome resulting from metastatic adrenal
cancer within 48 h [352].
2. Hypothalamic-Pituitary-Thyroid Axis
Patients with hypothyroidism can appear indistinguishable from those patients sufferingfrom major depression. There is a substantial overlap of symptoms in both conditions,
including depressed mood, cognitive impairment, and neurovegetative symptoms. For thisreason, the hypothalamic-pituitary-thyroid (HPT) axis has received intense study. It isestimated that only 20 to 30% of patients with depression have discernible thyroid dysfunction. In two studies, the CFS concentration of thyrotropin-releasing hormone (TRH) was
reported to be increased in depressed patients compared to neurological and nondepressed
controls [25,158]. In contrast, the study by Roy and colleagues [288] did not support
this ﬁnding. This ﬁnding appears to be speciﬁc to patients with depression as increased
concentrations of CSF TRH were not observed in patients with Alzheimer’s disease, alcoholism, or anxiety disorders. The HPT function in depression has also been examined by
way of the TRH stimulation test. In this test, plasma TRH concentrations are measured
at baseline and at 30-min intervals after a challenge dose of TRH. A series of studies
have found that between 25 and 30% of depressed patients have a blunted TSH responseto TRH challenge [148,272]. This ﬁnding is not due to a primary thyroid disorder because
these depressed patients are reported to be euthyroid at the time of the assessment. A
modiﬁed version of the TRH test has been developed to speciﬁcally assess the night-time
TSH response to TRH challenge [104]. In this test, the subject receives a TRH challenge
at 8:00 AM, with subsequent blood sampling for TSH measure and a second TRH challenge at 11:00 PM, with subsequent TSH determination. It has been reported that this test
displays a 95% speciﬁcity and 89% sensitivity for the diagnosis of major depression.
3. Hypothalamic-Pituitary-Ovarian Axis
Changes in the hypothalamic-pituitary-ovarian (HPO) axis have been reported to be associated with depression. A recent study found that the mean plasma estradiol level was
30% lower in the follicular phase in women with depression than in their matched controls.
In addition, the half-life of luteinizing hormone was found to be signiﬁcantly shorter inwomen with depression than in their matched controls in both the follicular and luteal
phases [380]. Estradiol has effects on multiple brain systems including memory, synaptic
density, and the neurotransmitter systems of serotonin and norepinephrine [208,320]. In
addition, some open-label studies have reported beneﬁcial effects with estrogen as an
adjunct to treatment of major depression [183,273], although the results of placebocontrolled trials are mixed.
E.

Neurodegeneration in Mood Disorders?

Recent evidence suggests that neurodegeneration may be involved in the pathophysiology
of major depression. The astroglial peptide S-100B plays a role in axonal growth andsynaptogenesis during development and synaptic remodeling. Increased CSF and plasma
levels of S-100B were detected after traumatic brain injury, toxic or ischemic brain damage
in multiple sclerosis, Alzheimer’s disease, and schizophrenia [128,365]. Rothermundt andcolleagues [285] reported that patients suffering from melancholic depression showed signiﬁcantly increased S-100B levels compared to healthy controls while nonmelancholicpatients demonstrated normal levels.

Neurobiology of Depression

F.

483

Vascular Disease and Increased Platelet Aggregability
in Major Depression

Increasing evidence suggests that depression constitutes an independent risk factor for
cardiovascular morbidity and mortality. The vascular depression hypothesis proposes that
late-life depression is associated with vascular disease [4,165]. Many of these ﬁndings
are summarized in the neuroimaging section of this chapter. Brieﬂy, this hypothesis isbased on the strong associations between depression and vascular disease and MRI ﬁndings in depressed subjects of elevated rates of deep white matter hyperintensities, which
may be vascular in origin [250]. Intercellular adhesion molecule-1 (ICAM-1) is a vascularmarker of inﬂammation, and its expression is increased by ischemia. Recently, Thomas
and colleagues [345] reported that ICAM-1 was signiﬁcantly higher in the postmortem
tissue of the depressed subjects’ dorsolateral prefrontal cortex compared to comparison
subjects.
Markowitz and colleagues [199] reported increased platelet secretion after in vitro
stimulation with collagen along with decreased platelet serotonin receptor density in depressed patients. Lederbogen and colleagues [173] reported that major depression is associated with increased platelet aggregability, which seems to persist even under a marked
improvement in depressive symptomatology. This effect has been reported to contributeto the increased cardiovascular morbidity in depressed patients.
G.

Pineal Function Circadian Rhythm

Several studies have suggested the possible role of the circadian pacemaker in depression[329,351,370]. Partly supporting this theory is the fact that, in the melancholic type of
depression, patients typically feel worse in the morning and have early morning awakenings [329,351,370]. The suprachiasmatic nucleus is the circadian pacemaker of the mammalian brain, responsible for maintaining and coordinating different bodily functions including sleep-wake cycles, body temperature, and hormonal rhythms [337], and has beenreported to be functionally impaired in depression [381]. Zhou and colleagues [381] suggested that, in depressed patients, both the synthesis and release of arginine vasopressinin the suprachiasmatic nucleus is reduced, resulting in an impaired functional ability.
H. Immunological Function
Recent studies have suggested that major depression is accompanied by signiﬁcant activation in immune-inﬂammatory markers. Several studies of depressed patients have shown
an increased number of peripheral blood mononuclear cells such as leukocytes, monocytes,
CD4⫹, T helper cells, an increased serum concentration of soluble interleukin-2 receptor,
and an increased polymorphonuclear elastase in serum [87,190,326]. There is evidence
that the activation of immune cells is related to overproduction of reaction oxygen species(ROS) [363]. ROS are highly reactive chemical species with an unpaired electron, andtheir formation is catalyzed by transition metals like iron, manganese, and copper. It has
been suggested that the activation of immune-inﬂammatory processes, increase in monoamine catabolism, and abnormalities in lipid compound may cause overproduction of ROS
and, in turn, antioxidative enzyme activities and lipid peroxidation. Bilici and colleagues[41] reported that major depressed patients, especially melancholic patients, had higher
antioxidative enzyme activities and lipid peroxidation levels than those of healthy controls.
In addition, the authors reported that after 3 months of treatment with SSRIs, antioxidative484

Zarate and Charney

enzyme activities and lipid peroxidation levels of patients were signiﬁcantly decreased tonormal levels.

IV. CONCLUSIONS
Preclinical and clinical studies over the past 40 years have attempted to uncover pathophysiology of major depressive disorder ﬁrst by uncovering the speciﬁc defects in theseneurotransmitter systems by using a variety of biochemical and neuroendocrine strategies.
Although such investigations have provided useful information, they have been of limited
value in elucidating the pathogenesis of these disorders. It is clear from these studies that
depression is much more than increasing intrasynaptic levels of biogenic amines. Morerecently, research into the pathophysiology and treatment of major depressive disorders
has focused on intracellular signaling pathways. The pathophysiology of major depressive
disorders remains unknown but probably involves a complex interaction and overlap ofmultiple systems including neurotransmitter, endocrine, and immune systems and cellularsignaling pathways.

REFERENCES
1. Aberg-Wistedt A, Ross SB, Jostell KG, Sjoquist B. A double-blind study of zimelidine, aserotonin uptake inhibitor, and desipramine, a noradrenaline uptake inhibitor, in endogenous
depression. II. Biochemical ﬁndings. Acta Psychiatr Scand 1982; 66:66–82.
2. Agren H, Reibring L, Hartvig P, Tedroff J, Bjurling P, Hornfeldt K, Andersson Y, Lundqvist
H, Langstrom B. Low brain uptake of L-[11C]5-hydroxytryptophan in major depression: apositron emission tomography study on patients and healthy volunteers. Acta Psychiatr Scand
1991; 83:449–455.
3. Ahearn EP, Jamison KR, Steffens DC, Cassidy F, Provenzale JM, Lehman A, Weisler RH,
Carroll BJ, Krishnan KR. MRI correlates of suicide attempt history in unipolar depression.
Biol Psychiatry 2001; 50:266–270.
4. Alexopoulos GS, Meyers BS, Young RC, Kakuma T, Silbersweig D, Charlson M. Clinicallydeﬁned vascular depression. Am J Psychiatry 1997; 154:562–565.
5. Altamura CA, Mauri MC, Ferrara A, Moro AR, D’Andrea G, Zamberlan F. Plasma andplatelet excitatory amino acids in psychiatric disorders. Am J Psychiatry 1993; 150:1731–
1733.
6. Amsterdam JD, Berwish NJ. High dose tranylcypromine therapy for refractory depression.
Pharmacopsychiatry 1989; 22(1):21–25.
7. Amsterdam JD, Winokur A, Bryant S, Larkin J, Rickels K. The dexamethasone suppression
test as a predictor of antidepressant response. Psychopharmacology (Berl) 1983; 80:43–
45.
8. Anand A, Charney DS, Delgado PL, McDougle CJ, Heninger GR, Price LH. Neuroendocrineand behavioral responses to intravenous m-chlorophenylpiperazine (mCPP) in depressed patients and healthy comparison subjects. Am J Psychiatry 1994; 151:1626–1630.
9. Anand A, Malison R, McDougle CJ, Price LH. Antiglucocorticoid treatment of refractory
depression with ketoconazole: a case report. Biol Psychiatry 1995; 37:338–340.
10. Arango V, Underwood MD, Gubbi AV, Mann JJ. Localized alterations in pre- and postsynaptic serotonin bindings sites in the ventrolateral prefrontal cortex of suicide victims. Brain
Res 1995; 7;688:121–133.
11. Arato M, Banki CM, Bissette G, Nemeroff CB. Elevated CSF CRF in suicide victims. Biol
Psychiatry 1989; 25:355–359.

Neurobiology of Depression

485

12. Arora RC, Meltzer HY. 3H-imipramine binding in the frontal cortex of suicides. Psychiatry
Res 1989; 30:125–135.
13. Asberg M, Ringberger VA, Sjoqvist F, Thoren P, Traskman L, Tuck JR. Monoamine metabolites in cerebrospinal ﬂuid and serotonin uptake inhibition during treatment with chlorimipramine. Clin Pharmacol Ther 1977; 21:201–207.
14. Asnis GM, Wetzler S, Sanderson WC, Kahn RS, van Praag HM. Functional interrelationshipof serotonin and norepinephrine: cortisol response to MCPP and DMI in patients with panic
disorder, patients with depression, and normal control subjects. Psychiatry Res 1992; 43:65–
76.
15. Atre-Vaidya N, Jampala VC. Electroconvulsive therapy in parkinsonism with affective disorder. Br J Psychiatry 1988; 152:55–58.
16. Attar-Levy D, Martinot JL, Blin J, Dao-Castellana MH, Crouzel C, Mazoyer B, Poirier MF,
Bourdel MC, Aymard N, Syrota A, Feline A. The cortical serotonin-2 receptors studied withpositron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine. Biol Psychiatry 1999; 45:180–186.
17. Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F. Reduced glutamate in the anterior
cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study.
Biol Psychiatry 2000; 47:305–313.
18. Austin MP, Ross M, Murray C, O’Carroll RE, Ebmeier KP, Goodwin GM. Cognitive function in major depression. J Affect Disord 1992; 25:21–29.
19. Austin MP, Mitchell P, Goodwin GM. Cognitive deﬁcits in depression: possible implications
for functional neuropathology. Br J Psychiatry 2001; 178:200–206.
20. Austin MP, Mitchell P, Wilhelm K, et al. Cognitive function in depression: a distinct patternof frontal impairment in melancholia? Psychol Med 1999; 29:73–85.
21. Axelson DA, Doraiswamy PM, Boyko OB, Rodrigo Escalona P, McDonald WM, Ritchie
JC, Patterson LJ, Ellinwood EH Jr, Nemeroff CB, Krishnan KR. In vivo assessment of pituitary volume with magnetic resonance imaging and systematic stereology: relationship to
dexamethasone suppression test results in patients. Psychiatry Res 1992; 44:63–70.
22. Axelson DA, Doraiswamy PM, McDonald WM, Boyko OB, Tupler LA, Patterson LJ, Nemeroff CB, Ellinwood EH Jr, Krishnan KR. Hypercortisolemia and hippocampal changes in
depression. Psychiatry Res 1993; 47:163–173.
23. Balldin J. Factors inﬂuencing prolactin release induced by electroconvulsive therapy. Acta
Psychiatr Scand 1982; 65:365-369.
24. Banki CM, Bissette G, Arato M, O’Connor L, Nemeroff CB. CSF corticotropin-releasing
factor-like immunoreactivity in depression and schizophrenia. Am J Psychiatry 1987; 144:
873–877.
25. Banki CM, Bissette G, Arato M, Nemeroff CB. Elevation of immunoreactive CSF TRH in
depressed patients. Am J Psychiatry 1988; 145:1526–1531.
26. Banki CM, Karmacsi L, Bissette G, Nemeroff CB. CSF corticotropin-releasing hormone
and somatostatin in major depression: response to antidepressant treatment and relapse. Eur
Neuropsychopharmacol 1992; 2:107–113.
27. Baumann B, Danos P, Krell D, Diekmann S, Leschinger A, Stauch R, Wurthmann C, Bernstein HG, Bogerts B. Reduced volume of limbic system-afﬁliated basal ganglia in mooddisorders: preliminary data from a post mortem study. J Neuropsych Clin Neurosci 1999;
11:71–78.
28. Baxter LR Jr, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE, Gerner RH,
Sumida RM. Reduction of prefrontal cortex glucose metabolism common to three types ofdepression. Arch Gen Psychiatry 1989; 46:243–250.
29. Bemelmans KJ, Goekoop JG, van Kempen GM. Recall performance in acutely depressed
patients and cortisol. Biol Psychiatry 1996; 39:750–752.
30. Benazzi F. Course and outcome of bipolar II disorder: a retrospective study. Psychiatry Clin
Neurosci 2001; 55:67–70.

486

Zarate and Charney

31. Bench CJ, Friston KJ, Brown RG, Frackowiak RS, Dolan RJ. Regional cerebral blood ﬂow
in depression measured by positron emission tomography: the relationship with clinical dimensions. Psychol Med 1993; 23:579–590.
32. Benes FM, Kwok EW, Vincent SL, Todtenkopf MS. A reduction of nonpyramidal cells in
sector CA2 of schizophrenics and manic depressives. Biol Psychiatry 1998; 44:88–97.
33. Benkelfat C, Ellenbogen MA, Dean P, Palmour RM, Young SN. Mood-lowering effect oftryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective
disorders. Arch Gen Psychiatry 1994; 51:687–697.
34. Berk M, Plein H, Belsham B. The speciﬁcity of platelet glutamate receptor supersensitivity
in psychotic disorders. Life Sci 2000; 66:2427–2432.
35. Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH.
Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47:351–354.
36. Berrettini WH, Ferraro TN, Goldin LR, Weeks DE, Detera-Wadleigh S, Nurnberger JI Jr,
Gershon ES. Chromosome 18 DNA markers and manic-depressive illness: evidence for asusceptibility gene. Proc Natl Acad Sci USA 1994; 91:5918–5921.
37. Biegon A, Israeli M. Regionally selective increases in beta-adrenergic receptor density inthe brains of suicide victims. Brain Res 1988; 23;442:199–203.
38. Biegon A, Essar N, Israeli M, Elizur A, Bruch S, Bar-Nathan AA. Serotonin 5-HT2 receptor
binding on blood platelets as a state dependent marker in major affective disorder. Psychopharmacology (Berl) 1990; 102:73–75.
39. Biver F, Wikler D, Lotstra F, Damhaut P, Goldman S, Mendlewicz J. Serotinin 5-HT2 receptor imaging in major depression: focal changes in orbito-insular cortex. Br J Psychiatry 1997;
171:444–448.
40. Bligh-Glover W, Kolli TN, Shapiro-Kulnane L, Dilley GE, Friedman L, Balraj E, Rajkowska
G, Stockmeier CA. The serotonin transporter in the midbrain of suicide victims with major
depression. Biol Psychiatry 2000; 47:1015–1024.
41. Bilici M, Efe H, Koroglu MA, Uydu HA, Bekaroglu M, Deger O. Antioxidative enzyme
activities and lipid peroxidation in major depression: alterations by antidepressant treatments.
J Affect Disord 2001; 64:43–51.
42. Birmaher B, Dahl RE, Perel J, Williamson DE, Nelson B, Stull S, Kaufman J, Waterman
GS, Rao U, Nguyen N, Puig-Antich J, Ryan ND. Corticotropin-releasing hormone challenge
in prepubertal major depression. Biol Psychiatry 1996; 39:267–277.
43. Biver F, Wikler D, Lotstra F, Damhaut P, Goldman S, Mendlewicz J. Serotonin 5-HT2 receptor imaging in major depression: focal changes in orbitio-insular cortex. Br J Psychiatry
1997; 171:444–448.
44. Blackwood DH, He L, Morris SW, McLean A, Whitton C, Thomson M, Walker MT, Woodburn K, Sharp CM, Wright AF, Shibasaki Y, St Clair DM, Porteous DJ, Muir WJ. A locus
for bipolar affective disorder on chromosome 4p. Nat Genet 1996; 12:427–430.
45. Bocchetta A, Piccardi MP, Del Zompo M. Is bipolar disorder linked to Xp28? (letter). Nat
Genet 1994; 6:224.
46. Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, Dilsaver SC,
Davis JM, Rush AJ, Small JG, Garza-Threvino ES, Risch SC, Goodnick PJ, Morris DD, or
the Depakote Mania Study Group. Efﬁcacy of divalproex vs lithium and placebo in the treatment of mania. JAMA 1994; 271:918–924.
47. Bowen DM, Najlerahim A, Procter AW, Francis PT, Murphy E. Circumscribed changes of
the cerebral cortex in neuropsychiatric disorders of later life. Proc Natl Acad Sci USA 1989;
86:9504–9508.
48. Bremner JD, Innis RB, Salomon RM, Staib LH, Ng CK, Miller HL, Bronen RA, Krystal
JH, Duncan J, Rich D, Price LH, Malison R, Dey H, Soufer R, Charney DS. Positron emission
tomography measurement of cerebral metabolic correlates of tryptophan depletioninduced depressive relapse. Arch Gen Psych 1997; 54:346–374.

Neurobiology of Depression

487

49. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal
volume reduction in major depression. Am J Psychiatry 2000; 157:115–118.
50. Briley MS, Raisman R, Langer SZ. Human platelets possess high-afﬁnity binding sites for
3H-imipramine. Eur J Pharmacol 1979; 58:347–348.
51. Briley MS, Langer SZ, Raisman R, Sechter D, Zariﬁan E. Tritiated imipramine binding sites
are decreased in platelets of untreated depressed patients. Science 1980; 209:303–305.
52. Brody AL, Saxena S, Stoessel P, Gillies LA, Fairbanks LA, Alborzian S, Phelps ME, Huang
S-C, Wu H-M, Ho ML, Ho MK, Au SC, Maidment K, Baxter LR. Regional brain metabolicchanges in patients with major depression treated with either paroxetine or interpersonal
therapy. Arch Gen Psychiatry 2001; 58:631–640.
53. Brown ES, Rush AJ, McEwen BS. Hippocampal remodeling and damage by corticosteroids:
implications for mood disorders. Neuropsychopharmacology 1999; 21:474–484.
54. Brown ES, Bobadilla L, Rush AJ. Ketoconazole in bipolar patients with depressive symptoms: a case series and literature review. Bipolar Disord 2001; 3:23–29.
55. Brown WA, Qualls CB. Pituitary-adrenal disinhibition in depression: marker of a subtype
with characteristic clinical features and response to treatment? Psychiatry Res 1981; 4:115–
128.
56. Bunney WE Jr, Davis JM. Norepinephrine in depressive reactions. A review. Arch Gen Psychiatry 1965; 13:483–494.
57. Bunney WE Jr, Fawcett JA, Davis JM, Gifford S. Further evaluation of urinary 17-hydroxycorticosteroids in suicidal patients. Arch Gen Psychiatry 1969; 21:138–150.
58. Butler PW, Besser GM. Pituitary-adrenal function in severe depressive illness. Lancet 1968;
1:1234–1236.
59. Cadepond F, Ulmann A, Baulieu EE. RU486 (mifepristone): mechanisms of action and clinical uses. Annu Rev Med 1997; 48:129–156.
60. Cadoret RJ. Evidence for genetic inheritance of primary affective disorder in adoptees. Am
J Psychiatry 1978; 135:463–466.
61. Calabrese JR, Suppes T, Bowden CL, Sachs GS, Swann AC, McElroy SL, Kusumakar V,
Ascher JA, Earl NL, Greene PL, Monaghan ET. A double-blind placebo-controlled study oflamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group.
J Clin Psychiatry 1999; 60:79–88.
62. Cappiello A, Malison RT, McDougle CJ, Vegso SJ, Charney DS, Heninger GR, Price LH.
Seasonal variation in neuroendocrine and mood responses to i.v. L-tryptophan in depressed
patients and healthy subjects. Neuropsychopharmacology 1996; 15:475–483.
63. Cassidy F, Murry E, Weiner RD, Carroll BJ. Lack of relapse with tryptophan depletion following successful treatment with ECT. Am J Psychiatry 1997; 154:1151–1152.
64. Castillo M, Kwock L, Courvoisie H, Hooper SR. Proton MR spectroscopy in children
with bipolar affective disorder: preliminary observations. Am J Neuroradiol 2000; 21:832–
838.
65. Charney DS, Heninger GR, Sternberg DE, Redmond DE, Leckman JF, Maas JW, Roth RH.
Presynaptic adrenergic receptor sensitivity in depression. The effect of long-term desipramine
treatment. Arch Gen Psychiatry 1981; 38:1334–1340.
66. Chen AC, Shirayama Y, Shin KH, Neve RL, Duman RS. Expression of the cAMP response
element binding protein (CREB) in hippocampus produces an antidepressant effect. Biol
Psychiatry 2001; 49:753–762.
67. Choi D. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988; 1:623–
634.
68. Christensen P, Gram LF, Kragh-Soensen P, Christensen L, Kristensen CB, Pedersen OL,
Thomsen HY. Spontaneous afternoon plasma cortisol in depression. J Affect Disord 1985;
8:271–278.
69. Christensen P, Gram LF, Kragh-Sorensen P, Nielsen S. Afternoon cortisol levels before

488

70.

71.

72.
73.
74.

75.
76.
77.
78.
79.

80.
81.

82.

83.

84.

85.

86.
87.
88.

89.

Zarate and Charney(spontaneous) and after suppression with dexamethasone or oxazepam in depressed patients.
J Affect Disord 1986; 10:171–176.
Christensen P, Lolk A, Gram LF, Kragh-Sorensen P, Pedersen OL, Nielsen S. Cortisol andtreatment of depression: predictive value of spontaneous and suppressed cortisol levels andcourse of spontaneous plasma cortisol. Psychopharmacology (Berl) 1989; 97:471–475.
Coon H, Jensen S, Hoff M, et al. A genome-wide search for genes predisposing to manicdepression, assuming autosomal dominant inheritance. Am J Hum Genet 1993; 52:1234–
1249.
Cooney JM, Lucey JV, O’Keane V, Dinan TG. Speciﬁcity of the pyridostigmine/growth
hormone challenge in the diagnosis of depression. Biol Psychiatry 1997; 42:827–833.
Coryell W, Schlesser M. The dexamethasone suppression test and suicide prediction. Am J
Psychiatry 2001; 158:748–753.
Cousins JP, Harper G. Neurobiochemical changes from Taxol/Neupogen chemotherapy formetastatic breast carcinoma corresponds with suicidal depression. Cancer Lett 1996; 110:
163–167.
Cowen PJ. A role for 5-HT in the action of antidepressant drugs. Pharmacol Ther 1990; 46:
43–51.
Cowen PJ, Power AC, Ware CJ, Anderson IM. 5-HT1A receptor sensitivity in major depression. A neuroendocrine study with buspirone. Br J Psychiatry 1994; 164:372–379.
Cowen PJ. Psychopharmacology of 5-HT(1A) receptors. Nucl Med Biol 2000; 27:437–439.
Coyle JT, Schwarcz R. Mind glue: implications of glial cell biology for psychiatry. ArchGen Psychiatry 2000; 57:90–93.
Crow TJ, Cross AJ, Cooper SJ, Deakin JF, Ferrier IN, Johnson JA, Joseph MH, Owen F,
Poulter M, Lofthouse R. Neurotransmitter receptors and monoamine metabolites in the brainsof patients with Alzheimer-type dementia and depression, and suicides. Neuropharmacology
1984; 23:1561–1569.
Craddock N, McGufﬁn P, Owen M. Darier’s disease cosegregating with affective disorder(letter). Br J Psychiatry 1994; 165:272.
Dahl LE, Lundin L, Le Fevre Honore P, Dencker SJ. Antidepressant effect of femoxetineand desipramine and relationship to the concentration of amine metabolites in cerebrospinal
ﬂuid. A double-blind evaluation. Acta Psychiatr Scand 1982; 66:9–17.
Deakin JFW, Pennell I, Upadhyaya AJ, et al. A neuroendocrine study of 5-HT function in
depression: evidence for biological mechanisms of endogenous and psychosocial causation.
Psychopharmacology (Berl) 1990; 101:85–92.
de Asis JM, Stern E, Alexopoulos GS, Pan H, Van Gorp W, Blumberg H, Kalayam B, Eidelberg D, Kiosses D, Silbersweig DA. Hippocampal and anterior cingulate activation deﬁcits
in patients with geriatric depression. Am J Psychiatry 2001; 158:1321–1323.
de Groot JC, de Leeuw FE, Oudkerk M, Hofman A, Jolles J, Breteler MM. Cerebral whitematter lesions and depressive symptoms in elderly adults. Arch Gen Psychiatry 2000; 57:
1071-1076.
DeBattista C, Posener JA, Kalehzan BM, Schatzberg AF. Acute antidepressant effects
of intravenous hydrocortisone and CRH in depressed patients: a double-blind, placebocontrolled study. Am J Psychiatry 2000; 157:1334–1337.
DeBellis MD, Gold PW, Geracioti TD, et al. Fluoxetine signiﬁcantly reduces CSF CRH and
AVP concentrations in patients with major depression. Am J Psychiatry 1993; 150:656–657.
Deger O, Bekaroglu M, Orem A, Orem S, Uluutku N, Soylu C. Polymorphonuclear (PMN)
elastase levels in depressive disorder. Biol Psychiatry 1996; 39:357–363.
De Kloet ER, De Kock S, Schild V, Veldhuis HD. Antiglucocorticoid RU 38486 attenuates
retention of a behaviour and disinhibits the hypothalamic-pituitary adrenal axis at different
brain sites. Neuroendocrinology 1988; 47:109–115.
Delgado PL, Charney DS, Price LH, Landis H, Heninger GR. Neuroendocrine and behavioral
effects of dietary tryptophan restriction in healthy subjects. Life Sci 1990; 45:2323–2332.

Neurobiology of Depression

489

90. D’Haenen H, Bossuyt A, Mertens J, Bossuyt-Piron C, Gijsemans M, Kaufman L. SPECT
imaging of serotonin-2 receptors in depression. Psychiatry Res 1992; 45:227–237.
91. D’Haenen HA, Bossuyt A. Dopamine D2 receptors in depression measured with single photon emission computed tomography. Biol Psychiatry 1994; 35:128–132.
92. Dorovini-Zis K, Zis AP. Increased adrenal weight in victims of violent suicide. Am J Psychiatry 1987; 144:1214–1215.
93. Douyon R, Serby M, Klutchko B, Rotrosen J. ECT and Parkinson’s disease revisited: a “naturalistic” study. Am J Psychiatry 1989; 146:1451–1455.
94. Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. A functional
anatomical study of unipolar depression. J Neurosci 1992; 12:3628–3641.
95. Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997; 386:824–827.
96. Drevets WC, Gadde K, Krishnan R. Neuroimaging studies of depression. In: Charney DS,
Nestler EJ, Bunney BJ, eds. The Neurobiological Foundation of Mental Illness. New York:
Oxford University Press, 1999:394–418.
97. Drevets WC. Functional anatomical abnormalities in limbic and prefrontal cortical structuresin major depression. Prog Brain Res 2000; 126:413–431.
98. Drevets WC, Frank E, Price JC, Kupfer DJ, Greer PJ, Mathis C. Serotonin type-1A receptor
imaging in depression. Nucl Med Biol 2000; 27:499–507.
99. Dube S, Kumar N, Ettedgui E, Pohl R, Jones D, Sitaram N. Cholinergic REM induction
response: separation of anxiety and depression. Biol Psychiatry 1985; 20:408–418.
100. Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. ArchGen Psychiatry 1997; 54:597–606.
101. Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment.
Biol Psychiatry 1999; 46:1181–1191.
102. Duman RS, Malberg J, Nakagawa S, D’Sa C. Neuronal plasticity and survival in mood disorders. Biol Psychiatry 2000; 48:732–739.
103. Dunkin JJ, Leuchter AF, Cook IA, Kasl-Godley JE, Abrams M, Rosenberg-Thompson S.
Executive dysfunction predicts nonresponse to ﬂuoxetine in major depression. J Affect Disord 2000; 60:13–21.
104. Duval F, Macher JP, Mokrani MC. Difference between evening and morning thyrotropin
responses to protirelin in major depressive episode. Arch Gen Psychiatry 1990; 47:443–448.
105. Ebert D, Feistel H, Barocka A. Effects of sleep deprivation on the limbic system and thefrontal lobes in affective disorders: A study with Tc-99m-HMPAO SPECT. Psychiatry Res
Neuroimag 1991; 40:247–251.
106. Ebert D, Feistel H, Loew T, Pirner A. Dopamine and depression—striatal dopamine D2
receptor SPECT before and after antidepressant therapy. Psychopharmacology (Berl) 1996;
126:91–94.
107. Egeland JA, Gerhard DS, Pauls DL, Sussex JN, Kidd KK, Allen CR, Hostetter AM, Housman
DE. Bipolar affective disorders linked to DNA markers on chromosome 11. Nature 1987;
325:783–787.
108. Elkis H, Friedman L, Wise A, Meltzer HY. Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders. Comparisons with controls or patientswith schizophrenia. Arch Gen Psychiatry 1995; 52:735–746.
109. Ellenbogen MA, Young SN, Dean P, Palmour RM, Benkelfat C. Mood response to acutetryptophan depletion in healthy volunteers: sex differences and temporal stability. Neuropsychopharmacology 1996; 15:465–474.
110. Ellis PM, Salmond C. Is platelet imipramine binding reduced in depression? A meta-analysis.
Biol Psychiatry 1994; 36:292–299.
111. El-Yousef MK, Janowsky DS, Davis JM, Rosenblatt JE. Induction of severe depression byphysostigmine in marihuana intoxicated individuals. Br J Addict Alcohol Other Drugs 1973;
68:321–325.

490

Zarate and Charney112. Ewald H, Mors O, Flint T, et al. A possible locus for manic depressive illness on chomosome
16p13. Psychiatric Genet 1995; 5:71–81.
113. Figiel GS, Krishnan KR, Doraiswamy PM. Subcortical structural changes in ECT-induced
delirium. J Geriatr Psychiatry Neurol 1990; 3:172–176.
114. Figiel GS, Hassen MA, Zorumski C, Krishnan KR, Doraiswamy PM, Jarvis MR, Smith DS.
ECT-induced delirium in depressed patients with Parkinson’s disease. J Neuropsychiatry Clin
Neurosci 1991; 3:405–411.
115. Galva MD, Bondiolotti GP, Olasmaa M, Picotti GB. Effect of aging on lazabemide binding,monoamine oxidase activity and monoamine metabolites in human frontal cortex. J Neural
Transm Gen Sect 1995; 101:83–94.
116. Garcia-Sevilla JA, Padro D, Giralt MT, Guimon J, Areso P. Alpha-2 adrenoreceptor-mediatedinhibition of platelet adenyl cyclase and induction of aggregation in major depression. ArchGen Psychiatry 1990; 47:125–132.
117. George MS, Ketter TA, Parekh PI, Rosinsky N, Ring HA, Pazzaglia PJ, Marangell LB,
Callahan AM, Post RM. Blunted left cingulate activation in mood disorder subjects during
a response interference task (the Stroop). J Neuropsychiatry Clin Neurosci 1997; 9:55–63.
118. Geracioti TD Jr, Loosen PT, Orth DN. Low cerebrospinal ﬂuid corticotropin-releasing hormone concentrations in eucortisolemic depression. Biol Psychiatry 1997; 42:165–174.
119. Ghadirian AM, Engelsmann F, Dhar V, Filipini D, Keller R, Chouinard G, Murphy BE. The
psychotropic effects of inhibitors of steroid biosynthesis in depressed patients refractory totreatment. Biol Psychiatry 1995; 37:369–375.
120. Gold PW, Chrousos G, Kellner C, Post R, Roy A, Augerinos P, Schulte H, Oldﬁeld E,
Loriaux DL. Psychiatric implications of basic and clinical studies with corticotropin-releasing
factor. Am J Psychiatry 1984; 141:619–627.
121. Gold PW, Chrousos GP. Clinical studies with corticotropin releasing factor: implications forthe diagnosis and pathophysiology of depression, Cushing’s disease, and adrenal insufﬁciency. Psychoneuroendocrinology 1985; 10:401–419.
122. Gold PW, Calabrese JR, Kling MA, Avgerinos P, Khan I, Gallucci WT, Tomai TP, Chrousos
GP. Abnormal ACTH and cortisol responses to ovine corticotropin releasing factor in patientswith primary affective disorder. Prog Neuropsychopharmacol Biol Psychiatry 1986; 10:57–
65.
123. Golden RN, Rudorfer MV, Sherer MA, Linnoila M, Potter WZ. Bupropion in depression.
I. Biochemical effects and clinical response. Arch Gen Psychiatry 1988; 45:139–143.
124. Gonzales-Heydrich J, Peroutka SJ. Serotonin receptor and reuptake sites: pharmacologic signiﬁcance. J Clin Psychiatry 1990; 51(suppl):5–12.
125. Grant MM, Thase ME, Sweeney JA. Cognitive disturbance in outpatient depressed younger
adults: evidence of modest impairment. Biol Psychiatry 2001; 50:35–43.
126. Greenberg PE, Sisitsky T, Kessler RC, Finkelstein SN, Berndt ER, Davidson JR, Ballenger
JC, Fyer AJ. The economic burden of anxiety disorders in the 1990s. J Clin Psychiatry 1999;
60:427–435.
127. Greenwald BS, Kramer-Ginsberg E, Krishnan RR, Ashtari M, Aupperle PM, Patel M. MRI
signal hyperintensities in geriatric depression. Am J Psychiatry 1996; 153:1212–1215.
128. Grifﬁn WST, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White III CL, Araoz
C. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome andAlzheimer disease. Proc Natl Acad Sci USA 1998; 86:7611–7615.
129. Gurevich EV, Joyce JN. Comparison of [3H]paroxetine and [3H]cyanoimipramine for quantitative measurement of serotonin transporter sites in human brain. Neuropsychopharmacology
1996; 14:309–323.
130. Halaris AE. Plasma 3-methoxy-4-hydroxyphenylglycol in manic psychosis. Am J Psychiatry
1978; 135:493–494.
131. Hayakawa H, Yokota N, Kawai K, Okamoto Y, Osada M, Kikumoto O, Motohashi N,
Yamawaki S, Nishida A, Shimizu M. Effects of electroconvulsive shock on the serotoninNeurobiology of Depression

132.

133.

134.

135.
136.

137.
138.
139.
140.
141.

142.

143.

144.
145.

146.
147.
148.

149.

150.

151.

491

metabolism and serotonin1A receptors in the rat brain. Jpn J Psychiatry Neurol 1993; 47:
418–419.
Healy D, Carney PA, O’Halloran A, Leonard BE. Peripheral adrenoreceptors and serotoninreceptors in depression: changes associated with response to treatment with trazodone oramitriptyline. J Affect Disord 1985; 9:285–296.
Heresco-Levy U, Javitt DC. The role of N-methyl-D-aspartate (NMDA) receptor-mediatedneurotransmission in the pathophysiology and therapeutics of psychiatric syndromes. Eur
Neuropsychopharmacol 1998; 8:141–152.
Hickie I, Scott E, Mitchell P, Wilhelm K, Austin MP, Bennett B. Subcortical hyperintensities
on magnetic resonance imaging: clinical correlates and prognostic signiﬁcance in patientswith severe depression. Biol Psychiatry 1995; 37:151–160.
Himmelhoch JM, Thase ME, Mallinger AG, Houck P. Tranylcypromine versus imipramine
in anergic bipolar depression. Am J Psychiatry 1991; 148:910–916.
Hirayasu Y, Shenton ME, Salisbury DF, Kwon JS, Wible CG, Fischer IA, Yurgelun-Todd
D, Zarate C, Kikinis R, Jolesz FA, McCarley RW. Subgenual cingulate cortex volume inﬁrst-episode psychosis. Am J Psychiatry 1999; 156:1091–1093.
Hollister LE, Davis KL, Berger PA. Subtypes of depression based on excretion of MHPG
and response to nortriptyline. Arch Gen Psychiatry 1980; 37:1107–1110.
Holsboer F, Benkert O, Demisch L. Changes in MAO activity during estrogen treatment offemales with endogenous depression. Mod Probl Pharmacopsychiatry 1983; 19:321–326.
Holsboer F. The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists
to treat depression and anxiety. J Psychiatr Res 1999; 33:181–214.
Hurwitz TA, Clark C, Murphy E, Klonoff H, Martin WR, Pate BD. Regional cerebral glucose
metabolism in major depressive disorder. Can J Psychiatry 1990; 35:684–688.
Husain MM, McDonald WM, Doraiswamy PM, Figiel GS, Na C, Escalona PR, Boyko OB,
Nemeroff CB, Krishnan KR. A magnetic resonance imaging study of putamen nuclei inmajor depression. Psychiatry Res 1991; 40:95–99.
Inoue T, Tsuchiya K, Miura J, Sakakibara S, Denda K, Kasahara T, Koyama T. Bromocriptine treatment of tricyclic and heterocyclic antidepressant-resistant depression. Biol Psychiatry 1996; 40:151–153.
Israel E, Baerjee RR, Garrett MF, Kotlov TV, LaHive K, LeBoff MS. Effects of inhaled
glucocorticoids on bone density in premenopausal women. N Engl J Med 2001; 345:941–
947.
Jacobson L, Sapolsky R. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenal axis. Endocr Rev 1991; 12:118–134.
Joyce JN, Shane A, Lexow N, Winokur A, Casanova MF, Kleinman JE. Serotonin uptake
sites and serotonin receptors are altered in the limbic system of schizophrenics. Neuropsychopharmacology 1993; 8:315–336.
Janowsky DS, el-Yousef MK, Davis JM, Sekerke HJ. A cholinergic-adrenergic hypothesisof mania and depression. Lancet 1972; 2:632–635.
Janowsky DS, Risch SC, Gillin JC. Adrenergic-cholinergic balance and the treatment ofaffective disorders. Prog Neuropsychopharmacol Biol Psychiatry 1983; 7:297–307.
Kastin AJ, Ehrensing RH, Schalch DS, Anderson MS. Improvement in mental depression
with decreased thyrotropin response after administration of thyrotropin-releasing hormone.
Lancet 1972; 2:740–742.
Kelsoe JR, Ginns EI, Egeland JA, et al. Re-evaluation of the linkage relationship between
chromosome 11 p loci and the gene for bipolar affective disorder in the Old Order Amish.
Nature 1989; 342:238–243.
Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. A population-based twin studyof major depression in women: the impact of varying deﬁnitions of illness. Arch Gen Psychiatry 1992; 49:257–266.
Kendler KS, Pedersen N, Johnson L, Neale MC, Mathe AA. A pilot Swedish twin study

492

152.
153.

154.
155.

156.
157.
158.
159.
160.
161.

162.
163.

164.

165.
166.

167.

168.
169.

170.

Zarate and Charneyof affective illness, including hospital- and population-ascertained subsamples. Arch Gen
Psychiatry 1993; 50:699–706.
Kendler KS, Kessler RC, Neale MC, Heath AC, Eaves LJ. The prediction of major depression
in women: toward an integrated etiologic model. Am J Psychiatry 1993; 150:1139–1148.
Kennedy SH, Evans KR, Kruger S, Mayberg HS, Meyer JH, McCann S, Arifuzzman AI,
Houle S, Vaccarino FJ. Changes in regional brain glucose metabolism measured with positronemission tomography after paroxetine treatment of major depression. Am J Psychiatry 2001;
158:899–905.
Kessing LV. Cognitive impairment in the euthymic phase of affective disorder. Psychol Med
1998; 28:1027–1038.
Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU,
Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the
United States. Arch Gen Psychiatry 1994; 51:8–19.
Kim JS, Schmid-Burgk W, Claus D, Kornhuber HH. Increased serum glutamate in depressed
patients. Arch Psychiatrie Nervenkrankheiten 1982; 232:299–304.
Kim JS. Cytokines and adhesion molecules in stroke and related diseases. J Neurol Sci 1996;
137:69–78.
Kirkegaard C, Olgaard K, Faber J, Siersbaek-Nielsen K, Friis T. Thyrotropin-releasinghormone tests. Lancet 1979; 1:556.
Klaiber EL, Broverman DM, Vogel W, Kobayashi Y. Estrogen therapy for severe persistentdepressions in women. Arch Gen Psychiatry 1979; 163:1721–1727.
Klijn JG, Setyono-Han B, Foekens JA. Progesterone antagonists and progesterone receptor
modulators in the treatment of breast cancer. Steroids 2000; 65:825–830.
Klimke A, Larisch R, Janz A, Vosberg H, Muller-Gartner HW, Gaebel W. Dopamine D2
receptor binding before and after treatment of major depression measured by [12I]IBZM
SPECT. Psychiatry Res 1999; 90:91–101.
Kopin IJ, Gordon EK, Jimerson DC, Polinsky RJ. Relation between plasma and cerebrospinal
ﬂuid levels of 3-methoxy-4-hydroxyphenylglycol. Science 1983; 219:73–75.
Kopin IJ, Jimerson DC, Markey SP, Ebert MH, Polinsky RJ. Disposition and metabolism of MHPG in humans: application to studies in depression. Pharmacopsychiatry 1984;
17:3–8.
Koyama T, Meltzer HY: A biochemical and neuroendocrine study of the serotonergic system
in depression. In: Hippius H, Klerman GL, Matussek N, eds. New Results in Depression
Research. New York: Springer-Verlag, 1986:169–188.
Krishnan KR, Hays JC, Blazer DG. MRI-deﬁned vascular depression. Am J Psychiatry 1997;
154:497–501.
Krishnan KR, Husain MM, McDonald WM, Doraiswamy PM, Figiel GS, Boyko OB, Ellinwood EH, Nemeroff CB. In vivo stereological assessment of caudate volume in man: effectof normal aging. Life Sci 1990; 47:1325–1329.
Krishnan KR, Doraiswamy PM, Lurie SN, Figiel GS, Husain MM, Boyko OB, Ellinwood
EH Jr, Nemeroff CB. Pituitary size in depression. J Clin Endocrinol Metab 1991; 72:256–
259.
Krishnan KR. Organic bases of depression in the elderly. Annu Rev Med 1991; 42:261–
266.
Kung HF, Kasliwal R, Pan SG, Kung MP, Mach RH, Guo YZ. Dopamine D-2 receptor
imaging radiopharmaceuticals: synthesis, radiolabeling, and in vitro binding of (R)-(⫹)- and(S)-(⫺)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]benzamide. J Med
Chem 1988; 31:1039–1043.
Laruelle M, D’Souza CD, Baldwin RM, Abi-Dargham A, Kanes SJ, Fingado CL, Seibyl JP,
Zoghbi SS, Bowers MB, Jatlow P, Charney DS, Innis RB. Imaging D2 receptor occupancy
by endogenous dopamine in humans. Neuropsychopharmacology 1997; 17:162–174.

Neurobiology of Depression

493

171. Laruelle M. Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 2000; 20:423–451.
172. Lecrubier Y, Puech AJ, Frances H, Jouvent R, Widlocher D, Simon P. Beta-adrenergic stimulation and antidepressant activity. Acta Psychiatr Scand 1981; 290(suppl):173–178.
173. Lederbogen F, Gilles M, Maras A, Hamann B, Colla M, Heuser I, Deuschle M. Increased
platelet aggregability in major depression? Psychiatry Res 2001; 102:255–261.
174. Lerer B. Neurochemical and other neurobiological consequences of ECT: implications forthe pathogenesis and treatment of affective disorders. In: Meltzer HY, eds. Psychopharmacology: The Third Generation of Progress. New York: Raven, 1987:577–588.
175. Lesser IM, Boone KB, Mehringer CM, Wohl MA, Miller BL, Berman NG. Cognition andwhite matter hyperintensities in older depressed patients. Am J Psychiatry 1996; 153:1280–
1287.
176. Levine J, Panchalingam K, Rapoport A, Gershon S, McClure RJ, Pettegrew JW. Increased
cerebrospinal ﬂuid glutamine levels in depressed patients. Biol Psychiatry 2000; 47:586–
593.
177. Leyton M, Young SN, Blier P, Ellenbogen MA, Palmour RM, Ghadirian AM, Benkelfat C.
The effect of tryptophan depletion on mood in medication-free, former patients with majoraffective disorder. Neuropsychopharmacology 1997; 16:294–297.
178. Lopez JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin 1A, glucocorticoid,and mineralocorticoid receptor in rat and human hippocampus: implications for the neurobiology of depression. Biol Psychiatry 1998; 43:547–573.
179. LoTurco JJ. Neural circuits in the 21st century: synaptic networks of neurons and glia. Proc
Natl Acad Sci USA 2000; 97:8196–8197.
180. Louis WJ, Doyle AE, Anavekar SN. Plasma noradrenaline concentration and blood pressurein essential hypertension, phaeochromocytoma and depression. Clin Sci Molec Med 1975;
48:239s–242s.
181. Lucca A, Lucini V, Piatti E, Ronchi P, Smeraldi E. Plasma tryptophan levels and plasma
tryptophan/neutral amino acids ratio in patients with mood disorder, patients with obsessivecompulsive disorder, and normal subjects. Psychiatry Res 1992; 44:85–91.
182. Lund A, Mjellem-Jolly N, Hole K. Desipramine, administered chronically, inﬂuences 5hydroxytryptamine 1A-receptors, as measured by behavioral tests and receptor binding inrats. Neuropharmacol 1992; 31:25–32.
183. Lupien SJ, Gillin CJ, Hauger RL. Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: a dose-response study in humans. Behav Neurosci
1999; 113:420–430.
184. Maas JW, Fawcett JA, Dekirmenjian H. Catecholamine metabolism, depressive illness anddrug response. Arch Gen Psychiatry 1972; 26:252–262.
185. Maas JW, Koslow SH, Katz MM, et al. Pretreatment neurotransmitter metabolite levels andresponse to tricyclic antidepressant drugs. Am J Psychiatry 1984; 141:1159–1171.
186. Maes M, de Ruyter M, Suy E. Cortisol response to dexamethasone and noradrenergic function in depression. Acta Psychiatr Scand 1987; 75:171–175.
187. Maes M, Jacobs MP, Suy E, Minner B, Leclercq C, Christiaens F, Raus J. Supressant effects
of dexamethasone on the availability of plasma L-tryptophan and tyrosine in healthy controls
and in depressed patients. Acta Psychiatr Scand 1990; 81:19–23.
188. Maes M, Calabrese J, Meltzer HY. The relevance of the in- versus outpatient status for studies
on HPA-axis in depression: spontaneous hypercortisolism is a feature of major depressed
inpatients and not of major depression per se. Prog Neuropsychopharmacol Biol Psychiatry
1994; 18:503–517.
189. Maes M, Van Gastel A, Delmeire L, Meltzer HY. Decreased platelet alpha-2 adrenoceptor
density in major depression: effects of tricyclic antidepressants and ﬂuoxetine. Biol Psychiatry 1999; 45:278–284.

494

Zarate and Charney190. Maes M, Lambrechts J, Bosmans E, Jacobs J, Suy E, Vandervorst C, de Jonckheere C, Minner
B, Raus J. Evidence for a systemic immune activation during depression: results of leukocyte
enumeration by ﬂow cytometry in conjunction with monoclonal antibody staining. Psychol
Med 1992; 22:45–53.
191. Maj M, Ariano MG, Arena F, et al. Plasma cortisol, catecholamine and cyclic AMP levels,
response to dexamethasone suppression test and platelet MAO activity in manic-depressive
patients: a longitudinal study. Neuropsychobiology 1984; 11:168–173.
192. Maj J, Wedzony K. Repeated treatment with imipramine or amitriptyline increases the locomotor response of rats to (⫹)-amphetamine given into the nucleus accumbens. J Pharm Pharmacol 1985; 37:362–364.
193. Paul IA. NMDA receptors and affective disorders. In: Skolnick P, ed. Antidepressants: New
Pharmacological Strategies. Totowa, NJ: Humana, 1997:145–158.
194. Malison RT, Pelton G, Carpenter L, et al. Reduced midbrain serotonin transporter binding
in depressed vs. healthy subjects as measured by [123I]b-CIT SPECT. Soc Neurosci Abstr
1997; 23:1220.
195. Malone KM, Thase ME, Mieczkowski T, Myers JE, Stull SD, Cooper TB, Mann JJ. Fenﬂuramine challenge test as a predictor of outcome in major depression. Psychopharmacol Bull
1993; 29:155-161.
196. Manji HK. G proteins: implications for psychiatry. Am J Psychiatry 1992; 149:746–760.
197. Mann JJ, Stanley M, McBride PA, et al. Increased serotonin 2 and β-adrenergic receptor
binding in the frontal cortices of suicide victims. Arch Gen Psychiatry 1986; 43:954–
959.
198. Mann JJ, Malone KM, Diehl DJ, Perel J, Cooper TB, Mintun MA. Demonstration in vivoof reduced serotonin responsivity in the brain of untreated depressed patients. Am J Psychiatry 1996; 153:174–182.
199. Markowitz JH, Shuster JL, Chitwood WS, May RS, Tolbert LC. Platelet activation in depression and effects of sertraline treatment: an open-label study. Am J Psychiatry 2000; 157:
1006–1008.
200. Martensson B, Nyberg S, Toresson G, Brodin E, Bertilsson L. Fluoxetine treatment of depression. Clinical effects, drug concentrations and monoamine metabolites and N-terminally extended substance P in cerebrospinal ﬂuid. Acta Psychiatr Scand 1989; 79:586–596.
201. Mathis P, Schmitt L, Benatia M, Granier F, Ghisolﬁ J, Moron P. Plasma amino acid disturbances and depression. Encephale 1988; 14:77–82.
202. Matussek N, Ackenheil M, Hippius H, et al. Effects of clonidine on growth hormone releasein psychiatric patients and controls. Psychiatry Res 1980; 2:25–36.
203. Mattsubara S, Arora RC, Meltzer HY. Serotonergic measures in suicide brain: 5-HT1A binding sites in frontal cortex of suicide victims. J Neural Transm 1991; 85:181–194.
204. Mauri MC, Ferrara A, Boscati L, Bravin S, Zamberlan F, Alecci M, Invernizzi G. Plasmaand platelet amino acid concentrations in patients affected by major depression and underﬂuvoxamine treatment. Neuropsychobiology 1998; 37:124–129.
205. Mayberg HS, Lewis PJ, Regenold W, Wagner HN Jr. Paralimbic hypoperfusion in unipolar
depression. J Nucl Med 1994; 35:929–934.
206. Mayberg HS, Brannan SK, Mahurin RK, Jerabek PA, Brickman JS, Tekell JL, Silva JA,
McGinnis S, Glass TG, Martin CC, Fox PT. Cingulate function in depression: a potential
predictor of treatment response. Neuroreport 1997; 8:1057–1061.
207. Mayberg HS, Brannan SK, Tekell JL, Silva JA, Mahurin RK, McGinnis S, Jerabek PA.
Regional metabolic effects of ﬂuoxetine in major depression: serial changes and relationshipto clinical response. Biol Psychiatry 2000; 48:830–843.
208. McEwen BS, Gould E, Orchinik M, Weiland NG, Wooley CS. Oestrogens and the structuraland functional plasticity of neurons: implications for memory, ageing and neurodegenerative
processes. Ciba Found Symp 1995; 191:52–66.

Neurobiology of Depression495

209. McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Opin Neurobiol 1995; 5:
205–216.
210. McGrath PJ, Stewart JW, Nunes EV, Ocepek-Welikson K, Rabkin JG, Quitkin FM, Klein
DF. A double-blind crossover trial of imipramine and phenelzine for outpatients with treatment-refractory depression. Am J Psychiatry 1993; 150:118–123.
211. McGrath PJ, Quitkin FM, Klein DF. Bromocriptine treatment of relapses seen during selective serotonin re-uptake inhibitor treatment of depression. J Clin Psychopharmacol 1995; 15:
289–291.
212. McGrath PJ, Stewart JW, Harrison W, Quitkin FM. Treatment of tricyclic refractory depression with a monoamine oxidase inhibitor antidepressant. Psychopharmacol Bull 1987; 23:
169–172.
213. McGufﬁn P, Katz R, Rutherford J. Nature, nurture and depression: a twin study. Psychol
Med 1991; 21:329–335.
214. McGufﬁn P, Katz R, Watkins S, Rutherford J. A hospital-based twin register of the heritability of DSM-IV unipolar depression. Arch Gen Psychiatry 1996; 53:129–136.
215. McIntosh LJ, Hong KE, Sapolsky RM. Glucocorticoids may alter antioxidant enzyme capacity in the brain: baseline studies. Brain Res 1998; 791:209–214.
216. McKinney WT. Animal models of depression: an overview. Psychiatr Dev 1984; 2:77–
96.
217. McMahon F, Simpson SG, McInnis MG, Badner JA, MacKinnon DF, DePaulo R. Linkageof bipolar disorder to chromosome 18q and the validity of bipolar II disorder. Arch Gen
Psychiatry 2001; 58:1025–1031.
218. Meana JJ, Barturen F, Garcia-Sevilla JA: Alpha2-adrenoreceptors in the brain of suicide
victims: increased receptor density associated with major depression. Biol Psychiatry 1992;
31:471–490.
219. Meltzer HY, Lowy MT. The serotonin hypothesis of depression. In: Meltzer HY, ed. Psychopharmacology: The Third Generation of Progress. New York: Raven, 1987:513–526.
220. Mendlewicz J, Rainer J. Adoption study supporting genetic transmission in manic-depressive
illness. Nature 1977; 268:326–329.
221. Mendlewicz J, Pinder RM, Stulemeijer SM, Van Dorth R. Monoamine metabolites in cerebrospinal ﬂuid of depressed patients during treatment with mianserin or amitriptyline. J Affect Disord 1982; 4:219–226.
222. Merriam EP, Thase ME, Haas GL, Keshavan MS, Sweeney JA. Prefrontal cortical dysfunction in depression determined by Wisconsin Card Sorting Test performance. Am J Psychiatry
1999; 156:780–782.
223. Mervaala E, Fohr J, Kononen M, Valkonen-Korhonen M, Vainio P, Partanen K, Partanen
J, Tiihonen J, Viinamaki H, Karjalainen AK, Lehtonen J. Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol Med 2000; 30:117–125.
224. Meyer JH, Kapur S, Houle S, DaSilva J, Owczarek B, Brown GM, Wilson AA, Kennedy
SH. Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study.
Am J Psychiatry 1999; 156:1029–1034.
225. Miller HL, Delgado PL, Salomon RM, Heninger GR, Charney DS. Effects of alpha-methylpara-tyrosine (AMPT) in drug-free depressed patients. Neuropsychopharmacology 1996; 14:
151–157.
226. Mitchell P, Smythe G. Hormonal responses to fenﬂuramine in depressed and control subjects.
J Affect Disord 1990; 19:43–51.
227. Moller SE, de Beurs P, Timmerman L, Tan BK, Leijnse-Ybema HJ, Stuart MH, Petersen HE.
Plasma tryptophan and tyrosine ratios to competing amino acids in relation to antidepressant
response to citalopram and maprotiline. A preliminary study. Psychopharmacology (Berl)
1986; 88:96–100.
228. Moore P, Gillin C, Bhatti T, DeModena A, Seifritz E, Clark C, Stahl S, Rapaport M, Kelsoe

496

229.

230.
231.
232.
233.
234.

235.

236.
237.
238.
239.

240.

241.

242.

243.
244.

245.

246.

247.

Zarate and Charney
J. Rapid tryptophan depletion, sleep electroencephalogram, and mood in men with remitted
depression on serotonin inhibitors. Arch Gen Psychiatry 1998; 55:534–539.
Murphy BE, Filipini D, Ghadirian AM. Possible use of glucocorticoid receptor antagonists
in the treatment of major depression: preliminary results using RU 486. J Psychiatry Neurosci
1993; 18:209–213.
Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors:
Global Burden of Disease Study. Lancet 1997; 349:1436–1442.
Musselman DL, Evans DL, Nemeroff CB. The relationship of depression to cardiovasculardisease: epidemiology, biology, and treatment. Arch Gen Psychiatry 1998; 55:580–592.
Nelson JC, Davis JM. DST studies in psychotic depression: a meta-analysis. Am J Psychiatry
1997; 154:1497–1503.
Nelson EB, Sax KW, Strakowski SM. Attentional performance in patients with psychotic
and nonpsychotic major depression and schizophrenia. Am J Psychiatry 1998; 155:137–139.
Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, Kilts CD, Loosen
PT, Vale W. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984; 226:1342–1344.
Nemeroff CB, Knight DL, Krishnan KRR, et al. Marked reduction in the number of platelet[3H] imipramine binding sites in geriatric depression. Arch Gen Psychiatry 1988; 45:577–
579.
Nemeroff CB, Knight DL, Krishnan KRR. Reduced platelet [3H]-paroxetine and [3H]-imipramine binding in major depression. Soc Neurosci Abstr 1991; 17:1472.
Nemeroff CB, Knight DL, Franks J, Craighead WE, Krishnan KR. Further studies on platelet
serotonin transporter binding in depression. Am J Psychiatry 1994; 151:1623–1625.
Nemeroff CB. The corticotropin-releasing factor (CRF) hypothesis of depression: new ﬁndings and new directions. Mol Psychiatry 1996; 1:336–342.
Neumeister A, Praschak-Rieder N, Hesselmann B, Vitouch O, Rauh M, Barocka A, Kasper
S. Rapid tryptophan depletion in drug-free depressed patients with seasonal affective disorder. Am J Psychiatry 1997; 154:1153–1155.
Newman ME, Lerer B. Effects of chronic electroconvulsive shock on D1 and D2 dopamine
receptor-mediated activity of adenylate cyclase in homogenates of striatum and limbic forebrain of rat. Neuropharmacology 1989; 28:787–790.
Newcomer JW, Selke G, Melson AK, Hershey T, Craft S, Richards K, Alderson AL. Decreased memory performance in healthy humans induced by stress-level cortisol treatment.
Arch Gen Psychiatry 1999; 56:527–533.
Nieman LK, Chrousos GP, Kellner C, Spitz IM, Nisula BC, Cutler GB, Merriam GR, Bardin
CW, Loriaux DL. Successful treatment of Cushing’s syndrome with the glucocorticoid antagonist RU 486. J Clin Endocrinol Metab 1985; 61:536–540.
Nierenberg AA, Dougherty D, Rosenbaum JF. Dopaminergic agents and stimulants as antidepressant augmentation strategies. J Clin Psychiatry 1998; 59(suppl 5):60–63.
Nobler MS, Sackeim HA, Prohovnik I, Moeller JR, Mukherjee S, Schnur DB, Prudic J,
Devanand DP. Regional cerebral blood ﬂow in mood disorders, III. Treatment and clinicalresponse. Arch Gen Psychiatry 1994; 51:884–897.
Nolen WA, van de Putte JJ, Dijken WA, Kamp JS, Blansjaar BA, Kramer HJ, Haffmans J.
Treatment strategy in depression. II. MAO inhibitors in depression resistant to cyclic antidepressants: two controlled crossover studies with tranylcypromine versus L-5-hydroxytryptophan and nomifensine. Acta Psychiatr Scand 1988; 78:676–683.
Nordin C, Bertilsson L, Siwers B. Clinical and biochemical effects during treatment of depression with nortriptyline: the role of 10-hydroxynortriptyline. Clin Pharmacol Ther 1987;
42:10–19.
Nordin C, Bertilsson L, Dahl ML, Resul B, Toresson G, Sjoqvist F. Treatment of depression
with E-10-hydroxynortriptyline—a pilot study on biochemical effects and pharmacokinetics.
Psychopharmacology (Berl) 1991; 103:287–290.

Neurobiology of Depression

497

248. Nowak G, Trullas R, Layer RT, Skolnick P, Paul IA. Adaptive changes in the N-methyl-Daspartate receptor complex after chronic treatment with imipramine and 1-aminocyclopropanecarboxylic acid. J Pharmacol Exp Ther 1993; 265:1380–1386.
249. Nowak G, Ordway GA, Paul IA. Alteration in the N-methyl-D-aspartate (NMDA) receptor
complex in the frontal cortex of suicide victims. Brain Res 1995; 675:157–164.
250. O’Brien J, Desmond P, Ames D, Schweitzer I, Harrigan S, Tress B. A magnetic resonanceimaging study of white matter lesions in depression and Alzheimer’s disease. Br J Psychiatry
1996; 168:477–485.
251. Ongini E, Longo VG. Dopamine receptor subtypes and arousal. Int Rev Neurobiol 1989;
31:239–255.
252. Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mooddisorders. Proc Natl Acad Sci USA 1998; 95:13290–13295.
253. Ordway GA, Farley JT, Dilley GE, Overholser JC, Meltzer HY, Balraj EK, Stockmeier CA,
Klimek V. Quantitative distribution of monoamine oxidase A in brainstem monoamine nuclei
is normal in major depression. Brain Res 1999; 847:71–79.
254. Ossowska K, Pietraszek M, Wardas J, Nowak G, Zajaczkowski W, Wolfarth S, Pilc A. The
role of glutamate receptors in antipsychotic drug action. Amino Acids 2000; 19:87–94.
255. Pardes H, Kaufmann CA, Pincus HA, West A. Genetics and psychiatry: past discoveries,
current dilemmas, and future directions. Am J Psychiatry 1989; 146:435–443.
256. Parsey RV, Oquendo MA, Zea-Ponce Y, Rodenhiser J, Kegeles LS, Pratap M, Cooper TB,
Van Heertum R, Mann JJ, Laruelle M. Dopamine D(2) receptor availability and amphetamine-induced dopamine release in unipolar depression. Biol Psychiatry 2001; 50:313–
322.
257. Paul IA, Nowak G, Layer RT, Popik P, Skolnick P. Adaptation of the N-methyl-D-aspartate
receptor complex following chronic antidepressant treatments. J Pharmacol Exp Ther 1994;
269:95–102.
258. Paul IA. NMDA receptors and affective disorders. In: Skolnick P, ed. Antidepressants: New
Pharmacological Strategies. Totowa NJ: Humana, 1997:145–158.
259. Perris C, Tjallden G, Bossi L, Perris H. Progabide versus nortriptyline in depression: a controlled trial. In: Bartholini G, Lloyd KG, Morselli PL, eds. LERS Monograph Series. New
York: Raven Press, 1986:135–138.
260. Perry EK, Marshall EF, Blessed G, Tomlinson BE, Perry RH. Decreased imipramine binding
in the brains of patients with depressive illness. Br J Psychiatry 1983; 142:188–192.
261. Petty F, Kramer GL, Dunnam D, Rush AJ. Plasma GABA in mood disorders. Psychopharmacol Bull 1990; 26:157–161.
262. Petty F, Schlesser MA. Plasma GABA in affective illness. A preliminary investigation. J
Affect Disord 1981; 3:339–343.
263. Petty F, Fulton M, Moeller FG, Kramer G, Wilson L, Fraser K, Isbell P. Plasma gammaaminobutyric acid (GABA) is low in alcoholics. Psychopharmacol Bull 1993; 29:277–281.
264. Petty F, Trivedi MH, Fulton M, Rush AJ. Benzodiazepines as antidepressants: does GABA
play a role in depression? Biol Psychiatry 1995; 38:578–591.
265. Pfohl B, Sherman B, Schlechte J, Stone R. Pituitary-adrenal axis rhythm disturbances in
psychiatric depression. Arch Gen Psychiatry 1985; 42:897–903.
266. Pizzagalli D, Pascual-Marqui RD, Nitschke JB, Oakes TR, Larson CL, Abercrombie HC,
Schaefer SM, Koger JV, Benca RM, Davidson RJ. Anterior cingulate activity as a predictor of
degree of treatment response in major depression: evidence from brain electrical tomography
analysis. Am J Psychiatry 2001; 158:405-415.
267. Plotsky PM, Owens MJ, Nemeroff CB. Psychoneuroendocrinology of depression. Hypothalamic-pituitary-adrenal axis. Psychiatr Clin North Am 1998; 21:293–307.
268. Posener JA, DeBattista C, Williams GH, Chmura Kraemer H, Kalehzan BM, Schatzberg AF.
24-Hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic
major depression. Arch Gen Psychiatry 2000; 57:755–760.

498

Zarate and Charney269. Potter WZ, Rudorfer MV, Pickar D, Linnoila M. Effects of psychotropic drugs on neurotransmitters in man. Life Sci 1987; 41:817–820.
270. Potter WZ, Manji HK. Catecholamines in depression: an update. Clin Chem 1994; 40:279–
287.
271. Prange AJ. Estrogen may well affect response to antidepressant. JAMA 1972; 219:143–144.
272. Prange AJ Jr, Lara PP, Wilson IC, Alltop LB, Breese GR. Effects of thyrotropin-releasing
hormone in depression. Lancet 1972; 2:999–1002.
273. Price LH, Charney DS, Rubin AL, Heninger GR. Alpha 2-adrenergic receptor function in
depression. The cortisol response to yohimbine. Arch Gen Psychiatry 1986; 43:849–858.
274. Price LH, Charney DS, Delgado PL, Heninger GR. Serotonin function and depression: neuroendocrine and mood responses to intravenous L-tryptophan in depressed patients and healthy
comparison subjects. Am J Psychiatry 1991; 148:1518–1525.
275. Price LH, Malison RT, McDougle CJ, McCance-Katz EF, Owen KR, Heninger GR. Neurobiology of tryptophan depletion in depression: effects of m-chlorophenylpiperazine (mCPP).
Neuropsychopharmacology 1997; 17:342–350.
276. Rajkowska G. Postmortem studies in mood disorders indicate altered numbers of neurons
and glial cells. Biol Psychiatry 2000; 48:766–777.
277. Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G, Pittman SD, Meltzer HY, Overholser
JC, Roth BL, Stockmeier CA. Morphometric evidence for neuronal and glial prefrontal cell
pathology in major depression. Biol Psychiatry 1999; 45:1085–1098.
278. Rao VP, Krishnan KR, Goli V, Saunders WB, Ellinwood EH Jr, Blazer DG, Nemeroff CB.
Neuroanatomical changes and hypothalamo-pituitary-adrenal axis abnormalities. Biol Psychiatry 1989; 26:729–732.
279. Ravaris CL, Sateia MJ, Beroza KW, Noordsy DL, Brinck-Johnsen T. Effect of ketoconazole
on a hypophysectomized, hypercortisolemic, psychotically depressed woman. Arch Gen Psychiatry 1988; 45:966–967.
280. Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK. The de facto
US mental and addictive disorders service system: epidemiological catchment area prospective 1 year prevalence rates of disorders and services. Arch Gen Psychiatry 1993; 50:85–
94.
281. Reul JMHM, De Kloet ER. Anatomical resolution of two types of corticosterone receptor
sites in rat brain with in vitro autoradiography and computerized image analysis. J Steroid
Biochem 1986; 24:269–272.
282. Ribeiro SC, Tandon R, Grunhaus L, Greden JF. The DST as a predictor of outcome in depression: a meta-analysis. Am J Psychiatry 1993; 150:1618–1629.
283. Risch SC, Golshan S, Rapaport MH, Dupont R, Outenreath R, Gillin JC, Janowsky DS.
Neuroendocrine effects of intravenous ovine corticotropin-releasing factor in affective disorder patients and normal controls. Biol Psychiatry 1988; 23:755–758.
284. Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart CM, Moore GJ. Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorderpatients taking paroxetine. J Am Acad Child Adolesc Psychiatry 2000; 39:1096–1103.
285. Rothermundt M, Arolt V, Wiesmann M, Missler U, Peters M, Rudolf S, Kirchner H. S-100B
is increased in melancholic but not in non-melancholic major depression. J Affect Disord
2001; 66:89–93.
286. Rothschild AJ, Schatzberg AF, Langlais PJ, Lerbinger JE, Miller MM, Cole JO. Psychotic
and nonpsychotic depressions: I. Comparison of plasma catecholamines and cortisol measures. Psychiatry Res 1987; 20:143–153.
287. Roy A, Guthrie S, Pickar D, Linnoila M. Plasma NE responses to cold challenge in depressed
patients and normal controls. Psychiatry Res 1987; 21:161–168.
288. Roy A, Pickar D, De Jong J, Karoum F, Linnoila M. Norepinephrine and its metabolites
in cerebrospinal ﬂuid, plasma and urine: relationship to hypothalamic-pituitary-adrenal axis
function in depression. Arch Gen Psychiatry 1988; 45:849–857.

Neurobiology of Depression

499

289. Roy A, Pickar D. TRH-induced prolactin release in unipolar depressed patients and controls.
J Psychiatr Res 1988; 22:221–225.
290. Rubin RT, Phillips JJ, Sadow TF, McCracken JT. Adrenal gland volume in major depression.
Increase during the depressive episode and decrease with successful treatment. Arch Gen
Psychiatry 1995; 52:213–218.
291. Rubinow DR, Post RM, Savard R, Gold PW. Cortisol hypersecretion and cognitive impairment in depression. Arch Gen Psychiatry 1984; 41:279–283.
292. Rudorfer MV, Ross RJ, Linnoila M, Sherer MA, Potter WZ. Exaggerated orthostatic responsivity of plasma norepinephrine in depression. Arch Gen Psychiatry 1985; 42:1186–1192.
293. Rudorfer MV, Risby ED, Hsiao JK, Linnoila M, Potter WZ. ECT alters human monoamines
in a different manner from that of antidepressant drugs. Psychopharmacol Bull 1988; 24:
396–399.
294. Rush AJ, Weissenburger J, Vinson DB, Giles DE. Neuropsychological dysfunctions in unipolar nonpsychotic major depressions. J Affect Disord 1983; 5:281–287.
295. Rush AJ, Giles DE, Schlesser MA, Orsulak PJ, Parker CR Jr, Weissenburger JE, Crowley
GT, Khatami M, Vasavada N. The dexamethasone suppression test in patients with mooddisorders. J Clin Psychiatry 1996; 57:470–484.
296. Sackeim HA. Functional brain circuits in major depression and remission. Arch Gen Psychiatry 2001; 58:649–650.
297. Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OA, Berman RM, Charney
DS, Krystal JH. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1999; 56:1043–
1047.
298. Sapolosky R. A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults. J Neurosci 1985; 5:1228–1232.
299. Sapolsky RM. Stress, glucocorticoids, and damage to the nervous system: the current stateof confusion. Stress 1996; 1:1–19.
300. Sapolsky RM. The possibility of neurotoxicity in the hippocampus in major depression: aprimer on neuron death. Biol Psychiatry 2000; 48:755–765.
301. Schmider J, Lammers CH, Gotthardt U, Dettling M, Holsboer F, Heuser IJ. Combined
dexamethasone/corticotropin-releasing hormone test in acute and remitted manic patients,
in acute depression, and in normal controls: I. Biol Psychiatry 1995; 38:797–802.
302. Secunda SK, Cross CK, Koslow S, Katz MM, Kocsis J, Maas JW, Landis H. Biochemistry
and suicidal behavior in depressed patients. Biol Psychiatry 1986; 21:756–767.
303. Schatzberg AF, Samson JA, Bloomingdale KL, Orsulak PJ, Gerson B, Kizuka PP, Cole
JO, Schildkraut JJ. Toward a biochemical classiﬁcation of depressive disorders, X: urinary
catecholamines, their metabolites, and D-type scores in subgroups of depressive disorders.
Arch Gen Psychiatry 1989; 46:260–268.
304. Schatzberg AF, Rothschild AJ. Serotonin activity in psychotic (delusional) major depression.
J Clin Psychiatry 1992; 53 (10 suppl):52–55.
305. Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting
evidence. Am J Psychiatry 1965; 122:509–522.
306. Schildkraut JJ, Orsulak PJ, Schatzberg AF, et al. Toward a biochemical classiﬁcation ofdepressive disorders, I: differences in urinary excretion of MHPG and other catecholamine
metabolites in clinically deﬁned subtypes of depression. Arch Gen Psychiatry 1978; 35:
1427–1433.
307. Schildkraut JJ, Orsulak PJ, Schatzberg AF, et al. Possible pathophysiological mechanisms
in subtypes of unipolar depressive disorders based on differences in urinary MHPG levels.
Psychopharmacol Bull 1981; 17:90–91.
308. Schmider J, Lammers CH, Gotthardt U, Dettling M, Holsboer F, Heuser IJ. Combined
dexamethasone/corticotropin-releasing hormone test in acute and remitted manic patients,
in acute depression, and in normal controls: I. Biol Psychiatry 1995; 38:797–802.

500

Zarate and Charney309. Schulz R, Beach SR, Ives DG, Martire LM, Ariyo AA, Kop WJ. Association between depression and mortality in older adults: the Cardiovascular Health Study. Arch Intern Med 2000;
160:1761–1768.
310. Shah SA, Doraiswamy PM, Husain MM, Escalona PR, Na C, Figiel GS, Patterson LJ, Ellinwood EH Jr, McDonald WM, Boyko OB. Posterior fossa abnormalities in major depression:a controlled magnetic resonance imaging study. Acta Psychiatr Scand 1992; 85:474–479.
311. Shah PJ, Ogilvie AD, Goodwin GM, Ebmeier KP. Clinical and psychometric correlates of
dopamine D2 binding in depression. Psychol Med 1997; 27:1247–1256.
312. Shapira B, Oppenheim G, Zohar J, Segal M, Malach D, Belmaker RH. Lack of efﬁcacy of
estrogen supplementation to imipramine in resistant female depressives. Biol Psychiatry
1985; 20:570–583.
313. Shapira B, Lerer B, Kindler S, Lichtenberg P, Gropp C, Cooper T, Calev A. Serotonin function and depression: neuroendocrine and mood responses to intravenous L-tryptophan in depressed patients and healthy comparison subjects. Am J Psychiatry 1991; 148:1518–1525.
314. Shapira B, Cohen J, Newman ME, Lerer B. Prolactin response to fenﬂuramine and placebo
challenge following maintenance pharmacotherapy withdrawal in remitted depressed patients. Biol Psychiatry 1993; 33:531–535.
315. Sharma RP, Javaid JI, Faull K, Davis JM, Janicak PG. CSF and plasma MHPG, and CSF
MHPG index: pretreatment levels in diagnostic groups and response to somatic treatments.
Psychiatry Res 1994; 51:51–60.
316. Sheline YI, Wang PW, Gado MH, Csernansky JG, Vannier MW. Hippocampal atrophy inrecurrent major depression. Proc Natl Acad Sci USA 1996; 93:3908–3913.
317. Sheline Y, Bardgett ME, Csernansky JG. Correlated reductions in cerebrospinal ﬂuid 5-HIAA
and MHPG concentrations after treatment with selective serotonin reuptake inhibitors. J Clin
Psychopharmacol 1997; 17:11–14.
318. Sheline YI, Sanghavi M, Mintun MA, Gado MH. Depression duration but not age predicts
hippocampal volume loss in medically health women with recurrent major depression. J
Neurosci 1999; 19:5034–5043.
319. Sherif F, Marcusson J, Oreland L. Brain gamma-aminobutyrate transaminase and monoamineoxidase activities in suicide victims. Eur Arch Psychiatry Clin Neurosci 1991; 241:139–144.
320. Sherwin BB. Estrogen and cognitive functioning in women. Proc Soc Exp Biol Med 1998;
217:17–22.
321. Siever LJ, Uhde TW. New studies and perspectives on the noradrenergic receptor system in
depression: effects of the alpha 2-adrenergic agonist clonidine. Biol Psychiatry 1984; 19:
131–156.
322. Siever LJ, Trestman RL, Coccaro EF, Bernstein D, Gabriel SM, Owen K, Moran M, Lawrence T, Rosenthal J, Horvath TB. The growth hormone response to clonidine in acute andremitted depressed male patients. Neuropsychopharmacology 1992; 6:165–177.
323. Silverstone T. Response to bromocriptine distinguishes bipolar from unipolar depression.
Lancet 1984; 1:903–904.
324. Sitaram N, Nurnberger JI Jr, Gershon ES, Gillin JC. Cholinergic regulation of mood andREM sleep: potential model and marker of vulnerability to affective disorder. Am J Psychiatry 1982; 139:571–576.
325. Skolnick P. Antidepressants for the new millennium. Eur J Pharmacol 1999; 375:31–40.
326. Sluzewska A, Rybakowski J, Bosmans E, Sobieska M, Berghmans R, Maes M, Wiktorowicz
K. Indicators of immune activation in major depression. Psychiatry Res 1996; 64:161–167.
327. Solomon DA, Keller MB, Leon AC, Mueller TI, Lavori PW, Shea MT, Coryell W, Warshaw
M, Turvey C, Maser JD, Endicott J. Multiple recurrences of major depressive disorder. Am
J Psychiatry 2000; 157:229–233.
328. Souery D, Van Gestel S, Massat I, Blairy S, Adolfsson R, Blackwood D, Del-Favero J,
Dikeos D, Jakovljevic M, Kaneva R, Lattuada E, Lerer B, Lilli R, Milanova V, Muir W,
Nothen M, Oruc L, Papadimitriou G, Propping P, Schulze T, Serretti A, Shapira B, Smeraldi

Neurobiology of Depression

329.

330.
331.
332.
333.

334.
335.

336.
337.

338.
339.

340.

341.

342.
343.

344.

345.

346.

347.

501

E, Stefanis C, Thomson M, Van Broeckhoven C, Mendlewicz J. Tryptophan hydroxylase
polymorphism and suicidality in unipolar and bipolar affective disorders: a multicenter association study. Biol Psychiatry 2001; 49:405–409.
Souetre E, Salvati E, Belugou JL, Pringuey D, Candito M, Krebs B, Ardisson JL, Darcourt
G. Circadian rhythms in depression and recovery: evidence for blunted amplitude as the main
chronobiological abnormality. Psychiatry Res 1989; 28:263–278.
Stanley M, Virgilio J, Gershon S. Tritiated imipramine binding sites are decreased in thefrontal cortex of suicides. Science 1982; 18;216:1337–1339.
Steffens DC, Krishnan KR. Structural neuroimaging and mood disorders: recent ﬁndings,
implications for classiﬁcation, and future directions. Biol Psychiatry 1998; 43:705–712.
Stockmeier CA, Dilley GE, Shapiro LA, et al. Serotonin receptors in suicide victims withmajor depression. Neuropsychopharmacol 1997; 16:162–173.
Stockmeier CA, Shapiro LA, Dilley GE, Kolli TN, Friedman L, Rajkowska G. Increase
in serotonin-1A autoreceptors in the midbrain of suicide victims with major depressionpostmortem evidence for decreased serotonin activity. J Neurosci 1998; 18:7394–7401.
Stokes PE, Frazer A, Casper R. Unexpected neuroendocrine transmitter relationships. Psychopharmacol Bull 1981; 17:72–75.
Straub RE, Lehner T, Luo Y, Loth JE, Shao W, Sharpe L, Alexander JR, Das K, Simon R,
Fieve RR. A possible vulnerability locus for bipolar disorder on chromosome 21q22.3. Nat
Genet 1994; 8:292–296.
Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: review andmeta-analysis. Am J Psychiatry 2000; 157:1552–1562.
Swaab DF, Van Someren EJ, Zhou JN, Hofman MA. Biological rhythms in the human life
cycle and their relationship to functional changes in the suprachiasmatic nucleus. Prog Brain
Res 1996; 111:349–368.
Swann AC, Koslow SH, Katz MM, et al. Lithium carbonate treatment of mania. Arch Gen
Psychiatry 1987; 44:345–354.
Swann AC, Secunda SK, Strokes PE, et al. Stress, depression, and mania; relationship between perceived role of stressful events and clinical and biochemical characteristics. Acta
Psychiatr Scand 1990; 81:389–397.
Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Mania: differential effects
of previous depressive and manic episodes on response to treatment. Acta Psychiatr Scand
2000; 101:444–451.
Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acutemania. Am J Psychiatry 1999; 156:1264–1266.
Szigethy E, Conwell Y, Forbes NT, Cox C, Caine ED. Adrenal weight and morphology invictims of completed suicide. Biol Psychiatry 1994; 36:374–380.
Thase ME, Mallinger AG, McKnight D, Himmelhoch JM. Treatment of imipramine-resistantrecurrent depression, IV: A double-blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry 1992; 149:195–198.
Thase ME, Rush AJ. Treatment-resistant depression. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation Progress. New York: Raven Press, 1995:1081–
1098.
Thomas AJ, Ferrier IN, Kalaria RN, Woodward SA, Ballard C, Oakley A, Perry RH, O’Brien
JT. Elevation in late-life depression of intercellular adhesion molecule-1 expression in thedorsolateral prefrontal cortex. J Psychiatry 2000; 157:1682–1684.
Timmerman L, de Beurs P, Tan BK, Leijnse-Ybema H, Sanchez C, Hopfner Petersen HE,
Cohen Stuart MH. A double-blind comparative clinical trial of citalopram vs maprotiline in
hospitalized depressed patients. Int Clin Psychopharmacol 1987; 2:239–253.
Tohen M, Hennen J, Zarate CM Jr, Baldessarini RJ, Strakowski SM, Stoll AL, Faedda GL,
Suppes T, Gebre-Medhin P, Cohen BM. Two-year syndromal and functional recovery in 219

502

348.
349.

350.

351.
352.

353.
354.

355.

356.

357.

358.
359.

360.

361.

362.

363.
364.

365.

Zarate and Charneycases of ﬁrst-episode major affective disorder with psychotic features. Am J Psychiatry 2000;
157:220–228.
Turner WJ, King S. BPD2: an autosomal dominant form of bipolar affective disorder. Biol
Psychiatry 1983; 18:63–87.
Tsuji M, Yamane H, Yamada N, Iida H, Taga C, Myojin T. Studies on 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG) levels in human urine,
plasma and cerebrospinal ﬂuids, and their signiﬁcance in studies of depression. Jpn J Psychiatry Neurol 1986; 40:47–56.
Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, Yurgelun-Todd
DA. Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry 2000; 47:1087–1090.
Van den Hoofdakker RH. Chronobiological theories of nonseasonal affective disorders andtheir implications for treatment. J Biol Rhythms 1994; 9:157–183.
van der Lely AJ, Foeken K, van der Mast RC, Lamberts SW. Rapid reversal of acute psychosis in the Cushing syndrome with the cortisol-receptor antagonist mifepristone (RU 486).
Ann Intern Med 1991; 114:143–144.
Van Praag HM. Depression, suicide, and the metabolites of serotonin in the brain. J Affect
Disord 1982; 4:21–29.
Veith RC, Lewis N, Linares OA, Barnes RF, Raskind MA, Villacres EC, Murburg MM,
Ashleigh EA, Castillo S, Peskind ER. Sympathetic nervous system activity in major depression: basal and desipramine-induced alterations in plasma NE kinetics. Arch Gen Psychiatry
1994; 51:411–422.
Vieta E, Gasto C, Martinez de Osaba MJ, Nieto E, Canto TJ, Otero A, Vallejo J. Predictionof depressive relapse in remitted bipolar patients using corticotrophin-releasing hormone
challenge test. Acta Psychiatr Scand 1997; 95:205–211.
Virkkunen M, De Jong J, Bartko J, Linnoila M. Psychobiological concomitants of historyof suicide attempts among violent offenders and impulsive ﬁre setters. Arch Gen Psychiatry
1989; 46:604–606.
von Bardeleben U, Stalla GK, Muller OA, Holsboer F. Blunting of ACTH response to human
CRH in depressed patients is avoided by metyrapone pretreatment. Biol Psychiatry 1988;
24:782–786.
von Knorring AL, Cloninger CR, Bohman M, Sigvardsson S. An adoption study of depressive
disorders and substance abuse. Arch Gen Psychiatry 1983; 40:943–950.
Weinberger DR, Berman KF, Iadarola M, Driesen N, Zec RF. Prefrontal cortical blood ﬂow
and cognitive function in Huntington’s disease. J Neurol Neurosurg Psychiatry 1988; 51:
94–104.
Weissman MM, Gershon ES, Kidd KK, et al. Psychiatric disorders in the relatives of probands with affective disorders: the Yale University–National Institute of Mental Health Collaborative Study. Arch Gen Psychiatry 1984; 41:13–21.
Wiesmann M, Wandinger KP, Missler U, Eckhoff D, Rothermundt M, Arolt V, Kirchner H.
Elevated plasma levels of S-100b protein in schizophrenic patients. Biol Psychiatry 1999;
45:1508–1511.
Wender PH, Kety SS, Rosenthal D, Schulsinger F, Ortmann J, Lunde I. Psychiatric disorders
in the biological and adoptive families of adopted individuals with affective disorders. ArchGen Psychiatry 1986; 43:923–929.
Whittemore ER, Loo DT, Watt JA, Cotman CW. A detailed analysis of hydrogen peroxideinduced cell death in primary neuronal culture. Neuroscience 1995; 67:921–932.
Weissman MM, Gershon ES, Kidd KK, Prusoff BA, Leckman JF, Dibble E, Hamovit J,
Thompson WD, Pauls DL, Guroff JJ. Psychiatric disorders in the relatives of probands withaffective disorders. The Yale University–National Institute of Mental Health Collaborative
Study. Arch Gen Psychiatry 1984; 41:13–21.
Wiesmann M, Wandinger KP, Missler U, Eckhoff D, Rothermundt M, Arolt V, Kirchner H.

Neurobiology of Depression

366.
367.
368.
369.
370.

371.
372.

373.
374.
375.

376.

377.
378.
379.

380.
381.

503

Elevated plasma levels of S-100b protein in schizophrenic patients. Biol Psychiatry 1999;
45:1508–1511.
Willner P. Dopamine and depression: a review of recent evidence. II. Theoretical approaches.
Brain Res 1983; 287:225–236.
Willner P. Dopamine and depression: a review of recent evidence. III. The effects of antidepressant treatments. Brain Res 1983; 287:237–246.
Willner P, Lappas S, Cheeta S, Muscat R. Reversal of stress-induced anhedonia by the dopamine receptor agonist, pramipexole. Psychopharmacology (Berl) 1994; 115:454–462.
Winokur G, Black DW, Nasrallah A. DST nonsuppressor status: relationship to speciﬁc aspects of the depressive syndrome. Biol Psychiatry 1987; 22:360–368.
Wirz-Justice A. Biological rhythms in mood disorders. In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress, 4th ed. New York: Raven Press, 1995:
999–1017.
Wise RA, Rompre PP. Brain dopamine and reward. Annu Rev Psychol 1989; 40:191–225.
Wolfe N, Katz DI, Albert ML, Almozlino A, Durso R, Smith MC, Volicer L. Neuropsychological proﬁle linked to low dopamine: in Alzheimer’s disease, major depression, and Parkinson’s disease. J Neurol Neurosurg Psychiatry 1990; 53:915–917.
Wolkowitz OM, Reus VI, Weingartner H, Thompson K, Breier A, Doran A, Rubinow D,
Pickar D. Cognitive effects of corticosteroids. Am J Psychiatry 1990; 147:1297–1303.
Wolkowitz OM, Reus VI. Treatment of depression with antiglucocorticoid drugs. Psychosom
Med 1999; 61:698–711.
Wolkowitz OM, Reus VI, Chan T, Manfredi F, Raum W, Johnson R, Canick J. Antiglucocorticoid treatment of depression: double-blind ketoconazole. Biol Psychiatry 1999; 45:1070–
1074.
Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P, Karp B, McCutcheon IE,
Geracioti TD Jr, DeBellis MD, Rice KC, Goldstein DS, Veldhuis JD, Chrousos GP, Oldﬁeld
EH, McCann SM, Gold PW. Pronounced and sustained central hypernoradrenergic function
in major depression with melancholic features: relation to hypercortisolism and corticotropinreleasing hormone. Proc Natl Acad Sci USA 2000; 97:325–330.
Wu JC, Gillin JC, Buchsbaum MS, Hershey T, Johnson JC, Bunney WE Jr. Effect of sleep
deprivation on brain metabolism of depressed patients. Am J Psychiatry 1992; 149:538–543.
Wyatt RJ, Henter I. An economic evaluation of manic-depressive illness—1991. Soc Psychiatry Psychiatr Epidemiol 1995; 30:213–219.
Yatham LN, Liddle PF, Shiah IS, Scarrow G, Lam RW, Adam MJ, Zis AP, Ruth TJ. Brain
serotonin2 receptors in major depression: a positron emission tomography study. Arch Gen
Psychiatry 2000; 57:850–858.
Young EA, Midgley R, Carlson NE, Brown MB. Alteration in the hypothalamic-pituitaryovarian axis in depressed women. Arch Gen Psychiatry 2000; 57:1157–1162.
Zhou J-N, Riemersma RF, Unmehopa UA, Hoogendijk WJG, van Heerikhuize JJ, Hofman
MA, Swaab DF. Alterations in arginine vasopressin neurons in the suprachiasmatic nucleus
in depression. Arch Gen Psychiatry 2001; 58:655–662.

20
Animal Models of Subtypes
of Depression
PAUL WILLNER
University of Wales Swansea
Swansea, Wales
PAUL J. MITCHELL
University of BathBath, England

I.

INTRODUCTION

Animal models of depression are used both as screening tests to discover and develop
novel antidepressant drug therapies, and as simulations for investigating various aspectsof the neurobiology of depressive illness, including the neuropharmacological mechanisms
mediating the effects of antidepressant treatments. These different functions of animalmodels have different and, to some extent, conﬂicting requirements.
A simulation of depression aims to mimic aspects of the clinical situation and should
embody a degree of complexity to permit investigation of the validity of the model. In
addition, if a model is to be used to investigate antidepressant actions, a slow onset comparable to the clinical time course is highly desirable, and the model should therefore exhibit
differences (either in direction of response, or in response magnitude) between single(acute) and repeated (chronic or continuous) treatment regimes. By contrast, the only
essential requirement for antidepressant screening tests is that they make accurate predictions of antidepressant activity. For practical reasons, they should also be cheap, robust,reliable, and easy to use [63,292], and for all of these subsidiary reasons, a screening test
should in principle be as simple as possible. However, the view that such screening tests
should also respond acutely has changed during the last decade, in line with the drivefrom the clinic to identify rapid-onset antidepressant treatments. By necessity, this ap505

506

Willner and Mitchellproach involves the assessment of drug action associated with chronic/continuous drug
treatment regimes and an acute response is thus of little value. Appropriate screening tests
to be used relatively early during drug development should therefore have the ability toidentify the time course of drug action associated with repeated treatment schedules.
The present chapter is concerned primarily with evaluating the suitability of theavailable animal models as research tools, and we therefore focus initially on issues relating to the validity of the available models as simulations of depression. In line withcurrent thinking, our assessment of the validity of animal models of depression addresses
the three dimensions of predictive, face, and construct validity [286,292]. The concept ofpredictive validity implies that manipulations known to inﬂuence the pathological stateshould have similar effects in the model. Face validity refers to a phenomenological similarity between the model and the disorder being modeled. Construct validity implies thatthe model has a sound theoretical rationale. While some reviewers have advocated theprimacy of one or the other of these approaches, we favor a balanced approach in whicha view of the validity of a model is formed only after considering all three sources ofevidence. We therefore begin by reviewing brieﬂy the three sets of validation criteria as
they apply to animal models of depression.
II. PREDICTIVE VALIDITY
In practice, the predictive validity of animal models of depression is determined solely
by their response to antidepressant drugs. A valid test should be sensitive and speciﬁc:it should respond to effective antidepressant treatments (true positive effects), including
electroconvulsive shock (ECS), and should fail to respond to ineffective agents (true negative effects). A model with high predictive validity should therefore maximize identiﬁcation of both true positives and true negatives, but should minimize identiﬁcation of false
positives and false negatives. Furthermore, positive responses should occur at behaviorally
selective doses (i.e., those which do not generally disrupt behavior nor induce motor impairment) that are within or close to the clinical range, and should be demonstrable witha range of structurally diverse compounds. It should be recognized that no animal model
has a 100% prediction rate, although some complex experimental paradigms have approached this level of predictive ability. Part of the problem lies not so much with thepreclinical model but with several gray areas in the clinical literature where it is not known
whether certain drugs (e.g., anticholinergics) possess antidepressant activity or not. It is
generally agreed that the most effective treatment for depressive illness is electroconvulsive therapy (ECT). A suitable starting point to test the validity of an animal model should
therefore be to demonstrate a positive response to repeated ECS. Failure to respond appropriately to ECS would severely question the predictive validity of the model.
About 30% of depressed patients fail to respond to antidepressant drug treatment
while the response rate for ECT is slightly higher. The occurrence of refractory patientsprobably reﬂects the heterogeneity of depressive illness. Nevertheless, a model that did not
respond to the benchmark tricyclic antidepressants (TCAs), selective serotonin reuptake
inhibitors (SSRIs), or the recently developed serotonin-noradrenaline reuptake inhibitors(SNRIs), would not be taken seriously. This situation is unlikely to change in the absenceof well-established therapies for TCA-resistant depression.
Beyond the clinically established antidepressant treatments—TCAs, monoamineoxidase inhibitors (MAOIs), SSRIs, SNRIs, and some atypical antidepressants (e.g., mianserin)—are a wide range of newer compounds for which antidepressant activity has beenAnimal Models of Depression

507

claimed, ranging from pharmacologically selective compounds that are probably effective(such as α2-adrenoceptor antagonists; ligands for serotonin (5-hydroxytryptamine; 5HT)
receptor subtypes including 5HT1A-receptor ligands that possess agonist activity [and partial agonists), ligands for 5HT2A and 5HT2C-receptor subtypes, and n-methyl-d-aspartate(NMDA) receptor ligands], through preparations of mixed pharmacological activity (SSRI
with selective 5HT1A-receptor antagonist activity) to compounds of uncertain status (e.g.,
phosphodiesterase inhibitors; calcium antagonists; anticonvulsants). Even in the case of
the SSRIs, whose antidepressant efﬁcacy is beyond doubt, it is still uncertain whether
their spectrum of activity is identical to that of the TCAs. Therefore, while a well-rounded
description of an animal model of depression should include an account of its pharmacological proﬁle broader than that provided by its response to traditional antidepressants,
the contribution of these newer compounds to validation is limited.
To some extent, similar uncertainties exist in relation to drugs that are ineffective
as antidepressants. The false positives most commonly encountered in animal models ofdepression are psychomotor stimulants, anticholinergics, and opiates. However, prior to
the development of antidepressants, drugs from all three of these classes were regularlyprescribed for the relief of depression [287]. Indeed, certain opiates (e.g., buprenorphine)
have antidepressant activity [75], but anticholinergics and stimulants have never been
properly assessed, as their use was discontinued prior to the introduction of blind clinical
trials. Again, the uncertain status of these compounds to some extent undermines theirvalue as deﬁnitive standards of negative control.
Finally, the response to antidepressant drugs is insufﬁcient to deﬁne an animal modelof depression. Some antidepressants are active in some animal models of anxiety andpanic following chronic treatment [31,86] and, indeed, are increasingly seen as the drugsof choice in many forms of anxiety. It is therefore crucial for establishing the predictive
validity of an animal model of depression to demonstrate that the model does not respondto benzodiazepines.
III. FACE VALIDITY
To assess face validity, the extent of similarity between the model and the disorder is
examined, on as wide as possible a range of symptoms and signs. However, not all symptoms of a psychiatric condition carry equal weight and for an animal model to be valid,a resemblance to the clinically deﬁned core symptoms of the disorder carries more weight
than a resemblance to any subsidiary symptoms [1]. The latest edition of the Diagnostics
and Statistics Manual (DSM-IV) provides a framework within which to assess these similarities. However, not all of the clinical symptoms of depression can be modeled in animals; symptoms conveyed by subjective verbal report (e.g., excessive guilt, feelings ofworthlessness, suicide ideation) are in principle excluded [286,291].
A DSM-IV diagnosis of major depression requires the presence of a least one oftwo core symptoms: loss of interest or pleasure (anhedonia) and depressed mood. Of thesetwo core symptoms, anhedonia can be modeled in animals, but depressed mood cannot.
In assessing the face validity of animal models of depression, anhedonia therefore assumesa central position. The problem here, however, is that anhedonia is also a core symptomof psychosis. Drug-induced reversal of anhedonia in animal models, while highly encouraging, should thus be considered in relation to DSM-IV criteria for both depressive illness
and schizophrenia.
The subsidiary symptoms of depression in DSM-IV that are amenable to modeling

508

Willner and Mitchellin animals include psychomotor changes, fatigue or loss of energy (which might be modeled as decreased persistence), and disturbances of sleep or food intake. Interestingly,
psychomotor activity, sleep, and appetite may be increased or decreased, and diametrically
opposite changes in locomotion have both been cited in support of the validity of a model.
This lack of precision, together with the fact that the clinical phenomena of psychomotor
retardation and agitation (which are considerably more complex than gross changes inlocomotor activity) may even coexist [203], suggests that simulations in which a change
in locomotor activity is the major, or only, behavioral feature should not be taken too
seriously. Unfortunately, it is precisely these behaviors that feature most prominently inmany animal models of depression [293].
Because the pharmacotherapy of depression typically requires chronic drug treatment, the validity of an animal model is called into question by an acute response toconventional (e.g., tricyclic) antidepressant treatment. There is some evidence of very
early antidepressant responses in clinical studies designed explicitly to detect them [88,289], but, even so, repeated treatment is required for a full response. Acute treatment refers to a single bolus dose of drug and any acute treatment effects are usually observed
within minutes or hours following the bolus dose. Multiple acute doses may be administered, over a short period, simply to increase levels of drug in the biophase without evoking
secondary adaptive changes in neurotransmitter mechanisms. In contrast, chronic treatment refers to repeated bolus doses administered for extended periods (days, weeks,months). Chronic treatment effects may be associated with drug-induced adaptive changes
in neurotransmitter receptor-mediated systems, rather than increased drug levels in theplasma. Thus, in comparison to chronic treatment effects, an acute response in an animalmodel may be opposite, orthogonal (due to side effects, like sedation), or absent. Regardless of how it responds to acute antidepressant treatment, to be valid, an animal modelof depression must respond to chronic treatment. Furthermore, since tolerance does notoccur to the clinical effects of antidepressants, the response in the model must be maintained until the cessation of antidepressant treatment. This test has not been universally
applied to animal models of depression but, in general, those models to which the test has
been applied have passed it, though tolerance to antidepressant effects has been reported insome behavioral paradigms [62,204].
IV. CONSTRUCT VALIDITY
An evaluation of the theoretical rationale of an animal model requires a means of bringing
the theoretical accounts of both the disorder itself and the disordered behavior exhibitedby the model into alignment. However, any evaluation of animal models of depression is
intrinsically limited by the rudimentary state of the various pathological theories of depression. Indeed, there is little in the extensive literature describing neurochemical abnormalities or biochemical markers reportedly associated with depression that can be usefully
employed to provide a theoretical standard against which to validate animal models. Even
the most basic questions of whether the level of activity in monoaminergic systems iselevated or decreased in depression were and remain controversial [287].
Similar problems arise in relation to modeling the etiology of depression. It is now
clear that a variety of different factors are implicated in the etiology of depression: psychological factors include undesirable life events, chronic mild stress, adverse childhood experiences, and personality traits such as introversion and impulsiveness; biological factors
include genetic inﬂuences and a variety of physical illnesses and medications [4,5,287].

Animal Models of Depression

509

However, for most of these factors, there is little theoretical understanding of the processes
by which they inﬂuence the physiological processes underlying mood. In certain cases,
the immediate precipitant of a depression may be clearly identiﬁed: for example, seasonalaffective disorder (SAD) and postpartum depression. More usually, the pathogenesis ofdepression is better understood as the result of an accumulation of a number of different
risk factors [4,9,38]. This point has been largely overlooked in the construction of animalmodels of depression, which in general have assumed a single causal factor. This may be
counterproductive, since few of the identiﬁed etiological factors appear sufﬁciently potent
to precipitate depression in an otherwise risk-free individual.
Although attempts to assess the theoretical rationale of animal models are limitedby this lack of theoretical structure at the clinical level, a number of generalizations are
possible. The major group of animal models of depression is based on responses tostressors of various kinds, and are usually justiﬁed by reference to the role of stressful
life events in the etiology of depression [38,39,156]. However, if very severe acute stressis used [284], the relevance of these procedures to depression, rather than, for example,
post-traumatic stress disorder, is questionable. Furthermore, the adverse consequences oflife events endure for a prolonged period of 6 to 12 months, in part by exacerbating
ongoing life difﬁculties [37,39]. Thus, life events should not be viewed as acute stressors(indeed, in the case of bereavement, a diagnosis of depression is explicitly excluded during
the period of acute loss); from this perspective, it may be more appropriate to use chronic
stress regimes, rather than acute stressors, to model the etiological role of life events.
Other factors have been identiﬁed that confer a long-lasting vulnerability to depression,in particular, an inadequate level of social support, which to a large extent arises frominadequate socialization [9,37–39,290]. From these starting points, a number of animalmodels of depression have been developed that are based on the adverse effects of social
isolation. However, with the exception of some of the primate studies (see below), thesemodels have largely ignored both the complexity of childhood social deprivation phenomena and the mediation of their effects through later social relationships.
Although assessment of the theoretical rationale of animal models of depression islimited by the paucity of theory, construct validity can also be evaluated at the level ofconstructs—that is, whether the behavioral phenomena are correctly described. This approach is best exempliﬁed by the extensive experimental analysis of whether learned helplessness is an appropriate term to describe the impairments of escape learning that follow
exposure to inescapable electric shock [247]. The term learned helplessness implies thatthe animals perform poorly because they have learned that their responses are ineffective
in controlling their environment [247]. However, inescapable shock has a variety of other,simpler effects, which could also explain many of the behavioral impairments, such as
decreased locomotor activity [11,101] and analgesia [151]. In addition, while inescapableshock results in cognitive impairment [115], such behavioral effects arise from impairment
at the level of attentional processing rather than helplessness [181]. Thus, there are manyreasons to question whether the learned helplessness procedure does in fact produce helplessness.
Anhedonia is another construct that has been subjected to this kind of experimental
attention. In this case, the question is whether the animals fail to perform rewarded behavior because they are insensitive to rewards or for some other reason. This question has
been most extensively investigated in relation to the effects of chronic sequential exposure
to a variety of mild stressors—chronic mild stress (CMS). CMS has been shown to cause
an antidepressant-reversible decrease in the consumption of dilute sucrose solutions, which

510

Willner and Mitchellis hypothesized to reﬂect a decrease in the reward value of the sucrose [294,297]. Initialstudies showed that, in contrast to the effect on dilute solutions of sucrose or saccharin,
CMS did not decrease the intake of plain water, food pellets, or concentrated sucrose
solutions; thus the effects are not simply nonspeciﬁc changes in consummatory behavior[198]. Some studies have suggested that decreases in sucrose intake reﬂect loss of bodyweight [172], but there is ample evidence [294] to reject this suggestion, including thefact that the effects are seen in the absence of body weight changes. Furthermore, theeffects of CMS are not conﬁned to consummatory behaviors. CMS also attenuated orabolished place preferences established using a variety of natural or drug rewards. However, drug-induced place aversions were unaffected by CMS. Thus, the effect of CMS on
place conditioning cannot be explained by nonspeciﬁc motivational impairments or a failure of associative learning [294]. Finally, CMS has also been shown to cause an increasein the threshold for brain stimulation reward [196]. Together, these results support theposition that CMS causes a generalized decrease in sensitivity to rewards and that, underappropriate experimental conditions, decreases in sucrose intake provide a simple meansof detecting this anhedonia.
These examples of successful experimental analyses of construct validity contrast
sharply with a third example, the behavioral despair test [226]. These term was introduced
to describe the immobility seen in rats or mice forced to swim in a conﬁned space, basedon the assumption that when the animals adopted an immobile posture, they had despairedof escaping. Unfortunately, this interpretation is not susceptible to experimental analysis.
Consequently, although the test continues to be very widely used, the name behavioral
despair has been largely abandoned and replaced by the theoretically neutral term theforced swim test.
V.

MODELS OF DSM-IV MELANCHOLIA

It has frequently been remarked [84] that the approach adopted in successive editions of
the Diagnostic and Statistical Manual (DSM), which identiﬁes psychiatric disorders by
the presence of a sufﬁcient number of symptoms from a longer list, results in very different
clinical presentations receiving the same diagnosis. However, discussion of the heterogeneity of depression is several decades older than the DSM system. It has been recognizedsince the 1920s that there are at least two forms of depression, but only one of them hasenjoyed general agreement as to its nature [287]. This is the syndrome that has been
known, variously, as autonomous depression, endogenous depression, endogenomorphic
depression, and, more recently, melancholia. Because a consensus exist as to its existence
and symptom proﬁle, melancholia has emerged as the major subtype of depression, andits deﬁnition in DSM-IV (major depressive episode with melancholic features) is somewhat more restrictive than that of the parent syndrome, major depressive disorder.
In previous reviews, animal models of depression have been classiﬁed according totheir level of validity [286] or their inducing conditions [291]. An attractive alternativeclassiﬁcation could be based upon the subtype of depression modeled. The art of modelinghas not yet progressed to the point where this is entirely feasible. However, a number ofmodels include anhedonia as one of their features. In DSM-IV, anhedonia is the deﬁning
feature of melancholia as well as the only core symptom of major depression that is amenable to modeling in animals. Anhedonia may be readily modeled as decreased sensitivity
to rewards, though, as noted above, this construct is considerably more complex than asimple decrease in the performance of a rewarded behavior. In relation to the other symp-

Animal Models of Depression

511

toms that can be modeled, the diagnosis of melancholia speciﬁes the direction of changes
in appetite and sleep (decreased), although, as in the diagnosis of major depressive disorder, psychomotor changes could be in either direction (retardation or agitation). In many
empirical studies, psychomotor retardation has emerged as the symptom most characteristic of melancholia, while psychomotor agitation tends to be more closely associated withpsychotic features such as delusions of guilt [203]. Nevertheless, there is considerable
overlap between these two groups of symptoms, and agitated melancholias are not uncommon. Unlike nonmelancholic depressions, melancholia is characterized by a decrease in
the latency to enter the ﬁrst period of rapid eye movement (REM) sleep [141] and anincreased activity of the hypothalamic-pituitary-adrenal (HPA) system usually detectedby the dexamethasone suppression test (DST) [45]. In a valid simulation of melancholia,
these biological markers would be expected to coexist alongside decreased sensitivity to
rewards. However, the speciﬁcity of both of these markers for melancholia is less thanoriginally claimed.
The ﬁrst section of this review considers those models in which anhedonia has been
demonstrated. Also included are the forced-swim and tail-suspension tests, in which anhedonia has not been demonstrated, but which appear to be conceptually related to thelearned helplessness model.
A. Acute Stress: The Learned Helplessness Model
As noted earlier, the learned helplessness paradigm is based on the observation that animals exposed to uncontrollable stress (usually electric shocks) are subsequently impairedin learning to escape shock, an effect that is not seen in animals exposed to comparable,
or indeed identical, patterns of controllable shock. The protective effect of control appears
to result from lower levels of fear [114], which raises important questions about the relationship between depression and anxiety. Seligman [247] proposed that exposure to uncontrollable stress provides the basis, in animals as in people, for learning that stress is uncontrollable (helplessness), and that this learning has a number of debilitating consequences,including depression. However, this interpretation has been the subject of considerable
controversy, in both the human [2,3] and animal literature [181,182,284], and is probably
incorrect as previously stated [288,296]. Nevertheless, the learning difﬁculties that follow
exposure to uncontrollable shock are reversed with reasonable selectivity by multiple
acute, subchronic (3–5 days) treatment with TCAs or atypical antidepressants [249].
SSRIs also appear to be effective, but only within a limited dose range [171], as well as
a number of other potential antidepressants such as 5HT1A-receptor agonists [100] and βadrenoceptor agonists [169], although some of these effects have been disputed [49], as
well as extracts of St. John’s wort (hypericum perforatum) [93,140]. Interestingly, chronic,
but not acute, treatment with lithium prevents the development of learned helplessness inrodents [263]. There are a few false positives, including the 5HT2-receptor antagonist,
methysergide [41], p-chlorophenylalanine (pCPA) [74], and piracetam [47], while neuroleptics, stimulants, sedatives, and anxiolytics are generally ineffective [228,249].
The learned helplessness paradigm shows many symptomatic parallels to major depression—so much so that it has been suggested that rodents subjected to uncontrollable
shock could meet DSM diagnostic criteria [284]. However, the learned helplessness paradigm is implemented in a variety of different ways in different laboratories, and the versionof the paradigm giving rise to the broadest range of symptoms [284] uses extremely highshock levels (4–6 mA), which are of doubtful relevance to depression. Furthermore, the512Willner and Mitchelleffects of this regime largely dissipate within 2 to 3 days, and the effects of antidepressant
pretreatment have not been studied using this procedure. The effects of antidepressantshave typically been studied using shocks of a considerably lower intensity (1.0–1.5 mA),
which cause a far less pervasive pattern of behavioral impairment.
Paradoxically, the effects of milder shock intensities are of longer duration, making
it possible to interpose multiple acute (subchronic) drug treatment (typically for 3–5 days)
between the initial uncontrollable shock session and the learning test. Furthermore, theduration of learned helplessness may be prolonged indeﬁnitely by repeatedly exposing
the subjects to the environment in which inescapable shock had occurred [162], whichstrengthens the face validity of this model of depression. However, a further problem isthat different components of the learned helplessness syndrome may be related to different
aspects of the induction procedure. For example, a long-term (7 weeks) suppression ofhome-cage locomotor activity has been reported following a single shock session [68],but this effect is unrelated to shock controllability and so is clearly distinct from otherlearned helplessness phenomena [303]. It is clear that the learned helplessness paradigm
should more correctly be considered as a mixture of paradigms, and care should be taken
in generalizing conclusions between them.
Among the consequences of low-intensity, uncontrollable (but not controllable)
shock is a poor performance of rewarded behavior, which, as noted above, may be ofparticular relevance to melancholia. One manifestation of this effect is a long-lasting decrease in responding for brain stimulation reward (intracranial self-stimulation; ICSS), in
mice, which is speciﬁc to certain electrode placement and therefore suggests a subsensitivity within part of the brain mechanism of reward, rather than, for example, a motor impairment [305,306]. Normal sensitivity to ICSS reward was restored by chronic, but not acute,treatment with TCAs [304,305]. Interestingly, a long-lasting anhedonia is seen only if theanimals are tested in the immediate aftermath of stress; otherwise the effect dissipates
rapidly [305]. A related observation is that mild stressors, which are without effect innormal animals, may reinstate behavioral deﬁcits resulting from an initial exposure tosevere stress [10]. These studies suggest that it may be possible to develop conditioning
models to explain how the risk of depression is elevated for several months in the aftermathof a stressful life event.
Another important observation is that uncontrollable electric shock has variable behavioral effects (most of which are antidepressant-reversible) in different inbred mousestrains. To take an extreme example, in the C57BL/67 strain, uncontrollable shock severely impaired subsequent learning to escape shock, but had no effect on responding
ICSS, while the DBA/2J strain showed exactly the opposite pattern of deﬁcits [248,306].
These studies may provide a starting point from which to investigate the physiologicalmechanisms underlying individual differences in responses to stress.
Vollmayr and Henn [280] have recently described a procedure in which mild shocks
induce learned helplessness in only some of the subjects, which may mimic the variable
human predisposition for depressive illness. This procedure has been used as the basis
for a selective breeding program, which has produced a congenital learned helplessness(cLH) and a congenital non-learned helplessness strain. An impressive recent neuroimaging study of cLH rats reported that metabolism was decreased in dorsal frontal, medial
orbital, and anterior cingulated cortex, but increased in the subgenual region of the cingulated cortex [250]; these exact changes have been described in depressed patients [72,173].
However, there are also anomalies: in particular, cLH rats show a decreased andrenocortical response to stress [127]. There is also uncertainty as to just what is being selected inAnimal Models of Depression

513

the cLH breeding program. cLH animals have been shown to exhibit stress-induced analgesia [127], raising the possibility that an increase in pain threshold might provide a very
simple explanation of their escape-learning impairments. And given the separation ofshock-induced escape deﬁcits and anhedonia in inbred mouse strains [248,306], there is
no reason to assume that the cLH strain, which was bred by selecting on the basis ofshock-induced escape deﬁcits, would also exhibit shock-induced anhedonia.
There is a relatively extensive literature dealing with the neurochemical bases ofstress-induced motor inactivation [161,287]. Brieﬂy, the debilitating effect of uncontrollable stress on later performance may be reversed by agonists at µ-opioid, dopamine (DA),α1- and β-adrenergic receptors, or by anticholinergic drugs; conversely, helplessness may
be simulated pharmacologically by drugs that reduce DA and/or noradrenaline (NA) function, or by drugs that increase cholinergic function [10,25–27]. Any inﬂuence of dopamine
neurotransmission on learned helplessness appears to be mediated by the D1 dopamine
receptor [91,92]. Furthermore, reduced catecholamine neurotransmission, either by inhibition of catecholamine synthesis with α-methyl-ρ-tyrosine [66] or by treatment with α1and β-adrenoceptor antagonists (as well as the opiate receptor antagonist naloxone) has
been shown to block the therapeutic effect of TCAs [170]. Similarly, blockade of NMDA
receptor-mediated neurotransmission also blocks TCA-induced reversal of learned helplessness [179]. Gamma-aminobutyric acid (GABA) neurotransmission also seems to be
involved in learned helplessness behavior. Thus a long-term increase in GABAB neurotransmission is associated with exacerbation of learned helplessness, while the action ofantidepressant drugs in this model is associated with a long-term reduction in GABAB
neurotransmission [200,201]. In contrast, studies of the role of 5HT in learned helplessness
are inconsistent [291]. Some 5HT-receptor agonists may reverse learned helplessness,while 5HT lesions did not prevent the action of TCAs in this model [258]. The inductionof behavioral depression/learned helplessness may be regulated, at least in part, by serotonergic input into the hippocampal CA3 subﬁeld. Papolos et al. [214] have shown that
intracerebroventricular administration of an antisense oligonucleotide to the 5HT2A-receptor reduced receptor density in the CA3 area and induced learned helplessness behavior.
B. The Forced-Swim Test
In the forced-swim test, rats or mice are forced to swim in a conﬁned space. While mice
are subjected to a single swim test following a single drug administration, rats are generally
subjected to two tests, usually spaced 24 h apart, to generate increased immobility scores.
The onset of immobility exhibited by rats in the second test is delayed by pretreatment
with a wide variety of antidepressants, usually administered in a multiple acute (subacute)treatment schedule consisting of three injections over the time period between the two
swim sessions. The fact that the forced-swim test responds to acute drug treatment has
been a frequent source of criticism. Small antidepressant effects may be present after asingle high dose. Larger effects are observed after multiple acute treatments at lower doses,
but these changes may simply reﬂect an elevation of brain drug concentrations.
Effective treatments include TCAs, MAOIs, most atypical antidepressants, the selective NA reuptake inhibitor, reboxetine [54], 5HT1A, 5HT1B, and 5HT2C-receptor agonists[207,59], extracts of St. John’s wort (hypericum perforatum) [43], ECS, and REM sleep
deprivation [224,228,33]. The test is not usually sensitive to SSRIs [32,33,55], although
activity of these compounds has sometimes been reported, and this appears to reﬂect a
subtle technical change, an increase in the water depth [59,272]. There have also been a514

Willner and Mitchellvariety of other negative reports; nevertheless, some 90% of clinically active antidepressants are active in the forced-swim test, with the proportion rising in studies using chronic
drug treatment [33,228]. It has been suggested that both serotonergic and noradrenergic
systems may be involved in mediating antidepressant-induced reductions in immobility;
serotonergic-mediated effects result from increased swimming time while noradrenergicmediated effects reﬂect increased climbing behavior [69].
Reduced immobility scores have also been observed following treatment with neurosteroids [234], neuropeptide-Y [260], and NMDA-receptor antagonists [213,271]. The
effect of NMDA-receptor antagonists is to reduce calmodulin-mediated activation of nitricoxide (NO) synthase. Likewise, NO synthase inhibitors have been reported to be as effective in reducing immobility as imipramine [103]. In rat studies, selective antagonists forsubtypes of the cholecystokinin (CCK) receptor have been shown to reduce immobility
scores. However, these positive effects are dependent on time of drug administration.
Thus, the CCKA antagonist, devazepide, is only effective when given before the conditioning pretest [108], while the CCKB antagonist, L-365,260, is effective when given immediately prior to the retest [107]. These observations suggest a role for CCK in behavioral
adaptations to acute stress.
On the negative side, while the test successfully discriminates antidepressants fromneuroleptics and anxiolytics [225], false positives have been reported for stimulants, convulsants, anticholinergics, antihistamines, pentobarbital, opiates, a variety of brain peptides (see above), and a number of other drugs [33,228]. Some false-positive responses
have been reported to disappear if chronic drug treatment is used or the duration of thetest is prolonged [123,128], but the generality of these effects has not been established.
While the predictive validity of the forced-swim test may be better than has sometimes been assumed, its face and construct validity are minimal. The only symptomatic
resemblance to depression is an inability or reluctance to maintain effort. Interestingly,
positive responses to antidepressant drug treatment (i.e., reduced immobility) are only
observed if subjects are forced to swim in water at least 10 °C below core body temperature(P.J. Mitchell, personal observations) and consequently develop severe hypothermia. If
mice are forced to swim in water maintained at body temperature, then immobility still
occurs, but the response to antidepressant treatment is abolished. These observations
clearly implicate the importance of severe cold stress and the consequent induction of
hypothermia in this model, which further weakens the parallel with depression.
The theoretical rationale of this test derives entirely from its supposed relationshipto learned helplessness. However, the relationship between the two models is unclear.
Prior inescapable, but not escapable, shock has been found to increase immobility in theforced-swim test [205,283], but in view of the consistent ﬁndings of depressed motor
activity following inescapable shock [10], it would be surprising if this were not the case.
The reciprocal ﬁnding has not been demonstrated: forced swimming did not impair subsequent escape performance in a shock-avoidance task in which performance deﬁcits are
typically seen following inescapable shock [206].
Nevertheless, the two tests do seem to share similar physiological substrates. Immobility in the swim test is also reversed by stimulating 5HT1A, 5HT1B, and 5HT2C receptors[59,207,272], DA or α1-adrenergic receptors, or by anticholinergics, and potentiated bytreatments that decrease the activation of DA (e.g., amisulpride) [216], or NA systems orincrease cholinergic transmission. Similarly, the therapeutic actions of antidepressants inthis model are blocked by DA-receptor antagonists and by treatments that reduce NAfunction, including neurotoxic destruction of the ascending NA pathways and α1-adreno-Animal Models of Depression

515

ceptor antagonists. As in the learned helplessness test, impairment of 5HT transmission
neither increases immobility nor blocks its reversal by antidepressants [33,291].
C. The Tail-Suspension Test
A number of variants of the forced-swim test have been proposed. One of these, the tailsuspension test, has been claimed to be ethically superior to the forced-swim test, as stresslevels appear to be reduced [227,259]. In this model, mice suspended by the tail show atemporal pattern of struggling followed by immobility, similar to that seen in the forcedswim test. Antidepressants, at strikingly low doses, have been shown to increase the duration of mobility and also, in an automated version of the test, to increase the power ofthe movements (although the latter effect is rather less convincing). Effective agents include TCAs, MAOIs, and atypical antidepressants; the latter include mianserin, the selective NA reuptake inhibitor, reboxetine [302], extracts of St. John’s wort (Hypericum perforatum) [43], the NMDA-receptor antagonist, MK-801 [213], and, signiﬁcantly, some(but by no means all) 5HT uptake inhibitors [65,90,222,264], which are usually ineffectivein the forced-swim test (see above). Immobility was also reduced by stimulant drugs, but
was potentiated by neuroleptics or anxiolytics [227,259].
While it is tempting to see the tail-suspension test as a more sensitive version of
the forced-swim test, there are subtle differences between them that are not at present
understood but involve signiﬁcant mediation by a noradrenergic receptor-mediated mechanism(s) [83]. In particular, 5HT1A-receptor agonists are active in the forced-swim test, but
are ineffective in the tail-suspension test [228], whereas the mixed 5HT1A/1B-receptor agonist, RU 24969, was active in the latter. Like the forced-swim test, the face and constructvalidity of the tail-suspension test are minimal.
D. Chronic Stress Models
Repeated presentation of the same stressor usually leads to adaptation. However, adaptation can be prevented by presenting a variety of stressors in an unpredictable sequence.
Katz and colleagues showed that 3 weeks of exposure to electric shocks, immersion incold water, immobilization, reversal of the light/dark cycle, and a variety of other stressors
caused a decrease in the activating effect of acute stress in an open ﬁeld test. However, theactivating effect of acute stress was maintained in animals receiving daily antidepressanttreatment during the chronic stress period; the effects of administering antidepressants
after exposure to stress have not been studied in this model. A variety of antidepressantdrugs, as well as ECS, were found to prevent the effect of chronic stress, but the MAOI
tranylcypromine was ineffective. Various nonantidepressants failed to prevent the effectof stress. In addition to causing changes in open ﬁeld activity, chronic stress also increased
plasma corticosteroid levels. This effect showed the same spectrum of pharmacologicalsensitivity, with the exception that an anticholinergic was also effective [122,291]. Similareffects have also been reported in mice; corticosteroid levels and the response to an acutestress were normalized by TCAs, but not by the SSRI, ﬂuoxetine [255].
A further effect observed in rats after chronic stress was a failure to increase ﬂuid
consumption when saccharine was added to the drinking water, suggesting that chronic
stress might cause anhedonia; this deﬁcit was partially restored by imipramine [121]. The
chronic stress model has been used very little since the original series of publications, inpart because the levels of severity employed raise serious ethical problems. However, a516

Willner and Mitchellvariant of the model has been devised in an attempt to achieve the same endpoints as thechronic stress model, but in a more ethically acceptable manner.
1. Chronic Mild Stress
The CMS procedure involves relatively continuous exposure of rats or mice to a varietyof mild stressors, such as periods of food and water deprivation, small temperature reductions, changes of cagemates, and other similarly innocuous manipulations. Over a periodof weeks of chronic exposure to the mild stress regime, rats gradually reduced their consumption of a preferred dilute sucrose solution and, in untreated animals, this deﬁcit persisted for several weeks following the cessation of stress [297,299]. As discussed in Section IV, a variety of studies have been performed to conﬁrm that these effects reﬂect ageneralized insensitivity to reward; in particular, chronic mild stress also impairs responsiveness to reward as assessed by different methods, including suppression of place preference conditioning [217–219] and increased threshold for ICSS [196]. Studies of the effectsof the individual elements of the chronic mild stress regime revealed that one element,social housing (in animals usually housed individually), was particularly potent, but noindividual element (including social housing) was neither necessary to induce anhedonia
nor sufﬁcient to maintain anhedonia for a prolonged period [198].
Antidepressant treatment has no effect on sucrose consumption or ICSS thresholdin nonstressed animals, but following the reduction of sucrose intake by stress, normal
behavior was gradually restored by chronic treatment (2–5 weeks) with a wide variety ofantidepressants, including TCAs, SSRIs, a speciﬁc NA reuptake inhibitor, MAO-A inhibitors, atypical antidepressants such as mianserin, buspirone, and amisulpride, and ECS.
Also effective were some agents of uncertain antidepressant status, such as antihistaminic
and anticholinergic drugs. Ineffective drugs include the anxiolytic chlordiazepoxide, various neuroleptics, amphetamine, and morphine [294,295]. Fluoxetine, maprotiline, and mianserin (but not chlordiazepoxide) were also found to restore the rewarding properties offood, as assessed in the place-conditioning paradigm [48,199]. In contrast to the extensive
array of drugs correctly classiﬁed in CMS experiments, very few false positives or false
negatives have been reported.
The reversal of an established behavioral deﬁcit during the continued presence ofthe stressor is an important feature of this model: if, as seems likely, chronic stress does
play a role in the etiology of melancholia [9,194,239], its continued presence during antidepressant therapy would usually be the norm. Also important is the extended time courseof antidepressant action, which makes it feasible to detect rapid onset of action. Many
novel agents have been identiﬁed as potential antidepressants using the CMS procedure,
and these include some that appear to act more rapidly than TCAs or SSRIs, including
the D2/D3 antagonist amisulpride [216], the glycine antagonist 1-aminocyclopropanecarboxylic acid (ACPC) [215], the 5HT1A-receptor agonist BIMT-17 [64], and the SNRI
venlafaxine (M. Papp, personal communication). Potentiation of antidepressant action bylithium and pindolol has also been reported [252,253]. In at least three instances (theD2/D3 agonist pramipexole, the corticosterone synthesis inhibitor ketoconazole, and thecatechol-O-methyl transferase (COMT) inhibitor tolcapone), the antidepressant effect ofthese compounds was demonstrated in the clinic only after these actions had been predicted in the CMS model [294].
In addition to decreasing responsiveness to rewards, CMS also causes the appearanceof many other symptoms of major depressive disorder. Behavioral changes in animals
exposed to CMS include decreases in sexual, aggressive, and investigative behaviors, andAnimal Models of Depression

517

decreases in locomotor activity. These are seen during the dark phase of the light–darkcycle, which is the rat’s active period; electroencephalogram (EEG) measures of active
waking are also decreased during the dark phase. In contrast, CMS did not cause theappearance of an anxious proﬁle in two animal models of anxiety, the elevated plusmaze and the social interaction test, suggesting that the behavioral changes are speciﬁc
for depression. Animals exposed to CMS show an advanced phase shift of diurnal rhythms,
diurnal variation, with symptoms worse at the start of the dark (active) phase, and a variety
of sleep disorders characteristic of depression, including decreased REM sleep latency,
an increased number of REM sleep episodes, and more fragmented sleep patterns. They
also gain weight more slowly, leading to a relative loss of body weight, and show signsof increased activity in the HPA axis, including adrenal hypertrophy and corticosterone
hypersecretion. Abnormalities have also been detected in the immune system, including
an increase in serum, decreases in thymus weight, natural killer-cell activity and reactivity
to T-cell mitogens, and an increase in acute-phase proteins that was reversed by chronic
antidepressant treatment. Taken together with the generalized decrease in responsivenessto rewards, these parallels to the symptoms of depression and, in particular, to melancholia,
are both extensive and comprehensive [294]. Indeed, it is arguable that the only symptoms
of depression that have not been demonstrated in animals exposed to CMS are thoseuniquely human symptoms that are only accessible to verbal enquiry. Even without these
symptoms, a rat exposed to CMS could, in principle, legitimately attract a DSM-IV diagnosis of either major depressive disorder or major depressive disorder with melancholicfeatures.
Studies of the neural basis of the CMS-induced anhedonia have focused primarilyon the mesolimbic DA system. The behavioral changes in animals subjected to CMS areaccompanied by a decrease in D2/D3-receptor binding and D2-mRNA expression in the
nucleus accumbens, and a pronounced functional subsensitivity to the rewarding and locomotor stimulant effects of the D2/D3 agonist quinpirole administered systemically or
within the nucleus accumbens. All of these effects are also reversed by chronic antidepressant treatment [73,295]. In other studies, animals successfully treated with antidepressantswere treated acutely with D2/D3 receptor antagonists, at low doses that were without
effect in nonstressed animals or in untreated stressed animals. This treatment reversed theeffects of a wide variety of antidepressants on rewarded behavior [295]. These data argue
strongly that an increase in D2/D3-receptor responsiveness may be responsible for thetherapeutic action of antidepressants in this model [295]. A similar reversal of SSRI action
by the D2 antagonist sulpiride has been observed in a clinical study, as predicted fromthe CSM data [294].
A recent CMS study suggests that a neural mechanism could mediate the negative
information-processing bias characteristic of depression [22]. In this study [70], DA release in nucleus accumbens and prefrontal cortex was monitored by microdialysis following exposure to a palatable reward and a stressor (tail pinch). CMS markedly inhibited DA release in response to rewards, but potentiated responses to the stressor; bothof these effects of CMS were reversed by chronic treatment with the TCA desipramine(DMI).
While the CMS model has a great many positive features, and is probably the mostvalid animal model of depression currently available, a major drawback is that the model
has proven extremely difﬁcult to implement reliably, and while many laboratories havesucceeded in doing so, many others have not. The reasons for this lack of reliability havebeen extensively debated [294], but are as yet unresolved.

518

Willner and Mitchell

2. Stress Induction and Mild Stress Maintenance
Tagliamonte and colleagues have described a model that represents a cross between
learned helplessness and CMS. In this procedure, an altered state is ﬁrst induced by acuteexposure to a session of moderately intense inescapable tail shock, and then maintained,
apparently indeﬁnitely, by exposure to milder stressors (brief restraint, a small number ofshocks, or exposure to the inescapable shock apparatus), presented at 2-day intervals. This
treatment resulted in an impairment of shock escape learning, as in learned helplessness,
and a failure to learn a simple maze task reinforced by a highly palatable food (vanillasugar), as in CMS. Both of these deﬁcits were prevented by chronic pretreatment with
TCAs or ﬂuoxetine [67,97]. The stress procedure also decreased basal levels of extracellular DA in the nucleus accumbens shell, and this change also was prevented by chronic
TCA treatment [94].
We noted earlier (Sec. IV) that the effect of severe life events on precipitating depression was best characterized as an acute severe stress followed by a chronic increasein mild stress. Stress induction followed by mild stress maintenance exactly parallels theseprocesses and is the only animal model of depression to do so. This procedure could
potentially provide a more reliable and robust alternative to the CMS procedure, but few
data are currently available. In particular, while antidepressants have been shown to prevent the development of behavioral abnormalities, they have not been shown to reverse
an established deﬁcit. Also, the portability of the procedure to other laboratories has notbeen demonstrated.
E.

Withdrawal from Chronic Psychomotor Stimulants

A number of studies have reported that responding for ICSS was reduced in the days
following withdrawal from chronic amphetamine treatment. In these studies, amphetamine
was administered to rats for between 4 and 10 days, typically using several administrations
each day, at increasing doses [19,129,145,251]. The threshold for ICSS was elevated following amphetamine withdrawal, conﬁrming that the rate reduction reﬂects a subsensitivity to brain stimulation reward rather than a depression of motor activity [46,146]. After
14 days of amphetamine treatment, the decreased sensitivity to ICSS did not recover during 18 days of further testing [146], reﬂecting subsensitivity of reward systems rather thansimple depression of motor activity. In a single pharmacological study, this effect wasalleviated by 2 days of imipramine or amitriptyline treatment, and with continued treatment, normal responding was restored [130].
In a variant of this procedure, animals self-administer cocaine, rather than being
administered amphetamine [131]. In these experiments, the threshold for brain stimulation
reward, administered through electrodes in the posterior lateral hypothalamus, was obtained using a discrete trial procedure [133], which is sensitive to changes in reward value,
but not to changes in motor performance [167]. Following 24 h of cocaine self-administration, ICSS thresholds were elevated for several hours [131], indicating that cocaine withdrawal induced a state of anhedonia. Acute administration of the DA receptor agonist,
bromocriptine, restored ICSS thresholds to normal [166]. Only one conventional antidepressant has been tested in this procedure: repeated administration of the TCA, DMI,
was reported to shorten the duration of post-cocaine anhedonia [168].
It has frequently been assumed that stimulant drug treatment is a form of stress,
since in many respects stimulant treatment and stress appear to be interchangeable [12,229]. Indeed, withdrawal from chronic cocaine treatment in rats is associated with intense

Animal Models of Depression

519

anxiety-related behavior and extrahypothalamic-limbic corticotropin-releasing hormone(CRH) hypersecretion [242]. The similarities between stress and stimulant withdrawal arethought to arise from the fact that, like stimulant drugs, stressors activate the mesolimbic
and mesocortical DA projections [30]. Independent of a relationship to stress, there isan obvious parallel between the effects of stimulant withdrawal and the depressions thatfrequently follow the cessation of chronic stimulant use [282], although in the animalmodel the time course is rather more compressed.
As the stimulant withdrawal models are based exclusively upon changes in ICSS
behavior, their construct validity depends largely on the assumption that brain stimulation
reward activates natural reward pathways [111]. Although early studies suggested thatICSS had unusual properties compared to natural rewards (e.g., rapid extinction), it waslater recognized that these properties derive from differences in the experimental procedures typically employed (such as the delay of reinforcement); when such extraneous
factors are equated, ICSS appears very comparable to a high-incentive natural reward
presented under conditions of low drive [98]. These parallels, together with the observationthat responding for ICSS performance is inﬂuenced by many of the factors that control
responding for natural rewards, have justiﬁed the assumption that the ICSS electrode stimulates directly the neural substrates that are activated indirectly by natural rewards [111].
A degree of caution is required, because although people implanted with ICSS electrodes
report a variety of pleasurable sensations, they also report other reasons for stimulating,such as curiosity [14,270]. Nevertheless, the commonality of anatomical substrate between
ICSS and other types of reward supports the use of this procedure as an animal model ofhedonic behavior [131,301]. However, the relationship of drug-induced depression to major depressive disorder is uncertain, and validity of this model is therefore questionable.
F.

Social Dominance Models

Parallels have often been noted between depressive and submissive behaviors [95,230],
and a number of laboratories have attempted to model depression by using animals of
low social rank. Subordinates, and those who have lost status as a result of defeat in social
conﬂict situations, are at greater risk for psychopathology. Biological similarities between
defeated animals and human depression have frequently been noted [99,106,268], andthere is considerable evidence that depressed individuals see themselves as inferior andbehave submissively [99]. Indeed, social skills training, of which assertiveness training
represents a major component, is used clinically as a psychotherapy for depression, which
has been found to be equally effective as TCA treatment [109]. Like the chronic mild
stress procedure, animal models based on social dominance employ realistic inducing
conditions that are of particular ecological relevance.
1. Social Defeat
Social defeat is a potent stressor, and repeated defeat is a form of chronic stress, whichis associated with a decrease in aggressive behavior [6]. A single social defeat has beenreported to produce a gradual, but long-lasting, increase in immobility in the forced-swim
test, which was prevented by chronic treatment with clomipramine [132]. A similar model
has been developed in submissive C57BL/6J mice: a single defeat by a dominant male
mouse of the same strain was reported to cause a gradual increase over weeks in passive
behavior in response to a mild stressor, which could be antagonized by clomipramine;
defeated animals also had higher immobility times in the forced-swim test [134]. In a

520

Willner and Mitchell

chronic version of a similar procedure, mice were housed in social contact, but were
physically separated except for one daily 3-min encounter. Again, increased immobility
in the forced-swim test was observed in repeatedly defeated animals, and this effect wasprevented by chronic treatment with imipramine, although in this study imipramine did
not normalize social behavior in the defeated animals [139].
In a modiﬁed rat model, defeat of dominant pair-housed rats by rats of a different,
more aggressive, strain resulted in the loss of dominant status relative to their previously
submissive partners, which was restored by chronic imipramine treatment [300]. This lossof status was accompanied by the abolition of morphine-induced place conditioning, most
likely reﬂecting a decrease in hedonic tone [58]. This suggests that it may be appropriate
to view submission models potentially as models of melancholia. However, more evidenceis needed for any ﬁrm conclusion.
In a modiﬁed mouse social defeat paradigm, subordinate mice subjected to repeatedsocial defeat showed reduced growth compared to dominant subjects, together with citalopram-sensitive anxiogenic-like behavior [124,125]. The defeated mice exhibited a maintained increase in both core temperature and circulating corticosterone levels indicativeof chronic stress, although social defeat had no effect on either ethanol consumption or
immobility time measured in the forced-swim test. Similarly, a single social defeat ofLewis rats resulted in hypophagia and weight loss, together with increased measures ofanxiety, and these effects were reduced following acute ﬂuoxetine treatment [24].
Overall, these various studies suggest that social defeat may in principle provide avalid and ecologically sound model of depression. However, a variety of procedures havebeen used and, at present, the data are not entirely consistent.
2. Social Hierarchy
A related procedure is based on the observation that rats housed in closed groups develop
a social hierarchy and the relative social position of each group member may be identiﬁedby assessing each individual’s level of success during agonistic encounters with othergroup members. If rats are housed in triads, then a social hierarchy consisting of a dominant, subdominant, and subordinate develops. Two-week chronic administration of either
clomipramine or mianserin to the subdominant animal results in an increase in that subject’s rank position at the expense of the level of dominance enjoyed by the dominantgroup member [188]. The increase in the social position of the antidepressant-treated subdominant rat is likely to be related to increased assertiveness expressed during social
encounters. An attractive feature of this model is that daily assessment of social structure
allows the time course of antidepressant-induced elevation of social position to be determined. However, not all features of subordinate animals are necessarily of relevance todepression, and the relationship between social dominance and social competition is potentially problematic. In group-housed rats competing for limited access to a high-incentive
reward, the performance of subordinate animals was improved by acute or chronic anxiolytic treatment [96,118], suggesting that the social competition test is relevant to anxiety
rather than depression. Consistent with this view is the observation that chronic treatment
with m-chlorophenylpiperazine (mCPP), a major metabolite of the antidepressant trazodone which also possesses antidepressant activity, failed to increase the performance of
subdominant rats in a social competition test [193] at a dose previously shown to increase
the aggressive behavior of resident rats in a resident-intruder test (see below) [192]. However, the benzodiazepine anxiolytic diazepam, which improves performance in a social
competition test, did not increase aggressive behavior in dyadic encounters, after either

Animal Models of Depression521

acute or chronic administration [189]. Further studies will be necessary to conﬁrm thisineffectiveness of anxiolytics in social dominance tests.
3. The Resident-Intruder Test
Antidepressant treatment has consistently been shown to have profound effects on rat, but
not necessarily mouse, social and agonistic behavior. While acute treatment with pharmacologically disparate antidepressant drugs (including TCAs, MAOIs, SSRIs, SNRIs, 5HT1A-receptor agonists and partial agonists, 5HT2C-receptor agonists) commonly reduces
the aggressive behavior of resident rats when confronted with an unknown conspeciﬁc
intruder, chronic antidepressant treatment (including repeated ECS) increases such aggressive behavior [51,52,183–187,189–192]. These observations are consistent with the viewthat aggression is the only type of rodent social behavior consistently increased following
chronic treatment with antidepressants [85].
The fact that chronic antidepressant treatment increases aggressive behavior appears
at ﬁrst sight to be incompatible with the use of SSRIs in the clinical treatment of impulsive
aggression [53,76,82]. However, this is a clinical, rather than an experimental, paradox,
since clinically, antidepressants both increase aggression in submissive depressed individuals (manifest as a reversal of intropunitive aggression and/or impaired sociability:[71,119,231] and decrease pathological aggression [112,275]). A resolution of this paradox
may be that antidepressant treatment increases assertiveness, since this would increase
low levels of social dominance while at the same time decreasing high levels of physicalaggression. Hence, the ability of chronic antidepressant treatment to increase aggression
in rats may reﬂect the increased assertiveness and associated externalization of emotions
expressed during recovery from depressive illness. Such increased assertive/aggressive
behavior is consistent with the effects of such treatment in the social hierarchy model (seeabove). However, face validity of the resident-intruder model is reduced by the fact thatthe test involves normal unmanipulated animals; nondepressed people do not respond to
antidepressant treatment. Interestingly, and in contrast to the rat studies, the aggressive
behavior of male mice in murine resident-intruder studies is particularly sensitive to anxiolytic, rather than antidepressant, drug activity [159].
By programming daily dyadic encounters, the resident-intruder paradigm can beused to compare the rate of onset of antidepressant-induced elevation in aggression between antidepressant treatments, and to assess the utility of potential adjuvant treatment
to accelerate antidepressant-related changes in rodent behavior. Indeed, the ﬁrst publishedstudies to demonstrate the ability of a selective 5HT1A-receptor antagonist (WAY-100635)
to accelerate time-dependent antidepressant-induced behavioral changes used the residentintruder test [191].
G.

Neonatal Antidepressant Treatment

Neonatal treatment of rat pups with the TCA clomipramine has been reported to cause aspectrum of symptoms reminiscent of depression, including decreases in sexual and aggressive behavior, a shortening of REM sleep latency, and subsensitivity to ICSS. Treatedanimals were also hyperactive in some tests [278,279]. Animals were typically tested whenmature, at ages that varied between tests. Most of the behavioral and sleep abnormalities
were present on ﬁrst testing at approximately 3 months; however, the ICSS abnormalities
were absent at 4 to 5 months, but present at 6 to 8 months. ICSS was not tested in older
animals, but some other abnormalities appeared to normalize at around 11 months [278].

522

Willner and Mitchell

These effects are probably not speciﬁc to clomipramine, since neonatal treatment with
DMI, zimeldine, or the SSRI, Lu 10-134-C, also increases immobility in the forced-swim
test in adult rats [102,110,276], while neonatal treatment with the SSRI citalopram similarly reduces adult aggressive behavior [163]. Zimeldine, like clomipramine but not DMI,
also reduces or disrupts adult rat sleep patterns by shortening the duration of REM sleep
bouts [87]. In contrast, neonatal treatment with scopolamine, a cholinergic receptor antagonist, suppressed REM sleep, as observed with neonatal clomipramine treatment but, unlike
clomipramine, facilitated adult male sexual behavior. These results suggest that the neonatal clomipramine-induced reduction in male sexual behavior is not due to early REM
sleep deprivation [277].
As yet, information concerning the pharmacological responsiveness of this modelis minimal: some effects of imipramine and REM sleep deprivation have been reported,but the numbers of subjects tested were too low to allow reliable conclusions to be drawn[278]. While this model appears to have good face validity in terms of the range of symptoms displayed and the insidous onset of anhedonia, the mechanisms by which neonatal
antidepressant treatment has adverse effects in mature animals are unknown. In particular,
it is unclear what, if any, is the relationship between neonatal antidepressant treatment
and the etiology of depression in humans. The extent to which the symptoms can bereversed by antidepressants is uncertain. Nevertheless, these studies raise the disconcerting
possibility that a breast-fed infant could develop a susceptibility to melancholia by ingesting TCAs prescribed to the nursing mother for the relief of postpartum depression.
1. Perinatal Stress
Possibly related to the neonatal antidepressant treatment model are models based on prenatal and neonatal stress. Anhedonia has not been demonstrated in these models, andindeed their relevance to depression, as opposed to other forms of psychopathology, isfar from established, but some endocrinological data suggest a possible relevance to melancholia.
Prenatally stressed (PS) rats (where the dam is subjected to repeated foot shock
during the early stages of pregnancy) exhibit elevated activity of the HPA axis and defensive behavior before weaning, and the heightened defensive behavior, as well as exaggerated behavioral, physiological, and neuroendocrine responses to stressful stimuli, persist
into adulthood [262,281,285]. Current behavioral data suggest similarities between the
behavioral proﬁles of PS rats and the anxiogenic changes in behavior induced by yohimbine and idazoxan [285]; these data indicate high levels of anxiety in PS rats. However,female, but not male, PS mice exhibit an antidepressant-reversible increase in immobility
time in the forced-swim test, indicating that PS might induced a gender-dependent increasein the risk of depression-like behavior [7,8].
Neonatal stress in nonhuman primates has been shown to induce hypersecretion of
CRH [57] and abnormal social behavior in adulthood, indicative of enhanced response tostressors [50]. Similarly, neonatal stress in rat pups, achieved by maternal separation, also
increases CRH levels in adulthood [142].
H.

Selective Breeding for Muscarinic Hypersensitivity

The Flinders Sensitive Line (FSL) rat is the result of selective breeding for sensitivity to
the hypothermic effect of cholinergic agonists and is based on the hypothesis that central
cholinergic systems are important in depression since increased cholinergic sensitivity has

Animal Models of Depression

523

been reported in depressed patients. Although bred for cholinergic hypersensitivity, FSL
animals also show a number of other pharmacological abnormalities, including serotonergic hypersensitivity and dopaminergic hyposensitivity [210]. Relative to the control Flinders Resistant Line, FSL animals have a number of characteristics reminiscent of depression, including cholinergic supersensitivity, increased REM sleep, and reduced locomotor
activity, which is further pronounced following electric footshock [209]. FSL animals also
show greater immobility in the forced-swim test [210]. This behavior was normalized bychronic treatment with a high dose of imipramine, and partly reversed by DMI or sertraline, but was not restored by chronic amphetamine or scopolamine [208,211,244]. FSL
rats also exhibit a greater vulnerability to the suppressive effect of chronic mild stress on
responsiveness to sweet reward [232,233], but behave normally in the elevated plus maze,a putative animal model of anxiety [208].
While these observations are consistent with a depressive diathesis and greater behavioral responsiveness to stress, other data are not. FSL rats have markedly elevatedlevels of 5HT, NA, and DA in speciﬁc brain areas that are normalized during chronic
treatment with DMI [307,308], and hypothalamic levels of CRH and circulating levels of
adrenocorticotrophic hormone (ACTH) are lower in FSL rats [212], indicating reduced
HPA axis activity, in contrast to the increased HPA axis activity observed in depression.
Similarly, acute and chronic treatments with nicotine, a nonantidepressant, both exhibit
an antidepressant-like effect on the behavior of FSL rats in the forced-swim test [266],
which was blocked by prior treatment with the nicotinic receptor antagonist, mecamylamine [267]. It should be noted that the major pharmacological evidence supporting the
FSL strain as a model of depression derives from studies using the forced-swim test, which
is itself of questionable validity.
VI. MODELS OF OTHER SUBTYPES OF DEPRESSION
Little attention has been paid to the question of subtypes of depression in the developmentof animal models, which have tended to focus either on an undifferentiated depressive
state or on melancholia.
Unlike melancholia, no consensus exists that nonmelancholic depression is a homogeneous entity, and this issue has been extensively debated. Within the nonmelancholic
spectrum, two syndromes have been described that are of interest in the present context.
One of these is not recognized in DSM-IV, but has features that suggest it might represent
a coherent biological entity. This is a form of depression in which central 5HT activity
is decreased, as indicated by low concentrations of the 5HT metabolite 5-hydroxyindole
acetic acid (5HIAA) in cerebrospinal ﬂuid. These depressions are characterized by highlevels of anxiety and agitation, and Van Praag [273] has suggested that these symptoms
are primary, with depressed mood as a secondary response to a failure to cope with theconsequences. It has been suggested that some animal models of depression which arecharacterized by high levels of locomotor activity and/or aggression, may represent models of this subtype, and these are described below.
A second nonmelancholic subtype of depression is delusional depression (previously
known as psychotic depression). Delusional depression (DSM-IV major depressive episode with psychotic features) is difﬁcult to translate into behavioral terms, being differentiated from nondelusional depression only by a greater association with psychomotor agitation [203]. Delusional depressions are pharmacologically distinct in that they respondto ECT or combinations of TCAs with neuroleptics, but not to TCAs alone [202]. The

524

Willner and Mitchelldevelopment of an animal model that responds to ECS but not to TCAs has not yet beenachieved.
Bipolar disorder is another well-deﬁned diagnostic category for which there are no
animal models. There are a number of animal models of mania [160], but the alterationof depressive-like and manic-like behavior in an animal model has not yet been systematically addressed. Indeed, the episodic nature of unipolar depression (e.g., brief recurrent
depression) also remains to be explored in animal models.
A.

Social Separation

The presumed etiological role in depression of loss events, and particularly, loss of a loved
one, has led to the development of a number of animal models of depression based on
separation phenomena.
Although the evolutionary proximity of primates has led some authors to consider
primate separation models to be of particular importance [78], they have produced remarkably little of value. Precisely because of their evolutionary proximity, the use of primatessacriﬁces many of the advantages of animal models, such as the easing of ethical constraints, and the possibility of testing adequately sized groups of subjects.
1. Neonatal Isolation
The most familiar of these models involve nonhuman primates, either infants isolated
from their parents, or juveniles isolated from their peer group. The separation response
consists of an initial stage of protest, characterized by agitation, sleeplessness, and distresscalls, followed by despair, characterized by a decrease in activity, appetite, play and social
interaction, and the assumption of a hunched posture and sad facial expression [105,261].
These symptoms are strikingly similar to those of anaclitic depression in institutionalized
children [238]. However, while parental loss in childhood, and bereavement in adults, are
implicated in the etiology of depression, they also increase the risk of a variety of otherpsychiatric and nonpsychiatric disorders [40,245]. The nature of the separation response
is sensitive to the environment in which the experiments are carried out [235,261], andthe incidence of depressive behaviors may in some experiments be as low as 15% [150].
The few pharmacological studies using these models have not been impressive. Veryfew published studies have attempted to use antidepressant treatments to modify primate
separation behavior, and because of the expense of using primates, the size of experimentalgroups in most studies has usually been too small to provide reliable data. Chronic treatment with DMI [113], imipramine [261], oxaprotiline [177], and ECS [149] have beenreported to reverse some, but not all, of the effects of separation in monkeys. Triﬂuoperazine, amphetamine, and diazepam did not affect responses to social isolation in chimpanzees [180,269], but some therapeutic effects of chlorpromazine were seen in rhesus monkeys [178]. Depressive-like behaviors in singly housed rhesus monkeys are associatedwith decreased concentrations of NA in the cerebrospinal ﬂuid, with relatively little effecton DA or 5HT [138]. Following a return to social housing, NA levels normalize, but the
animals remain hypersensitive to pharmacological challenges of the NA system [136,137].
In fact, separation phenomena of protest followed by despair are present to someextent in many other species, including cats, dogs, rodents, and precocial birds [120,176],and several of these phenomena have also been used as the basis of the development ofanimal models of depression. One of these, the reactivation of distress calling in 1-week-Animal Models of Depression525

old chicks, appears to perform relatively well as an antidepressant screening test [144].
The vocalizations of guinea pig pups separated from their mothers also respond to antidepressants, and this test was used successfully to detect antidepressant-like activity ofthe substance P neurokinin-1 (NK1) receptor antagonists [240].
2. Adult Isolation
Chronic (4–6 weeks) isolation of adult rats has been found to cause a disruption of cooperative social behavior [23] reminiscent of the poor social performance of depressed people[148]. In a single study of the effects of antidepressant treatment, the impairment of social
cooperation in isolated rats was reversed by chronic treatment with either imipramine or
ﬂuoxetine, and the effect of imipramine in this model was abolished by the 5HT antagonist
metergoline [298].
B. Olfactory Bulbectomy
The other major animal model of depression is based on the destruction of the olfactory
bulb in rats, which disrupts the limbic-hypothalamic axis. Bulbectomized (OB) animals
display a variety of behavioral changes, including irritability, hyperactivity, and impairment of passive avoidance learning [44]. Recent observations suggest that OB rats exhibit
increased reactivity together with a reduced rate of habituation to novel stimuli [164] andchanges in the immune system and NA, DA, 5HT, GABA, cholinergic, and glutaminergic
neurotransmitter systems [126]. They also show an elevation of circulating corticosteriod
levels (as do stressed animals), which appears to be an increased corticosteroid responseto stress rather than an increase in basal levels [36]. These changes are reversed by antidepressants, including compounds with 5HT1A-receptor agonist activity [34,175], SNRIs[174], and selective NA reuptake inhibitors [104] in addition to the TCAs. The most
speciﬁc antidepressant effect is the reversal of the passive avoidance learning deﬁcit[44,274], although attenuation of hyperactivity in the open ﬁeld is nowadays the mostcommonly used behavioral predictor of antidepressant activity [126]. However, while all
TCA and atypical antidepressants appear to be effective in this test, MAOIs are not [116].
While repeated administration of TCAs is necessary to normalize behavior in this model,
a limited number of studies suggest that some SSRIs act after acute treatment [117,157].
Recent studies suggest that the OB rat model of depression is insensitive to the potential
rapid-onset antidepressant action induced by concomitant treatment with 5HT1A-receptor
antagonists [60,61]. The implication that the model involves primarily serotonergic mechanisms is supported by the observation that the effects of subchronic treatment with imipramine and mianserin were reverse by acute adminstration of the 5HT2-receptor antagonist
metergoline [35].
Although pharmacologically speciﬁc for antidepressants, the face validity of theolfactory bulbectomy model appears slight. Unlike the stress models, the bulbectomized
rat resembles an agitated hyposerotonergic, rather than a retarded, depression [158], but
beyond hyperactivity, it is difﬁcult to discern any further points of behavioral resemblance.
Indeed, increased irritability and aggression, together with exaggerated reactivity to auditory and tactile stimulation, may reﬂect additional septal damage. Nevertheless, bulbectomized rats do resemble depressed humans on a surprisingly wide range of peripheral
neurochemical and immunological markers, such as abnormalities of platelet 5HT transport and neutrophil phagocytosis [147].

526

C.

Willner and Mitchell

Waiting Behavior

To the extent that they appear to involve serotonergic mechanisms, two ﬁnal models may
be related to olfactory bulbectomy. These are two paradigms in which antidepressantsincrease the ability of rats to withhold responses.
In one paradigm (differential reinforcement of low rate–72 s; DRL–72 s), premature responding delays the delivery of reward; the ability of drugs to improve performance in this model has been claimed to be an efﬁcient antidepressant screening test[246], although this has been disputed [223]. In the second paradigm, a larger reward
may be earned by waiting; again, the improvement of performance in this model appears
to be a speciﬁc property of a wide range of antidepressants [28]. Drugs that possess
5HT1A-receptor agonist activity are antidepressant-like in both of these waiting paradigms[13,29,135,236], and in the DRL-72 test, antidepressant effects were blocked by 5HTreceptor antagonist [165]. The relevance of these behaviors to depression is unclear. In adifferent schedule designed to examine accurate estimation of time intervals, acute treatment with antidepressant drugs (imipramine, clomipramine, and zimeldine) failed to modify timing accuracy [20], suggesting that improvement in performance on DRL schedules,
including SSRIs [256], is most likey due to a reduced rate of lever pressing rather than
improved timing. It has been reported that antidepressant effects in the DRL vary considerably between rats of different strains, or rats of the same strain obtained from different
suppliers [15], and this may account for the discrepancies between different laboratories[223,246].
Clinical evidence strongly suggests that similar disorders of 5HT function cut acrossdiagnostic boundaries and are expressed as pathologically impulsive behavior rather thanas any particular disorder [257,290]. Indeed, mice lacking the 5HT1B receptor (5HT1B
knock-out mice) exhibit more impulsive aggressive behavior, drink more ethanol, andacquire cocaine self-administration faster than wild-type mice [42,243], which reﬂects (inpart at least) reduced 5HT function [77], and may provide an animal with addiction andmotor impulsivity. In vervet monkeys (Cercopithecus aethiops sabaeus), there appears to
be a clear inverse relationship between serotonin turnover and social impulsivity [80].
The inability to withhold responses in the two rodent waiting models may constitute instances of impulsive behavior and, as such, the effect of antidepressants in these paradigms
may not relate speciﬁcally to depression.

VII. GENOMIC MODELSIn this review, we have focused on behaviorally deﬁned animal models of depression,and exclude from consideration a number of older tests, now little used, based on interaction between antidepressants and a range of other pharmacological agents, such as reserpine, tetrabenazine, amphetamine, yohombine, apomorphine, and clonidine. Generally
speaking, the predictive validity of these tests is poor, and their face and construct validity
as simulations of depression is minimal or zero. Although still in use, this is largely conﬁned to mechanistic studies.
Of greater current interest, a number of genomic models have recently been examined for their possible relevance to depression. Although their success is as yet limited,
we review them here as potentially the shape of things to come.

Animal Models of Depression

527

A. HPA Transgenic
In depressive illness, the secretion of CRH from the paraventricular nucleus of the hypothalamus is under the control of a glucocorticoid receptor-mediated inhibitory feedback
system. Conditions of extreme, prolonged stress cause reduced sensitivity of the glucocorticoid receptor, thereby reducing the effectiveness of the feedback loop, resulting in hypercortisolemia. A transgenic mouse strain expressing glucocorticoid receptor antisense has
been described which exhibits dysfunction of the HPA axis in a manner similar to thatseen in depressive illness [195,220]. Chronic treatment with antidepressants reduces
plasma cortisol and ACTH levels [195,221] by increasing glucocorticoid-receptor mRNA
expression [17], with a subsequent elevation of glucocorticoid-receptor activity resulting
in increased sensitivity of the HPA axis to glucocorticoid negative feedback [18]. However, while behavioral and neuroendocrine responses to stress are modiﬁed in transgenic
mice [81,155], the direction of these changes is inconsistent with a model of depressive
illness: relative to wild-type controls, transgenic mice exhibit reduced immobility in theforced-swim test and less anxiety-related behavior on the elevated plus maze but increased
aggressive behavior [21,195]. All of these changes are in the direction opposite to those
expected.
B. 5HT Transporter Knockout
The serotonin reuptake transporter (5HTT) is pivotal in the inactivation and control ofserotonergic neurotransmission, and blockade of the serotonin transporter is the principal
target of the TCA, SSRI, and SNRI drugs. Investigations of subjects that lack the serotonergic transporter, while not a model of depression, may provide insight into the adaptive
mechanisms associated with a permanent lack of serotonin reuptake. Recent studies suggest that 5HTT knock-out mice show regional differences from wild-type mice in termsof 5HT1A-receptor protein and mRNA expression (reduced in dorsal raphe, hypothalamus,
amygdala, and septum, but increased in hippocampus [79,143,153], that are associatedwith reduced functional sensitivity to the hypothermic effects of the 5HT1A-receptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) [152]. Similarly, 5HT2A-receptor density is also reduced in 5HTT knock-out mice [237]. Interestingly, the desensitization of 5HT1A autoreceptors in 5HTT knock-out mice is further enhanced by exposure
to stressful conditions [143].
C. CRH Receptor Subtype Knockouts
CRH is a critical coordinator of the HPA axis and subtypes of CRH receptors, CRH-R1
and CRH-R2, are found throughout the central nervous system and peripheral tissue. CRH
has higher afﬁnity for the CRH-R1 receptor, while urocortin (a CRH-related peptide)
exhibits 40-fold selectivity for the CRH-R2 receptor. CRH-R1 knockout mice exhibit anxiolytic-like behavior, which may be due to impaired spatial recognition memory [56], together with characteristic responses to stress [265] indicative of disrupted HPA axis [254].
In contrast, CRH-R2 knockout mice exhibit increased anxiety-like behavior and are hypersensitive to stress [16].
D. Tachykinin Receptor Knockout
The NK1 receptor is expressed in brain areas associated with the control and managementof depressive illness, anxiety, stress, and sensitivity to the rewarding properties of food and528

Willner and Mitchelldrugs of abuse. Indeed, antagonists at the NK1 receptor have been suggested as potential
antidepressant drugs with a novel mode of action [89,240,241]. The NK1-receptor knockout mouse is not an animal model of depression. Rather, these mice show behavioral
changes similar to those elicited by antidepressants in normal mice, including a decreasein neonatal vocalization following maternal separation, decreased aggressive behavior in
the resident-intruder test, and decreased immobility in the forced-swim and tail-suspension
tests [241]. NK1-receptor knock-out mice also exhibit a loss of the rewarding propertiesof morphine, together with reduced physical response to opiate withdrawal, but their response to cocaine is unchanged [197], suggesting that this may reﬂect a speciﬁc interaction
with opioid systems, rather than a general effect on brain reward mechanisms.
VIII. OBSERVATIONSAnimal models of depression have traditionally been deﬁned primarily by their responsiveness to antidepressant drugs, and, consequently, this term encompasses a range ofdifferent procedures that are difﬁcult to subsume within a simple conceptual structure.
Previous reviews [291] have suggested that a broad distinction can be made between two
groups of models, which is preserved in the present review. There are various, partiallyoverlapping, ways of deﬁning the two groups: by etiology, symptomatology, and physiological basis. Thus, one group of models, here deﬁned as models of anhedonia (although
this is not demonstrated for the forced-swim test or submissive behavior models) arebrought about largely by stress (although this is difﬁcult to argue in the case of the neonatal
antidepressant model), and reﬂect primarily impairments of catecholaminergic transmission (to the extent that the physiological substrates are known). The second group (othermodels) may involve aspects of impulsive behavior, may be related to social isolation,and may reﬂect impairment primarily of 5HT. The tentative nature of the generalizations
is all too obvious. However, they do provide hypotheses that bring animal models into
contact in traditional monoamine theories of depression, and suggest ways in which thosetheories might be tested and ampliﬁed [287,291]. It does seem important that the diversityof depressive symptomatology is matched by a similar diversity in the phenomenology
expressed in animal models, and this consideration may justify the continued use of models
that have little face or construct validity.
It was noted earlier that while the etiology of depression probably involves multiple
factors, animal models have tended to be unifactorial. An interesting trend is that symptoms characteristic, or at least reminiscent, of depression may be generated in animalmodels in various ways. Thus, anhedonia is subject to genetic inﬂuences (strain differencesin the anhedonic effects of uncontrollable shock or chronic mild stress) [232,304]; epigenetic inﬂuences (neonatal antidepressant treatment) [278]; acute severe stress (uncontrollable shock) [304]; chronic mild stress [299]; and psychomotor stimulant withdrawal[131]. Similarly, immobility time in the forced-swim test is increased by genetic inﬂuences(strain differences) [210]; epigenetic inﬂuences (neonatal antidepressant treatment) [110];acute stress (defeat or uncontrollable shock) [134,284]; and chronic stress (defeat) [139].
Studies of combinations of etiological factors are clearly warranted: an understanding of
the manner in which different factors (in particular, predisposing and precipitating factors)
interact to generate depression-like symptoms in animals models would be of considerable
interest to both basic researchers and clinicians.
It remains the case that the greatest immediate contribution of animal models ofdepression is likely to be in relation to the elucidation of the mechanisms of action ofAnimal Models of Depression529

antidepressant drugs. Thirty years of clinical experience have given rise to two widely
accepted axioms: that only rarely do antidepressants cause discernible clinical improvement within the ﬁrst 2 weeks of treatment and that they are devoid of mood-elevating
effects in normal human subjects. The clinical requirement for chronic treatment regimes
has led to a considerable literature describing the effects of chronic antidepressant administration in normal animals, and numerous changes in pre- and/or postsynaptic receptor
function have been reported in a variety of systems. These descriptive studies are an essential ﬁrst step toward establishing mechanisms of antidepressant action. However, the inability to determine which of the many effects of antidepressants are responsible for their
therapeutic actions constitutes a fundamental limitation of this approach, which has notbeen widely recognized. The development of chronic animal models, in which an abnormal
state is induced and maintained for a prolonged period during which therapy can be administered, provides a powerful methodology for investigating these problems.
Although they have as yet made little impact, it is to be expected that genomic
models will play a signiﬁcant role in these developments. However, it will be important
not to lose sight of the fact that genetic and genomic models are mostly of relevance tothe predisposition to depression rather than to precipitation of depressive episode. Studies
in which valid and realistic models of predisposition to depression are combined withvalid and realistic precipitation models are awaited with interest.
Finally, although this review has not been concerned with the problem of screening
for antidepressant activity, it is clear that some of the models discussed could proﬁtably
be incorporated into antidepressant screening programs. It has traditionally been a major
consideration in the design of antidepressant screening tests that they respond to acute or
subacute drug administration. As a direct consequence, they are incapable, by virtue of
their design, of responding to the major current challenge of discovering new antidepressants that have a shorter onset of action. By contrast, it is implicit in their protracted timecourse that chronic realistic animal models do have the capacity to detect a rapidly acting
novel antidepressant. In fact, most pharmaceutical companies have now abandoned thehigh volume, random screening approach in favor of the development of a small numberof compounds speciﬁcally designed to meet predetermined pharmacological criteria. In
such a program, the place of behavioral screening methods shifts from the discovery phaseto the development phase, and the logistical disadvantages of using complex, chronicmodels are small relative to the costs of testing an ineffective drug in the clinic.
REFERENCES
1. Abramson LY, Seligman MEP. Modeling psychopathology in the laboratory: history andrationale. In: Maser JD, Seligman MEP, eds. Psychopathology: Experimental Models. San
Francisco: Freeman, 1978:1–26.
2. Abramson LY, Seligman MEP, Teasdale JD. Learned helplessness in humans: critique andreformulation. J Abnorm Psychol 1978; 87:49–74.
3. Abramson LY, Metalsky G, Alloy LB. Hopelessness depression: a theory-based subtype of
depression. Psychol Revs 1989; 96:358–372.
4. Akiskal HS. Interaction of biologic and psychologic factors in the origin of depressive disorders. Acta Psychiatr Scand 1985; 71:131–139.
5. Akiskal HS. A developmental perspective on recurrent mood disorders: a review of studies
in man. Psychopharmacol Bull 1986; 22:579–586.
6. Albonetti ME, Farabollini F. Social stress by repeated defeat: effects on social behaviour
and emotionality. Behav Brain Res 1994; 62:187–193.

530

Willner and Mitchell

7. Alonso SJ, Castellano MA, Quintero M, Navarro E. Action of antidepressant drugs on maternal stress-induced hypoactivity in female rats. Methods Find Exp Clin Pharmacol 1999; 21:
291–295.
8. Alonso SJ, Damas C, Navarro E. Behavioral despair in mice after prenatal stress. J Physiol
Biochem 2000; 56:77–82.
9. Aneshensel CS, Stone JD. Stress and depression: a test of the buffering model of social
support. Arch Gen Psychiatr 1982; 39:1392–1396.
10. Anisman HA, Zacharko RM. Depression: the predisposing inﬂuence of stress. Behav Brain
Sci 1982; 5:89–137.
11. Anisman H, Irwin J, Sklar LS. Deﬁcits of escape performance following catecholamine
depletion: implications for behavioural deﬁcits induced by uncontrollable stress. Psychopharmacology 1979; 64:163–170.
12. Antelman SM, Eichler AJ, Black CA, Kocan D. Interchangeability of stress and amphetamine
sensitization. Science 1980; 207:329–331.
13. Archer T. Animal models and drug screens for depression: pragmatism and the validity requirement. In Olivier B, Mos J, Slangen J, eds. Animal Models in Psychopharmacology.
Basel: Birkhauser, 1991:243–250.
14. Atrens DM. Self-stimulation and psychotropic drugs: a methodological and conceptual critique. In: Bond NS, ed. Animal Models in Psychopathology. Sydney: Academic, 1984:227–
256.
15. Balcells-Olivero M, Cousins MS, Seiden LS. Holtzman and Harlan Sprague-Dawley rats:
differences in DRL 72-sec performance and 8-hydroxy-di-propylamino tetralin-induced hypothermia. J Pharmacol Exp Ther 1998; 286:742–752.
16. Bale TL, Contarino A, Smith GW, Chan R, Gold LH, Sawchenko PE, Koob GF, Vale WW,
Lee KF. Mice deﬁcient for corticotropin-releasing hormone receptor-2 display anxiety-likebehaviour and are hypersensitive to stress. Nat Genet 2000; 24:410–414.
17. Barden N. Modulation of glucocorticoid receptor gene expression by antidepressant drugs.
Pharmacopsychiatry 1996; 29:12–22.
18. Barden N. Regulation of corticosteroid receptor gene expression in depression and antidepressant action. J Psychiatry Neurosci 1999; 24:25–39.
19. Barrett RJ, White DK. Reward system depression following chronic amphetamine: antagonism by haloperidol. Pharmacol Biochem Behav 1980; 13:555–559.
20. Bayley PJ, Bentley GD, Dawson GR. The effects of selected antidepressant drugs on timing
behaviour in rats. Psychopharmacology (Berl) 1998; 136:114–122.
21. Beaulieu S, Rousse I, Gratton A, Barden N, Rochford J. Behavioural characterization of atransgenic mouse model of impaired type II glucocorticoid receptor function. Soc Neurosci
Abstr 1993; 19:489.8.
22. Beck AT. Depression: Clinical, Experimental and Theoretical Aspects. New York: Harper& Row, 1967.
23. Berger BD, Schuster R. An animal model of social interaction: implications for the analysis
of drug action. In: Spiegelstein MY, Levy A, eds. Behavioral Models and the Analysis ofDrug Action. Amsterdam: Elsevier, 1982:415–428.
24. Berton O, Durand M, Aguerre S, Mormede P, Chaouloff F. Behavioral, neuroendocrine andserotonergic consequences of single social defeat and repeated ﬂuoxetine pretreatment in the
Lewis rat strain. Nueroscience 1999; 92:327–341.
25. Besson A, Privat AM, Eschalier A, Fialip J. Effects of morphine, naloxone and their interaction in the learned-helplessness paradigm in rats. Psychopharmacology (Berl) 1996; 123:71–
78.
26. Besson A, Privat AM, Eschalier A, Fialip J. Reversal of learned helplessness by morphine in rats:
involvement of a dopamine mediation. Pharmacol Biochem Behav 1998; 60:519–525.
27. Besson A, Privat AM, Eschalier A, Fialip J. Dopaminergic and opioidergic mediations ofAnimal Models of Depression

28.

29.
30.

31.

32.
33.
34.

35.

36.

37.
38.
39.
40.
41.
42.
43.

44.
45.
46.
47.
48.
49.

531

tricyclic antidepressants in the learned helplessness paradigm. Pharmacol Biochem Behav
1999; 64:541–548.
Bizot JC, Thiebot MH, Le Bihan C, Soubrie P, Simon P. Effects of imipramine-like drugs andserotonin uptake blockers on delay of reward in rats: possible implication in the behavioral
mechanism of action of antidepressants. J Pharmacol Exp Ther 1998; 286:1144–1151.
Bizot JC, Thiebot MH, Puech AJ. Effects of 5-HT-related drugs on waiting capacities inrats. Psychopharmacology 1998; 96:S5.
Blanc G, Herve D, Simon H, Lisoprawski A, Glowinski J, Tassin JP. Response to stress of
mesocortical frontal dopaminergic neurons in rats after long-term isolation. Nature 1980;
284:265–276.
Bodnoff SR, Suranyi-Codotte B, Aitken DH, Quirion R, Meaney MY. The effects of chronic
antidepressant treatment in an animal model of anxiety. Psychopharmacology 1988; 95:298–
302.
Borsini F. Role of serotonergic system in the forced swimming test. Neurosci Biobehav Rev
1995; 19:377–395.
Borsini F, Meli A. Is the forced swimming test a suitable model for revealing antidepressantactivity? Psychopharmacology 1988; 94:147–160.
Borsini F, Cesana R, Kelly J, Leonard BE, McNamara M, Richards J, Seiden L. BIMT 17:
a putative antidepressant with a fast onset of action? Psychopharmacology (Berl) 1997; 134:
378–386.
Broekkamp CL, Garrigou D, Lloyd KG. Serotonin-mimetic and antidepressant drugs on passive avoidance learning by olfactory bulbectomized rats. Pharmacol Biochem Behav 1980;
13:643–646.
Broekkamp CL, O’Connor WT, Tonnaer JADM, Rijk HW, Van Delft AML. Corticosterone,choline acetyltransferase and noradrenaline levels in olfactory bulbectomized rats in relation
to changes in passive avoidance acquisition and open ﬁeld activity. Physiol Behav 1986; 37:
429–434.
Brown GW (1989). A psychosocial view of depression. In: Bennett DH, Freeman H, eds.
Community Psychiatry. London: Churchill-Livingstone, 1989:71–114.
Brown GW, Harris T. Social Origins of Depression. London: Tavistock, 1978.
Brown GW, Harris T, eds. Life Events and Illness. New York: Guilford Press, 1988.
Brown GW, Sklair F, Harris TO, Birley JLT. Life events and psychiatric disorders. I. Somemethodological issues. Psychol Med 1973; 3:74–87.
Brown L, Rosellini RA, Samuels OB, Riley EP. Evidence for a serotonergic mechanism of
the learned helplessness phenomenon. Pharmacol Biochem Behav 1982; 17:877–883.
Brunner D, Hen R. Insights into the neurobiology of impulsive behavior from serotoninreceptor knockout mice. Ann NY Acad Sci 1997; 836:81–105.
Butterweck V, Wall A, Lieﬂander-Wulf U, Winterhoff H, Nahrstedt A. Effects of the total
extract and fractions of Hypericum perforatum in animal assays for antidepressant activity.
Pharmacopsychiatry 1997; 30(suppl 2):117–124.
Cairncross KD, Cox B, Forster C, Wren AF. Olfactory projection systems, drugs and behaviour: a review. Psychoneuroendocrinology 1979; 4:253–272.
Carroll BJ. The dexamethasone suppression test for melancholia. Br J Psychiatr 1982; 140:
292–304.
Cassens GP, Actor C, Kling M, Schildkraut JJ. Amphetamine withdrawal effects thresholdof intracranial self-stimulation. Psychopharmacology 1981; 73:318–322.
Cavoy A, Ennaceur A, Delacour J. Effects of piracetam on learned helplessness in rats. Physiol Behav 1988; 42:545–549.
Cheeta S, Broekkamp C, Willner P. Stereospeciﬁc reversal of stress-induced anhedonia bymianserin and its (⫹)-enantiomer. Psychopharmacology 1994; 116:523–528.
Christensen AV, Geoffroy M. The effect of different serotonergic drugs in the learned help-

532

50.
51.

52.

53.
54.

55.

56.

57.

58.
59.
60.

61.

62.

63.

64.

65.

66.
67.

Willner and Mitchelllessness model of depression. In: Olivier B, Mos J, Slangen J, eds. Animal Models in Psychopharmacology. Basel: Birkhauser, 1991:205–209.
Clarke AS, Schneider ML. Prenatal stress has long-term effects on behavioral responses tostress in juvenile rhesus monkeys. Dev Psychobiol 1993; 26:293–304.
Cobain MR, Forster EA, Mitchell PJ, Fletcher A. Effect of acute treatment with selective
5-HT1A ligands on the agonistic behaviour of rats. J Psychopharmacology Abstract Book
BAP/ISBP meeting, 1994. Abstract 24.
Cobain MR, Forster EA, Mitchell PJ, Fletcher A. The antidepressant effect of 5-HT1A ligands
is mediated by agonist activity at 5-HT1A receptors. J Psychopharmacology Abstract Book
BAP/ISBP meeting, 1994. Abstract 25.
Coccaro EF, Kavoussi RJ. Fluoxetine and impulsive aggressive behavior in personality-disordered subjects. Arch Gen Psychiatry 1997; 54:1081–1088.
Connor TJ, Kelliher P, Harkin A, Kelly JP, Leonard BE. Reboxetine attenuates forced swim
test-induced behavioural and neurochemical alterations in the rat. Eur J Pharmacol 1999;
379:125–133.
Connor TJ, Kelliher P, Shen Y, Harkin A, Kelly JP, Leonard BE. Effect of subchronic antidepressant treatments on behavioral, neurochemical, and endocrine changes in the forced-swim
test. Pharmacol Biochem Behav 2000; 65:591–597.
Contarino A, Dellu F, Koob GF, Smith GW, Lee KF, Vale W, Gold LH. Reduced anxietylike and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1.
Brain Res 1999; 835:1–9.
Coplan JD, Andrews MW, Rosenblum LA, Owens MJ, Friedman S, Gorman JM, Nemeroff
CB. Persistent elevations of cerebrospinal ﬂuid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors—implications for the pathophysiology of mood and anxiety disorders. Proc Natl Acad Sci 1996; 93:1619–1623.
Coventry TL, D’Aquila PS, Brain P, Willner P. Social inﬂuences on morphine conditioned
place preference. Behav Pharmacol 1997; 6–7:575–584.
Cryan JF, Lucki I. Antidepressant-like behavioral effects mediated by 5-hydroxytryptamine(2C) receptors. J Pharmacol Exp Ther 2000; 295:1120–1126.
Cryan JF, McGrath C, Leonard BE, Norman TR. Combining pindolol and paroxetine in an
animal model of chronic antidepressant action—can early onset of action be detected? Eur
J Pharmacol 1998; 352:23–28.
Cryan JF, McGrath C, Leonard BE, Norman TR. Onset of the effects of the 5-HT1A antagonist, WAY-100635, alone, and in combination with paroxetine, on olfactory bulbectomy and
8-OH-DPAT-induced changes in the rat. Pharmacol Biochem Behav 1999; 63:333–338.
Cuomo V, Cagiano R, Brunello N, Fumagalli R, Racagni G. Behavioural changes after acuteand chronic administration of typical and atypical antidepressants in rat: interactions withreserpine. Neurosci Lett 1983; 40:315–319.
Danysz W, Archer T, Fowler CJ. Screening for new antidepressant compounds. In: Willner
P, ed. Behavioural Models in Psychopharmacology: Theoretical, Industrial and Clinical Perspectives. Cambridge: Cambridge University Press, 1991:126–156.
D’Aquila P, Monleon S, Borsini F, Brain P, Willner P. Anti-anhedonic actions of the novel
serotonergic agent ﬂibanserin, a potential rapidly-acting antidepressant. Eur J Pharmacol
1997; 340:121–132.
David DJ, Nic Dhonnchadha BA, Jolliet P, Hascoet M, Bourin M. Are there gender differences in the temperature proﬁle of mice after acute antidepressant administration and exposure to two animal models of depression? Behav Brain Res 2001; 119:203–211.
De Montis MG, Gambarana C, Meloni D. Alpha-methyl-para-tyrosine antagonizes the effectof chronic imipramine on learned helplessness in rats. Eur J Pharmacol 1993; 249:179–183.
De Montis MG, Gambarana C, Ghiglieri O, Tagliamonte A. Reversal of stable behaviouralmodiﬁcations through NMDA receptor inhibition in rats. Behav Pharmacol 1995; 6:562–
567.

Animal Models of Depression

533

68. Desan PH, Silbert LH, Maier SF. Long-term effects of inescapable stress on daily running
activity and antagonism by desipramine. Pharmacol Biochem Behav 1988; 30:21–29.
69. Detke MJ, Rickels M, Lucki I. Active behaviors in the rat forced swimming test differentially
produced by serotonergic and noradrenergic antidepressants. Psychopharmacology 1995;
121:66–72.
70. Di Chiara G, Loddo P, Tanda G. Reciprocal changes in prefrontal and limbic dopamine
responsiveness to aversive and rewarding stimuli after chronic mild stress: Implications forthe psychobiology of depression. Biol Psychiatr 1999; 46:1624–1633.
71. Dixon AK, Fisch HU, Huber C, Walser A. Ethological studies in animals and man: theiruse in psychiatry. Pharmacopsychiatry 1989; 22(suppl 1):44–50.
72. Drevets WC, Raichle ME. Reciprocal suppression of regional cerebral blood ﬂow during
emotional versus higher cognitive processes: Implications for interactions between emotion
and cognition. Cogn Emotion 1998; 12:353–385.
73. Dziedzicka-Wasylewska M, Willner P, Papp M. Changes in dopamine receptor mRNA expression following chronic mild stress and chronic antidepressant treatment. Behav Pharmacol 1997; 8:607–618.
74. Edwards E, Johnson J, Anderson D, Turano P, Henn FA. Neurochemical and behavioral
consequences of mild uncontrollable shock: effects of PCPA. Pharmacol Biochem Behav
1986; 25:415–421.
75. Emrich HM, Vogt P, Herz A. Possible antidepressant effects of opioids: action of buprenorphine. Ann NY Acad Sci 1983; 398:108–112.
76. Evenden J. Impulsivity: a discussion of clinical and experimental ﬁndings. J Psychopharmacol 1999; 13:180–192.
77. Evenden J. Varieties of impulsivity. Psychopharmacology (Berl) 1999; 146:348–361.
78. Everitt BJ, Keverne EB. Models of depression based on behavioural observations of experimental animals. In: Paykel ES, Coppen A, eds. Psychopharmacology of Affective Disorders.
Oxford: Oxford University Press, 1979:41–59.
79. Fabre V, Beaufour C, Evrard A, Rioux A, Hanoun N, Lesch KP, Murphy DL, Lanfumey L,
Hamon M, Martres MP. Altered expression and functions of serotonin 5-HT1A and 5-HT1B
receptors in knock-out mice lacking the 5-HT transporter. Eur J Neurosci 2000; 12:2299–
2310.
80. Fairbanks LA, Melega WP, Jorgensen MJ, Kaplan JR, McGuire MT. Social impulsivity inversely associated with CSF 5-HIAA and ﬂuoxetine exposure in vervet monkeys. Neuropsychopharmacology 2001; 24:370–378.
81. Farisse J, Boulenguez P, Semont A, Hery F, Barden N, Faudon M, Hery M. Regional serotonin metabolism under basal and restraint stress conditions in the brain of transgenic micewith impaired glucocorticoid receptor funtion. Neuroendocrinology 1999; 70:413–421.
82. Fava M, Rosenbaum JF. Psychopharmacology of pathologic aggression. Harvard Rev Psychiatry 1993; 1:244–246.
83. Ferrari F, Cassinadri M, Tartoni PL, Tampieri A. Effects of B-HT 920 in the tail-suspension
test. Pharmacol Res 1991; 24:75–81.
84. Fibiger HC. The dopamine hypotheses of schizophrenia and depression: Contradictions andspeculations. In: Willner P, Scheel-Kruger J, eds. The Mesolimbic Dopamine System: From
Motivation to Action. Chichester: John Wiley and Sons, 1991:615–637.
85. File SE, Tucker JC. Behavioral consequences of antidepressant treatment in rodents. Neurosci
Biobehav Rev 1986; 10:123–134.
86. Fontana DJ, Carbary TJ, Commisaris RL. Effects of acute and chronic anti-panic drug administration on conﬂict behavior in the rat. Psychopharmacology 1989; 98:157–162.
87. Frank MG, Heller HC. Neonatal treatments with the serotonin uptake inhibitors clomipramineand zimelidine, but not the noradrenaline uptake inhibitor desipramine, disrupt sleep patterns
in adult rats. Brain Res 1997; 768:287–293.
88. Frazer A., Lucki I, Sills M. Alterations in monoamine-containing neuronal function due to

534

89.

90.

91.

92.

93.

94.

95.
96.

97.

98.
99.
100.
101.
102.

103.

104.

105.
106.
107.

Willner and Mitchelladministration of antidepressants repeatedly to rats. Acta Pharmacol Toxicol 1985; 56(Suppl
1):21–34.
Froger N, Gardier AM, Moratalla R, Alberti I, Lena I, Boni C, De Felipe C, Hunt SP, Jacquot
C, Hamon M, Lanfumey L. 5-Hydroxytryptamine (5-HT)1A autoreceptor adaptive changes
in P (neurokinin 1) receptor knock-out mice mimic antidepressant desensitization. J Neurosci
2001; 21:8188–8197.
Fujishiro J, Imanishi T, Baba J, Kosaka K. Comparison of noradrenergic and serotonergic
antidepressants in reducing immobility time in the tail suspension test. Jpn J Pharmacol 2001;
85:327–330.
Gambarana C, Ghiglieri O, Tagliamonte A, D’Alessandro N, de Montis MG. Crucial roleof D1 dopamine receptors in mediating the antidepressant effect of imipramine. Pharmacol
Biochem Behav 1995; 50:147–151.
Gambarana C, Ghiglieri O, de Montis MG. Desensitization of the D1 dopamine receptors
in rats reproduces a model of escape deﬁcit reverted by imipramine, ﬂuoxetine and clomipramine. Prog Neuropsychopharmacol Biol Psychiatry 1995; 19:741–755.
Gambarana C, Ghiglieri O, Tolu P, De Montis MG, Giachetti D, Bombardelli E, Tagliamonte
A. Efﬁcacy of an Hypericum perforatum (St. John’s wort) extract in preventing and revertinga condition of escape deﬁcit in rats. Neuropsychopharmacology 1999; 21:247–257.
Gambarana C, Masi F, Tagliamonte A, Scheggi S, Ghiglieri O, De Montis MG. A chronic
stress that impairs reactivity in rats also decreases dopaminergic transmission in the nucleus
accumbens: A microdialysis study. J Neurochem 1999; 72:2039–2046.
Gardner R. Mechanisms in manic-depressive disorder: An evolutionary model. Arch Gen
Psychiatr 1982; 39:1436–1441.
Gentsch C, Lichsteiner M, Feer H. Competition for sucrose pellets in triads of male Wistar
rats: effects of acute and subchronic chlordiazepoxide. Psychopharmacology 1990; 100:530–
534.
Ghiglieri O, Gambarana C, Scheggi S, Tagliamonte A, Willner P, De Montis G. Palatable
food induces an appetitive behaviour in satiated rats which can be inhibited by chronic stress.
Behav Pharmacol 1997; 8:619–628.
Gibson WE, Reid LD, Sakai M, Porter PB. Intracranial reinforcement compared with sugarwater reinforcement. Science 1965; 148:1357–1358.
Gilbert P, Allan S. The role of defeat and entrapment (arrested ﬂight) in depression: an
exploration of an evolutionary view. Psychol Med 1998; 28:585–598.
Giral P, Martin P, Soubrie P, Simon P. Reversal of helpless behaviour in rats by putative
5HT1A agonists. Biol Psychiatry 1988; 23:237–242.
Glazer HI, Weiss JM. Long-term interference effect: an alternative to “learned helplessness.”
J Exp Psychol: Anim Behav Proc 1976; 2:201–213.
Hansen HH, Sanchez C, Meier E. Neonatal administration of the selective serotonin reuptake
inhibitor Lu 10-134-C increases forced swimming-induced immobility in adult rats: a putative animal model of depression? J Pharmacol Exp Ther 1997; 283:1333–1341.
Harkin AJ, Bruce KH, Craft B, Paul IA. Nitric oxide synthase inhibitors have antidepressantlike properties in mice. 1: Acute treatments are active in the forced swim test. Eur J Pharmacol
1998; 372:207–213.
Harkin A, Kelly JP, McNamara M, Connor TJ, Dredge K, Redmond A, Leonard BE. Activity
and onset of action of reboxetine and effect of combination with sertraline in an animalmodel of depression. Eur J Pharmacol 1999; 364:123–132.
Henn FA, McKinney WT. Animal models in psychiatry. In: Meltzer HY, ed. Psychopharmacology: The Third Generation of Progress. New York: Raven, 1987:697–704.
Henry JP. The relation of social to biological processes in disease. Soc Sci Med 1982; 16:
369–380.
Hernando F, Fuentes JA, Roques BP, Ruiz-Gayo M. The CCKB receptor antagonist, L-

Animal Models of Depression

108.
109.
110.

111.

112.
113.
114.

115.
116.
117.
118.
119.
120.
121.
122.
123.
124.

125.

126.
127.
128.
129.

535

365,260, elicits antidepressant-type effects in the forced-swim test in mice. Eur J Pharmacol
1994; 261:257–263.
Hernando F, Fuentes JA, Ruiz-Gayo M. Impairment of stress adaptive behaviours in rats by
the CCKA receptor antagonist, devazepide. Br J Pharmacol 1996; 118:400–406.
Hersen M, Bellack AS, Himmelhoch JM, Thase ME. Effect of social skill training, amitriptyline and psychotherapy in unipolar depressed women. Behav Therapy 1984; 15:21–40.
Hilakivi LA, Hilakivi I. Increased adult behavioural despair in rats neonatally exposed todesipramine or zimelidine: An animal model of depression. Pharmacol Biochem Behav 1987;
28:267–269.
Hoebel BG. Brain-stimulation reward and aversion in relation to behaviour. In: WauquierA, Rolls E, eds. Brain-Stimulation Reward. New York: North Holland/American Elsevier,
1976: 331–372.
Hollander E. Managing aggressive behavior in patients with obsessive-compulsive disorderand borderline personality disorder. J Clin Psychiatry 1999; 60:S38–S44.
Hrdina PD, Von Kulmiz P, Stretch R. Pharmacological modiﬁcation of experimental depression in infant macaques. Psychopharmacology 1979; 64:89–93.
Jackson RL, Minor TR. Effects of signaling inescapable shock on subsequent escape learning:
Implications for theories of coping and “learned helplessness.” J Exp Psychol: Anim Behav
Proc 1988; 14:390–400.
Jackson RL, Maier SF, Rapoport PM. Exposure to inescapable shock produces both activity
and associative deﬁcits in rats. Learn Motiv 1978; 9:69–98.
Jesberger JA, Richardson JS. Effects of antidepressant drugs on the behavior of olfactorybulbectomized and sham-operated rats. Behav Neurosci 1986; 100:256–274.
Joly D, Sanger DJ. The effects of ﬂuoxetine and zimelidine on the behavior of olfactorybulbectomized rats. Pharmacol Biochem Behav 1986; 24:199–204.
Joly D, Sanger DJ. Social competition in rats: a test sensitive to acutely administered anxiolytics. Behav Pharmacol 1991; 2:205–213.
Kaplan SM, Kravetz RS, Ross WD. The effects of imipramine on the depressive componentsof medical disorders. Proc Third World Congr Psychiatry 1961; 2:1362–1367.
Katz RJ. Animal models and human depressive disorders. Neurosci Biobehav Rev 1981; 5:
231–246.
Katz RJ. Animal model of depression: pharmacological sensitivity of a hedonic deﬁcit. Pharmacol Biochem Behav 1982; 16:965–968.
Katz RJ, Roth KA, Carroll BJ. Acute and chronic stress effects on open ﬁeld activity in the
rat: implications for a model of depression. Neurosci Biobehav Rev 1981; 5:247–251.
Kawashima K, Araki H, Aihara H. Effect of chronic administration of antidepressants on
duration of immobility in rats forced to swim. Jpn J Pharmacol 1986; 40:199–204.
Keeney AJ, Hogg S. Behavioural consequences of repeated social defeat in the mouse: preliminary evaluation of a potential animal model of depression. Behav Pharmacol 1999; 10:753–764.
Keeney AJ, Hogg S, Marsden CA. Alterations in core body temperature, locomotor activity,and corticosterone following acute and repeated social defeat of male NMRI mice. Physiol
Behav 2001; 74:177–184.
Kelly JP, Wrynn AS, Leonard BE. The olfactory bulbectomized rat as a model of depression:
an update. Pharmacol Ther 1997; 74:299–316.
King JA, Abend S, Edwards E. Genetic predisposition and the development of posttraumaticstress disorder in an animal model. Biol Psychiatry 2001; 50:231–237.
Kitada Y, Miyauchi T, Satoh A, Satoh S. Effects of antidepressants in the rat forced swimming test. Eur J Pharmacol 1981; 72:145–152.
Kokkinidis L, Zacharko RM. Response sensitization and depression following long-term amphetamine treatment in a self-stimulation paradigm. Psychopharmacology 1980; 68:73–76.

536

Willner and Mitchell

130. Kokkinidis L, Zacharko RM, Predy PA. Post-amphetamine depression of self-stimulation
responding from the substantia nigra: reversal by tricyclic antidepressants. Pharmacol Biochem Behav 1980; 13:379–383.
131. Koob GF. Anhedonia as an animal model of depression. In: Koob GF, Ehlers CL, Kupfer
DJ, eds. Animal Models of Depression. Boston: Birkhauser, 1989:162–183.
132. Koolhaas JM, Hermann PM, Kemperman C, Bohus B, van der Hoofdakker RH, Beersma
DGM. Single social defeat in male rats induces a gradual but long lasting behavioral change:a model of depression? Neurosci Res Com 1990; 7:35–41.
133. Kornetsky C, Esposito RU. Reward and detection thresholds for brain stimulation: dissociative effects of cocaine. Brain Res 1981; 209:496–500.
134. Korte SM, Smit J, Bouws GAH, Koolhaas JM, Bohus B. Neuroendocrine evidence for hypersensitivity in serotonergic neuronal system after psychosocial stress of defeat. In: Olivier B,
Mos J, Slangen J, eds. Animal Models in Psychopharmacology. Basel: Birkhauser, 1991:
199–203.
135. Kostowski W, Dyr W, Krzascik P, Jarbe T, Archer T. 5-Hydroxytryptamine1A receptor agonists in animal models of depression and anxiety. Pharmacol Toxicol 1992; 71:24–30.
136. Kraemer GW, Ebert MH, Lake CR, Mckinney WT. Hypersensitivity to d-amphetamine several years after early social deprivation in rhesus monkeys. Psychopharmacology 1984; 82:
266–271.
137. Kraemer GW, Ebert MH, Lake CR, McKinney WT. Cerebrospinal ﬂuid measures of neurotransmitter changes associated in the pharmacological alteration of the despair response tosocial separation in rhesus monkeys. Psychiatr Res 1984; 11:303–315.
138. Kraemer GW, Ebert MH, Schmidt DE, McKinney WT. A longitudinal study of the effectof different rearing conditions on cerebrospinal ﬂuid norepinephrine and biogenic amine metabolism in rhesus monkeys. Neuropsychopharmacology 1989; 2:175–189.
139. Kudryatseva NN, Bakshtanovskaya IV, Koryakina LA. Social model of depression in miceof C57BL/6J strain. Pharmacol Biochem Behav 1991; 38:315–320.
140. Kumar V, Singh PN, Bhattacharya SK. Anti-stress activity of Indian Hypericum perforatum
L. Ind J Exp Biol 2001; 39:344–349.
141. Kupfer DJ, Thase ME. The use of the sleep laboratory in the diagnosis of affective disorders.
Psychiatr Clin North Am 1983; 6:3–25.
142. Ladd CO, Owens MJ, Nemeroff CB. Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology 1996; 137:1212–1218.
143. Lanfumey L, Mannoury La Cour C, Froger N, Hamon M. 5-HT-HPA interactions in twomodels of transgenic mice relevant to major depression. Neurochem Res 2000; 25:1199–
1206.
144. Lehr E. Distress-call reactivation in isolated chicks: a behavioural indicator with high selectivity for antidepressants. Psychopharmacology 1989; 97:145–146.
145. Leith NJ, Barrett RJ. Amphetamine and the reward system: evidence for tolerance and postdrug depression. Psychopharmacology 1976; 46:19–25.
146. Leith NJ, Barrett RJ. Effects of chronic amphetamine or reserpine on self-stimulation: animalmodel of depression? Psychopharmacology 1980; 72:9–15.
147. Leonard B. The olfactory bulbectomized rat as model of depression. Eur Neuropsychopharmacol 1991; 1:297–298.
148. Lewinsohn PM. A behavioural approach to depression. In: Friedman RJ, Katz MM, eds. The
Psychology of Depression: Contemporary Theory and Research. New York: Winston/Wiley,
1974:157–185.
149. Lewis JK, McKinney WT. Effects of electroconvulsive shock on the behaviour of normal
and abnormal rhesus monkeys. Behav Psychiatr 1976; 37:687–693.
150. Lewis JK, McKinney WT, Young LD, Kraemer GW. Mother-infant separation in rhesus
monkeys as a model of human depression: A reconsideration. Arch Gen Psychiatr 1976; 33:
699–705.

Animal Models of Depression

537

151. Lewis JW, Cannon JT, Liebeskind JC. Opioid and non-opioid mechanisms of stress-induced
analgesia. Science 1980; 208:623–625.
152. Li Q, Wichems C, Heils A, Van De Kar LD, Lesch KP, Murphy DL. Reduction of
5-hydroxytryptamine (5-HT)1A-mediated temperature and neuroendocrine responses and 5HT1A binding sites in 5-HT transporter knockout mice. J Pharmacol Exp Ther 1999; 291:
999–1007.
153. Li Q, Wichems C, Heils A, Lesch KP, Murphy DL. Reduction in the density and expression,
but not G-protein coupling, of serotonin receptors (5-HT1A) in 5-HT transporter knock-out
mice: gender and brain region differences. J Neurosci 2000; 20:7888–7895.
154. Linthorst AC, Flachskamm C, Barden N, Holsboer F, Reul JM. Glucocorticoid receptor impairment alters CNS responses to a psychological stressor: an in vivo microdialysis study
in transgenic mice. Eur J Neurosci 2000; 12:283–291.
155. Lloyd C. Life events and depressive disorder reviewed. Arch Gen Psychiatr 1980; 37:529–
548.
156. Lloyd KG, Garrigou D, Broekkamp CLE. The action of monoaminergic, cholinergic andgabaergic compounds in the olfactory bulbectomized rat model of depression. In: Langer
SZ, Takahashi R, Segawa T, Briley M, eds. New Vistas in Depression. New York: Pergamon
Press, 1982:179–186.
157. Lumia AR, Teicher MH, Salchli F, Ayers E, Possidente B. Olfactory bulbectomy as a model
for agitated hyposerotonergic depression. Brain Res 1992; 587:181–185.
158. Lumley LA, Charles RF, Charles RC, Hebert MA, Morton DM, Meyerhoff JL. Effects ofsocial defeat and of diazepam on behavior in a resident-intruder test in male DBA/2 mice.
Pharmacol Biochem Behav 2000; 67:433–447.
159. Lyon M. Animal models of mania and schizophrenia. In: Willner P, ed. Behavioural Models
in Psychopharmacology: Theoretical, Industrial and Clinical Perspectives. Cambridge: Cambridge University Press, 1991:253–310.
160. Maier SF. Learned helplessness and animal models of depression. Prog Neuropsychopharmacol Biol Psychiatr 1984; 8:435-446.
161. Maier SF. Exposure to the stressor environment prevents the temporal dissipation of behavioral depression/learned helplessness. Biol Psychiatry 2001; 49:763–773.
162. Manhaes de Castro R, Barreto Medeiros JM, Mendes da Silva C, Ferreira LM, Guedes RC,
Cabral Filho JE, Costa JA. Reduction of intraspeciﬁc aggression in adult rats by neonatal
treatment with a selective serotonin reuptake inhibitor. Braz J Med Biol Res 2001; 34:121–
124.
163. Mar A, Spreekmeester E, Rochford J. Antidepressants preferentially enhance habituation tonovelty in the olfactory bulbectomized rat. Psychopharmacology (Berl) 2000; 150:52–60.
164. Marek GJ, Li A, Seiden LS. Selective 5-hydroxytryptamine-2 antagonists have antidepressant-like effects on differential-reinforcement-of-low rate 72-s schedule. J Pharmacol Exp
Ther 1989; 250:60–71.
165. Markou A, Koob GF. Bromocriptine reverses post-cocaine anhedonia in a rat model of cocaine withdrawal. Am Coll Neuropsychopharmacol 1989; Abstr 157.
166. Markou A, Hanley SJ, Chehade AK, Koob GF. Effects of performance and reward manipulations on current-intensity thresholds and other measures derived from a discrete-trial selfstimulation procedure in rats. Soc Neurosci 1989; abstr 15.
167. Markou A, Hauger RL, Koob GF. Desmethylimipramine attenuates cocaine withdrawal inrats. Psychopharmacology (Berl) 1992; 109:305–314.
168. Martin P, Soubrie P, Simon P. Shuttle-box deﬁcits induced by inescapable shocks in rats:
reversal by the beta-adrenoreceptor stimulants clenbuterol and salbutamol. Pharmacol Biochem Behav 1986; 24:177–181.
169. Martin P, Soubrie P, Simon P. Noradrenergic and opioid mediation of tricyclic-induced reversal of escape deﬁcits caused by inescapable shock pretreatment in rats. Psychopharmacology
1986; 90:90–94.

538

Willner and Mitchell170. Martin P, Laporte AM, Soubrie P, El Mestikawy S, Hamon S. Reversal of helpless behaviour
by seretonin reuptake inhibitors. In: Bevan P, Cools AR, Archer T, eds. Behavioural Pharmacology of 5HT. New York: Erlbaum, 1989:231–234.
171. Matthews K, Forbes N, Reid IC. Sucrose consumption as a hedonic measure following
chronic unpredictable mild stress. Physiol Behav 1995; 57:241–248.
172. Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurian RK, Jerabek PA, Silva JA,
Tekell JL, Martin CC, Lancaster JL, Fox PT. Reciprocal limbic-cortical function and negative
mood: Converging PET ﬁndings in depression and normal sadness. Am J Psychiatry 1999;
156:675–682.
173. McGrath C, Norman TR. The effect of venlafaxine treatment on the behavioural and neurochemical changes in the olfactory bulbectomised rat. Psychopharmacology (Berl) 1998; 136:
394-401.
174. McGrath C, Norman TR. (⫹)-S-20499—a potential antidepressant? A behavioural and neurochemical investigation in the olfactory bulbectomised rat. Eur Neuropsychopharmacol
1999; 9:21–27.
175. McKinney WT, Bunney WE. Animal model of depression: review of evidence and implications for research. Arch Gen Psychiatr 1969; 21:240–248.
176. McKinney WT, Kraemer GW. Effects of oxaprotiline on the response to peer separation in
rhesus monkeys. Biol Psychiatr 1989; 25:818–821.
177. McKinney WT, Young LD, Suomi SJ. Chlorpromazine treatment of disturbed monkeys. ArchGen Psychiatr 1973; 29:490–494.
178. Meloni D, Gambarana C, De Montis MG, Dal Pra P, Taddei I, Tagliamonte A. Dizoclipine
antagonizes the effect of chronic imipramine on learned helplessness in rats. Pharmacol Biochem Behav 1993; 46:423–426.
179. Menzel EW, Davenport RK, Rogers CM. Effects of enviromental restriction upon the chimpanzee’s responsiveness to objects. J Comp Physiol Psychol 1963; 56:78–85.
180. Minor TR, Jackson RL, Maier SF. Effects of task-irrelevant cues and reinforcement delay
on choice-escape learning following inescapable shock: evidence for a deﬁcit in selective
attention. J Exp Psychol: Anim Behav Proc 1984; 10:543–556.
181. Minor TR, Pelleymounter MA, Maier SF. Uncontrollable shock, forebrain norepinephrine,and stimulus selection during choice-escape learning. Psychobiology 1988; 16:135–145.
182. Mitchell PJ, Fletcher A. Venlafaxine exhibits pre-clinical antidepressant activity in the resident-intruder social interaction paradigm. Neuropharmacology 1993; 32:1001–1009.
183. Mitchell PJ, Fletcher A. Repeated electroconvulsive shock increases aggressive behaviour
in resident rats. Soc Neurosci Abstr 1994; 20:164.12.
184. Mitchell PJ, Forster EA. Gepirone exhibits antidepressant-like activity on the social/agonistic
behaviour of resident rats. J Psychopharmacol Abstr Book BAP/EBPS meeting, 1992; abstract 335.
185. Mitchell PJ, Hogg S. Escitalopram: Behavioural model predicts antidepressant activity.
World J Biol Psychiatry 2001; 2(suppl 1):Abstr P024–21.
186. Mitchell PJ, Hogg S. Escitalopram: rapid antidepressant activity in rats. World J Biol Psychiatry 2001; 2(suppl 1):abstr P024–19.
187. Mitchell PJ, Redfern PH. Chronic treatment with clomipramine and mianserin increases thehierarchical position of subdominant rats housed in triads. Behav Pharmacol 1992; 3:239247.
188. Mitchell PJ, Redfern PH. Acute and chronic antidepressant drug treatments induce opposite
effects in the social behaviour of rats. J Psychopharmacol 1992; 6:241–257.
189. Mitchell PJ, Redfern PH. Effects of citalopram and paroxetine on rodent social and agonistic
behaviour. J Psychopharmacol 1997; 11(suppl):abstr 161.
190. Mitchell PJ, Redfern PH. Potentiation of the time-dependent, antidepressant-induced changes
in the agonistic behaviour of resident rats by the 5-HT1A receptor antagonist, WAY-100635.
Behav Pharmacol 1997; 8:585–606.

Animal Models of Depression

539

191. Mitchell PJ, Redfern PH. Effects of m-chlorophenylpiperazine and mesulergine on rodent
agonistic behaviour. J Psychopharmacol 2000; 14(suppl):A32(PD2).
192. Moledina A, Mitchell PJ, Redfern PH. Effects of m-chlorophenylpiperazine on social competition in male Wistar rats. J Psychopharmacol 2000; 14(suppl):A39(PD28).
193. Monroe SM, Thase ME, Hersen M, Himmelhochh JM, Bellack AS. Life events and theendogenous-nonendogenous distinction in the treatment and posttreatment course of depression. Compr Psychiatr 1985; 26:175–186.
194. Montkowski A, Barden N, Wotjak C, Stec I, Ganster J, Meaney M, Engelman M, Reul
JMHM, Landgraf R, Holsboer F. Long-term antidepressant treatment reduces behaviouraldeﬁcits in transgenic mice with impaired glucocorticoid receptor function. J Neuroendocrinol
1995; 7:841–845.
195. Moreau J.-L, Jenck F, Martin JR, Mortas P, Haefely WE. Antidepressant treatment prevents
chronic unpredictable mild stress-induced anhedonia as assessed by ventral tegmental selfstimulation behavior in rats. Eur Neuropsychopharmacol 1992; 2:43–49.
196. Murtra P, Sheasby AM, Hunt SP, De Felipe C. Rewarding effects of opiates are absent inmice lacking the receptor for substance P. Nature 2000; 405:180–183.
197. Muscat R, Willner P. Suppression of sucrose drinking by chronic mild unpredictable stress:
A methodological analysis. Neurosci Biobehav Rev 1992; 16:519–524.
198. Muscat R, Papp M, Willner P. Reversal of stress-induced anhedonia by the atypical antidepressants, ﬂuoxetine and maprotiline. Psychopharmacol (Berl) 1992; 109:433–438.
199. Nakagawa Y, Ishima T, Ishibashi Y, Tsuji M, Takashima T. Involvement of GABAB receptor
systems in experimental depression: baclofen but not bicuculline exacerbates helplessness
in rats. Brain Res 1996; 741:240–245.
200. Nakagawa Y, Ishima T, Ishibashi Y, Tsuji M, Takashima T. Involvement of GABAB receptor
systems in action of antidepressants. II: Baclofen attenuates the effect of desipramine whereas
muscimol has no effect in learned helplessness paradigm in rats. Brain Res 1996; 728:225–30.
201. Nelson JC. The use of antipsychotic drugs in the treatment of depression. In: Zohar J, Belmaker RH, eds. Treating Resistant Depression. New York: PMA Corp, 1987:131–146.
202. Nelson JC, Charney DS. The symptoms of major depression. Am J Psychiat 1981; 138:1–
13.
203. Niesink RJM, van Ree JM. Antidepressant drugs normalize the increased social behaviourof pairs of male rats induced by short term isolation. Neuropharmacology 1982; 21:1343–
1348.
204. Nomura A, Shimizu J, Kamateni H, Kinjo M, Watanabe M, Nakazawa T. Swimming mice:
In search of an animal model for human depression. In: Langer SZ, Takahashi R, Segawa
T, Briley M, eds. New Vistas in Depression. New York: Pergamon, 1982:203–210.
205. O’Neill KA, Valentino D. Escapability and generalization: effect on behavioural despair.
Eur J Pharmacol 1982; 78:379–380.
206. O’Neill MF, Conway MW. Role of 5-HT1A and 5-HT1B receptors in the mediation of behavior
in the forced swim test in mice. Neuropsychopharmacology 2001; 24:391–398.
207. Overstreet DH. A behavioral, psychopharmacological and neurochemical update on the Flinders Sensitive Line rat, a potential genetic animal model of depression. Behav Genet 1991;
21:67–74.
208. Overstreet DH. The Flinders sensitive line rats: A genetic animal model of depression. Neurosci Biobehav Rev 1993; 17:51–68.
209. Overstreet DH, Janowsky DS. A cholinergic supersensitivity model of depression. In: Boulton A, Baker G, Martin-Iverson M, eds. Neuromethods, Vol 20: Animal Models in Psychiatry. Basel: Birkhauser, 1991:81–114.
210. Overstreet DH, Pucilowski O, Rezvani AH, Janowsky DS. Administration of antidepressants,
diazepam and psychomotor stimulants further conﬁrms the utility of Flinders Sensitive Linerats as an animal model of depression. Psychopharmacology (Berl) 1995; 121:27–37.

540

Willner and Mitchell211. Owens MJ, Overstreet DH, Knight DL, Rezvani AH, Ritchie JC, Bissette G, Janowsky DS,
Nemeroff CB. Alterations in the hypothalamic-pituitary-adrenal axis in a proposed animalmodel of depression with genetic muscarinic supersensitivity. Neuropsychopharmacology
1991; 4:87–93.
212. Panconi E, Roux J, Altenbaumer M, Hampe S, Porsolt RD. MK-801 and enantiomers: potential antidepressants of false positives in classical screening models? Pharmacol Biochem Behav 1993; 46:15–20.
213. Papolos DF, Yu YM, Rosenbaum E, Lachman HM. Modulation of learned helplessness by
5-hydroxytryptamine2A receptor antisense oligodeoxynucleotides. Psychiatry Res 1996; 63:
197–203.
214. Papp M, Moryl E. Antidepressant-like effects of 1-aminocyclopropanecarboxylic acid andd-cycloserine in an animal model of depression. Eur J Pharmacol 1996; 316:145–151.
215. Papp M, Wieronska J. Antidepressant-like activity of amisulpride in two animal models ofdepression. J Psychopharmacol 2000; 14:46–52.
216. Papp M, Willner P, Muscat R. An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress. Psychopharmacology 1991; 104:255–259.
217. Papp M, Lappas S, Muscat R, Willner P. Attenuation of place preference conditioning but
not place aversion conditioning by chronic mild stress. J Psychopharmacol 1992; 6:352–
356.
218. Papp M, Muscat R, Willner P. Subsensitivity of rewarding and locomotor stimulant effects
of a dopamine agonist following chronic mild stress. Psychopharmacol 1993; 110:152–158.
219. Pepin MC, Pothier F, Barden N. Impaired type II glucocorticoid-receptor function in micebearing antisense RNA transgene. Nature 1992; 355:725–728.
220. Pepin MC, Pothier F, Barden N. Antidepressant drug action in a transgenic mouse modelof endocrine changes seen in depression. Mol Pharmacol 1992; 42:991–995.
221. Perrault G, Morel E, Zivkovic B, Sanger DJ. Activity of litoxetine and other serotonin uptake
inhibitors in the tail suspension test in mice. Pharmacol Biochem Behav 1992; 42:45–47.
222. Pollard GT, Howard JL. Similar effects of antidepressant and non-antidepressant drugs on
behavior under an interresponse-time ⬎ 72-s schedule. Psychopharmacology 1986; 89:253–
258.
223. Porsolt RD. Behavioral despair. In: Enna SJ, Malick JB, Richelson E, eds. Antidepressants:
Neurochemical, Behavioral and Clinical Perspectives. New York: Raven Press, 1981:121–
139.
224. Porsolt RD, LePichon M, Jalfre M. Depression: A new animal model sensitive to antidepressant treatment. Nature 1977; 266:730–732.
225. Porsolt RD, Bertin A, Blavet M, Deniel M, Jalfre M. Immobility induced by forced swimmingin rats: Effects of agents which modify central catecholamine and serotonin activity. Eur J
Pharmacol 1979; 57:201–210.
226. Porsolt RD, Chermat R, Simon P, Steru L. The tail suspension test: Computerized device
for evaluating psychotropic activity proﬁles. Psychopharmacology 1986; 89:S28.
227. Porsolt RD, Lenegre A, McArthur RA. Pharmacological models of depression. In: Olivier
B, Mos J, Slangen JL, eds. Animal Models in Psychopharmacology. Basel: Birkhauser, 1991:
137–159.
228. Post MD. Cocaine psychoses: a continuum model. Am J Psychiatr 1975; 132:225–231.
229. Price JS. Genetic and phylogenetic aspects of mood variation. Int J Ment Health 1972; 1:
124–144.
230. Priest RG, Beaumont G, Raptopoulos P. Suicide, attempted suicide and antidepressant drugs.
J Int Med Res 1980; 8(suppl 3):8–13.
231. Pucilowski O, Danysz W, Overstreet DH, Rezvani AH, Eichelman B, Janowsky DS. Decreased hyperthermic effect of MK-801 in selectively bred hypercholinergic rats. Brain Res
Bull 1991; 26:621–625.

Animal Models of Depression

541

232. Pucilowski O, Overstreet DH, Rezvani AH, Janowsky DS. Chronic mild stress-induced anhedonia: greater effect in a genetic rat model of depression. Physiol Behav 1993; 54:1215–
1220.
233. Reddy DS, Kaur G, Kulkarni SK. Sigma (sigma1) receptor mediated anti-depressant-like
effects of neurosteroids in the Porsolt forced swim test. Neuroreport 1998; 9:3069–3073.
234. Reite M, Short R, Seiler C, Pauley JD. Attachment, loss and depression. J Child Psychol
Psychiatry 1981; 22:141–169.
235. Richards JB, Sabol KE, Hand TH, Jolly DC, Marek GJ, Seiden LS. Buspirone, gepirone,
ipsapirone, and zalospirone have distinct effects on the differential-reinforcement-of-lowrate 72-s schedule when compared with 5-HTP and diazepam. Psychopharmacology (Berl)
1994; 114:39–46.
236. Rioux A, Fabre V, Lesch KP, Moessner R, Murphy DL, Lanfumey L, Hamon M, Martres
MP. Adaptive changes of serotonin 5-HT2A receptors in mice lacking the serotonin transporter. Neurosci Lett 1999; 262:113–116.
237. Robertson J, Bowlby J. Responses of young children to separation from their mothers. Courdu Centre Int L’Enf 1952; 2:131–142.
238. Rodgers B. Models of stress, vulnerability and affective disorder. J Affect Disord 1991; 21:
1–13.
239. Rupniak NM, Carlson EC, Harrison T, Oates B, Seward E, Owens S, de Felipe C, Hunt
S, Wheeldon A. Pharmacological blockade or genetic deletion of substance P (NK1) receptors attenuates neonatal vocalization in guinea-pigs and mice. Neuropharmacology 2000; 39:1413–1421.
240. Rupniak NMJ, Carllson EJ, Webb JK, Harrison T, Porsolt RD, Roux S, de Felipe C, Hunt SP,
Oates B, Wheeldon A. Comparison of the phenotype of NK1R-/- mice with pharmacologicalblockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs.
Behav Pharmacol 2001; 12:497–508.
241. Sarnyai Z, Biro E, Gardi J, Vecsernyes M, Julesz J, Telegdy G. Brain corticotropin-releasing
factor mediates ‘anxiety-like’ behavior induced by cocaine withdrawal in rats. Brain Res
1995; 675:89–97.
242. Scearce-Levie K, Chen JP, Gardner E, Hen R. 5-HT receptor knockout mice: pharmacological tools or models of psychiatric disorders. Ann NY Acad Sci 1999; 868:701–715.
243. Schiller GD, Pucilowski O, Wienicke C, Overstreet DH. Immobility-reducing effects ofantidepressants in a genetic animal model of depression. Brain Res Bull 1992; 28:821–
823.
244. Schmale AH. Adaptive role of depression in health and disease. In: Scott JP, Senay E, eds.
Separation and Depression. Washington: American Association of Advances in Science,
1973: 187–214.
245. Seiden LS, Dahms JL, Shaughnessy RA. Behavioral screen for antidepressants: The effects
of drugs and electroconvulsive shock on performance under a differential-reinforcement-oflow-rate schedule. Psychopharmacology 1985; 86:55–60.
246. Seligman MEP. Helplessness: On Depression, Development and Death. San Francisco: Freeman, 1975.
247. Shanks N, Anisman H. Stressor-provoked behavioral changes in six strains of mice. Behav
Neurosci 1988; 102:894–905.
248. Sherman AD, Sacquitne JL, Petty F. Speciﬁcity of the learned helplessness model of depression. Pharmacol Biochem Behav 1982; 16:449–454.
249. Shumake J, Poremba A, Edwards E, Gonzalez-Lima F. Congenital helpless rats as a genetic
model for cortex metabolism in depression. Neuro Rep 2000; 11:3793–3798.
250. Simpson DM, Annau Z. Behavioral withdrawal following several psychoactive drugs. Pharmacol Biochem Behav 1977; 7:59–64.
251. Sluzewska A, Szczawinska K. Lithium potentiation of antidepressants in chronic mild stressmodel of depression in rats. Behav Pharmacol 1996; 7(suppl 1):105.

542

Willner and Mitchell252. Sluzewska A, Szczawinska K. The effects of pindolol addition to ﬂuvoxamine and buspirone
in chronic mild stress model of depression. Behav Pharmacol 1996; 7(suppl 1):105.
253. Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, Chen R, Marchuk
Y, Hauser C, Bentley CA, Sawchenko PE, Koob GF, Vale W, Lee KF. Corticotropin releasing factor receptor-1-deﬁcient mice display decreased anxiety, impaired stress response, andaberrant neuroendocrine development. Neuron 1998; 20:1093–1102.
254. Soblosky JS, Thurmond JB. Biochemical and behavioral correlates of chronic stress: effectsof tricyclic antidepressants. Pharmacol Biochem Behav 1986; 24:1361–1368.
255. Sokolowski JD, Seiden LS. The behavioral effects of sertraline, ﬂuoxetine, and paroxetine
differ on the differential-reinforcement-of-low-rate 72-second operant schedule in the rat.
Psychopharmacology (Berl) 1999; 147:153–161.
256. Soubrie P. Reconciling the role of central serotonin neurons in human and animal behaviour.
Behav Brain Sci 1986; 9:319–364.
257. Soubrie P, Martin P, El Mestikawy S, Thiebot MH, Simon P, Hamon M. The lesion ofserotonergic neurons does not prevent antidepressant-induced reversal of escape failures produced by inescapable shocks in rats. Pharmacol Biochem Behav 1986; 25:1–6.
258. Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacology 1985; 85:367–370.
259. Stogner KA, Holmes PV. Neuropeptide-Y exerts antidepressant-like effects in the forced
swim test in rats. Eur J Pharmacol 2000; 387:R9–R10.
260. Suomi SJ. Factors affecting responses to social separation in rhesus monkeys. In: Serban G,
Kling A, eds. Animal Models in Human Psychobiology. New York: Plenum Press, 1976:
9–26.
261. Suomi SL, Seaman SF, Lewis JK, et al. Effects of imipramine treatment on separationinduced social disorders in rhesus monkeys. Arch Gen Psychiat 1978; 35:321–325.
262. Takahashi LK, Turner JG, Kalin NH. Prenatal stress alters brain catecholaminergic activity
and potentiates stress-induced behavior in adult rats. Brain Res 1992; 574:131–137.
263. Teixeira NA, Pereira DG, Hermini AH. Chronic but not acute Li⫹ treatment prevents behavioral depression in rats. Braz J Med Biol Res 1995; 28:1003–1007.
264. Teste JF, Pelsy-Johann I, Decelle T, Boulu RG. Anti-immobility activity of different antidepressant drugs using the tail suspension test in normal or reserpinized mice. Fundam Clin
Pharmacol 1993; 7:219–226.
265. Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, Blanquet V, Steckler T,
Holsboer F, Wurst W. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor. Nat Genet 1998; 19:162–166.
266. Tizabi Y, Overstreet DH, Rezvanil AH, Louis VA, Clark E Jr, Jonowsky DS, Kling MA.
Antidepressant effects of nicotine in an animal model of depression. Psychopharmacology(Berl) 1999; 142:193–199.
267. Tizabi Y, Rezvanil AH, Russell LT, Tyler KY, Overstreet DH. Depressive characteristics
of FSL rats: involvement of central nicotinic receptors. Pharmacol Biochem Behav 2000;
66:73–77.
268. Toates F. Stress: Conceptual and Biological Aspects. Chichester: Wiley, 1995.
269. Turner C, Davenport R, Rogers C. The effect of early deprivation on the social behaviourof adolescent chimpanzees. Am J Psychiatr 1969; 125:1531–1536.
270. Valenstein ES. Brain Control: A Critical Examination of Brain Stimulation and Psychosurgery. New York: Wiley, 1973.
271. van den Bos R, Charria Ortiz GA, Cools AR. Injections of the NMDA-antagonist D-2-amino7-phosphonoheptanoic acid (AP-7) into the nucleus accumbens of rats enchance switching
between cue-directed behaviours in a swimming test procedure. Behav Brain Res 1992; 48:
165–170.
272. van der Heyden JAM, Olivier B, Zethof TJJ. The behavioural despair model as a predictor

Animal Models of Depression

273.
274.

275.

276.

277.

278.
279.

280.
281.

282.
283.

284.

285.

286.
287.
288.

289.

290.

291.
292.

543

of antidepressant activity: Effects of serotonergic drugs. In: Olivier B, Mos J, Slangen J,
eds. Animal Models in Psychopharmacology. Basel: Birkhauser, 1991:211–215.
Van Praag HM. 5-HT-related anxiety- and/or aggression-driven depression. Int Clin Psychopharmacol 1994; 9(suppl 1):5–6.
Van Riezen H, Leonard BE. Effects of psychotropic drugs on the behaviour and neurochemistry of olfactory bulbectomized rats. In: File SE, ed. Psychopharmacology of Anxiolytics andAntidepressants. New York: Pergamon, 1990:231–250.
Vartiainen H, Tiihonen J, Putkonen A, Koponen H, Virkkunen M, Hakola P, Lehto H. Citalopram, a selective serotonin reuptake inhibitor, in the treatment of aggression in schizophrenia.
Acta Psychiatrica Scand 1995; 91:348–351.
Velazquez-Moctezuma J, Diaz Ruiz O. Neonatal treatment with clomipramine increased immobility in the forced swim test: an attribute of animal models of depression. Pharmacol
Biochem Behav 1992; 42:737–739.
Velazquez-Moctezuma J, Aguilar-Garcia A, Diaz Ruiz O. Behavioral effects of neonatal
treatment with clomipramine, scopolamine, and idazoxan in male rats. Pharmacol Biochem
Behav 1993; 46:215–217.
Vogel G, Neill D, Hagler M, Kors D. A new animal model of endogenous depression: asummary of present ﬁndings. Neurosci Biobehav Rev 1990; 14:85–91.
Vogel G, Hagler M, Hennessey A, Richard C. Dose-dependent decrements in adult male rat
sexual behavior after neonatal clorimipramine treatment. Pharmacol Biochem Behav 1996;
54:605–609.
Vollmayr B, Henn FA. Learned helplessness in the rat: improvements in validity and reliability. Brain Res Brain Res Protoc 2001; 8:1–7.
Ward HE, Johnson EA, Salm AK, Birkle DL. Effects of prenatal stress on defensive withdrawal behavior and corticotropin releasing factor systems in rat brain. Physiol Behav 2000;
70:359–366.
Watson R, Hartman E, Schildkraut JJ. Amphetamine withdrawal: affective state, sleep patterns and MHPG excretion. Am J Psychiatr 1972; 129:263–269.
Weiss JM, Goodman PA, Losito BG, Corrigan S, Charry JM, Bailey WH. Behavioral depression produced by an uncontrollable stressor: relationship to noreprinephrine, dopamine, andserotonin levels in various regions of rat brain. Brain Res Rev 1981; 3:167–205.
Weiss JM, Bailey WH, Goodman PA, Hoffman LJ, Ambrose MJ, Salman S, Charry JM. A
model for neurochemical study of depression. In: Spiegelstein MY, Levy A, eds. Behavioural
Models and the Analysis of Drug Action. Amsterdam: Elsevier, 1982:195–223.
White DA, Birkle DL. The differential effects of prenatal stress in rats on the acoustic startle
reﬂex under baseline conditions and in response to anxiogenic drugs. Psychopharmacology(Berl) 2001; 154:169–176.
Willner P. The validity of animal models of depression. Psychopharmacology 1984; 83:1–
16.
Willner P. Depression: A Psychobiological Synthesis. New York: Wiley, 1985.
Willner P. Validating criteria for animal models of human mental disorders: learned
helplessness as a paradigm case. Prog Neuropsychopharmacol Biol Psychiatr 1986; 10:677–
690.
Willner P. Sensitization to the actions of antidepressant drugs. In: Emmett-Oglesby MW,
Goudie AJ, eds. Psychoactive Drugs: Tolerance and Sensitization. Totowa, NJ: Humana
Press, 1989:407–459.
Willner P. Towards a theory of serotonergic dysfunction in depression. In: Archer T, Bevan
P, Cools A, eds. Behavioural Pharmacology of 5-HT. New York: Lawrence Erlbaum, 1989:
157–178.
Willner P. Animal models of depression: an overview. Pharmacol Ther 1990; 45:425–455.
Willner P. Behavioural models in psychopharmacology. In: Willner P, ed. Behavioural Mod-

544

293.
294.

295.

296.

297.

298.

299.

300.
301.
302.

303.

304.

305.

306.

307.

308.

Willner and Mitchellels in Psychopharmacology: Theoretical, Industrial and Clinical Perspectives. Cambridge:
Cambridge University Press, 1991:3–18.
Willner P. Animal models as simulations of depression. Trends Pharmacol Sci 1991; 12:
131–136.
Willner P. Validity, reliability and utility of the chronic mild stress (CMS) model of depression: A ten-year review and evaluation. (Plus 17 peer commentaries and author’s response.)
Psychopharmacology 1997; 134:319–377.
Willner P, Papp M. Animal models to detect antidepressants: Are new strategies necessary
to detect new agents? In: Skolnick P, ed. Antidepressants: New Pharmacological Strategies.
Totowa: Humana, 1997:213–234.
Willner P, Theodorou A, Montgomery AMJ. Subchronic treatment with the tricyclic antidepressant DMI increases isolation-induced ﬁghting in rats. Pharmacol Biochem Behav 1981;
14:475–479.
Willner P, Towell A, Sampson D, Sophokleous S, Muscat R. Reduction of sucrose preferenceby chronic mild unpredictable stress, and its restoration by a tricyclic antidepresant. Psychopharmacology 1987; 93:358–364.
Willner P, Sampson D, Phillips G, Fichera R, Foxlow P, Muscat R. Effects of isolated housing
and chronic antidepressant treatment on cooperative social behaviour in rats. Behav Pharmacol 1989; 1:85–90.
Willner P, Sampson D, Papp M, Phillips G, Muscat R. Animal models of anhedonia. In:
Soubrie P, ed. Animal Models of Psychiatric Disorders, Vol. 3, Anxiety, Depression andMania. Basel: Karger, 1991:71–99.
Willner P. D’Aquila PS, Coventry T, Brain P. Loss of social status: preliminary evaluationof a novel animal model of depression. J Psychopharmacol 1995; 9:207–213.
Wise RA. The brain and reward. In: Liebmann JM, Cooper SJ, eds. The Neuropharmacological Basis of Reward. Oxford: Oxford University Press, 1989:377–424.
Wong EH, Sonders MS, Amara SG, Tinholt PM, Piercey MF, Hoffmann WP, Hyslop DK,Franklin S, Porsolt RD, Bonsignori A, Carfagna N, McArthur RA. Reboxetine: a pharmacologically potent, selective, and speciﬁc norepinephrine reuptake inhibitor. Biol Psychiatry
2000; 47:818–829.
Woodmansee WW, Silbert LH, Maier SF. Stress-induced changes in daily activity in the rat
are modulated by different factors than are stress-induced escape-learning deﬁcits. Soc Neurosci Abstr 1991; 17:146.
Zacharko RM, Anisman H. Stressor-provoked alterations of intracranial self-stimulation in
the mesocortiolimbic dopamine system: an animal model of depression. In: Willner P, ScheelKruger J, eds. The Mesolimbic Dopamine System, From Motivation to Action. Chichester:
Wiley, 1991:411–442.
Zacharko RM, Bowers WJ, Kokkinidis L, Anisman H. Region-speciﬁc reductions of intracranial self-stimulation after uncontrollable stress: Possible effects on reward processes. Behav Brain Res 1983; 9:129–141.
Zacharko RM, Lalonde GT, Kasian M, Anisman H. Strain-speciﬁc effects of inescapableshock on intracranial self-stimulation from the nucleus accumbens. Brain Res 1987; 426:
164–168.
Zangen A, Overstreet DH, Yadid G. High serotonin and 5-hydroxyindoleacetic acid levels
in limbic brain regions in a rat model of depression: normalization by chronic antidepressanttreatment. J Neurochem 1997; 69:2477–2483.
Zangen A, Overstreet DH, Yadid G. Increased catecholamine levels in speciﬁc brain regionsof rat model of depression: normalization by chronic antidepressant treatment. Brain Res
1999; 824:243–250.

21
Pathogenesis of Depression:
Reconsideration of Neurotransmitter
Data by Depletion Paradigms
ALEXANDER NEUMEISTER
National Institute of Mental HealthNational Institutes of Health
Bethesda, Maryland, U.S.A.
ANASTASIOS KONSTANTINIDIS
University of Vienna
Vienna, Austria

I.

INTRODUCTION

Considerable evidence is available in the literature that supports the idea that brain monoamine systems play a key role in the pathogenesis of affective disorders, in particulardepression. These hypotheses have primarily taken the form of proposing abnormal regulation in serotonin (5HT) [1], and the catecholamines norepinephrine [2,3], and dopamine[4] in the disorder. 5HT is known to be involved in the regulation of a wide variety offunctions, including mood, anxiety, aggression, sleep, appetite, and sexual function, although it has to be acknowledged that the precise details of the mechanisms involved are
not fully understood. There are many data available showing that, besides 5HT, both
dopamine and norepinephrine also are involved in the pathogenesis of depression and its
treatment. Brain catecholamines are thought to be involved in the regulation of mood,anxiety, appetite motivation, rewards, and attention to novel environmental stimuli andmost patients with depression show disturbances in these functions.
The situation regarding how to evaluate the potential role of monoamines in depression has been hampered by the fact that, until recently, it has not been possible to measure
545

546

Neumeister and Konstantinidis

brain 5HT and catecholamines directly, which means that researchers had to rely on indirect evidence for the involvement of these transmitter systems in the pathogenesis of depression and their role in antidepressant treatment modalities. Over the past years, neurotransmitter depletion paradigms have provided another means of examining the systems
involved and have become important tools in investigating the role of monoamines in
depression and its pharmacological and nonpharmacological treatments. The purpose ofthis chapter is to present biochemical and behavioral data concerning the role of monoamine systems in the pathogenesis of depression and antidepressant treatment modalities.
II. BASIC CONCEPTS
A.

Catecholamine Depletion

Of various methods employed for modifying the functions of sympathetic nervous systems, a unique and successful one has been the inhibition of catecholamine biosynthesisby α-methyl-para-tyrosine (AMPT) [5,6]. AMPT decreases norepinephrine and dopaminelevels via inhibition of tyrosine hydroxylase, a rate-limiting enzyme in the synthesis ofboth transmitters [7]. AMPT is adequately absorbed from the gastrointestinal tract andthe degree of inhibition achieved in humans approximates the values, which could be
predicted from the plasma levels of the drug [8]. Originally, the drug was used to successfully treat pheochromocytoma, whereas in cases with essential hypertension the drug was
not successful. In clinical investigations, AMPT (in dosages ranging from 1 to 4 g/day)leads to profound decreases in urinary excretion of catecholamine metabolites and cerebrospinal ﬂuid levels of the dopamine metabolite homovanillic acid (HVA), with no change
in the 5HT metabolite 5-hydroxyindoleacetic acid (5HIAA) [5,6,9]. A maximal reductionof catecholamine metabolites during AMPT treatment occurs after 2 to 3 days of treatment[8,10].
In the initial studies unrelated to depression, researchers noted the central nervous
system effects of AMPT, and reported sedation (generally mild, but to varying degrees),anxiety, agitated depression, and changes in sleep pattern after withdrawal of the medication. In addition to these changes in mood and mental activity, adverse effects related toneuromuscular activity appeared in some patients. The symptoms included mild tremorof the hands and, in the most severe form, gross tremor of the hands and legs unaffectedby rest or movement. Other side effects are diarrhea, galactorrhea, crystalluria and urolithiasis, and decreased salivation. As with mood changes, all these effects disappeared rapidly
with cessation or reduction of drug dose. Altogether, balancing the risks of toxicity versus
therapeutic beneﬁt, it seemed reasonable to continue to utilize AMPT for therapeutic purposes only in speciﬁc cases of patients with malignant pheochromocytoma. In contrast,
in carefully conducted clinical trials including medically healthy subjects, manipulationsof central catecholamines with AMPT offer a unique opportunity to identify transmitter
systems that are believed to play a role in depression, and to further understand brain
structures and transmitter systems being involved in the effects of antidepressants.
B.

Tryptophan Depletion

The aim of tryptophan depletion is to lower brain 5HT by depleting its precursor tryptophan. Most of the tryptophan in plasma is protein bound, with only about 5% being left
free and available for transport across the blood–brain barrier by an active protein shuttle
for which ﬁve other large amino acids (valine, leucine, isoleucine, phenylalanine, andPathogenesis of Depression

547

tyrosine) also compete. Once in the brain, the initial step in the biosynthesis of 5HT is
the conversion of L-tryptophan to 5-hydroxytryptophan, a reaction catalyzed by the ratelimiting enzyme tryptophan hydroxylase [11]. The Michaelis constant for tryptophan hydroxylase is higher than tryptophan concentration in the brain, suggesting that under physiological conditions the activity of this enzyme is limited by the availability of the substrate[12]. Animal studies have shown that the synthesis and content of 5HT in rat brain varyin parallel with brain tryptophan concentrations [13]. Moreover, it has been shown that
increase in brain tryptophan concentration raises 5HT release in vitro [14,15] and in vivo
[16,17], although some studies disagree with these ﬁndings [18,19]. In summary, the concentration of brain 5HT depends upon the availability of its precursor tryptophan.
Preclinical data show that the acute administration of a tryptophan-free amino acidmixture of essential amino acids produces a rapid and substantial decrease in plasma tryptophan levels, associated with a decrease in brain tryptophan, brain 5HT, and 5HIAA
levels in rats [20]. Studies in humans show profound decreases of plasma tryptophan levels[21,22], and cerebrospinal ﬂuid levels of 5HIAA [23,24] after oral administration of anamino acid mixture without tryptophan. A positron emission tomography study of humans
showing a marked lowering of brain 5HT synthesis induced by tryptophan depletion conﬁrms the assumption that brain serotonergic activity is transiently reduced during tryptophan depletion [25]. However, it has to be acknowledged that uptake of alpha-methyl Ltryptophan is not clearly established as a reliable indicator of 5HT synthesis.
Two mechanisms are responsible for the transient decrease in brain 5HT activity
during tryptophan depletion: (1) the amino acid mixture (Table 1) given to the subjects
during tryptophan depletion stimulates protein synthesis in the liver, which uses up plasma
tryptophan, and (2) the amino acid mixture contains large amounts of other neutral amino

Table 1 Amino Acids Used for Tryptophan Depletion
Versus Sham Depletion
Makes one beverage
L-Alanine
Glycine
L-Histidine
L-Isoleucine
L-Leucine
L-Lysine
L-Phenylalanine
L-Proline
L-Serine
L-Threonine
L-Tyrosine
L-Valine
L-Methionine
L-Arginine
L-Cysteine

5.5 g
3.2 g
3.2 g
8.0 g
13.5 g11.0 g5.7g12.2 g
6.9 g
6.9 g
6.9 g
8.9 g
12.0 g19.6 g10.8 gDuring sham depletion the beveragecontains additional amino acid

L-Tryptophan

2.3 g

548

Neumeister and Konstantinidis

acids, which compete with tryptophan for transport across the blood–brain barrier andthus restrict uptake of tryptophan into the brain. Both mechanisms lead to the rapid andsubstantial, albeit transient, reduced synaptic availability of 5HT in the brain. The valueof a depletion paradigm depends on whether the method is reliable, reversible, and speciﬁc.
All three issues have been addressed in several studies and have shown that the tryptophan
depletion method fulﬁlls all three requirements for a meaningful research tool [26–29].
In particular, studies in monkeys [30] and humans [31] showed that tryptophan depletion
did not change the metabolism of other neurotransmitters, whereas levels of tryptophan
and 5HIAA in plasma and cerebrospinal ﬂuid, respectively, were lowered. Thus, if theeffects of tryptophan depletion can be attributed to changes in a transmitter system in thebrain, it is probably 5HT systems that are affected.
III. CATECHOLAMINE DEPLETION STUDIESA.

Healthy Subjects

In order to evaluate the role of catecholamines in regulation of mood, anxiety, alertness,and its potential role in the pathogenesis of psychiatric disorders, it is important to study
the effects of catecholamine depletion in healthy volunteers. Treatment with AMPT has
been shown to induce pronounced increases in sleepiness and mild increases in negative
mood and anxiety when administered to healthy male controls [32]. Noteworthy is the factthat replacement of catecholamine stores with L-dopa reverses the effects of catecholamine
depletion, and is associated with a more rapid recovery from AMPT effects than whensubjects are treated with AMPT alone. Another study of the same group comparing thepsychological effects of AMPT alone versus AMPT plus 40.5 h of total sleep deprivation[33] suggests that catecholamines may be involved in mood changes during sleep deprivation. Combined treatment with AMPT and sleep deprivation led to signiﬁcant increases
in negative mood, whereas no treatment alone produced consistent mood changes. Withthe use of a different methodology to deplete catecholamines, by administering an aminoacid mixture deﬁcient of phenylalanine and tyrosine, Leyton and colleagues [34] induced
lowered mood and energy and increased irritability scores in a group of healthy women.
Interestingly, the behavioral changes induced by catecholamine depletion were similar to
those found during tryptophan depletion in the same group of subjects. In both conditions,the behavioral effects were more pronounced following exposure to aversive psychologicalevents. Another study suggests that acutely decreased catecholamine transmission may
disrupt mechanisms mediating alcohol self-administration [35]. Together, these studies
support the role of catecholamines in a variety of human behaviors and also suggest that
disturbed catecholamine transmission may predispose humans to various psychiatric disorders, including depression and anxiety.
B.

Depression

The role of norepinephrine and dopamine in the pathogenesis of depression and in themechanisms of action of antidepressant drugs has been the subject of intensive researchduring the past decades. A comprehensive overview of catecholaminergic function in depression is beyond the scope of this chapter, which is to show the biochemical and behavioral effects of catecholamine depletion in depressed patients in different states of theirillness, and the implications for our understanding of the pathogenesis of depression andits treatment. In the initial studies performed by Bunney and colleagues at the National
Institute of Health [10] demonstrated the antimanic effects of AMPT in a small group ofPathogenesis of Depression

549

manic patients, whereas three of four unipolar psychotic depressed patients showed anincrease in depression on AMPT. However, small sample sizes and the lack of a control
or placebo group limit the interpretation of these initial ﬁndings. More recent studies
addressing these methodological shortcomings showed that drug-free, untreated, symptomatic depressed patients had signiﬁcant increased visual analogue ratings of “tired,” anddecreased ratings of “energetic.” However, there was no alteration in mood reported by theauthors [36]. This ﬁnding suggests that a simple norepinephrine or dopamine deﬁciency
hypothesis is insufﬁcient to explain the neurobiological basis of depression. Rather, therole of noradrenergic systems needs to be considered in relation to many other neurobiological factors that may be involved in the pathogenesis of depression. An alternative
explanation could be that, during a depressive state, the catecholamine systems are alreadymaximally dysfunctional and thus further manipulations do not worsen the condition of
the patient.
Studies of the effects of AMPT on patients remitted on antidepressants or remitted
off medications provided further insight into the pathogenesis of depression and mechanisms of action of different antidepressants (Table 2). Depressed patients in remission andon noradrenergic antidepressants (desipramine and mazindol) experienced a depressive
relapse during catecholamine depletion, whereas those patients whose remissions weremaintained with the selective 5HT reuptake inhibitors (SSRIs) ﬂuoxetine and sertraline
remained well during catecholamine depletion [37]. The administration of AMPT induced
core symptoms of depression, such as depressed mood, loss of interest, anhedonia, cognitive disturbances, and sense of worthlessness and failure. Another study reported the recurrence of depressive symptoms induced by catecholamine depletion in a group of patientswith seasonal affective disorder remitted on light therapy [31]. These ﬁndings disagreewith a small study of three depressed patients with a favorable treatment response to
imipramine [38]. However, besides the fact that the sample size of that study was small
and there was no control situation, it has to be considered that imipramine is a potent
5HT reuptake inhibitor as well as a norepinephrine reuptake inhibitor. Findings that catecholamine depletion disrupts the antidepressant effects of catecholaminergic, but not serotonergic, antidepressants, whereas tryptophan depletion reverses the antidepressant effects
of serotonergic antidepressants, but not catecholaminergic antidepressants [39], argue
against a single monoamine-related mechanism of action of antidepressants. However,such studies suggest that enhanced catecholamine function is important to maintain response to noradrenergic antidepressants, and enhanced serotonergic function is important
to maintain response to serotonergic antidepressants.
State-related changes in catecholamine function have been described in depressedsubjects, whereas enduring abnormalities have been less reliably identiﬁed. A recent catecholamine depletion study in fully remitted, medication-free, formerly depressed subjects
showed a depressive relapse in these subjects during catecholamine depletion, but notduring sham depletion [40]. The authors argue that this depressive relapse may represent
a reliable marker for a history of depression. Further studies are needed to clarify theimportance of this ﬁnding.

IV. TRYPTOPHAN DEPLETION
A. Healthy Subjects
Studies of tryptophan depletion in healthy subjects have shown inconsistent results.
Healthy male subjects with their baseline ratings of depression in the upper normal range

550

Table 2

Monoamine Depletion Studies in Patients with Depression

Structure

Study design

Ref.

Subjects (n)Intervention

OutcomeA. Untreated depressed patients
Double-blind, placebocontrolled, balanced crossover study

57

43

TD vs. SD

Untreated symptomatic
depressed patients

Double-blind, placebocontrolled, balanced crossover study
Double-blind, placebo-controlled, balanced cross-overstudy
Double-blind, placebocontrolled, balanced crossover study
Double-blind, placebocontrolled, balanced crossover study

36

17

AMPT vs. diphenhydramine

56

11

TD vs. SD

No exacerbation of depressive
syndrome

55

22

TD vs. SD

54

38

TD vs. SD

Cortisol response to i.v.
mCPP greater during TD
than SD
Depressive symptoms decreased after i.v. TRP following TD, not SD

Untreated, symptomatic depressed patients
Untreated, symptomatic
depressed patients, mCPP
Infusion during depletion
Untreated, symptomatic
depressed patients, TRPInfusion at maximum pointof depletion

Bimodal mood response one
day after TD: 37% of patients show decrease of
HDRS total score, 23% increase of HDRS score
No exacerbation of depressive
syndrome

Neumeister and Konstantinidis

Untreated, symptomatic
depressed patientsResponders to imipramine

Open label

38

8

AMPT vs. PCPA

Remitted depressed patientson SSRI citalopram

Double-blind, placebocontrolled, parallel-group
designDouble-blind, placebocontrolled, balanced crossover study
Double-blind, placebocontrolled, balanced crossover study
Double-blind, placebocontrolled, balanced crossover study

58

20

TD vs. SD

59

21

TD vs. SD

27

21

TD vs. SD

Transient depressive relapse in
14 of 21 after TD

39

30

TD vs. SD

31

30

TD vs. SD

21, 67

10

TD vs. SD

8/15 FLU responders relapsed, 1/15 DMI responders relapsed after TD, notSD
TD did not induce depressive
relapse, but prevented relapse after recovery night
Transient depressive relapse

Remitted depressed patientson SSRIs
Remitted depressed patientsin antidepressant-induced
remissionFluoxetin- or desipraminresponders

Sleep deprivation responders

Light therapy-induced remission ⬎14 days

Double-blind, placebocontrolled, balanced parallel-group design
Double-blind, placebocontrolled, balanced crossover study

Transient depressive relapse
after PCPA
Transient depressive relapse in
5/12 patients after TD, not
SDTransient depressive relapse in
7 patients after TD, not SD

Pathogenesis of Depression

B. Remitted depressed patients on treatment

12

551

552

Table 2

Continued

Structure

Study design

Ref.

Subjects (n)Intervention

Outcome

Double-blind, placebocontrolled, balanced crossover study
Double-blind, placebocontrolled, balanced crossover study
Double-blind, controlled,balanced cross-over study

40

14

TD vs. SD

Transient depressive relapse

63

12

TD vs. SD

Transient depressive relapse

64

TD vs. SD

Transient depressive relapse
HC⬍P

Double-blind, placebocontrolled, balanced crossover study
Double-blind, placebocontrolled, balanced crossover study, including
healthy controls
Double-blind, placebocontrolled, balanced crossover study

65

24 (including
12 healthy
controls)
15 Women

TD vs. SD

Transient depressive relapse
after TD, not SD

67

22 (including
10 healthy
controls)

TD vs. SD

No deterioration of conditionin patients and controls

66

14

TD

No exacerbation of depressive
syndrome

C. Remitted depressed patients off treatment
Fully remitted drug-freepatients
Patients fully remitted, offtherapy during summer
Remitted drug-free patients

Remitted drug-free patients

Patients fully remitted, offtherapy during summer(SAD)

TD, tryptophan depletion; SD, sham depletion; CD, catecholamine depletion; AMPT, α-methyl-para-tyrosine.

Neumeister and Konstantinidis

Patients fully remitted, offtherapyPathogenesis of Depression

553

exhibit a transient worsening of their mood during tryptophan depletion, although neveramounting to clinical depression [22,28]. In contrast, healthy male subjects who were
euthymic at baseline and who were rigorously screened for any psychiatric or somatic
illness remained unaffected by tryptophan depletion [41]. Healthy male controls with amultigenerational family history for major affective disorders reported a greater reduction
in mood induced by tryptophan depletion than healthy controls without a positive family
history [42]. Tryptophan depletion studies in female subjects with no personal history ofdepression showed an increased risk of developing depressive symptoms during tryptophan depletion. In some tryptophan depletion studies in healthy female controls, family
histories of affective disorders were assessed and were positive [43], negative [26,43],
and in one study unknown [44]. These studies consistently showed an increased risk for an
exacerbation of depressive symptoms during tryptophan depletion with more pronounced
effects when the family history is positive. However, another study reported no moodlowering effects of tryptophan depletion in healthy females with a negative family historyof depression [45], and several studies report no mood-lowering effects of tryptophan
depletion in healthy female subjects [46,47].
Other studies have focused on the memory and cognitive effects of tryptophan depletion and showed that tryptophan depletion impairs long-term memory formation and interferes with the process of memory consolidation [48,49]. Tryptophan depletion did notaffect other measures of frontal functioning. Sleep disturbances represent another key
symptom of depressive disorders and thus it has also been of interest whether tryptophan
depletion induces sleep abnormalities including changes in sleep continuity or architecture.
Studies reported reduced REM latency after tryptophan depletion [50,51], but one study
disagrees with this ﬁnding [46]. Another ﬁeld of interest is whether reduced 5HT activity
during tryptophan depletion induces changes in aggressive behavior since reduced brain
serotonergic activity is believed to play a role in aggression or suicidal behavior. A recent
study in humans shows that tryptophan depletion indeed induces a rise in ratings of aggression in subjects with high-trait aggression but has little effect on those with low-trait
aggression [52]. Acute ethanol consumption may be associated with a decrease in tryptophan availability, and may induce aggressive behavior in susceptible individuals [53].
Behavioral responses to tryptophan depletion in healthy subjects show a high variability. There are subgroups of subjects who appear to be at a greater risk of developing
depressive symptoms during tryptophan depletion. Possible explanations include a positive
family history of depression, gender, and possibly high, albeit not reaching the levels ofclinical depression, baseline ratings of depression. An intriguing ﬁnding is the association
between the serotonin transporter gene promoter polymorphism (5HTTLPR) and the behavioral responses to tryptophan depletion in a group of healthy female subjects with andwithout family history of depression [53a]. The study showed subjects with the shortallele of the promoter region at increased risk of developing depressive symptoms duringtryptophan depletion relative to subjects with the long allele. Future studies must conﬁrm
the relevance of this initial ﬁnding and will answer the clinically and scientiﬁcally relevant
question of whether the short allele of the 5HTTLPR polymorphism is associated withan increased risk of developing depression, as was hypothesized by the authors.
B. Depression
To test the hypothesis that decreased 5HT function is associated with depression, several
studies were performed, including untreated, symptomatic depressed patients prior to initi-

554

Neumeister and Konstantinidis

ation of antidepressant treatment [54–57]. It was hypothesized that tryptophan depletion
would lead to an exacerbation of the depressive syndrome.
However, the results of these studies were somewhat unexpected. It was consistently
shown that tryptophan depletion did not exacerbate depressive symptoms in these subjects.
In two studies [54,57], some patients showed an improvement in their condition on the
day after tryptophan depletion. The failure to aggravate depression by depleting brain 5HT
can be explained by the fact that brain 5HT function is already maximally dysfunctionalin depressed patients and thus further lowering of 5HT activity has no greater effects on
depressive symptoms. Alternatively, it can be hypothesized that disturbed 5HT function
does not explain the biological basis of depression, and that there is no direct relationshipbetween severity of depressive symptoms and brain 5HT function. A possible explanation
for the improvement in symptoms the day after tryptophan depletion is an upregulationof postsynaptic 5HT receptors because of the decreased release of 5HT at the synapse
during tryptophan depletion. Typically, 5HT levels are restored the day after tryptophan
depletion and the net effect is an enhancement of brain 5HT function, resulting in an
improvement of the patient’s condition.
Intensive research using tryptophan depletion has been done during the past years
to study the role of 5HT in the mechanism of action of antidepressant drugs, and nonpharmacological treatments for depression, such as light therapy and sleep deprivation. The
hypothesis of these studies was that antidepressant treatments lead to an enhancement ofbrain 5HT function and that tryptophan depletion will disrupt the antidepressant effects.
This has now been tested in multiple studies and researchers found that tryptophan depletion indeed reverses the antidepressant effect of antidepressant treatments, in particularthat of SSRIs [27,39,58,59]. The depressive symptoms evoked by tryptophan depletion
were often similar to those experienced by the patient during a depressive episode. The
behavioral responses to tryptophan depletion were substantially more pronounced in subjects who had been successfully treated with SSRIs relative to responses in subjects who
were treated with noradrenergic antidepressants [37,39]. This ﬁnding, and the ﬁnding thatcatecholamine depletion predominantly induces a depressive relapse in subjects treatedwith noradrenergic antidepressants, suggests that enhanced serotonergic or noradrenergictransmission is necessary to maintain the antidepressant responses to SSRIs or noradrenergic agents, respectively. Another issue that affected the depressive relapse after tryptophan
depletion was the length of the remitted state of the patient. Patients who were recently
remitted were at higher risk of developing depressive symptoms during tryptophan depletion than those being remitted for a longer period. This suggests that antidepressants induce
biological changes in the neuron that make the subjects less vulnerable to acute changes
in brain 5HT function.
Nonpharmacological, albeit biologically based, treatments for depression include
light therapy and sleep deprivation. Light therapy is the treatment of ﬁrst choice for patients suffering from seasonal depression during fall and winter and has been shown to beeffective in nonseasonal depression when given in conjunction with other antidepressanttreatment modalities [60]. Tryptophan depletion [31,61] and catecholamine depletion [31]reversed the antidepressant effects of light therapy, suggesting that both transmitter systems are involved in the mechanism of action of light therapy. Several lines of evidence
suggest that sleep deprivation exerts its antidepressant effects by enhancing serotonergictransmission. To test this hypothesis, patients who responded to a single night of total
sleep deprivation underwent tryptophan depletion or sham depletion [62]. It was expectedthat tryptophan depletion would reverse the antidepressant effects of sleep deprivation.

Pathogenesis of Depression

555

Unexpectedly, tryptophan depletion did not reverse the antidepressant effects of sleep
deprivation, but rather prevented the otherwise naturally occurring depressive relapse after
the recovery night. The authors concluded that it seems to be unlikely that serotonin alone
mediates the antidepressant effects of sleep deprivation; however, serotonergic mechanisms may play an important role.
The effects of tryptophan depletion in formerly depressed, fully remitted patients off
medication is of particular interest for understanding the role of 5HT in the pathogenesis of
the disorder. It might be expected that these subjects are speciﬁcally vulnerable to thedepressogenic effects of tryptophan depletion. The majority of the studies [63–65] reported a depressive relapse induced by tryptophan depletion whereas subjects remained
well during sham depletion. However, two studies found no exacerbation of depression
during tryptophan depletion [66,67]. These discrepancies may be explained by the differing length of remission among the different studies as well as by differing study populations. The depressive relapse induced by tryptophan depletion in remitted patients off
therapy suggests that these subjects remain vulnerable to changes in 5HT function. Interestingly, one study showed that the majority of subjects who relapsed during tryptophan
depletion experienced further depressive episodes in the near future [68]. Thus, tryptophan
depletion may be capable of predicting the future course of depression.
V.

SUMMARY

The data obtained from monoamine depletion studies provided us with further insight into
the neurobiological systems involved in the pathogenesis of depression and also into themechanisms of action of pharmacological and some nonpharmacological treatment modalities, such as light therapy and sleep deprivation. It became obvious that monoamines do
not have a direct effect on regulating mood, but rather have a modulator role on otherneurobiological systems that have to be identiﬁed. However, adequate function of monoamines is necessary to achieve and maintain an antidepressant response in depressed patients on and off medications. Thus far, tryptophan depletion has been a research tool,and most probably this will not change in the near future. Future reasearch should further
increase our knowledge about the changes in transmitter function and its implications onother neurobiological systems induced by tryptophan depletion. This may become of clinical relevance since preliminary evidence suggests that, at least in a subgroup of depressed
patients, tryptophan depletion is capable of inducing a transient, albeit clinically signiﬁcant, improvement in depressive symptoms.
ACKNOWLEDGMENT
Dr. Neumeister is supported by APART (Austrian Program for Advanced Research andTechnology).
REFERENCES
1. Coppen A. The biochemistry of affective disorders. Br J Psychiatry 1967; 113(504):1237–
1264.
2. Schatzberg AF, Schildkraut JJ. Recent studies on norepinephrine systems in mood disorders.
In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New
York: Raven Press, 1995:911–920.

556

Neumeister and Konstantinidis

3. Bunney WE, Jr, Davis JM. Norepinephrine in depressive reactions. A review. Arch Gen Psychiatry 1965; 13(6):483–494.
4. Kapur S, Mann JJ. Role of the dopaminergic system in depression. Biol Psychiatry 1992;
32(1):1–17.
5. Engelman K, Horwitz D, Jequier E, Sjoerdsma A. Biochemical and pharmacologic effects ofalpha-methyltyrosine in man. J Clin Invest 1968; 47(3):577–594.
6. Sjoerdsma A, Engelman K, Spector S, Udenfriend S. Inhibition of catecholamine synthesis
in man with alpha-methyl-tyrosine, an inhibitor of tyrosine hydroxylase. Lancet 1965; 2(7422):
1092–1094.
7. Widerlov E, Lewander T. Inhibition of the in vivo biosynthesis and changes of catecholamine levels in rat brain after alpha-methyl-p-tyrosine; time- and dose-response relationships.
Naunyn Schmiedebergs Arch Pharmacol 1978; 304(2):111–123.
8. Engelman K, Jequier E, Udenfriend S, Sjoerdsma A. Metabolism of alpha-methyltyrosine inman: relationship to its potency as an inhibitor of catecholamine biosynthesis. J Clin Invest
1968; 47(3):568–576.
9. Brodie HK, Murphy DL, Goodwin FK, Bunney WE, Jr. Catecholamines and mania: the effectof alpha-methyl-para-tyrosine on manic behavior and catecholamine metabolism. Clin Pharmacol Ther 1971; 12(2):218–224.
10. Bunney WE, Jr, Brodie HK, Murphy DL, Goodwin FK. Studies of alpha-methyl-para-tyrosine,
L-dopa, and L-tryptophan in depression and mania. Am J Psychiatry 1971; 127(7):872–881.
11. Fernstrom JD. Role of precursor availability in control of monoamine biosynthesis in brain.
Physiol Rev 1983; 63(2):484–546.
12. Friedman PA, Kappelman AH, Kaufman S. Partial puriﬁcation and characterization of tryptophan hydroxylase from rabbit hindbrain. J Biol Chem 1972; 247(13):4165–4173.
13. Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological dependence on plasma
tryptophan levels. Science 1971; 173(992):149–152.
14. Schaechter JD, Wurtman RJ. Tryptophan availability modulates serotonin release from rat
hypothalamic slices. J Neurochem 1989; 53(6):1925–1933.
15. Auerbach S, Lipton P. Regulation of serotonin release from the in vitro rat hippocampus:
effects of alterations in levels of depolarization and in rates of serotonin metabolism. J Neurochem 1985; 44(4):1116–1130.
16. Sharp T, Bramwell SR, Grahame-Smith DG. Effect of acute administration of L-tryptophan
on the release of 5-HT in rat hippocampus in relation to serotoninergic neuronal activity: an
in vivo microdialysis study. Life Sci 1992; 50(17):1215–1223.
17. Carboni E, Cadoni C, Tanda GL, Di Chiara G. Calcium-dependent, tetrodotoxin-sensitive stimulation of cortical serotonin release after a tryptophan load. J Neurochem 1989; 53(3):976–
978.
18. Marsden CA, Conti J, Strope E, Curzon G, Adams RN. Monitoring 5-hydroxytryptamine release in the brain of the freely moving unanaesthetized rat using in vivo voltammetry. Brain
Res 1979; 171(1):85–99.
19. Elks ML, Youngblood WW, Kizer JS. Serotonin synthesis and release in brain slices: independence of tryptophan. Brain Res 1979; 172(3):471–486.
20. Gessa GL, Biggio G, Fadda F, Corsini GU, Tagliamonte A. Effect of the oral administrationof tryptophan-free amino acid mixtures on serum tryptophan, brain tryptophan and serotonin
metabolism. J Neurochem 1974; 22(5):869–870.
21. Neumeister A, Praschak-Rieder N, Hesselmann B, Tauscher J, Kasper S. [The tryptophan
depletion test. Basic principles and clinical relevance]. Nervenarzt 1997; 68(7):556–562.
22. Young SN, Smith SE, Pihl RO, Ervin FR. Tryptophan depletion causes a rapid lowering ofmood in normal males. Psychopharmacology 1985; 87(2):173–177.
23. Williams WA, Shoaf SE, Hommer D, Rawlings R, Linnoila M. Effects of acute tryptophan
depletion on plasma and cerebrospinal ﬂuid tryptophan and 5-hydroxyindoleacetic acid in normal volunteers. J Neurochem 1999; 72(4):1641–1647.

Pathogenesis of Depression

557

24. Carpenter LL, Anderson GM, Pelton GH, Gudin JA, Kirwin PD, Price LH, Heninger GR,
McDougle CJ. Tryptophan depletion during continuous CSF sampling in healthy human subjects. Neuropsychopharmacology 1998; 19(1):26–35.
25. Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza S, de Montigny C, Blier P, Diksic
M. Differences between males and females in rates of serotonin synthesis in human brain.
Proc Natl Acad Sci USA 1997; 94(10):5308–5313.
26. Ellenbogen MA, Young SN, Dean P, Palmour RM, Benkelfat C. Mood response to acutetryptophan depletion in healthy volunteers: sex differences and temporal stability. Neuropsychopharmacology 1996; 15(5):465–474.
27. Delgado PL, Charney DS, Price LH, Aghajanian GK, Landis H, Heninger GR. Serotoninfunction and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990; 47(5):411–418.
28. Smith SE, Pihl RO, Young SN, Ervin FR. A test of possible cognitive and environmental
inﬂuences on the mood lowering effect of tryptophan depletion in normal males. Psychopharmacology 1987; 91(4):451–457.
29. Moja EA, Cipolla P, Castoldi D, Tofanetti O. Dose-response decrease in plasma tryptophan
and in brain tryptophan and serotonin after tryptophan-free amino acid mixtures in rats. LifeSci 1989; 44(14):971–976.
30. Young SN, Ervin FR, Pihl RO, Finn P. Biochemical aspects of tryptophan depletion in primates. Psychopharmacology 1989; 98(4):508–511.
31. Neumeister A, Turner EH, Matthews JR, Postolache TT, Barnett RL, Rauh M, Vetticad RG,
Kasper S, Rosenthal NE. Effects of tryptophan depletion vs catecholamine depletion in patientswith seasonal affective disorder in remission with light therapy. Arch Gen Psychiatry 1998;
55(6):524–530.
32. McCann UD, Thorne D, Hall M, Popp K, Avery W, Sing H, Thomas M, Belenky G. The
effects of L-dihydroxyphenylalanine on alertness and mood in alpha-methyl-para-tyrosinetreated healthy humans. Further evidence for the role of catecholamines in arousal and anxiety.
Neuropsychopharmacology 1995; 13(1):41–52.
33. McCann UD, Penetar DM, Shaham Y, Thorne DR, Sing HC, Thomas ML, Gillin JC, Belenky
G. Effects of catecholamine depletion on alertness and mood in rested and sleep deprived
normal volunteers. Neuropsychopharmacology 1993; 8(4):345–356.
34. Leyton M, Young SN, Pihl RO, Etezadi S, Lauze C, Blier P, Baker GB, Benkelfat C. Effects
on mood of acute phenylalanine/tyrosine depletion in healthy women. Neuropsychopharmacology 2000; 22(1):52–63.
35. Leyton M, Young SN, Blier P, Baker GB, Pihl RO, Benkelfat C. Acute tyrosine depletion
and alcohol ingestion in healthy women. Alcohol Clin Exp Res 2000; 24(4):459–464.
36. Miller HL, Delgado PL, Salomon RM, Heninger GR, Charney DS. Effects of alpha-methylpara-tyrosine (AMPT) in drug-free depressed patients. Neuropsychopharmacology 1996;
14(3):151–157.
37. Miller HL, Delgado PL, Salomon RM, Berman R, Krystal JH, Heninger GR, Charney DS.
Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression. Arch Gen Psychiatry 1996; 53(2):117–128.
38. Shopsin B, Gershon S, Goldstein M, Friedman E, Wilk S. Use of synthesis inhibitors in deﬁning a role for biogenic amines during imipramine treatment in depressed patients. Psychopharmacol Commun 1975; 1(2):239–249.
39. Delgado PL, Miller HL, Salomon RM, Licinio J, Krystal JH, Moreno FA, Heninger GR, Charney DS. Tryptophan-depletion challenge in depressed patients treated with desipramine or
ﬂuoxetine: implications for the role of serotonin in the mechanism of antidepressant action.
Biol Psychiatry 1999; 46(2):212–220.
40. Berman RM, Narasimhan M, Miller HL, Anand A, Cappiello A, Oren DA, Heninger GR,
Charney DS. Transient depressive relapse induced by catecholamine depletion: potential phenotypic vulnerability marker? Arch Gen Psychiatry 1999; 56(5):395–403.

558

Neumeister and Konstantinidis

41. Abbott FV, Etienne P, Franklin KB, Morgan MJ, Sewitch MJ, Young SN. Acute tryptophan
depletion blocks morphine analgesia in the cold-pressor test in humans. Psychopharmacology
1992; 108(1–2):60–66.
42. Benkelfat C, Ellenbogen MA, Dean P, Palmour RM, Young SN. Mood-lowering effect oftryptophan depletion. Enhanced susceptibility in young men at genetic risk for major affective
disorders. Arch Gen Psychiatry 1994; 51(9):687–697.
43. Klaassen T, Riedel WJ, van Someren A, Deutz NE, Honig A, van Praag HM. Mood effectsof 24-hour tryptophan depletion in healthy ﬁrst-degree relatives of patients with affective disorders. Biol Psychiatry 1999; 46(4):489–497.
44. Weltzin TE, Fernstrom MH, Fernstrom JD, Neuberger SK, Kaye WH. Acute tryptophan depletion and increased food intake and irritability in bulimia nervosa. Am J Psychiatry 1995;
152(11):1668–1671.
45. Delgado PL, Charney DS, Price LH, Landis H, Heninger GR. Neuroendocrine and behavioral effects of dietary tryptophan restriction in healthy subjects. Life Sci 1989; 45(24):23232332.
46. Voderholzer U, Hornyak M, Thiel B, Huwig-Poppe C, Kiemen A, Konig A, Backhaus J,
Riemann D, Berger M, Hohagen F. Impact of experimentally induced serotonin deﬁciency bytryptophan depletion on sleep EEG in healthy subjects. Neuropsychopharmacology 1998;
18(2):112–124.
47. Salomon RM, Miller HL, Krystal JH, Heninger GR, Charney DS. Lack of behavioral effects
of monoamine depletion in healthy subjects. Biol Psychiatry 1997; 41(1):58–64.
48. Riedel WJ, Klaassen T, Deutz NE, van Someren A, van Praag HM. Tryptophan depletion innormal volunteers produces selective impairment in memory consolidation. Psychopharmacology (Berl) 1999; 141(4):362–369.
49. Schmitt JA, Jorissen BL, Sobczak S, van Boxtel MP, Hogervorst E, Deutz NE, Riedel WJ.
Tryptophan depletion impairs memory consolidation but improves focussed attention in
healthy young volunteers. J Psychopharmacol 2000; 14(1):21–29.
50. Moja EA, Mendelson WB, Stoff DM, Gillin JC, Wyatt RJ. Reduction of REM sleep by atryptophan-free amino acid diet. Life Sci 1979; 24(16):1467–1470.
51. Bhatti T, Gillin JC, Seifritz E, Moore P, Clark C, Golshan S, Stahl S, Rapaport M, Kelsoe J.
Effects of a tryptophan-free amino acid drink challenge on normal human sleep electroencephalogram and mood. Biol Psychiatry 1998; 43(1):52–59.
52. Bjork JM, Dougherty DM, Moeller FG, Swann AC. Differential behavioral effects of plasma
tryptophan depletion and loading in aggressive and nonaggressive men. Neuropsychopharmacology 2000; 22(4):357–369.
53. Badawy AA, Morgan CJ, Lovett JW, Bradley DM, Thomas R. Decrease in circulating tryptophan availability to the brain after acute ethanol consumption by normal volunteers: implications for alcohol-induced aggressive behaviour and depression. Pharmacopsychiatry 1995;
28(suppl 2):93–97.
53a. Neumeister A, Konstantinidis A, Stastny J, Schwarz M, Vitouch O, Willeit M, Praschak-Rieder
N, Zach J, deZwaan M, Bondy B, Ackenheil M, Kasper S. Association between serotonintransporter gene promotor polymorphism (5-HTTLPR) and behavioral responses to tryptophan
depletion in healthy women with and without family history of depression. Arch Gen Psychiatry 2002; 59:613–620.
54. Price LH, Malison RT, McDougle CJ, Pelton GH, Heninger GR. The neurobiology of tryptophan depletion in depression: effects of intravenous tryptophan infusion. Biol Psychiatry 1998;
43(5):339–347.
55. Price LH, Malison RT, McDougle CJ, McCance-Katz EF, Owen KR, Heninger GR. Neurobiology of tryptophan depletion in depression: effects of m-chlorophenylpiperazine (mCPP). Neuropsychopharmacology 1997; 17(5):342–350.
56. Neumeister A, Praschak-Rieder N, Hesselmann B, Vitouch O, Rauh M, Barocka A, Kasper
S. Rapid tryptophan depletion in drug-free depressed patients with seasonal affective disorder.
Am J Psychiatry 1997; 154(8):1153–1155.

Pathogenesis of Depression

559

57. Delgado PL, Price LH, Miller HL, Salomon RM, Aghajanian GK, Heninger GR, Charney DS.
Serotonin and the neurobiology of depression. Effects of tryptophan depletion in drug-freedepressed patients. Arch Gen Psychiatry 1994; 51(11):865–874.
58. Aberg-Wistedt A, Hasselmark L, Stain-Malmgren R, Aperia B, Kjellman BF, Mathe AA.
Serotonergic ‚vulnerability‚ in affective disorder: a study of the tryptophan depletion test andrelationships between peripheral and central serotonin indexes in citalopram-responders. Acta
Psychiatr Scand 1998; 97(5):374–380.
59. Bremner JD, Innis RB, Salomon RM, Staib LH, Ng CK, Miller HL, Bronen RA, Krystal JH,
Duncan J, Rich D, Price LH, Malison R, Dey H, Soufer R, Charney DS. Positron emission
tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced
depressive relapse. Arch Gen Psychiatry 1997; 54(4):364–374.
60. Neumeister A, Stastny J, Praschak-Rieder N, Willeit M, Kasper S. Light treatment in depression (SAD, s-SAD & non-SAD). In: Holick MF, Jung EG, eds. Biologic Effects of Light.
Basel: Kluwer Academic Press, 1999:409–416.
61. Neumeister A, Praschak-Rieder N, Besselmann B, Rao ML, Gluck J, Kasper S. Effects oftryptophan depletion on drug-free patients with seasonal affective disorder during a stable
response to bright light therapy. Arch Gen Psychiatry 1997; 54(2):133–138.
62. Neumeister A, Praschak-Rieder N, Hesselmann B, Vitouch O, Rauh M, Barocka A, Tauscher
J, Kasper S. Effects of tryptophan depletion in drug-free depressed patients who responded
to total sleep deprivation. Arch Gen Psychiatry 1998; 55(2):167–172.
63. Neumeister A, Praschak-Rieder N, Hesselmann B, Vitouch O, Rauh M, Barocka A, Kasper
S. Effects of tryptophan depletion in fully remitted patients with seasonal affective disorderduring summer. Psychol Med 1998; 28(2):257–264.
64 Moreno FA, Gelenberg AJ, Heninger GR, Potter RL, McKnight KM, Allen J, Phillips AP,
Delgado PL. Tryptophan depletion and depressive vulnerability. Biol Psychiatry 1999; 46(4):498–505.
65. Smith KA, Fairburn CG, Cowen PJ. Relapse of depression after rapid depletion of tryptophan.
Lancet 1997; 349(9056):915–919.
66. Leyton M, Young SN, Blier P, Ellenbogen MA, Palmour RM, Ghadirian AM, Benkelfat C.
The effect of tryptophan depletion on mood in medication-free, former patients with majoraffective disorder. Neuropsychopharmacology 1997; 16(4):294–297.
67. Lam RW, Bowering TA, Tam EM, Grewal A, Yatham LN, Shiah IS, Zis AP. Effects of rapid
tryptophan depletion in patients with seasonal affective disorder in natural summer remission.
Psychol Med 2000; 30(1):79–87.
68. Neumeister A, Habeler A, Praschak-Rieder N, Willeit M, Kasper S. Tryptophan depletion: apredictor of future depressive episodes in seasonal affective disorder? Int Clin Psychopharmacol 1999; 14(5):313–315.

22
Effects of Antidepressants on Speciﬁc
Neurotransmitters: Are Such Effects
Relevant to Therapeutic Actions?
BRIAN LEONARD
National University of Ireland
Galway, IrelandI.

INTRODUCTION

Depression is a growing burden, both in terms of quality of life of the patient and his or
her family and economic burden to society. Current projections indicate that the global
burden of depression will rank second only to ischemic heart disease by 2020 [69a], while
the current costs of depression are comparable to those of other major illnesses such as
cancer, AIDS, and coronary heart disease [42]. An additional factor that adds to the longterm clinical and economic impact of depression is its recurrence and chronicity. Yet
despite the adverse effects of depression on the patient and on society, for over 40 years
effective antidepressants have been available that can reduce the burden of the condition.
Indeed it has been calculated that of those depressed patients who seek treatment, lessthan half are prescribed antidepressants and, of these, only about 25% are adequately
treated [50]. This situation has led to the concept of the iceburg of depression, which
implies that only a minority of patients in the community suffering from the condition
are properly diagnosed and even fewer treated with an appropriate antidepressant in an
adequate dose for an adequate length of time. Consensus guidelines are available thatrecommend the appropriate dose and length of treatment necessary [11].
The advent of better tolerated antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs) and a host of second-generation antidepressants, combined withnumerous educational programs to increase the awareness of clinicians and the generalpublic of the burden of depression, has had only very limited impact on the diagnosis and
561

562

Leonardtreatment of the condition [27]. The reasons for this unfortunate state of affairs are numerous and complex [66], but the perception that the efﬁcacy of antidepressants is limited andthat their side effects are frequent and unacceptable to the patient undoubtedly contribute topoor compliance and treatment failure.
The purpose of this chapter is to consider some of the pharmacological factors that
may contribute to the limitations in the efﬁcacy of antidepressants and how these issues
are being addressed by the application of new research arising from studies of the etiology
of depression and how antidepressants may act on subcellular mechanisms within theneuron.
II. BIOLOGICAL MARKERS OF DEPRESSION
Over the past 10 years, a number of biological changes have been reported to occur fairly
consistently in untreated patients with major depression. These are summarized in Table
1. Such markers may have not only a diagnostic value but also a means to monitor treatment response. These markers may be divided into ﬁve main areas, namely those involving
changes in the neuroendocrine axis, in serotonin neurotransmission, in the sleep architecture, in brain structure, and, more recently, in the expression of genes that regulate neurotransmitter function. These will be brieﬂy considered.
A.

Changes in the Neuroendocrine Axis

It is well established that the hypothalamic–pituitary–adrenal (HPA) axis is hyperactivein patients suffering from major depression, particularly those with melancholic and/or
psychotic features [18,57,89]. The predominant abnormalities in the dysfunction of the
HPA axis in such patients include hypercortisolemia, increased 24-h urinary excretion ofcortisol, resistance to the suppression of cortisol by dexamethasone, a blunted adrenocorticotropic hormone (ACTH) response to corticotropic releasing factor (CRF), and hypersecretion of CRF. Most of these changes in the HPA axis are normalized following theeffective treatment of the depressed patient and would therefore appear to be state markersof the condition. Other factors that indicate that the HPA axis is hyperactive in depression
include an enlargement of the adrenal glands [87] and a hypersecretion of arginine vasopressin (AVP) by the pituitary gland [26]. It is also of interest that an increase in the sizeof the pituitary gland has been reported in a small group of patients with major depression[51], which lends support to the view that a hypersecretion of CRF is a major factor incausing these changes in the HPA axis.
1. Role of CRF in Depression
It is widely accepted that stress acts as a major trigger factor in depression in geneticallyvulnerable individuals. CRF, together with AVP, plays a major role in the physiologicaland behavioral responses to stress. For example, in experimental studies it has been shownthat the central administration of CRF produces symptoms such as anorexia, loss of libido,
disruption of the sleep proﬁle, and changes in general activity that simulate those seen inpatients with major depression [102]. CRF produces its physiological effects by stimulating CRF1 and CRF 2 receptors. These receptors are members of the G-protein-coupledfamily, which stimulates intracellular adenylate cyclase activity. Both types of CRF receptor occur in the brain, but it would appear that the CRF1 receptors are particularly involved
in mediating the central components of the stress response and also the main symptoms

Antidepressant Effects on Neurotransmitters

563

Table 1 Some Biological Markers Found in Depressed Patients
Changes in the neuroendocrine axis
A. Evidence of HPA axis hyperactivity
Increased urinary free cortisol
Dexamethasone nonsuppression
Blunted ACTH response to CRF challenge
Elevated concentration of CRF in the CSF
Hypertrophy of the adrenal and pituitary glands
B. Changes in the HPT axis
Blunted TSH response to TRF
Elevated concentration of TRH in the CSF
Autoimmune thyroiditis
C. Changes in somatostatin
Decreased concentration of somatostatin in the CSF
Changes in serotonin neurotransmission
A. Reduced concentration of 5HIAA in the CSF of suicide attempters
B. Reduced brain and platelet afﬁnity of serotonin transporter for 3H-serotonin
C. Increased density of 5HT receptors on platelet membrane
D. Decreased platelet aggregation induced by serotonin
E. Decreased free plasma tryptophan
Changes in other neurotransmitters
A. Increased platelet α2-adrenoceptors and lymphocyte beta-adrenoceptors
B. Increased functional activity of the cholinergic system
C. Reduced concentration of HVA in the CSF
Changes in the sleep architecture
A. Reduced REM latency
B. Decreased delta-wave sleep
C. Redistribution of REM sleep during the night phase
Changes in brain structure
A. Presence of subcortical and periventricular hyperintensities
B. Decreased hippocampal and temporal lobe volumes
C. Reduction in neurogenesis and increased apoptosis (?)
Changes in immune system
A. Evidence of immune activation as shown by increased plasma proinﬂammatory
cytokines and acute phase proteins
B. Decrease in T-cell replication and natural killer cell activityof depression that arise as a consequence of an increase in HPA axis activity [1]. In
addition to its role in activating the HPA axis, CRF also activates receptors located on
the raphe and locus coeruleus, the main serotonergic and noradrenergic cell bodies in thebrain, circuits long postulated to be involved in the etiology of anxiety and depression.
While there has been much attention directed toward the role of CRF as the primary
regulator of the HPA axis, more recently attention has been directed toward the role of564

Leonard

AVP, a peptide that is known to act synergistically with CRF on the adenohypophysis toelevate the plasma ACTH concentration. Dinan et al. [26] have shown that whereas the
CRF-induced elevation of ACTH was blunted in patients with major depression, the CRF
plus AVP response was unchanged in these patients. They interpret this as evidence infavor of a decreased sensitivity of the CRF1 receptor, but an increase in the activity ofthe vasopressin V1b receptor in depression, which implies that there is a switch in theregulation of the HPA axis in which the vasopressin pathway become hyperactive while
the CRF pathway is hypoactive. This contributes to the hypercortisolemia that characterizes depression.
In addition to the changes in CRF and AVP receptor function in depression, there
is also evidence that the glucocorticoid receptor feedback mechanism is dysfunctional.
Two types of glucocorticoid receptor have been identiﬁed in the brain, namely, type 1(mineralocorticoid) and type 2 (glucocorticoid) receptors. These receptors have different
afﬁnities for glucocorticoids, the former having a high afﬁnity for the steroids that is
important in the regulation of the basal secretion of cortisol and the latter having a low
afﬁnity for the steroids, therefore regulating the stress-induced hypersecretion of cortisol.
There is evidence that in depression or following chronic stress, the glucocorticoid type
2 receptors are desensitized and therefore less likely to respond to feedback inhibition
following the elevation in the plasma cortisol concentration. Both types of receptor are
widely distributed in the brain, particularly in those regions assumed to be important indepression.
Given the close association between major depression and hypercortisolemia, it is
not unreasonable to speculate that the changes in central neurotransmitter function thatare assumed to underlie depression are secondary to those occurring in the HPA axis [25].
This hypothesis is supported by the observation that glucocorticoid synthesis inhibitors,
such as ketoconazole, and receptor antagonists, such as metyrapone, exhibit antidepressantactivity presumably by normalizing the inhibitory feedback mechanism thereby leading
to a reduction in circulating glucocorticoids [108]. Another approach to the treatment ofdepression has been to block the hypersecretion of CRF by the administration of CRF1
receptor antagonists. This approach has led to the development of a series of CRF1 receptor antagonists that exhibit anxiolytic activity in rodent models of stress, depressions, andanxiety [75].
2. Changes in the Hypothalamic–Pituitary–Thyroid–Axis in Depression
Prange et al [85] ﬁrst reported that approximately 25% of patients with major depression
but with normal plasma concentrations of thyroid stimulating hormone (TSH) and thyroid
hormones showed a blunted TSH response following the administration of thyrotropin
stimulating hormone (TRH). This observation has been widely replicated. While the mechanism underlying such changes is uncertain, it has been shown that the cerebrospinal ﬂuid
concentration of TRH is signiﬁcantly elevated in depressed patients [5], which suggeststhat TRH is hypersecreted. This could contribute to the hyperplasia of the pituitary gland,
which has been detected in patients with major depression.
3. Changes in Growth Hormone Secretion in Depression: Involvementof Somatostatin
Somatostatin (SRIF) inhibits the release of growth hormone (GH) in addition to TSH,
prolactin, cholecystokinin, and vasoactive intestinal peptide (VIP). Several studies haveshown that the CSF concentration of SRIF is reduced in depressed patients, a change that

Antidepressant Effects on Neurotransmitters565

has been shown to correlate with the dexamethasone nonsuppressor status of the patients[29,38]. These changes in SRIF thus correlate with those seen in the HPA axis. Although
the precise role of SRIF in depression is uncertain, it has been hypothesized that the
peptide may play a role in cognitive function in addition to its regulatory effect on the
HPA axis. It is well known that cognitive dysfunction frequently occurs in patients suffering from chronic depression [21] and other major psychiatric conditions.
4. Changes in Serotonergic Neurotransmission in Depression
Interest in the role of serotonin in mood disorders stems from the early clinical studies
that demonstrated that the concentration of the main serotonin metabolite 5-hydroxyindolecetic acid (5HIAA) was reduced in the CSF of depressed patients who had attempted
violent suicide [2] and similar changes were reported to occur in depressed patients who
had successfully committed suicide [105]. The decrease in the functional availability ofserotonin that such ﬁndings suggest may be linked to increased impulsivity, which is afeature not only of suicidal behavior but also of alcoholism, compulsive gambling, andaggression.
A number of investigators have conﬁrmed the original observation that the numberof 3H-imipramine binding sites on the platelet membrane is reduced in untreated depressed
patients [10,81,103], while others have reported that a reduction in the number of 3Himipramine binding sites occur in the cortex and hypothalamus of suicide victims who
were depressed at the time of their death [83]. As the decrease in the imipramine bindingsites does not apparently change following effective antidepressant treatment, it can beconcluded that such a parameter may be a suitable trait marker for depression. More recently, the speciﬁc ligand for the serotonin transporter 3H-paroxetine has been used and,at least in some studies [63], has also been shown to exhibit reduced binding in depressed
patients.
Platelets are, like neurons, of ectodermal origin and contain enzymes such as enolasethat are otherwise restricted to neurons. In addition, platelets contain storage vesicles forserotonin from which the amine is released by a calcium-dependent mechanism. An
energy-dependent transport site for the uptake of serotonin also occurs on the platelet
membrane, the structures of which are identical to those that found in the brain. A detailed
discussion of the importance of platelets in psychiatric research has been the subject ofa recent review [56]. The platelet membrane also contains both 5HT2 and α2-adrenoceptors
that are functionally involved in platelet aggregation; there is evidence that the densitiesof these receptors are increased in patients with depression and return to control values
following effective treatment [13,14,45,46]. The transport of 3H–5HT into the platelet issigniﬁcantly reduced in untreated patients with depression, but largely returns to normal
following effective treatment [54]. Thus it appears that the changes in adrenoceptor andserotonin receptor densities and serotonin transport are state markers of depression andoccur regardless of the nature of the antidepressant treatment.
The function of the 5HT2 receptor appears to be subnormal in depression, as shownby a diminished aggregatory response to serotonin in vitro [14]; the function normalizes
following effective antidepressant treatment. Conversely, the density of 5HT2 receptors
on the platelet membrane is increased in the untreated depressed patient which suggeststhat the link between the receptor and the second messenger system is malfunctional,
presumably at the level of the G-protein. While it is uncertain how these changes in platelet
serotonin function are reﬂected in the brain, there is evidence from studies in which thechanges in serotonin transport in platelets and neurons was compared in a bulbectomized

566

Leonardrat model of depression that the neuronal transporter is also defective [15]. These changes
could be a reﬂection of the hypercortisolemia that is a feature not only of the depressed
patient but also of the olfactory bulbectomized rat. There is also evidence that the changes
could be due to low-molecular-weight plasma factors that impede the serotonin transporter
prior to effective antidepressant treatment [74a]. There is evidence, however, to support
the view that changes in the mobility of calcium within the platelet are key factors indetermining the abnormal responsiveness of the platelets to agonists such as serotonin
and thrombin [33].
Patients undergoing treatment with SSRI antidepressants have been shown to relapse
rapidly when given an amino acid–containing drink that is deﬁcient in tryptophan [22].
The onset of the symptoms of depression is rapid (within 24 h) and it has been proposedthat the lowering of the mood of the patients is due to a reduction in brain serotonin synthesis. This view is supported by experimental studies in which rats, given a tryptophanfree ﬂuid, show a reduced release of serotonin from the frontal cortex. Delgado et al. [22]also showed that those depressed patients who had responded to the noradrenaline reuptake
inhibitor desipramine did not relapse when given the tryptophan-free drink but did relapse
when given the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine. These ﬁndings
raise the question of whether depressed patients may have a deﬁcit in noradrenaline orserotonin that may account for the differential response to the serotonin- or noradrenalinedepleting agents. However, this would conﬂict with the widely observed situation wheremost classes of antidepressants are effective regardless of their presumed speciﬁcity forthe noradrenergic or serotonergic systems.
5. Changes in Sleep Architecture in Depression
The development of all-night electroencephalographic (EEG) monitoring has enabled investigators to objectively and precisely assess the degree of sleep disturbance in depressed
patients. From such studies it has been established that there are four main types of abnormality found in depressed patients. These are a shortened rapid eye movement (REM)
sleep latency, increased REM activity, reduced delta slow-wave sleep, and a disturbancein the overall continuity of sleep [52]. Sleep EEG studies may become an important areafor understanding the neurobiology of depression in the future. For example, the sleep
EEG at baseline and following the acute administration of a tricyclic antidepressant may
predict the response of the patient to antidepressant therapy. Similarly the change in REM
sleep latency may help to identify those patients who are at risk for early and more frequent
recurrences of depression following effective treatment. These aspects have been reviewed
by Buysse and Kupfer [16]. The detection of REM sleep abnormalities in depressed patients and in their biological relatives may be a useful means of examining the familial
and genetic aspects of the condition in the future [20].
6. Changes in Brain Structure in Depression
McDaniel and Nemeroff [61] brieﬂy reviewed the literature that indicated that changes
in brain structure frequently occur in patients with major depression. Thus enlarged ventricles, particularly lateral ventricles, have been identiﬁed by CAT and MRI imaging techniques and there is some evidence that the cerebellar vermis is smaller in patients withmood disorders than in healthy controls. In addition, there is evidence that there is a higher
rate of subcortical and periventricular hyperintensities in elderly depressed patients.
However, changes in brain structure also occur in other psychiatric conditions andAntidepressant Effects on Neurotransmitters567

the precise relevance of the structural changes seen in depressed patients to the symptoms
exhibited and to their response to treatment is unknown.
Recently, attention has been directed to changes in hippocampal structure in depression. Thus several studies have shown that chronic stress or the administration of glucocorticoids causes neuronal atrophy, reduced neurogenesis, and cell death in experimental animals. In brain imaging studies of patients with depression it has been demonstrated thathippocampal volume is reduced [9,90]. In addition, in patients with Cushing’s disease or
adrenal hypertrophy, a reduction in the hippocampal volume has been reported which isreversed following the reduction in the circulating glucocorticoid levels. In the elderly
depressive, the changes in hippocampal volume have also been shown to correlate with
deﬁcits in memory [58a]. Such ﬁndings lend support to the hypothesis that the changes inbrain structure seen in depression are correlated with hypercortisolemia, although inﬂammatory processes involving such cytokines as interleukin 1, 2 and tumor necrosis factor(TNF)-alpha may also play an important role. With regard to atrophic changes in the prefrontal cortex, brain-imaging studies have demonstrated that both the structure and theblood ﬂow to the area is reduced in depressed patients [30]. In addition, both the numberof neurons and the glia in the prefrontal cortex and the orbitofrontal cortex have been shown
to be reduced [86]. These structural changes in brain regions concerned with memory andcognition may be of importance in understanding the cause of such symptoms in depression.
7. Polymorphisms of the Enzymes Involved in Monoamine Synthesis
as Possible Factors in Depression
In humans, it has been estimated that there are approximately 100,000 genes, each ofwhich has a characteristic pattern of expression in different cells and tissues. The individual differences, polymorphisms, are useful genetic markers but may also represent pathological mutations at the level of the single gene. These mutations are unique, necessary,and sufﬁcient to engender a hereditary disease. So far, however, there is no evidence thatsuch a mutation occurs in any of the affective disorders. In addition to these rare mutations,most common variations at the genomic level that are responsible for the uniqueness ofeach individual are not pathological but they may intervene in the regulation of gene
expression. As a consequence, they may interact with environmental factors, shape quantitative traits, and thereby contribute to a pathological change. Thus, depression, genes may
increase the risk whereby the disorder is expressed.
In depression, the monoamine neurotransmitters are thought to play a crucial roleand twin, adoption, and family segregation analyses have established that there is a strong,albeit complex, genetic component to the disorder. Thus the enzymes that control thesynthesis of these neurotransmitters may be strong candidate genes. In summary, it has
been shown that the tryptophan hydroxylase gene is associated with impulsivity and violent suicide and that some investigators have identiﬁed an allelic form (the U-allele) that
correlates with aggression and anger-related personality traits in some individuals [10].
In another study of patients in Finland, two polymorphic forms of the tryptophan hydroxylase gene have been correlated to suicidality [72]. In regard to tyrosine hydroxlase, there
is conﬂicting evidence in the literature regarding the link between different polymorphic
forms of this enzyme and depression in patients with bipolar disorder [65]. No evidenceof a linkage between the DOPA-decarboxylase and the dopamine-beta-hydroxylase genes
and psychiatric disease have so far been found. Clearly this is an important area for future
research into the role that abnormal allelic forms of the enzymes and receptors that are
involved in neurotransmission may play in depression.

568

LeonardIII. EFFICACY OF ANTIDEPRESSANTS AND LIMITATIONS
OF CLINICAL TRIALS IN ASSESSING EFFICACY
The efﬁcacy of antidepressants in the treatment of depression has been well establishedin randomized controlled trials [37,99]. Such studies have demonstrated that taking theantidepressant at an effective dose for an adequate period reduces the number and severityof the acute symptoms, improves the ability of the patient to function, and minimizes therisk of relapse and recurrence. In major depression, pooled data from meta-analyses ofclinical trials have demonstrated similar efﬁcacy in all classes of antidepressants and superiority to placebo [3]. However, the conditions under which clinical trials are conducteddiffer considerably from clinical practice. Typically such trials take place in highly selected populations treated under controlled and optimal conditions, with treatment determined by clear study protocol. This type of study reduces the potential for bias and ensuresthat any differences detected are attributable to the drugs under investigation. In contrast,
treatment conditions in general practice do not involve patient selection or randomizationin addition to variations in the behavior of prescribers and patients and in the systems ofhealth care in which the treatment is delivered [95]. Thus the efﬁcacy of randomized
controlled trials, while important in the selection of an antidepressant, is a reﬂection of
the efﬁcacy of the drug under standardized and optimal conditions. A more useful concept
has been termed “real world efﬁcacy,” and concerns the use of the antidepressant to ensurethat the desired outcome of treatment can be achieved [66]. This approach may lead toan overestimation of the efﬁcacy of an antidepressant as demonstrated by clinical trials.
Thus the widely quoted efﬁcacy of antidepressants in achieving 60% response after 6 to
8 weeks of treatment, with placebo treatment achieving a 30% response, may be overoptimistic in the “real world” situation. A discussion of the importance of efﬁcacy of antidepressants versus their effectiveness in clinical practice has been the subject of a recent
review [28].
While a detailed discussion of the differences between the efﬁcacy and effectivenessof antidepressants is beyond the scope of this chapter, a brief summary will be given since
it impacts upon the differences between various classes of antidepressants in current use.
For example, the tolerability of an antidepressant would be anticipated to inﬂuence boththe adherence of the patient to treatment, the duration of treatment, and the consequent
outcome of treatment. Thus the selective serotonin uptake inhibitors (SSRIs) are generally
considered to be better tolerated with an improved adverse effect proﬁle when comparedto the older tricyclic antidepressants [23,68]. This is conﬁrmed in studies where the percentage of patients who discontinue treatment has been evaluated [69]. However, it is
now apparent that differences arise between antidepressants of the same class. For example, early studies showed that the pharmacological differences between the SSRIs were
small and none has been shown to be consistently better tolerated [36,53]. However, following their extensive use, differences have been shown in their side effect proﬁles. Thus
paroxetine has the highest incidence of anticholinergic side effects associated with its
antimuscarinic activity at normal therapeutic doses [24], while citalopram has been associated with some sedation at higher therapeutic doses because of its slight afﬁnity to histamine-1 receptors [36]. Fluoxetine has been reported to produce an increase in the frequency of anxiety-related symptoms including nervousness and agitation [24,60], together
with weight loss and anorexia [85a]. Conversely, weight gain has been associated withparoxetine and citalopram [8,34]. However, based on data from clinical practice, the incidence of adverse events has been reported to be the highest with ﬂuvoxamine [59], particu-

Antidepressant Effects on Neurotransmitters569

larly in terms of gastrointestinal events, although paroxetine and sertraline have also beenreported to cause a higher frequency of such side effects than occurs with citalopram andﬂuoxetine. Sexual dysfunction is a common side effect of all the SSRIs but appears to
be more frequent after paroxetine and sertraline [59]. This summary serves to illustrate
the differences between controlled clinical trial data and that obtained in “real world”
settings. Whereas the former show no signiﬁcant differences between the SSRIs, community-based studies demonstrate important differences between them that could have a bearing on compliance and therefore efﬁcacy.
A. Limitation of Clinical Trials of Antidepressants
A typical trial of an antidepressant consists of groups of 50 to 60 patients, including aplacebo-treated arm and a reference drug, usually amitriptyline or imipramine, assigned
to patients in a second arm. Such trials usually last 6 to 8 weeks even though the recommended duration of treatment in clinical practice is at least 6 months. Most clinical protocols do not provide justiﬁcation for the sample size or even specify the statistical power.
As the proportion of nonresponders to antidepressant treatment ranges from 20 to 30%,
and the low statistical power for showing any differences between treatments together
with the usual exclusion of noncompliant subjects from the ﬁnal analysis, it is unlikelythat any absolute difference would emerge between a new and a standard antidepressant.
In practice, this means that virtually all clinical trials only show equivalence between a
new and a standard antidepressant and little difference in clinical efﬁcacy. It has been
estimated that the sample size that would be required in order to show a difference of 5%
between two drugs, assuming 20% nonresponders to treatment, would be between 1250
and 2380 patients per arm of the trial [11]. This implies that the widely held view that
all antidepressants, regardless of their presumed mechanism of action, are only effective
in about 70% of depressed patients, is more a reﬂection of the limited design of clinical
trials than the real potential differences.
IV. HOW DO ANTIDEPRESSANTS WORK? THE LIMITATIONS
OF THE AMINE HYPOTHESISIt is widely accepted that, despite the success of antidepressants in treating the symptoms
of major depression for the past 40 years, little advance has been made in improving the
efﬁcacy or time of onset of such treatments. Undoubtedly there are many reasons for thisbut an important reason may rest with the assumption that as all effective antidepressantsmodulate the function of noradrenaline and/or serotonin in the brain, the biogenic amines
probably play a deﬁnitive role in their mechanism of action. This is the basis of the monoamine hypothesis of depression that has played an important role in the development of
antidepressants and in interpreting the pathological basis of depression over the past 40
years. However, in recent years, evidence has emerged that challenges the amine hypothesis and links the therapeutic effects of antidepressants to the subcellular changes that occur
distal to the neurotransmitter receptor. In addition, other approaches have considered therole of excitatory neurotransmitters such as glutamate and inﬂammatory mediators suchas the proinﬂammatory cytokines in the etiology of depression and in the mechanism ofaction of antidepressants. Such approaches may serve not only to enrich our understandingof depression but also to facilitate in the development of novel approaches to its treatment.
These possibilities will now be discussed.

570

A.

Leonard

The Action of Antidepressants on Subcellular Processes

Studies on the action of stress and antidepressants suggest that changes in the basic mechanisms that underlie neural plasticity are involved in the etiology and treatment of depression. Thus exposure to stress, which is a major trigger factor in precipitating depression,
opposes the mechanisms that underlie neural plasticity involved in learning and memory.
Conversely, antidepressant treatments induce changes in signal transduction and gene expression that could either block the effect of stress or induce the appropriate response inneuroplasticity.
In the past, research into the mechanism of action of antidepressants has focused on
the proximal actions of antidepressants (such as effects on amine reuptake and intracellular
metabolism) or on the adaptive changes in noradrenergic or serotonergic receptors. Such
adaptive changes include the “downregulation” of beta-adrenoceptors, 5HT2, and 5HT7
receptors [19,31]. Such discoveries lead to the monoamine hypothesis of depression becoming the monoamine receptor adaptation hypothesis. However, this hypothesis has its
limitations. For example, some beta-adrenoceptor agonists have been shown to exhibit
antidepressant properties whereas it would be anticipated that such drugs would precipitate
depression. Furthermore, desensitization of beta receptors by antidepressants occurs withina few days even though it takes several weeks for the drugs to show a therapeutic response.
With regard to the changes in the density of 5HT2 receptors, not all antidepressants desensitize these receptors. electroconvulsive shock treatment increases the density of 5HT2 receptors in rat brain. Thus it seems reasonable to hypothesize that adaptive changes in postsynaptic intracellular sites, rather than in postsynaptic receptors per se, may be critical to theaction of all antidepressant treatments.
One signal transduction pathway that is regulated by antidepressant treatment is
the cyclic AMP intracellular cascade and recent studies have demonstrated that chronic
antidepressant treatment results in the upregulation of this system. Thus it has been shownthat antidepressant treatment increases the activation of adenylyl cyclase by the stimulatory G protein, Gs, in limbic regions of the rat brain [78]. In addition, it has been shownthat chronic, but not acute, antidepressant treatments increase the activity of camp-dependent protein kinase [70,82]. As such, antidepressant treatments also increase the activityof protein kinase A in nuclear fractions from rat brain, and it appears that gene transcription
factors are regulated by these changes. This is supported by the ﬁnding that the response of
the camp response element binding protein (CREB) is increased by antidepressant treatment[71]. Thus, the expression of CREB mRNA and protein was shown to be upregulated bychronic, but not acute, antidepressant treatments; both SSRI and SNRI antidepressants were
found to produce similar responses, which suggests that such changes may be a common
action of antidepressants that modulate the noradrenergic and serotonergic systems.
CREB regulates gene transcription by binding to a speciﬁc nucleotide sequence, thecamp response element (CRE), in the promotor region of the gene. Although CREB may
remain bound to DNA under basal conditions, activation of this transcription factor occurs
primarily via phosphorylation at Ser 133. Chronic antidepressant treatments have also
been shown to increase the phosphorylation of CREB in rat hippocampus, and in several
other structures including the cerebral cortex [104]. Thus CREB may act as a common
postreceptor target for different classes of antidepressants [31].
In support of the hypothesis that antidepressants activate speciﬁc target genes, experimental studies have shown that the regulation of neurotrophic factor gene expression
is of particular interest. The nerve growth factor (NGF) family includes brain-derived
neurotrophic factor (BDNF), neurotrophin-3, and neurotrophin-4. These neurotrophic fac-Antidepressant Effects on Neurotransmitters

571

tors have been shown to regulate the guidance and survival of neurons in both the immatureand the mature brain, where they inﬂuence both neuronal ﬁring and synaptic plasticity.
These actions are dependent upon the activation of tyrosine kinase receptors (Trk)[88].
Of these Trk receptors, TrkA is selective for nerve growth factor, TrkB for BDNF, and
TrkC for neurotrophin-3. Activation by these receptors results in autophosphorylation ofseveral intracellular sites.
The link between these intracellular changes and stress is provided by the observation that immobilization stress in rats causes a decrease in the concentration of BDNF in
the hippocampus. This effect is mediated by high concentrations of glucocorticoids [98].
Chronic antidepressant treatments have been shown to increase the expression of BDNF
in the hippocampus [71]. This increase in the concentration of BDNF was not found tooccur following the chronic administration of psychotropic drugs which lack antidepressant activity. These results suggest that antidepressants block the effect of stress by increasing the synthesis of BDNF. In addition, BDNF has been shown to have antidepressanteffects when administered chronically to rats subjected to the forced-swim and learned
helplessness models of depression [96]. Thus BDNF may provide a ﬁnal common pathway
for the action of antidepressants.
Chronic stress, glucocorticoid treatment, and prolonged episodes of depression all
result in neuronal atrophy and reduced neurogenesis. Thus it has been shown that thevolume of the hippocampus is reduced in those suffering from depression or post-traumaticstress disorder [9,90]. In patients with Cushing’s disease, these changes are reversed when
the corticosteroids return to basal concentrations. Such results lend support to the hypothesis that the hypersecretion of cortisol, which is a common feature of major depression,plays a crucial role in initiating the intracellular changes that result in neuronal atrophyand cell death and has been the subject of a recent review by McEwen and Magarinos[62]. This is supported by the ﬁndings that the volume of the prefrontal cortex is decreased,
together with a reduction in blood ﬂow, in depressed patients [30]; the number of cells
in the prefrontal cortex is also decreased in the postmortem brain of depressed patients[77]. Thus, chronic stress and depression appear to be part of a continuum that ultimately
results in premature neuronal death; effective antidepressant treatments appear to blockthese adverse effects possibly by enhancing the synthesis of neurotrophic factors such as
BDNF. This forms the basis of the neurotrophic hypothesis of depression ﬁrst proposed byDuman and coworkers [31]. The importance of this hypothesis is that it not only proposes acommon site of action of the different classes of antidepressants but also convincingly
accounts for the delay in the onset of action of these drugs. In addition, the neurotrophic
hypothesis suggests novel ways in which antidepressants may be developed by acting on
targets that selectively enhance neurotrophic factors in the brain. Regarding the psychopathology of depression, this hypothesis suggests that it is a subtle neurodegenerative disorder and that early diagnosis and vigorous antidepressant treatment is important for preventing the degenerative changes. However, much of the research that has been describedabove is based on animal studies and clearly needs to be replicated, if possible, in depressed patients. Extrapolation from the results of animal studies to humans must always
be treated with caution!
B. The Action of Antidepressants on Nonaminergic
Neurotransmitters
Whereas much emphasis has been placed on the monoamine neurotransmitters with respect to the mode of action of antidepressants, little attention has been given to the possible

572

Leonardrole of the glutamatergic system which is the primary excitatory pathway in the brain[109]. There is experimental evidence to show that tricyclic antidepressants inhibit thebinding of dizolcipine (MK-801) to the ion channel of the main glutamate receptor, theN-methyl-D-aspartate (NMDA) receptor.
These initial studies have been extended to show that both typical and atypical antidepressants have a qualitatively similar effect of inhibiting the binding of dizolcipine tothe ion channel of the NMDA receptor [50a]. Whether this is because of the direct actionof antidepressants on the ion channel or an indirect effect, possibly by enhancing theaction of glycine on the glycine receptor which forms part of the NMDA receptor complex
on the cell surface, is uncertain. However, there is evidence that glycine and drugs that
directly stimulate the glycine site on the NMDA receptor [74] have antidepressant-like
properties in animal models of depression. Thus, the possibility arises that antidepressantsselectively enhance glutamatergic activity in the brain by modulating the glycine site.
Support for the role of the NMDA receptor system in depression and in the mode of actionof antidepressants is provided by studies in suicide victims who suffered from depression.
Thus, Nowak et al. [73] and Paul [80] have shown that the high-afﬁnity binding of a
selective ligand (3H-CGP-39653) to the glycine site for cortical tissue is reduced in suicide
victims; a dysfunctional NMDA receptor complex seems to be involved in the psychopathology of suicide and presumably depression. It is also of interest to note that intravenously administered ketamine, a NMDA receptor antagonist, has been reported to produce
a rapid antidepressant response in patients with major depression [6].
The central cholinergic system has also been neglected as a possible site of action,of antidepressants. The anticholinergic activity of tricyclic antidepressants is usually associated with their unacceptable peripheral side effects, which most second-generation drugs
lack. However, there is experimental evidence to show that different classes of antidepressants increase the density of muscarinic (MI) receptors in rat brain after chronic administration. This applies regardless of the actions of the drugs on peripheral cholinergic function [32]. These ﬁndings provide support for the cholinergic hypothesis of depression. It
is of interest that studies in depressed patients have also led to the detection of an abnormality in the central cholinergic system. Thus O’Keane et al. [76] showed that the shortacting anticholinesterase, pyridostigmine, when administered to drug-free depressed patients, caused an enhanced release of growth hormone from the pituitary gland. Thissuggests that the cholinergic receptors are supersensitive in depressed patients and that
one of the actions of antidepressants is to normalize the functioning of these receptors.
The mechanism whereby antidepressants bring about these changes is presently unknown
but is unlikely to be direct. It is of interest that Janowsky et al. [48] postulated that depression arises as a result of an imbalance between the central cholinergic and noradrenergic
systems within the brain. Janowsky postulated that depression arises as a consequence ofan overactivity of the cholinergic system, whereas mania is a consequence of an overactivity of the noradrenergic system. Experimental evidence suggests that all antidepressants,
regardless of their presumed mode of action, enhance central noradrenergic function. Thus,
the cholinergic hypothesis proposes that the central cholinergic system is overactive in
depression and that chronic antidepressant treatments reduce this system by enhancing
noradrenergic function and/or by enhancing the activity of the glycine site on the NMDA
receptor.
In addition to changes in the major excitatory neurotransmitter glutamate there isalso evidence that antidepressants modulate the action of the principal inhibitory transmitter, gamma-amino butyric acid (GABA). Over 20 years ago it was shown that the concen-

Antidepressant Effects on Neurotransmitters573

tration of GABA in the cerebrospinal ﬂuid and plasma from depressed patients is reduced[49,83a]. Experimental studies have also shown that different classes of antidepressants,
including ECT, increased the density of GABA-B receptors in the frontal cortex and hippocampus of rat brain [58,84]. Other experimental studies in which several GABAmimetic
drugs were tested also showed that they had a similar behavioral proﬁle in the olfactorybulbectomized rat model of depression to standard antidepressants [106]. The possible
mechanism whereby antidepressants modulate GABA-B receptor activity is uncertain, butthere is evidence that GABA-B receptors may act as heteroceptors on serotonergic terminals in limbic regions of the rat brain [41]. Thus it was shown that the GABamimetic
drug progabide increased the head-twitch response induced by serotonin in rodents; thedensity of cortical 5HT2 receptors was also shown to be increased under these conditions.
Thus, it would appear that the functional changes in the GABAergic system are closelyinterrelated to those in the serotonergic and noradrenergic systems.
C. The Link Between the Monoaminergic Systems
and the Speciﬁcity of Antidepressants
The ability of most classes of antidepressants to modulate beta-adrenoceptors and 5HT2
receptors in the frontal cortex of the rat brain following their chronic administration suggests that an important interaction occurs between these two neurotransmitter systems.
There is abundant evidence from experimental studies to show
1. Lesions of the central serotonergic tracts prevent the reduction in the densityof cortical beta-adrenoceptors that follows the chronic administration of desipramine, a noradrenaline reuptake inhibitor [127].
2. In vitro studies have shown that stimulation of beta-adrenoceptors in corticalslices of rat brain is associated with an increase in the density of 5HT2 receptors[92], whereas α2-adrenoceptor antagonists such as yohimbine can enhance thedesensitization (downregulation) of both the beta-adrenoceptors and the 5HT2
receptors.
3. The α2-agonist clonidine causes locomotor hypoactivity in rodents, which isenhanced following lesions of the central serotonergic system [44a]. These investigators also showed that such treatment attenuated the reversal of the clonidine hypoactivity caused by the chronic administration of desipramine. These
results suggest that sedrotonin, or a peptide cotransmitter contained within serotonergic neurons [35], modulates noradrenergic function.
4. Gravel and De Montigny [40] showed that lesions of central noradrenergic neurons with 6-hydroxydopamine failed to enhance the responsiveness of hippocampal pyramidal neurons to microiontophoretically applied serotonin without
affecting the responsiveness to noradrenaline or acetylcholine. This suggeststhat the integrity of the noradrenergic system is essential for antidepressants tomodulate central serotonergic function.
5. Several studies have investigated the role of serotonin in the regulation ofnoradrenaline-coupled adenylate cyclase in the rat cortex. Gillespie et al. [39]showed that although in vitro serotonin did not affect the maximum binding of
the beta-adrenoceptor antagonist 3H-dihydroalprenolol to cortical tissue, it did
abolish the increase in beta-adrenoceptor density, and the increase in isoprenaline-induced cAMP synthesis in cortical membranes following the selective lesions of the serotonergic tracts. These investigators also showed that the changes

574

Leonardin beta-adrenoceptor density were restricted to the low-afﬁnity conformation
state for the agonist and that the increase in the density of this subpopulationof receptors occurred approximately 11 days following the lesions of the serotonergic system. From these and other investigations, it appears that the pivotal
role of serotonin in the dual regulation of the linked serotonin–noradrenaline
beta-adrenoceptor-coupled adenylcyclase system acts at a different site to noradrenaline. Thus noradrenaline regulates the population of beta-adrenoceptors
in the antagonist high-afﬁnity state whereas serotonin regulates those in the lowafﬁnity state.
The results of these studies serve to illustrate the interaction that occurs between
the serotonergic and noradrenergic systems within the brain and helps to explain the resultsof behavioral studies in which chronically administered antidepressants, regardless of their
speciﬁcity for the noradrenergic or serotonergic systems in in vitro studies, or following
their acute administration to rats, enhances both noradrenergic and serotonergic function
following their chronic administration [43].
In addition to the experimental evidence that the serotonergic and noradrenergic
systems are integrally linked, there is also evidence that serotonin can regulate dopamine
turnover in the brain. Over 20 years ago it was demonstrated that in depressed patients
positive correlation exists between the cerebrospinal ﬂuid concentrations of the major
dopamine metabolite homovanillic acid and the main serotonin metabolite 5-hydroxyindole indole acetic acid (5HIAA) [4]. Experimentally it has been shown that stimulationof the serotonergic cell bodies in the median raphe nucleus reduces the ﬁring of the substantia nigra, a main dopaminergic area of the brain. In addition, there is evidence to showthat different classes of antidepressants decrease the functional activity of presynaptic
dopamine receptors as demonstrated in rats by the antagonism of the locomotor effect oflow doses of apomorphine. This effect was only observed following the chronic administration of the drugs [44]. Such ﬁndings imply that the effects of antidepressants, despite
their apparent selectivity in acute studies and in in vitro preparations, could be equally
ascribed to changes in all the monoaminergic systems that are functionally interrelated.
Presumably the improved sense of pleasure and reward that effective antidepressant treatments induce is partly attributable to the increase in the functioning of the dopaminergic
system in mesocortical regions of the brain.
D.

The Modulatory Effects of Antidepressants on Proinﬂammatory
Cytokines

Stress is frequently a trigger factor for depression in vulnerable patients. There is clinicalevidence, already referred to above, that the concentration of corticotropin-releasing factor
is increased in the CSF of depressed patients which contributes to the hypercortisolemiathat usually occurs in major depression. It would therefore be assumed that a sustained
increase in the cortisol concentration would result in a suppression of humoral and cellularimmunity that could help to explain the susceptibility of depressed patients to an increased
risk of cancers, infections, and autoimmune diseases. However, despite the well-established ﬁndings that there are profound changes in both humoral and cellular immunity indepression [55,63], there is clear evidence from both depressed patients and the bulbectomized rat model of depression [101] that activation of some aspects of cellular immunity
also occurs despite the rise in circulating glucocorticoids. One possible explanation of thisparadox is related to the decrease in the sensitivity of the glucocorticoid receptors locatedAntidepressant Effects on Neurotransmitters575

on the immunocytes, a situation that is analogous to the decrease in the sensitivity of thecentral glucocorticoid receptors to feedback inhibition that occurs in the depressed patient.
It is known that chronic antidepressant treatment not only normalizes the functioning of
the HPA axis but also the immune changes that occur in depression [79].
Despite the complexity of the interactions that occur between the proinﬂammatory
cytokines, central neurotransmitters, and glucocorticoids, there is growing evidence tosupport the view that the proinﬂammatory cytokines play a primary role in the etiology
of depression [7]. This forms the basis of the macrophage hypothesis of depression [98].
This hypothesis postulates that the macrophages in both the periphery and in the brain
where microglia and astrocytes perform the function of macrophages) are overactive in
depression and that many of the key symptoms of the disorder are a consequence of therelease of proinﬂammatory cytokines such as interleukins (IL)-1 and -6 and tumor necrosis
factor-alpha (TNF-α). Support for this hypothesis comes from studies of the effects ofproinﬂammatory cytokines and interferon-alpha in nondepressed patients undergoingtreatments for certain types of cancer. Such treatments frequently result in depressed mood,anxiety, cognitive impairment, loss of libido, anorexia, disturbed sleep proﬁle and generalfatigue, symptoms that are very similar to those occurring in patients with major depression[67]. Such changes would appear to be a consequence of the neurotransmitter and endocrine changes induced by the cytokines rather than a result of the pathological changes
induced by the cancer. Research into the immune changes that occur in depressed patients
has identiﬁed changes in the plasma proinﬂammatory cytokines, soluble cytokine receptors, and acute phase proteins. Thus Song et al. [100] have reported that the plasma concentrations of the positive acute phase proteins (alpha-1 acid glycoprotein, haptoglobin, andalpha-1 antitrypsin, for example) were raised in the depressed patient while negative acutephase proteins, such as albumin, were decreased. Such changes are a reﬂection of theactions of IL-1 and IL-6 on the liver. In addition, it has been shown that the complement
proteins (C3,C4, and immunoglobulin M) are increased in depressed patients [100]. Thisevidence implicates an activation of the immune system involving the proinﬂammatory
cytokines and the B cells that are responsible for antibody synthesis. Further evidence
that immune activation occurs in depression is provided by the studies of Sluzewska etal. [93], who showed that the plasma concentrations of the proinﬂammatory cytokines andthe soluble IL-6 and IL-2 receptors and IL-1 receptor antagonist, were raised in depressed
patients. These changes returned to normal following effective antidepressant treatment[94]. How these alterations in immune function are linked to those in the central neurotransmitters is unclear. But there is evidence that the serum antibody titers to serotonin
are increased which, if present in the brain, could impair serotonergic function [91]. In
addition, it has been shown that the serium and CSF concentrations of prostaglandins (PG)
E1 and E2 are increased in depressed patients. These changes are at least partly initiatedby the stimulation of cyclooxygenase activity by the proinﬂammatory cytokines within
the brain [17].
The rise in the concentrations of the prostaglandins may contribute to the central
deﬁcit in monoamine neurotransmitter function due to a reduction in the release of monoamines. This, together with the increased release of CRF caused by the proinﬂammatory
cytokines, may provide a link between immune activation, central neurotransmitter dysfunction, and the onset of depression. To date, relatively few studies have examined theeffects of antidepressant treatments on these changes. However, there is some evidence
that effective antidepressant treatment is correlated with a reduction in the activated immune system, which suggests that many of these changes are state-, rather than trait-,

576

Leonarddependent markers of depression. Thus antidepressants act as immunomodulators that
normalize the immune function that characterizes the condition. If the macrophage hypothesis of depression is correct, then it may be argued that antidepressants ﬁrst reduce thesynthesis and release of the proinﬂammatory cytokines from activated macrophages andrelated immunocytes. The precise mechanism whereby this occurs is unknown but could
involve an antidepressant-induced increase in anti-inﬂammatory cytokines (such as IL-410, and –13) and soluble antagonists (such as IL-1 receptor antagonist) coupled with areduction in the synthesis of PGE-1 and –2. Maes [64] has reviewed the immunomodulatory effects of antidepressants.
Despite the substantial body of evidence that implicates a disorder of immune function with depression, controversy exists regarding the causal connection between the increase in proinﬂammatory cytokines, PGEs, and the symptoms of the disorder. However,consideration of these factors is important in stimulating new concepts regarding the etiology of depression and how antidepressants bring about their therapeutic effects.
V.

CONCLUSIONSThe precise mechanism of action of antidepressants still remains an enigma. Nevertheless,evidence from both clinical and experimental studies suggests that all effective antidepressants, regardless of their presumed selectivity of action determined by acute experimental
studies, ultimately bring about adaptive changes in both monoaminergic and nonaminergic
systems. This raises some important and fundamental questions. If, for example, the SSRI
antidepressants do not inhibit serotonin reuptake into platelets from depressed patients(despite their proven effect in healthy volunteers and in rat brain), their classiﬁcation as
selective serotonin reuptake inhibitors is a misnomer [47]. Similarly, SNRI antidepressantsaffect the turnover of serotonin following their chronic administration and also normalize
the defective reuptake of 3H serotonin into platelets from depressed patients, thereby losing
their presumed selectivity. Such ﬁndings lend support to the hypothesis that the neuralnetwork of interconnected neurotransmitter systems is malfunctioning in depression andthat all antidepressants, by initially acting at different parts of the network, eventuallybring the system back to homeostasis. Clearly, the monoamine hypothesis of depression,
despite its value in the past, needs to be radically restructured or even replaced to take into
account the latest research emanating from molecular biology. The increasingly important
contribution of molecular biology to our understanding of the mode of action of antidepressants, and indirectly to the biology of depression, has helped to focus attention on thechanges that occur in the secondary and tertiary messenger systems and, ultimately, in gene
expression. These intracellular changes only occur following the chronic administration ofantidepressants and are independent of the type of antidepressant. From experimental studies, it appears that speciﬁc neurotrophic factors provide the ﬁnal common pathway that
leads to changes in synaptic plasticity and improved neuronal contacts.
In addition to the changes in various neurotransmitter systems that occur in depression and following chronic antidepressant treatment, attention has recently focused on the
HPA axis and the immune system. The profound changes in these systems that occur in
depression probably contribute to those in neurotransmitter function that are directly linked
to the behavioral state. Such studies have also served to direct the attention of researchers
to a more holistic interpretation of depression rather than restricting studies to the brain
alone. This approach may help to explain the increased morbidity and mortality due toinfectious disease, heart disease, cancer, and autoimmune diseases that frequently occur

Antidepressant Effects on Neurotransmitters577

in patients with major depression. The decade of the 1970s was largely devoted to an
explanation of the mode of action of antidepressants in terms of their effects on the concentrations of amines and their metabolites. In the 1980s, emphasis switched to the adaptivechanges in postsynaptic monoamine receptors, while in the 1990s attention was directed to
the link between the postsynaptic receptors and the second and tertiary messenger systems.
Perhaps in this present century there will be a shift in emphasis away from the monoaminesto the endocrine and immune systems as causal factors in depression and in the mode ofaction of antidepressants.
REFERENCES
1.
2.
3.
4.
5.
6.
7.

8.
9.
10.
11.
12.
13.
14.
15.

16.
17.
18.
19.

Arborelius L, Owens M, Plotsky P, Nemeroff CB. The role of corticotrophin-releasing factor
in depression and anxiety disorders. J Endocrinol 1999; 160:1–12.
Asberg M, Traskman L, Toren P. 5HIAA in the cerebrospinal ﬂuid: a biochemical suicide
predictor. Arch Gen Psychiat 1976; 33:1193–1197.
Anderson IM. Selective serotonin reuptake inhibitors verses tricyclic antidepressants: a metaanalysis of efﬁcacy and tolerability. J Affect Dis 2000; 58:19–36.
Agren H. Symptom patterns in unipolar and bipolar depression correlates with monoamine
metabolites in the CSF 2. Suicide. Psychiat Res 1980; 3:225–236.
Banki CM, Bissette G, Arato M, Nemeroff CB. Elevation of immunoreactive CSF-TRH in
depressed patients. Am J Psychiat 1998; 145:1526–1531.
Berman RM, Cappirello A, Anand A, Oren DA, Heninger GR, Antidepressant effects ofketamine in depressed patients. Psychiat Res 2000; 51:107–114.
Bluthe RM, Casanon N, Pousset F, Bristow A, Ball C, Dantzer R. Central injection of IL10 antagonists antagonises the behavioural effects of lipopolysaccharide in rats. Psychoneuroimmunol 1996; 24:301–311.
Bouwer CD, Harvey BH. Phasic craving for carbohydrate observed with citalopram. Clin
Psychopharmacol 1996; 11:273-278.
Bremner JD, Narayan M, Anderson ER. Smaller hippocampal volume in major depression.
Am J Psychiat 1999; 157:115–117.
Briley MS, Langer SZ, Raisman R, Sechter D, Zariﬁan E. 3H-imipramine binding sites are
decreased on platelets from untreated depressed patients. Science 1980; 303:1209–1211.
Br Assoc Psychopharmacol. Guidelines for treating depressive illness with antidepressants.
J Psychopharmacol 1993; 7:19–23.
Brunello N, Chuang D, Costa E. Different synaptic localizations of mianserin and imipramine
binding sites. Science 1982; 215:1112–1114.
Butler J, Leonard BE. The platelet serotonergic system in depression and following sertraline
treatment. Int Clin Psychopharmacol 1988; 3:343–347.
Butler J, Leonard BE. Comparison of mianserin and dothiepin on the serotonergic systemof depressed patients. Hum Psychopharmacol 1990; 5:369–372.
Butler J, Tannian M, Leonard BE. The chronic effects of desipramine and sertraline on platelet and synaptosomal serotonin uptake on olfactory bulbectomised rats. Prog Neuro Psychopharmacol Biol Psychiat 1998; 12:585–594.
Buysse DJ, Kupfer DJ. Diagnostic and research applications of EEG sleep studies in depression: conceptual and methodological issues. J Nerve Ment Dis 1990; 178:405–414.
Calabrese J, Skwerter RG, Barna B. Depression, immunocompetence and prostaglandins of
the E-series. Psychiat Res 1986; 17:44–47.
Carroll BJ. The dexamethasone suppression test for melancholia. Br J Psychiat 1982; 140:
292–304.
Charne DS, Menkes DB, Heninger GR. Receptor sensitivity and the mechanisms of actionof antidepressant treatments. Arch Gen Psychiat 1981; 38:1160–1173.

578

Leonard20.

Coble PA, Scher MS, Reynolds CF. Preliminary ﬁndings of the neonatal sleep of offspringof women with and without a prior history of affective disorder. Sleep Res 1988; 17:120–
125.
Cook LL, Bissette G, Dole K, Nemeroff CB. A critical evaluation of cysteamine as a tool
to deplete somatostatin in the rat central nervous system. Endocrinology 1989; 124:855–
861.
Delgado PL, Charney DS, Price LH. Serotonin function and the mechanism of antidepressantaction: reversal of antidepressant induced remission by rapid depletion of plasma tryptophan.
Arch Gen Psychiat 1990; 47:411–418.
Demyttenaere K. Noncompliance with antidepressants: who’s to blame? Int Clin Psychopharmacol 1998; 13(suppl 2):S19-S25.
DeVane CL. Comparative safety and tolerability of SSRI’s. Hum Psychopharmacol 1995;
10(suppl 3):S185-S193.
Dinan TG. Glucocorticoids and the genesis of depressive illness: a psychobiological model.
Br J Psychiat 1994; 164:365-371.
Dinan TG, Lavelle E, Scott LV, Medbak S, Grossman A. Desmopressin normalises theblunted ACTH response to CRF in melancholic depression: evidence of enhanced vasopressinergic responsivity. J Clin Endoncrinol Metab 1999; 84:2238–2246.
Donoghue JM. Selective serotonin reuptake inhibitor use in primary care: a ﬁve year naturalistic study. Clin Drug Invest 1998; 16:453–462.
Donoghue J, Hylan TR. Antidepressant use in clinical practice: efﬁcacy verses effectiveness.
Br J Psychiat 2001; 179(suppl 42):S9-S17.
Doran AR, Rubinow DR, Roy A, Pickar D. CSF somatostatin and abnormal response to
dexamethasone administration in schizophrenia and depressed patients. Am J Psychiat 1986;
43:365-369.
Drevets WC, Price JL, Simpson JR. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997; 386:824-827.
Duman RS, Henninger GR, Nestler EJ. A molecular and cellular theory of depression. ArchGen Psychiat 1997; 54:597-606.
Earley B, Glennon M, Lally M Leonard BE, Junien J-L. Autoradiographic distribution ofcholinergic muscarinic receptors and 5HT-2 receptors in olfactory bulbectomized rats after
chronic treatment with mianserin and desipramme. Hum Psychopharmacol 1994; 9:397–407.
Eckert A, Gann H, Rieman D, Aldenhoff J, Muweller WE. Platelet and lymphocyte free
intracellular calcium in affective disorders. Eur Arch Psychiat Clin Neurosci 1994; 243:235–
239.
Fava M, Rosenbaum J, Hoog S. Fluoxetine verses sertraline and paroxetine in major depression: long term changes in weight. Eur Neuropsychopharmacol 1998; 8(suppl 2):S204.
Fillion G, Grimaldi B, Cloez-Tayarani I, Bonnin A, Fillion M-P. Modulation of the serotonergic system by 5 HT modulin. In: Briley M, Montgomery SA, eds. Antidepressant Therapy:
At the Dawn of the Millennium. London. Martin Dunitz, 1998: 55–68.
Finley APR. SSRI’s: pharmacological proﬁles and potential therapeutic distinctions. Ann
Pharmacother 1994; 28:1359–1369.
Geddes JR, Freemantle N, Mason J. SSRI’s verses alternative antidepressants in depressive
disorder. Cochrane Library Issue 4: update software.
Gerner RH, Yamada T. Altered neuropeptide concentrations in cerebrospinal ﬂuid of psychiatric patients. Brain Res 1982; 238:298–302.
Gillespie DD, Mnaier DH, Sanders-Bush E, Sulser F. The serotonin/norepinephrine link in
brain 2. Role of serotonin in the regulation of beta adrenoceptors in low agonist afﬁnity
conformation. J Pharmacol Exp Therap 1988; 244:154–167.
Gravel P, de Montigny C. Noradrenergic denervation prevents sensitisation of rat forebrainneurons to serotonin by tricyclic antidepressant treatment. Synapse 1987; I:233–240.
Gray JA, Metz A, Goodwin GM, Green AR. The effects of GABA-mimetic drugs, progabide

21.

22.

23.
24.
25.
26.

27.
28.
29.

30.
31.
32.

33.

34.
35.

36.
37.
38.
39.

40.
41.

Antidepressant Effects on Neurotransmitters579

and baclofen, on the biochemistry and function of serotonin and noradrenaline. Neuropharmacol 1986; 23:711–718.
42. Greenberg P, Stiglin LE, Finkelstein S. The economic burden of depression in 1990. J Clin
Psychiat 1993; 54:405–418.
43. Harkin A, Kelly JP, McNamara M, Connor TJ, Dredge K, Redmoind A, Leonard BE. Activity
and onset of action of reboxetine and effect of combination with sertraline in animal; modelof depression. Eur J Pharmacol 1999; 364:123–132.
44. Hassan F, Leonard BE. Changes in behaviour and neurotransmitter metabolism in the rat
following acute and chronic sulpiride administration. In: Ackenheil M, Matussek N, eds. Special Aspects of Psychopharmacology. Paris: Expansion Scientiﬁque Francaise, 1983: 67–82.
44a. Heal DJ. The effect of drugs on behavioural models of central noradrenergic function. In:
The pharmacology of noradrenaline in the central nervous system. Heal DJ, Marsden CA,
eds. Oxford, UK: Oxford University Press, 1990: 266–315.
45. Healy D, Carney PA, Leonard BE. Monoamine related markers of depression: changes following treatment. J Psychiat Res 1983; 17:251–260.
46. Healy D, O’Halloran A, Carney PA, Leonard BE. Peripheral adrecoceptors and serotoninreceptors in depression: changes associated with trazodone and amitriptyline. J Affect Disord
1985; 9:285–296.
47. Healy D, O’Halloran A, Leonard BE. Increase in platelet serotonin uptake rates following
treatment with uptake drugs. Int Clin Pharmacol 1986; 1:332–339.
48. Janowsky DS, Risch SC, Kennedy B. Central muscarinic effects of physostigmine on mood,cardiovascular function, pituitary and adrenal neuroendocrine release. Psychopharmacology
1986; 89:150–154.
49. Kasa K, Otuki M, Iyamamoto M, Suto H, Juroda H, Ogawa N. CSF GABA and homovanillicacid in depressive disorders. Biol Psychiat 1982; 17:877–882.
50. Katon W, van Korff M, Lin E. Adequacy and duration of treatment in primary care. Med
Care 1992; 39:67–76.
50a. Kitayama I, Yaga T, Kayahara T. Long term stress degenerates but imipramine regenerates
noradrenergic axons in the rat cerebral cortex. Biol Psychiat 1997; 42:687–696.
51. Krishnan KRR, Doraiswamy PM, Lurie SN. Pituitary size in depression. J Clin Endocrinol
Metab 1990; 75:256–259.
52. Kupfer DJ, Thase ME. The use of the sleep laboratory in the diagnosis of affective disorders.
Psychiat Clin N Am 1983; 6:3-25.
53. Leonard BE. The comparative pharmacology of new antidepressants. Clin Psychiat 1993;
15(suppl 3):54–58.
54. Leonard BE. Effect of antidepressants on speciﬁc neurotransmitters: are such effects relevantto their therapeutic action? In: Den Boer AJ, Sitsen JMA, eds. Handbook of Depression andAnxiety. New York: Marcel Dekker, 1994: 379–404.
55. Leonard BE. Brain cytokines and psychopathology of depression. In: Leonard BE, ed. Antidepressants. Basel: Birkhauser Verlag, 2000: 109–122.
56. Leonard BE. Platelets in psychiatric and neurological disorders. In: Platelets. In press.
57. Linkowski P, Mendlewicz J, Lclerq R. The 24 hour proﬁle of ACTH and cortisol in major
depressive illness. J Clin Endocrinol Metab 1985; 61:429–438.
58. Lloyd KG, Thuret F, Pilc A. Upregulation of GABA-B binding sites in rat frontal cortex: acommon action of repeated administration of different classes of antidepressants and ECS.
J Pharmacol Exp Therap 1985; 235:191–203.
58a. Lupien SJ, de Leon M, de Santi S, Convit A, Tarshish C, Nair NP. Cortisol levels during
human aging predict hippocampal atrophy and memory deﬁcits. Nature Neurosci 1998; 1:
69–73.
59. MacKay FR, Dxunn NR, Wilton LV. A comparison of ﬂuvoxamine, Fluoxetine, Sertraline,
and Paroxetine examined by observational; cohort studies. Pharmacoepidemiol Drug Safety
1997; 6:235–246.

580
60.

Leonard

MacKay FR, Martin RM. Newer antidepressants: a comparision of their tolerability in genera;practic. Br J Gen Pract 1999; 49:892–896.
61. McDaniel JS, Nemeroff CB. Depression in the cancer patient. In: Chapman CR, Foley, KM,
eds. Current Emerging Issues in Cancer Pain—Research and Practice. New York: Raven
Press, 1993: 1–19.
62. McEwen BS, Magarinos AM. Stress and hippocampal plasticity: implications for thepathophysiology of affective disorders. Hum Psychopharmacol 2001; 16(suppl 1):S7–
S20.
63. Maes M, Smith R, Scharpe S. The monocyte and T-lymphocyte hypothesis of major depression. Psychoneuroendocrinology 1995; 20:111–116.
64. Maes M. The immunoregulatory effects of antidepressants. Hum Psychopharmacol 2001;
16:95–103.
65. Meloni R, Biguet NF, Mallet J. Polymorphisms of the enzymes involved in monoaminesynthesis. In: Briley M, Sulser F, eds. Molecular Genetics of Mental Disorders. London:
Martin Dunitz, 2001:205–220.
66. Mendlewicz J. Optimising antidepressant use in clinical practice: towards criteria for antidepressant selection. Br J Psychiat 2001; 179(suppl 42):S1-S3.
67. Meyers CA, Valentine AD. Neurological and psychiatric adverse effects of immunologicaltherapy. CNS Drugs 1995; 3:56-68.
68. Montgomery SA, Kasper S. Side effects and drop outs from antidepressant treatment andcost consequences. Int Clin Psychopharmacol 1998; 13(suppl 2):S1-S5.
69. Montgomery SA, Henry J, McDonald G. Selective serotonin reuptake inhibitors: meta-analysis of discontinuation rates. Int Clin Psychopharmacol 1994; 9:47–53.
69a. Murray CJ, Lopez AD. Evidence based health policy-lessons from the global burden of disease study. Science 1996; 274:740–743.
70. Nestler EJ, Terwilliger RZ, Duman RS Chronic antidepressant administration alters the subcellular distribution of cyclic AMP-dependent protein kinase in rat frontal cortex. J Neurochem 1989; 53:1644–1647.
71. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain bychronic ECS and antidepressant drug treatments. J Neurosci 1995; 15:7539–7547.
72. Nielsen DA, Jenkins GL, Stefanisko KM. Sequence, splice site and population frequency
distribution analysis of the polymorphic human tryptophan hydroxylase intron 7. Brain Res
Mol Brain Res 1997; 45:145–148.
73. Nowak G, Ordway GA, Paul IA. Alterations in the NMDA receptor complex in the frontal
cortex of suicide victims. Brain Res 1995; 675:157–164.
74. Nowak G, Redmond A, McNamara M, Paul IA. Swim stress increases the potency of glycine
at the NMDA receptor complex. J Neurochem 1995; 64:925–927.
74a. Nugent D, Dinan D, Leonard BE. Alteration by a plasma factor(s) of platelet aggregationin unmedicated unipolar patients. J Affect Disord 1994; 31:61–66.
75. O’Brien D, Skelton KH, Owens MJ, Nemeroff CB. Are CRF receptor antagonists potential
antidepressants? Hum Psychopharmacol 2001; 16:81–87.
76. O’Keane V, O’Flynn K, Lucey J, Dinan TG. Pyridostigmine involved growth hormone response in healthy and depressed patients—evidence for cholinergic supersensitivity in depression. Psychol Med 1992; 22:55–60.
77. Ongur D, Drevets WC, Price JL. Glial loss in the subgenual prefrontal cortex in familial
mood disorders. Abs Soc Neurosci 1998; 24:990.
78. Ozawa H, Rasenick MM. Chronic ECS treatment augments coupling of the GTP-binding
protein Gs to the catalytic moiety of adenylyl cyclase in a manner similar to that seen withchronic antidepressant drugs. J Neurochem 1991; 56:330–338.
79. Pariante CM, Pearce BD, Pisell TL, Owens MJ, Miller AH. Steroid independent translocationof the glucocorticoid receptor by the antidepressant desipramine. Eur Neuropsychopharmacol
1997; 7:184.

Antidepressant Effects on Neurotransmitters
80.

581

Paul IA. NMDA receptors and affective disorder. In: Skolnick PP, ed. Antidepressants: New
Pharmacological Strategies. Towowa, NJ: Humana Press, 1997: 145–158.
81. Paul SM, Rehavi M, Skolnick P, Ballenger JC, Goodwin FK. Depressed patients have decreased binding of 3H-imipramine to the platelet serotonin transporter. Arch Gen Psychiat
1981; 38:1315-1319.
82. Perez J, Tinelli D, Brunello N, Racagni G. Camp dependent phosphorylation of soluble andcrude microtubule fractions of rat cerebral cortex after prolonged desipramine treatment. Eur
J Pharmacol 1989; 172:305–316.
83. Perry EK, Marshall EF, Blessed BE, Tominson BE, Perry RH. Decreased imipramine binding
in the brains of patients with depressive illness. Br J Psychiat 1983; 141:188–192.
83a. Petty F, Sherman AD. Plasma GABA levels in psychiatric illness. J Affect Dis 1984; 6:131–
138.
84. Pilc A, Lloyd KG. Chronic antidepressants and GABA-B receptors: a GABA hypothesis ofantidepressant drug action. Life Sci 1984; 35:2149–2156.
85. Prange AJ, Wilson IC, Rabon AM, Lipton MA. Enhancement of imipramine antidepressantactivity by thyroid hormone. Am J Psychiat 1969; 126:457–469.
85a. Preskorn SH. Comparison of the tolerability of buproprion, ﬂuoxetine, imipramine, nefazodone, paroxetine, sertraline and venlafaxine. J Clin Psychiat 1995; 56(Suppl 6):12–21.
86. Rajkowska G, Miguel-Hidalgo JJ, Wei J. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiat 1999; 45:1085–1098.
87. Rubin RT, Phillips JJ, Sadow TF, McCracken JT. Adrenal gland volume in major depression:increased during the depressive episode and decreased with successful treatment. Arch Gen
Psychiat 1995; 52:213–218.
88. Russell DS. Neurotrophins: mechanism of action. Neuroscientist 1995; 1:3–6.
89. Sachar EJ, Hellman L, Fukushima DK, Gallagher RF. Cortisol production in depressive illness. Arch Gen Psychiat 1970; 23:289-298.
90. Sapolsky RM. Glucocorticoids and atrophy of the human hippocampus. Science 1996; 273:
749–750.
91. Schott K, Batra A, Klein R, Bartels M, Koch W, Berg P. Increased serum antibody titres toserotonin in depressed patients. Eur Psychiat 1992; 7:209–212.
92. Scott JA, Crews FJ. Down regulation of 5HT-2 receptors but not beta-adrenergic receptors
during chronic treatment with amitriptyline is independent of stimulation of 5HT-2 and betaadrenergic receptors. Neuropharmacol 1986; 25:1301–1311.
93. Sluzewska A, Rybakowski J, Bosmans E. Interleukin-6 serum levels in depressed patients
before and after treatment with ﬂuoxetine. Ann NY Acad Sci 1996; 62:474–477.
94. Sluzewska A, Rybakowski J, Laciak AM. Indication of immune activation in major depression. Psychiat Res 1995; 64:161–167.
95. Simon GE, Wagner E, van Korff M. Cost-effectiveness comparisons using real-world randomised trials: the case for new antidepressant drugs. J Clin Epidemiol 1995; 48:363–373.
96. Siuciak JA, Lewis DR, Wiegand SJ, Linsay RM. Antidepressant-like effects of BDNF. Pharmacol Biochem Behav 1996; 56:131-137.
97. Smith MA, Makino S, Kvetnansky R, Post RM. Stress alters the expression of BDNF andneurotrophic factor-3 mRNA in the hippocampus. J Neurosci 1995; 15:1768–1777.
98. Smith RS. The macrophage theory of depression. Med Hypothesis 1991; 35:298–306.
99. Song F, Freemantle N, Sheldon TA. Selective serotonin reuptake inhibitors: meta-analysis
of efﬁcacy and acceptability. Br Med J 1993; 306:683–687.
100. Song C, Dinan TG, Leonard BE. Changes in immunoglobulins, complement and acute phase
proteins in depressed patients and normal controls. J Affect Dis 1994; 30:283–288.
101. Song C, Leonard BE. The effects of olfactory bulbectomy in the rat alaone, and in combination with antidepressants and endogenous factors, on immune function. Hum Psychopharmacol 1995; 10:7–18.
102. Song C, Earley B, Leonard, BE. Behavioural, neurochemical and immunological response

582

103.
104.
105.
106.
107.
108.

109.

Leonardto CRF administration: is CRF a mediator of stress? Ann NY Acad Sci 1995; 771:55–
72.
Suranyi-Cadotte BE, Wood PL, Nain NP, Schwarz G. Normalisation of platelet 3H-imipramine binding in depressed patients following treatment. Eur J Pharmacol 1982; 85:357-362.
Thome J, Sakai N, Shin Kh. camp response element mediated gene transcription is up-regulated by chronic antidepressant treatment. J Neurochem 2000; 20:4030–4036.
Van Praag HM, Asnis GM, Kahn RS, Brown SL, Korn M. Monoamines and abnormal behaviour: a multi-aminergic perspective. Br J Psychiat 1990; 157:723–734.
Van Riezen H, Leonard BE. Effects of psychotropic drugs on the behaviour and neurochemistry of olfactory bulbectomised rats. Pharmacol Ther 1990; 47:21–34.
Virkkunen M, Goldman D, Nielsen DA, Linnoila, M. Low brain serotonin turnover rate andimpulsive violence. J Psychiat Neurosci 1995; 20:271–276.
Ur E, Dinan TG, O’Keane V, Grossman A, Besser M. Effect of metyrapone on the pituitaryadrenal axis and depression: relation to dexamethasone suppression status. Neuroendocrinology 1992; 56:533–539.
Watkins JC. L-glutamate as a central neurotransmitter: looking back. Biochem Soc Trans
2000; 28:297–310.

23
Pharmacotherapy of Depression:
The Acute and Long-Term
Perspective
ROBERT J. BOLAND
Brown University
Miriam Hospital/LifeSpan
Providence, Rhode Island, U.S.A.
MARTIN B. KELLER
Brown University
Providence, Rhode Island, U.S.A.

I.

INTRODUCTION

In the past several decades, we have seen important changes in the way that we view
depression. Previously seen as simply an episodic illness, we now appreciate a more longitudinal perspective. For many, depression is a chronic, lifetime illness. This change inperspective has also changed the treatment of depression. Although most research continues to concentrate on the acute treatment of the major depressive episode, a growing bodyof investigation is taking a more longitudinal view. We have begun a shift that includes
the investigation of antidepressant treatment at later stages of the disorder. This chapter
will explore part of this shift. This body of research continues to grow, but questions
remain unanswered, and these will be examined as well.
II. BASIC CONCEPT
A. Deﬁnition of Terms: The Change Points in Depression
Before discussing research on the treatment of depression, we must ﬁrst deﬁne terms. Thisis particularly important because early research on the longitudinal treatment of depression
583

584

Boland and Keller

was confused by conﬂicting and contradictory uses of terminology. It was for this reason
that a MacArthur Foundation task force [1] recommended that the change points be described with these terms: episode, remission, response, relapse, and recurrence (Fig. 1).
An episode can be thought of both conceptually and categorically. Conceptually, itis the acute episode of a disorder: if one is in the condition of having a disorder, one isexperiencing an episode. Such a conceptual deﬁnition is difﬁcult to demonstrate withreliability, and a categorical deﬁnition is necessary to reliably agree on when an episodehas started and ﬁnished. In general, an episode can be practically deﬁned as having acertain number of symptoms for a certain period of time. It relies more on statisticaldeﬁnitions than any “absolute” gold standard. In choosing such a deﬁnition, a decisionmust be made as to where to place the “bar” for a disorder: whether it should be conservative or liberal, and how much of what type of error to accept. This type of decision making
must be made at each change point of the disorder, both in terms of number of symptoms
and length of time.
Remission, conceptually, is the point at which an episode ends. It is deﬁned by anaccepted period of time in which an individual no longer meets (an agreed upon numberof ) criteria for the disorder. Remissions can be partial or full. In partial remission, an
individual still has more than minimal symptoms. Full remission is deﬁned as the point
at which an individual no longer meets criteria for the disorder and has no more thanminimal symptoms.
The terms discussed thus far relate to the natural history of depression and imply
no speciﬁc intervention. Some terms, however, are related to an intervention. A response,
for example, is a remission that is the result of a treatment intervention. All responses arereally “apparent” responses, because one can never fully establish a direct relationshipbetween treatment and remission. A remission that occurs proximately to an intervention
is, most likely, causally related. Similar to a remission, a response can also be full or
partial. Again, such terms can be deﬁned by setting a required number of symptoms.

Figure 1 The change points in depression. The arrows denote a hypothetical course oftreatment, superimposed on the natural course, beginning during the acute episode (arrow
1) and discontinuing after remission (arrow 2).

Pharmacotherapy of Depression

585

A relapse is deﬁned as the early return of symptoms following an apparent response.
Conventionally, continuation treatment means treatment during the initial 4 to 6 months
after response. Episodes that occur during this period are relapses.
A recovery is deﬁned as a full remission that lasts for a deﬁned period of time.
Conceptually, it implies the end of an episode of a disorder, not the disorder per se. An
episode that occurs after this period of recovery is called a recurrence. Treatment during
this period is referred to as maintenance treatment.
Differentiating between a relapse and a recurrence can be difﬁcult. During continuation treatment, one expects a relapse to occur soon after the discontinuation of treatment.
For a recurrence, a reemergence of symptoms does not necessarily occur soon after stopping treatment; actually, the opposite is often true, and the recurrence of symptoms is notcausally related to treatment discontinuation, but rather reﬂects a new episode of illness
altogether.
The introduction of clinically useful biological markers for depression would makeit easier to deﬁne the beginning and end of an episode of depression. Until such markers
are introduced, these deﬁnitions represent reasonable working deﬁnitions and are used bymost of the studies that are reviewed here.
B. Longitudinal Course Modiﬁers for Depression
The concept of longitudinal change points was added to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) [2]. DSM
depressive diagnoses (major depression and dysthymia), and the variety of longitudinalpresentations were incorporated in the DSM-IV longitudinal course modiﬁers (Fig. 2).
For these modiﬁers, major depression was divided based on whether episodes are single
or recurrent, whether there is an interepisode recovery, and whether there is concomitant
dysthymia in addition to the episodes. Combining these variables yields several possible
courses: (1) single episode without antecedent dysthymia; (2) single episode with antecedent dysthymia; (3) recurrent, with full interepisode recovery, with no dysthymic disorder;(4) recurrent, without full interepisode recovery, with no dysthymic disorder; (5) recurrent,with full interepisode recovery, superimposed on dysthymic disorder; and (6) recurrent,
without full interepisode recovery, superimposed on dysthymic disorder (i.e., double depression).
The Mood Disorders Field Trial for DSM-IV [3] examined the frequencies of thedifferent possible courses (Fig. 3). Of these courses, several are important from a treatment
perspective. Course 1 (single episode without antecedent dysthymia) is the “classic” typeof major depression in which there is a single episode with full recovery. As seen in Figure
3, however, this type of depression does not represent the majority of cases of major
depression. Also important is recurrent depression, with and without full interepisode recovery (3 and 4); and its treatment will be discussed shortly.
Chronic depression also has various types. There are patients with types of depression who do not fully recover and may go on to develop a chronic condition, such as
major depression (Fig. 2). However, there are other chronic depressions that may be lesssevere than major depression, but still debilitating. The most common is dysthymia, inwhich the symptoms may be less severe than those for major depression, but still debilitating. Besides dysthymia, there may be various “subsyndromal” depressions in which thelevel of symptomatology is not sufﬁcient to meet the criteria for major depression or evendysthymia. Though minor, however, the persistence of even a few depressive symptoms

586

Boland and Keller

Figure 2 Longitudinal course modiﬁers. (Adapted from DSM-IV.)
can cause disability, and the longitudinal factors may be as important in considering disability from a mood disorder as cross-sectional factors.
III. THE COURSE AND TREATMENT OF DEPRESSION
A.

Acute Depression

1. The Problem of Acute Depression
In the United States, the lifetime prevalence rate of major depression is estimated at 17%[4], which is consistent with several other epidemiological studies conducted in different
regions of the world [5,6].
The morbidity and mortality from major depression are comparable to that found inother chronic medical conditions. Wells and colleagues, for the Medical Outcomes Study,
found that the disability from depressive symptoms and disorders was comparable with orworse than that for eight major chronic medical disorders [7]. Estimates are that the economic
costs associated with major depression in the United States are more than $53 billion per year[8]. The World Health Organization calculated that, in 1990, depression was the most costlyof all medical illnesses in the developed countries of the world [9].
2. Treatment of an Acute EpisodeA great deal of data exist to support the contention that treatment of depression can shorten
the time to recovery. Such data represent the primary justiﬁcation for the use of antidepres-Pharmacotherapy of Depression

587

Figure 3 Prevalence of DSM-IV–deﬁned course types. Classic “acute depression” is separated from the rest. (Data from the Mood Disorders Field Trial).

sant medications and several psychotherapies. Though some individual studies occasionally suggest an increased efﬁcacy of one antidepressant compared with others, the weightof evidence suggests that the efﬁcacy of all available antidepressants is approximately thesame [10]. Although antidepressants vary greatly in their pharmacokinetic proﬁles (halflife, time until steady state, and solubility) and differ widely in their potency for various
receptors and transporters, their pharmacodynamic effects are surprisingly similar. Thus,
all antidepressants show a similar delayed onset of action (approximately 2–6 weeks),and have about the same efﬁcacy rate (about 60–70%) in treating an acute depressive
episode. (These efﬁcacy studies will not be reviewed in detail here because they are detailed in all standard reference texts on psychiatry.) There has been considerable successin improving pharmacokinetic proﬁles, particularly those factors affecting safety and tolerability. However, improving such pharmacodynamic factors as efﬁcacy and time to effecthas been more difﬁcult. There is some evidence for newer compounds with unique tomultiple modes of action, with preliminary but hopeful evidence of improved efﬁcacy[11] and time to effect [12]. Although research in this area shows some promise, it should
be noted that the primary challenge in treating acute episodes of depression is not so muchin ﬁnding newer and better treatments, but in ensuring that patients receive such treatment.
The Collaborative Depression Study (CDS) and other naturalistic studies continue to support the assertion that only a minority of patients with major depression will receive adequate treatment for their disorder [8].
B. Relapse and the Continuation Period
1. The Problem of Relapse
Approximately 20% of patients who recover from major depressive episodes will experience a relapse of symptoms after initial recovery. For some of these patients (again, about20%), achieving a subsequent remission will be more difﬁcult. For the 141 patients in the
CDS who recovered from their index episode of major depression, 22% relapsed within
1 year of follow-up [13]. Factors predicting a relapse included multiple episodes of major
depression, older age, and a history of comorbidity with another (non-mood) psychiatric588

Boland and Keller

Table 1 Relapse Rates Versus Placebo: Continuation Studies

Drug
Fluoxetine
Paroxetine
Sertraline
Citalopram
Mirtazapine
Nefazodone
Venlafaxine

Weeks oftreatment

Relapse(drug)%

Relapse(placebo)%

p value

52
52
44
24
40
36
52

26
16
13
11
19
17
22

57
43
46
31
44
33
55

⬍0.01
⬍0.001⬍0.001⬍0.05⬍0.001⬍0.05⬍0.001

illness. The number of previous episodes of depression was a particularly strong predictorof a relapse. For this relapsed group, the likelihood of remaining depressed for at least ayear after a relapse was 22%. Predictors of prolonged time to recovery included a longer
length of the index episode, older age, and a lower family income.
2. Treatment of Depression During the Continuation Period
The goal of continuation treatment is to prevent a relapse. Compared with the wealth ofdata about the treatment of acute depression, the data to guide us in continuation therapy
are much more limited. However, for most of the commonly used antidepressants there
exists at least one rigorous study to support the use of most of the currently used antidepressants, including the selective serotonin reuptake inhibitors (SSRI) ﬂuoxetine [14],paroxetine [15], sertraline [16], and citalopram [17], as well as venlafaxine [18], nefazodone [19], and mirtazapine [20]. Although the speciﬁc methodologies used differ, in general each study randomized patients to receive either the study drug or a placebo after anacute treatment phase. In each study, relapses were much higher among the placebo group(Table 1). Viewed in aggregate, these studies lend reasonable support for the belief thatmost antidepressants that are effective in the acute period also lessen the risk for relapse
during the continuation period.
C.

Recurrent Major Depression

1. The Problem of Recurrent Depression
The risk of recurrent depression is surprisingly high: the CDS found a 25 to 40% risk ofrecurrence after two years [21]. These rates continued to increase over time, which meansthat patients had a 60% risk of recurrence after 5 years, 75% after 10 years, and 87%
after 15 years [20]. Thus, the risk of recurrence increased with time, and there was no clear
plateau for this increase. This remained true with subsequent new episodes of depression
observed over the period of the study (Fig. 4).
2. Treatment of Recurrent Depression
Few data exist to guide us in the use of antidepressants during the maintenance period.
Prien and colleagues [22] reported on a 2-year maintenance study of patients with major
depression. In this study, patients successfully treated for acute depression were then randomized into a maintenance treatment phase using imipramine, lithium carbonate, bothdrugs, or placebo for 2 years beyond acute treatment. Of 150 patients beginning mainte-

Pharmacotherapy of Depression

589

Figure 4 Probability of recurrence of depression following the index and subsequent episodes of depression.
nance treatment, 36% did not have a recurrence of depression during the 2-year maintenance period. The lowest rates of recurrence were in the groups receiving imipramine, or
imipramine with lithium. The rate for these groups was 47%, which still seems uncomfortably high (Fig. 5).
A second study of maintenance treatment looked speciﬁcally at patients with a history of recurrence. This study, the Pittsburgh Study of Maintenance Treatment for Recurrent Depression [23], involved patients who ﬁrst were successfully treated for an acuteepisode of major depression, and then randomized into one of ﬁve treatment conditions:(1) monthly interpersonal psychotherapy (IPT) alone; (2) medication clinic and imipramine; (3) monthly IPT and placebo; (4) imipramine and placebo; and (5) imipramine andmonthly IPT. Of the 218 patients beginning the 3-year maintenance study, 106 completed
it. Patients receiving imipramine, either alone or in combination with interpersonal therapy, had an 80% chance of remaining well for the 3 years of the study (Fig. 6).
This study was then continued for another 2 years, albeit with a much smaller (n⫽20) sample of patients [24]. Those who had remained well for the 3 years of the initialstudy were randomized to receive either continued imipramine or placebo. The imipramine-treated group had a much lower rate of recurrence (10%) compared with the placebogroup (approximately 66%).
D. Chronic Major Depression
1. The Problem of Chronic Major Depression
The CDS found that most patients (70%) recovered from an episode of depression by theﬁrst year [25]. However, of those patients who did not recover by 1 year, 66% still had

590

Boland and Keller

Figure 5 Prien and colleagues: maintenance treatment with imipramine, with or withoutlithium.

Figure 6 The Pittsburgh Study of Maintenance Treatment for Recurrence.

Pharmacotherapy of Depression591

not recovered by 2 years, 40% by 5 years, and 23% by 10 years. By 15 years, the rateleveled off at about 20% [20]. The CDS observed multiple episodes of depression for asingle individual, and these rates were generally true for each individual episode, whether
it was the ﬁrst or the ﬁfth episode of depression (Fig. 7). Thus, there appears to be a
cumulative risk for developing chronic depression with multiple episodes.
2. Treatment of Chronic Major Depression
Most data on the treatment of chronic major depression focus on the acute phase of treatment (i.e., the treatment of a depressive episode in patients with a history of chronic major
depression). However, these data are still important because most antidepressant studies(particularly studies designed to assess efﬁcacy) speciﬁcally exclude patients with chronic
depression.
Kocsis and colleagues [26] studied the use of desipramine to treat chronic depression. Their study had three phases: an acute open treatment with desipramine (10 weeks),an open continuation phase (16 weeks), and a randomized placebo-controlled treatment
with desipramine for up to 2 years. Only patients successfully treated in the ﬁrst phase
continued on to the open treatment with desipramine. In the acute treatment phase, 41%of patients were full responders and 22% were partial responders. Sixty patients who were
either full or partial “remitters” continued onto the next phase. In the continuation phase,the majority of patients (83%) maintained their response status: 7 partial remitters became
full remitters; 3 full remitters became partial remitters; and 1 partial remitter relapsed. In
the maintenance phase, patients receiving a placebo were four times more likely than thetreatment group to have a recurrence of major depression.
A second study by Keller and colleagues used a similar approach of three phasesof treatment, with the beneﬁt of a large sample size and the ability to randomize subjects
at each phase. The treatment consisted of either sertraline or imipramine [27,28]. Similar
to Kocsis’s study, only full or partial responders proceeded to the next phase of the study.
In the acute phase of treatment, 60% of patients responded to treatment. Although therates of response were the same for both treatment groups, the sertraline group found the

Figure 7 Proportion of subjects recovering from the index and subsequent episodes ofdepression.

592

Boland and Keller

Table 2 Continuation Treatment of Chronic Depression:Acute-Phase Full Responders
Sertraline

Imipramine

Combined

140

88

228

11
12
17
71

9
15
13
73

11
13
15
72

n
Continuation status% discontinued% nonresponders% remaining partial responders% improved to full response

treatment to be more tolerable. Of the patients who had a full response during the acutephase, 72% continued to be full responders during the continuation phase. An additional
15% were partial responders, and 13% did not respond to treatment. Once again, treatment
response did not differ between the two treatment groups (Tables 2 and 3). In the maintenance phase, patients receiving a placebo were four times more likely to have a recurrenceof depression, a ﬁnding similar to that of Kocsis and colleagues.
Another study by Keller [29] has looked at the effect of combined medication andpsychotherapy in the treatment of chronic depression, with some surprisingly positiveﬁndings. In this study, 681 adults received acute-phase treatment with either 12 weeks ofnefazodone treatment, cognitive-behavioral therapy, or both. Approximately 50% of patients in both the medication-alone and psychotherapy-alone groups had at least satisfactory responses to treatment. Most interesting in this study was the fact that the combined
treatment (nefazodone and cognitive-behavioral therapy) had a much higher rate of response (73%) than with either treatment alone. Those patients who responded to the acutephase of treatment were then continued for a 52-week continuation phase. The great majority of patients (90%) in the continuation phase maintained their initial response; 90%of those in remission in the acute phase remained responders in the continuation phase.
Once again, the combined treatment group fared somewhat better than the monotherapy
groups [30].
E.

Other Affective Disorders

1. The Problem of Non-Major Depression
In addition to the major forms of depression, there are several minor, but signiﬁcant, forms
of depression, many of which can cause substantial morbidity. One of the most commonly
Table 3 Continuation Treatment of Chronic Depression:Acute-Phase Full Responders

N
Continuation status% discontinued% nonresponders% remaining partial responders% improved to full response

Sertraline

Imipramine

Combined

99

59

158

19
15
34
51

17
29
27
45

18
20
31
49

Pharmacotherapy of Depression

593

recognized forms of minor depression is dysthymia, which by deﬁnition is a chronic disorder and may occur in 3% of the population [31]. It has a long duration of illness, ranging
from 2 to 20 years with a mean of 5 years. In children, dysthymia has an average lengthof 3 years.
People suffering from dysthymia have an increased risk of major depression. Manypatients have both: the concurrent presence of major depression and dysthymia is double
depression. Double depression affects perhaps 30% of individuals with major depression[32]. Generally, remissions are not to states of euthymia but rather to dysthymia, andrelapses to major depression are perhaps twice as likely for those with double depression
than for patients with major depression alone [33].
Other forms of depression are less well understood but are beginning to be recognized more in the United States. Among these conditions is recurrent brief depression(RBD), which describes multiple brief occurrence of depressive symptoms that do notmeet the 2-week time criteria for major depression. The prevalence of this disorder may
be as high as that for major depression [34]. The lengths of episodes are short, around 3
to 5 days; however, the average number of episodes can be as high as 20 per year. During
these brief, but frequent, periods, an individual can meet the full criteria for major depression (except for the time criteria)—thus, for individuals with RBD, a good proportion of
the year will be spent coping with the disruption of serious depressive symptoms. Currently, RBD is included in the Appendix of the DSM-IV under Criteria Sets and Axes
Provided for Further Study as research criteria.
Similarly, minor depression is described in the Appendix of DSM-IV. This disorderappears to be a subthreshold variant of a major depression, in which individuals have fewer
than the required number of depressive symptoms. Otherwise, it appears to be similar incourse and outcome to major depression and is probably at least as common [35]. Althoughminor depression is less severe and impairing than major depression, these patients areoften less likely to receive treatment, the assumption being that treatment is either ineffective or not needed for this “less serious” disorder.
2. Treatment of Other Affective Disorders
The treatment of minor and subthreshold forms of depression remains controversial. Because of difﬁculties in recognition and diagnosis, these disorders have been grossly undertreated. For example, in one study of the least controversial of these diagnoses, dysthymia,
only about half of the patients received psychotherapy and even fewer received pharmacotherapy [36].
For many years, pharmacotherapy was not considered a viable treatment for dysthymia and other minor depressions. This was largely due to the conceptualization of dysthymia and other disorders as more akin to personality disorders than to major depression.
Thus, there is a paucity of rigorous studies on the pharmacotherapy of dysthymia andother affective disorders that do not meet the criteria for major depression. Most published studies investigate the treatment of dysthymia and show at least modest responses
to medication [37]. Overall, randomized controlled studies show efﬁcacy for most available agents, including tricyclic antidepressants [38,39], serotonin reuptake inhibitors [40–43], and such atypical agents as ritanserin [44], moclobemide [45], and amisulpride [46](Table 4). As with major depression, there are no deﬁnitive data to suggest that any one
agent is more efﬁcacious that the other. Instead, the bulk of data suggests that any available
agent used for treating major depression is likely to be effective for treating dysthymia
and other forms of minor depression.

594

Boland and Keller

Table 4 Pharmacotherapy of Dysthymia

Drug
Imipramine
Desipramine
Fluoxetine
Sertraline

Ritanserin
Moclobemide
AmisulprideCompared toStudy

Durationof study(weeks)placebophenelzine, placebo
placeboplaceboplacebo
imipramine, placebo
imipramine
imipramine, placebo
placebo
imipramine, placeboamineptine, placebo
ﬂuoxetine

38
39
39
40,43
42
41
28
44
45
48
46
49

6
6
6
8;12
12
12
12
7
4
8
12
12

IV. SUMMARYA.

Unanswered Questions

The past several decades have changed our view of depression from an acute illness to
one with a variety of possible longitudinal courses. This chapter has discussed some ofthese longitudinal courses, and their implications for the outcome of depression. With abetter understanding of the course of depression, it becomes critical to examine the approach to treatment, including the use of pharmacotherapy. The critical issue is the optimal
length of treatment for depression. Clinical data and experience suggest that choices forduration of treatment tend to be made arbitrarily. Most treatment guidelines recommend
at least 16 to 20 weeks of pharmacotherapy [47]. The rationale for this recommendation
is based on data about relapse—most relapses will occur before this time. However, as
we have shown, a signiﬁcant number of relapses still occur after this period, and thequestion remains whether longer than conventional periods help decrease the rates ofrelapses in clinical samples. In addition, it remains unclear whether we can generalize
across different treatments and whether different agents, or different classes of agents, aremore likely to prevent relapses.
Beyond the question of treating an acute episode of depression, one must also consider when to choose longer term maintenance treatment. As we have discussed, as thelength of treatment time increases, the available data decreases, and we have surprisingly
little data to guide us in treatment decisions beyond 2 years. Currently, the standard recommendation is to offer long-term treatment to patients with histories of recurrent depression.
However, this recommendation, as well as suggested lengths of long-term treatment, isbased on a small amount of data. Finally, should antidepressant treatment ever be withdrawn from patients with recurrent depression and, if so, in what manner?
Dosing strategies during maintenance treatment are also understudied. In the 1970s
and 1980s, it was standard practice to treat at one-half the acute period dose; a decision
based largely on data from the Pittsburgh Maintenance Study [23], which found that patients kept at half of the acute dose had a higher recurrence rate during the maintenanceperiod than patients maintained on their original dose. This study used imipramine, andPharmacotherapy of Depression

595

there is a paucity of data comparing maintenance dosing strategies for other agents; thus,
the question of maintaining a patient on acute dosing with newer agents is not answered.
Other treatment questions remain unanswered as well. Anecdotally, most patients,and some clinicians believe that the effects of antidepressants tend to “wear off” overtime. No data exist to support this belief, and limited data are available to refute it. In
terms of nonpharmacological treatments, electroconvulsive therapy has an important rolein treating acute depression and may be useful as a form of maintenance treatment. The
use of psychotherapy, either as an adjunct or an alternative to antidepressants, needs more
research. A recent study [29], for example, showed dramatic improvements in responsewhen a modiﬁed type of cognitive therapy (with elements of interpersonal therapy added)
was compared with pharmacotherapy alone.
B. Recommendations
Allowing for limited data, we can generalize from available data to recommend the following:
1. All patients with acute major depression should be considered reasonable candidates for pharmacotherapy. Currently, there is no strong evidence for choosing
one medication over another, and treatment recommendations should be madeon the basis of tolerability and, when appropriate, cost.
2. All patients with other forms of depression should be treated as suggested inrecommendation No. 1. This is particularly true for dysthymia, and may be true
for other minor forms of depression.
3. Patients with chronic depression and recurrent depression should receive extended treatment.
4. Maintenance treatment should consist of the same dose of antidepressant as
used to achieve acute-phase remission.
5. Although the optimal length of maintenance treatment is not known, decisions
about indeﬁnite treatment should be based on risk–beneﬁt analyses, made withthe consent of the patient who is entitled to be informed as to the limitationsof our knowledge.
REFERENCES
1. Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, Rush AJ, Weissman MM.
Conceptualization and rationale for consensus deﬁnitions of terms in major depressive disorder: Remission, recovery, relapse, and recurrence. Arch Gen Psychiatry 1991; 48:851–855.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4thed. Washington, DC: American Psychiatric Association, 1994.
3. Keller MB, Klerman GL, Lavori PW, Coryell W, Endicott J, Taylor J. Long-term outcomeof episodes of major depression: Clinical and public health signiﬁcance. JAMA 1984; 252:
788–792.
4. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU,
Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the
United States: Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994; 51:
8–19.
5. Weissman MM. Members of the Cross-National Collaborative Group. The changing rate ofmajor depression: cross-national comparisons. JAMA 1992; 268:3098–3105.

596

Boland and Keller

6. Hwu H-G, Yeh IK, Chang LY. Prevalence of psychiatric disorders in Taiwan deﬁned by the
Chinese Diagnostic Interview Schedule. Acta Psychiatr Scand 1989; 79:136–147.
7. Wells KB, Steward A, Hays RD, Burnam MA, Rogers W, Daniels M, Berry S, Greenﬁeld S,
Ware J. The functioning and well-being of depressed patients: Results of the Medical Outcomes Study. JAMA 1989; 262:914–919.
8. Hirschﬁeld RMA, Keller MB Panico S, Arons BS, Barlow D, Davidoff F, Endicott J, Froom
J, Goldstein M, Gorman JM, Marek RG, Maurer TA, Meyer R, Phillips K, Ross J, Schwenk
TL, Sharfstein SS, Thase ME, Wyatt RJ. The National Depressive and Manic-Depressive Association consensus statement on the undertreatment of depression. JAMA 1997; 277:333–
340.
9. Murray CJL, Lopez AD. Global Burden of Disease and Injury Series. Volume 1: The Global
Burden of Disease: A comprehensive assessment of mortality and disability from diseases,
injuries and risk factors in 1990 and projected to 2020. Boston: Harvard University Press,
1996.
10. Steffens DC, Krishnan KR, Helms ML. Are SSRIs better than TCAs: a meta-analysis. Depress
Anxiety l997; 610–618.
11. Einarson TR, Arikian SR, Casciano J, Doyle JJ. Comparison of extended-release venlafaxine,
selective serotonin reuptake inhibitors, and tricyclic antidepressants in the treatment of depression: a meta-analysis of randomized controlled trials. Clin Ther 1999; 2:296–308.
12. Benkert O, Szegedi A, Kohnen R. Rapid onset of action in major depression: a comparative
trial of mirtazapine and paroxetine [Poster]. 37th Annual Meeting of the American Collegeof Neuropsychopharmacology, Puerto Rico, 1998.
13. Keller MB, Lavori PW, Lewis CE, Klerman GL. Predictors of relapse in major depressive
disorder. JAMA 1983; 2509:3299–3304.
14. Montgomery SA, Dunfour H, Brion S, Gailledreau J, Laqueille X, Ferrey G, Moron P, ParantLucena N, Singer L, Danion JM. The prophylactic efﬁcacy of ﬂuoxetine in unipolar depression.
Br J Psychiatry 1988; 153(suppl 3):69–76.
15. Montgomery SA, Dunbar G. Paroxetine is better than placebo in relapse prevention and theprophylaxis of recurrent depression. Intl Clin Psychopharmacol 1993; 8:189–219.
16. Doogan DP, Caillard V. Sertraline in the prevention of depression. Br J Psychiatry 1992; 160:
271–222.
17. Montgomery SA, Rasmussen JG, Tanghol P. A 24-week study of 20 mg citalopram, 40 mg
citalopram and placebo in the prevention of relapse of major depression. Int Clin Psychopharmacol 1993; 8:181–188.
18. Kunz NR, Entsuah R, Lei D, Rudolph RL, Hackett D. Venlafaxine in the preventive treatmentof recurrent major depressive disorder. Munich: ECNP, 2000.
19. Feiger AD, Bielski RJ, Bremner J, Heiser JF, Trivedi M, Wilcox CS, Roberts DL, Kensler
TT, McQuade RD, Kaplita SB, Archibald DG. Double-blind placebo-substitution study ofnefazodone in the prevention of relapse during continuation treatment of outpatients with major
depression. Int Clin Psychopharmacol 1999; 14:19–28.
20. Thase ME, Nierenberg AA, Keller MB, Panagides JTI. Efﬁcacy of mirtazapine for preventionof depressive relapse: a placebo-controlled double-blind trial of recently remitted high-riskpatients. J Clin Psychiatry 2001; 62:782–788.
21. Keller MB, Boland RJ. Implications of failing to achieve successful long-term maintenancetreatment of recurrent unipolar major depression. Biol Psychiatry 1998; 44:348–360.
22. Prien RF, Kupfer DJ, Mansky PA, Small JG, Tuason VB, Voss CB, Johnson WE. Drug therapy
in the prevention of recurrences in unipolar and bipolar affective disorders. Arch Gen Psychiatry 1984; 41:1096–1104.
23. Frank E, Kupfer DJ, Perel JM, Cornes C, Jarrett DB, Mallinger AG, Thase ME, McEachranAB, Grochocinski VJ. Three-year outcomes for maintenance therapies in recurrent depression.
Arch Gen Psychiatry 1990; 47:1093–1099.
24. Kupfer DJ, Frank E, Perel JM, Cornes C, Mallinger AG, Thase ME, McEachran AB, Grocho-

Pharmacotherapy of Depression

25.
26.

27.

28.

29.

30.

31.
32.
33.
34.
35.

36.
37.
38.
39.

40.

41.

42.
43.

597

cinski VJ. Five-year outcome for maintenance therapies in recurrent depression. Arch Gen
Psychiatry 1992; 49:769–773.
Keller MB, Lavori PW, Lewis CE, Klerman GL. Predictors of relapse in major depressive
disorder. JAMA 1983; 250:3299-3304.
Kocsis JH, Friedman RA, Markowitz JC, Leon AC, Miller NL, Gniwesch L, Parides M. Maintenance therapy for chronic depression. A controlled clinical trial of desipramine. Arch Gen
Psychiatry 1996; 53:769–774.
Keller MB, Kocsis JH, Thase ME, Gelenberg AJ, Rush AJ, Koran L, Schatzberg A, Russell
J, Hirschfeld R, Klein D, McCullough JP, Fawcett JA, Kornstein S, LaVange L, Harrison W.
Maintenance phase efﬁcacy of sertraline for chronic depression: a randomized controlled trial.
JAMA 1998; 280:1665–1672.
Keller MB, Harrison W, Fawcett JA, Gelenberg A, Hirschfeld RM, Klein D, Kocsis JH,
McCullough JP, Rush AJ, Schatzberg A. Treatment of chronic depression with sertraline or
imipramine: preliminary blinded response rates and high rates of undertreatment in the community. Psychopharmacol Bull 1995; 31:205–212.
Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, Markowitz JC,
Nemeroff CB, Russell JM, Thase ME, Trivedi MH, Zajecka J. A comparison of nefazodone,
the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med 2000; 342:1462–1470.
Keller MB. New treatment ﬁndings on comorbid pharmacotherapy and psychotherapy forchronic depression. Data presented at the American Psychiatric Association 153rd Meeting,
Chicago, Illinois, 2000.
Keller MB. Dysthymia in clinical practice: course, outcome and impact on the community.
Acta Psychiatr Scand 1994; 383(suppl):24–34.
Keller MB, Shapiro RW. “Double depression”: Superimposition of acute depressive episodes
on chronic depressive disorders. Am J Psychiatry 1982; 139:438–442.
Keller MB, Lavori PW, Endicott J, Coryell W, Klerman GL. “Double depression”: two-year
follow-up. Am J Psychiatry 1983; 140:689–694.
Angst J, Merikangas KR, Scheidegger P, Wicki W. Recurrent brief depression: a new subtypeof affective disorder. J Affect Disord 1990; 19:87–88.
Keller MB, Klein DN, Hirschfeld RMA, Kocsis JH, McCullough JP, Miller I, First MB, Holzer
CP, Keitner GI, Marin DB. Results of the DSM-IV Mood Disorders Field Trial. Am J Psychiatry 1995; 152:843–849.
Shelton RC, Davidson J, Yonkers KA, Koran L, Thase ME, Pearlstein T, Halbreich U. The
undertreatment of dysthymia. J Clin Psychiatry 1997; 58:59–65.
Howland RH. Pharmacotherapy of dysthymia: a review. J Clin Psychopharmacol 1991; 11:
83–92.
Kocsis JH, Frances AJ, Voss C, Mann JJ, Mason BJ, Sweeney J. Imipramine treatment forchronic depression. Arch Gen Psychiatry 1985; 45:253–257.
Stewart JW, McGrath PJ, Quitkin FM, Rabkin JG, Harrison W, Wager S, Nunes E, OcepekWelikson K, Tricamo E. Chronic depression: response to placebo, imipramine and phenelzine.
J Clin Psychopharmacol 1993; 13:391–396.
Hellerstein DJ, Yanowitch P, Rosenthal J, Samstag LW, Maurer M, Kasch K, Burrows L,
Poster M, Cantillon M, Winston A. A randomized double-blind study of ﬂuoxetine versus
placebo in the treatment of dysthymia. Am J Psychiatry 1993; 150:1169–1175.
Thase ME, Fava M, Halbreich U, Kocsis JH, Koran L, Davidson J, Rosenbaum J, Harrison
W. A placebo-controlled, randomized clinical trial comparing sertraline and imipramine forthe treatment of dysthymia. Arch Gen Psychiatry 1996; 53:777–784.
Ravindran AV, Bialik RJ, Lapierre YD. Therapeutic efﬁcacy of speciﬁc serotonin reuptake
inhibitors (SSRIs) in dysthymia. Can J Psychiatry 1994; 39:21–26.
Vanelle JM. Controlled efﬁcacy study of ﬂuoxetine in dysthymia. Br J Psychiatry 1997; 170:
345–350.

598

Boland and Keller

44. Bakish D, Ravindran A, Hooper C, Lapierre Y. Psychopharmacological treatment responseof patients with a DSM-III diagnosis of dysthymia disorder. Psychopharm Bull 1994; 30:53–
59.
45. Botte J, Evrard JL, Gilles C, Stenier P, Wolfrum C. Controlled comparison of RO-11-1163(moclobemide) and placebo in the treatment of depression. Acta Psychiatry Belg 1992; 92:
355–369.
46. Boyer P, Lecrubier Y. Atypical antipsychotic drugs in dysthymia: placebo controlled studiesof amisulpride versus imipramine, versus amineptine. Eur Psychiatry 1996; 11(suppl 3):135S–
140S.
47. Work Group on Major Depressive Disorder. Practice guideline for the treatment of patientswith major depressive disorder (revision). Am J Psychiatry 2000; 157(4 suppl):1–45.
48. Versiani M, Amrein R, Stabl M. Moclobemide and imipramine in chronic depression (dysthymia): an international double-blind, placebo-controlled trial. International Collaborative Study
Group. Int Clin Psychopharmacol 1997; 12:183—193.
49. Smeraldi E. Amisulpride versus ﬂuoxetine in patients with dysthymia or major depression inpartial remission: a double-blnd, comparative study. J Affect Disord 1998; 48:47–56.

24
Pharmacotherapy of Bipolar Disorder
KENNETH THAU and ANNA MARIA STREERUWITZ
University of Vienna
Vienna, Austria

I.

INTRODUCTION

Bipolar disorder has a high risk of recurrence; it is a disorder that accompanies the affected
all their life and therefore necessitates long-term treatment and prophylaxis with moodstabilizers. Bipolar disorder ranks high on the WHO list of leading causes of disability
among the global population, higher than schizophrenia [1], for instance. In all cases ofprophylactic treatment, “if patients do not take treatment with good medical supervision,
they will not stay well” [2]. What is true for lithium might in the long run also apply tothe other mood stabilizers, as the chasm between the efﬁcacy of lithium as established incontrolled clinical trials and its effectiveness in naturalistic settings could at least in partbe explained by lack of compliance among both patients and health providers [3,4].
II. MOOD-STABILIZING SUBSTANCES
A. Lithium
After 50 years of ongoing research, lithium remains the classic mood stabilizer both forthe acute manic phase as well as for the prophylaxis of recurrent manic and depressive
episodes [5]. Lithium is an element (cation) discovered in the early nineteenth century.
However, it took until 1949 for John Cade to introduce lithium in the therapy of manic
patients, and until the early 1950s for Schou to revolutionize the treatment of manicdepressive illness [6].
The impact of lithium on the development of psychiatry is unique, reshaping medical, scientiﬁc, and popular concepts of severe mental illness [7]. Lithium remains ﬁrstline therapy, especially in patients with an episodic course of illness. Besides its mood599

600

Thau and Streeruwitz

stabilizing effect, lithium seems to exert an antisuicidal and antiaggressive effect [8,9]. It
is the only mood stabilizer with a proven effect on the excessive mortality rate of bipolar
patients.
Because lithium seems to have several different clinical effects, it is unlikely thatany single biochemical aspect is responsible for all of them. One effect of lithium is thatit only acts on overactive systems or overstimulated receptors to bring them back to normal
state, but does not affect the stable system. It might inhibit components of various neurotransmitter signaling pathways and inositol monophosphatase activity, resulting in depletion of an endogenous source of inositol. Blocking inositol 1,4,5-triphosphate-dependent
response has a powerful modulatory inﬂuence on neuronal excitability and neurotransmitter release. Nevertheless, lithium also has an effect on cells with an exogenous source ofinositol [10]. Taking lithium for a prolonged period may regulate transcriptional factors
and in this way modulate gene expression [11].
B.

AnticonvulsantsIn the 1970s, preliminary data on the possible mood-stabilizing properties of carbamazepine and valproate started to evolve. One hypothesis underlying the use of anticonvulsants in the therapy of bipolar disorder is the concept of “kindling,” which has its origin
in epileptology. There seems to be a local hypersensitivity in the amygdala precipitating
affective episodes. Anticonvulsants like carbamazepine have a membrane-stabilizing effect on this area and seem to decrease sensitivity in the amygdala. This might also be
their way of action in bipolar disorder. Valproate is thought to involve a GABAergic
mechanism [12] and therefore to have an additional antipanic anxiolytic effect.
Carbamazepine and valproate showed some superiority over lithium in the treatment
of atypical courses. In rapid cycling, a very severe course of illness, valproate seems tobe the best therapy. Newly introduced anticonvulsants are lamotrigine, gabapentin, andtopiramate. Their usefulness in bipolar disorder is still to be proven, although in somecases promising results exist either as monotherapy or in combination with another moodstabilizer [13,14].
C.

Other Substances with Mood-Stabilizing Capacity

Calcium channel blockers like verapamil and nimodipine are used in the therapy of bipolar
disorder as add-on medication. Nimodipine, in particular, seems to have some merit in
the therapy of ultrarapid or ultradian cycling.
Atypical neuroleptics like clozapine, olanzapine, and risperidone are of growinginterest in the treatment of bipolar disorder. Some authors claim that they have a moodstabilizing potency of their own [15,16]. In any case, compared to typical neuroleptics,
they have a much lower risk of side effects such as tardive dyskinesia, for which bipolar
patients seem to be at greater risk. Thyroid hormones have been used to augment theeffect of mood stabilizers, especially in cases of therapy-resistant bipolar depression. In
the last years, supraphysiological doses of thyroid hormone have been used as treatment
in resistant cases of bipolar disorder. There are some hints that cholinesterase inhibitors
carry a mood-stabilizing potency, but more research is still needed.
III. ACUTE TREATMENT OF MANIC, MIXED,AND HYPOMANIC EPISODES
Although 1 to 3% of the general population suffer from bipolar disorder, the severityof this condition is often underestimated. Patients suffering from it have a high risk ofPharmacotherapy of Bipolar Disorder

601

suicide, hospitalizations, rapid cycling, and other complications. Lithium remains the ﬁrst
choice in cases of classic euphoric mania. Valproate can also be seen as a ﬁrst-line choice
in classic mania and can be regarded as the treatment of choice in mixed episodes, dysphoric episodes, and mania in rapid cycling. An alternative in mixed or dysphoric episodes
can be either lithium or carbamazepine. For mania in rapid cycling, carbamazepine is theﬁrst-line alternative to valproate [17,18].
When rapid stabilization is required in severe mania, valproate is the choice, as
therapeutic blood levels can be achieved quickly by means of oral loading-dose strategy(20 mg/kg/day) [19,20]. Because the effect of mood stabilizers can be delayed, it is often
necessary to use additional medication in the beginning, especially in patients with psychotic symptoms, insomnia, or agitation. In mania with psychotic symptoms, it may benecessary to add high- or medium-potency antipsychotics. For further sedation, a benzodiazepine or a low-potency antipsychotic may be added. Insomnia can be treated with abenzodiazepine. In this case, a high- or medium-potency antipsychotic is rarely needed.
When there is no or only partial response to the ﬁrst mood stabilizer after 1 to 3
weeks, the initial mood stabilizer can be changed or a second mood stabilizer can be
added. Lithium and valproate seem to be the most reliable combination in such cases[21]. Preferably carbamazepine is combined with lithium [22]. If all above options fail,combining carbamazepine and valproate might be considered, or even a combination of
all three.
Drug interactions have to be noted carefully. Carbamazepine induces metabolism
of both itself and valproate via the cytochrome P450 3A3/4 system. This may decrease
the serum concentration of both drugs and the risk of relapse may increase. On the other
hand, valproate may displace protein-bound carbamazepine and in this way increase thelevel of free carbamazepine, which could result in neurotoxicity.
Comorbidity of bipolar disorder and substance abuse can be found in more than athird of bipolar patients. It might be linked to a poorer course of illness and states of
mixed mania. There are some hints that patients with a comorbidity of substance abusemight proﬁt more from a treatment with anticonvulsive mood stabilizers than from lithium [23].
An alternative choice in treatment-resistant severe manic and/or mixed episodes canbe electroconvulsive therapy. The concomitant use of benzodiazepines and lithium is verysafe and effective. There have been some cases reported where benzodiazepines could
replace neuroleptics in the treatment of acute mania. In any case, benzodiazepines decrease
the need for neuroleptics and treat comorbid anxiety. The situation may become criticalwhen patients with a history of substance abuse develop a problem with long-term benzodiazepine treatment.
Research now focuses on atypical neuroleptics and their mood-stabilizing properties.
They have a greatly reduced liability to cause extrapyramidal syndromes and tardive dyskinesia. Clozapine seems to exert greater antimanic than antidepressive effects [24,25]
and it could have some effect on treatment-resistant bipolar disorder [26]. Early clinicalexperience suggests that risperidone might have a greater antidepressive than antimanic
property [27]. Studies to test the antimanic properties of olanzapine are ongoing [28,29].
However, its mood-stabilizing properties seem to be limited [30]. Anecdotal records show
an antimanic effect of quetiapine [31].
Gabapentin—another anticonvulsive medication just recently introduced into thetreatment of bipolar disorder—has the advantage of no drug interactions in the cytochrome
P450 system. The combination with lithium or other mood stabilizers, therefore, seems
to be safe and has already shown moderate effectiveness [32].

602Thau and Streeruwitz

Lamotrigine appears to be promising both as a mood stabilizer alone and in combination with lithium or valproate [33,34]. It is important to note that valproate increases the
blood level of lamotrigine because it inhibits glucuronidation. This combination might behighly effective, but extreme caution is warranted. There is an increased risk of dermatological reactions like severe skin rash—even of Stevens–Johnson syndrome—and encephalopathy [35].
An even newer anticonvulsant drug thought to have antimanic potency is topiramate.
More data on its properties as an add-on to mood stabilizers are still needed. It has abroad spectrum of activity, including GABAergic and antiglutamatergic mechanisms, aswell as calcium channel antagonism. Topiramate is known to have adverse cognitive effects, such as decreased attention and word ﬂuency in some patients, which might be alimiting factor. On the other hand, topiramate offers the potential to induce weight loss
in obese subjects [36–38].
Mexiletine is a drug already well known in the treatment of epileptic patients. It
seems to be somewhat promising in the treatment of manic episodes, but more trials are
warranted [39]. There are some data on the usefulness of cholinesterase inhibitors like
donepezil in the treatment of acute mania [40].
Calcium channel blockers may be hazardous in combination with lithium: multiple
cases of toxicity, particularly neurotoxicity, have been reported. This side effect might becritical for elderly patients who may also suffer from bradycardia. The risk of neurotoxictiyseems to be somewhat higher with verapamil and diltiazem than in nifedipine. The stabilization of the sleep–wake cycle can be an important part of therapy. Disrupted sleep cycles,
as in jet lag, can induce manic episodes in psychosocially stressful times or in the postpartum period. All avoidable disturbances should be cut down to a minimum [41,42].
IV. ACUTE TREATMENT OF BIPOLAR DEPRESSION
In any case of bipolar depression, the role of switch from severe depression to acute mania
has to be taken into account. There seems to be a high risk with tricyclic antidepressantsbut also with new antidepressants such as mirtazepine. Bupropion seems to be the drugwith the lowest risk of inducing mania.
A.

Treatment of Bipolar I Depression

In psychotic depression, the combination of a mood stabilizer, an antidepressant, and an
antipsychotic is the recommended treatment. ECT can be an alternative therapy. For severe
depression without psychotic features, a mood stabilizer and an antidepressant are thetreatment of choice. In milder depressive episodes, a mood stabilizer alone might be effective. Psychotherapy in addition to medication may also be effective in such patients.
B.

Treatment of Bipolar II Depression

The treatment of bipolar II depression is very similar to the treatment of bipolar I depression. In milder cases, psychotherapy seems to be even more effective than in bipolar I
depression. If there is only a minimal history of hypomania, mood stabilizers might becautiously omitted; an antidepressant like an SSRI alone [43] or combined with psychotherapy could be considered the treatment of choice.
In depression with psychotic features, an antipsychotic should be added to moodstabilizing and antidepressant medication. In some of these cases, electroconvulsive therapy can prove helpful but, on the other hand, it has the disadvantage of sometimes produc-Pharmacotherapy of Bipolar Disorder603

ing a relatively high relapse rate and there is little information about which medication
would be most helpful for the maintenance phase in these patients.
C. Therapy-Refractory Depression in Bipolar Disorder
The antidepressant potential of all mood stabilizers is lower than their antimanic potential.
In this context, refractoriness can be a great problem [44]. Lithium responsivity seems todecrease in certain illness patterns characterized by a depressive episode ﬁrst, followed
by a swing into a manic episode [45]. This suggests that lithium in these cases failed to improvethe ﬁrst depressive episode so that a compensatory overswing results in a second manic episode. In some cases, lithium discontinuation can lead to a failure to respond to lithium again
as well as to other treatment approaches. One-third of the patients show an initially good
response to lithium followed by a gradual loss of efﬁcacy. Some clinical ﬁndings demonstratethat the addition of a second mood stabilizer leads to better results in these cases, better thanintroducing an antidepressant, but treatment is more often discontinued [46].
Lamotrigine has a high response rate in refractory depression, alone or in combination with previously ineffective mood stabilizers [47].
Antidepressants should be chosen carefully in both bipolar I and II depression, always keeping in mind their ability to switch depression into full-blown mania. Traditional
unimodal antidepressants can precipitate mania in approximately one-third of bipolar patients [48] and cause cycle acceleration in one-ﬁfth of this population. There is somesuggestion that administering mood stabilizers as lithium, carbamazepine, or valproic acidat the same time may reduce the risk of switching into maniform states. (49)
Bupropion or serotonin reuptake inhibitors are the ﬁrst-line choice for patients
known to switch easily into mania or rapid cycling [50]. Bupropion is assumed to havemood-stabilizing properties of its own and is believed to be the antidepressant with theleast tendency to induce manic switches. Furthermore, it is less likely than SSRIs to cause
sexual dysfunction and is one of the few antidepressants associated with a weight loss
rather than gain. Monoamine oxidase inhibitors and venlafaxine are supposed to be analternative to these choices. Tricyclics should be avoided when clinicians are concerned
about a possible manic switch. Patients who maintain high lithium serum levels may notneed additional antidepressant medication at all [51]. As in mania, insomnia can be treatedwith an additional benzodiazepine. In psychotic syndromes or severe agitation, high- or
medium-potency antipsychotics are the appropriate treatment.
If there is no adequate response to the ﬁrst-line treatment, lithium should be added
when not already part of the treatment. Psychotherapy should be considered in mild or
moderate depression. If the patient develops a lithium-related hypothyroidism or elevatedTSH, thyroid hormone should treat this. The treatment of a euthyroid patient could also be
augmented with thyroid hormone, especially in cases of subtle rapid cycling. Physiologicalreplacement dose of 75–11 µg/day may be useful especially in women. High-dose treatment of 150–400 µg/day is recommended for rapid cycling patients. Light therapy might
be used in the seasonal pattern of bipolar disorder. Bright light (greater than 7500 lux)
may be worth considering in patients with marked disruption of circadian rhythmicity
and bipolar hypersomnia. Sleep deprivation may bring brief improvement, but could alsoprecipitate hypomania or mania.
V.

RAPID CYCLING

According to DSM-IV, whenever a patient has four or more episodes in 12 months (either
manic, hypomanic, mixed, or major depressive), he is diagnosed as rapid cycling bipolar

604

Thau and Streeruwitz

disorder. There has to be a phase of remission between episodes of at least 2 months or
episodes have to switch from one polarity to the opposite. The ultrarapid or even ultradian
cycling is a course of illness neglected in DSM-IV; it means that a mood swing occurs
within the same day or even the same hour. A great deal of research now focuses on thesetreatment-challenging courses of bipolar disorder.
Of bipolar patients, 13 to 20% suffer from rapid cycling [52–54]. The majority of
the rapid cycling disorders have a late onset. Factors known to contribute to this courseof illness are female gender, middle age, and hypothyroidism. Rapid cycling is approximately three times more common in women than in men [55]. The diagnosis of rapid
cycling has implications for therapy. There is wide agreement that tricyclic antidepressantscan induce this course, so they should be avoided in the treatment of depression in bipolar
disorder. All antidepressants should be tapered more quickly than in unipolar depression.
The agent believed to be the safest to treat depression in bipolar disorder is bupropion.
Patients should be advised to record daily mood ratings—cycle acceleration can be hard
to recognize in the beginning because of its subtle onset. Depression in rapid cycling is
an extremely challenging condition for the clinician.
There also seem to be some nonpharmacological factors that can lead to cycle acceleration such as pregnancy, Graves’ disease, or electroconvulsive therapy. Lithium in rapid
cycling loses some of its usual power. Anticonvulsants seem to have a more beneﬁcial
effect. The ﬁrst-line treatment for rapid cycling is valproate. The use of supraphysiologicaldoses of thyroxine has been helpful in some patients with rapid cycling and lamotrigine
proved to have some power in treating depression in patients with bipolar II disorder anda rapid cycling course [56].
VI. MEDICATION FOR CONTINUATION TREATMENT
The initial period lasting 4 to 6 months after an acute illness episode is the continuation
period. The acute episode should have ended, but the patient may still have some symptoms and experience functional problems. The usual procedure is to continue mood stabilizer(s) while trying to taper other medications (antidepressants, antipsychotics, benzodiazepine). The dose of the mood stabilizer should be adjusted to balance maximum beneﬁtagainst side effects.
During the continuation period, medication should be monitored weekly or every
2 weeks to prevent noncompliance. Antidepressants should be tapered sooner than in unipolar depression (e.g., sooner than 6–12 months).
VII. STRATEGIES FOR LONG-TERM MAINTENANCE
After the initial period has ended, the stabilized patient can still be vulnerable to newcycles of illness. To prevent this, a long-term or lifetime plan for prophylaxis must be
considered. In bipolar I disorder, long-term or lifetime prophylaxis is the treatment ofchoice after two manic episodes, but should already be considered after one manic episode
if it was severe or if there is a family history of bipolar disorder. Some experts advise
long-time prophylaxis after one manic episode in patients with an onset before the ageof 20.
In bipolar II disorder, prophylaxis can be considered after three hypomanic episodes,
if severe or closely spaced or if there are antidepressant mood elevations, frequent depression, or a family history of bipolar I disorder. Long-term tolerability is highest in lithiumPharmacotherapy of Bipolar Disorder605

and valproate. Compliance with the prescribed medication should be an issue in each of
the patient’s visits. There should be a quick review of life events since the last visit. Topics
that should also be addressed are substance abuse, sleep patterns, management of excessive
stress, and suicidal ideations. Psychotherapeutic approaches like psychoeducation, cognitive-behavioral therapy, family and marital therapy intervention, and adjunctive therapies
can be an integral part of therapy [57]. A visit for medication management is recommended
every 2 to 3 months at minimum in a milder course and if the patient is stable. If some
symptoms still persist or the patient still has some problems functioning, medication management should take place monthly.
In an especially severe course with ongoing care (e.g., as in rapid cycling),weekly
medication management is recommended. Medication monitoring includes serum levelsof lithium, valproate, carbamazepine, selected tricyclics every 3 to 6 months, thyroid function at least yearly, a general chemistry screen, and a physical exam if the patient’s medical
history is unknown, urine analysis if starting lithium and renal function tests every 6 to
12 months, and pregnancy test, if applicable.
There is a subgroup of patients who might not proﬁt from prophylactic treatment.
There is no consensus of how to identify this subgroup. When discontinuing a moodstabilizer this should always be done gradually over several weeks.
VIII. DEALING WITH COMMON SIDE EFFECTS
OF MOOD STABILIZERS
Thirst and polyuria are side effects quite often seen in the beginning of lithium therapy.
They can be very annoying and risk the patient’s compliance. The reason for this effectis that vasopressin receptors and expression of water channels are diminished by lithium.
Polyuria can be treated with amiloride, thiazides, or indomethacine. It is important to treat
this symptom, since nocturia causes sleep disruption, which in return can result in mooddisruption. Furthermore, the use of high-calorie beverages to treat polydipsia can cause
weight gain. If mild renal insufﬁciency with elevated levels of creatinine is diagnosed, adifferent mood stabilizer should be added and lithium should be gradually tapered.
Cognitive complaints such as feeling dull or ﬂat under lithium medication are not
manageable with any add-ons. They are a reason to gradually switch to valproate or carbamazepine. Rigor or nystagmus is another effect on the CNS that can be induced by lithium
medication. EEG can show abnormalities. Risk factors for these adverse effects are preexisting CNS structural disease, especially in elderly patients and with the combined therapyof lithium and neuroleptic drugs.
ECG abnormalities are due to changes in myocardial repolarization induced by lithium salts. Arrhythmia is seen very rarely within therapeutic ranges of lithium plasma
levels. Dysfunction of the sinoatrial node and bradyarrhythmia are relative contraindications for lithium therapy.
Tremor caused by lithium therapy can be treated with β-blockers. Weight gain isseen in about one-third of patients treated with lithium. The average weight gain is 4 to
10 kg. Patients should check their weight regularly. Diets should be planned together withthe clinician to avoid intoxication. Weight gain can be very challenging to the patient’s
compliance, especially in women. If the weight gain becomes unacceptable for the patient,another mood stabilizer should be considered for long-term therapy.
Sedation is another side effect that can occur under lithium therapy. If lithium induces diarrhea and nausea, then patients have to be observed closely. Dehydration can

606

Thau and Streeruwitz

lead to toxicity and therefore the clinician must be careful in balancing the ﬂuid volume
of lithium-treated patients. Milder nausea experienced early in treatment improves whenlithium is administered with meals. Changing the time of day when dosing takes place
can also bring some relief [58]. Diarrhea can be persistent, and antidiarrheal agents canbe helpful.
Hypothyroidism is another adverse effect of lithium. Iodine uptake into the thyroid
gland is decreased under lithium therapy. Formation and release of thyroxin are inhibited.
TSH levels should be monitored regularly. If they are elevated, L-thyroxin should be
added to the therapy.
Hyperparathyroidism and consequently hypocalcemia can be seen in nearly onethird of patients treated with lithium. Most of the patients do not have symptoms. Lithium
has to be tapered if and when hypocalcemia becomes symptomatic.
The most common dermatological complaint of lithium users is about dry skin.
Topical lotions are sufﬁcient to treat this symptom. Psoriasis vulgaris can occur for theﬁrst time under lithium medication but can also be worsened if already preexisting. Acneis another effect of lithium on the skin. Any dermatosis induced by lithium should betreated in cooperation with a dermatologist. In most cases, it is sufﬁcient to reduce lithium
dosage; it is seldom the case that lithium has to be tapered due to dermatosis.
Lithium intoxication is seen in patients with decreased renal lithium excretion orwith overdosage either accidentally or in a suicide attempt. Nearly all of these patientsshow central nervous system symptoms like tremor, ataxia, nystagmus, and a decrease ofvigilance. Lithium’s renal excretion can be reduced for several reasons. Gastroenteritis,
renal insufﬁciency, dehydration, narcosis, delivery, and drugs like diuretics, NSAP, orsome antibiotics are factors that can inﬂuence lithium excretion. Intoxication caused bydecreased excretion of lithium can be avoided in most cases. The role of patient education
should not be underestimated.
Valproate shares some side effects with lithium. Again, tremor can be treated with
β-blockers. If sedation and weight gain (valproate is the anticonvulsant most often associated with weight gain) [59] become unbearable to the patient, another mood stabilizer
should be considered for therapy. Diarrhea can be induced by valproate, but is less dangerous than under lithium medication. Nausea can be treated with H2-blockers. Hair loss ispreventable by adding on zinc and selenium supplements. Mild elevation of liver function
parameters should be watched closely. Carbamazepine can have some alarming side effects: headache, nystagmus, ataxia, or sedation can be very disabling for the patient, as
well as rash, which is rather common [60].
Leukopenia is the most dangerous side effect of carbamazepine, and should never be
combined with clozapine, another drug that can induce a drop in leukocytes. Leukopenia isa reason to taper carbamazepine immediately. As with valproate, liver function parameters
can be elevated.
Carbamazepine induces cytochrome P450 liver enzymes and shows drug–drug interactions very frequently. It can decrease plasma levels of other medications. Oxcarbazepine,
a well-known drug in Europe, has the advantage of not requiring hematological or hepatic
monitoring. It has recently become available in the United States.
Lamotrigine can lead to Stevens–Johnson syndrome. Rashes typically develop
within the ﬁrst 2 to 8 weeks of treatment. The risk can be minimized if the physician
initiates therapy at the lowest possible dosage.
Psychiatrists prescribing anticonvulsants should be familiar with the skin eruptions
that can be caused by them.

Pharmacotherapy of Bipolar Disorder

607

IX. SELECTING MOOD STABILIZERS FOR PATIENTSWITH MEDICAL COMPLICATIONSReduced liver function is a contraindication to use of anticonvulsants; in such cases, lithium is the preferred treatment option. In patients with CNS structural disease or renal
disease, valproate or carbamazepine are recommended for treatment of bipolar disorder.
Patients who have a comorbidity of alcohol or cocaine abuse should not be treated withcarbamazepine. Valproate would be the best mood stabilizer for patients with heart failure.
X.

SELECTING MOOD STABILIZERS FOR PATIENTSWITH AGE OVER 65

Valproate or lithium is the preferable treatment option for bipolar disorder in the elderly[61]. Carbamazepine often is not recommended because of its multiple drug interactions
and because it can cause cardiac conduction disease. Some clinical trials suggest thatlithium may be more efﬁcacious than valproate in this special group of patients. For valproate, a “therapeutic window” (other than that in younger adults) was found, namely, 65
to 90 µg/mL. Generally, low rather than high doses should be used. Lithium dosage inthe elderly requires adjustment because of changes in renal clearance and reduction of
total body water [61]. If medication is added to the patient’s current regimen, modest
doses should be increased slowly. Drug interactions have to be considered carefully inthe elderly population. Some widely used drugs that increase the blood level of lithium arethiazide diuretics, nonsteroidal anti-inﬂammatory drugs, angiotensin-converting enzyme
inhibitors, and β-blockers.
Physically healthy elderly patients generally tolerate lithium well. The very old,
physically ill, frail, or cognitively impaired may experience an increase in the frequencyof side effects. The most prominent side effects in this special population are polyuria,
gastrointestinal abnormalities, trauma, ataxia, and cognitive impairment. Polyuria may
cause problems in patients with a comorbid prostatic hypertrophy. This combination canlead to urinary retention and promote urinary tract infections. Toxic blood lithium levels
result in seizures and coma. Slow-release lithium tablets reduce the maximum blood level
concentration.
The condition of mania is often misdiagnosed in the elderly. Confusion, irritability,
paranoia, and impaired concentration are seen more commonly than in younger patients.
Before starting treatment with lithium, neurological examinations should be administered.
Patients with an onset of illness later than age 55 are not supposed to differ in their drug
response from patients with an earlier onset.
XI. MANAGEMENT OF BIPOLAR DISORDER DURING PREGNANCYAND BREAST-FEEDING
Bipolar disorder occurs commonly in women during their childbearing years. The impactof untreated psychiatric illness on pregnant women and their offspring is often underestimated. Impulsive or self-injurious behavior and suicide, substance abuse, or inattention
to prenatal care are only some of the risks. Discontinuing the mood stabilizer makes therisk of recurrence during pregnancy similar to the risk of recurrence at other times. The
postpartum risk of recurrence is 3 times as high [63]. The risk of a subsequent relapse isgreater if the number of prior affective episodes was high. Lithium, carbamazepine, and608

Thau and Streeruwitz

Figure 1 Management of patients with bipolar disorder during pregnancy—treatment
options.

valproate all carry fetal teratogenic risk in early pregnancy and adverse effects in latepregnancy, labor, and delivery. Regardless of which medication is used, the treating clinician should document the contraceptive methods used and discuss the potential risks ofintrauterine exposure to the different drugs in all female patients during their childbearing
years.
Decisions should be made by the patient (and her partner) after being fully informed
about all risks. Discontinuation might be considered in cases with a good previous courseof illness (Fig. 1). Discontinuation of mood stabilizers should occur gradually over 15 to
30 days (i.e., not rapidly, if at all possible). This reduces the number of recurrences during
pregnancy and the same applies to the patient subject to an unplanned pregnancy, as might
often be the case. Medication should not be tapered abruptly but gradually over 2 weeks

Pharmacotherapy of Bipolar Disorder609(50% of all conceptions are inadvertent and most women learn that they are pregnant aftera missed period and are already at 3 to 7 weeks gestation).
In the ﬁrst trimester, neuroleptics, SSRIs, and ECT carry a lower teratogenic risk
than lithium. There are very controversial ﬁndings about the teratogenic potency of lithium
in the ﬁrst trimester. Some studies suggest a connection between a cardiac malformation
known as Ebstein’s anomaly; others cannot conﬁrm these ﬁndings (Ebstein’s anomaly ischaracterized by right ventricular hypoplasia and congenital downward displacementof the tricuspid valve into the right ventricle) [64]. Ebstein’s anomaly has a prevalenceof 1:20,000 in the general population. Under lithium therapy, the risk increases 10 to 20
times or approximately 0.1 to 0.05%. A tricky decision is to be made by the clinician andthe situation of each individual patient must be taken into account. If lithium therapy isalso continued through the critical period of organogenesis (4 to 12 weeks after the last
menstruation), the patient should be examined with prenatal high-resolution echocardiography around 16 to 18 weeks gestation [65]. The lowest effective dose of medication
should be taken.
Newborn infants of lithium-treated mothers can develop a “ﬂoppy infant syndrome,”as though under treatment with benzodiazepines or neuroleptics. When tapering lithium
postpartum, reintroducing lithium prophylaxis right after delivery or during late pregnancy
can reduce risk of recurrence. The doses have to be drastically reduced during delivery
since the blood and ﬂuid volume decreases immediately after the child is born and therisk of toxicity rises. When continuing anticonvulsives, folic acid supplements should be
added to the regimen. It should be noted that anticonvulsants are believed to be highly
teratogenic. An increased occurrence of spina biﬁda has been observed in the offspring of
mothers treated with anticonvulsives. For carbamazepine, a so-called fetal carbamazepine
syndrome, with dysmorphic features and mild mental retardation, is reported. The fetal
valproate syndrome includes craniofacial, abdominal wall, cardiovascular, urogenital, anddigital malformations. Therefore, if possible, usage of these drugs should be avoided during pregnancy.
There is no evidence of teratogenic potential of ECT—a therapy alternative to medication exposure. Risks to the fetus can be minimized by positioning the patient in the leftlateral decubitus position, by monitoring the fetus and uterus, and by limiting the exposure
to anticholinergic medications.
Antidepressants continued throughout delivery can cause symptoms of drug withdrawal in the newborn. These symptoms can include irritability, eye rolling, temperature
instability, tachycardia, and seizures. All mood stabilizers are secreted through breast milk.
Although there are some data suggesting that these medications do not pose an immediaterisk to the newborn, breast-feeding is not recommended. However, there may be some
women who insist on breast-feeding. Nursing infants’ serum lithium concentrations havebeen reported to be 10 to 50% of the mothers’ serum levels. The baby’s hydration status
should be monitored very carefully.
Valproate and carbamazepine are considered compatible with breast-feeding bysome authors and the American Academy of Pediatrics (1994), although possible side
effects include leukopenia and hepatitis. Liver function of the infant must be monitored.
XII. MOOD STABILIZERS AND SUICIDE RISK IN PATIENTSWITH BIPOLAR DISORDER
Bipolar patients are at great risk of committing suicide [66]. The mortality of bipolar
patients is two to three times higher than that of the general population. (Bipolar disorder610

Thau and Streeruwitz

Figure 2 Bipolar disorder and suicide—treatment options.

is responsible for an estimated 30,000 deaths per year in the United States.) Of patientswith bipolar disorder, 25 to 50% attempt suicide at least once! Only about 5% commit
suicide by overdosing on their antidepressants—more women than men. So it does notseem to make sense to prescribe less toxic drugs—it might even be harmful if the drugs
are less efﬁcient [67].
Established risk factors for completed suicide in affective disorder are acute depression, mixed episodes, rapid cycling, substance abuse, aggression, and/or impulsivity.
Young men in the early phase of their illness are the group at highest risk.
Mortality during lithium treatment is not signiﬁcantly higher or only moderately
higher than in the general population; after discontinuation of lithium, mortality again issigniﬁcantly higher. The suicide rate in bipolar patients not treated with lithium is morethan seven times higher than the suicide rate in bipolar patients treated with lithium [68].
This is strong evidence for the antisuicidal action of lithium—also for patients not showing
satisfactory response to its episode-preventing effect! Similar observations have not beenreported for other mood stabilizers, although anticonvulsants may have merit in the treatment of mixed states, rapid cycling, and comorbid substance abuse [69]. There is insufﬁcient evidence that long-term antidepressant treatment diminishes suicide risk and thisshould be considered when choosing a mood stabilizer for long-time prophylaxis (Fig.
2), especially in patients with severe depression, suicidal thoughts, previous suicide attempts, or a combination of these.
REFERENCES
1. Murray CJL, Lopez AD. The global burden of disease (summary). WHO and Harvard Schoolof Public Health. Boston: Harvard University Press, 1996.
2. Guscott R, Taylor L. Lithium prophylaxis in recurrent affective illness. Br J Psychiatry 1994;
164:741–746.
3. Vestergaard P, Licht RW, Brodersen A, Rasmussen NA, Christensen H, Arngrim T, Gronvall
B, Kristensen E, Poulstrup I, Wentzer-Licht R. Outcome of lithium prophylaxis: a prospective
follow-up of affective disorder patients asigned to high and low serum lithium levels. Acta
Psychiatr Scand 1998; 98:310–315.

Pharmacotherapy of Bipolar Disorder611

4. Maarberg K, Aargard J, Vestergaard P. Adherence to lithium prophylaxis: I. Clinical predictors
and patient’s reasons for nonadherence. Pharmacopsychiatry 1998; 21:121–125.
5. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York: Oxford University Press,
1990.
6. Soares JC, Gershon SG. The psychopharmacological speciﬁty of the lithium ion: origins andtrajectory. J Clin Psychiatry 2000;61(suppl 9):16–22.
7. Goodwin FK, Ghaemi SN. The impact of the discovery of lithium on psychiatric thought andpractice in the USA and Europe. Aust NZ J Psychiatry 1999; 33:S54–S64.
8. Schou M. The effect of prophylactic lithium treatment on mortality and suicidal behaviour:a review for clinicians. J Affect Disord 1998; 50:253–259.
9. Müller-Oerlinghausen B, Wolf T, Ahrens B, Glaenz T, Schou M, Grof E, Grof P, Lenz G,
Simhandl C, Thau K, Vestergaard P, Wolf R. Mortality of patients who dropped out from
regular lithium prophylaxis: a collaborative study by the International Group for the Study ofLithium-Treated Patients (IGSLI). Acta Psychiatr Scand 1996; 94:344–347.
10. Shastry BS. On the functions of lithium: the mood stabilizer. BioEssays 1997; 19(3):199–
200.
11. Lenox RH, Hahn CG. Overview of the mechanism of action of lithium in the brain: ﬁfty-year
update. J Clin Psychiatry 2000; 61(suppl 9):5–15.
12. Post RM, Denicoff KD, Frye MA, Dunn RT, Leverich GS, Osuch E, Speer A. A history of
the use of anticonvulsants as mood stabilizers in the last two decades of the 20th century.
Neuropsychobiology 1998; 38:152–166.
13. Marcotte D. Use of topiramate, a new anti-epileptic as a mood stabilizer. J Affect Disord
1998; 50:245–251.
14. Mitchell PB. The place of anticonvulsants and other putative mood stabilisers in the treatmentof bipolar disorder. Aust NZ J Psychiatry 1999; 33:S99–S107.
15. Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ. Clinical outcome in a randomised 1-year trial of clozapine versus treatment as usual for patients with treatment-resistantillness and a history of mania. Am J Psychiatry 1999; 156:1164–1169.
16. Zarate CA, Tohen M, Weiss MK, Cole JO. Is clozapine a mood stabilizer? J Clin Psychiatry
1995; 56(3):108–112.
17. Frances AJ, Docherty J, Kahn DA. The expert consensus guideline series: treatment of bipolar
disorder. J Clin Psychiatry 1996; 57(suppl 12A):1–88.
18. Sharma V, Yatham LN, Haslam DRS, Silverstone PH, Parikh SV, Matte R, Kutcher SP, Kusumakar V. Continuation and prophylactic treatment of bipolar disorder. Can J Psychiatry 1997;
42(suppl 2):92S–100S.
19. Keck PE, McElroy SL, Bennett JA. Health-economic implications of the onset of action of
antimanic agents. J Clin Psychiatry 1996; 57(suppl 13):13–18.
20. Hirschfeld RMA, Allen MH, McEvoy JP, Keck PE, Russell JM. Safety and tolerability oforal loading divalproex sodium in acutely manic bipolar patients. J Clin Psychiatry 1999;
60(12):815–818.
21. Freeman MP, Stoll AL. Mood stabilizer combinations: a review of safety and efﬁcacy. Am
J Psychiatry 1998; 155:12–21.
22. Denicoff KD,Smith-Jackson EE, Disney ER, Ali SO, Leverich GS, Post RM. Comparative
prophylactic efﬁcacy of lithium, carbamazepine and the combination in bipolar disorder. J
Clin Psychiatry 1997; 58(11):470–478.
23. Goldberg JF, Garno JL, Leon AC, Kocsis JH, Portera L. A history of substance abuse complicates remission from acute mania in bipolar disorder. J Clin Psychiatry 1999; 60(11):733–
740.
24. Calabrese JR, Gajwani P. Lamotrigine and clozapine for bipolar disorder. Am J Psychiatry
2000; 157(9):1523.
25. Kimmel SE, Calabrese JR, Woyshville MJ, Meltzer HY. Clozapine in treatment-refractorymood disorders. J Clin Psychiatry 1994; 55(9 suppl B):91–93.

612

Thau and Streeruwitz

26. Green AI, Tohen M, Patel JK, Banov M, DuRand C, Berman I, Chang H, Zarate C, PosenerJ, Lee H, Dawson R, Richards C, Cole JO, Schatzberg AF. Clozapine in the treatment ofrefractory psychotic mania. Am J Psychiatry 2000; 157:982–986.
27. Frye MA, Ketter TA, Altshuler LL, Denicoff K, Dunn RT, Kimbrell TA, Cora-Locatelli G,
Post RM. Clozapine in bipolar disorder: treatment implications for other atypical antipsychotics. J Affect Disord 1998; 48:91–104.
28. McElroy SL, Frye M, Denicoff K, Altshuler L, Nolen W, Kupka R, Suppes T, Keck PE,
Leverich GS, Kmetz GF, Post RM. Olanzapine in treatment-resistant bipolar disorder. J Affect
Disord 1998; 49:119–122.
29. Soutullo CA, Sorter MT, Foster KD, McElroy SL, Keck PE. Olanzapine in the treatment ofadolescent acute mania: a report of seven cases. J Affect Disord 1999; 53:279–283.
30. Narendran R, Young CM, Valenti AM, Pristach CA, Pato MT, Grace JJ. Olanzapine therapy
in treatment-resistant psychotic mood disorders: a long-term follow-up study. J Clin Psychiatry
2001; 62(7):509–516.
31. Dunayevich E, Strakowski SM. Quetiapine for treatment-resistant mania. Am J Psychiatry
2000; 157(8):1341.
32. Ghaemi SN, Goodwin FK. Gabapentin treatment of the non-refractory bipolar spectrum: anopen case series. J Affect Disord 2001; 65:167–171.
33. Calebrese JR, Bowden CL, McElroy SL, Cookson J, Andersen J, Keck PE, Rhodes L, BoldenWatson C, Zhou J, Asher JA. Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder. Am J Psychiatry 1999; 156:1019–1023.
34. Zerjav-Lacombe S, Tabarsi E. Lamotrigine: a review of clinical studies in bipolar disorders.
Can J Psychiatry 2001; 46:328–333.
35. Fogelson DL, Sternbach H. Lamotrigine treatment of refractory bipolar disorder. J Clin Psychiatry 1997; 58(6):271–273.
36. Chengappa KNR, Gershon S, Levine J. The evolving role of topiramate among other moodstabilizers in the management of bipolar disorder. Bipolar Disord 2001; 3:215–232.
37. Goldberg J, Burdick KE. Cognitive side effects of anticonvulsants. J Clin Psychiatry 2001;
62(suppl 14):27–33.
38. Normann C, Langosch J, Schaerer LO, Grunze H, Walden J. Treatment of acute mania with
topiramate. Am J Psychiatry 1999; 156(12):2014.
39. Schaffer A, Levitt AJ, Joffe RT. Mexiletine in treatment-resistant bipolar disorder. J Affect
Disord 2000; 57:249–253.
40. Burt T, Sachs GS, Demopulos C. Donezepil in treatment-resistant bipolar disorder. Biol Psychiatry 1999; 45:959–964.
41. Leibenluft E, Suppes T. Treating bipolar illness: focus on treatment algorithms and management of the sleep-wake cycle. Am J Psychiatry 1999; 156(12):1976–1981.
42. Ramirez Basco M, Rush AJ. Cognitive-Behavioral Therapy for Bipolar Disorder. New York:The Guilford Press, 1996:190–198.
43. Amsterdam JD, Garcia-Espana F, Fawcett J, Quitkin FM, Reimherr FW, Rosenbaum JF,
Schweizer E, Beasley C. Efﬁcacy and safety of ﬂuoxetine in treating bipolar II major depressive episode. J Clin Psychopharmacol 1998; 18(6):435–440.
44. Post RM, Leverich GS, Denicoff KD, Frye MA, Kimbrell TA, Dunn R. Alternative approaches
to refractory depression in bipolar illness. Depression Anxiety 1997; 5:175–189.
45. Potter WZ, Ozcan ME. Methodological considerations for the development of new treatments
for bipolar disorder. Aust NZ J Psychiatry 1999; 33:S84–S98.
46. Young LT, Joffe RT, Robb JC, MacQueen GM, Marrioti M, Patelis-Siotis I. Double-blind
comparison of addition of a second mood stabilizer versus an antidepressant to an initial moodstabilizer for treatment of patients with bipolar depression. Am J Psychiatry 2000; 157:124–
126.
47. Compton MT, Nemeroff CB. The treatment of bipolar depression. J Clin Psychiatry 2000;
61(suppl 9):57–67.

Pharmacotherapy of Bipolar Disorder613

48. Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressantinduced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995; 152:
1130–1138.
49. Bottlender R, Rudolf D, Strauss A, Möller HJ. Mood stabilisers reduce the risk of developing
antidepressant-induced maniform states in acute treatment of bipolar I depressed patients. J
Affect Disord 2001; 63:79–83.
50. Frances AJ, Kahn DA, Carpenter D, Docherty JP, Donovan SL. The expert consensus guidelines for treating depression in bipolar disorder. J Clin Psychiatry 1998; 59(suppl 4):73–79.
51. Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP, Oakes R, Pitts CD.
Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatmentof bipolar depression. Am J Psychiatry 2001; 158:906–912.
52. Persad E, Oluboka OJ, Sharma V, Mazmanian D, Kueneman K. The phenomenon of rapid
cycling in bipolar mood disorders: a review. Can J Psychiatry 1996; 41:23–27.
53. Tondo L, Baldessarini RJ. Rapid cycling in women and men with bipolar manic-depressive
disorders. Am J Psychiatry 1998; 155:1434–1436.
54. Maj M. Rapid cycling in bipolar disorder. Am J Psychiatry 1999; 156(11):1837–1838.
55. Leibenluft E. Issues in the treatment of women with bipolar illness. J Clin Psychiatry 1997;
58(suppl 15):5–11.
56. Calabrese JR, Shelton MD, Bowden CL, Rapport DJ, Suppes T, Shirley ER, Kimmel SE,
Caban SJ. Bipolar rapid cycling: focus on depression as its hallmark. J Clin Psychiatry 2001;
62(suppl 14):34–41.
57. Rothbaum BO, Astin MC. Integration of pharmacotherapy and psychotherapy for bipolar disorder. J Clin Psychiatry 2000; 61(suppl 9):68–75.
58. Dunner DL. Optimizing lithium treatment. J Clin Psychiatry 2000; 61(suppl 9):76–81.
59. Swann AC. Major system toxicities and side effects of anticonvulsants. J Clin Psychiatry 2001;
62(suppl 14):16–21.
60. Hebert AA, Ralston JP. Cutaneous reactions to anticonvulsant medication. J Clin Psychiatry
2001; 62(suppl 14):22–26.
61. Chen ST, Altshuler LL, Melnyk KA, Erhart SM, Miller E, Mintz J. Efﬁcacy of lithium versus
valproate in the treatment of mania in the elderly: a retrospective study. J Clin Psychiatry
1999; 60:181–186.
62. Tueth MJ, Murphy TK, Evans DL. Special considerations: use of lithium in children, adolescents, and elderly populations. J Clin Psychiatry 1998; 59(suppl 6):66–73.
63. Viguera AC, Nonacs R, Cohen LS, Tondo L, Murray A, Baldessarini RJ. Risk of recurrenceof bipolar disorder in pregnant and nonpregnant women after discontinuinig lithium maintenance. Am J Psychiatry 2000; 157:179–184.
64. Llewellyn A, Stowe ZN, Strader JR. The use of lithium and management of women withbipolar disorder during pregnancy and lactation. J Clin Psychiatry 1998; 59(suppl 6):57–64.
65. Schou M. Treating recurrent affective disorders during and after pregnancy. Drug Safety 1998;
18(2):143–152.
66. Jamison KR. Suicide and bipolar disorder. J Clin Psychiatry 2000; 61(suppl 9):47–51.
67. Müller-Oerlinghausen B, Berghöfer A. Antidepressants and suicidal risk. J Clin Psychiatry
1999; 60(suppl 2):94–99.
68. Tondo L, Baldessarini RJ. Reduced suicide risk during lithium maintenance treatment. J Clin
Psychiatry 2000; 61(suppl 9):97–104.
69. Goodwin FK. Anticonvulsant therapy and suicide risk in affective disorders. J Clin Psychiatry
1999; 60(suppl 2):89–93.

25
Development of New Treatment
Options for Depression
SIEGFRIED KASPER
University of Vienna
Vienna, Austria
ALAN F. SCHATZBERG
Stanford University School of Medicine
Stanford, California, U.S.A.

I.

INTRODUCTION

Whereas antidepressants of the ﬁrst generation were developed primarily on the basis of
their chemical structure (e.g., tricyclic antidepressants), the newer generation of antidepressants has been developed strictly on the basis of their mechanism of action (e.g.,
selective serotonin or noradrenaline reuptake inhibitors). Although there was no evidence
that the elderly antidepressants like imipramine are psychostimulants or a “happy pill,”
this notion is still often discussed in the media, over 40 years after the introduction ofantidepressants for the treatment of depression. Figure 1 displays the development of antidepressive treatment modalities over the past 100 years, and the emerging treatment opportunities in the last 20 years are apparent.
When Kuhn [49,50] ﬁrst described the antidepressant effect of imipramine, he based
his assumption only on clinical observation. There were no standardized diagnostic criteria, no psychometric instruments, like the Hamilton Depression Rating Scale (HAM-D),
and no computer to establish statistical signiﬁcance levels and conﬁdence intervals. Subsequent development resulted in a reﬁned methodology, which is now the basis for internationally accepted drug development programs that make medications available in Europe
and worldwide [24]. Whereas the methodology and the quality of the studies are now
acceptable throughout different health authorities worldwide, pricing of the product is thelimiting factor for the availability of medication in the individual countries.
One of the aims for developing new antidepressants was to have a better tolerability
615

616

Kasper and Schatzberg

Figure 1 Different pharmacological and nonpharmacological, though biologically based,
therapies in depression. ECT: electroconvulsive treatment; SD: sleep deprivation; LT: lighttherapy; rTMS: repeated transcranial magnetic stimulation; VNS: vagus nerve stimulation;
MAO-I: inhibitors of monoamine oxidase; TCA: tricyclic antidepressants; SSRI: selective
serotonin reuptake inhibitors; RIMA: reversible inhibitor of monoamine oxidase A; NaSSA:
noradrenaline serotonin-speciﬁc antidepressant; SNRI: serotonin noradrenaline reuptake
inhibitor; NRI: noradrenaline reuptake inhibitor; DSA: dual serotonergic antidepressant;SRA: sigma receptor antagonist; SPA: substance P antagonist; CRH-RBP: corticotropinreceptor-blocking peptide; GRH-RBP: glucocorticotropin-receptor-blocking peptide; PP:
pentapeptides.

proﬁle than the older antidepressants, especially regarding toxicity in overdose [18,32].
To achieve this goal, a more circumscribed mechanism of action was studied that was
speciﬁcally targeted to eliminate anticholinergic (dry mouth, constipation, cognitive dysfunction), antihistaminergic (sedation, weight gain), as well as α1-adrenolytic (orthostatic
hypotension)-mediated side effects [61]. Particularly in the elderly, a beneﬁcial side effectproﬁle is important when lifelong antidepressant treatment is initiated, as it is for hypertension [78].

II. ANTIDEPRESSANTS OF THE FIRST GENERATION
Soon after antidepressants have been shown to be effective in open trials, randomized
controlled trials (RCT) with the use of placebo were introduced in depression research.
Morris and Beck [63] published the ﬁrst comprehensive review of RCT. The authors
noticed that there were many differences (e.g., diagnostic assessment of depression, control treatment, deﬁnition of response, and statistical analysis), which make it difﬁcult tocompare the individual studies. Interestingly, the ﬁrst trial conducted in a setting of ageneral practice (GP) was published in 1970 [73]. This is of importance because morethan 80% of prescriptions come from general practitioners.
Overall, the RCT indicated that tricyclic antidepressants (TCAs) as well as monoamine oxidase inhibitors (MAO-I) are signiﬁcantly superior to placebo, but with a burdensome side effect proﬁle. The largest long-term study of antidepressants has been performed
with imipramine [30], which indicated that the dose that had been proven to be effectivein the short-term treatment should also be used for continuation and prophylactic treatment

New Treatment Options

617[31]. Furthermore, this study elegantly demonstrated the superiority of antidepressive medication over placebo and interpersonal psychotherapy.
The necessity of long-term treatment for depression soon underlined the importanceof a low side effect proﬁle for antidepressants, which was the impetus for the developmentof newer antidepressants.
III. NEWER ANTIDEPRESSANTS
Compared to the RCTs carried out with TCAs, newer antidepressants have been studied
with a more reﬁned methodology, because DSM-III and later DSM-IV diagnoses of major
depression as well as standardized research instruments were more accepted [6]. Thesemethodological standardizations facilitated the use of meta-analyses such as those by
Loonen and Zwanikken [57], Bech and Cialdella [7], and Anderson and Tomenson [1].
A. Selective Serotonin Reuptake Inhibitors
To date, there are ﬁve selective serotonin reuptake inhibitors (SSRI) available worldwide:citalopram, ﬂuoxetine, ﬂuvoxamine, paroxetine, and sertraline [42,44]. They all have serotonin reuptake inhibition as the common mechanism of action but differ in pharmacokinetic properties. For instance, ﬂuoxetine and its active metabolite have a half-life of 10
to 14 days, while other SSRIs are in the range of about 1 day. The metabolic pathway ofP450 cytochromes also differentiates the individual SSRIs. The least interaction with othermedications can be expected from citalopram and sertraline [12].
RCT indicated that the SSRIs are superior to placebo in their antidepressant efﬁcacy
and not different from TCAs, except possibly in severe depression, if clomipramine[20,21] or dual-acting antidepressants [58,60,83] are used for comparison.
Long-term studies with SSRIs support the notion that SSRIs are effective in preventing relapse (e.g., in the ﬁrst 4–6 months after acute episode) and recurrence (6 months
after remission has been achieved) [37,89].
Compared to TCAs, SSRIs have a more favorable side effect proﬁle and it is ofclinical importance that the side effects of SSRIs mitigate after 2 to 3 weeks, whereas
those of TCAs persist [76].
In addition to the currently available SSRIs another SSRI, escitalopram, the S-enantiomer of citalopram, is now under clinical investigation and the ﬁrst studies show agood tolerability and efﬁcacy proﬁle [62,68,85], which might exceed that of citalopram.
B. Selective Noradrenaline Reuptake Inhibitor
Recently, the selective noradrenaline reuptake inhibitor (SNRI) reboxetine has been introduced in Europe and will soon be available in the United States, which has a speciﬁc
noradrenaline reuptake mechanism [22,46]. Besides antidepressant efﬁcacy, this compound promises to speciﬁcally improve on social functioning compared to SSRIs [39,40].
One of the side effects of a speciﬁc noradrenaline reuptake inhibitor—urinary hesitancy
in patients with prostate enlargement—has been shown to be treated effectively with tamsulosine [47].
C. Dual and Receptor-Speciﬁc AntidepressantsAfter the success of the SSRIs, researchers set out to develop compounds that exert both
serotonin and norepinephrine reuptake blocking properties (⫽ SNRIs). Antidepressants618

Kasper and Schatzberg

with this mechanism of action have been termed dual-acting antidepressants. Venlafaxine[13,55], milnacipran [11,38], and duloxetine [72] fall into this category and, based on
available data, it seems that low-dose (50 mg) venlafaxine is more a 5HT inhibitor thana noradrenaline reuptake inhibitor and vice versa for milnacipran. Both compounds (venlafaxine and milnacipran) have been shown to be signiﬁcantly superior to placebo and as
effective as TCAs [8,38]. However, compared with SSRIs, a signiﬁcantly superior efﬁcacy
has been demonstrated in severely depressed patients [83]. The side effect proﬁle of SNRIs
is linked to their pharmacodynamic properties with nausea and agitation being the mostfrequent. Recently, another dual-acting antidepressant, duloxetine, was studied in a clinicaldevelopment program in Japan and elsewhere [72,80].
Mirtazapine is a speciﬁc-acting antidepressant that enhances noradrenaline as well
as serotonin neurotransmission via blockade of the presynaptic autoreceptor sites [45]. In
addition, it exerts its antidepressant properties via blockade of postsynaptic 5HT2 and5HT3 receptors. RCT demonstrated superior efﬁcacy to placebo and comparable efﬁcacy
to TCAs, including clomipramine. Superior antidepressant properties have been demonstrated for ﬂuoxetine. The side effect proﬁle is superior compared to TCAs and different
from SSRIs. The postsynaptic blockade of the 5HT2- and 5HT3-receptor site translates inclinical practice to typical SSRI side effects like nausea, agitation, headache and sexual
dysfunction, which cannot be found with mirtazapine. However, weight gain is a limiting
factor for some patients.
Nefazodone is another newly introduced compound with a combined serotonergic
mechanism of action (5HT reuptake inhibition, 5HT2 blockade), which offers the beneﬁt
of not having sexual side effects [4]. However, the dosing regimen as well as some side
effects (like lightheadedness) does not give this compound an overall advantage over
SSRIs [26].
Whereas buspirone, a 5HT1A agonist, was not used to a large extent in clinical practice, new compounds under investigation, such as gepirone [25,59], demonstrated clinically relevant efﬁcacy in recent RCT. Flesinoxan and ipsapirone, on the other hand, also
5-HT1A-activating compounds, have not been developed further since RCT did not showsuperiority over placebo.
Moclobemide, a reversible inhibitor of MAO-A, is marketed in Europe but not theUnited States [2,54]. This compound can be viewed as efﬁcacious in mild-to-moderate,
but not severe, depression. However, speciﬁc studies have not been carried out.
The mechanism of action of tianeptin is not as yet fully understood; however, clinicalresults reveal good efﬁcacy, speciﬁcally if the symptomatology of the patients comprises
both anxiety and depression [35,86]. Bupropion, a selective dopamine reuptake inhibitor,
is marketed in the United States for depression and in Europe for smoking cessation. The
availability for those different indications in different parts of the world stems more frommarketing considerations than from data obtained in RCT.
D.

St. John’s Wort as an AntidepressantSince ancient times, preparations of St. John’s Wort (“Johanniskraut”) have been used
for antidepressant treatment properties [5,9,64]. In Germany, this treatment modality comprises up to 40% of the antidepressant market. Recently, it has been demonstrated for a few
standardized formulations (e.g., LI-160, WS 5570) that the pharmacodynamic properties
include serotonin, noradrenaline, and dopamine reuptake modulation together with

New Treatment Options

619

GABAergic effects [65]. Among the various constituents of St. John’s wort extract, hyperforin seems to play a major role in exerting the antidepressant efﬁcacy. This has been
demonstrated not only in animal studies but also in placebo-controlled clinical trials[36,43,51,53]. There are a number of RCT with standardized hypericum extracts, withmore to come. These studies indicate superiority over placebo and no difference to TCA.
However, the quality of these trials is not always comparable to synthetic antidepressantswith regard to sample size, dosage of reference compound, etc. [81]. The ongoing trials,
speciﬁcally placebo-controlled continuation and maintenance trials, will answer thesequestions in the near future. A recent placebo-controlled study performed by Volz et al.
[84] indicated that it might be worthwhile to further investigate hypericum extracts forsomatoform disorder. Compared to synthetic antidepressants, hypericum extracts exhibit
signiﬁcantly fewer side effects and most likely this is one of the reasons for its highprescription rates [41].
Table 1 Available Antidepressants and Their Pharmacodynamic Properties

Modern antidepressants
SSRI: selective serotonin reuptake inhibitors
Citalopram, escitalopram, ﬂuoxetine, ﬂuvoxamine,paroxetine, sertraline
NaSSA: noradrenaline and serotonin-speciﬁc
antidepressantMirtazapine
SNRI: (selective) serotonin and noradrenaline reuptake
inhibitors
Milnacipran, venlafaxine, duloxetine(Selective) noradrenaline reuptake inhibitors
Reboxetine
Serotonin-reuptake enhancer
Tianeptin
Serotonin 5HT1A-agonists
Buspirone, Gepirone
Dopamine reuptake inhibitor
Bupropion
DSA: dual serotonin antidepressantNefazodone
Older antidepressants
Tricyclics:
e.g., Amitriptyline, clomipramine, desipramine, imipramine
Tetracyclics
Maprotiline
Others:Mianserine
Trazodone
MAO inhibitors
MAO-A inhibitors (reversible):
Moclobemide

NA

5-HT

DA

Ach

H

⫺

⫹⫹⫹

⫺

⫺

⫺

⫹⫹

⫹⫹

⫺

⫺

⫹

⫹⫹⫹

⫹⫹⫹

⫺

⫺

⫺

⫹⫹⫹

⫺

⫺

⫺

⫺

⫺

⫺

⫺

⫹⫹⫹ ⫹⫹(⫹)

⫺

⫹⫹⫹

⫹

⫹⫹⫹

⫺

⫺

⫹⫹⫹ ⫹⫹

⫹⫹
⫺
⫹⫹⫹

⫺
⫹
⫹⫹⫹

⫺
⫺
⫹⫹

⫹
⫹

⫹⫹
⫹

⫹⫹

⫹⫹

⫺

⫺

⫺

??
⫹⫹
⫹⫹⫹
⫺

⫹⫹

DA: dopamine; NA: noradrenaline, Ach: acetylcholine, 5HT: serotonin, H: histamine.

620

Kasper and Schatzberg

IV. NOVEL ANTIDEPRESSANTS
Efforts at developing new antidepressants are currently pursuing drugs with novel mechanisms of action. In particular, a number of strategies have focused on agents that block
receptors for brain peptides. These approaches have been built upon theories that alterations in the activity of speciﬁc brain peptides could play a major role in stress responses
or in the development of symptoms of anxiety or depression.
The most advanced of these pharmacological approaches is the use of substance P
antagonists. Substance P is a neurokinin peptide with wide distribution in the brain [71].
It was identiﬁed in the early 1930s by von Euler and its amino acid sequence was identiﬁedsome 40 years later [87]. Its potential role as a neurotransmitter in the brain was demonstrated in 1975. In the late 1980s, a neurokinin receptor (NK1) that preferred substance P
was cloned and early antagonists, which were large molecules and had less than optimal
availability, were developed. Recently, a number of companies have developed relatively
small molecules with better availability and these are under active clinical investigation
for their potential efﬁcacy in depression. One compound—MK-869—has been tested in
major depression and has been reported to be effective [48].
Initially, substance P antagonists were tested as pain modulators, but studies wereremarkable in their consistent lack of efﬁcacy for this indication. The mapping of substanceP in mammalian brain pointed to high concentrations in areas (e.g., the amygdala) thought
to be involved in stress modulation, anxiety, or depression and this led investigators to
explore the possible use of NK1 antagonists in animal models of stress. Kramer and colleagues have described elegantly that MK-869—an NK1 antagonist— can exert signiﬁcant
suppression effects on separation-induced vocalizations in an animal model of stress. In
addition, NK1 antagonists have been reported to have potent antiemetic effects.
MK-869 has been tested in a multicenter trial in which 300 mg/day of the agent
were compared with paroxetine (20 mg/day) and placebo in 213 patients [48]. Both drugs
separated from placebo in reducing total scores on the Hamilton Depression Rating Scale(HDRS) and the Hamilton Anxiety Rating Scale (HARS) and there was a suggestion—although not statistically signiﬁcant—of possible superiority of MK-869 over paroxetine
on anxiety measures at the conclusion of the study. MK-869 did not appear to produce
more rapid effects.
The drug’s side effect proﬁle appeared relatively benign. Principal side effects appeared to be irritability, nausea, and fatigue. The drug appeared to produce signiﬁcantly
less sexual dysfunction than did the SSRIs.
Subsequently, the manufacturer of MK-869 has decided to suspend development of
this particular compound in favor of much more potent second-generation antagonists thatcan be prescribed at lower doses. In addition, a number of pharmaceutical companies
with small-molecule antagonists in their portfolios have also started investigation of theircompounds in major depression. This approach is innovative and opens new avenues fortreatment.
Recently, netamiftide, a novel pentapeptide, has been studied by Feighner et al.
[27–29] and found to be effective in severe treatment-resistant depression. Interestingly,
efﬁcacy was achieved by ﬁve or ten doses which continued for the remaining month of
the initial phase.
Another recent approach has been to develop antagonists for corticotropin-releasing
hormone (CRH). This peptide, found in the hypothalamus and hippocampus, has beenreported to play an initiating role in the hypothalamic–pituitary–adrenal (HPA) axis re-New Treatment Options621

sponse to stress. The peptide stimulates the pituitary to release adrenocorticotropin hormone (ACTH) which, in turn, stimulates the adrenal gland to secrete cortisol. Cortisol
feeds back at the levels of the brain and pituitary to inhibit further stimulation of CRH
and ACTH and ultimately to decrease its own release. Potential antagonism of the stressinduced increases in HPA axis activity underlie early attempts to develop CRH antagonists
as antidepressants. However, more recent studies have concentrated on CRH outside the
HPA axis (e.g., in the amygdala) which is not responsive to negative feedback by cortisol.
CRH outside the HPA axis may play an important role in general stress responsivity andthe pathogenesis of anxiety and depressive disorders. A glucocorticoid receptor antagonist
is currently under investigation [66,75].
Early prototypes (e.g., a helical CRH) were potent antagonists but, again, their large
structures led to poor bioavailability or permeability of the blood–brain barrier. Studies
in rats required intracerebral administration. More recently, a number of antagonists havebeen developed and these are generally smaller and enjoy greater permeability into thebrain. Several prototypes have passed phase I screening for safety and are now headed
for early dose ﬁnding phase II efﬁcacy studies. The CRH antagonist R121919 had beenstudied in an open clinical trial by Zobel et al. [91] and reported to be effective in a lower,
compared to a higher, dosage. The authors compared the results of this open trial with ahistorical open trial with paroxetine and concluded similar efﬁcacy. However, due to unforeseen side effects on the liver, development had been stopped.
A third approach has been to develop drugs that act as antagonists of the sigma
receptor [79]. The sigma receptor was thought for many years to be linked to opioid
systems, but over time data have emerged that indicate that this receptor has less to dowith opioids than was originally thought. More recently, a number of studies have pointed
to some sigma antagonists as exerting effects on other systems such as glutamate, GABAB acetylcholine, and neuropeptides. Sigma antagonists may increase release of norepinephrine from presynaptic terminals and are effective in several animal models used
to determine possible antidepressant properties. Still, the exact mechanisms of action visà-vis relief of depression are unclear.
Sigma antagonists were originally studied in schizophrenia, with relatively limited
efﬁcacy on positive symptoms. Recently, one such compound, igmesine, has begun to be
Table 2 Novel Treatment Approaches
Proposed mechanism

Substance

Substance P antagonists (NK1antagonist)
Corticotropin-releasing hormone(CRH) antagonists

MK-869

Glucocorticoid-receptor antagonist
Sigma-receptor antagonist
Blockage of melatonin receptors
Pentapeptide—
Igmesine
Agomelatin
Netamiftide

5HT2C inverse agonist

Deramciclane—

Clinical results
Equal efﬁcacy to paroxetine, better side
effect proﬁleOpen trial exerts antidepressantefﬁcacy. Development stopped due
to side effects
Not yet available
Not yet available
Not yet available
Open trial positive for severe treatment-resistant depression, even after
5–10 doses
Positive studies in generalized anxiety
disorders available

622

Kasper and Schatzberg

Table 3 Current and Possible Future Mood Stabilizers
Substance

Dosagemg/day a

Blood level

Lithium carbonate
Carbamazepine
Oxcarbamazepine
Valproic acid, Na-Valproate
Lamotrigine
Topiramate
Atypical antipsychotic

400–800
400–1200
600–1500
750–1500
200–400
100–200
TBD

0,6–0,8 mVal/L
17–42 µmol/L
10–50 µg/mL
50–120 µg/mL
1–10 µg/mL
3–15 µmol/L—a
Initial dosage lower.
TBD: to be determined, likely as an add-on strategy to mood stabilizers.

studied in major depression. Results are not yet available. Still, sigma antagonists represent
a novel approach to antidepressant therapy [79]. Recently, deramciclane, a speciﬁc-acting
serotonergic antidepressant, has come under investigation [52,69]. The other novel compound studied in animal experiments is agomelatin [88].

V.

EMERGING OPPORTUNITIES WITH MOOD STABILIZERS

Whereas for a long time only lithium was used for long-term treatment of bipolar (BP)disorder, now there are valproic acid, carbamazepine, and, as an add-on therapy, clonazepam available with mood stabilizing properties [23,33,77]. The side effect proﬁle andtoxicity of lithium are not the only reasons why further developments were necessary[3,34]. Based on the kindling hypothesis of Post et al. [74], it is thought that BP patientsin a later stage of their illness respond more positively to anticonvulsants than to lithium.
Within the group of mood stabilizers, there is a transatlantic gap (e.g., in the United States
valproic acid and in Europe carbamazepine are predominantly used as monotherapy or as
combination therapy with lithium). The U.S. approach is backed up by RCT [10], whereas
open data obtained in Europe speak for carbamazepine. There is some indication thatcarbamazepine has a favorable proﬁle in schizoaffective disorders [82], whereas valproic
acid is beneﬁcial speciﬁcally in rapid cycling [17]. Both compounds have limiting side
effects, such as weight gain or changes in plasma levels of concomitant medication (carbamazepine lowers and valproic acid increases levels of concomitant medication).
Further candidates for treatment of bipolar disorder under current investigation arelamotrigine [15,90] and topiramate [56,70]. So far, topiramate is promising because it is
not burdened with the side effect of weight gain. Lamotrigine recently demonstrated efﬁcacy in the treatment of acute depression within BP [14]. The studies for gabapentin,
however, did not show a signiﬁcant mood-stabilizing property. It emerged that this compound is more helpful for the anxiety component of the BP spectrum. Although oxcarbamazepin is signiﬁcantly less burdened with enzyme-inducing properties than carbamazepine, there are no studies in BP disorder available in the literature. Our clinicalexperience, however, indicates that oxcarbamazepine is as effective as carbamazepine.
The role of atypical antipsychotics for treatment of not only the acute phase of mania
but also mood-stabilizing properties is now under current investigation [15,77].

New Treatment Options

623

VI. CONCLUSION
The introduction of TCAs in the 1950s was the ﬁrst revolution of antidepressant therapy
followed by the SSRIs in the late 1980s. The relative lack of side effects of the SSRIs
and their efﬁcacy in disorders other than major depression (including anxiety disorders
and eating disorders) made them widely prescribed and accepted medications [42]. The
SSRIs fostered a mechanism-based approach to antidepressant research that will hopefully
lead to antidepressants with more distinct mechanisms of action (e.g., substance P antagonists) [48]. More effective and better tolerated antidepressant medications improve patient’s quality of life, foster greater acceptance of the disease in our society, and ultimately
provide wider beneﬁts for patients [19]. This is important because depression ranks highest
among the identiﬁed diseases in the loss of daily adjusted life years (DALYs), a measurethat indicates the loss of an individual’s productivity due to the disease from which they
suffer [67].
REFERENCES
1. Anderson IM, Tomenson BM. The efﬁcacy of selective serotonin re-uptake inhibitors in depression: a meta-analysis of studies against tricyclic antidepressants. J Psychopharmacol 1994;
8:238–249.
2. Angst J, Stabl M. Efﬁcacy of moclobemide in different patient groups: A meta-analysis ofstudies. Psychopharmacology 1992; 106:109–113.
3. Baldessarini RJ, Tondo I. Does lithium treatment still work? Arch Gen Psychiatry 2000; 57:
187–190.
4. Baldwin DS, Birtwhistle J. Antidepressant drugs and sexual function: improving the recognition and management of sexual dysfunction in depressed patients. In: Briley M, Montgomery SA, eds. Antidepressant Therapy at the Dawn of the Third Millennium. London: Martin
Dunitz, 1998; 231–253.
5. Barnes J, Anderson LA, Phillipson JD. St. John’s wort (Hypericum perforatum L.): a review
of its chemistry, pharmacology and clinical properties. J Pharm Pharmacol 2001; 53:583–600.
6. Bech P. Rating scales for affective disorders: Their validity and consistency. Acta Psychiatr
Scand 1981; 64(suppl 295):1–101.
7. Bech P, Cialdella P. Citalopram in depression: meta-analysis of intended and unintended effects. Int Clin Psychopharmacol 1992; 6(suppl 5):45–54.
8. Benkert O, Gründer G, Wetzel H, Hackett D. A randomized double-blind comparison of a
rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression andmelancholia. J Psychiatr Res 1996; 30:444–451.
9. Biocenter Symposium on drug therapy, advances of St. John’s Wort research. Pharmacopsychiatry (Suppl 1) 2001.
10. Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F, Pope HG Jr, Chou JC,
Keck PE Jr, Rhodes LJ, Swann AC, Hirschfeld RM, Wozniak PJ. A randomized, placebocontrolled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I
disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry 2000; 57:481–489.
11. Briley M, Prost J, Moret C. Preclinical pharmacology of milnacipran. Int Clin Psychopharmacol 1996; 11:9–14.
12. Brøsen K, Rasmussen BB. Selective Serotonin Reuptake Inhibitors: Pharmacokinetics andDrug Interactions, 2nd ed. Chichester: John Wiley, 1996:87–108.
13. Burnett FE, Dinan TG. The clinical efﬁcacy of venlafaxine in the treatment of depression.
Rev Contemp Pharmacother 1998; 9:303–320.
14. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind

624

15.
16.

17.
18.
19.
20.

21.

22.

23.
24.
25.
26.

27.
28.

29.

30.
31.

32.

33.

Kasper and Schatzberg
placebo controlled study of lamotrigine monotherapy in outpatients with Bipolar I depression.
J Clin Psychiatry 1999; 60:79–88.
Calabrese JR, Gajwani P. Lamotrigine and clozapine for bipolar disorder. Am J Psychiatry
2000; 157:1523.
Calabrese JR, Suppes T, Bowden CL, Sachs GS, Swann AC, McElroy SL, Kusumakar V,
Ascher JA, Earl NL, Greene PL, Monaghan ET. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group. J Clin
Psychiatry 2000; 61:841–850.
Calabrese JR, Woyshville MJ, Kimmel SE, Rapport DJ. Mixed states and bipolar rapid cycling
and their treatment with VPA. Psychiatr Ann 1993; 23:70–78.
Cassidy S, Henry J. Fatal toxicity of antidepressant drugs in overdose. Br Med J 1987; 295:
1021–1024.
Currie DJ, Fairweather DB, Hindmarch I. Social aspects of treating depression. In: Jönsson
B, Rosenbaum J, eds. Health Economics of Depression. Chichester: Wiley, 1993:129–139.
Danish University Antidepressant Group (DUAG). Citalopram: Clinical effect proﬁle in comparison with clomipramine: A controlled multicenter study. Psychopharmacology 1986; 90:
131–138.
Danish University Antidepressant Group (DUAG). Paroxetine: A selective serotonin reuptake
inhibitor showing better tolerance but weaker antidepressant effect than clomipramine in acontrolled multicenter trial. J Affect Disord 1990; 18:289–299.
Dubini A, Bosc M, Polin V. Noradrenaline-selective versus serotonin-selective antidepressanttherapy: Differential effects on social functioning. J Psychopharmacol 1997; 11(suppl 4):17–23.
ECNP Consensus Meeting March 2000 Nice. Guidelines for Investigating Efﬁcacy in Bipolar
Disorder. Eur Neuropsychopharmacol 2001; 11:79–88.
European Community. Guidelines on psychotropic drugs: Antidepressant medical products.
Eur Neuropsychopharmacol 1994; 4:62–65.
Feiger AD. A double-blind comparison of gepirone extended release, imipramine, and placeboin the treatment of outpatient major depression. Psychopharmacol Bull 1996; 32:659–665.
Feighner J, Targum SD, Bennett ME, Roberts DL, Kensler TT, D’Amico MF, Hardy SA. A
double-blind, placebo-controlled trial of nefazodone in the treatment of patients hospitalized
for major depression. J Clin Psychiatry 1998; 59:246–253.
Feighner JP. Preclinical and clinical overview of INN 00835, a novel pentapeptide antidepressant. Eur Neuropsychopharmacol 2001; 11(suppl. 3):S155–S156.
Feighner JP, Ehrensing RH, Kastin AJ, Leonard BE, Sverdlov L, Nicolau G, Patel A, Hlavka
J, Abajian H, Noble JF. A double-blind, placebo-controlled, efﬁcacy, safety, and pharmacokinetic study of INN 00835, a novel antidepressant peptide, in the treatment of major depression. J Affect Disord 2000; 61:119–126.
Feighner JP, Sverdlov L, Nicolau G, Noble JF. Cluster analysis of clinical data to identify
subtypes within a study population following treatment with a new pentapeptide antidepressant. International J Neuropsychopharmacol 2000; 3:237–242.
Frank E, Kupfer DJ, Perel JM. Three-year outcomes for maintenance therapies in recurrent
depression. Arch Gen Psychiatry 1990; 47:1093–1099.
Frank E, Kupfer DJ, Perel JM, Cornes C, Mallinger AG, Thase ME, McEachran AB, Grochocinski VJ. Comparison of full-dose versus half-dose pharmacotherapy in the maintenance treatment of recurrent depression. J Affect Disord 1993; 27:135–149.
Frey R, Schreinzer D, Stimpﬂ T, Vycudilik W, Berzlanovich A, Kasper S. Suicide by antidepressant intoxication at autopsy in Vienna between 1991–1997: the favourable consequences of the increasing use of SSRIs. Eur Neuropsychopharmacol 2000; 10:133–142.
Goldberg JF. Treatment guidelines: current and future management of bipolar depression. Int
Clin Psychiatry 2000; 61(suppl 13):12–18.

New Treatment Options

625

34. Grof P, Alda M. Discrepancies in the efﬁcacy of lithium (letter). Arch Gen Psychiatry 2000;
57:191.
35. Hindmarch I. Expanding the horizons of depression: beyond the monoamine hypothesis. Hum
Psychopharmacol 2001; 16:203–218.
36. Kalb R, Trautmann-Sponsel RB, Kieser M. Efﬁcacy and tolerability of Hypericum extract WS
5572 versus placebo in mildly to moderately depressed patients. A randomized double-blind
multicenter clinical trial. Pharmacopsychiatry 2001; 34:96–103.
37. Kasper S. The rationale for long-term antidepressant therapy. Int Clin Psychopharmacol 1993;
8:225–235.
38. Kasper S. The place of milnacipran in the treatment of depression. Hum Psychopharmacol
1997; 12(3):S135–S141.
39. Kasper S. Treatment beneﬁts of reboxetine. Int J Psychiatry Clin Pract 1999; 3(suppl 1):S3–
S8.
40. Kasper S. From symptoms to social functioning: differential effects of antidepressant therapy.
Int Clin Psychopharmacol 1999; 14(suppl 1):S27–S31.
41. Kasper S. Hypericum perforatum-a review of clinical studies. Pharmacopsychiatry 2001; 34(suppl 1):S51–S55.
42. Kasper S, Carlsson A, eds. Selective Serotonin Reuptake Inhibitors 1990–2000. A Decade ofDevelopments. Lundbeck Publishing, 2001.
43. Kasper S, Dienel A (2001) Cluster analysis of symptoms during antidepressant treatment withhypericum extract in mildly to moderately depressed out-patients. A meta-analysis of datafrom three randomized, placebo-controlled trials. Psychopharmacology (submitted for publication).
44. Kasper S, Heiden A. Do SSRIs differ in their antidepressant efﬁcacy? Human Psychopharmacol 1995; 10:163–171.
45. Kasper S, Praschak-Rieder N, Tauscher J, Wolf R. A risk-beneﬁt assessment of mirtazapine
in the treatment of depression. CNS Drug Safety 1997; 17(4):251–264.
46. Kasper S, Resinger-Kepl E. Efﬁcacy of noradrenergic-selective agents in the treatment ofneuropsychiatric diseases. CNS Spectrums 2001; 6:710–713.
47. Kasper S, Wolf R. Successful tamsulosin treatment of reboxetine-induced urinary hesitancy. Abstractbook: American Psychiatric Association (APA) Meeting, New Orleans, 2001:
65.
48. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ, Reines SA, Liu G,
Snavely D, Wyatt-Knowles E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harris T, Hill RG,
Hefti F, Scolnick EM, Cascieri MA, Chicchi GG, Sadowski S, Williams AR, Hewson L, Smith
D, Carlson EJ, Hargreaves RJ, Rupniak NMJ. Distinct mechanism for antidepressant activity
by blockade of central substance P receptors. Science 1998; 281:1640.
49. Kuhn R. Über die Behandlung depressiver Zustände mit einem Iminodibenzylderivat (G22355). Schweiz Med Wochenschr 1957; 87:1135–1140.
50. Kuhn R. The treatment of depressive states with G 22355 (imipramine hydrochloride). Am J
Psychiatr 1958; 115:459–464.
51. Laakmann G, Schüle C, Baghai T, Kieser M. St. John’s wort in mild to moderate depression:
the relevance of hyperforin for the clinical efﬁcacy. Pharmacopsychiatry 1998; 31(suppl):5459.
52. Ladanyi L, Sztruhar I, Budai Z, Lukacs G, Mezei T, Argay G, Kalman A, Simig G. Stereochemistry and enantiomeric purity of a novel anxiolytic agent, deramciclane fumarate. Chirality 1999; 11:689–693.
53. Lecrubier Y. The efﬁcacy of hypericum: does severity matter? Eur Neuropsychopharmacol
2001; 11(suppl 3):S105–S106.
54. Lecrubier Y, Guelﬁ JD. Efﬁcacy of reversible inhibitors of monoamine oxidase A in various
forms of depression. Acta Psychiatr Scand 1990; 82(suppl 1):74–87.

626

Kasper and Schatzberg

55. Lecrubier Y, Moon CAL, Schifano F. Efﬁcacy of venlafaxine in depressive illness in generalpractice. Acta Psychiatr Scand 1997; 95:485–493.
56. Letmaier M, Schreinzer D, Wolf R, Kasper S. Topiramate as a mood stabilizer. Int Clin Psychopharmacol 2001; 16:295–298.
57. Loonen AJM, Zwanikken GJ. Continuation and maintenance therapy with antidepressive
agents. An overview of research. Pharm Weekbl (Sci Ed) 1990; 12:128–141.
58. Lopez-Ibor J, Guelﬁ JD, Pletan Y, Tournoux A, Prost JF. Milnacipran and selective serotonin
reuptake inhibitors in major depression. Int Clin Psychopharmacol 1996; 11(suppl 4):41–
46.
59. McGrath PJ, Stewart JW, Quitkin FM, Wager S, Jenkins SW, Archibald DG, Stringfellow JC,
Robinson DS. Gepirone treatment of atypical depression: preliminary evidence of serotonergic
involvement. J Clin Psychopharmacol 1994; 14:347–352.
60. Montgomery SA. From theory to practice—everyday use of milnacipran. Psychiatr Clin Prac
1999; 3(suppl 2):S29–S33.
61. Montgomery SA, Kasper S. Comparison of compliance between serotonin reuptake inhibitors
and tricyclic antidepressants: a meta-analysis. Int Clin Psychopharmacol 1995; 9(suppl 4):33–
40.
62. Montgomery SA, Loft H, Sanchez C, Reines EH, Papp M. Escitalopram (S-enantiomer ofcitalopram): clinical efﬁcacy and onset of action predicted from a rat model. Pharmacol Toxicol 2001; 88:282–286.
63. Morris JB, Beck AT. The efﬁcacy of antidepressant drugs. Arch Gen Psychiatry 1974; 30:
667–674.
64. Müller WE, Kasper S, eds. Hypericum extract (LI 160) as a herbal antidepressant. Pharmacopsychiatry 1997; 30(suppl):71-134.
65. Müller WE, Rolli M, Schäfer C, Hafner U. Effects of hypericum extract (LI 160) in biochemical models of antidepressant activity. Pharmacopsychiatry 1997; 30(suppl):102–107.
66. Murphy BEP, Filipini D, Ghadirian AM. Possible use of glucocorticoid receptor antagonists
in the treatment of major depression: preliminary results using RU 486. J Psychiatry Neurosci
1993; 18:209–213.
67. Murray CJL, Lopez AD. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Cambridge, MA: Harvard University Press, 1996.
68. Owens MJ, Knight DL, Nemeroff CB. Second-generation SSRIs: human monoamine transporter binding proﬁle of escitalopram and R-ﬂuoxetine. Biol Psychiatry 2001; 50:345–350.
69. Palvimaki EP, Majasuo H, Kuoppamaki M, Mannisto PT, Syvalahti E, Hietala J. Deramciclane, a putative anxiolytic drug, is a serotonin 5-HT2C receptor inverse agonist but fails
to induce 5-HT2C receptor down-regulation. Psychopharmacology (Berlin) 1998; 136:99–
104.
70. Pecuch PW, Erfurth A. Topiramate in the treatment of acute mania. J Clin Psychopharmacol
2001; 21:243–244.
71. Pernow B. Substance P. Pharmacol Rev 1983; 35:85–141.
72. Pitsikas N. Duloxetine Eli Lilly & Co. Curr Opin Invest Drugs 2000; 1:116–121.
73. Porter AMW. Depressive illness in a general practice. A demographic study and a controlled
trial of imipramine. Br Med J 1970; 1:773–778.
74. Post RM, Leverich GS, Altshuler LL, Mikalauskas K. Lithium-discontinuation-induced refractoriness: preliminary observations. Am J Psychiatry 1992; 149:1727–1729.
75. Price LH, Malison RT, McDougle CJ, Pelton GH. Antiglucocorticoids as treatments for depression. CNS Drugs 1996; 5:311–320.
76. Reimherr FW, Chouinard G, Cohn CK, Cole JO, Itel TM, LaPierre YD, Masco HL, Mendels
J. Antidepressant efﬁcacy of sertraline: A double-blind placebo- and amitriptyline-controlled
multicenter comparison study in outpatients with major depression. J Clin Psychiatry 1990;
51(suppl 12):18–27.

New Treatment Options

627

77. Sachs GS, Thase ME. Bipolar disorder therapeutics: maintenance treatment. Biol Psychiatry
2000; 48:573–581.
78. Salzman C. Pharmacological treatment of depression in the elderly. J Clin Psychiatry 1993;
54(suppl 2):23–28.
79. Sanchez C, Arnt J, Costall B, Kelly ME, Naylor RJ, Perregaard J. The selective sigma 2 ligand
Lu 28-179 has potent anxiolytic-like effects in rodents. J Pharm Exp Ther 1997; 283:1323–
1332.
80. Sharma A, Goldberg MJ, Cerimele BJ. Pharmacokinetics and safety of duloxetine, a dualserotonin and norepinephrine reuptake inhibitor. J Clin Pharmacol 2000; 40:161–167.
81. Shelton RC, Keller MB, Gelenberg A, Dunner DL, Hirschfeld R, Thase ME, Russell J, Lydiard
RB, Crits-Cristoph P, Gallop R, Todd L, Hellerstein D, Goodnick P, Keitner G, Stahl SM,
Halbreich U. Effectiveness of St. John’s wort in major depression. A randomized controlled
trial. JAMA 2001; 285:1978–1986.
82. Stuppäck C, Barnas C, Schwitzer J, Fleischhacker WW. Carbamazepine in the prophylaxisof major depression. A 5-year follow up. J Clin Psychiatry 1994; 55:146–150.
83. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or
selective serotonin reuptake inhibitors. Br J Psychiat 2001; 178:234–241.
84. Volz HP, Murck H, Möller HJ. St. John’s wort extract (Li 160) in somatoform disorders.
Results of a double blind study. (submitted)
85. von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation,
inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos 2001; 29:1102–1109.
86. Wagstaff AJ, Ormrod D, Spencer CM. Tianeptine: a review of its use in depressive disorders.
CNS Drugs 2001; 15:231–259.
87. Wahlestedt C. Reward for persistence in substance P research. Science 1998; 281:1624–1625.
88. Wiley JL, Dance ME, Balster RL. Preclinical evaluation of the reinforcing and discriminative
stimulus effects of agomelatine (S-20098), a melatonin agonist. Psychopharmacology (Berlin)
1998; 140:503–509.
89. Winkler D, Tauscher J, Kasper S. Maintenance treatment in depression. The role of pharmacological and psychological treatment. Curr Opin Psychiatry 2000; 15:63–68.
90. Zerjav-Lacombe S, Tabarsi E. Lamotrigine: a review of clinical studies in bipolar disorders.
Can J Psychiatry 2001; 46:328–333.
91. Zobel AW, Nickel T, Sonntag A, Uhr M, Holsboer F, Ising M. Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression.
a prospective study. J Psychiatr Res 2001; 35:83–94.

26
The Depressed Patient: From
Nonresponse to Complete Remission
KOEN DEMYTTENAERE and JÜRGEN DeFRUYTUniversity Hospital Gasthuisberg
Leuven, Belgium

I.

INTRODUCTION

Major depressive disorder is a highly prevalent and disabling psychiatric disorder. Data
from the National Comorbidity Survey showed a 4.9% prevalence of current major depression and a 17.1% prevalence of lifetime major depression [l]. When compared with chronic
medical illnesses, depression results in equal or exceeding decrements in functioning andwell-being [2]. Major depression not only afﬂicts the individual but also has an importantsocietal impact. Due to its direct and indirect costs, major depression places a heavy burden
on the community. Different therapies of major depressive disorder have been developedin an attempt to reduce this impact on a person’s life and society. The effectiveness ofantidepressant treatment is said to be very high and, according to the Agency for HealthCare Policy and Research guidelines, depression can almost always be treated successfully
with medication, psychotherapy, or a combination of both [3,4]. This therapeutic optimism
is somewhat conﬂicting with everyday clinical practice where major depression often does
not resolve completely and recurs frequently. One of the main reasons for this discrepancy
may be found in the different deﬁnitions of “successful treatment.” Indeed, treatment
outcome is not a uniform concept and different deﬁnitions are applied according to theparties doing the deﬁning (e.g., pharmaceutical industry, society, and health-care providers, physicians, and patients). This chapter will take a closer look at treatment outcome
in major depression and will attempt to disentangle the many overlapping and often
vaguely deﬁned descriptions of (un)successful treatment for depression.

629

630

Demyttenaere and DeFruyt

II. OUTCOME DEFINITIONS IN MAJOR DEPRESSION
Many deﬁnitions exist and are used inconsistently (e.g., nonresponse, partial response,
response, partial remission, remission with residual symptoms, asymptomatic remission,and recovery). These inconsistencies make research ﬁndings difﬁcult to interpret and hinder comparisons across studies. Frank et al. [5] proposed an internally consistent, empirically deﬁned conceptual scheme for the terms episode, response and partial remission,
full remission, recovery, relapse, and recurrence (Table 1). It was stated that such a coherent scheme “would aid in the design, conduct and analysis of investigations aimed atunderstanding cause and pathogenesis, as well as those focused on the evaluation of shortand long-term effects of treatment.” Besides the conceptual scheme, Frank et al. also
put forward some operational criteria based on the Schedule for Affective Disorders andSchizophrenia [6], the 17-item Hamilton Rating Scale for Depression (HDRS) [7], or the
21-item Beck Depression Inventory (BDI) [8] (Table 2). A remarkable ﬁnding in thesedeﬁnitions is that different duration criteria were suggested for the different measures(e.g., an episode deﬁned by the 17-item HDRS implies a HDRS score ⬎15 for longer
than 2 weeks, while an episode deﬁned by the 21-item BDI requires a BDI score ⬎15
for longer than 4 weeks). This might also lead to different duration criteria in the deﬁnitionof episode, full remission, and recovery.
However, besides the categorical outcome criteria proposed by Frank et al. [5], many
continuous outcome deﬁnitions of depressive disorder are currently employed: endpoint
severity (absolute score on a chosen depression rating scale), depression improvement(absolute change in score from baseline to endpoint), and percent improvement (percent
change from baseline to endpoint). Some discrepancies found in the literature covering
predictors of outcome can be attributed to whether a categorical or continuous outcome
deﬁnition was used as illustrated by Tedlow et al. [9]. In the study by Tedlow et al., 248
patients with DSM-IIIR diagnosis of major depression were treated with ﬂuoxetine 20

Table 1 Deﬁnitions of Terms Designating Change Points in Major Depressive Disorder
An episode is a period, lasting longer than D days, during which the patient is consistently
within the fully symptomatic range on a sufﬁcient number of symptoms to meet syndromal criteria.
A response is the point at which a partial remission begins.
A partial remission is a period during which an improvement of sufﬁcient magnitude is observedthat the individual is no longer fully symptomatic (i.e., no longer meets syndromal criteria forthe disorder) but continues to evidence more than minimal symptoms. Treatment is not a requirement of the deﬁnition; partial remission can be spontaneous.
A full remission is a relatively brief (⬎E days but ⬍F days) period during which an improvement of sufﬁcient magnitude is observed that the individual is asymptomatic (i.e., no longer
meets syndromal criteria for the disorder and has no more than minimal symptoms). Treatment is not a requirement of the deﬁnition; partial remission can be spontaneous.
A remission that lasts for F days or longer is a recovery. Recovery can be spontaneous and canlast for an indeﬁnite period.
A relapse is a return of symptoms satisfying the full syndrome criteria for an episode that occurs
during the period of (partial) remission, but before recovery as deﬁned above.
A recurrence is the appearance of a new episode of major depressive disorder and, thus, can occur only during a recovery.
Source: Ref. 5.

From Nonresponse to Remission in Depression

631

Table 2 Operational Criteria for Terms Designating
Change Points in Major Depressive Disorder
Schedule for affective disorders and schizophrenia
Clinical ranges
Asymptomatic
2 symptoms present
Fully symptomatic
5 symptoms present
Durations
Episode4-week symptomatic
Full remission
2-week to ⬍8-week asymptomatic
Recovery
8-week asymptomatic
17-item Hamilton rating scale for depression
Clinical ranges
Asymptomatic
Fully symptomatic
Durations
EpisodeFull remission
Recoveryscore of 7score of 15
2-week fully symptomatic
2-week to ⬍6-month
asymptomatic
6-month asymptomatic

21-item Beck depression inventory
Clinical ranges
Asymptomatic
Fully symptomatic
Durations
EpisodeFull remission
Recoveryscore of 8score of 15
4-week fully symptomatic
3-week to ⬍4-month
asymptomatic
4-month asymptomatic

Source: Ref. 5.

mg/day for 8 weeks. Patients were evaluated both pre- and post-treatment with the 17item HRDS, the Clinical Global Impression Scales for Severity (CGI-S) and Improvement(CGI-I) [10]. The authors investigated the relationship between baseline severity of depression and anxiety, and different deﬁnitions of treatment outcome. Both continuous andcategorical outcome deﬁnitions were used. Continuous outcome deﬁnitions were endpoint
severity (endpoint HDRS score), depression improvement (absolute change in HDRS frombaseline to endpoint), global improvement (CGI-I score at endpoint), and percent depression improvement (percent change in HDRS score from baselin!e to endpoint). Categoricaldeﬁnitions were HDRS score ⬎10, 50% reduction in HDRS; HDRS score ⬎10 and 50%
reduction in HDRS; HDRS score ⬎7, 75% reduction in HDRS; HDRS score ⬎7, 75%
reduction in HDRS CGI-S ⫽ 1. The absolute change in depression score (depression
improvement) showed no relationship with baseline severity of depression or anxiety.
However, when using percent change in the HDRS score as an outcome variable, treatment
proved to be modestly better for subjects with lesser baseline anxiety or depression. This

632

Demyttenaere and DeFruyt

relationship became more robust when categorical deﬁnitions of outcome were applied,with lesser baseline symptoms predicting a better response.

III. RESPONSE
In the deﬁnition of Frank et al. [5], a response is thought of as the point at which partial
remission begins. Unlike other outcome deﬁnitions like remission and recovery, response
requires treatment. It is often applied in clinical trials to evaluate efﬁcacy of an antidepressant in the early phase of treatment. The most commonly used criterion of response is a
50% reduction or more from a baseline score on a depression rating scale like the HDRS,
the BDI, or Montgomery and Åsberg Depression Rating Scale [11]. These different scales
show a different item coverage and a different perspective of observer (self-rating versus
observer-rating) and so may yield different rates of response when used in a common
study sample. Epidemiological data and clinical trials have shown that the standard of a
50% improvement fails to reﬂect the reality of depression outcome and does not coveroutcomes like partial remission and residual symptoms. Indeed, a 50% reduction in the
HDRS score of a severely depressed patient may classify him as a responder but stillleaves him with prominent depressive symptoms.
Different deﬁnitions or subclassiﬁcations of response may concern the magnitude
and the pattern of improvement (timing and course), and were recently summarized by
Trivedi and Baker [12]: response, minimal response, nonresponse, early and late response,sustained response (Table 3). These latter outcome deﬁnitions (minimal response, earlyand late response, sustained response) are important in determining the onset of action ofantidepressants and may differentiate between true drug response and placebo response.
For many years, investigators have tried to measure the speed of onset of antidepressant drugs. In timing this onset of action, response must be an early, signiﬁcant reduction
in depressive symptoms and must be linked to a subsequent, clinically signiﬁcant treatment
outcome (i.e., a sustained response) [13]. Different deﬁnitions for early response (e.g., an
absolute change or percent improvement in HDRS score) are used and may affect theresults of studies, with stricter response criteria resulting in a later onset of action [14–18] (Table 4). In an elegantly designed study by Nierenberg et al. [16], the time until
onset of antidepressant response was assessed in 182 outpatients with DSM-IIIR major
depression who had a sustained response to ﬂuoxetine (8 weeks of treatment with 20 mg/
day of ﬂuoxetine). Onset of action was deﬁned as a 30% decrease in score on the 17-

Table 3 Classiﬁcation of Response According to Symptom Improvement and Timingof Improvement
Response: 50% improvement in symptom severity from baseline on the HDRS.
Minimal response: a 25 to 49% improvement in symptom severity from baseline on the HDRS.
Nonresponse: ⬍25% reduction improvement in symptom severity from baseline on the HDRS
Early response: 50% improvement in symptom severity from baseline on the HDRS, before
week 4.
Late response: 50% improvement in symptom severity from baseline on the HDRS, after
week 4.
Sustained response: two consecutive weeks of improvement in symptoms that meet the response
criterion.

From Nonresponse to Remission in Depression

633

Table 4 Different Criteria for Onset of Action
20% reduction in 17-item HDRS score.
30% reduction in 17-item HDRS score.
Decrease of 4 points in the MADRS score.
CGI score of either 2 (much improved) or 1 (very much improved)

Ref. 15
Ref. 16
Ref. 17
Ref. 18

item HDRS, which persisted and led to a 50% decrease by week 8. The authors foundthat at weeks 2, 4, and 6, the probabilities of having on onset of action were 56%, 25%,
and 9%, respectively. The mean time to onset of action was 3.8 weeks. When response
was deﬁned as a 50% decrease in HDRS score, the probabilities of having a response atweeks 2, 4, and 6 became 18%, 37%, and 26%. The mean time to response became 4.9
weeks.
However, besides the magnitude and timing of response, research has also focusedon the temporal pattern of this response. Quitkin et al. [18] developed a method of describing the longitudinal pattern of response to antidepressants. Patterns of response were basedon weekly ratings of clinical status (CGI-I). Improvement was deﬁned as a CGI score ofeither 2 (much improved) or 1 (very much improved). Delayed improvement was judged
as being ﬁrst observed after 2 weeks of treatment. Improvement was said to be persistent
if it was not followed by a relapse in any succeeding week. In a sample of 150 nonmelancholic depressed patients (treated in a double-blinded study during 6 weeks with phenelzine, imipramine, or placebo), true drug effect was characterized by a 2-week delay of
onset and persistence of improvement. These ﬁndings were further elaborated by Stewart
et al. [19] using pattern analysis to predict differential relapse of remitted patients withmajor depression during 1 year of treatment with ﬂuoxetine or placebo. The efﬁcacy of
ﬂuoxetine during the continuation phase (the period from the end of the short-term treatment until 6 months) and maintenance phase (beyond 6 months) seemed to be limited topatients with an initial true drug response (delayed and persistent improvement).
IV. PARTIAL REMISSION
Partial remission is deﬁned as a period during which an improvement of sufﬁcient magnitude is observed that the individual is no longer fully symptomatic (i.e., no longer meets
syndromal criteria for the disorder), but continues to evidence more than minimal symptoms. Operational criteria are a 17-item HDRS score ranging from 8 to 14, or a 21-item
BDI ranging from 9 to 14 [5]. About 50 to 70% of patients in clinical trials will respond(⬎50% improvement) to antidepressants and only 25 to 35% will experience full remission[20]. Thus, many patients will only achieve partial remission (i.e., the patient is no longer
fully symptomatic but continues to evidence residual symptoms).
Studies by Paykel et al. [21] and Van Londen et al. [22] have highlighted some
remarkable ﬁndings regarding the prevalence, nature, and consequences of the residual
symptoms in partial remission. First, residual symptoms in partially remitted patients arehighly prevalent. Second, they resemble the typical depressive symptomatology. Third,
residual symptoms in partial remission are associated with a higher risk of relapse.
In a study by Paykel et al. [21], patients with primary unipolar major depression(Research Diagnostic Criteria) were followed every 3 months to remission and thereafter.
Remission was deﬁned as no longer meeting the inclusion criterion of major depression

634

Demyttenaere and DeFruyt

Table 5 HDRS Distribution in
Patients No Longer ReachingCriteria for Major Depression
17-item HDRS score

%

0–4
5–7
8–10
11–12
13–15
16–18

47
22
7
12
5
8

Source: Ref. 21.

during two consecutive months. In the remitted patients, residual symptoms were regarded
as present when the 17-item HDRS score was ⬎8. Residual symptoms were found in 32%
of the remitted sample; the HDRS score ranged from 8 to 18 (Table 5). The symptoms
present were those typical of depression: at least 47% of subjects showed ratings at thelevel of moderate or more on the items of depressed mood, work, and interests, psychic
anxiety, and genital symptoms. Mean scores on all individual items of the HDRS could
differentiate signiﬁcantly between subjects with or without residual symptoms, except forsome items typical of severe depression (late insomnia, retardation, agitation, hypochondriasis, weight loss, and loss of insight). Residual symptoms were predictive of relapse.
Overall, 76% of subjects with residual symptoms relapsed over follow-up, as opposed to
25% of those without residual symptoms. Analogous results were obtained by Van Londen
et al. (22) in a follow-up study of patients with DSM-III-R major depression. After 9months, 49% of patients had reached full remission and 45% were in partial remission.
Full remission was deﬁned as at least two consecutive months with symptoms below thethreshold for depression and without residual symptoms. The absence off residual symptoms was conceptualized by a score of ⬍2 per symptom on the MADRS. Partial remission
was deﬁned as at least two consecutive months, with symptoms below the threshold for
depression but with residual symptoms. For subjects with partial remission, the sum score
had to be 10 on the MADRS, and only one symptom was allowed to have a score equal
to 3; any further symptom score had to be ⬍3. Subjects with only partial remission were
found to have a signiﬁcantly greater risk of relapse in the subsequent 12 months thanpatients in full remission. Patients with partial remission relapsed particularly in the ﬁrst
4 months, while fully remitted patients had recurrence for the most part after 12 monthsof remission.
V.

FULL REMISSION AND RECOVERY

Full remission is a relatively brief period during which an improvement of sufﬁcient magnitude is observed that the individual is asymptomatic (i.e., no longer meets the syndromal
criteria for the disorder and has no more than minimal symptoms). When this asymptomatic state is maintained during a longer period, full remission becomes recovery [5]. The
deﬁnition of remission and recovery implies a common criterion of severity (asymptomaticor no more than minimal symptoms) and a different criterion of duration. Being asymp-

From Nonresponse to Remission in Depression

635

tomatic is often translated into a 17-item HDRS ⬎7 or a BDI ⬎8. More controversy exists
about the different criteria of duration. In the original proposition by Frank et al. [5], fullremission was deﬁned as a period ⬎2 weeks and ⬍6 months and recovery ⬎6 months.
However, in the subsequently mentioned research articles other duration criteria are usedor are not speciﬁed at all.
Full remission is considered to be the gold standard in antidepressant therapy. However, having a closer look at these fully remitted patients may reveal that they are not as
asymptomatic as they are supposed to be. Residual symptoms seem to persist, not onlyin the depressive realm but also in the area of social and cognitive functioning.
In a study by Nierenberg et al. [23] 215 outpatients with DSM-III-R major depression were treated with a ﬁxed dose of ﬂuoxetine (20 mg/day) for 8 weeks. Of these 215
patients, 108 (50%) reached full response (17-item HDRS score ⬎7). In these full responders, the authors then assessed the presence of subthreshold or threshold depressive symptoms, according to the Structured Clinical Interview for DSM-III-R, Patient Edition(SCID-P). Only a minority (18%) of those with a ﬁnal 17-item HDRS score ⬎7 were
found to be totally free of SCID-P major depressive symptoms, while the majority were
not as asympomatic as they were thought to be (Table 6). The three most common symptoms were sleep disturbances, fatigue, and diminished interest or pleasure. Fava et al. [24]looked for residual symptoms in 49 outpatients with primary major depressive disorder(Research Diagnostic Criteria), who were successfully treated with antidepressant drugs
and had reached full remission [5]. Residual symptoms were assessed with a modiﬁed
version of Paykel’s Clinical Interview for Depression [25]. Only 6 (12%) of the 49 patients
screened did not present with residual symptoms. The most frequently reported symptoms
were generalized anxiety, somatic anxiety, and irritability.
The importance of residual depressive symptomatology in fully remitted/recovered
patients is pointed out by a prospective study by Judd et al. [26] in which patients withunipolar major depressive disorder were followed naturalistically for 10 years or longer.
Recovered patients were divided into two groups: asymptomatic recovery and recovery
with subthreshold depressive symptoms (SSD). Residual SSD compared to asymptomatic
recovery patients relapsed ⬎3 times faster to their next major depressive episode (me-Table 6 Frequency ofThreshold and Subthreshold
Depressive Symtoms (asdeﬁned in the SCID-P) in Fully
Remitted Patients
Number of symptoms

%

1
2
3
4
5
6
7

18
26
23
19
10
2
3

Source: Ref. 23.

636

Demyttenaere and DeFruyt

dian ⫽ 68 vs. 231 weeks). The risk for early relapse associated with residual SSD recovery
was so strong that it appeared to override the effect of the history of prior major depressive
episodes.
However, residual symptoms in fully remitted patients extend beyond the core depressive symptomatology. Research has gathered substantial evidence for long-lastingchanges in social functioning and cognition, even after succesful treatment (i.e., full remission) of major depressive disorder. Some of these research ﬁndings will be discussed
further.
As early as 1973, Paykel and Weissman [27] demonstrated the persistence of impaired social functioning in women after symptomatic improvement. Although improvements in social functioning occurred over an 8-month follow-up period, residual impairment remained. In the study of Mintz et al. [28], analogous conclusions were made. Bymeans of a comprehensive review of the scientiﬁc literature, the authors investigated theeffects of antidepressants and psychotherapy on work impairment in depressed patients.
The trajectory of outcome for work appeared to be slower than that observed for symptoms. In fully remitted patients, work outcome became better and better as the durationof treatment increased, reaching a maximum at about 4 to 6 months. More recently, Furukawa et al. [29] studied the time course of symptomatic change and social functioning inpatients recovering from major depression. The study included 95 patients with DSM-IV
unipolar major depressive disorder, who had received no antidepressant or antipsychotic
medication in the preceding 3 months. Symptomatic change was measured with the 17item HDRS, while social functioning was assessed by the Global Assessment Scale (GAS)[30] and the Social Adjustment Scale-Self Report (SAS-SR) [31]. A patient was considered as remitted when he/she scored ⬎7 on the 17-item HDRS, and recovered when he/she scored ⬎7 for two consecutive months or more. Within 2 years of follow-up, 74 (78%)
reached remission and 53 (56%) reached recovery. Twenty (21%) of the recovered patientsdemonstrated sustained recovery over 6 months. In remitted patients, GAS ratings, although greatly improved from baseline, still were not in the normal range. GAS ratings
only reached the normal range in recovered patients and still improved if recovery was
sustained. Similar trends were observed for the SAS-SR.
Besides impaired social functioning, other aspects of depression, such as dysfunctional attitudes and depressive cognitions, may persist after the resolution of depressive
symptomatology. An example of these cognitive residual symptoms was given by Poweret al. [32]. Using a subscale version of the Dysfunctional Attitude Scale [33] in fully
remitted depressed patients (BDI ⬎6), the authors found a dependency subscale score thatremained elevated. In a study by Fava et al. [34], the relationship between dysfunctional
attitudes and depression severity was examined during 8 weeks of treatment with ﬂuoxetine in 115 outpatients with DSM-III-R major depressive disorder. Dysfunctional attitudes
were assessed by the Dysfunctional Attitude Scale (DAS) [35] and the Cognitions Questionnaire (CQ) [36]. Depression severity was measured by the 17-item HDRS and the21-item BDI. The DAS measures cognitive distortions, ﬁxed negative values, and perfectionistic attitudes, while the CQ is directed toward negative attitudes and perceived
uncontrollability as a response to hypothetical situations. Treatment with ﬂuoxetine wasassociated with a signiﬁcant decrease in dysfunctional attitudes as measured by the DAS
and the CQ, linearly associated with the decrease in depression severity. However, themean DAS and CQ scores after treatment did not approach normal values. The importanceof residual cognitive components is perhaps best shown indirectly by the positive effectFrom Nonresponse to Remission in Depression637

of cognitive behavioral therapy in the prevention of recurrent depression as evidenced in
the studies by Fava et al. [37] and Paykel et al. [38].
VI. CATEGORICAL OR CONTINUOUS DEFINITIONS OF OUTCOME
VERSUS THE FLUCTUATING TIME COURSE OF THE
DEPRESSIVE ILLNESSThe aforementioned outcome deﬁnitions are subject to temporal changes. During an extended period of time, a depressed patient will move from one criterion to another, inboth directions. This dynamic course of symptoms was convincingly proved by Judd etal. [39] in a prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorder. The authors conducted weekly analyses ofdepressive symptom severity in a large cohort of major depressed patients evaluated prospectively for up to 12 years. Depressive symptoms were divided into four levels of severity: (1) depressive symptoms at the threshold for major depression (MDD); (2) depressive
symptoms at the threshold for minor depression or dysthymic disorder (MinD); (3) subsyndromal or subthreshold depressive symptoms (SSDs); and (4) no depressive symptoms.
During follow-up, patients were symptomatically ill 59% of the time (Table 7). The vast
majority of patients spent their follow-up weeks at 3 or 4 different levels of depressive
symptom severity, and they changed symptom levels almost twice a year. Depressive
symptoms at the level of SSDs, MinD, and MDD were associated with a stepwise increment in psychosocial disability [40].
VII. SUMMARY
About 50 to 70% of patients in clinical trials will respond (⬎50% improvement) to antidepressants, but only 25 to 35% will experience full remission. About 80 to 90% of fully
remitted patients will experience some further core depressive symptomatology. Residual
symptoms found in fully and partially remitted patients are an important risk factor for
subsequent relapse or recurrence.
Treatment outcome is not a unitary concept and covers different domains of pathology (e.g., core depressive symptomatology, social, and cognitive dysfunctioning). Although these different dimensions of pathology are well correlated, all showing a gradualdecrement in the course of recovery from major depression, social and cognitive functioning seem to exhibit a more protracted trajectory. A consequence of this may be that different deﬁnitions of outcome should be applied according to the phase in the process ofTable 7 Percentage of Weeks Spent at 4
Different Levels of Depressive Symptom Severityin Patient with MDD During a 12-Year Follow-Up
No depressive symptoms
Subsyndromal depressive symptoms
Depressive symptoms at the MinD level
Depressive symptoms at the MDD level
Source: Ref. 39.

42%
17%
27%
15%

638

Demyttenaere and DeFruyt

recovery (e.g., outcome criteria based on depressive symptomatology from the early stageof treatment to full remission, followed by measurements of social and cognitive functioning). This differential assessment of treatment outcome may then be linked to differential therapeutic interventions—the so-called concept of staging and sequential therapy[41,42]. A failure to attain fully symptomatic remission in the early phase of treatment
should invite the modiﬁcation of the antidepressant treatment (augmentation, combination,change) while the persistence of cognitive/social dysfunctioning after symptomatic resolution could be targeted by cognitive behavioral psychotherapy or interpersonal psychotherapy.
An often neglected part of the outcome deﬁnitions in major depressive disorder isthe time criterion. In many research studies, outcome criteria like response, remission,and residual symptoms are used without specifying the speciﬁc time point in the courseof treatment, and are thereby difﬁcult to interpret. However, in clinical practice, outcome
must be measured at speciﬁc time points (critical decision points), after which the treatment strategy should be maintained or changed.
Recovery from major depression is a complex phenomenon, as reﬂected in the many
obscure deﬁnitions designed to describe its course. This obscurity involves both the content and the time point of deﬁnitions and may hamper current and future depression research. Although stated by Frank et al. [5] two decades ago, there is still a need for acoherent scheme, that “would aid in the design, conduct, and analysis of investigations
aimed at understanding cause and pathogenesis, as well as those focused on the evaluationof short- and long-term effects of treatment.”
REFERENCES
1. Blazer DG, Kessler RC, McGonagle KA, Swartz MS. The prevalence and distribution of major
depression in a national community sample: the national comorbidity survey. Am J Psychiatry
1994; 151:979–986.
2. Wells KB, Stewart A, Hays R, Burnam A, Rogers W, Daniels M, Berry S, Greenﬁeld S, WareJ. The functioning and well-being of depressed patients. JAMA 1989; 262:914–919.
3. Depression Guideline Panel. Clinical Practice Guideline: Depression in Primary Care, 1. Detection and Diagnosis. Rockville, MD: U.S. Department of Health and Human Services,
Agency for Health Care Policy and Research, 1993. AHCPR publication 93-0550.
4. Depression Guideline Panel. Clinical Practice Guideline: Depression in Primary Care, 2. Treatment of major depression. Rockville, MD: U.S. Department of Health and Human Services,
Agency for Health Care Policy and Research, 1993. AHCPR publication 93-0551.
5. Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, Rush JA, Weissman MM.
Conceptualization and rationale for consensus deﬁnitions of terms in major depressive disorder. Arch Gen Psychiatry 1991; 48:851–855.
6. Spitzer RL, Endicott J, Robins E. Research Diagnostic Criteria: rationale and reliability. ArchGen Psychiatry 1978; 35:773–782.
7. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62.
8. Beck AT, Ward CH, Mendelson M. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561–571.
9. Tedlow J, Fava M, Uebelacker L, Nierenberg AA, Alpert JE, Rosenbaum J. Outcome deﬁnitions and predictors in depression. Psychother Psychosom 1998; 67:266–270.
10. Guy W. ECDEU Assessment Manual for Psychopharmacology. DHEW Publ No (ADM) 76338. Rockville, Maryland, NIMH, 1976.
11. Montgomery S, Åsberg M. A new depression rating scale designed to be sensitive to change.
Br J Psychiatry 1979; 134:382–389.

From Nonresponse to Remission in Depression639

12. Trivedi MH, Baker SM. Clinical signiﬁcance of monitoring early symptom change to predict
outcome. J Clin Psychiatry 2001; 62(suppl 4):27–33.
13. Leon AC. Measuring onset of antidepressant action in clinical trials: an overview of deﬁnitions
and methodology. J Clin Psychiatry 2001; 62(suppl 4):12–16.
14. Möller HJ, Müller H, Volz HP. How to assess the onset of antidepressant effect: comparisonof global ratings and ﬁndings based on depression scales. Pharmacopsychiatry 1996; 29:57–
62.
15. Stassen HH, Delini-Stula A, Angst J. Time course of improvement under antidepressant treatment: a survival-analytical approach. Eur Neuropsychopharmacol 1993; 3:127–135.
16. Nierenberg AA, Farabaugh AH, Alpert JE, Gordon J, Worthington JJ, Rosenbaum JF, Fava
M. Timing of onset of antidepressant response with ﬂuoxetine treatment. Am J Psychiatry
2000; 157:1423–1428.
17. Montgomery SA. Are 2-week trials sufﬁcient to indicate efﬁcacy? Psychopharmacol Bull
1995; 31:41–44.
18. Quitkin FM, Rabkin JD, Markowitz JM, Stewart JW, McGrath PJ, Harrison W. Use of patternanalysis to identify true drug response. Arch Gen Psychiatry 1987; 44:259–264.
19. Stewart JW, Quitkin FM, McGrath PJ, Amsterdam J, Fava M, Fawcett J, Reimherr F, Rosenbaum J, Beasly C, Roback P. Use of pattern analysis to predict differential relapse of remitted
patients with major depression during 1 year of treatment with ﬂuoxetine or placebo. ArchGen Psychiatry 1998; 55:334–343.
20. Nierenberg AA, Wright EC. Evolution of remission as the new standard in the treatment ofdepression. J Clin Psychiatry 1999; 60(suppl 22):7–11.
21. Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms afterpartial remission: an important outcome in depression. Psychol Med 1995; 25:1171–1180.
22. Van Londen L, Molenaar RPG, Goekoop JG, Zwinderman AH, Rooijmans HGM. Three- to
5-year prospective follow-up of outcome in major depression. Psychol Med 1998; 28:731–
735.
23. Nierenberg AA, Keefe BR, Leslie VC, Alpert JE, Pava JA, Worthington JJ, Rosenbaum JF,
Fava M. Residual symptoms in depressed patients who respond acutely to ﬂuoxetine. J Clin
Psychiatry 1999; 60:221–225.
24. Fava GA, Grandi S, Zielezny M, Canestrari R, Morphy MA. Cognitive behavioral treatmentof residual symptoms in primary major depressive disorder. Am J Psychiatry 1994; 151:1295–
1299.
25. Paykel ES. The clinical interview for depression. J Affect Disord 1985; 9:85–96.
26. Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Paulus MP, Kunovac JL,
Leon AC, Mueller TI, Rice JA, Keller MB. Major depressive disorder: a prospective studyof residual subthreshold depressive symptoms as predictor of rapid relapse. J Affect Disord
1998; 50:97–108.
27. Paykel ES, Weissman MM. Social adjustment and depression: a longitudinal study. Arch Gen
Psychiatry 1973; 28:659–663.
28. Mintz J, Mintz LI, Arruda MJ, Hwang SS. Treatments of depression and the functional capacity to work. Arch Gen Psychiatry 1992; 49:761–768.
29. Furukawa TA, Takeuchi H, Hiroe T, Mashiko H, Kamei K, Kitamura T, Takahashi K. Symptomatic recovery and social functioning in major depression. Acta Psychiatr Scand 2001; 103:257–261.
30. Spitzer RL, Gibbon M, Endicott J. Global Assessment Scale. New York: New York State
Psychiatric Institute, 1978.
31. Weissman MM, Bothwell S. Assessment of social adjustment by patient self-report. Arch Gen
Psychiatry 1976; 33:1111–1115.
32. Power MJ, Duggan CF, Lee AS, Murray RM. Dysfunctional attitudes in depressed and recovered depressed patients and their ﬁrst-degree relatives. Psychol Med 1995; 25:87–93.
33. Power MJ, Katz R, McGufﬁn P, Duggan DC, Lam D, Beck AT. The Dysfunctional Attitude

640

34.
35.
36.
37.
38.

39.

40.

41.
42.

Demyttenaere and DeFruyt
Scale (DAS): a comparison of forms A and B and proposals for a new subscaled version. J
Res Pers 1994; 28:263–276.
Fava M, Bless E, Otto MW, Pava JA, Rosenbaum JF. Dysfunctional attitudes in major depression. J Nerv Ment Dis 1994; 182:45–49.
Weissman A. The Dysfunctional Attitude Scale: a validation study. Diss Abstr Int 1979; 40(B):1389–1390.
Fennell MJV, Campbell EA. The Cognitions Questionnaire: speciﬁc thinking errors in depression. Br J Clin Psychol 1984; 23:81–92.
Fava GA, Rafanelli C, Grandi S, Conti S, Belluardo P. Prevention of recurrent depression
with cognitive behavioral therapy. Arch Gen Psychiatry 1998; 55:816–820.
Paykel ES, Scott J, Teasdale JD, Johnson AL, Garland A, Moore R, Jenaway A, Cornwall
PL, Hayhurst H, Abbott R, Pope M. Prevention of relapse in residual depression by cognitive
therapy. Arch Gen Psychiatry 1999; 56:829–835.
Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J, Coryell W, Paulus MP, Kunovac JL,
Leon AC, Mueller TI, Rice JA, Keller MB. A prospective 12-year study of subsyndromal andsyndromal depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry
1998; 55:694–700.
Judd LL, Akiskal HS, Zeller PJ, Paulus M, Leon AC, Maser JD, Endicott J, Coryell W, Kunovac JL, Mueller TI, Rice JP, Keller MB. Psychosocial disability during the long-term courseof unipolar major depresssive disorder. Arch Gen Psychiatry 2000; 57:375–380.
Fava GA, Kellner R. Staging: a neglected dimension in psychiatric classiﬁcation. Acta Psychiatr Scand 1993; 87:225–230.
Fava GA. Subclinical symptoms in mood disorders: pathophysiological and therapeutic implications. Psychol Med 1999; 29:47–61.

27
Pharmacogenetics of Mood Disorders:
Is There a Future?
BERNARD LERER and OFER AGID
Hadassah–Hebrew University Medical Center
Jerusalem, Israel
FABIO MACCIARDI
University of Toronto
Toronto, Ontario, CanadaI.

INTRODUCTION

Pharmacogenetics is the study of genetically based, inter-individual variability in response
to drugs and susceptibility to drug-induced adverse effects. Almost a century ago, it wasrecognized that differences among individuals in their response to ingested substancesmight have a genetic basis [1,2]. In the 1950s, the role of genetic susceptibility in adverse
drug reactions was described by Motulsky [3]. Vogel [4] introduced the term pharmacogenetics. The major role of genetic polymorphism of the cytochrome P450 system in differences in drug metabolism was ﬁrst described in the 1970s [5] and has been extensively
studied since then.
Since pharmacogenetics has been around for some time, why has it only now become
the focus of the great interest that has been expressed in a number of inﬂuential papers
in major scientiﬁc journals (e.g., Ref. 6)? The answer to this question lies in the recent
delivery of the draft sequence of the human genome, culminating more than a decade ofintensive government-sponsored and privately funded research. In the current, so-called“post genomic” era, the next major task is to deﬁne and catalogue the totality of genetic
variation within the human genome sequence. This variation, it is anticipated, will serveas the major tool in mapping genes for complex traits [7,8]. Prominent among such traits
are most of the major psychiatric disorders and also pharmacogenetic characteristics that
641

642

Lerer et al.

have a polygenic basis. A number of government-sponsored, private, and academic consortia are devoting enormous resources to identifying the most common of the genetic variants, single nucleotide polymorphisms (SNPs). These are variations in a single base pairof DNA sequence and they are estimated to occur every 1000 bases. The information thatis being gathered is deposited in publicly accessible databases. Since pharmacogenetics
seeks to correlate variation in gene structure (genotype) with variations in response todrugs and susceptibility to adverse effects, this is an invaluable resource. The ultimate,end product of these efforts are diagnostic tests available to the clinician that will be used
to guide the choice of treatment. Pharmacogenetic information will also be of immense
value in streamlining clinical trials of new drugs by stratifying patients according to genetic predictors of response and adverse effects. This will greatly reduce the sample sizes
needed and thereby the time lag and expense of bringing new therapeutic agents to theclinic. Although the chip technology needed for tests of this type is well advanced, it isstill prohibitively expensive. However, by the time large-scale pharmacogenetic testingis practically feasible, this obstacle will be overcome.
An important ﬁeld allied to pharmacogenetics is pharmacogenomics. While the starting point of pharmacogenetics is patient-oriented research, the human genome sequenceis the starting point of pharmacogenomics. Putative drug targets derived from the humangenome sequence (to a great extent “in silica,” i.e., at the computer level) are screened
for their potential in developing therapeutic agents. This process differs markedly fromconventional approaches in which compounds are screened for their potential to act on
known targets. Targets can also be identiﬁed by means of a variety of techniques that areused to screen relevant tissues for messenger RNAs that are expressed either in relation
to the target disease or as a consequence of drug effects. The emerging ﬁeld of proteomics
is an important element of these efforts. While pharmacogenetics and pharmacogenomics
are closely related and the terms are often used interchangeably, the different starting
points and agendas of the two ﬁelds suggest that it is useful to maintain the distinction.
What promise does pharmacogenetics hold for the treatment of mood disorders andwhat are the problems and pitfalls on the way to its realization? These issues will beconsidered in this chapter. Initially, we will review basic concepts in the pharmacogenetics
of mood disorders and outline the clinical and genetic rationale. Then, we will review therole of genetic inﬂuences on the pharmacokinetics of antidepressant drugs. We will next
consider pharmacodynamic factors on the background of data on the role of serotonintransporter gene variation in predicting antidepressant response. The section thereafter
will deal with studies on the pharmacogenetics of mood-stabilizing drugs, particularly
lithium. Finally, we will consider pivotal issues in the design and execution of researchstudies in the pharmacogenetics of mood disorders, primarily from the perspective ofclinical research. For a more extensive discussion of the role of pharmacogenetics inpsychopharmacology, the reader is referred to a forthcoming volume devoted to this
topic [9].
II. RATIONALE FOR THE PHARMACOGENETICS
OF MOOD DISORDERSA.

Clinical Rationale

From their experience in the clinic and in the context of clinical trials, psychiatrists are
fully aware of the very substantial variability in the response of patients with the same

Pharmacogenetics of Mood Disorders

643

Figure 1 Distribution of 21-item Hamilton Depression Scale (HAM-D) change scores(percent change from baseline) in patients with unipolar, nonpsychotic major depression
treated with SSRI 20 mg for 4 weeks (Agid and Lerer, unpublished data).

diagnosis to the same drug. Figure 1 shows data from a prospective, algorithm-based study
conducted in our clinic (Agid and Lerer, unpublished data). In this study, 90 patients withunipolar, nonpsychotic major depression (DSM-IV) who had not received antidepressant
medication in the current episode of illness were treated according to a standard treatment
algorithm. The initial step of the algorithm was treatment with a speciﬁc serotonin reuptake
inhibitor (SSRI)—ﬂuoxetine in most cases—at a dose of 20 mg/day for 4 weeks. Subsequent steps are not relevant to the present discussion. Among the 74 patients who completed the full 4 weeks of SSRI, 20 mg/day (last observation carried forward data weresimilar but are not presented here), 44 (59.5%) were responders, as deﬁned by a ClinicalGlobal Impression (CGI) rating of at least “much improved” at week 4. This rate of response is similar to that observed in clinical trials of ﬂuoxetine and paroxetine. The striking
point made by Figure 1 is the tremendous variability of response.
We analyzed the demographic and clinical data of the sample in order to identify
possible predictors of response. Nonresponders to ﬂuoxetine had less schooling ( p ⫽0.03), fewer adverse life events ( p ⫽ 0.01), were more likely to have been previously
hospitalized ( p ⫽ 0.04), had higher HAM-D scores at baseline ( p ⫽ 0.0003), and rated
themselves as more depressed on a 10-cm visual analog scale ( p ⫽ 0.0002). HAM-D
items that signiﬁcantly differentiated responders from nonresponders were late insomnia( p ⫽ 0.008), psychic anxiety (p ⫽ 0.0007), somatic symptoms and appetite ( p ⫽ 0.04),
and diurnal variation (p ⫽ 0.04).
A number of the items that differentiated responders and nonresponders are consistent with previous reports. Overall they seem to point to a more severe clinical picture in
the nonresponders that is less situational. While interesting, these ﬁndings as well as othersin the literature cannot serve as a basis for reliable, a priori discrimination of potential644

Lerer et al.

responders and nonresponders to SSRI treatment. It is this niche that pharmacogenetics
seeks to ﬁll.
B.

Genetic Rationale

A putative role for pharmacogenetics in predicting response to antidepressant and othermood-stabilizing drugs requires consideration of the role of genetic factors in such effects.
Are there sufﬁcient data upon which to base such an assumption? In fact, there are few
clinical studies that explore a role for genetic factors in response to antidepressant drugs.
Pare et al. [10] examined the records of 170 patients who had been treated with antidepressant drugs [imipramine or monoamine oxidase inhibitors (MAOI)], mostly in the context
of controlled trials. Seven cases were identiﬁed in which a ﬁrst-degree relative had also
been treated with a drug from one of these two classes; in some cases there were morethan one ﬁrst-degree relative, giving 12 pairs in all. Treatment effects were concordant inall proband-relative pairs (response in 5 and nonresponse in 7). The authors also observed atendency for patients to respond (or not to respond) to a drug of the same class on repeatedadministrations (13 of 17 patients consistent for MAOI and 7 of 9 consistent for imipramine), although it was not always certain that different episodes of illness were being
considered in each case. Subsequently, Pare [11] reported even higher levels of consistencyof response within the same patient for MAO inhibitors (two different drugs in this class):
9 of 16 concordant for response and 7 of 16 concordant for nonresponse; none discordant
for response. For two different drugs of the tricyclic antidepressant (TCA) group, there
was only one discordant response out of 12 cases. Conversely, of 65 cases in which thesame patient was administered a TCA and MAOI, there were only 35 concordant responses
out of 65 trials in the same patient. Similar ﬁndings were reported by Dally and Rhode[12]. Pare and Mack [11] reanalyzed familial response data from the Pare et al. [10] study
and showed that concordance of response to antidepressants between relative pairs wasin the context of an antidepressant from the same group (MAOI or TCA) and not fromdifferent groups. In a new series of patients, Pare and Mack [11] again observed concordance of response to antidepressants among ﬁrst-degree relative pairs (10 out of 12 pairs),
which was again most evident for drugs of the same class. Concordance of response to
imipramine among relative pairs was also observed by Angst [13,14] in patients with“endogenous depression.” Another report of interest is that of O’Reilly et al. [15], who
observed that 4 of 8 members of a single-, two-generation family who met DSM-IIIR
criteria for major depression, did not respond to TCA treatment but did respond to the
MAOI, tranylcypromine. In the absence of family and twin studies, which are the classic
methods for demonstrating the genetic basis of a complex trait (such studies are very
difﬁcult to conduct in a pharmacogenetic context), the above ﬁndings are of considerable
interest and suggest that genetic factors may indeed play a role in response to antidepressants. Data on genetic factors in response to lithium are discussed later in this chapter.
Differences between individuals in their response to drugs can be attributed to two
major sets of factors. Pharmacokinetic factors encompass the processes that inﬂuence bioavailability of a drug (i.e., the concentration of the drug that is available at its site ofaction). Pharmacodynamic factors are differences in the targets upon which the drug acts.
A simple view is that pharmacokinetics refers to the effect of the individual upon the drug
and pharmacodynamics to the effect of the drug on the individual [16]. Both sets of factors
are under a variable degree of genetic control. Both inﬂuence the response of the individual
to a given drug and may interact within the same individual and with the environment

Pharmacogenetics of Mood Disorders645[17]. The aim of pharmacogenetics is to identify these factors, establish their genetic basis,
and incorporate the information in diagnostic procedures that will enhance clinical practiceby a more effective match between patient and drug.
Classical genetics of human disease deals with monogenic disorders in which asingle mutation in a single gene is causatively related to the phenotype. The genetics ofcomplex illnesses such as diabetes, hypertension, coronary artery disease, and most of the
major psychiatric disorders do not ﬁt this simple paradigm. The same distinction is applicable to pharmacogenetics. Genetic factors that underlie pharmacokinetic effects and inﬂuence drug bioavailability (such as the effect of CYP2D6 polymorphism on the metabolism
of a variety of psychotropic and other drugs, which is inherited as an autosomal recessive
trait) may be monogenic [17]. For the most part, however, pharmacogenetic traits arelikely to be polygenic and multifactorial. A polygenic trait is one that is inﬂuenced by anumber of different genes, each of which contributes a portion of the effect and may doso additively as well as interactively (epistasis). The term multifactorial indicates that both
genetic and environmental factors contribute substantially and variably to the phenotype.
Traditionally, pharmacogenetic studies seek an association between a speciﬁc geneand the response or adverse effect phenotype under study. This is a classic candidate geneapproach that is based on an a priori hypothesis regarding the role of the protein codedby the gene in the particular phenotype. The genetic variation that is most frequently
studied in pharmacogenetic studies is the single nucleotide polymorphisms [18]. A polymorphism is a genetic variation that occurs with a frequency of 1% or more in the population. SNPs are differences between individuals in a single base of the genomic sequence.
SNPs occur throughout the human genome at a density of approximately 1 per 1000 basesof DNA. SNPs may be classiﬁed by their location, occurring in exons (coding regions)or introns (noncoding regions) of genes and in regulatory regions such as the promoter.
SNPs in coding regions need not necessarily inﬂuence the structure of the protein and aretermed synonymous. SNPs that do alter the structure of the proteins need not have functional consequences and are termed conservative or nonfunctional. On the other hand,
SNPs located in intronic regions can have an impact on the coded protein by inﬂuencing
splicing [19]. SNPs in regulatory regions can have major effects on the expression of thegene. Major efforts are now in progress by public and industry-based consortia to generate
SNP databases that will be an invaluable resource for pharmacogenetics in the very near
future. It should be noted that an SNP or other genetic variation might be statisticallyassociated with a phenotype without having a direct effect. This phenomenon is due tolinkage disequilibrium (LD) and it results from the fact that the variant examined is closeenough to the true predisposing variant that it does not undergo recombination duringmeiosis and is inherited with it. The marker may be at a different site in the gene itself
or may be located outside the gene.
III. GENETIC VARIATION IN DRUG-METABOLIZING ENZYMESThe dose of a drug that is ingested by a patient is only indirectly related to its concentration
at the effector site(s) where the drug acts (bioavailability). Numerous other factors determine this concentration. They include the absorption, transport, metabolism, and elimination of the drug and its metabolites. Age, gender, and disease may all inﬂuence the efﬁciency of each step of the process and thus the bioavailability of the drug.
Drug metabolism is generally divided into two stages termed phase I and phase II
reactions. Phase I reactions include oxidation, reduction, and hydrolysis, introducing a646

Lerer et al.

polar group into the molecule. In phase II, an endogenous hydrophilic substance is conjugated with a polar group in the molecule generating water-soluble compounds. Oxidation
is an important mechanism in phase I and it is primarily catalyzed by the cytochrome
P450 enzymes that are principally located in the liver endoplasmic reticulum. Cytochrome
P450 (CYP) enzymes are subdivided into families designated by a number (CYP2), subfamilies designated by a letter (CYP2D), and individual enzymes designated by a number(CYP2D6). CYP enzymes, particularly CYP2C9, CYP2C19, and CYP2D6 are polymorphic. CYP2D6 polymorphism results in there being poor (PM), extensive (EM), and ultrarapid (UM) metabolism of the test drug, debrisoquine, as well as a number of antidepressant and other psychotropic drugs that are metabolized by CYP2D6. Poor metabolism isinherited as an autosomal recessive trait and is found in approximately 7% of Caucasians.
Ampliﬁcation of functional CYP2D6 genes accounts for ultrarapid metabolism. Poor metabolizers will have abnormally high blood levels of the drug, even when administeredat regular doses, and are more susceptible to adverse effects. Ultrarapid metabolizers willbe less likely to beneﬁt from the therapeutic action of the drug. Variability of plasma
levels within the EM group may be accounted for by differences between heterozygotes
for the defective allele and homozygotes for the wild type. Among the psychotropic drugs
that are metabolized by CYP2D6 are the tricyclic antidepressants, nortriptyline, amitryptyline, clomipramine, desipramine, and imipramine; the SSRIs, ﬂuoxetine and paroxetine;
and also maprotiline and mianserin [16,17,20].
Pharmacokinetic variability between individuals may be evaluated at 3 levels, eachof which carries advantages and disadvantages [20]. Plasma levels of the drug may bemonitored (therapeutic drug monitoring), the phenotype may be established by administration of a test drug (debrisoquine, sparteine, or dextromethorphane in the case of CYP2D6),or the genotype may be examined directly. Genotype is not inﬂuenced by extraneous
factors and can serve as an important role in screening for potential nonresponders tostandard drug doses (UM) or susceptibility to adverse effects (PM). Tricyclic antidepressants are good candidates for pretreatment genotyping because of their narrow therapeuticindex and the reasonably well-established correlation between plasma levels and clinicaleffects. For SSRIs, the utility is less clear since a clear correlation between plasma levels
and therapeutic effectiveness has not been established. Moreover, standard drug doses areused and these produce plasma levels within the therapeutic range. These conclusions mayneed to be reevaluated in the context of possible interactions between drug bioavailability
and relevant variations in the target proteins of the drug. In such a case, more subtle
differences could be important even though they do not have a major inﬂuence in and ofthemselves.
Antidepressants are also metabolized by other CYP450 enzymes such as CYP2C19,
CYP3A4, and CYP1A2. A detailed consideration of genetic variability in these enzymes
and its clinical relevance is beyond the scope of this chapter [16,17,20]. Each enzyme has
the potential to impact signiﬁcantly on individual variability in responsiveness to antidepressant drugs and susceptibility to adverse effects. With the advent of DNA chip technology, it will be possible to implement large-scale studies and to gather the type of datathat are needed to draw conclusions and plan strategy for pharmacogenetic testing at theclinical level. There may be a higher concentration of patients with genetically basedabnormalities of drug metabolism in hospitals and tertiary care facilities than in the community. This could be due to the fact that patients in such centers are more likely to be
nonresponders or to have suffered adverse effects.

Pharmacogenetics of Mood Disorders

647

IV. PHARMACODYNAMIC FACTORS IN ANTIDEPRESSANTRESPONSE
The serotonin transporter (5HTT) is located on the presynaptic neuron of serotonergic
nerve terminals and is the site of action of SSRIs and other antidepressants that block the
uptake of serotonin. Therefore, it is an important potential candidate for pharmacogenetic
studies of antidepressants. The 5HTT is encoded by a single gene, SLC6A4 on chromosome 17, and includes 14 exons spanning approximately 35 kb. There are two common
polymorphisms in SLC6A4. One is in the promoter region and is termed 5HTTLPR (5HTtransporter-linked polymorphic region). It consists of a 44-base pair insertion or deletion.
The long [l] variant has been reported to generate more gene transcription than the shorter
variant(s) [21]. The other polymorphism in SLC6A4 consists of a variable number oftandem repeats (VNTR) in the second intron. It has three alleles (STin2*9, Stin2*10,
Stin2*12) represented by different numbers of repeats. 5HTTLPR was reported to be associated with personality traits [21] and has been extensively studied as a candidate genefor mood disorders with variable results [22]. Association of the intron 2 VNTR polymorphism with mood disorders is also variable [23].
An association between the serotonin transporter gene and response to antidepressants was ﬁrst reported by Smeraldi et al. [24] (Table 1). One-hundred-two patients with
DSM-IV major depression and psychotic features received ﬂuvoxamine ⫹ pindolol or
ﬂuvoxamine ⫹ placebo in a 6-week double-blind controlled study. Response to the study
drugs was compared among the patients grouped according to 5HTTLPR genotype. It was
found that patients carrying either one or two copies of the long (l) allele had a signiﬁcantly
better response to ﬂuvoxamine (⫹ placebo) than patients homozygous for the short (s)allele. When the same comparison was conducted for patients receiving ﬂuvoxamine ⫹pindolol, there was no difference between the genotypes. It was speculated that differencesin gene transcription between the genotypes expressed in the number of transporters might
be associated with different degrees of negative feedback on 5HT release (mediated via
5HT1A somatodendritic receptors in the raphe nuclei). Pindolol blocks 5HT1A receptors
and would thus abolish these differences.
Subsequent studies (Table 1) have provided a fair amount of support for the initialobservation of Smeraldi et al. [24]. In a further report from the same group, Zanardi etal. [25] studied patients treated with paroxetine for 6 weeks. Genotypes including the I
allele of 5HTTLPR were associated with better and also faster response to paroxetine.
Patients with l-l genotypes had better response than patients with l-s genotypes and patientswith l-s genotypes had better responses than those with s-s genotypes. Pollock et al. [26]studied patients with late-life depression treated with paroxetine or nortriptyline. Onsetof antidepressant effect was faster in patients homozygous for the l variant of 5HTTLPR
than in l-s heterozygotes or s-s homozygotes. There were no differences among the genotypes in response to nortriptyline. The difference between paroxetine and nortriptyline isof great interest because of the noradrenergic mechanism of nortriptyline and tends tosupport a pharmacogenetic hypothesis linked to the principal site of action of SSRIs.
Substantial complexity is introduced by the ﬁndings of Kim et al. [27] who studied
Korean patients with major depression treated with ﬂuoxetine or paroxetine and genotyped
both 5HTTLPR and the VNTR in intron 2 of the gene. They too found an association of
5HTTLPR with treatment response but with the short variant. 5HTTLPR s-s homozygotes
were more frequently represented among good responders than l-s or l-l genotypes. Kim

Ref.

Pharmacogenetics of Antidepressant Response: Studies on the Role of the Serotonin Transporter Gene
Subjects

DesignPolymorphism

Findingll homozygotes and ls heterozygotes—
better response to ﬂuvoxamine than ss
homozygotes
With addition of pindolol—no difference between the genotypes
Better response in 5HTTLPR ll homozygotes

102 patients(Northern Italian)
DSM-IV Major Depression
Psychotic Features

Double-blind, 6 weeks
Fluvoxamine 300 mg/d ⫹ pindolol 2.5
mg/d vs. ﬂuvoxamine 300 mg/d ⫹placebo

5HTTLPR(Promoter)28

68 patients(Northern Italian)
DSM-IV bipolar I, depressive episode
Nonpsychotic
120 patients(Korean)
DSM-IIIR Major Depression

Total sleep deprivation, one night

5HTTLPR(Promoter)

Prospective, random assignment 6 weeks
Fluoxetine 20–50 mg/d or paroxetine
20–60 mg/d

26

57 patients completing trial(Ethnicity not speciﬁed)
DSM-IV Major Depression
Nonpsychotic, nonbipolar

Double-blind, 12 weeks
Paroxetine 20–30 mg/d vs. nortriptyline
from 25 mg/d (per blood level, 50–
150 ng/mL

5HTTLPR(Promoter)
VNTR(Intron 2)
5HTTLPR(Promoter)25

60 patients(Northern Italian)
DSM-IV Major Depression
Nonpsychotic

Open with single-blind placebo run-in,
4 weeks
Paroxetine 40 mg/d

5HTTLPR(Promoter)29

63 patients(Ethnicity not speciﬁed)
DSM-IV bipolar I or II

Retrospective
Patients with history of antidepressantinduced mania (IM⫹) compared topatients with no history (IM⫺)

5HTTLPR(Promoter)
VNTR(Intron 2)

ss 5HTTLPR homozygotes—better response than ll or ls genotypes
ll intron 2 homozygotes—better response than other genotypes
Faster response to paroxetine in ll homozygotes than ls heterozygotes or ss homozygotes
No difference among genotypes in response to nortriptyline
Presence of l copy of 5HTTLPR associated with better and faster response toparoxetine ll genotypes, better response than ls; ls genotypes, better
than ss
Excess frequency of 5HTTLR s allele
and ss homozygotes in IM⫹ group
No difference in VNTR allele or genotype frequency

Lerer et al.

24

27

648

Table 1

Pharmacogenetics of Mood Disorders649

et al. [27] also found an association with the intron 2 VNTR. There was a signiﬁcant excess
of patients homozygous for the 12-repeat variant among the drug-responsive patients. It
should be noted that the allele distribution of the 5HTT polymorphisms studied was very
different among the Korean subjects than among European populations. This was true ofboth the intron 2 VNTR and 5HTTLPR. For example, homozygosity for the short variantof 5HTTLPR was 19% in the patients studied by Benedetti et al. [28], but was 56.7% in
the Korean subjects of Kim et al. [27]. As discussed in an earlier section of this chapter,frequency of alleles varies greatly among populations. It is possible that association bedemonstrated with a polymorphic locus in two populations but that different alleles be
implicated in the respective populations. This would suggest that the locus itself is not
implicated but is in linkage disequilibrium with another implicated locus close by.
Two other studies of the 5HT transporter gene should be noted (Table 1). Benedetti
et al. [28] studied the relationship of 5HTTLPR to the antidepressant effect of total sleep
deprivation in patients with bipolar depression. Patients homozygous for the l variant were
found to manifest the strongest effect. Recently, Mundo et al. [29] examined the relationship of the 5HT transporter gene to induction of mania by antidepressants in patients withbipolar disorder. While the intron 2 VNTR did not show an effect, the authors observed
a higher rate of homozygosity for the short variant of 5HTTLPR in patients with a historyof antidepressant-induced mania.
Overall, the ﬁndings relating to 5HT transporter gene and antidepressant effects
provide an intriguing insight into the potential and also the complexities that characterize
the pharmacogenetics of mood disorders. A great deal of further work will be needed
involving large patient samples carefully stratiﬁed for intervening variables such as ethnicity before it will be possible to draw deﬁnitive conclusions and to proceed to the stageof clinical application.

V.

PHARMACOGENETICS OF MOOD-STABILIZING DRUGS

Beginning in the 1970s, a series of studies has examined the relationship between response
to prophylactic lithium administration and family history of bipolar disorder [30]. The
overall trend of these studies is to ﬁnd that a positive family history of bipolar disorderis associated with lithium response or that rates of bipolar disorder are higher among therelatives of lithium-responsive patients than among the relatives of lithium nonresponders[31–33]. There are some notable exceptions, however [34]. An excess of mood disorders
among the relatives of lithium-responsive patients can be interpreted in two ways. Lithium
responsiveness may characterize a subtype of bipolar disorder that has higher familialloading. The alternative possibility is that lithium responsiveness is a familial, pharmacogenetic trait. It is difﬁcult to separate these possibilities. If the ﬁrst possibility is correct,
then “lithium-responsive” families could be of particular importance in the search forbipolar disorder genes by linkage analysis. The second possibility can also be the focus
of linkage analysis by setting lithium responsiveness rather than bipolar disorder as thephenotype for which linkage is sought. Early results from work of this type are discussed
below.
Compared to studies on the prevalence of bipolar disorder in the relatives of lithium
responders and nonresponders, there are far fewer family studies in which the pharmacogenetic trait of lithium response has been used as the phenotype. There is a report thatchildren of bipolar lithium responders have a response concordant with that of their parents

650

Lerer et al.

[35]. Similarly, Grof et al. [36] reported a signiﬁcantly higher response rate to lithium inthe relatives of bipolar probands who were lithium responders than in a comparison group.
The putative mode of inheritance of lithium-responsive bipolar disorder has beenstudied by segregation analysis. Smeraldi et al. [32] found support for a major gene effectin the families of responders. Alda et al. [37,38] found evidence for an autosomal recessivemode of inheritance. These analyses could serve as a backdrop for linkage studies, butthere are not enough data to allow the mode of inheritance to be deﬁnitively speciﬁed.
In spite of the fact that mode of inheritance has not been established, linkage studiesof bipolar disorder, using lithium responsiveness to reﬁne the phenotype, have been performed. In one study that used both association and linkage approaches, a polymorphismin the phospholipase C gamma-1 genes was examined. In a case control sample, modest
association with lithium-responsive bipolar disorder was observed (OR ⫽ 1.88). A linkage
study in a family sample also showed some support (lod ⫽ 1.45; p ⫽ 0.04) [39]. Tureckiand colleagues [40] have completed a whole genome scan of 21 families (247 subjects,
108 affected) in which regions on chromosome 6, 7, 15, 21, and 22 yielded lod scoressuggestive of linkage. In the chromosome 15q14 region, a lod score of 3.46 ( p ⫽0.000014) was obtained with the marker ACTC and on chromosome 7q11.2 and a lodscore of 2.62 (p ⫽ 0.0001) with the marker D7S1816. Using responsiveness to lithium
as the phenotype, the highest lod score was 1.53 ( p ⫽ 0.003) for the marker D7S1816.
This group has also conducted association studies comparing lithium-responsive patientsand controls. Besides the modestly positive association for phospholipase C gamma-1
noted above, negative results were obtained for several candidate genes including MAOA, CRN, proenkephalin, and genes related to GABA function [30].
There are also a number of association studies directly comparing responders andnonresponders to lithium in a case control design. Negative results were obtained by Serretti et al. for the dopamine D3 receptor gene [41], GABA–21 subunit and dopamine D2
and D4 receptors [42], tryptophan hydroxylase [43], and the serotonin 2A, 2C, and 1A
genes [44]. Steen et al. [45] found association of a polymorphism in the inositol phosphate
1-phosphatase gene with lithium responsiveness in Norwegian but not Israeli patients.
Del Zompo et al. [46] examined the serotonin transporter gene and found a trend toward
association of lithium nonresponsiveness with the 1 allele.
Overall, no clear trend has emerged as yet from association studies of candidate
genes with lithium responsiveness and most results have been negative. However, thefamily data that tend to support a genetically distinct lithium-responsive subtype of bipolar
disorder and the genome scan results reported by Turecki et al. [40] are promising. Taken
together, they suggest that pharmacogenetic stratiﬁcation could be a key to localizing
genes that predispose to a pharmacogenetically distinct variant of bipolar disorder. The
potential implications for understanding the pathogenesis of the illness and for individually
tailoring treatment are substantial.
VI. STUDY DESIGN FOR THE PHARMACOGENETICS
OF MOOD DISORDERS
Most current pharmacogenetic studies in mood and other psychiatric disorders are “opportunistic” in the sense that they are not designed for the purpose of asking questions speciﬁcally relevant to pharmacogenetics and do not take into account special design considerations. They make use of previously studied clinical samples for which drug response or
adverse effect data are available, taking blood for DNA and genotyping, or blood samplingPharmacogenetics of Mood Disorders

651

for DNA is added on to a clinical trial without modifying the protocol in any way. Suchapproaches have yielded some important ﬁndings and can have an important place at theearly stages of research. Eventually, purpose-built pharmacogenetic studies will be needed.
This section considers pivotal issues in their design.
A. Which Design to Use
The most frequently used experimental context for determining pharmacogenetic inﬂuences on drug response is a comparison of responders and nonresponders to the drug orof individuals who develop adverse effects and those who do not. This appealingly simple
case-control design should be readily applicable in psychopharmacology. Data from suchstudies are amenable to analysis by either of two approaches: the ﬁrst is a categoricalapproach in which patients are grouped according to the phenotype (responder or nonresponder, develops adverse effect or does not) and the frequency of the genotype of interestin these groups is compared. The second approach utilizes the response variable (or adverse effect measure) in a continuous fashion and compares scores at a single time point
or over a period of treatment in patients grouped according to genotype. There are alreadynumerous examples of the application of these approaches to psychopharmacology.
Case-control designs are very susceptible to the effects of population stratiﬁcation(i.e., differences in allele frequencies between populations can lead to spurious results ifpatients from different population groups are represented in different proportions in thecase and control groups). Family-based association studies employ a proband and bothparents and use the untransmitted alleles of the parents as a virtual control group. Data
can be analyzed by the haplotype relative risk (HRR) method or by the transmission disequilibrium test (TDT) [47]. While this approach addresses the problem of population
stratiﬁcation efﬁciently, since parents and probands are by deﬁnition from the same population group, recruitment of samples is more difﬁcult and it is not applicable to older
patients whose parents may not be available. Family-based designs are more applicablein children and adolescents, such as in pharmacogenetic studies of attention deﬁcit hyperactivity disorder. Other approaches implemented in the search for disease-predisposing
loci, such as affected and discordant sibling pair designs, are unlikely to be of value topharmacogenetics because of recruitment difﬁculties because such designs can only be
implemented retrospectively and because it is highly unlikely that siblings will be matched
for exposure to the drug of interest. Therefore, it is clear that case-control designs willremain the cornerstone of pharmacogenetic research in mood and other disorders.
B. Is a Placebo Control Group Needed?
Random assignment, placebo-controlled, double-blind designs are the “gold standard” forclinical trials research in medicine. In studies where a pharmacogenetic component is“added on,” placebo controls will be available because they are part of the basic designof the study. Are placebo controls needed for “purpose-built” pharmacogenetic studies?
In clinical trials of drug efﬁcacy, the placebo group controls for nonspeciﬁc effects andallows a superior effect of the active drug to be demonstrated with a satisfactory level ofstatistical conﬁdence. In a pharmacogenetic study, control for efﬁcacy is not needed, unless
it is a trial of a new drug. Therefore, the placebo group is controlling for an associationof the gene or genes being tested with response to treatment at a nonspeciﬁc level (i.e.,
it allows it to be established whether the gene variation is associated with response to theactive drug or is associated with response regardless of the nature of the treatment). Pla-

652

Lerer et al.

cebo control substantially increases the complexity and expense of a study. Also, placebo
control groups for studies that are pharmacogenetically oriented and not efﬁcacy oriented
raise ethical questions and are likely to encounter signiﬁcant difﬁculties with Internal
Review Boards, particularly in countries where approval for efﬁcacy-oriented placebocontrolled studies is already difﬁcult to obtain. However, it must be acknowledged thatthe exclusion of nonspeciﬁc effects will reduce false positives and enhance the likelihoodof replication. Ultimately, investigators will need to carefully balance cost-beneﬁt considerations. Placebo run-in phases could be a partial answer since they reduce the placebo
response rate in the trial itself and ethically are less problematic.
C.

Sample Size

Large samples are required for pharmacogenetic studies because of the inherent nature of
the research design, which seeks to associate response to a drug with a genetic variant,such as SNP. In the case of a bi-allelic SNP, the frequency of the rarer allele in the
population dictates the minimum sample size. This can be calculated by power analysis
in which the minimum difference in the frequency of the allele of interest between responders and nonresponders that the study seeks to detect is entered. The rarer the allele in the
population, the larger the sample that will be needed. Also, the more alleles the variant
has, the larger the sample size that will be required.
Another important aspect must be considered. Consider a hypothetical trial in which
200 patients are randomly assigned to an antidepressant drug or to a placebo. It is widely
accepted that placebo response rates in antidepressant trials are 40% or more. If the rateof response to the active drug is 60%, it must be assumed that 40% of these responders
are patients who would have responded to placebo. Therefore, only 36 of the 60 responders
to active drug are true drug responders. These patients are the true targets of our pharmacogenetic study. The fact that a study is placebo-controlled does not resolve this problem.
It can only be effectively addressed by studying a sufﬁciently large sample.
D.

Further Considerations in the Design of Studies

1. Demographic Variables
Since the basis of interindividual variability in drug response is multifactorial, the impact
of demographic variables such as age and gender cannot be ignored. A particular genetic
variant may not be functionally relevant without the addition of other factors that also
inﬂuence the phenotype. An example is the inﬂuence of certain 5HT-receptor variants on
predisposition to neuroleptic-induced tardive dyskinesia, which was demonstrated in asample of older patients but was not observed in a sample of patients who were two
decades younger [48].
2. Population Effects
It is well known that the frequency of genetic polymorphisms can differ markedly among
ethnic groups. An example is given in Figure 2 from a multicenter European study inwhich the frequency of a 5HT2C receptor ser9gly polymorphism was studied in mooddisorders [49]. The difference in frequency of the gly9 allele among the different countries
that participated in the study is striking, from more than double (⬎20%) in Greek normal
control subjects as compared to Bulgarian and Croatian normal controls. These data clearly
indicate how the unequal inclusion of individuals of different ethnic backgrounds in groups

Pharmacogenetics of Mood Disorders

653

Figure 2 Frequency of 5HT2C ser allele in European populations. (GR ⫽ Greece;
BEL ⫽ Belgium; GER ⫽ Germany; ITA ⫽ Italy; ISR ⫽ Israel; CRO ⫽ Croatia; BUL ⫽Bulgaria.)
of subjects being compared can lead to spurious results that reﬂect ethnic stratiﬁcation.
Methods have been proposed to address these issues [49,50]. Nevertheless, it is essentialthat studies be designed to take them into account prospectively.
3. Deﬁnition and Evaluation of the Phenotype
Drug response to psychotropic drugs is a phenotype that is very difﬁcult to operationalize.
There is an extensive literature that debates how to deﬁne a “responder” to an antidepressant drug in the context of a clinical trial. Deﬁnitions may be based on percent improvement on a particular rating scale or by using a speciﬁc score on that scale as a threshold.
There are conventions that are fairly well accepted for clinical trials of psychopharmacological agents. It remains to be established whether these conventions can be readily transferred to pharmacogenetic studies.
4. Interaction Among Multiple Loci
Traditionally, pharmacogenetic studies have focused on single genes and on single polymorphisms within these genes. It is becoming clear that this approach is too limited toadequately address the complexity of the situation. Single SNPs may not show an association with treatment effects or with disease susceptibility while combinations do. Thesemay be within a single gene, as demonstrated for the effect of complex haplotypes of
SNPs in the coding region and the promoter of the β2-adrenergic receptor gene on the
bronchodilator response to asthma therapy [51]. Interactions (epistasis) may be demonstrated between SNPs in different genes as recently observed in a study of genetic susceptibility to sporadic breast cancer [52]. In the context of pharmacogenetics, Segman et al.
[53] have observed an interaction between a polymorphism in the cytochrome P17 geneand the dopamine D3 receptor gene that is associated with more neuroleptic-related abnormal involuntary movements in patients who carry both mutant genotypes. These considerations will need to be given particular emphasis in the design of pharmacogenetic studies
in the future because they have a major impact upon the size of the samples that need tobe collected.

654

Lerer et al.

VII. CONCLUSIONS
Pharmacogenetics is the study of genetically determined, interindividual differences intherapeutic response to drugs and susceptibility to adverse effects. The principal objectiveof pharmacogenetics is to identify and categorize the genetic factors that underlie thesedifferences and to apply these observations in the clinic. Pharmacogenetics addresses acore issue in pharmacotherapeutics, the individualization of drug treatment to the speciﬁcpatient, and promises to provide the tools for making rational clinical decisions that are
based on the patient’s genetic proﬁle. This will be a major advance in therapeutics that will
have enormous impact on patient care and also important pharmacoeconomic implications.
Furthermore, the complex and lengthy process of new drug development could be considerably shortened. While there is certainly a future for the pharmacogenetics of mood disorders, translating the promise into reality is likely to take substantially longer than anticipated. It will require considerable investment of resources in the design and execution of
appropriate clinical studies as well as the development of novel and considerably more
efﬁcient approaches to data analysis.

REFERENCES
1. Garrod AE. The incidence of alcaptonuria: A study in chemical individuality. Lancet 1902;
2:1616–1620.
2. Garrod AE. Inborn Errors of Metabolism. Oxford: Oxford University Press, 1909.
3. Motulsky A. Drug reactions, enzymes and biochemical genetics. JAMA 1957; 165:835–837.
4. Vogel F. Moderne probleme der humangenetik. Ergebn inn Kinderheilk 1959; 12:52–125.
5. Maghous A, Idle JR, Dring LG, Lancaster R, Smith RL. Polymorphic hydroxylation of debrisoquine in man. Lancet 1977; 2:584–586.
6. Roses AD. Pharmacogenetics and the practice of medicine. Nature 2000; 405:857–865.
7. Chakravarti A. Population genetics—making sense out of sequence. Nat Genet 1999; 21:56–
60.
8. Risch NJ. Searching for genetic determinants in the new millennium. Nature 2000; 405:847–
856.
9. Lerer B, ed. Pharmacogenetics of Psychotropic Drugs. Cambridge: Cambridge University
Press, 2002.
10. Pare CMB, Rees L, Sainsbury MJ. Differentiation of two genetically speciﬁc types of depression by the response to antidepressant. Lancet 1962; 1340–1343.
11. Pare CMB, Mack JW. Differentiation of two genetically speciﬁc types of depression by the
response to antidepressant drugs. J Med Genet 1971; 8:306–309.
12. Dally PJ, Rhode P. Comparison of antidepressant drugs in depressive illnesses. Lancet 1961;
1:18–20.
13. Angst J. A clinical analysis of the effects of tofranil in depression. Longitudinal and followup studies. Treatment of blood relations. Psychopharmacologia 1961; 2:381–407.
14. Angst J. Antidepressiver Effekt und genetische Faktoren. Arzneimittel-Forschung 1964;
14(suppl):496–500.
15. O’Reilly RL, Bouge L, Singh FM. Pharmacogenetic response to antidepressant in a multicase
family with affective disorder. Biol Psychiatry 1994; 36:467–471.
16. Poolsup N, Li Wan Po A, Knight TL. Pharmacogenetics and psychopharmacotherapy. J Clin
Pharm Ther 2000; 25:197–220.
17. Ozdemir V, Kahuba ADM, Basile VS, Kennedy JL. Pharmacogenetics of psychotropic drug
metabolism. In: Lerer B, ed. Pharmacogenetics of Psychotropic Drugs. Cambridge: Cambridge
University Press, 2002.

Pharmacogenetics of Mood Disorders655

18. Schork NJ, Fallin D, Lanchbury S. Single nucleotide polymorphisms and the future of genetic
epidemiology. Clin Genet 2000; 58:250–264.
19. Krawezak M, Reiss J, Cooper DN. The mutational spectrum of single base-pair substitutions
in mRNA splice junctions of human genes: causes and consequences. Hum Genet 1992; 90:
41–54.
20. Steimer W, Muller B, Leucht S, Kissling W. Pharmacogenetics: a new diagnostic tool in the
management of antidepressive drug therapy. Clin Chim Acta 2001; 308:33–41.
21. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Muller CR,
Hamer DH, Murphy DL. Association of anxiety-related traits with a polymorphism in theserotonin transporter gene regulatory region. Science 1996; 274:1527–1530.
22. Hoene MR, Wendel B, Grunewald I, Chiaroni P, Levy N, Marris-Rosendahal D, Macher JP,
Sander T, Crocq MA. Serotonin transporter (5HTT) gene polymorphisms are not associatedwith susceptibility to mood disorders. Am J Med Genet 1998; 81:1–3.
23. Rees M, Norton N, Jones I, McCandless F, Scourﬁeld J, Holmans P, Moorhead S, Feldman
E, Sadler S, Cole T, Redman K, Farmer A, McGufﬁn P, Owen MJ, Craddock N. Association
studies of bipolar disorder at the human serotonin transporter gene (hSERT; 5HTT). Mol Psychiatry 1997; 2:398–402.
24. Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M. Polymorphism within
the serotonin transporter and antidepressant efﬁcacy of ﬂuvoxamine. Mol Psychiatry 1998; 3:
508–511.
25. Zanardi R, Benedetti F, Di Bella D, Catalano M, Smeraldi E. Efﬁcacy of paroxetine in depression is inﬂuenced by a functional polymorphism within the promoter of the serotonin transporter gene. J Clin Psychopharmacol 2000; 20:105–107.
26. Pollock BG, Ferrell RE, Mulsant BH, Mazumdar S, Miller M, Sweet RA, Davis S, Kirshner
MA, Houck PR, Stack JA, Reynolds CF, Kupfer DJ. Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 2000; 23:587–590.
27. Kim KD, Lim SW, Lee S, En Sohn S, Kim S, Gyu Hahn C, Carroll BJ. Serotonin transporter
gene polymorphism and antidepressant response. NeuroReport 2000; 11:215–219.
28. Benedetti F, Serretti A, Colombo C, Campori E, Barbini B, Di Bella D, Smeraldi E. Inﬂuenceof a functional polymorphism within the promoter of the serotonin transporter gene on theeffects of total sleep deprivation in bipolar depression. Am J Psychiatry 1999; 156:1450–
1452.
29. Mundo E, Walker M, Cate T, Macciardi F, Kennedy JL. The role of serotonin transporter
protein gene in antidepressant-induced mania in bipolar disorder. Arch Gen Psychiatry 2001;
58:539–544.
30. Alda M. Genetic factors and response to prophylactic treatment in bipolar disorder. In: Lerer
B, ed. Pharmacogenetics of Psychotropic Drugs. Cambridge: Cambridge University Press,
2002.
31. Mendlewicz J, Fieve RR, Stallone F. Relationship between the effectiveness of lithium therapy
and family history. Am J Psychiatry 1973; 130:1011–1013.
32. Smeraldi E, Petroccione A, Gasperini M, Macciardi F, Orsini A, Kidd KK. Outcomes onlithium treatment as a tool for genetic studies in affective disorders. J Affect Disord 1984; 6:
139–151.
33. Grof P, Alda M, Grof E, Zvolsky P, Walsh M. Lithium response and genetics of affective
disorders. J Affect Disord 1994; 32:85–95.
34. Coryell W, Akiskal H, Leon AC, Turvey C, Solomon D, Endicott J. Family history and symptom levels during treatment for bipolar I affective disorder. Biol Psychiatry 2000; 47:1034–
1042.
35. McKnew DH, Cytryn L, Buchsbaum MS, Hamovit J, Lamour M, Rapoport JL, Gershon ES.
Lithium in children of lithium-reponding parents. Psychiatry Res 1981; 4:171–180.
36. Grof P, Duffy A, Cavazzoni P, Grof E, Garnham J, MacDougall M, O’Donovan C, Alda

656

37.
38.

39.

40.

41.

42.

43.
44.
45.

46.
47.
48.

49.

50.
51.

52.

53.

Lerer et al.
M. Is response to prophylactic lithium a familial trait? Int J Neuropsychopharmacol 2000;
3(suppl 1):339.
Alda M, Grof P, Grof E, Zvolsky P, Walsh M. Mode of inheritance in families of patientswith lithium–responsive affective disorders. Acta Psychiatr Scand 1994; 90:304–310.
Alda M, Grof E, Cavazzoni P, Duffy A, Martin R, Ravindran L, Grof P. Autosomal recessive
inheritance of affective disorders in families of responders to lithium prophylaxis? J Affect
Disord 1997; 44:153–157.
Turecki G, Grof P, Cavazzoni P, Duffy A, Grof E, Ahrens B, Berghofer A, Muller-Oerlinghausen B, Dvorakova M, Libigerova E, Vojtechovsky M, Zvolsky P, Joober R, Nilsson A,
Prochazka H, Licht RW, Rasmussen NA, Schou M, Vestergaard P, Holzinger A, SchumannC, Thau K, Rouleau GA, Alda M. Evidence for a role of phospholipase C-gamma1 in thepathogenesis of bipolar disorder. Mol Psychiatry 1998; 3:534–538.
Turecki G, Grof P, Grof E, D’Souza V, Lebuis L, Marineau C, Cavazzoni P, Duffy A, B’tard
C, Zvolskyý P, Brewer C, Hudson TJ, Rouleau GA, Alda M. Mapping susceptibility genes
for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium. Mol
Psychiatry 2001; 6:570–578.
Serretti A, Lilli R, Lorenzi C, Franchini L, Smeraldi E. Dopamine receptor D3 gene and response to lithium prophylaxis in mood disorders. International J Neuropsychopharmacol 1998;
1:125–129.
Serretti A, Lilli R, Lorenzi C, Franchini L, Di Bella D, Catalano M, Smeraldi E. Dopamine
receptor D2 and D4 genes, GABA(A) alpha-1 subunit genes and response to lithium prophylaxis in mood disorders. Psychiatry Res 1999; 30:7–19.
Serretti A, Lilli R, Lorenzi C, Gasperini M, Smeraldi E. Tryptophan hydroxylase gene andresponse to lithium prophylaxis in mood disorders. J Psychiatric Res 1999; 33:371–377.
Serretti A, Lorenzi C, Lilli R, Smeraldi E. Serotonin receptor 2A, 2C, 1A genes and response
to lithium prophylaxis in mood disorders. J Psychiatric Res 2000; 34:89–98.
Steen VM, Lovlie R, Osher Y, Belmaker RH, Berle JO, Gulbrandsen AK. The polymorphic
inositol polyphosphate 1-phosphatase gene as a candidate for pharmacogenetic prediction oflithium-responsive manic-depressive illness. Pharmacogenetics 1998; 8:259–268.
Del Zompo M, Ardau R, Palmas MA, Bocchetta A, Reina A, Piccardi MP. Lithium response:
association study with two candidate genes. Mol Psychiatry 1999; 4:66–67.
Macciardi F. Statistical approaches in psychopharmacogenetics. In: Lerer B, ed. Pharmacogenetics of Psychotropic Drugs. Cambridge: Cambridge University Press, 2002.
Segman RH, Lerer B. Age and the relationship of dopamine D3, serotonin 2C and serotonin
2A receptor genes to abnormal involuntary movements in chronic schizophrenia. Mol Psychiatry 2002; 7:137–139.
Lerer B, Macciardi F, Segman RH, Adolfsson R, Blackwood D, Blairy S, Del-Favero J, Dikeos
D, Kaneva E, Lilli R, Massat I, Milanova V, Muir W, Noethen M, Oruc L, Petrova T, Papadimitriou GN, Rietschel M, Serretti A, Souery D, Van Gestel S, Van Broeckhoven C, Mendlewicz JM. Variability of 5-HT2C receptor cys23ser polymorphism among European populationsand vulnerability to affective disorder. Mol Psychiatry 2001; 6:579–585.
Devlin B, Roeder K. Genomic control for association studies. Biometrics 1999; 55:997–1004.
Drysdale CM, McGraw DW, Stack CB, Stephens JC, Judson RS, Nandabalan K, Arnold K,
Ruano G, Liggett SB. Complex promoter and coding region β2-adrenergic receptor haplotypes
alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 2000;
10483–10488.
Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH. Multifactordimensionality reduction reveals high-order interactions among estrogen-metabolism genes insporadic breast cancer. Am J Hum Genet 2001; 69:138–147.
Segman RH, Heresco-Levy U, Yakir A, Goltser T, Strous R, Greenberg D, Lerner A, Lerer
B. Interactive effect of cytochrome P450 17a-hydroxylase and dopamine D3 receptor gene
polymorphisms on abnormal involuntary movements in chronic schizophrenia. Biol Psychiatry
2002; 51:261–263.

28
Theories of the Etiology of Anxiety
TREVOR R. NORMAN, GRAHAM D. BURROWS,
and JAMES S. OLVER
Austin and Repatriation Medical Centre
University of Melbourne
Heidelberg, Victoria, Australia

I.

INTRODUCTION

Anxiety is a multidimensional concept that includes cognitive, affective, physical, andbehavioral elements. Cognitions such as intense worry and uncertainty are coupled withfeelings of apprehension and fear. Physiological reactions based on the autonomic nervous
system, including increased heart rate, sweating, tremor, vascular, and gastrointestinal
changes, are frequently accompanied by behavioral changes such as escape, avoidance,or, in extreme cases, paralysis (freezing). This constellation of reactions is normal andadaptive, but in some there are exaggerations to the point where the individual’s psychosocial well being is threatened. In these cases, an anxiety disorder has emerged and these
are among the most common of all psychiatric disturbances [1]. In this chapter, we begin
with a historical account of theories of anxiety formation followed by an examination of
the major contemporary understanding of the etiology of anxiety disorders. As there is ahigh degree of clinical overlap and comorbidity among the anxiety disorders as deﬁned
in modern classiﬁcatory systems such as DSM-IV [2], we will take a unitary view, mentioning speciﬁc disorders when indicated.

II. HISTORICAL OVERVIEWGiven the primal nature of anxiety as an emotional phenomenon, identiﬁable throughout
the animal kingdom, it is surprising that ancient medical texts did not devote more attention
to its description. Hippocrates (460–370 B.C.) appears to have overlooked anxiety when
657

658

Norman et al.

he proposed his theory of emotions, giving predominance to the four bodily humors of
black bile (sad, loveless, “melancholic”), yellow bile (angry, irritable, “choleric”), phlegm(rigid, passive, “phlegmatic”), and blood (lively, optimistic, “sanguine”). One possibility
is that anxious phenomena were considered more the domain of the philosophers. Marcus
Tullius Cicero, the Roman orator, politician, and philosopher (106–43 B.C.), made a clear
distinction between “state” and “trait” anxiety and hinted at a learning theory of anxiety
and conditioned fear in his book Tusculaum Disputationum.
William Cullen (1769), the Edinburgh physician, introduced the term “neurosis,”which he believed was a disorder of the nervous system in the absence of fever. The term
included disorders such as hysteria, hypochondriasis, melancholia, and asthenia. Despite
this, discussions of anxiety remained predominantly philosophical when Soren Kierkegaard (1813–1855) began exploring the problem of “human dread.” This remained sowith the writings of the existential philosophers that followed (see existential theories).
During the 19th century, increased scientiﬁc attention was paid to anxiety with detailed
chapters on “angst” in both German and French psychiatric textbooks. A surge of interest
in anxiety followed Charles Darwin’s “The Expression of Emotions in Man and Animals”[3], in which he presents evidence for an adaptive value of anxiety and its importance inevolution. Darwin also highlighted the importance of early bonding experiences that werelater developed by Freud and Bowlby. One of the ﬁrst biological theories of anxiety
emerged from the separate writings of the Danish physician Carl Lange (1834–1900) andthe American psychologist William James (1842–1910). James and Lange proposed thatdifferent emotions arise as a result of peripheral sensory feedback. The James–Langetheory implied that behavioral components of anxiety were automatic and that emotionaland cognitive responses were secondary to autonomic manifestations of anxiety in the
periphery. Argument about central versus peripheral origins of anxiety began and to someextent continue today. The most provocative and detailed modern theories of anxiety began, however, with the work of Sigmund Freud (1856–1939).
III. PSYCHODYNAMIC THEORIES OF ANXIETY
Anxiety lies at the very heart of Freud’s view of neurosis. There is no single psychodynamic theory of anxiety but a series of views held by Freud which, when traced, reﬂect
the evolution of his thought on the human psychic apparatus. Freud’s interest began following a visit to the Salpetriere in the 1880s that introduced him to the study of hysteria.
Freud was aware of the peripheral model known as the James–Lange theory and the
opposing central theories based on neurocircuits involving the medulla oblongata—andrejected them [4]. Instead, he embarked on a search for the central psychological mechanisms of anxiety that changed throughout his life, and even at the age of 70 he was producing revisions to his earlier theories of anxiety [5]. Freud contrasted realistic anxiety withneurotic anxiety. Realistic anxiety was seen as the rational and understandable reaction todanger and had adaptive advantage in Darwinian terms [4]. The understanding of neurotic
anxiety, on the other hand, required an exploration of the inner workings of the mind. It
is impossible here to summarize Freud’s proliﬁc writings on the topic of anxiety andemphasis will be given to some of the major advances made by Freud and developed
subsequently by the neo-Freudians.
In Freud’s ﬁrst major paper on anxiety, he argued for a separation of anxiety neurosis
from neurasthenia, splitting the neuroses into “actual neurosis” (anxiety neurosis) and the“psychoneuroses,” which included hysteria and obsessive-compulsive neurosis [6]. In his

Etiology of Anxiety

659

analysis of patients with anxiety neurosis, Freud did not ﬁnd the psychological conﬂicts
that characterized the psychoneuroses. Instead, he found common sexual practices suchas continence and coitus interruptus, which were believed to result in accumulated libido
undischarged as sexual energy in orgasm. Libidinal energy was transformed directly into
the somatic symptoms of anxiety. Freud was aware of potential criticism of this theory
on the basis that those who are by nature anxious and apprehensive may be more inclined
to practice restraint in sexual matters and other aspects of their life. He counter-argued
that women, being passively dependent on the sexual behavior of men, be used as an
example. Passionate women, being more inclined to sexual behavior and satisfaction than“anesthetic” women, are more certain to react to manifestations of male anxiety (impotence, coitus interruptus) [4].
Understanding the origins of anxiety in the psychoneuroses depended on Freud’s
developing idea of the unconscious and the psychic apparatus. Freud’s discovery of childhood sexuality and the Oedipus complex led to the topographical model of the mind,
which he later altered to include the superego and so conceived the structural model. The
structural model consists of a tripartite psyche consisting of the ego, the id, and the superego. The id is seen as being the source of the instinctual drives that energize it. The ego
consists of a number of related functions that control and divert id drives, permitting their
gratiﬁcation within the limits of superego control. The superego, formed following theresolution of the Oedipus complex, is the repository of ideals and social conscience thatguides the ego’s execution of id driving forces [7].
In later reformulations, Freud conceived of anxiety not emerging merely as a mechanical overﬂow of affect, but as a signal to the ego. In realistic anxiety, anxiety could
be seen adaptively as a warning of danger and the signal for taking ﬂight. In the case of
neurotic anxiety, the ego generates anxiety as a signal to ﬂight from libidinal demands(i.e., treating the internal danger as if it were external). Defensive maneuvers, such as
ﬁght/ﬂight required in the case of external anxiety, also hold true for neurotic anxiety
where the anxiety is transformed into symptoms (predominantly repression and allied
defenses) which results in the anxiety becoming bound [4]. Anxiety, therefore, can beseen as involving all components of the psychic apparatus whether as undischarged libidinalenergy or as an affect generated by the ego in reaction to internal danger and a signal tomobilize internal defenses where there is a conﬂict between id drives and superego control.
IV. DEVELOPMENTAL THEORIES OF ANXIETY
Freud initiated the exploration of anxiety in a developmental context. The prototypicalexperience of anxiety comes with the act of birth and the interruption of internal respiration. While this may remind us of Klein’s later theory of suffocation in panic disorder,
Freud believed this ﬁrst experience of anxiety has been thoroughly incorporated into us
through evolution. Two aspects were of particular relevance for Freud; ﬁrst, the experienceof anxiety was toxic and second, this ﬁrst state of anxiety arose out of separation fromthe mother. In later childhood, these feelings are revisited at times of separation or whenconfronted with strangers. The disappointment and longing for the mother are transformed
into anxiety. Infantile anxiety was closely related to neurotic anxiety, as it is derived fromunemployed libido and replaces the missing love object by an external object or situation[4]. In later years, such “free-ﬂoating” anxiety could readily attach to any suitable idea
[4] that relates to modern conceptualizations of generalized anxiety, or to objects andsituations as in the phobias.

660

Norman et al.

The next major developmental phase of relevance to the neuroses is the Oedipus
complex. In both sexes, there is a striving for the parent of the opposite sex. In males,
rivalrous feelings toward the father come to a head with murderous fantasies, guilt, andfear of retaliation by the father in the form of castration. The castration anxiety is resolved
following internalization of the father as the superego. In the female, the child renounces
her wishes toward her father upon realization of her mother’s disapproval in order tomaintain the bond with her mother [7]. The Oedipal stage occurs around the ages of 3 to
5. In Eriksson’s reformulation, this is the developmental phase of “initiative versus guilt.”
The child who inadequately resolves the conﬂict between initiative and guilt is hypothesized by Eriksson to be at risk of developing phobic disorders [8].
Bowlby, drawing on ethological and psychodynamic sources, suggests that earlyattachment experiences may be important in the genesis of anxiety and other disorders.
A key function of parenting is to establish a secure base from which the child can explore
the world. Appropriately secure attachments are of central importance in providing thesecure base [9]. Anxiety has an adaptive function in promoting attachment and has evolved
because of its contribution to species survival. Of the three principal patterns of attachment
described by Ainsworth and colleagues [10], Bowlby has focused on the pattern of “anxious attachment” as being of particular relevance to the anxiety disorders. Children withthis type of attachment are prone to uncertainty when their parent is unavailable and tend
to be clinging and anxious in their exploration of the world. Anxious attachment is promoted by inconsistent availability of the parent, separations, and threats of abandonmentby the parent as a means of control [9].
Bowlby proposed that separation anxiety in children and agoraphobia in adults are
best understood through the earlier development of anxious attachments. Uncontrolled
studies in agoraphobic patients have suggested parental overprotection and lack of affection are common [11,12]. Parker [13], using the Parental Bonding Instrument (PBI),
found agoraphobic and social phobic patients were more likely to report low-care–highprotection or “affectionless control.” Maternal overprotection has been conﬁrmed in someother [14,15] but not all studies [16,17]. Studies investigating Bowlby’s suggestion thatthreatened or actual early parental separation and loss predispose to the development ofanxiety in adulthood are contradictory. Early studies [18–20] did not ﬁnd increased
rates of parental loss and separation while a controlled study reported a positive correlation [14].
Correlational studies suggesting links between early-life experiences and later anxiety disorders may reﬂect a causal relationship but several alternative explanations needconsideration. First, self-report measures of early parenting may reﬂect response bias secondary to mood or personality disturbance. Second, family styles of overprotection andlow care may be secondary to the child’s anxiety disorder or premorbid anxious personality. Third, a genetic predisposition to anxiety may affect both child and parent, resulting
in altered parenting styles of overprotection [21].
V.

LIFE EVENTS AND THE DEVELOPMENT OF ANXIETY

Systematic enquiry into the relationship between events rated as stressful and subsequentillness began with the work of Hinkle and Wolff [22] who found clusters of illness mostfrequently appeared following an individual’s perception of difﬁculty in adapting to life
situations. The development of the Social Readjustment Rating Scale [23] and subsequentEtiology of Anxiety

661

techniques of measuring stressful life events has kindled interest in the role such events
may play in the causation and timing of mental illness. Most of this research is retrospective and has concentrated on discrete temporal events usually relating to the 12-month
period prior to the onset of symptoms. While there are many methodological difﬁculties
in conducting such research [24], there appears to be a relationship between anxiety symptoms or disorders and stressful life events.
A number of studies have evaluated the relationship between stressful life events(as measured by either questionnaire or interview) and self-report anxiety symptoms innonpsychiatrically ill populations. Lauer [25] administered the Social Readjustment Scaleto a large group of English and American university students and found a signiﬁcantassociation between anxiety scores and self-reported life changes over an unstated period.
This relationship was conﬁrmed in most subsequent studies involving students, generalpractice attenders, and normal controls [26,27]. On the other hand, Flannery [28], in astudy of 97 adults attending evening classes, found a relationship between anxiety andstressful life events in the women but not in the men studied.
Studies assessing the relationship between life events and the onset of anxiety disorder have demonstrated strong associations. Barrett [29] assessed 202 volunteers with a
Research Diagnostic Criteria diagnosis of anxiety or depressive disorder for life eventsin the 6 months prior to the onset of the disorder. Both groups reported more events
than a reference group and anxiety patients rated ﬁnancial difﬁculties and arguments asparticularly distressing. In a classic study of 164 young women attending a general practicein London and interviewed by a psychiatrist using the Present State Examination, FinlayJones and Brown [30] reported on the type of life event associated with depression, anxiety, and mixed anxiety/depression. Life events for the 12 months prior to onset of disorderwere rated using the Bedford College Interview Schedule and compared with 80 womenwith no psychiatric diagnosis and 39 women who had an onset of depression or anxiety
more than 12 months earlier. Loss events were signiﬁcantly associated with depression,
danger events with anxiety, and women with mixed anxiety/depression were more likely
to report both severe loss and danger.
Of the anxiety disorders, the relationship between life events and agoraphobia has
been the most studied. Roth [31] ﬁrst noted the high incidence of threatening life events
before the onset of agoraphobia with panic attacks in 135 patients. Since that time, anumber of studies have noted the association between life events and the onset of agoraphobia [18,20,32,33]. Interpersonal difﬁculties are the most commonly reported precipitating event occurring in up to 76% of agoraphobics [34]. Events viewed as uncontrollable,
undesirable, or lowering of self-esteem were found to precede the onset of panic attacks
in patients with panic disorder [35].
VI. PERSONALITY AND ANXIETY DISORDERS
Personality is deﬁned as the enduring pattern of “perceiving, relating to, and thinking
about the environment and oneself ” [36]. Implicit in this deﬁnition is that the repertoireof cognitions, emotions, and behaviors has stability over time and across a range of socialand personal contexts. Personality description is usually made according to dimensional
characteristics or with respect to speciﬁc core features grouped together to deﬁne a category (e.g. DSM-IV). Traditionally, the relationship between personality and major mental
illness has been viewed in two opposing ways. First, personality dimensions may essen-

662

Norman et al.

tially reﬂect a subclinical form of the major mood disturbance. The second view is exempliﬁed by the psychoanalytic tradition where the major illness is seen as developing outof personality traits that make an individual vulnerable. In the former view, the form of
the illness is seen in continuity with premorbid character traits, whereas in the latter, thesymptomatic state is distinct from the form of the personality. Although limited, the literature suggests there is a linkage between some personality dimensions or categories andclinical anxiety states; however, most studies have identiﬁed personality factors in retrospect following the diagnosis of a major anxiety disorder. This methodology limits theﬁndings for a number of reasons: (1) there is no accurate determination of the personality
predating the illness; (2) personality traits may be exacerbated by the illness; and (3) theillness itself may distort the individual’s view of the premorbid personality [37].
Studies assessing dimensional personality characteristics in anxious patients havegenerally suggested there is high neuroticism and low extroversion [38–40]. Kerr et al.
[38] used the Maudsley Personality Scale to investigate personality characteristics of 57
patients with multiple phobias, generalized anxiety, and probable panic attacks. Highscores of neuroticism in anxious patients were found to normalize in the well state, whereas
scores on the introversion scale remained low relative to controls on follow up. Highneuroticism/low extroversion was conﬁrmed by Hoehn-Saric [39] in patients with generalized anxiety and panic attacks. Extroversion was found to be signiﬁcantly lower in thosewith generalized anxiety compared with panic patients. Using factor analytic techniques,
Cloninger has determined a personality model based upon three genetically independent
factors with predictable responses to novel, aversive, and appetitive stimuli [41]. Cloninger
suggests that individuals with high scores of “harm avoidance” and low scores on “novelty
seeking” dimensions are susceptible to cognitive anxiety while the opposite conﬁguration
is associated with somatic anxiety. Allgulander and coworkers [42] demonstrated marked
reductions in harm avoidance in patients with generalized anxiety disorder following treatment with paroxetine, suggesting some of these personality dimensions may be state dependent.
In comparison with depressed patients, anxious patients reported more premorbid
personality traits of social anxiety, hypersensitivity, dependence, immaturity, hysteria, andanergia [43]. In contrast, Murray and Blackburn [44] found similar premorbid personality
characteristics in depressed and anxious groups. Using the Cattel 16 Personality Factor
Questionnaire, the anxious patients reported abnormalities of emotional immaturity, shyness, worry, seclusiveness, tension, and introversion that remained on recovery. In oneof the few prospective studies in the area, Nystrom and Lindegard [45] tested 3019 males
recruited while registering their car. Six years later, 114 of these were identiﬁed throughregisters of public psychiatric units of whom 34 had an anxiety disorder and 37 unipolar
depression. Premorbid psychasthenia and subclinical anxiety traits, as measured by the
Sjobring Personality Scale, were found to have a strong relationship with anxiety states.
Psychasthenia and subclinical depressive traits were also found in depressed individuals.
Studies using categorical diagnoses have found elevated rates of personality disturbance in anxious patients. Koenigsberg and colleagues [46] found high rates of DSM-III
Personality Disorder in a study of 2462 patients with highest rates in panic disorder (50%)
and phobia (48%). Over 90% of these patients had either dependent, avoidant, borderline,or histrionic personality. Mavissakalian and Hanann [40] found 27% of 60 agoraphobic
patients had a DSM-III Axis 2 disorder, again the most common being avoidant, dependent, or histrionic. Reich and colleagues [47] conﬁrmed the predominance of Cluster CEtiology of Anxiety

663

disorders and, in particular, Dependent Personality Disorder in 88 patients with panic
disorder.
VII. COGNITIVE AND BEHAVIORAL THEORIES OF ANXIETY
Cognitive-behavior therapy (CBT) is a popular and effective treatment for most anxiety
disorders. As with psychoanalysis, no single theory pertains to the cognitive-behavioral
understanding of anxiety, but a group of theories related to thought and behavior abnormalities frequently work in concert to initiate and maintain anxiety. The understanding ofthese theories drives the therapy in CBT where there is a strong emphasis on educationof the patient.
In 1920, Watson and Rayner translated Pavlov’s classic conditioning experiments
in dogs to create a conditioned phobic response to rats in little Albert [48]. It was suggested
that fear may be learned as a conditioned response. Several criticisms have emerged fromthis work. First, while Watson’s student Mary Cover Jones [49] was able to replicate thisphenomenon, others could not [50,51]. Second, conditioning theory demands single-trial
conditioning, which is very rare in laboratory settings [52]. Third, establishing a conditioned response in the laboratory demands ﬁnely turned timing of conditioned and unconditioned stimuli, which are very unlikely to occur in real life situations [53]. The importance of Watson and Rayner’s work is that it led to extensive research into the behavioral
understanding of anxiety and the technique of systematic desensitization, an effective treatment for phobic avoidance, pioneered by Wolpe [54].
More recently, cognitive theories of anxiety have complemented behavioral understanding leading to a more complete model of the etiology of anxiety. Notions of “freeﬂoating anxiety” in the absence of clear danger have been challenged by cognitive theorists
who emphasize frequently reported thoughts and images of danger in the anxious patient.
Beck and colleagues [55] have argued that anxious individuals systematically overestimate
the threat of a given situation, galvanizing a set of inherited responses originally designed
to protect us from harm. These changes include autonomic hyperarousal, inhibition of
ongoing behavior, and vigilance for possible sources of danger [56]. Peripheral manifestations of autonomic arousal are then misinterpreted by the patient as a sign of serious
physical or mental derangement leading to further arousal. In this model, anxiety is maintained by peripheral mechanisms originally hypothesized in the James–Lange theory ofanxiety. Fearful cognitions in anxiety include medical emergency (e.g., heart attack), mental disorder (e.g., “going crazy”), or social catastrophe (e.g., public disgrace) [55]. Beckhas emphasized the role of dysfunctional thinking in anxious patients, which contributes
to the misattributions of peripheral stimuli. Cognitive distortions in the anxiety disorders
include “catastrophization” (dwelling on the worst possible outcome), selective abstraction(selecting negative rather than neutral or positive aspects of a situation), dichotomous(polarized or “black and white”) thinking, and hypervigilant scanning [55].
The cognitive and behavioral abnormalities discussed above can work alone or inconcert in the anxiety disorders. In generalized anxiety disorder, Beck and coworkers[55] suggest there is a reactivation of developmental fears (dysfunctional assumptions)regarding the person’s acceptability to others, competence, responsibility, and self control.
In the cognitive model of panic disorder, Clark [57] emphasizes the catastrophic misinterpretation of bodily sensations as threat of impending physical or mental disaster. The
initial stimuli can be external (e.g., the situation of a previous panic attack) or internal

664

Norman et al.

(thoughts, images, or bodily sensations). A vicious cycle of ampliﬁcation of anxiety ensues
fueled by apprehensive scanning and somatic misinterpretations. Once initiated, panic
disorder is maintained by a tendency to become hypervigilant for bodily cues of danger
and avoidance of situations known to initiate symptoms. Avoidance is a major factor in
the maintenance of the phobias and may contribute to the development of anticipatory
anxiety, apprehension, and dread [58].
VIII. EXISTENTIAL ANXIETY
The exploration of human anxiety is not the exclusive domain of psychology. Philosophersfrom early times have sought to understand the origins of anxiety with the existential
philosophers making the most recent contributions. “Existentialism” is a term given to adisparate group of philosophers dissatisﬁed with the traditional thinking of their time.
While existential themes can be seen in the writings of Dostoevsky, the term “existentialism” originates from the Danish philosopher Soren Kierkegaard following exploration ofmodes of existence in “The Point of View,” published posthumously in 1859 [59]. It was,however, Kierkegaard’s concepts of human dread and freedom that became central in
the thinking of later existentialists—Jaspers, Heidegger, and Sartre. While the various
existential thinkers differed widely in their views, a number of themes have emerged fromtheir work which directly address the origins of anxiety in humans. Yalom [60] identiﬁes
four ultimate concerns for the individual: death, freedom, isolation, and meaninglessness.
Death is an inescapable aspect of existence and it is hypothesized that we live withthe ultimate terror of death. Choron [61] distinguishes three types of death fear: (1) whatcomes after death; (2) the event of dying; and (3) ceasing to be. It is the third of thesefears that Kierkegaard emphasized as a dread of nothingness [62]. The existential anxiety
is the tension that emerges between the knowledge of the inevitability of death and thewish to continue to be. One way to combat the fear of nothingness is to transfer it tosomething so that we can mount a self-protective defense. As a result, primal death anxiety
is rarely encountered in clinical practice and is only seen when conventional defenses are
stripped away (e.g., in analysis or in dreams). Yalom [60] suggests a number of defenses
are particularly used to reduce death anxiety including denial, suicidal thoughts as a control
over the helplessness of death, compulsive working (e.g., “workaholic”), personal beliefs
of inviolability (narcissism), aggressive drives for power and control, and rescue fantasies(e.g., by God), etc.
While freedom is generally viewed as a positive concept, for the existentialist it isinextricably linked with dread. In its existential sense, “freedom” refers to the absence ofa well-structured universe. In the absence of inherent design, the individual is entirely
responsible for their world in terms of choices and actions. The individual strives for orderin a disordered world. For Heidegger and Sartre, the individual is free to constitute theworld however they wish but bares full responsibility for doing so—they are the authorsof their world and the responsibility is terrifying. As with death, there is no escaping thisfreedom. To avoid the responsibility of freedom is to live “inauthentically” [63] or in“bad faith” [64]. Yalom [60] suggests a number of responsibility-avoiding defenses arecommonly used to reduce the anxiety associated with freedom including: denial of responsibility, displacement of responsibility, compulsive behaviors, etc.
The third ultimate concern is isolation. Yalom [60] deﬁnes three types of isolation:(1) interpersonal isolation results when factors such as distance, personality style, etc.,
prevent social gratiﬁcation: (2) intrapersonal isolation results when unconscious mecha-

Etiology of Anxiety

665

nisms isolate one part of the self as in the defense of isolation of affect; and (3) existential
isolation. Existential isolation refers to an unbridgeable gap between individuals based on
the knowledge that each of us enters into existence alone and must leave alone. No matter
how close we may get to another, one must ultimately undergo the journey of death alone.
Isolation is then related to death and freedom in that the individual is alone in coming
into existence, being responsible for their own existence, and leaving existence. Mostof the defensive operations used to reduce the sense of isolation involve interpersonal
relationships and include searching for love, avoidance of being alone, fusion with another,or with a group, etc.
The ﬁnal existential concern identiﬁed by Yalom [60] is meaninglessness. Existential meaninglessness is related to freedom and responsibility. If the universe lacks structure
and meaning, then the individual needs to construct meaning in a personal sense. Anxiety
can result if insufﬁcient purpose and meaning is achieved, or if the individual fears that
this may be the appraisal on their death. Meaning can be achieved through altruism, creativity, and dedication to a cause, etc.
From a therapeutic viewpoint, there are many similarities with the psychodynamic
therapies. Anxious concerns are understood to be defended against by classic defense
mechanisms and are seen in a developmental context. The process of therapy is essentiallyaimed at gaining insight and effecting change on the basis of these insights. The majordifferences are related to the understanding of the origins of anxiety as outlined above
and how to combat them. Armed with an understanding of their inner conﬂicts, patients
may work through the grief related to the realization of fundamental life concerns andmake choices aiming for a more “authentic” existence.
IX. NEUROANATOMICAL SUBSTRATES OF ANXIETY
Identiﬁcation of key neural circuits involved in the genesis of anxiety has relied heavily
on studies in animals, primarily rodents [65,66]. Experimental models of anxiety in animals have relied on inhibition of behavioral tendencies in certain tasks [67]. Frequently
such tasks depend on learned behaviors that are probably less reliable for understanding
the neural basis of fear than are spontaneous fearful behaviors. Furthermore, many animalmodels are markedly dependent on responses to clinically effective pharmacologicalagents for validity [68]. Benzodiazepines have been the most widely employed agents inanimal testing and the extent to which such models can be generalized to other classesof agents is still open to question. Nevertheless, external signs of fear in animals arewell recognized. Both electrical stimulation of the brain and agents acting on speciﬁc
neurotransmitters have provided valuable insights into the neuroanatomical substrates offear and anxiety.
As noted by Charney and Bremner [69], during the development of an anxiety state,afferent inputs are relayed from sensory organs through the dorsal thalamus to corticalbrain regions. Secondary cortical association areas then process the information. Particularbrain regions have been identiﬁed as involved in fear and anxiety including the amygdala,hippocampus, entorhinal cortex, orbitofrontal cortex, and the cingulate. Processing of information within these regions is believed to account for the experience of anxiety byindividuals, while modulation of neurotransmitter inputs to neural circuits formed between
regions can account for the anxiolytic effect of various therapeutic drugs. A number ofhypotheses involving these brain regions have been advanced to account for fear andanxiety in humans and other species.

666

Norman et al.

Figure 1 Representation of Gray’s septohippocampal scheme for anxiety. Inputs to thesepto-hippocampal system activate the behavioral inhibition system and increase anxiety.
Increased neurotransmitter activity from both serotonergic pathways (the raphe nuclei) andnoradrenergic pathways (from the locus coeruleus) are proposed to increase anxiety. Anxiolytic drugs are proposed to have their therapeutic effects by decreasing the ﬁring of theraphe nuclei, the locus coeruleus, or both.
A.

Septohippocampal System

One hypothesis proposes that the septum and hippocampus form a behavioral inhibition
system (Fig. 1) that serves as a substrate upon which anxiolytic drugs exert their effects[70]. Gray also included the Papez circuit as part of the system, although subsequent work
has suggested that this pathway may have little involvement in emotion [71]. The septohippocampal system is posited to be part of a neural network that acts as a comparatorof actual and anticipated stimuli. When a mismatch is detected, the behavioral inhibition
system is activated. The system either inhibits ongoing behavior or increases vigilance,
depending on the nature of the inputs. Since septohippocampal lesions do not alter the
behavioral effects of anxiolytic agents in animals, key inputs to the system must be affectedby drug administration. Both serotonergic inputs from raphe nuclei and noradrenergic
inputs from the locus coeruleus have been implicated. It has been proposed that septohippocampal activity is enhanced by increased activity of both monoamines and that anxiolytics exerted their effects by reducing monoaminergic activity [70]. An additional circuit
comprising the amygdala, hypothalamus, and the periaqueductal gray (PAG) region of
the central gray has been proposed to mediate ﬂight-or-ﬁght responses.
B.

AmygdalaMore recently, the role of the amygdala in fear responses has been described [71,72].
Both the lateral and basolateral nuclei of the amygdala receive processed sensory information. Both of these nuclei project to the central nucleus of the amygdala, which in turnprojects to both the hypothalamus and the brainstem. These latter areas directly mediate
the signs of fear and anxiety. The amygdala, because of its relevant projections (seeFig. 2), may represent a central fear system [73]. For example, direct projections from thecentral nucleus of the amygdala to the lateral hypothalamus probably activate sympathetic

Etiology of Anxiety

667

Figure 2 Connections of the amygdala to other anatomical regions and the consequences of activation. The amygdala appears to play a key role in assessing threatening
stimuli and initiating response to those stimuli. Through activation of the various anatomicaltargets the autonomic and endocrine responses to threat are activated. (Modiﬁed from
Ref. 69.)

responses during fear and anxiety [74]. Similarly, projections to the dorsal motor nucleus,
vagus, and ventrolateral medulla most likely mediate changes in heart rate and bloodpressure. Furthermore, respiratory effects may be inﬂuenced through projections of central
amygdala to the parabrachial nucleus. Neuroendocrine responses to fear and anxiety arelikely mediated by projections of central amygdala to the paraventricular nucleus of the
hypothalamus or to the bed nucleus of the stria terminalis. Other projections and their
symptom consequences are summarized in Figure 2.
Further evidence for the role of the amygdala in anxiety states comes from clinicalobservations of behavioral and autonomic changes, resembling fear, following electricalactivation of the amygdala after temporal lobe seizures [75]. Similarly, direct electricalstimulation of the amygdala in humans results in subjective feelings of anxiety or fear,
as well as autonomic signs usually associated with fear [73]. Furthermore, in rats, chemical
stimulation of this brain region with drugs such as the GABA antagonist bicuculline,
produced elevated blood pressure and heart rate [76]. Together these observations suggestthat activation of the amygdala during fear may explain all of the fear/anxiety symptoms
experienced. Conversely, if the amygdala is critical for the interpretation and manifestationof anxiety states, then lesions to the area should be anxiolytic. Indeed, in monkeys, bilateralremoval of the temporal lobes including the amygdala, hippocampus, and surrounding
cortical areas resulted in so-called “psychic blindness” [77]. This is best described as alack of fear of usually feared animate and inanimate objects (e.g., snakes). While patientswith lesions to the amygdala rarely exhibit a full Kluver-Bucy syndrome, they do exhibit blunted emotional reactivity [73]. Similarly, in the rat lesions of the amygdala
result in a blockade of innate fears (e.g., increasing the number of contacts with a sedated cat) [78].
The amygdala represents one brain area that is critically involved in mediating thespeciﬁc signs of fear and anxiety. Inputs to the amygdala from other critical brain areas

668

Norman et al.

are also proposed to play a role in mediating anxiety and fear responses. In particular,
inputs from the dorsal raphe nucleus (DRN) utilizing serotonin as a neurotransmitter are
thought to augment avoidance of aversive stimuli [79]. A further serotonergic pathwayarising in the DRN, which inhibits the PAG, is proposed to underlie the ﬂight-or-ﬁght
response [79]. Furthermore, noradrenergic neurons arising in nucleus locus coeruleus havelong been associated with fear responses in animals [80].
Clearly, the neural circuits underlying anxiety are complex and rely upon the interaction of several different systems. In turn, these systems communicate with one anotherthrough the agency of chemical neurotransmitters. Of the various transmitters, most attention has been directed toward noradrenaline, serotonin, and γ-aminobutyric acid (GABA).
Other systems, dopamine, opiates, and neuropeptides have also been implicated in mediating anxiety responses.

X.

NEUROCHEMICAL BASIS OF ANXIETYA.

Noradrenergic System

Cannon ﬁrst proposed a role for noradrenaline in fear responses, while elevations of adrenaline and noradrenaline in the plasma of animals and humans in response to fear havebeen demonstrated [81]. Overactivity of the nucleus locus coeruleus and the ascending
noradrenergic systems has been implicated in anxiety [82]. The locus coeruleus is the
major noradrenergic-containing nucleus of the brain and is regulated by feedback onto α2
autoreceptors. Electrical stimulation, lesioning studies, and pharmacological manipulationof the locus coeruleus have been extensively studied in stump-tailed monkeys [80]. Stimulation of the locus coeruleus produces an alerting effect, similar to that observed after
threatening confrontations, leading to the notion that behavior was related to fear andanxiety [83]. The responses observed were speciﬁc to stimulation of the locus, as stimulating adjacent areas did not produce the behaviors. Similar responses to electrical stimulation
could be elicited by the α2 antagonists piperoxane and yohimbine administered intravenously. On the other hand, clonidine at a dose of 1 µg/kg infused intravenously was able
to reduce the behavioral effects resulting from locus coeruleus stimulation. The same doseof clonidine reversed the effects of yohimbine and piperoxane [84]. Such actions would
be predicted from the known effects of these agents on α2 autoreceptors. Propranolol, aβ-blocker, has also been shown to decrease behavioral responses and partially block theeffects of stimulating the locus. Agents as diverse as diazepam and morphine also blockelectrical stimulation and the effects of piperoxane and yohimbine [80]. Diazepam probably exerts its effects by promoting the inhibitory effects of GABA, thereby decreasing
the ﬁring rate of locus coeruleus neurons and noradrenaline turnover. Morphine binds toinhibitory opiate receptors on the locus coeruleus [84].
Evidence for a similar role in humans has been obtained by electrical stimulationof the locus coeruleus, which has been reported to result in feelings of fear and imminent
death [85]. Other evidence for a catecholamine hypothesis of anxiety is to be found in
the clinical effects of drugs known to inﬂuence adrenergic function. The effects of the βadrenergic agonist isoproterenol have been extensively studied. Frohlich and coworkers[86] identiﬁed a group of patients they described as having a “hyperdynamic β-adrenergic
circulatory state.” This was characterized by high left ventricular ejection rate, occasional
systolic hypertension, systolic ejection murmur, and bounding arterial pulse. Such patients,
but not normal controls, experienced increased cardiac awareness, increased pulse rate,

Etiology of Anxiety

669

and anxiety attacks during infusion of the β-agonist isoproteronol. Acute anxiety attacks
following isoproteronol infusion have been described in a small group of patients sufferingfrom episodic anxiety [87]. Intravenous administration of propranolol (2 to 5 mg in 2 to
3 min) was able to block the chemically induced anxiety. Later workers have shown that
panic attacks could be induced in patients susceptible to such attacks by intravenous infusions of isoproteronol [88,89]. The mechanism of the effect is not clear but probably does
not involve a direct effect of isoproteronol on the locus coeruleus, since the drug does
not cross the blood–brain barrier. More likely, the effect is indirect, activating the locus
coeruleus “alarm signal” by cues from the peripheral cardiac effects of isoproteronol (i.e.,
the James–Lange peripheral model of anxiety). On the other hand, the α2 antagonist yohimbine has been shown to cross the blood–brain barrier and is reportedly anxiogenic inhumans [90,91]. In panic disorder patients, about 80% had an anxiety response to yohimbine, which was subsequently blocked by 8 to 12 weeks of treatment with a benzodiazepine
anxiolytic [92]. The anxiogenic effects of yohimbine are probably mediated by a direct
action on presynaptic α2 adrenoreceptors located on the locus coeruleus [93].
B. Serotonergic System
Much of the evidence for a role of serotonin in anxiety states relies on data from animalstudies. It is well recognized that the main cell bodies of serotonin-containing neurons
arise in the brainstem and innervate virtually all cortical areas. Both the dorsal and medianraphe nuclei contain cell bodies that give rise to ascending serotonergic pathways. Within
this broad anatomical framework there are subtle functional connections of neurons [94].
Coupled with a plethora of serotonin receptor subtypes, it is clear that the serotonergic
system provides multiple anxiogenic/anxiolytic targets.
Animal studies suggest that inhibition of serotonergic neurotransmission is anxiolytic, while an increase is anxiogenic. Administration of the serotonin synthesis inhibitor,
p-choloro-phenylalanine (PCPA), has been shown to produce an anxiolytic proﬁle in several animal behavioral models [95,96]. These effects could be reversed by treatment withthe serotonin precursor, 5-hydroxytryptophan [97], as well as by 5HT1A agonists suchas 8-OH-DPAT [98]. Destruction of serotonin neurons with toxic agents such as 5,7dihydroxytryptamine (5,7-DHT) in localized regions leads to diminished anxiety responses. For example, File and coworkers [99] showed that DHT lesioning of the dorsal
raphe but not the median raphe resulted in anxiety reduction. On the other hand, more
recent investigations suggest that both electrolytic and neurotoxic lesions of the medianraphe nucleus are anxiolytic [100]. This may reﬂect the involvement of the different nuclei
in different aspects of the behavioral tests employed. Furthermore, it has been proposedthat the dorsal raphe is important for cognitive processes, while the median raphe modulates fear and anticipatory anxiety [101].
Studies with both serotonin agonists and antagonists, in general, produce anxiogenic
and anxiolytic responses, respectively [102]. Responses to individual agents depend on thenature of the receptor subtype involved and its anatomical location (pre- or postsynaptic).
Activation of speciﬁc serotonin receptors and the responses elicited in particular anxiety
disorders are described in detail elsewhere in this volume.
Clearly the role of serotonin in the etiology of anxiety disorders is a complex one.
Simple models based on increases or decreases of absolute levels of serotonin are inadequate. Neural circuits involving various serotonin-receptor subtypes and interactions withother neurotransmitters offer more sophisticated explanations of the etiology of anxiety.

670

Norman et al.

Furthermore, these models, even though they themselves are probably inadequate, are ofheuristic value providing speciﬁc testable hypotheses and further iterations of the model.
C.

GABA–Benzodiazepine System

The efﬁcacy of benzodiazepines and other drugs acting at GABA receptors in treating
anxiety have argued for a role of GABA and its receptor systems in the etiology of anxiety.
Manipulation of GABA levels or the use of GABA agonists does not produce a reliableanxiolytic effect in animals [103,104]. An important role for GABA was clearly implicatedwhen it was demonstrated that benzodiazepines and other drugs with anxiolytic properties(barbiturates, ethanol) potentiate and prolong the inhibitory effects of GABA at central
neurons. Subsequently, it was shown that benzodiazepines and GABA-A receptors form
part of the same macromolecular complex (see Fig. 3). Although they bind to different
sites on the complex, they are functionally coupled through modulation of the chloride ionchannel. Benzodiazepines facilitate GABA transmission by positive allosteric modulation[105]. The GABA-A receptors are pentameric membrane-bound proteins distinguished bytheir subunit composition. In mammalian brain, seven different classes of subunits, mostwith multiple isoforms, have been identiﬁed: α1 –α6, β1 –β3, γ1 –γ3, δ, ε, θ [106]. The majority of GABA-A receptors are composed of α, β and γ subunits [107]. The speciﬁc combination of subunits and isoforms varies across the central nervous system and accounts for thediversity of effects observed by drugs acting at GABA-A receptors [107]. Combinationsof α and γ subunits are necessary to bind benzodiazepines; speciﬁcally the N-terminal
extracellular domain of certain α subunits is critical. Only the α1, α2, α3, or α5 subunits
bind the benzodiazepines [106]. Gene knockout strategies have been employed to examine
the effects of alterations of GABA-A receptors on the physiological and pharmacologicalFigure 3 The GABA-A receptor. These receptors form a ligand-gated ion channel for thechloride ion. Binding of GABA to its site facilitates the inﬂux of chloride ions and inhibits theﬁring of that neuron. Multiple allosteric modulatory sites, including one for benzodiazepines,
are present on the GABA complex. The receptor consists of ﬁve peptide subunits, which
in turn have four membrane-spanning domains. The benzodiazepine binding site is present
on the extracellular domain of the α-subunit (see Fig. 4).

Etiology of Anxiety

671

responses of mutant mice. This strategy suggested that the α6 subunit is associated withmarked anxiety responses to natural and learned aversive stimuli; the β3 subunit is associated with motor impairment, epileptic seizures and hyperresponsiveness to sensory stimuli.
Notwithstanding the methodological limitations of the knockout paradigm, these observations provide interesting clues as to the possible role of GABA-A receptor subtypes inthe etiology of anxiety [106].
An alternate strategy has been to examine the role of so-called knockin point mutations [106]. The N-terminus of the extracellular domain of the α subunits, which bindbenzodiazepines, have a histidine (His) residue at position 101 (see Fig. 4). GABA-A
receptors composed of α4 and α6 subunits, which do not bind benzodiazepines, have an
arginine (Arg) at this residue. A point mutation that converts histidine to arginine at position 101 causes benzodiazepine-sensitive receptors to become insensitive. The His to Arg
point mutation has been introduced into the germ line of mice in the genes that encode
α1, α2, and α3 subunits and the behavioral effects examined. In mice with the mutationin the α1 subunit, diazepam administration failed to produce sedation and amnestic effects[108]. Similarly, the sedative and anticonvulsant effects of zolpidem, an agent with highafﬁnity for α1-containing GABA-A receptors, was abolished in these mice [109]. By
contrast, mice with the mutation in the α2 subunit showed resistance to the antianxiety
effects of diazepam, but not to its sedative, anticonvulsant, or muscle-relaxant effects[110]. Selective His to Arg mutations of the α3 subunit did not appear to have any of theresistance apparent in the other two strains [110].

Figure 4 The α-subunit of the GABA-A receptor containing the benzodiazepine-binding
domain. A conserved histidine residue at position 101 of the binding domain is indicated.
Point mutations that convert the histidine to arginine result in loss of binding of the classicalbenzodiazepines, such as diazepam. The four transmembrane-spanning domains of theα subunits are represented as the cylinders (α-helical protein structures) M1, M2, M3,
and M4.

672

Norman et al.

These ﬁndings clearly implicate GABA-A receptor subtypes in the mechanism ofaction of benzodiazepines and hold promise for the development of selective antianxiety
agents based on speciﬁc neuronal receptor targets. Furthermore, developments at the molecular level suggest that a reﬁnement of the understanding of the neurobiology and genetics of anxiety disorders may follow.
A unique feature of the GABA-A benzodiazepine receptor system is its bidirectional
agonism [102]. Conventional benzodiazepines act as agonists at the receptor while both
antagonists and inverse agonists have also been identiﬁed. Compounds acting as inverse
agonists at the receptor, such as the β-carboline FG7142, are anxiogenic in humans [111].
Observations such as these led to the notion that endogenous compounds may play a rolein the genesis of anxiety states. Several compounds have been proposed. Tribulin, a lowmolecular-weight compound found in normal human urine [112], has been shown to be
increased in some anxiety disorders and in lactate-induced panic attacks [113]. Diazepambinding inhibitor (DBI), an 86-amino-acid polypeptide, and one of its fragments, octadecaneuropeptide (ODN), have also been proposed as inverse agonists [114]. The demonstration that the benzodiazepine antagonist, ﬂumazenil, was-anxiogenic in panic
patients suggests that an endogenous agonist may occupy the receptor site [115]. Endogenous neurosteroids, including allopregnanolone (AP), allotetrahydrodeoxycorticosterone(THDOC), and 3-α-hydroxy-5-α-dihydroprogesterone (3-α-OH-DHP), produce modulatory effects by binding to steroid receptor sites on the GABA-A receptor complex, as
shown in Figure 3 [116]. The metabolite of pregnanolone (AP) can exert a positive allosteric effect on GABA at the GABA-A receptor [117], while THDOC has been shown to
reduce anxiety-related behaviors following i.c.v injection in the rat [118]. The role of suchcompounds in anxiety states in humans is attracting further interest both from the pointof view of etiology and therapeutics.
An interesting observation has been the demonstration of the presence of the diazepam metabolite, N-desmethyldiazepam, in postmortem brain tissue obtained before theintroduction of benzodiazepines into widespread clinical use [119]. It appears that suchcompounds may arise from dietary sources such as potatoes and other plants, and havebeen shown to contain this metabolite [105]. Perhaps the endogenous ligand for the benzodiazepine–GABA-A receptor is a benzodiazepine derivative itself. To date, there are no
studies of the levels of N-desmethyldiazepam in patients with anxiety disorders.

XI. GENETIC ETIOLOGY
Several approaches to the study of the genetic etiology of anxiety disorders have been
undertaken. These approaches are examined in more detail elsewhere in this volume inrelation to speciﬁc anxiety disorders. Many studies have attempted to determine the extent
to which anxiety disorders are familial and to estimate their heritability. Detailed reviewsof the genetic epidemiology of anxiety states [120] and their molecular genetics [121]have appeared. Recently a meta-analysis of the genetic epidemiology of anxiety disorders
have been published [122]. This study provides a concise summary of ﬁndings to date.
The meta-analysis supported the notion that anxiety disorders aggregate in families, thegreatest evidence being for panic disorder. The major source of familial risk of an anxiety
disorder was shown to be genetic. This was supported by large twin studies in panic
disorder, generalized anxiety disorder, and phobias. However, the estimated heritabilities
across the disorders was a relatively modest 30 to 40%. The largest proportion of theEtiology of Anxiety

673

variance in the liability to an anxiety disorder is explained by environmental factors peculiar to an individual.
Notwithstanding their weaknesses, twin and family studies suggest that molecular
strategies could be employed to identify speciﬁc genes associated with particular anxiety
disorders. To date, this approach has not been widely employed [121]. As noted above,
genes coding for the subunits of the GABA-A might be proﬁtably explored. A proline-toserine point mutation at residue 385 of the α6 subunit has been identiﬁed, which mediates
sensitivity to benzodiazepines [123]. While this ﬁnding may be more relevant to alcoholism, it does illustrate the utility of the approach. A study of 8 polymorphic subunits of
the GABA-A receptor in panic disorder showed no evidence of linkage [124]. Studies of
the GABA-A subunit genes in other anxiety disorders may be more fruitful.
Given the putative involvement of many neurotransmitters in the etiology of anxiety
disorders and their numerous receptor targets there is no doubt that further studies forcandidate genes in anxiety disorders will evolve. This approach coupled with linkage
studies and animal models (such as knockout and knockin strains as described above)
have the potential to identify important genes for the etiology of anxiety disorders. It is
unlikely that a single gene will completely explain the etiology of any one anxiety disorder.
However, genetic techniques may uncover previously unheralded therapeutic targets.
XII. CONCLUSION
Freud [6] remarked that anxiety was. . . a riddle whose solution would be bound to throw a ﬂood of light on our whole mental
existence.

Advances in the understanding of the function of the brain in recent years has seena renewed focus on the nature and treatment of anxiety, as well as an interest in theclassiﬁcation of anxiety states. The latter continues to be a subject of debate between the
advocates of a General Neurotic Syndrome [125] and those advocating separate disorders[126]. This has not been a barrier to intensive research on the neurobiology and neurocircuitry associated with anxiety. The neurobiological approach proceeds from the premisethat underlying a psychological dysfunction is a biological one. Knowledge of the relationship between functional processes in the brain and symptoms of anxiety is still evolving.
This evolution has been accompanied by a greater understanding of the neural circuits
involved in anxiety states. The amygdala now appears to be an important mediator ofsome facets of the conditioned fear response in animals and perhaps in humans, while
the septo-hippocampal system and its connections to the PAG region also plays a role inmediating the anxiety response. Continued research in animal models of anxiety states aswell as neuroimaging studies in humans should provide a greater understanding of these
aspects of anxiety, as well as provide new neural targets for therapeutics. Genetic studies
suggest a familial pattern of inheritance for anxiety disorders, but speciﬁc genes for individual disorders have not been identiﬁed. Family and twin studies suggest that environment makes a signiﬁcant contribution to the etiology of anxiety states. This suggests thatthe psychological approach to the understanding of the etiology of anxiety, far from being
in abeyance, can offer many insights. Both psychological and social approaches to anxiety
simply represent another perspective on the problem. Understanding anxiety based on theneurobiological, neuropsychological, and psychological point of view promises a greater
depth than in the past. Coupled with knowledge of the mechanism of action of effective

674

Norman et al.

treatments, further progress toward the etiology of the disorders should be forthcoming.
These endeavors are beginning to unravel the mystery that is anxiety.

REFERENCES
1. Robins LN, Helzer JE, Weisman MM, Orvaschel H, Gruenberg E, Burke JD, Reiger DA.
Lifetime prevalence of speciﬁc psychiatric disorders in three sites. Arch Gen Psych 1984;
41:949–958.
2. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen H-U,
Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the
United States. Arch Gen Psych 1994; 51:8–19.
3. Darwin C. The Expression of Emotions in Man and Animals. London: John Murray, 1872.
4. Freud S. Introductory Lectures on Psychoanalysis. The Standard Edition of the Complete
Works of Sigmund Freud. London: George Allen & Unwin, 1963.
5. Freud S. Inhibitions, Symptoms and Anxiety. London: Hogarth Press, 1926.
6. Freud S. On the grounds for detaching a particular syndrome from neurasthenia under thedescription “Anxiety neurosis.” In: Strachey J, ed. The Standard Edition of the Complete
Psychological Works of Sigmund Freud, Vol III. London: Hogarth Press, 1962.
7. Freud S. The ego and the id. In: Strachey J, ed. The Standard Edition of the Complete Psychological Works of Sigmund Freud, Vol XII. London: Hogarth Press, 1913.
8. Newton PM, Newton DS, Erikson EH. In: Kaplan HI, Sadock BL, eds. Comprehensive Textbook of Psychiatry VI. Baltimore: Williams and Wilkins, 1995.
9. Bowlby J. A Secure Base. Clinical application of attachment theory. London: Tavistock/
Routledge, 1992.
10. MDS Ainsworth, Bell SM, Stayton DJ. Individual differences in strange situation behaviourof one-year-olds. In Schaffer HR, ed. The Origins of Human Social Relations. London: Academic Press, 1971.
11. Terhune WB. The phobic syndrome. Arch Gen Psych 1949; 62:162–172.
12. Tucker WI. Diagnosis and treatment of phobic reaction. Am J Psychiat 1956; 122:825–830.
13. Parker G. Parental Overprotection: A Risk Factor in Psychological Development. New York:
Grune and Stratton, 1983.
14. Silove D. Perceived parental characteristics and reports of early parental deprivation in agoraphobic patients. Aust NZ J Psychiat 1986; 20:365–369.
15. Solyom L, Silbersfeld M, Solyom C. Maternal overprotection in the aetiology of agoraphobia.
Can Psychiat Assoc J 1976; 21:109–113.
16. Snaith RP. A clinical investigation of the phobias. Br J Psychiatry 1968; 114:673–697.
17. Arindell WA, Emmelkamp PMG, Monsma A, Brilman E. The role of perceived parental
rearing experiences in the aetiology of phobic disorders: A controlled study. Br J Psychiatry
1983; 143:183–187.
18. Buglass D, Clark J, Henderson AS, Kreitman N. A study of agoraphobic housewives. Psychol
Med 1977; 7:73–86.
19. Solyom L, Beck P, Solyom C, Hugel R. Some aetiological factors in phobic neurosis. Can
Psych Assoc J 1974; 19:69–78.
20. Shafar S. Aspects of phobic illness—a study of 90 personal cases. Br J Med Psychol 1976;
49:221–236.
21. Parker G. Developmental factors in anxiety. In: Noyes R Jr, Roth M, Burrows GD, eds.
Handbook of Anxiety, Vol 2. Amsterdam: Elsevier, 1988:147–162.
22. Hinkle LE, Wolff HG. The nature of man’s adaptation to his total environment and therelation of this to illness. Arch Intern Med 1957; 99:442–460.
23. Holmes TH, Rahe RH. The social readjustment rating scale. J Psychosom Res 1967; 11:
213–218.

Etiology of Anxiety

675

24. Tennant C. Life events and psychological morbidity: The evidence from prospective studies.
Psychol Med 1983; 13:483–486.
25. Lauer RH. The social readjustment scale and anxiety: A cross-cultural study. J Psychosom
Res 1973; 17:171–174.
26. Miller PM, Salter DP. Is there a short cut? An investigation into the life event interview.
Acta Psych Scand 1984; 70:417–427.
27. Sarason IG, Johnson JH, Siegel JM. Assessing the impact of life changes. Development of
the Life Experiences Survey. J Consult Clin Psychol 1978; 46:932–946.
28. Flannery RB. Major life events and daily hassles in predicting health status: methodologicalinquiry. J Clin Psychol 1986; 42:485–487.
29. Barrett JE. The relationship of life events to the onset of neurotic disorders. In: Barrett JE,
ed. Stress and Mental Disorders. New York: Raven Press, 1979: 87–110.
30. Finlay-Jones R, Brown GW. Types of stressful life event and the onset of anxiety and depressive disorders. Psychol Med 1981; 11:803–815.
31. Roth M. The phobic anxiety depersonalization syndrome. Proc R Soc Med 1959; 52:587–
595.
32. Sheehan DV, Sheehan KE, Minichello WE. Age of onset of phobic disorders: a re-evaluation.
Comp Psychiatry 1981; 22:544–553.
33. Franklin JA, Andrews G. Stress and the onset of agoraphobia. Aust Psychol 1989; 24:203–
219.
34. Bowen RC, Kohout J. The relationship between agoraphobia and primary affective disorders.
Can Psych Assoc J 1979; 24:317–322.
35. Roy-Burne PP, Geraci M, Uhde TW. Life events and the onset of panic disorder. Am J
Psychiat 1986; 143:1424–1427.
36. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington: American Psychiatric Association, 1994.
37. Judd FK, Norman TR, Burrows GD. Theories on the etiology of anxiety disorders. In: denBoer JA, Ad Sitsen JM, eds. Handbook of Anxiety and Depression: A Biological Approach.
New York: Marcel Dekker, Inc, 1994:225–246.
38. Kerr TA, Schapira K, Roth M, Garside RF. The relationship between the Maudsley Personality Inventory and the course of affective disorder. Br J Pychiatry 1970; 116:11–19.
39. Hoehn-Saric R. Characteristics of chronic anxiety patients. In: Klein DF, Rabkin J, eds. Anxiety: New Research and Changing Concepts. New York: Raven Press, 1981:339–409.
40. Mavissakalian M, Hamann MS. DSM-III personality disorder in agoraphobia. Comp Psychiatry 1986; 27:471–479.
41. Cloninger CR, Svrakic DM, Przybeck TR. A psychobiological model of temperament andcharacter. Arch Gen Psychiatry 1993; 50:975–990.
42. Allgulander C, Cloninger CR, Przybeck TR, Brandt L. Changes on the Temperament andCharacter Inventory after paroxetine in volunteers with generalized anxiety disorder. Psychopharmacol Bull 1998; 34:165–166.
43. Roth M, Gurney C, Garside RF, Kerr LA. Studies in the classiﬁcation of affective disorders:
The relationship between anxiety states and depressive illnesses—I. Br J Psychiatry 1972;
121:147–161.
44. Murray LG, Blackburn IM. Personality differences in patients with depressive illness andanxiety neurosis. Acta Psych Scand 1974; 50:183–191.
45. Nystrom S, Lindegard B. Predispositions for mental syndromes: a study comparing predisposition for depression, neurasthenia and anxiety state. Acta Psych Scand 1975; 15:69–76.
46. Koenigsberg HW, Kaplan RD, Gilmore MM, Cooper AM. The relationship between syndrome and personality disorder in DSM-III: experience with 2,462 patients. Am J Psychiat
1985; 142:207–212.
47. Reich J, Noyes R Jr, Troughton E. Dependent personality disorders associated with phobic
avoidance in patients with panic disorder. Am J Psych 1987; 144:323–326.

676

Norman et al.

48. Watson JB, Rayner R. Conditioned emotional reactions. J Exp Psychol 1920; 3:1–14.
49. Jones MC. The elimination of children’s fears. J Exp Psychol 1924; 7:382–390.
50. English HB. Three cases of “conditioned fear response.” J Abnorm Soc Psychol 1929; 34:
221–225.
51. Bregman E. An attempt to rectify the emotional attitudes of infants by the conditioned response technique. J Genet Psychol 1934; 45:169–198.
52. Seligman MEP. Chronic fear produced by unpredictable electric shock. J Comp Physiol Psychol 1968; 66:402–411.
53. Eysenck HJ. Psychological theories of anxiety. In: Burrow GD, Davies B, eds. Handbookof Studies on Anxiety. Amsterdam: Elsevier/North Holland Biomedical Press, 1980:21–38.
54. Wolpe J. Psychotherapy by Reciprocal Inhibition. California: Stanford University Press,
1958.
55. Beck AT, Emery G, Greenberg RL. Anxiety Disorders and Phobias: A Cognitive Perspective.
New York: Basic Books, Inc, 1985.
56. Clark DM. Anxiety states: Panic and generalized anxiety. In: Hawton K, Salkovskis PM,
Kirk J, Clark DM, eds. Cognitive Behaviour Therapy for Psychiatric Problems: A Practical
Guide. Oxford: Oxford University Press, 1989:52–96.
57. Clark DM. A cognitive approach to panic. Behav Res Therapy 1986; 24:461–470.
58. Butler G, Cullington A, Hibbert G, Klimes I, Gelder M. Anxiety management for persistent
generalized anxiety. Br J Psychiatry 1987; 151:535–542.
59. Kierkegaard S. The Point of View. In: Bretall R, ed. Kierkegaard Anthology, 1973:323–
337.
60. Yalom ID. Existential Psychotherapy. New York: Basic Books, 1980.
61. Choron J. Modern Man and Mortality. New York: Macmillan, 1964:44.
62. Kierkegaard S. The Concept of Dread. Princeton, NJ: Princeton University Press, 1957.
63. Heidegger M. What is metaphysics? In: Existence and Being, Hull RFC, Crick A, transl.
City: Henry Regnery Company, 1949.
64. Sartre J-P. Self-Deception. In: Kaufmann W, ed. Existentialism from Dostoevsky to Sartre.
New York: Meridian, 1975:299–328.
65. Weiss SRB, Uhde TW. Animal models of anxiety. In: Ballenger J, ed. Neurobiology ofAnxiety Disorder. New York: Alan R Liss, 1990:3–27.
66. Charney DS, Deutch A. A functional neuroanatomy of anxiety and fear: implications for thepathophysiology and treatment of anxiety disorders. Crit Rev Neurobiol 1996; 10:419–446.
67. Panksepp J. The psychoneurology of fear: evolutionary perspectives and the role of animalmodels in understanding human anxiety. In: Burrows GD, Roth M, Noyes R, eds. Handbookof Anxiety, vol 3: The Neurobiology of Anxiety. Amsterdam: Elsevier, 1990:3–58.
68. Treit D. Animal models of anxiety and anxiolytic drug action. In: den Boer JA, Sitsen A,
ed. Handbook of Depression and Anxiety. New York: Marcel Dekker, Inc, 1994:201–224.
69. Charney DS, Bremner JD. The neurobiology of anxiety disorders. In: Charney DS, Nestler
EJ, Bunney BS, eds. Neurobiology of Mental Illness. Oxford: Oxford University Press, 1999:
494–517.
70. Gray JA. The Neuropsychology of Anxiety: An Enquiry into the Septo-Hippocampal System.
New York: Oxford University Press, 1982.
71. LeDoux J. The Emotional Brain. London: Phoenix, 1998.
72. Davis M. Functional neuroanatomy of anxiety and fear: a focus on the amygdala. In: Charney
DS, Nestler EJ, Bunney BS, eds. Neurobiology of Mental Illness. Oxford: Oxford University
Press, 1999:463–474.
73. Davis M. Neurobiology of fear responses: the role of the amygdala. Neuropsych Clin Neurosci 1997; 9:382–402.
74. LeDoux JE, Iwata J, Cicchetti P, Reis DJ. Different projections of the central amygdaloid
nucleus mediate autonomic and behavioural correlates of conditioned fear. J Neurosci 1998;
8:2517–2529.

Etiology of Anxiety

677

75. Gloor P. Role of the amygdala in temporal lobe epilepsy. In: Aggleton J, ed. The Amygdala:
Neurobiological Aspects of Emotion, Memory and Mental Dysfunction. New York: WileyLiss, 1992:505–538.
76. Sarter M, Markowitsch HJ. Involvement of the amygdala in learning and memory: a criticalreview, with emphasis on anatomical relations. Behav Neurosci 1985; 99:342–380.
77. Kluver H, Bucy PC. Preliminary analysis of the functions of the temporal lobes in monkeys.
Arch Neurol Psychiatry 1939; 42:979–1000.
78. Blanchard DC, Blanchard RJ. Innate and conditioned reactions to threat in rats with amygdaloid lesions. J Comp Physiol Psychol 1972; 81:281–290.
79. Deakin JFW, Graeff FG. 5HT and mechanisms of defence. J Psychopharmacol 1991; 5:305–
315.
80. Redmond DE, Huang YH. New evidence for a locus coeruleus–norepinephrine connection
with anxiety. Life Sci 1979; 25:2149–2162.
81. Heninger GR, Charney DS. Monoamine receptor systems and anxiety disorders. Psychiatr
Clin North Am 1988; 11:309–326.
82. Judd FK, Burrows GD, Norman TR. The biological basis of anxiety: an overview. J Affect
Disord 1985; 9:271–284.
83. Redmond DE, Yuang YH, Synder DR, Maas JW. Behavioural effects of stimulation of thelocus coeruleus in the stumptail monkey (Macaca arctoides). Brain Res 1976; 116:502–510.
84. Redmond DE. Studies of the nucleus locus coeruleus in monkeys and hypotheses for neuropsychopharmacology. In: Meltzer HY, ed. Psychopharmacology: The Third Generation of
Progress. New York: Raven Press, 1987:967–975.
85. Kuhar MJ, Neuroanatomical substrates of anxiety: a brief survey. Trend Neurosci 1986; 9:
307–310.
86. Frohlich ED, Tarazi RC, Dustan HP. Hyperdynamic β-adrenergic circulatory state. Arch
Intern Med 1969; 123:1–7.
87. Easton JD, Sherman DG. Somatic anxiety attacks and propranolol. Arch Neurol 1982; 33:
689–691.
88. Rainey JM, Ettedgui E, Pohl R, Balon R, Weinberg P, Yelonek S, Berchou R. The β-receptor:
isoproteronol anxiety states. Psychopathology 1984; 17(suppl 3):40–51.
89. Nesse RM, Cameron OG, Curtis GC, McCann DS, Huber-Smith MJ. Adrenergic function
in patients with anxiety. Arch Gen Psychiatry 1984; 41:771–776.
90. Holmberg G, Gershon S. Autonomic and psychic effects of yohimbine hydrochloride. Psychopharmacology 1961; 2:93–106.
91. Garﬁeld SL, Gershon S, Sletten I, Sundland DM, Ballou S. Chemically induced anxiety. Int
J Neuropsych 1967; 3:426–433.
92. Charney DS, Heninger GR. Noradrenergic function and the mechanism of antianxiety treatment 1. The effect of long term alprazolam treatment. Arch Gen Psychiatry 1985; 42:458–
467.
93. Charney DS, Heninger GR, Brier A. Noradrenergic function in panic anxiety. Effects ofyohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen
Psychiatry 1984; 41:751–763.
94. Molliver ME. Serotonergic neuronal systems: what their anatomical organization tells us
about function. J Clin Psychopharmacol 1987; 7(suppl):35–235.
95. File SE, Deakin JFW. Chemical lesions of both dorsal and median raphe nuclei and changes
in social and aggressive behaviour in rats. Pharmacol Biochem Behav 1980; 12:855–859.
96. File SE, Hyde JRG. The effects of p-chlorophenylalanine and ethanolamine-O-sulphate inan animal test of anxiety. J Pharm Pharmacol 1977; 29:735–738.
97. Wise CD, Berger BD, Stein L. Evidence of α-noradrenergic reward receptors and serotonergic punishment receptors in the rat brain. Biol Psychol 1973; 6:3–21.
98. Engel JA, Hjorth S, Svensson K. Anticonﬂict effect of the putative serotonin receptor agonist
8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Eur J Pharmacol 1984; 105:365–368.

678

Norman et al.

99. File SE, Hyde JRG, Macleod NK. 5,7-Dihydroxytryptamine lesions of dorsal and medianraphe nuclei and performance in the social interaction test of anxiety and in a home-cageaggression test. J Affect Disord 1979; 1:115–122.
100. Andrade TGCS, Graeff FG. Effect of electrolytic and neurotoxic lesions of the median raphe
nucleus on anxiety and stress. Pharmacol Biochem Behav 2001; 70:1–14.
101. Grove G, Coplan JD, Hollander E. The neuroanatomy of 5-HT dysregulation and panic disorder. J Neuropsych Clin Neurosci 1997; 9:198–207.
102. Sandford JJ, Argyropoulos SV, Nutt DJ. The psychobiology of anxiolytic drugs, Part 1: basic
neurobiology. Pharm Ther 2000; 88:97–212.
103. Cook L, Sepinwall J. Behavioural analysis of the effects and mechanism of action of benzodiazepines. In: Costa E, Greengard P, eds. Mechanism of Action of Benzodiazepine. New
York: Raven Press, 1975:1–28.
104. Sepinwall J, Cook L. Relationship of γ-aminobutyric acid (GABA) to antianxiety effects ofbenzodiazepines. Brain Res Bull 1980; 5(suppl 2):839–848.
105. Haefely WE. The GABA-A benzodiazepine receptor: biology and pharmacology. In: Burrows GD, Roth M, Noyes R, eds. Handbook of Anxiety, vol 3: The Neurobiology of Anxiety.
Amsterdam: Elsevier, 1990:165–188.
106. Rudolph U, Crestani F, Mohler H. GABA-A receptor subtypes: dissecting their pharmacological actions. Trends Pharmacol Sci 2001; 22:188–194.
107. Weinberger DR. Anxiety at the frontier of molecular medicine. N Engl J Med 2001; 344:
1247–1249.
108. Rudolph U, Crestani F, Benke D, Brunig I, Benson J, Fritschy J-M, Martin JR, Bluethmann
H, Mohler H. Benzodiazepine actions mediated by speciﬁc γ-aminobutyric acid A receptor
subtypes. Nature 1999; 401:796–800.
109. Crestani F, Martin JR, Mohler H, Rudolph U. Mechanism of action of the hypnotic zolpidem
in vivo. Br J Pharmacol 2000; 131:1251–1254.
110. Low K, Crestani F, Keist R, Benke D, Brunig I, Benson JA, Fritschy J-M, Rulicke T,
Bluethmann H, Mohler H, Rudolph U. Molecular and neuronal substrate for the selective
attenuation of anxiety. Science 2000; 290:131–134.
111. Dorow R, Horowski R, Paschelke G, Amin M, Braestrup C. Severe anxiety induced by
FG7142, a β-carboline for benzodiazepine receptors. Lancet 1983; 2:98–99.
112. Glover V, Raveley MA, Sandler M. A monoamine oxidase inhibitor in human urine. Biochem
Pharmacol 1980; 28:467–470.
113. Clow A, Glover V, Sandler M, Tiller J. Increased urinary tribulin output in generalised anxiety disorder. Psychopharmacology 1988; 95:378–380.
114. Barbaccia ML, Costa E, Ferrero P, Guidotti A, Roy A, Sunderland T, Pickar D, Paul SM,
Goodwin FK. Diazepam binding inhibitor. Arch Gen Psychiatry 1986; 43:1143–1147.
115. Nutt DJ, Glue PJ, Lawson C, Wilson S. Evidence for altered benzodiazepine receptor sensitivity in panic disorder: effects of the benzodiazepine receptor antagonist ﬂumazenil. ArchGen Psychiatry 1990; 47:917–925.
116. Maitra R, Reynolds JN. Modulation of GABA-A receptor function by neuroactive steroids:
Evidence for heterogeneity of steroid sensitivity of recombinant GABA-A receptor isoforms.
Can J Physiol Pharmacol 1998; 76:909–920.
117. Barbaccia ML, Concas A, Serra M, Biggio G. Stress and neurosteroids in adult and aged
rats. Exp Gerontol 1998; 33:697–712.
118. Rodgers RJ, Johnson NJ. Behaviourally selective effects of neurosteroids on plus-maze anxiety in mice. Pharmacol Biochem Behav 1998; 59:221–232.
119. Wildmann J, Mohler H, Vetter W, Ranalder U, Schmidt K, Maurer R. Diazepam and Ndesmethyldiazepam are found in rat brain and adrenal and may be of plant origin. J Neural
Transm 1987; 70:383–398.
120. Marks IM. Genetics of fear and anxiety. Br J Psychiatry 1986; 149:406–418.
121. Crowe RR. Molecular genetics of anxiety disorders. In: Charney DS, Nestler EJ, Bunney

Etiology of Anxiety

122.
123.

124.

125.
126.

679

BS, eds. Neurobiology of Mental Illness. New York: Oxford University Press, 1999:451–
461.
Hettema JM, Neale MC, Kendler KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry 2001; 158:1568–1578.
Inata N, Cowley DS, Radel M, Roy-Byrne PP, Goldman D. Relationship between a GABAA α6 Pro 385 Ser substitution and benzodiazepine sensitivity. Am J Psychiatry 1999; 156:
1447–1449.
Crowe RR, Wang Z, Noyes R, Albrecht BE, Darlison MG, Bailey MES, Johnson KM, Zoega
T. A candidate gene study of 8 GABA-A receptor subunits in panic disorder. Am J Psychiatry
1997; 154:1096–1100.
Andrews G, Stewart G, Morris-Yates A, Holt P, Henderson AS. Evidence for a general
neurotic syndrome. Br J Psychiatry 1990; 157:6–12.
Klein DF. Anxiety reconceptualized. Comp Psychiatry 1980; 6:411–427.

29
Animal Models of Anxiety andAnxiolytic Drug Action
DALLAS TREIT, ALDEMAR DEGROOT, and AKEEL SHAH
University of Alberta
Edmonton, Alberta, CanadaI.

INTRODUCTION

A. Animal Models and Anxiolytic Drugs
Animal models of anxiety attempt to represent some aspect of the etiology, symptomatology, or treatment of human anxiety disorders in order to facilitate their scientiﬁc study[146,154,220]. Within this context, animal models of anxiolytic drug action can be viewed
as treatment models relevant to the pharmacological control of human anxiety. A major
purpose of these models is to identify novel anxiolytic compounds and to study the mechanisms whereby these compounds produce their anxiolytic effects (for reviews, see Refs.
10,37,45,64–66,79,132,137,192,202,209,218–221).
B. Correlation, Isomorphism, and Homology
Validation of behavioral animal models of psychotherapeutic drug action has typicallyproceeded along three lines: correlation, isomorphism, and homology [221]. A correlational model (or “screening test”) is selectively sensitive to target therapeutic agents (e.g.,diazepam), so that target compounds can be distinguished from nontarget compounds. An
isomorphic model implies that the animal’s “anxiety” response is in some way similar toa human “anxiety” response (e.g., avoidance), and a homologous model implies that thecause of an “anxiety” response in the animal is sufﬁcient to cause an anxiety response in
humans (e.g., the threat of an aversive stimulus). Isomorphism and homology are importantcriteria because some functional similarity between the animal model and human anxiety
is a logical requirement if the model is used to study the mechanisms of a drug’s anxiolytic
681

682

Treit et al.

action [221]. Whether these “anxiety” reactions in animals express a subjective state thatis similar to that experienced by anxious humans, or whether these reactions lie on thesame continuum as “abnormal” human anxiety conditions, are difﬁcult but important questions (for an insightful discussion of this issue, see Ref. 133). For animal models of anxiety,however, one simplifying assumption is that aversive stimulation, real or anticipated, canproduce anxiety-like behaviors in both humans and in infrahumans, and these should bediminished by antianxiety agents [220].
Historically, the correlational (or pharmacological) validation of animal models ofanxiety has been a preeminent concern, and even today is initiated on the basis of theirrelative sensitivity to a few, standard, clinically proven compounds, such as the 1,4-benzodiazepines (e.g., diazepam). However, the triazolobenzodiazepines (e.g., alprazolam) areclosely related to standard 1,4-benzodiazepines and produce anxiolytic as well as antidepressant effects in humans [57,117,190], as do 5HT1A-type agents such as buspirone[12,86,101,105,113,187,188] and classical antidepressant drugs such as imipramine[2,127,189,233]. The relative sensitivity of animal models to various classes of clinically
proven anxiolytic drugs is an important issue and will be the focus of the present review.
II. ANIMAL MODELS OF ANXIETY
For convenience, the models reviewed in the following sections are grouped into two
categories. The ﬁrst category involves animals’ reactions to nonpainful stressors (e.g.,
exposure to a novel test chamber). The second category involves animals’ reactions to
painful stressors (e.g., exposure to electric foot-shock). The models will be evaluated interms of their relative sensitivity to “classic” anxiolytic agents (e.g., benzodiazepines),
5HT1A compounds (e.g., buspirone), and antidepressants (e.g., imipramine).
Comparable sensitivity to the effects of benzodiazepines, 5HT1A anxiolytics, andantidepressants could be taken as support for the validity of a test as a general model ofanxiolytic drug action, because all three of these drug classes are effective in the treatmentof human anxiety disorders (see above). On the other hand, a model sensitive to only one
drug class (e.g., benzodiazepines) is “class-speciﬁc,” but may nevertheless be important(e.g., in the preclinical testing of benzodiazepine-type anxiolytics, and for studying themechanisms whereby these drugs produce their effects) [79,149]. Thus, while generalmodels of anxiolytic drug action are of particular interest, class-speciﬁc models should
not be discounted (see Ref. 97 for a review of the pharmacology of benzodiazepine-type
anxiolytics, and their actions at the GABAA-receptor subtype; 178 for a review of thepharmacology of buspirone-type anxiolytics and their interactions at the 5HT1A-receptor
subtype; and Ref. 78 for a review of the pharmacology of antidepressant drugs and theiractions on monoamine neurotransmission).
A.

Models Based on Reactions to Nonpainful Stressors

1. Light–Dark Exploration
In the light–dark exploration test, rodents (typically mice) normally avoid the brightly lit
side of a two-compartment chamber, preferring instead to explore the dimly lit side. Anxiety reduction is indicated by increased transitions between the two compartments, and/or increased exploration of the brighter compartment, whereas nonspeciﬁc effects are indicated by changes in general locomotor behavior [11,36–39]. Early studies showed that aAnimal Models and Anxiolytic Drug Action

683

variety of benzodiazepine anxiolytics, including diazepam, clonazepam, ﬂurazepam, andchlordiazepoxide, produced dose-dependent increases in the number of light/dark transitions in mice, whereas an antipsychotic (chlorpromazine) did not [36,38]. The relative
potency of benzodiazepine anxiolytics in increasing “exploratory” transitions was consistent with their relative potency in the clinical treatment of human anxiety [36]. Furthermore, a nonspeciﬁc stimulatory effect of anxiolytics on general activity did not explainthese increases in light–dark transitions [38].
Later studies showed that standard anxiolytics also increase exploratory activity inthe lit section of light–dark test chambers, or conversely, decrease exploration in the darkchamber, while a number of nonanxiolytic agents do not produce this pattern of results[29,31–33,126]. This suggests that the light intensity of the brightly lit compartment isaversive, suppressing exploration, and that this suppression is selectively antagonized bystandard anxiolytics [88,210].
Like traditional benzodiazepines, the mixed anxiolytic-antidepressant drug alprazolam also increased side transitions and time spent on the bright side of a light–dark apparatus [102,103,210]. Standard antidepressant drugs, such as the tricyclic (TCA) imipramine,
the monoamine oxidase inhibitor (MAOI) moclobemide, and the selective serotonin
reuptake inhibitors (SSRIs) ﬂuoxetine, paroxetine, and citralopram, have also yielded
anxiolytic-like effects in some cases [13,47,48,104,198]. However, in other cases, null oreven anxiogenic effects have been found [89,130,200,210,242]. In contrast, 5HT1A compounds such as buspirone, ipsapirone, and indorenate have had fairly uniform, anxiolytic
effects in the light–dark exploration test [20,31,33,58,126,170,199]. Only in a few cases,
however, has the magnitude of the effects of 5HT1A agents been comparable to that ofbenzodiazepines.
In summary, the light–dark exploration test is reliably sensitive to the anxiolytic
effects of benzodiazepines across a wide range of doses [37]. Although the effective dose
ranges tend to be narrower for 5HT1A agents, the test is sensitive to these compounds
as well, particularly buspirone and ipsapirone [198,210,242,243]. Finally, the effects ofantidepressant drugs on light–dark exploration are inconsistent, but clear anxiolytic effects
have been registered in some studies.
2. Social Interaction
In this test, pairs of rats are placed in an open arena, and the time they spend in active
social interaction (e.g., snifﬁng, grooming) is measured. Social interaction is suppressed
when animals are tested under bright lights or in an unfamiliar test environment, relative
to low light/familiar conditions, and this suppression is the index of anxiety [68]. As acontrol for nonspeciﬁc changes in locomotor activity, line crossings are also measured(for reviews, see Refs. 64–66). Several benzodiazepine anxiolytics, including chlordiazepoxide, diazepam, and ﬂurazepam, all antagonized the suppression of social interaction
under unfamiliar, high light conditions, without producing concomitant changes in motor
activity. Other compounds, such as neuroleptics and CNS stimulants, did not produce
selective anxiolytic effects on social interaction [67,68,70–73].
Using a modiﬁed procedure in which novelty of the partner is the primary anxiogenic
stimulus, Gardner and Guy [83] and Guy and Gardner [95] found increases in social interaction after administration of a number of different benzodiazepines (e.g., diazepam, oxazepam, loprazolam, nitrazepam) at doses that did not signiﬁcantly affect ambulation. Social
interaction in this modiﬁed test was not selectively affected by other centrally active agents

684

Treit et al.

(e.g., phentolamine, metergoline, propranolol, amphetamine). These results also suggestthat social interaction under conditions of novelty is very sensitive to the effects ofbenzodiazepine-type anxiolytics.
Antidepressant drugs, however, have inconsistent effects on social interaction. Fileand colleagues [74,116] reported that the mixed anxiolytic-antidepressant drug alprazolam
did not produce anxiolytic effects on social interaction, whereas Gardner and Guy [83]reported that alprazolam had anxiolytic effects in their version of the test. Similarly, Pellow
and File [176] found that the TCA imipramine was not anxiolytic after either acute or
chronic administration, whereas Popik and Vetulani [185] found that chronic imipramine
was anxiolytic. The MAOI antidepressant phenelzine produced an anxiogenic proﬁle inthe social interaction test even after chronic administration [116], whereas mianserin, atetracyclic antidepressant, produced a signiﬁcant anxiolytic proﬁle [124]. SSRIs such asparoxetine and sertraline can have signiﬁcant anxiolytic effects on social interaction after
chronic administration [54,123,135].
Although there are exceptions [64], 5HT1A agents such as buspirone generally havereliable, benzodiazepine-like proﬁles in the social interaction test [30,42,53,95,98,179].
In summary, the social interaction test, like the light–dark exploration test, is reasonably sensitive to both benzodiazepine and 5HT1A-type compounds; the effects of antidepressants are inconsistent. These tests may be analogous to human anxiety to the extent
that avoidance of novel social or environmental stimuli is common in both rodents andhumans.
3. Elevated Plus MazeIn the elevated plus maze, rodents normally avoid the two open arms of the maze, andrestrict most of their activity to the two closed arms. Open-arm avoidance appears to be
driven by an aversion to open spaces, leading to thigmotaxic behavior [229]. An antianxiety effect is indicated by an increase in the proportion of activity in the open arms of themaze (i.e., an increase in the percentage of time spent in the open arms and in the percentage of entries into the open arms). Changes in total entries and/or changes in the numberof closed-arm entries indicate nonspeciﬁc drug effects on locomotor activity. (For reviewsof procedures and methods, see Refs. 109, 173). Benzodiazepine anxiolytics (e.g., chlordiazepoxide, diazepam) increase the proportion of activity in the open arms, whereas
nonanxiolytic agents (e.g., amphetamine, caffeine) generally do not [3,100,114,115,138,
174,176].
Mixed anxiolytic-antidepressant compounds such as alprazolam also have reliableanxiolytic effects in the elevated plus maze [74,90,116,118,186]. However, the effects ofstandard antidepressant drugs in the plus maze have been inconsistent. On the one hand,both acute and chronic administration of TCAs (imipramine, amitriptyline) failed to produce anxiolytic proﬁles in the plus maze [23,69,138,142,174]. SSRIs such as ﬂuoxetine
have been reported to be anxiogenic [99,128,184,211,212], anxiolytic [16,89,92,131], or
ineffective [99,136,194]. These inconsistent effects have been found after both acute[92,211] and chronic [131,212] drug administration.
On the other hand, the tetracyclic antidepressant mianserin produced signiﬁcant anxiolytic effects after chronic administration [191], and MAOIs such as phenelzine andbeﬂoxatone produced anxiolytic effects whether given acutely [17,171] or chronically[116].
The effect of 5HT1A-type compounds (e.g., buspirone, ipsapirone, gepirone) in theelevated plus maze are also mixed. There are reports of clear anxiolytic effects [18,40,53,

Animal Models and Anxiolytic Drug Action

685

87,91,98,106,151,182,214], and reports of no clear anxiolytic effects [24,40,41,175,177,
211], even after chronic drug administrations [156,157,193].
Although chronic regimens with buspirone or ipsapirone did not produce anxiolytic
effects in the plus maze [156,239], there is some evidence that these negative ﬁndings
may have been related to dose. Soderpalm et al. [215] found that 5 weeks of buspirone(10 mg/kg b.i.d.) signiﬁcantly increased open-arm activity whereas the same regimen atlower doses (2.5 or 5.0 mg/kg) was without effect. A number of other studies support the
hypothesis that high doses of 5HT1A compounds may be necessary for their anxiolytic
effects to emerge after chronic treatment in the elevated plus maze [22,143,158,211].
In summary, the elevated plus maze is clearly sensitive to benzodiazepine-type anxiolytics. However, the effects of antidepressant drugs (both chronic and acute) are mixed, as
are the effects of 5HT1A compounds. There is some evidence that high doses of chronicallyadministered 5HT1A compounds may be necessary to detect their anxiolytic effects in theelevated plus-maze.
4. Separation-Induced Ultrasonic Distress Vocalization
Rat pups separated from their mother and littermates emit high-frequency (30–50 kHz)
distress calls which, in turn, elicit retrieval behavior from the mother [165]. Distress calls
are infrequent just after birth, increase up to maximal levels at about 10 days of age, andthen decrease to minimal levels at about 17 days of age. The eliciting stimulus (separation),under certain conditions (e.g., dependency), would seem capable of producing fear oranxiety in humans. An anxiolytic drug effect in this response system is indicated by asigniﬁcant reduction in high-frequency vocalization in the absence of behavioral sedation[56,80,81,112].
Separation-induced ultrasonic vocalizations are suppressed by benzodiazepine anxiolytics (e.g., diazepam, chlordiazepoxide) at doses that do not disrupt behavior in general,
while other agents (e.g., amphetamine, haloperidol, naloxone, clonidine) do not selectively
suppress vocalization [8,75,80,81,167]. A possible false positive was metergoline, which
inhibited ultrasound at doses that were not behaviorally impairing, as did morphine [19].
Benton and Nastiti [8] found that ultrasonic calling in mouse pups was also inhibitedby the 5HT1A-type anxiolytic ipsapirone, and they provided data that this inhibition was
not related to drug-induced decreases in body temperature. Kehne et al. [122] and Nastiti
et al. [160] found that buspirone, ipsapirone, and gepirone suppressed ultrasonic vocalization in preweanling rats at doses that did not disrupt motor coordination on an inclined
screen test. The selective 5HT1A agonists ﬂesinoxan and 8-OH-DPAT also inhibited ultrasonic vocalization, although some degree of hypothermia and sedation was associatedwith these effects [168], particularly at higher doses [75].
Alprazolam has potent suppressive effects on ultrasonic calling in separated pups[153]. Separation-induced vocalization in pups is also reliably reduced by a number ofantidepressant compounds such as clomipramine, ﬂuvoxamine, ﬂuoxetine, and zimelidine[168,169], all of which block the reuptake of 5HT to varying degrees. In contrast, antidepressants that are more selective for blockade of NE reuptake (e.g., desipramine andmaprotiline) actually increase distress vocalizations [237]. Although it seems possible thatthe inhibition of ultrasonic vocalizations by antidepressants depends speciﬁcally on theirability to inhibit 5HT reuptake, Olivier et al. [168] reported that the 5HT reuptake stimulant, tianeptine, also blocked ultrasonic vocalizations. In any case, the results thus far
suggest that separation-induced vocalizations in young rodents are sensitive to the anxiolytic effects of both benzodiazepine and serotonergic drugs.

686

B.

Treit et al.

Models Based on Reactions to Painful Stressors

1. Shock-Probe Burying
Rats shocked once from an electriﬁed probe that is attached to the wall of a test chambercharacteristically spray bedding material toward or over the probe, with rapid, alternating
movements of the forepaws (i.e., “burying behavior”) [181], while avoiding further contact
with the shock probe. A reduction in the duration of probe burying, in the absence of adecrease in general activity, is used as the primary index of anxiety reduction [230]. An
increase in the number of probe contacts is sometimes used as a second index of anxiety
reduction [224]. (For reviews of methods and procedures, see Refs. 221, 228.)
Low doses of standard anxiolytic agents (e.g., chlordiazepoxide, diazepam) reduce
the amount that rats bury the shock probe without suppressing general activity[7,9,195,221–225,227,230,231]. Chlordiazepoxide also antagonizes the shock-induced elevations in plasma corticosterone and adrenaline that occur during the burying test [49].
The effects of anxiolytic compounds on probe burying can be distinguished from thoseof several nonanxiolytic agents [7,195,225,230–232], although the drug-class speciﬁcityof the test is sensitive to procedural variations [15,35,163,224,230]. The suppression of
burying behavior by benzodiazepine anxiolytics does not appear to be secondary to analgesia [223] or associative deﬁcits [9].
An early study [227] found that buspirone, like chlordiazepoxide, decreased theamount of probe burying and concurrently increased the number of contact-induced probe
shocks rats received. These bidirectional, anxiolytic drug effects increased as a functionof drug dose and were independent of changes in general activity [227]. Higher doses of
buspirone (64 mg/kg), which suppress general activity, do not produce selective effects
on either probe avoidance [150] or probe burying [35].
Later studies [129] reported that ipsapirone also reduced burying behavior in theabsence of effects on general activity. Similar results have been found in an extensive
series of experiments by Lopez-Rubalcava et al. [141] and by Fernandez-Guasti and colleagues [59,61–63,139,140]. These researchers found dose-dependent decreases in theburying behavior of both male and female rats after the administration of buspirone, ipsapirone, indorenate, and the selective 5HT1A-receptor agonist 8-OH-DPAT. Flesinoxan, another selective 5HT1A-receptor agonist, was anxiolytic in the shock-probe burying test after
either acute [94] or chronic [93] administration.
Little work has been conducted examining the effects of antidepressants in theshock-probe burying test, and the results thus far are equivocal. One study [7] showedthat chronic treatments with imipramine, desipramine, and pargyline did not produce signiﬁcant effects on burying behavior, whereas two other studies [60,144] showed thatchronic desipramine reliably suppressed burying behavior. The mixed SSRI/5HT1Aagonist EMD 68843 produced a selective, dose-dependent reduction in burying behavior
after acute administration [226]. Whether the latter result was due to serotonin reuptake
inhibition, 5HT1A-receptor activation, or some combination of both is not known, but futurestudies should clarify this interesting ﬁnding.
Broekkamp et al. [15] and Njung’e and Handley [163,164] described a variant of
the burying test in which mice are individually placed in a test chamber with glass marbles
evenly distributed across the surface of the bedding material. The number of marbles“buried” is used as the index of anxiety. Various anxiolytics reduced marble “burying,”
including diazepam, chlordiazepoxide, ﬂunitrazepam, clonazepam, and meprobamate.
However, false positives were found for scopolamine and atropine. Although 5HT1A-type
compounds (e.g., buspirone) suppressed marble-burying behavior, the effect only occurredAnimal Models and Anxiolytic Drug Action687

at doses that also reduced general activity [164] and disappeared after chronic treatment[111].
The effects of cyclic antidepressants on mouse marble burying have been somewhat
unclear. Thus, for example, imipramine and mianserin suppressed marble burying, but at
doses that also suppressed general activity [15]. Ichimaru et al. [111] found that marble
burying was selectively suppressed by clomipramine but not by desipramine. The effectsof SSRIs in this paradigm have been more uniform. Njung’e and Handley [163,164] andIchimaru et al. [111] found that ﬂuvoxamine, zimeldine, and citalopram dose-dependently
inhibited marble-burying behavior without suppressing general activity.
Gyertyan [96] suggested that marble burying in mice is not burying behavior perse, but rather digging/burrowing behavior, a species-typical response in mice that occurs
in the absence of any observable aversive or threatening stimulus. In this sense, digging
behavior might be more analogous to compulsive behavior in humans and thus mouse
digging may represent a model of obsessive-compulsive disorder [96]. Although some ofthe pharmacological data reviewed above might be consistent with this view, insofar as
certain antiobsessional compounds (e.g., clomipramine) were effective in suppressing
marble burying, further work is needed before this hypothesis can be supported.
2. Fear-Potentiated Startle
The magnitude of rats’ startle reﬂex to an acoustic stimulus can be potentiated by presenting the acoustic startle stimulus together with a cue (e.g., light) that has previously been
paired with shock (for a review, see Ref. 44). An anxiolytic drug effect in this paradigm
is most clearly indicated by a speciﬁc reduction of potentiated startle (i.e., a reduction ofstartle on light-noise trials versus a reduction of startle on noise-alone trials) [44]. A number of benzodiazepine anxiolytics, including diazepam, ﬂurazepam, and midazolam, produced selective, dose-dependent reductions of fear-potentiated startle [43,107], whereas
a number of other agents, including cinanserin and p-chloroamphetamine, did not blockpotentiated startle [21,46]. However, false positives have been reported for morphine [44]and haloperidol [108].
Although the mixed anxiolytic-antidepressant drug alprazolam reduced fear-potentiated startle [108], studies using standard antidepressant compounds such as imipramine,
amitriptyline, and ﬂuvoxamine have failed to demonstrate reliable effects on fear-potentiated startle [21,108,119].
In contrast, fear-potentiated startle is reliably suppressed by 5HT1A-type anxiolytics.
Buspirone, gepirone, and ipsapirone each blocked potentiated startle across a wide rangeof doses [46,121,145,161]. In addition, the magnitude of these anxiolytic effects weresimilar to those of benzodiazepine anxiolytics. The selective 5HT1A agonists ﬂesinoxan and
8-OH-DPAT also produced dose-dependent anxiolytic effects on fear-potentiated startle[119,120].
Thus, the fear-potentiated startle test seems to be sensitive to the anxiolytic effects
of both benzodiazepine and 5HT1A compounds, but insensitive to traditional antidepressantagents. Given the positive effect found with the mixed anxiolytic-antidepressant drug alprazolam, however, more extensive work using chronic administration of traditional antidepressants may ultimately reveal anxiolytic effects of some of these compounds as well.
3. The “Conﬂict” Tests
Although there are many variants of conﬂict tests, they generally fall into one of two
categories. In the Geller-type conﬂict tests, well-trained rats are tested on alternatingschedules of unpunished (reward only) and punished (reward ⫹ shock) responding [84].

688

Treit et al.

In Vogel-type conﬂict tests, untrained, water-deprived rats are allowed to drink from awater spout where every nth lick is accompanied by shock [234]. In both types of tests,
responding is suppressed by shock and “anticonﬂict” (i.e., anxiolytic) effects are indicatedby increases in punished responding, whereas nonspeciﬁc effects (e.g., hyperphagia, dipsogenesis) are indicated by increases in unpunished responding. Additional tests are sometimes conducted to assess treatment effects on pain perception (e.g., ﬂinch/jump thresholds
to shock). (For a review, see Ref. 183.)
A variety of benzodiazepine-type anxiolytics produce reliable anticonﬂict effects,
whereas other compounds such as neuroleptics, analgesics, and stimulants do not. This
anticonﬂict effect of standard anxiolytic drugs has been demonstrated in a variety of species, including humans [134], and the relative potency of various anxiolytics in suppressing
conﬂict behavior in animals agrees well with their relative potency in treating humananxiety disorders [28]. Thus, the conﬂict test appears to satisfy many of the criteria of acorrelational model. In addition, insofar as conﬂict between opposing drives may be associated with human anxiety, conﬂict models may also have some degree of isomorphismand homology.
The mixed anxiolytic-antidepressant drug alprazolam produced reliable, dosedependent anticonﬂict effects in rats across a wide range of doses [55,85,102,125,196,
213]. Furthermore, the anticonﬂict effect of alprazolam was apparent after both acute andchronic administration.
A number of standard antidepressant drugs such as the TCAs imipramine, desipramine, and amitriptyline all produced signiﬁcant anticonﬂict effects after chronic or subchronic administration, but not after acute administration [25,76,77]. Chronic bupropion,mianserin, and trazodone also produced signiﬁcant anticonﬂict effects in this test [26], as
did the MAOIs phenelzine and pargyline [27,77]. These ﬁndings suggest that conﬂict tests
may be quite sensitive to the anxiolytic effects of antidepressant drugs under chronic drug
regimens.
In contrast to their reliable sensitivity to the anxiolytic effects of benzodiazepine
and antidepressant drugs, the conﬂict tests have shown erratic sensitivity to the anxiolytic
effects of 5HT1A drugs such as buspirone [110]. Furthermore, when anxiolytic effects of
5HT1A drugs are detected, their magnitude is often smaller than that of standard anxiolytics
such as diazepam and typically occur over a much narrower dose range [50,51,148,152,
180,203,204,235,241,244]. Howard and Pollard [110] studied the effects of buspirone in
the conﬂict test under a wide variety of experimental conditions and failed to ﬁnd a robust
anxiolytic effect under any condition. Other researchers have reported no signiﬁcant effects of buspirone in the conﬂict tests or even dose-related decreases in punished responses[14,34,82,125,147,201,217,238].
In contrast to the inconsistent anticonﬂict effects of buspirone-type anxiolytics inrats in the conﬂict tests, these drugs have very reliable anticonﬂict effects in pigeons[4,159,205]. The reasons for these species differences are unknown.
Thus, conﬂict tests appear to possess broad utility for detecting the anxiolytic effectsof benzodiazepine and antidepressant drugs, although the exact conditions under which
reliable anxiolytic effects of 5HT1A compounds can be detected have not been determined.
4. Shock-Induced Ultrasonic Vocalization
Another ultrasonic vocalization model has been developed in which adult rats are given
multiple, inescapable foot shocks [52]. Testing occurs after this “training” period. During
the test period, foot shocks are again administered and the duration of ultrasonic vocaliza-

Animal Models and Anxiolytic Drug Action

689

tions is measured during intershock intervals. The duration of these vocalizations is usedas the index of anxiety. Shock-induced ultrasonic vocalizations are dose-dependently suppressed by benzodiazepine-type anxiolytics (diazepam and chlordiazepoxide), but are generally unaffected by nonanxiolytic agents [52,162]. The test also appears to be quite sensitive to 5HT1A-type drugs such as buspirone, ipsapirone, gepirone, and 8-OH-DPAT, allof which dose-dependently suppress shock-induced ultrasonic vocalizations [5,6,52,155,
197,199,216,240].
A variety of antidepressant drugs, including the TCAs imipramine, amitriptyline,
doxepin, clomipramine, and the MAOI tranylcypromine, also reduced shock-induced ultrasonic vocalizations. Antidepressants that are more selective inhibitors of NE or DA
reuptake, such as maprotiline and bupropion, were not effective [52]. SSRIs such asparoxetine, citalopram, sertraline, and ﬂuvoxamine suppressed shock-induced vocalizations to varying degrees [52,200,206], although the effects of ﬂuoxetine have been inconsistent [5,200]. Nevertheless, the overall pattern of these results seems to point toward
inhibition of 5HT reuptake as one mechanism for the inhibition of shock-induced ultrasonic vocalizations in adult rats. In addition, the model appears to have broad utility forstudying the mechanisms of action of benzodiazepine and 5HT1A-type drugs.

III. SUMMARY AND CONCLUSIONSIn summary, the models reviewed in this chapter show at least some sensitivity to a variety
of agents known to produce anxiolysis in humans (i.e., the benzodiazepines, antidepressants, and 5HT1A compounds). All of the models show good sensitivity to benzodiazepine
anxiolytics. Light–dark exploration, social interaction, elevated plus maze, shock-probemarble burying, and the conﬂict tests have also shown some sensitivity to antidepressantsand 5HT1A compounds, but to varying degrees. Ultrasonic vocalization appears to be themost broadly sensitive measure. Fear-potentiated startle, although sensitive to both benzodiazepine and 5HT1A anxiolytics, has thus far failed to detect the anxiolytic effects oftraditional antidepressants.
While the majority of these models showed at least some sensitivity to antidepressantand 5HT1A compounds, the anxiolytic effects of these drugs were often more variable thanthe effects of benzodiazepine anxiolytics. In addition, there were a number of instancesin which antidepressant and 5HT1A agents produced effects opposite to those of standard
anxiolytics, suggestive of an anxiogenic action. There are several possible explanations
for these inconsistencies which have more general implications for animal models of anxiety and anxiolytic drug action.
A drug may have very reliable effects in an animal model of anxiety, but unlessthat drug also has reliable antianxiety effects in humans, it cannot be used to validate theanimal model. Conversely, a drug that has inconsistent or unreliable anxiolytic effects inhumans cannot be used to invalidate an animal model of anxiety. In this regard, there islittle clinical evidence that 5HT1A agents, other than buspirone, produce reliable antianxiety
effects in humans, and even the effects of buspirone appear to be more variable thanthe effects of benzodiazepine anxiolytics [172,207,208,236]. A number of clinical trials[166,207] suggest that the efﬁcacy of buspirone across different human anxiety disorders[1] is not as robust as the benzodiazepines (for a recent summary of comparative clinicalﬁndings see Ref. 2, Table 1, p. 224). These clinical data are certainly not deﬁnitive but,
if anxious humans respond more variably to buspirone than to benzodiazepine anxiolytics,

690

Treit et al.

one might expect the effects of 5HT1A agents in animal models of anxiolytic drug action
to be more variable than the effects of benzodiazepines.
The clinical efﬁcacy of antidepressant drugs in the treatment of anxiety disorders
is far more convincing, but there is still some variation in efﬁcacy (for a review, see Ref.
233). There is also some disagreement about whether speciﬁc antidepressants are requiredfor particular anxiety disorders (e.g., agoraphobia, panic), or are superior to benzodiazepine anxiolytics for these disorders. Furthermore, anxiety and depression in humans often
overlap so that interpretation of a therapeutic drug effect as being either anxiolytic or
antidepressant can sometimes be difﬁcult. Perhaps the most important clinical ﬁnding inthis literature, however, is that unlike classical benzodiazepines, the anxiolytic effects oftraditional antidepressants in humans are normally delayed (2 to 4 weeks), and the initial(acute) response may sometimes be an exacerbation of anxiety [2]. Thus, acute antidepressant treatment in an animal model of anxiety may be of questionable relevance to its
pharmacological validation.
Chronicity may be equally relevant to the effects of 5HT1A compounds in thesemodels. Whereas chronic administration of 5HT1A or antidepressant drugs often resulted
in reliable, anxiolytic effects in a variety of animal models [26,54,60,76,89,123,131,
135,185,191,204, 215,241], acute administration resulted in less reliable anxiolytic effects
or even anxiogenesis [89,99,156,211,213].
Another possibility is that different animal models represent qualitatively different
types of anxiety or fear, only some of which are reliably inhibited by 5HT1A agents orantidepressants. Thus one could speculate that the social interaction test primarily reﬂects
a type of social phobia, which is reliably suppressed by 5HT1A agents and certain antidepressants, whereas the elevated plus-maze test reﬂects a type of acrophobia, which is
not as reliably suppressed by 5HT1A agents or antidepressants. This would imply thatanimal fears can be pharmacologically dissected, which in turn would support the pharmacological dissection of human anxiety. Although such speculation seems to be consistent
with some of the animal data reviewed in this chapter, at this time there is no convincing
clinical evidence that speciﬁc anxiety disorders are differentially affected by benzodiazepine, 5HT1A, or antidepressant anxiolytics [2,233].
Thus, a number of factors, including clinical effectiveness, chronicity, and model
type, may alter the correspondence between the effects of benzodiazepines, 5HT1A agents,
and antidepressants in animal models of anxiety. On the whole, however, the data summarized above suggest that there is enough correspondence between drug effects across thesetests that future paradigmatic studies may ultimately establish their validity as generalmodels of antianxiety drug action. While this ideal may not be attained by all models, it
should be remembered that class-speciﬁc models can also serve as a valuable tool forstudying the mechanisms by which either benzodiazepine, 5HT1A, or antidepressant drugs
produce their anxiolytic effects.
ACKNOWLEDGMENT
This work was supported by NSERC.
REFERENCES
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,(DSM-IVTM), 4th ed. Washington, DC: American Psychiatric Association, 1994.

Animal Models and Anxiolytic Drug Action691

2. Argyropoulos SV, Sandford JJ, Nutt D. The psychobiology of anxiolytic drugs Part 2: pharmacological treatments of anxiety. Pharmacol Therapeut 2000; 88: 213–227.
3. Baldwin HA, Johnston AL, File SE. Antagonistic effects of caffeine and yohimbine in animal
tests of anxiety. Eur J Pharmacol 1989; 159:211–215.
4. Barrett JE, Witkin JM, Mansbach RS, Skolnick P, Weissman BA. Behavioral studies with
anxiolytic drugs. III. Antipunishment actions of buspirone in the pigeon do not involve
benodiazepine receptor mechanisms. J Pharmacol Exp Ther 1986; 238:1009–1013.
5. Bartoszyk GD, Hegenbart R, Ziegler H. EMD 68843, a serotonin reuptake inhibitor withselective presynaptic 5HT1A receptor agonistic properties. Eur J Pharmacol 1997; 322:147–
153.
6. Baudrie V, De Vry J, Broqua P, Schmidt B, Chaouloff F, Glaser T. Subchronic treatment
with anxiolytic doses of the 5-HT1A receptor agonist ipsapirone does not affect 5-HT2 receptor sensitivity in the rat. Eur J Pharmacol 1993; 231:395–406.
7. Beardslee SL, Papadakis E, Fontana DJ, Commissaris RL. Antipanic drug treatments: Failure
to exert anxiolytic-like effects on defensive burying behavior. Pharmacol Biochem Behav
1990; 35:451–455.
8. Benton D, Nastit K. The inﬂuence of psychotropic drugs on the ultrasonic calling of mouse
pups. Psychopharmacology (Berl) 1988; 95:99–102.
9. Blampied NM, Kirk RC. Defensive burying: effects of diazepam and oxprenolol measured
in extinction. Life Sci 1983; 33:695–699.
10. Blanchard DC, Griebel G, Rodgers RJ, Blanchard RJ. Benzodiazepine and serotonergic modulation of antipredator and conspeciﬁc defense. Neurosci Biobehav Rev 1998; 22:597–612.
11. Blumstein LK, Crawley JN. Further characterization of a simple, automated exploratorymodel for the anxiolytic effects of benzodiazepines. Pharmacol Biochem Behav 1983; 18:
37–40.
12. Borison RL, Albrecht JW, Diamond BI. Efﬁcacy and safety of a putative anxiolytic agent:
ipsapirone Psychopharmacol Bull 1990; 26:207–210.
13. Bourin M, Redrobe JP, Hascoet M, Baker GB, Colombel MC. A schematic representationof the psychopharmacological proﬁle of antidepressants. Prog Neuropsychopharmacol Biol
Psychiatry 1996; 20:1389–1402.
14. Brocco MJ, Koek W, Degryse AD, Colpaert FC. Comparative studies on the anti-punishment
effects of chlordiazepoxide, buspirone and ritanserin in the pigeon, Geller-Seifter and Vogel
conﬂict procedures. Behav Pharmacol 1990; 1:403–418.
15. Broekkamp CL, Rijk HW, Joly-Gelouin D, Lloyd KL. Major tranquilizers can be distinguished from minor tranquilizers on the basis of effects on marble burying and swim-induced
grooming in mice. Eur J Pharmacol 1986; 126:223–229.
16. Cadogan AK, Wright IK, Coombs I, Marsden CA, Kendall DA, Tulloch I. Repeated paxroxetine administration in the rat produces an anxiolytic proﬁle in the elevated X-maze and decreased [3H]-ketanserin binding. Neurosci Lett 1992; 42(suppl):S8.
17. Caille D, Bergis OE, Fankhauser C, Gardes A, Adam R, Charieras T, Grosset A, Rovei V,
Jarreau FX. Beﬂoxatone, a new reversible and selective monoamine oxidase-A inhibitor.
II. Pharmacological proﬁle. J Pharmacol Exp Ther 1996; 277:265–277.
18. Cao BJ, Rodgers RJ. Comparative behavioural proﬁles of buspirone and its metabolite 1(2-pyrimidinyl)-piperazine (1-PP) in the murine elevated plus-maze. Neuropharmacology
1997; 36:1089–1097.
19. Carden SE, Hofer MA. Independence of benzodiazepine and opiate action in the suppressionof isolation distress in rat pups. Behav Neurosci 1990; 104:160–166.
20. Carli M, Prontera C, Samanin R. Evidence that central 5-hydroxytryptaminergic neurons are
involved in the anxiolytic activity of buspirone. Br J Pharmacol 1989; 96:829–836.
21. Cassella JV, Davis M. Fear-enhanced acoustic startle is not attenuated by acute or chronic
imipramine treatment in rats. Psychopharmacology (Berl) 1985; 87:278–282.
22. Cole JC, Rodgers RJ. Ethological evaluation of the effects of acute and chronic buspirone

692

23.

24.

25.
26.

27.
28.

29.
30.

31.

32.
33.
34.

35.
36.
37.
38.
39.

40.
41.
42.

Treit et al.
treatment in the murine elevated plus-maze test: comparison with haloperidol. Psychopharmacology (Berl) 1994; 114:288–296.
Cole JC, Rodgers RJ. Ethological comparison of the effects of diazepam and acute/chronic
imipramine on the behaviour of mice in the elevated plus-maze. Pharmacol Biochem Behav
1995; 52:473–478.
Collinson N, Dawson GR. On the elevated plus-maze the anxiolytic-like effects of the 5HT1A agonist, 8-OH-DPAT; but not the anxiogenic-like effects of the 5-HT1A partial agonist, buspirone, are blocked by the 5-HT1A antagonist, WAY 100635. Psychopharmacology(Berl) 1997; 132:35–43.
Commissaris RL, Hill RJ. High-dose subchronic imipramine treatment: effects on anxietylike (conﬂict) behavior in rats. Anxiety 1995; 1:109–113.
Commissaris RL, Ellis DM, Hill TJ, Schefke DM, Becker CA, Fontana DJ. Chronic antidepressant and clonidine treatment effects on conﬂict behavior in the rat. Pharmacol Biochem
Behav 1990; 37:167–176.
Commissaris RL, Humrich J, Johns J, Greere DG, Fontana DJ. The effects of monoamineoxidase (MAO) inhibitors on conﬂict behavior in the rat. Behav Pharmacol 1995; 6:195–202.
Cook L, Davidson AB. Effects of behaviorally active drugs in a conﬂict-punishment procedure in rats. In: Garattini S, Mussini E, Randall LO, eds. The Benzodiazepines. New York:
Raven Press, 1973:327–345.
Costall B, Domeney AM, Gerrard PA, Kelly ME, Naylor RJ. Zacopride: anxiolytic proﬁlein rodent and primate models of anxiety. J Pharm Pharmacol 1988; 40:302–305.
Costall B, Domeney AM, Farre AJ, Kelly ME, Martinez L, Naylor RJ. Proﬁle of action of
a novel 5-hydroxytryptamine1A receptor ligand E-4424 to inhibit aversive behavior in themouse, rat and marmoset. J Pharmacol Exp Ther 1992; 262:90–98.
Costall B, Jones BJ, Kelly ME, Naylor RJ, Tomkins DM. Exploration of mice in a black
and white test box: validation as a model of anxiety. Pharmacol Biochem Behav 1989; 32:
777–785.
Costall B, Hendrie CA, Kelly ME, Naylor RJ. Actions of sulpiride and tiapride in a simple
model of anxiety in mice. Neuropharmacology 1987; 26:195–200.
Costall B, Kelly ME, Naylor RJ, Onaivi ES. Actions of buspirone in a putative model ofanxiety in the mouse. J Pharm Pharmacol 1988; 40:494–500.
Costello NL, Carlson JN, Glick SD. Acute administration of diazepam and buspirone in rats
trained on conﬂict schedules having different degrees of predictability. Pharmacol Biochem
Behav 1991; 40:787–794.
Craft RM, Howard JL, Pollard GT. Conditioned defensive burying as a model for identifying
anxiolytics. Pharmacol Biochem Behav 1988; 30:775–780.
Crawley JN. Neuropharmacologic speciﬁcity of a simple animal model for the behavioral
actions of benzodiazepines. Pharmacol Biochem Behav 1981; 15:695–699.
Crawley JN. Exploratory behavior models of anxiety in mice. Neurosci Biobehav Rev 1985;
9:37–44.
Crawley JN, Goodwin FK. Preliminary report of a simple animal behavior model for theanxiolytic effects of benzodiazepines. Pharmacol Biochem Behav 1980; 13:167–170.
Crawley JN, Skolnick P, Paul SM. Absence of intrinsic antagonist actions of benzodiazepine
antagonists on an exploratory model of anxiety in the mouse. Neuropharmacology 1984; 23:
531–537.
Critchley MAE, Handley SL. 5-HT 1A ligand effects in the X-maze anxiety test. Br J Pharmacol 1987; 92:660P.
Critchley MAE, Handley SL. Effects in the X-maze model of agents acting at 5-HT 1 and5-HT 2 receptors. Psychopharmacology (Berl) 1987; 93:502–506.
Cutler MG. An ethological study of the effects of buspirone and the 5-HT3 receptor antagonist, BRL 43694 (granisetron) on behaviour during social interactions in female and malemice. Neuropharmacology 1991; 30:299–306.

Animal Models and Anxiolytic Drug Action

693

43. Davis M. Diazepam and ﬂurazepam: effects on conditioned fear as measured with the potentiated startle paradigm. Psychopharmacology (Berl) 1979; 62:1–7.
44. Davis M. Pharmacological and anatomical analysis of fear conditioning using the fear potentiated startle paradigm. Behav Neurosci 1986; 100:814–824.
45. Davis M. Animal models of anxiety based on classical conditioning: the conditioned emotional response (CER) and the fear-potentiated startle effect. Pharm Ther 1990; 47:147–
165.
46. Davis M, Cassella JV, Kehne JH. Serotonin does not mediate anxiolytic effects of buspirone
in the fear-potentiated startle paradigm: comparison with 8-OH-DPAT and ipsapirone. Psychopharmacology (Berl) 1988; 94:14–20.
47. de Angelis L, Furlan C. The anxiolytic-like properties of two selective MAOIs, moclobemide
and selegiline, in a standard and an enhanced light/dark aversion test. Pharmacol Biochem
Behav 2000; 65:649–653.
48. de Angelis L. Experimental anxiety and antidepressant drugs: the effects of moclobemide,a selective reversible MAO A inhibitor, ﬂuoxetine and imipramine in mice. Naunyn Schmiedebergs Arch Pharmacol 1996; 354:379–383.
49. De Boer SF, Slangen JL, van der Gugten J. Plasma catecholamine and corticosterone levels
during active and passive shock-prod avoidance behavior in rats: effects of chlordiazepoxide.
Pharmacol Biochem Behav 1990; 47:1089–1098.
50. Dekeyne A, Brocco M, Adhumeau A, Gobert A. The selective serotonin (5-HT)1A receptor
ligand, S15535, displays anxiolytic-like effects in the social interaction and Vogel models
and suppresses dialysate levels of 5-HT in the dorsal hippocampus of freely-moving rats.
Psychopharmacology (Berl) 2000; 152:55–66.
51. Deren-Wesolek A, Tatarczynska E, Chojnacka-Wojcik E. The novel buspirone analogue, 8[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)[butyl]-8-azaspiro]decane-7,9-dione, with anxiolyticlike and antidepressant-like effects in rats. J Psychopharmacol (Berl) 1998; 12:380–384.
52. De Vry J, Benz U, Schreiber R, Traber J. Shock-induced ultrasonic vocalization in young
adult rats: a model for testing putative anti-anxiety agents. Eur J Pharmacol 1993; 249:331–
339.
53. Dunn RW, Corbett R, Fielding S. Effects of 5-HT1A receptor agonists and NMDA receptor
antagonists in the social interaction test and the elevated plus maze. Eur J Pharmacol 1989;
169:1–10.
54. Duxon MS, Starr KR, Upton N. Latency to paroxetine-induced anxiolysis in the rat is reducedby co-administration of the 5-HT1A receptor antagonist WAY100635. Br J Pharmacol 2000;
130:1713–1719.
55. Ellis DM, Fontana DJ, McCloskey C, Commissaris RL. Chronic anxiolytic treatment effects
on conﬂict behavior in the rat. Pharmacol Biochem Behav 1990; 37:177–186.
56. Engel J, Hard E, Lindh AS. Effects of diazepam, ethanol and Ro 15-1788 on ultrasonicvocalization, locomotor activity and body righting in the neonatal rat. Alcohol. Alcoholism
1987; (suppl 1):709–712.
57. Feighner JP, Aden GC, Fabre LF, Rickels K, Smith WT. Comparison of alprazolam, imipramine, and placebo in the treatment of depression. J Am Med Assoc 1983; 249:3057–3064.
58. Fernandez-Guasti A, Lopez-Rubalcava C. Evidence for the involvement of the 5-HT1A receptor in the anxiolytic action of indorenate and ipsapirone. Psychopharmacology (Berl)
1990; 101:354–358.
59. Fernandez-Guasti A, Lopez-Rubalcava C. Modiﬁcation of the anxiolytic action of 5-HT1A
compounds by GABA-benzodiazepine agents in rats. Pharmacol Biochem Behav 1998; 60:
27–32.
60. Fernandez-Guasti A, Mantinez-Mota L, Estrada-Camarena E, Contreras CM, LopezRubalcava C. Chronic treatment with desipramine induces an estrous cycle-dependent
anxiolytic-like action in the burying behavior, but not in the elevated plus-maze test.
Pharmacol Biochem Behav 1999; 63:13–20.

694

Treit et al.

61. Fernandez-Guasti A, Picazo O. Anxiolytic action of diazepam, but not of buspirone, areinﬂuenced by gender and the endocrine stage. Behav Brain Res 1997; 88:213–218.
62. Fernandez-Guasti A, Picazo O. The actions of diazepam and serotonergic anxiolytics vary
according to the gender and the estrous cycle phase. Pharmacol Biochem Behav 1990; 37:
77–81.
63. Fernandez-Guasti A, Hong E, Lopez-Rubalcava C. Species differences in the mechanism
through which the serotonergic agonists indorenate and ipsapirone produce their anxiolytic
action. Psychopharmacology (Berl) 1992; 107:61–68.
64. File SE. The validation of animal tests of anxiety: pharmacological implications. Pol J Pharmacol Pharm 1984; 36:505–512.
65. File SE. Animal models for predicting clinical efﬁcacy of anxiolytic drugs: social behaviour.
Neuropsychobiology 1985; 13:55–62.
66. File SE. The contribution of behavioral studies to the neuropharmacology of anxiety. Neuropharmacology 1987; 26:877–886.
67. File SE, Hyde JRG. A test of anxiety that distinguishes between the actions of benzodiazepines and those of other minor tranquilisers and stimulants. Pharmacol Biochem Behav 1979;
11:65–69.
68. File SE, Hyde JRG. Can social interaction be used to measure anxiety? Br J Pharmacol 1978;
62:19–24.
69. File SE, Johnston AL. Chronic treatment with imipramine does not reverse the effects of 3
anxiogenic compounds in a test of anxiety in the rat. Neuropsychobiology 1987; 17:187–192.
70. File SE, Pellow S. Anxiogenic action of a convulsant benzodiazepine: reversal by chlordiazepoxide. Brain Res 1983; 278:370–372.
71. File SE, Pellow S. The anxiogenic action of FG 7142 in the social interaction test is reversedby chlordiazepoxide and Ro 15-1788 but not by CGS 8216. Arch Int Pharmacodyn Ther
1984; 271:198–205.
72. File SE, Pellow S. The anxiogenic action of Ro 15-1788 is reversed by chronic, but not by
acute, treatment with chlordiazepoxide. Brain Res 1984; 310:154–156.
73. File SE, Pellow S. The anxiogenic action of RO 5-4864 in the social interaction test: effectof chlordiazepoxide, RO 15-1788 and CGS 8216. Naunyn Schmiedebergs Arch Pharmacol
1985; 328:225–228.
74. File SE, Pellow S. The effects of triazolobenzodiazepines in two animal tests of anxiety andin the holeboard. Br J Pharmacol 1985; 86:729–735.
75. Fish EW, Sekinda M, Ferrari PF, Dirks A, Miczek KA. Distress vocalizations in maternallyseparated mouse pups: modulation via 5-HT1A, 5-HT1B and GABAA receptors. Psychopharmacology (Berl) 2000; 149:277–285.
76. Fontana DJ, Commissaris RL. Effects of acute and chronic imipramine administration on
conﬂict behavior in the rat: a potential “animal model” for the study of panic disorder? Psychopharmacology (Berl) 1988; 95:147–150.
77. Fontana DJ, Carbary TM, Commissaris RL. Effects of acute and chronic anti-panic drug
administration on conﬂict behavior in the rat. Psychopharmacology (Berl) 1989; 98:157–
162.
78. Garattini S, Samanin R. Biochemical hypotheses on antidepressant drugs: a guide for clinicians or a toy for pharmacologists? Psychol Med 1988; 18:287–304.
79. Gardner CR. Functional in vivo correlates of the benzodiazepine agonist-inverse agonist continuum. Prog Neurobiol 1988; 31:425–476.
80. Gardner CR. Inhibition of ultrasonic distress vocalizations in rat pups by chlordiazepoxideand diazepam. Drug Dev Res 1985; 5:185–193.
81. Gardner CR. Distress vocalization in rat pups. A simple screening method for anxiolytic
drugs. J Pharmacol Meth 1985; 14:181–187.
82. Gardner CR. Recent developments in 5-HT-related pharmacology of animal models of anxiety. Pharmacol Biochem Behav 1986; 24:1479–1485.

Animal Models and Anxiolytic Drug Action

695

83. Gardner CR, Guy AP. A social interaction model of anxiety sensitive to acutely administeredbenzodiazepines. Drug Dev Res 1984; 4:207–216.
84. Geller I, Seifter J. The effects of meprobamate, barbiturates, d-amphetamine, and promazine
on experimentally induced conﬂict in the rat. Psychopharmacologia 1960; 1:482–492.
85. Giusti R, Guidetti G, Costa E, Guidotti A. The preferential antagonism of pentylenetetrazole
proconﬂict responses differentiates a class of anxiolytic benzodiazepines with potential antipanic action. J Pharmacol Exp Ther 1991; 257:1062–1068.
86. Goa K, Ward A. Buspirone: a preliminary review of its pharmacological properties and therapeutic efﬁcacy as an anxiolytic. Drugs 1986; 32:114–129.
87. Graeff FG, Audi EA, Almeida SS, Graeff EO, Hunziker MHL. Behavioral effects of 5-HT
receptor ligands in the aversive brain stimulation, elevated plus-maze and learned helplessness tests. Neurosci Biobehav Rev 1990; 14:501–506.
88. Griebel G, Misslin R, Pawlowski M, Vogel E. m-Chlorophenylpiperazine enhances neophobic and anxious behaviour in mice. Neuroreport 1991; 2:627–629.
89. Griebel G, Moreau JL, Jenck F, Misslin R, Martin JR. Acute and chronic treatment with 5-HT
reuptake inhibitors differentially modulate emotional responses in anxiety models in rodents.
Psychopharmacology (Berl) 1994; 113:463–470.
90. Griebel G, Sanger DJ, Perrault G. The use of the rat elevated plus-maze to discriminate
between non-selective and BZ-1 (omega) (1) selective, benzodiazepine receptor ligands. Psychopharmacology (Berl) 1996; 124:245–254.
91. Griebel G, Rodgers RJ, Perrault G, Sanger DJ. Risk assessment behaviour: evaluation ofutility in the study of 5-HT-related drugs in the rat elevated plus-maze test. Pharmacol Biochem Behav 1997; 57:817–827.
92. Griebel G, Cohen C, Perrault G, Sanger DJ. Behavioral effects of acute and chronic ﬂuoxetinein Wistar-Kyoto rats. Physiol Behav 1999; 67:315–320.
93. Groenink L, Van der Gugten J, Compaan JC, Maes RAA, Olivier B. Flesinoxan pretreatment
differentially affects corticosterone, prolactin and behavioural responses to a ﬂesinoxan challenge. Psychopharmacology (Berl) 1997; 131:93–100.
94. Groenink L, Van der Gugten J, Verdouw PM, Maes RAA, Olivier B. The anxiolytic effectsof ﬂesinoxan, a 5-HT1A receptor agonist, are not related to its neuroendocrine effects. Eur J
Pharmacol 1995; 280:185–193.
95. Guy AP, Gardner CR. Pharmacological characterisation of a modiﬁed social interaction
model of anxiety in the rat. Neuropsychobiology 1985; 13:194–200.
96. Gyertyan I. Analysis of the marble burying response: marbles serve to measure digging rather
than evoke burying. Behav Pharmacol 1995; 6:24–31.
97. Haefely W. Benzodiazepines, benzodiazepine receptors, and endogenous ligands. In: denBoer JA, Sitsen JA, eds. Handbook of Depression and Anxiety: A Biological Approach. New
York: Marcel Dekker, 1994: 573–607.
98. Hallar J, Halasz J, Makara GB. Housing conditions and the anxiolytic efﬁcacy of buspirone:
the relationship between main and side effects. Behav Pharmacol 2000; 11:403–412.
99. Handley SL, McBlane JW. Opposite effects of ﬂuoxetine in two animal models of anxiety.
Br J Pharmacol 1992; 107(suppl):446P.
100. Handley SL, Mithani S. Effects of alpha-adrenoreceptor agonists and antagonists in a Xmaze-exploration model of ‘fear’-motivated behaviour. Naunyn Schmiedeberg’s Arch Pharm
1984; 327:1–5.
101. Harto NE, Branconnier RJ, Spera KF, Dessain EC. Clinical proﬁle of gepirone, a nonbenzodiazepine anxiolytic. Psychopharmacol Bull 1988; 24:154–160.
102. Hascoet M, Bourin M. Anticonﬂict effect of alpidem as compared with the benzodiazepine
alprazolam in rats. Pharmacol Biochem Behav 1997; 56:317–324.
103. Hascoet M, Bourin M. A new approach to the light/dark test procedure in mice. Pharmacol
Biochem Behav 1998; 60:645–653.
104. Hascoet M, Bourin M, Dhonnchadha BAN. The inﬂuence of buspirone, and its metabolite

696

105.
106.

107.
108.

109.
110.
111.

112.
113.
114.
115.
116.
117.

118.

119.
120.

121.
122.

123.

124.

Treit et al.
1-PP on the activity of paroxetine in the mouse light/dark paradigm and four plates test.
Pharmacol Biochem Behav 2000; 67:45–53.
Heller AH, Beneke M, Kuemmel B, Spencer D, Kurtz NM. Ipsapirone: evidence for efﬁcacy
in depression. Psychopharmacol Bull 1990; 26:219–222.
Hendrie CA, Eilam D, Weiss SM. Effects of diazepam and buspirone on the behaviour ofwild voles (microtus socialis) in two models of anxiety. Pharmacol Biochem Behav 1997;
58:573–576.
Hijzen TH, Slangen JL. Effects of midazolam, DMCM and lindane on potentiated startle in
the rat. Psychopharmacology (Berl) 1989; 99:362–365.
Hijzen TH, Houtzager SW, Joordens RJ, Oliver B, Slangen JL. Predictive validity of thepotentiated startle response as a behavioral model for anxiolytic drugs. Psychopharmacology(Berl) 1995; 118:150–154.
Hogg S. A review of the validity and variability of the elevated plus-maze as an animalmodel of anxiety. Pharmacol Biochem Behav 1996; 54:21–30.
Howard JL, Pollard GT. Effects of buspirone in the Geller-Seifter conﬂict test with incremental shock. Drug Dev Res 1996; 19:37–47.
Ichimaru Y, Egawa T, Sawa A. 5-HT1A-receptor subtype mediates the effect of ﬂuvoxamine,a selective serotonin reuptake inhibitor, on marble-burying behavior in mice. Jpn J Pharmacol
1995; 68:65–70.
Insel TR, Hill JL, Mayor RB. Rat pup ultrasonic isolation calls: possible mediation by the
benzodiazepine receptor complex. Pharmacol Biochem Behav 1986; 24:1262–1267.
Jenkins SW, Robinson OS, Fabre LF Jr, Andary JJ, Messina ME, Reich LA. Gepirone in
the treatment of major depression. J Clin Psychopharmacol 1990; 10:77S.
Johnston AL, File SE. Yohimbine’s anxiogenic action; evidence for noradrenergic and dopaminergic sites. Pharmacol Biochem Behav 1989; 32:151–156.
Johnston AL, File SE. Sodium phenobarbitone reverses the anxiogenic effects of compounds
acting at three different central sites. Neuropharmacology 1989; 28:83–88.
Johnston AL, File SE. Proﬁles of the antipanic compounds, triazolobenzodiazepines andphenelzine, in two animal tests of anxiety. Psychiat Res 1988; 25:81–90.
Jonas JM, Cohon MS. A comparison of the safety and efﬁcacy of alprazolam versus otheragents in the treatment of anxiety, panic and depression: review of the literature. J Clin
Psychiat 1993; 54:25–48.
Jones GH, Schneider C, Schneider HH, Seider J, Cole BJ, Stephans DN. Comparison ofseveral benzodiazepine receptor ligands in two models of anxiolytic activity in the mouse:an analysis based on fractional receptor occupancies. Psychopharmacology (Berl) 1994; 114:
191–199.
Joordens RJ, Hijzen TH, Peeters BW, Olivier B. Fear potentiated startle response is remarkably similar in two laboratories. Psychopharmacology (Berl) 1996; 126:104–109.
Joordens RJ, Hijzen TH, Olivier B. The effects of 5-HT1A receptor agonists, 5-HT1A receptor
antagonists and their interaction on the fear-potentiated startle response. Psychopharmacology (Berl) 1998; 139:383–390.
Kehne JH, Cassella JV, Davis M. Anxiolytic effects of buspirone and gepirone in the fearpotentiated startle paradigm. Psychopharmacology (Berl) 1988; 94:8–13.
Kehne JH, McCloskey TC, Baron BM, EM Chi, Harrison BL, Whitten JP, Palfreyman MG.
NMDA receptor complex antagonists have potential anxiolytic effects as measured withseparation-induced ultrasonic vocalizations. Eur J Pharmacol 1991; 193:283–292.
Kennedy AJ, Gibson EL, O’Connell MT, Curzon G. Effects of housing, restraint and chronic
treatments with mCPP and sertraline on behavioural responses to mCPP. Psychopharmacology (Berl) 1993; 113:262–268.
Kennett GA. 5-HT1C receptor antagonists have anxiolytic-like actions in the rat social interaction model. Psychopharmacology (Berl) 1992; 107:379–384.

Animal Models and Anxiolytic Drug Action

697

125. Kennett GA, Trail B, Bright F. Anxiolytic-like actions of BW 723C86 in the rat Vogel conﬂict test are 5-HT2B receptor mediated. Neuropharmacology 1998; 37:1603–1610.
126. Kilfoil T, Michel A, Montgomery D, Whiting RL. Effects of anxiolytic and anxiogenic drugs
on exploratory activity in a simple model of anxiety in mice. Neuropharmacology 1989; 28:
901–905.
127. Klein DF. Anxiety reconceptualized. In: Klein DF, Rabkin J, eds. Anxiety: Research andchanging concepts. New York: Raven Press, 1981; 235–262.
128. Koks S, Beljajev S, Koovit I, Abramov U, Bourin M, Vasar E. 8-OH-DPAT, but not deramciclane, antagonizes the anxiogenic-like action of paroxetine in an elevated plus-maze. Psychopharmacology (Berl) 2001; 153:365–372.
129. Korte SM, Bohus B. The effect of ipsapirone on behavioral and cardiac responses in theshock-probe/defensive burying test in male rats. Eur J Pharmacol 1990; 181:307–310.
130. Kshama D, Hrishikeshavan HJ, Shanbhogue R, Munonyedi US. Modulation of baseline behavior in rats by putative serotonergic agents in three ethoexperimental paradigms. Behav
Neural Biol 1990; 54:234–253.
131. Kurt M, Arik AC, Celik S. The effects of sertraline and ﬂuoxetine on anxiety in the elevatedplus-maze test in mice. J Basic Clin Physiol Pharmacol 2000; 11:173–180.
132. Lal H, Emmett-Oglesby MW. Behavioral analogues of anxiety. Animal models. Neuropharmacology 1983; 22:1423–1444.
133. LeDoux J. The Emotional Brain: The Mysterious Underpinnings of Emotional Life. New
York: Simon & Schuster, 1998:104–303.
134. Lehmann HE, Ban TA. Effects of psychoactive drugs on conﬂict avoidance behavior in human subjects. Acta Nerv Sup 1971; 13:82–85.
135. Lightowler S, Kennett GA, Williamson IJ, Blackburn TP, Tulloch IF. Anxiolytic-like effectof paroxetine in a rat social interaction test. Pharmacol Biochem Behav 1994; 49:281–285.
136. Linnoila M, Eckardt M, Durcan M, Lister R, Martin P. Interactions of serotonin with ethanol:clinical and animal studies. Psychopharmacol Bull 1987; 23:452–457.
137. Lister RG. Ethologically-based animal models of anxiety disorders. Pharm Ther 1990; 46:
321–340.
138. Lister RG. The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology(Berl) 1987; 92:180–185.
139. Lopez-Rubalcava C. Pre- or postsynaptic activity of 5-HT1A compounds in mice depends on
the anxiety paradigm. Pharmacol Biochem Behav 1996; 54:677–686.
140. Lopez-Rubalcava C, Cruz SL, Fernandez-Guasti A. Blockade of the anxiolytic-like actionof ipsapirone and buspirone, but not that of 8-OH-DPAT, by adrenalectomy in male rats.
Psychoneuroendocrinology 1999; 24:409–422.
141. Lopez-Rubalcava C, Fernandez-Guasti A, Urba-Holmgren R. Age dependant differences in
the rat conditioned defensive burying behavior: effect of 5-HT1A compounds. Dev Psychobiol
1996; 29:157–169.
142. Luscombe GP, Mazurkiewicz SE, Buckett WR. Evaluation of tricyclic antidepressants in theelevated plus-maze in rats: anxiolytic effects of dothiepin and doxepine. Br J Pharmacol
1990; 100(suppl):356P.
143. Maisonnette S, Morato S, Brandao ML. Role of resocialization and of 5-HT1A receptor activation on the anxiogenic effects induced by isolation in the elevated plus-maze test. Physiol
Behav 1993; 54:753–758.
144. Martinez-Mota L, Estrada-Camarena E, Lopez-Rubalcava C, Contreras CM, FernandezGuasti A. Interaction of desipramine with steroid hormones on experimental anxiety. Psychoneuroendocrinology 2000; 25:109–120.
145. Mansbach RS, Geyer MA. Blockade of potentiated startle responding in rats by 5-hydroxytryptamine-1A receptor ligands. Eur J Pharmacol 1988; 156:375–383.
146. Marks IM. Fears, Phobias, and Rituals. New York: Oxford University Press, 1987.

698

Treit et al.

147. Mason P, Skinner J, Luttinger D. Two tests in rats for antianxiety effect of clinically anxiety
attenuating antidepressants. Psychopharmacology (Berl) 1987; 92:30–34.
148. McCloskey TC, Paul BK, Commissaris RL. Buspirone effects in an animal conﬂict procedure: comparison with diazepam and phenobarbital. Pharmacol Biochem Behav 1987; 27:
171–175.
149. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers
J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, MaCaulay A, Brown N, Howell O,
Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ. Sedative
but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptoralpha(1) subtype. Nat Neurosci 2000; 3:587–582.
150. Meert TF, Colpaert FC. The shock probe conﬂict procedure. A new assay responsive tobenzodiazepines, barbiturates and related compounds. Psychopharmacology (Berl) 1986; 88:445–450.
151. Mendoza DL, Bravo HA, Swanson HH. Antiaggressive and anxiolytic effects of gepirone
in mice, and their attenuation by WAY 100635. Pharmacol Biochem Behav 1999; 62:499–
509.
152. Meneses A, Hong E. Modiﬁcation of the anxiolytic effects of 5-HT1A agonists by shock
intensity. Pharmacol Biochem Behav 1993; 46:569–573.
153. Miczek KA, Weerts EM, Vivan JA, Barros HM. Aggression, anxiety and vocalizations inanimals: GABAA and 5-HT anxiolytics. Psychopharmacology (Berl) 1995; 121:38–56.
154. Mineka S. Animal models of anxiety-based disorders: their usefulness and limitations. In:
Tuma AH, Maser JD, eds. Anxiety and Anxiety Disorders. Hillsdale, NJ: Erlbaum, 1985:
191–244.
155. Molewijk HE, van der Poel AM, Mos J, van der Heyden JAM, Olivier B. Conditioned ultrasonic distress vocalizations in adult male rats as a behavioural paradigm for screening antipanic drugs. Psychopharmacology (Berl) 1995; 117:32–40.
156. Moser PO. An evaluation of the elevated plus-maze test using the novel anxiolytic buspirone.
Psychopharmacology (Berl) 1989; 99:48–53.
157. Moser PC, Tricklebank MD, Middlemiss DN, Mir AK, Hibert MF, Fozard JR. Characterization of MDL 73005EF as a 5-HT1A selective ligand and its effects in animal models of anxiety:comparison with buspirone, 8-OH-DPAT and diazepam. Br J Pharmacol 1990; 99:343–349.
158. Motta V, Maisonnette S, Morato S, Castrechini P, Brandao ML. Effects of blockade of 5HT2 receptors and activation of 5-HT1A receptors on the exploratory activity of rats in theelevated plus-maze. Psychopharmacology (Berl) 1992; 107:135–139.
159. Nanry KP, Howard JL, Pollard GT. Effects of buspirone and other anxiolytics on punishedkey-pecking in the pigeon. Drug Dev Res 1991; 24:269–276.
160. Nastiti K, Benton D, Brain PF, Haug M. The effects of 5-HT receptor ligands on ultrasoniccalling in mouse pups. Neurosci Biobehav Rev 1991; 15:483–487.
161. Nevins ME, Anthony EW. Antagonists at the serotonin-3 receptor can reduce the fear-potentiated startle response in the rat: evidence for different types of anxiolytic activity? J Pharmacol
Exp Ther 1994; 268:248–254.
162. Nielsen CK, Sanchez C. Effect of chronic diazepam treatment on footshock-induced ultrasonic vocalization in adult male rats. Pharmacol Toxicol 1995; 77:177–181.
163. Njung’e K, Handley SL. Evaluation of marble-burying as a model of anxiety. Pharmacol
Biochem Behav 1991; 38:63–67.
164. Njung’e K, Handley SL. Effects of 5-HT uptake inhibitors, agonists and antagonists on theburying of harmless objects by mice; a putative test for anxiolytic agents. Br J Pharmacol
1991; 104:105–112.
165. Noirot E. Ultrasounds and maternal behavior in small rodents. Dev Psychobiol 1972; 5:371–
387.
166. Olajide D, Lader M. A double-blind comparison of buspirone and diazepam in outpatientswith chronic anxiety states. Abstract at C.I.N.P. meeting, Florence, 1984.

Animal Models and Anxiolytic Drug Action699

167. Olivier B, Molewijk E, van Oorschot R, van der Heyden J, Ronken E, Mos J. Rat pup vocalization: effects of benzodiazepine receptor ligands. Eur J Pharmacol 1998; 358:117–128.
168. Olivier B, Molewijk E, van Oorschot R, van der Heyden J, Ronken E, Mos J, Miczek KA.
Ultrasonic vocalizations in rat pups: effects of serotonergic ligands. Neurosci Biobehav Rev
1998; 23:215–227.
169. Olivier B, Molewijk E, van Oorschot R, van der Poel G, Zethof T, van den Heyden J, Mos
J. New animal models of anxiety. Eur Neuropsychopharmacol 1994; 4:93–102.
170. Onaivi ES, Martin BR. Neuropharmacological and physiological validation of a computercontrolled two-compartment black and white box for the assessment of anxiety. Prog Neuropsychopharmacol Biol Psychiatry 1989; 13:963–976.
171. Paslawski T, Treit D, Baker GB, George M, Coutts RT. The antidepressant drug phenelzine
produces antianxiety effects in the plus-maze and increases in rat brain GABA. Psychopharmacology (Berl) 1996; 127:19–24.
172. Pecknold JC, Familamiri P, Chang H, Wilson R, Alarcia J, McClure DJ. Buspirone: anxiolytic? Prog Neuropsychopharmacol Biol Psychiatry 1985; 9:639–642.
173. Pellow S. Anxiolytic and anxiogenic drug effects in a novel test of anxiety: Are exploratorymodels of anxiety in rodents valid? Meth Find Exp Clin Pharmacol 1986; 8:557–565.
174. Pellow S, Chopin P, File SE, Briley M. Validation of open:closed arm entries in an elevatedplus-maze as a measure of anxiety in the rat. J Neurosci Meth 1985; 14:149–167.
175. Pellow S, File SE. Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus-maze: a novel test of anxiety in the rat. Pharmacol Biochem Behav 1986; 24:
525–529.
176. Pellow S, File SE. Can anti-panic drugs antagonise the anxiety produced in the rat by drugs
acting at the GABA-benzodiazepine receptor complex? Neuropsychobiology 1987; 17:60–
65.
177. Pellow S, Johnston AL, File SE. Selective agonists and antagonists for 5-hydroxytryptamine
receptor subtypes, and interactions with yohimbine and FG 7142 using the elevated plusmaze test in the rat. J Pharm Pharmacol 1987; 39:917–928.
178. Peroutka SJ. Selective interaction of novel anxiolytics with 5-hydroxytryptamine 1A receptors. Biol Psychiatry 1985; 20:971–979.
179. Picazo O, Lopez-Rubalcava C, Fernandez-Guasti A. Anxiolytic effect of the 5-HT1A compounds 8-hydroxy-2-(di-n-propylamino)tetralin and ipsapirone in the social interaction paradigm: evidence of a presynaptic action. Brain Res Bull 1995; 37:169–175.
180. Pich EM, Samanin R. Disinhibitory effects of buspirone and low doses of sulpiride andhaloperidol in two experimental anxiety models in rats: possible role of dopamine. Psychopharmacology (Berl) 1986: 89:125–130.
181. Pinel JPJ, Treit D. Burying as a defensive response in rats. J Comp Physiol Psychol 1978;
92:708–712.
182. Pokk P, Zharkovsky A. The effects of buspirone on the behaviour of control and stressed
mice. J Physiol Pharmacol 1998; 49:175–185.
183. Pollard GT, Howard JL. Effects of drugs on punished behavior: Pre-clinical test for anxiolytics. Pharmacol Ther 1990; 45:403–424.
184. Pollier F, Sarre S, Aguerre S, Ebinger G, Mormede P, Michotte Y, Chaouloff F. Serotonin
reuptake inhibition by citalopram in rat strains differing for their emotionality. Neuropsychopharmacology 2000; 22:64–76.
185. Popik P, Vetulani J. Similar action of imipramine and arginine-vasopressin in the social
interaction test. Pol J Pharmacol 1993; 45:323–325.
186. Prunell M, Escorihuela RM, Fernandez-Tereul A, Nunez JF, Tobena A. Anxiolytic proﬁlesof alprazolam and ethanol in the elevated plus-maze test and the early acquisition of shuttlebox avoidance. Pharmacol Res 1994; 29:37–46.
187. Rausch JL, Reugg R, Moeller FG. Gepirone as a 5-HT1A agonist in the treatment of major
depression. Psychopharmacol Bull 1990; 26:169–171.

700

Treit et al.

188. Rickels K, Amsterdam J, Clary C, Hassman J, London J, Puzzuoli G, Schweizer E. Buspirone
in depressed outpatients: a controlled study. Psychopharmacol Bull 1990; 26:163–167.
189. Rickels K, Downing R, Schweizer E, Hassman H. Antidepressants for the treatment of generalized anxiety disorder. Arch Gen Psychiatry 1993; 50:884–895.
190. Rickels K, Feighner JP, Smith WT. Alprazolam, amitriptyline, doxepine and placebo in thetreatment of depression. Arch Gen Psychiatry 1985; 42:134–141.
191. Rocha B, Rigo M, Di Scala G, Sander G, Hoyer D. Chronic mianserin or eltoprazine treatment in rats: effects on the elevated plus-maze test and on limbic 5-HT2C receptor levels.
Eur J Pharmacol 1994; 262:125–131.
192. Rodgers RJ. Animal models of anxiety: where next? Behav Pharmacol 1997; 8:477–496.
193. Rodgers RJ, Cutler MG, Jackson JE. Behavioural effects in mice of subchronic buspirone,
ondansetron and tianeptine. II. The elevated plus-maze. Pharmacol Biochem Behav 1997;
56:295–303.
194. Rodgers RJ, Cutler MG, Jackson JE. Behavioural effects in mice of subchronic chlordiazepoxide, maprotiline and ﬂuvoxamine. II. The elevated plus-maze. Pharmacol Biochem Behav
1997; 57:127–136.
195. Rohmer JG, Di Scala G, Sandner G. Behavioral analysis of the effects of benzodiazepine
receptor ligands in the conditioned burying paradigm. Behav Brain Res 1990; 38:45–54.
196. Rudzik AD, Hester JB, Tang AH, Straw RN, Priis W. Triazolobenzodiazepines, a new classof central nervous system depressant compounds. In: Garattini S, Mussini E, Randall LO,
eds. The Benzodiazepines. New York: Raven Press, 1973: 285–326.
197. Sanchez C. Effect of serotonergic drugs on footshock-induced ultrasonic vocalization in adultmale rats. Behav Pharmacol 1993; 4:269–277.
198. Sanchez C. Serotonergic mechanisms involved in the exploratory behaviour of mice in a
fully automated two compartment black and white test box. Pharmacol Toxicol 1995; 77:
71–78.
199. Sanchez C, Arnt J, Moltzen E. Assessment of relative efﬁcacies of 5-HT1A receptor ligands
by means of in vivo animal models. Eur J Pharmacol 1996; 315:245–254.
200. Sanchez C, Meier E. Behavioral proﬁles of SSRIs in animal models of depression, anxiety
and aggression. Are they all alike? Psychopharmacology (Berl) 1997; 129:197–205.
201. Sanger DJ. Effects of buspirone and related compounds on suppressed operant respondingin rats. J Pharmacol Exp Ther 1990; 254:420–426.
202. Sanger DJ. Animal models of anxiety and the screening and development of novel anxiolytic
drugs. In: Boulton AA, Baker GG, Martin-Iverson M, eds. Animal Models of Psychiatry II.
Clifton, NJ: Humana Press, 1991: 147–198.
203. Sanger DJ. Increased rates of responding produced by buspirone-like compounds in rats. J
Pharmacol Exp Ther 1992; 261:513–517.
204. Schefke DM, Fontana DJ, Commissaris RL. Anti-conﬂict efﬁcacy of buspirone following
acute versus chronic treatment. Psychopharmacology (Berl) 1989; 99:427–429.
205. Schreiber R, Brocco M, Lefebvre de Ladonchamps B, Millan MJ. Involvement of 5-HT1A
receptors in the anxiolytic action of S 14671 in the pigeon conﬂict test. Pharmacol Biochem
Behav 1995; 51:211–215.
206. Schreiber R, Melon C, De Vry J. The role of 5-HT receptor subtypes in the anxiolytic effects
of selective serotonin reuptake inhibitors in the rat ultrasonic vocalization test. Psychopharmacology (Berl) 1998; 135:383–391.
207. Sheehan DV, Raj AB, Sheehan KH, Soto S. Is buspirone effective for panic disorder? J Clin
Psychopharmacol 1990; 10:3–11.
208. Sheehan DV, Raj AB, Sheehan KH, Soto S. The relative efﬁcacy of buspirone, imipramineand placebo in panic disorder: A preliminary report. Pharmacol Biochem Behav 1988; 29:
815–817.
209. Shephard RA. Neurotransmitters, anxiety and benzodiazepines: a behavioral review. Neurosci Biobehav Rev 1986; 10:449–461.

Animal Models and Anxiolytic Drug Action

701

210. Shimada T, Matsumoto K, Osanai M, Matsuda H, Terasawa K, Watanabe H. The modiﬁed
light/dark transition test in mice, evaluation of classic and putative anxiolytic and axiogenic
drugs. Gen Pharmacol 1995; 26:205–210.
211. Silva RCB, Brandao ML. Acute and chronic effects of gepirone and ﬂuoxetine in rats tested
in the elevated plus-maze: an ethological analysis. Pharmacol Biochem Behav 2000; 65:209–
216.
212. Silva MTA, Alves CRR, Santarem EMM. Anxiogenic-like effect of acute and chronic ﬂuoxetine on rats tested on the elevated plus-maze. Braz J Med Biol Res 1999; 32:333–339.
213. Soderpalm B, Eriksson E, Engel JA. Anticonﬂict and rotarod impairing effects of alprazolam
and diazepam in rat after acute and subchronic administration. Progr Neuropsychopharmacol
Biol Psychiatry 1989; 13:269–283.
214. Soderpalm B, Hjorth S, Engel JA. Effects of 5-HT1A receptor agonists and L-5-HTP in Montgomery’s conﬂict test. Pharmacol Biochem Behav 1989; 32:259–265.
215. Soderpalm B, Lundin B, Hjorth S. Sustained 5-hydroxytryptamine release-inhibitory andanxiolytic-like action of the partial 5-HT1A receptor agonist, buspirone, after prolonged
chronic treatment. Eur J Pharmacol 1993; 239:69–73.
216. Sommermeyer H, Schreiber R, Greuel JM, De Vry J, Glaser T. Anxiolytic effects of the 5HT1A receptor agonist ipsapirone in the rat: neurobiological correlates. Eur J Pharmacol
1993; 240:29–37.
217. Stefanski R, Palejko W, Kotowski W, Plaznik A. The comparison of benzodiazepine derivatives and serotonergic agonists and antagonists in two animal models of anxiety. Neuropharmacology (Berl) 1992; 31:1252–1258.
218. Thiebot MH. Behavioral models of anxiety in animals. Encephale 1983; 9(4 suppl 2):167B–
176B.
219. Thiebot MH, Soubrie P, Sanger D. Anxiogenic properties of beta-CCE and FG 7142: a review
of promises and pitfalls. Psychopharmacology (Berl) 1988; 94:452–463.
220. Treit D. Animal models of anxiety and anxiolytic drug action. In: den Boer JA, Sitsen JMA,
eds. Handbook of Depression and Anxiety: A Biological Approach. New York: Marcel Dekker, 1994: 201–224.
221. Treit D. Animal models for the study of anti-anxiety agents: A review. Neurosci Biobehav
Rev 1985; 9:203–222.
222. Treit D. Evidence that tolerance develops to the anxiolytic effect of diazepam in rats. Pharmacol Biochem Behav 1985; 22:383–387.
223. Treit D. The inhibitory effect of diazepam on defensive burying: anxiolytic vs analgesic
effects. Pharmacol Biochem Behav 1985; 22:47–52.
224. Treit D. A comparison of anxiolytic and nonanxiolytic agents in the shock-probe/burying
test for anxiolytics. Pharmacol Biochem Behav 1990; 36:203–205.
225. Treit D. Ro 15-1788, CGS 8216, picrotoxin, and pentylenetetrazol: do they antagonize anxiolytic drug effects through an anxiogenic action? Brain Res Bull 1987; 19:401–405.
226. Treit D, Degroot A, Kashluba S, Bartoszyk ED. Systemic EMD 68843 injections reduce
anxiety in the shock-probe, but not the plus-maze test. Eur J Pharmacol 2001; 414:245–
248.
227. Treit D, Fundytus M. A comparison of buspirone and chlordiazepoxide in the shock-probe/burying test for anxiolytics. Pharmacol Biochem Behav 1988; 30:1071–1075.
228. Treit D, Menard J, Pesold C. The shock probe burying test. Neurosci Protocols Mod 1994;
3:9–17.
229. Treit D, Menard J, Royan C. Anxiogenic stimuli in the elevated plus-maze. Pharmacol Biochem Behav 1993; 44:463–469.
230. Treit D, Pinel JP, Fibiger HC. Conditioned defensive burying: a new paradigm for the studyof anxiolytic agents. Pharmacol Biochem Behav 1981; 15:619–626.
231. Tsuda A, Ida Y, Tanaka M. The contrasting effects of diazepam and yohimbine on conditioned defensive burying in rats. Psychobiol 1988; 16:213–217.

702

Treit et al.

232. Tsuda A, Ida Y, Nishimura H, Tanaka M. Anxiogenic effects of B-CCE as measured in two
different conditioning paradigms. Psychobiology 1989; 17:202–206.
233. Tyrer P, Tyrer J. Antidepressive drugs for treatment of anxiety disorders—and vice versa.
In: den Boer JA, Sitsen JMA, eds. Handbook of Depression and Anxiety: A Biological Approach. New York: Marcel Dekker, 1994: 497–514.
234. Vogel JR, Beer D, Clody DE. A simple and reliable conﬂict procedure for testing anti-anxiety
agents. Psychopharmacologia 1971; 21:1–7.
235. Weissman BA, Barrett JE, Brady LS, Witkin JM, Mendelson WB, Paul SM, Skolnick P.
Behavioral and neurochemical studies on the anticonﬂict actions of buspirone. Drug Dev
Res 1984; 4:83–93.
236. Wheatley D. Buspirone: Multicenter efﬁcacy study. J Clin Psychiat 1982; 43:92–94.
237. Winslow JT, Insel TR. Serotonergic and catecholaminergic reuptake inhibitors have opposite
effects on the ultrasonic isolation calls of rat pups. Neuropsychopharmacology (Berl) 1990;
3:51–59.
238. Witkin JM, Perez LA. Comparison of anticonﬂict effects of buspirone and gepirone withbenzodiazepines and antagonists of dopamine and serotonergic receptors in rats. Behav Pharmacol 1990; 1:247–254.
239. Wright IK, Heaton M, Upton N, Marsdon CA. Comparison of acute and chronic treatmentof various serotonergic agents with those of diazepam and idazoxan in the rat elevated Xmaze. Psychopharmacology (Berl) 1992; 107:405–414.
240. Xu L, Anwyl R, De Vry J, Rowan MJ. Effect of repeated ipsapirone treatment on hippocampal excitatory synaptic transmission in the freely behaving rat: role of 5-HT1A receptors andrelationship to anxiolytic effect. Eur J Pharmacol 1997; 323:59–68.
241. Yamashita S, Oishi R, Gomita Y. Anticonﬂict effects of acute and chronic treatments withbuspirone and gepirone in rats. Pharmacol Biochem Behav 1995; 50:477–479.
242. Young R, Johnson DN. A fully automated light/dark apparatus useful for comparing anxiolytic agents. Pharmacol Biochem Behav 1991; 40:739–743.
243. Young R, Johnson DN. Comparison of routes of administration and time course effects ofzacopride and buspirone in mice using an automated light/dark test. Pharmacol Biochem
Behav 1991; 40:733–737.
244. Young R, Urbancic A, Emrey TA, Hall PC, Metcalf G. Behavioral effects of several anxiolytics and putative anxiolytics. Eur J Pharmacol 1987; 143:361–371.

30
Provocation of Anxiety States in Humans
and Its Possible Signiﬁcance for the
Pathogenesis of These Disorders
RICHARD BALON, ROBERT POHL, VIKRAM K. YERAGANI,and RAVI K. SINGAREDDY
Wayne State University School of Medicine
Detroit, Michigan, U.S.A.

I.

INTRODUCTION

Panic attacks are the hallmark of panic disorder. However, they also occasionally occur
in other mental disorders and in up to 35% of the general population [1]. Spontaneous
panic attacks are incidental and unpredictable and, therefore, difﬁcult to study [2]. Earlier
studies focused on information about spontaneous panic attacks obtained from patients.
However, this information, as Griez and Schruers [2] pointed out, is essentially subjective
and entirely retrospective, and thus not very reliable and difﬁcult to quantify. Anotherapproach to the study of panic attacks has been the monitoring of various physiologicalchanges during spontaneously occurring attacks. This monitoring conﬁrmed the presenceof major physiological changes, such as heart rate increase and ﬁnger temperature changes
during self-reported panic attacks [3,4]. Nevertheless, monitoring physiological variables
and biochemical changes during spontaneously occurring panic attacks is technically quite
difﬁcult. In addition, as Balon and colleagues [5] pointed out, changes in physiologicalmeasures have not always correlated well with subjective anxiety. Thus, even thoughmonitoring various changes during spontaneously occurring panic attacks would be clearly
the most scientiﬁcally and methodologically appropriate approach, it has not been appliedin studies of pathophysiology of panic attacks.
Some of the early studies of anxiety states noticed various abnormal physiologicaland metabolic ﬁndings in subjects with panic anxiety. For instance, two studies [6,7]
703

704

Balon et al.

reported that anxious patients produce more lactate with exercise than do control subjects,
with the abnormality being greater in chronic neurocirculatory asthenia than in acute one[7]. Cohen and White pointed out the abnormal oxygen consumption and excessive lactate
production during exercise in anxiety states in several articles [8]. This led Pitts andMcClure [9] to test their hypothesis that anxiety during anxiety states might be directly
related to the rise in blood lactate. They found that the majority of patients with anxiety
neurosis in their study panicked during the infusion of sodium lactate. Their experimentushered in a new era of studying panic anxiety—provocation of panic attacks in the laboratory. It should be noted that although Pitts’ and McClure’s study [9] is considered the
beginning of the era of anxiety provocation in the laboratory, Wearn and Sturgis [10] used
epinephrine to reproduce the symptoms of irritable heart in anxiety patients as early as
1919.
Provocation of anxiety in the laboratory allows for relatively easy monitoring ofvarious physiological, biochemical, and lately even imaging changes during laboratoryinduced panic attacks. Thus, for decades, this has been one of the main biological approaches to the study of panic anxiety. During the 1970s and 1980s, sodium lactate has
been the most frequently studied provocative agent [11]. Other agents, such as β-carbolines[12], caffeine [13], carbon dioxide [14], cholecystokinin-tetrapeptide [15], epinephrine[16], ﬂumazenil [17], fenﬂuramine [18], isoproterenol [19], m-chlorophenylpiperazine[20], norepinephrine [21], yohimbine [22], and other nonpharmacological paradigms (hyperventilation, catastrophic misinterpretation) [23] have also been used for provocationof anxiety in the laboratory.
This chapter will review the most frequently used paradigms of anxiety provocationin humans. Similar to the interest in other biological tests (e.g., dexamethasone suppressiontest), the interest in anxiety provocation in the laboratory has waxed and waned. Although
provocation of anxiety states in humans has undergone signiﬁcant development during
the last decade, the ﬁndings from the previous decades provide the most important knowledge base. Thus, for each paradigm, we will review brieﬂy the most important older ﬁndings and then focus on an update from the last decade.
II. SODIUM LACTATE
In a carefully designed double-blind study, Pitts and McClure [9] observed that 13 of 14
patients, but only 2 of 10 healthy controls, developed anxiety during the infusion of 0.5
M sodium lactate. Glucose in saline did not produce any attacks. Patients rated lactateinduced anxiety as very similar, if not identical, to their real-life attacks. Several otherstudies replicated the ﬁnding of lactate-induced anxiety in panic disorder during the late1960s and early 1970s [24–26]. Kelly and colleagues [25] reported ﬁndings similar to
those of Pitts and McClure [9]. Most of their patients with chronic anxiety neurosis (16of 20) and 1 of 10 controls panicked during an infusion with 0.5 M sodium lactate. They
also reported that one patient panicked during the saline lead-in infusion, but not during
the lactate infusion (anticipatory anxiety?). Forearm blood ﬂow and heart rate were higher
during lactate than during saline infusion. Bonn and colleagues [26] used 1 M sodium
lactate in a fairly large sample of 66 subjects. They emphasized the striking hypophosphatemia during lactate infusions, and reported that propranolol could not modify thesymptoms produced by lactate. They were also the only ones who used lactate infusion
as a treatment modality. They described marked improvement in subjects with intractableanxiety after twice-weekly “ﬂooding” with sodium lactate. Other studies in the early 1980s

Provocation and Pathogenesis of Anxiety Disorders

705

established that sodium lactate provoked anxiety in panic disorder patients [27,28] andless frequently in healthy controls [28].
A. Studies Focused on Reliability and Validity
The provocation of panic attacks in patients with deﬁned anxiety neurosis or panic disorderhas been reproduced in various laboratories around the world, under various conditions,and with different concentrations of sodium lactate (0.5 or 1.0 M) [11,24,25,26,29–37).
Panic attacks in response to lactate infusion have also been demonstrated in patients with
infrequent panic attacks not meeting the DSM-III criteria for panic disorder [38]. However,in one study [39], patients with a low frequency of panic attacks (one or less per month)
did not respond positively to lactate. Though Ehlers and colleagues [32] argued that patients and controls respond to lactate similarly, most studies demonstrated that panic disorder patients respond to lactate differently than healthy controls (70–100% of patients
showed a panic response versus 0–40% of controls in various studies). Cowley and Arana[11] thus calculated that the lactate-induced panic had a sensitivity of 67% and speciﬁcityof 89% in differentiating patients with panic disorder from nonpsychiatric subject controls(thus, in a group of subjects with a 50% prevalence of panic disorder, the positive predictive value of the test would be 86%).
Several studies addressed the issue of whether lactate-induced panic attacks andnaturally occurring attacks were symptomatically similar or comparable. Liebowitz andcolleagues [29] found that both lactate-induced and naturally occurring panic attacks were
symptomatically similar. In a study by Balon and colleagues [40], patients rated bothdextrose (presumably spontaneous) and lactate-associated attacks between moderately andvery much similar to their usual attacks. Lactate attacks were rated slightly more similar,
possibly because they were rated as more severe and were associated with more somatic
symptoms of anxiety. Aronson and colleagues [37] also noted a high degree of similarity
between lactate-induced and naturally occurring panic attacks. In the largest single cohortof lactate-infused panic disorder subjects [41], the vast majority of subjects rated thelactate-induced panic attacks as very similar to their typical panic attack. The overall
severity level was very similar, and both the physical and anxiety symptoms were overwhelmingly rated as similar. However, a substantial minority of the lactate nonpanickers
also rated the lactate infusion experience as similar to their “usual” panic attacks. Three
symptoms—afraid in general, dyspnea, and desire to ﬂee—were the most predictive andrevealing of panic response to lactate [41].
Various studies examined the diagnostic speciﬁcity of lactate infusions. Only 1 of
7 obsessive-compulsive disorder but 26 of 48 panic disorder patients panicked duringsodium lactate infusion in a study by Gorman and colleagues [42]. Similarly, only 1 of
15 patients with social phobia and 10 of 20 panic disorder patients panicked during lactate
infusions in a study by Liebowitz and colleagues [43]. Sodium lactate induced ﬂashbacks
in all seven patients with post-traumatic stress disorder (PTSD), six of whom also met
the criteria for panic disorder [44]. Sodium lactate also induced panic attacks in six ofthese PTSD patients [44]. Interestingly, sodium-lactate-induced ﬂashbacks in six of seven
PTSD subjects without comorbid panic disorder, but no panic disorder or healthy subjects
reported ﬂashbacks or other intrusive PTSD symptoms during lactate infusion in a study
by Jensen and colleagues [45]. In the same study [46], ﬁve of seven subjects with PTSD
experienced sudden onset of anxiety sufﬁcient to meet the criteria for panic attacks. These
panic attacks were phenomenologically similar to lactate-induced panic attacks induced in706

Balon et al.

panic disorder patients. Cowley and colleagues [47] reported that patients with generalized
anxiety disorder reacted more like panic disorder patients during lactate infusions. Thisconclusion was criticized by Liebowitz and Hollander [48], who pointed out that only 1of 9 generalized anxiety patients panicked with lactate in the Cowley and colleagues study[47] compared to 9 of 22 panic disorder patients.
Other diagnostic categories outside the realm of anxiety disorders have also beenstudied. Alcoholic patients with panic disorder had fewer panic attacks in response tolactate than nonalcoholic patients with panic disorder [49] in a study by George and colleagues. Alcoholics with panic attacks had a signiﬁcantly higher rate of lactate-induced
panic than alcoholics without panic attacks in a study by Cowley and colleagues [50]. Ina study of bulimic patients by George and colleagues [51], none of the bulimic patientspanicked during lactate infusion. In a study by Lindy and colleagues [52] 4 of 18 bulimics(one with a history of panic disorder) had a panic attack during lactate infusions. Finally,
Pohl and colleagues [53] reported that four of eight bulimics experienced a panic attack
during lactate infusions. All bulimics in this study had concurrent panic attacks. Cowley
and colleagues [54] reported similar rates of panic response to lactate in patients withboth primary depression and secondary panic attacks and patients with panic disorder. In
another study [55], Cowley and colleagues also found that patients with major depression
without panic attacks had a much lower response to lactate than did panic disorder patients.
McGrath and colleagues [56] reported signiﬁcantly higher response to lactate in depressed
patients with panic attacks than in depressed patients without panic attacks. These ﬁndings
were conﬁrmed by Cowley and colleagues [57], Buller and colleagues [58], and Targum[59]. Sandberg and colleagues [60] reported that 7 of 13 women with marked premenstrual
dysphoric changes and none of seven controls panicked while infused with sodium lactate.
Finally, George and colleagues [61] reported that sodium lactate administration elicitedintense emotional response—rage, panic, greater changes in speech, breathing, and motor
activity—in perpetrators of domestic violence compared to nonviolent control subjects.
The majority of studies suggest that lactate-induced panic is associated with a recent
history of panic attacks rather than the diagnosis of panic disorder. It seems to be a staterather than a trait marker. Lactate has a moderate sensitivity and good speciﬁcity in distinguishing subjects with panic attacks from controls and from patients without coexisting
panic attacks [11].
B.

Studies Focused on Etiology

Various theories on the etiology of panic hypothesize most frequently the involvement of
the noradrenergic and serotonergic systems. Noradrenergic theories often focus on either
α- or β-receptor systems. Other theories suggest abnormalities in chemoreceptor sensitivity and sudden changes in peripheral biochemistry, such as acute respiratory alkalosis.
Most of the challenge studies focusing on the possible etiology of lactate-induced panic
were performed during the 1980s.
1. Noradrenergic Mechanism
The role of the noradrenergic mechanism in the etiology of lactate-induced panic has beenentertained by several authors [30,37,62–65]. Liebowitz et al. [30,63] hypothesized that
lactate-induced panic involves central noradrenergic discharge, with inconsistent peripheral manifestation, and that a peripheral catecholamine surge is not the mechanism oflactate-induced panic. In their study, lactate-induced panic attacks were regularly accom-

Provocation and Pathogenesis of Anxiety Disorders

707

panied by biological changes consistent with hyperventilation and central noradrenergic
activation (elevated heart rate and lowered PCO2 and bicarbonate levels). Elevations ofplasma norepinephrine and cortisol were irregular, and changes in lactate, pyruvate, pH,
phosphate, epinephrine, and diastolic blood pressure were not consistent during panic
attacks. The ﬁndings on epinephrine levels during lactate infusions in various studies havebeen contradictory [27,30,31].
Patients who panicked during lactate infusions showed higher mean plasma 3-methyl4-hydroxyethylene glycol (MHPG), a major metabolite of peripheral and central norepinephrine, and a higher anxiety rating at baseline in a study by den Boer and colleagues[66]. On the other hand, Pohl and colleagues [64] did not ﬁnd plasma MHPG elevation atbaseline, nor during lactate or isoproterenol infusions, in panic disorder patients and controls. Carr and colleagues [31] also found neither a signiﬁcant increase of MHPG duringlactate-induced panic nor any correlation between various biochemical and neuroendocrine
variables and lactate-induced panic. Urinary output of homovanillic acid and 4-hydroxy3-methoxymandelic acid (catecholamine metabolites) was decreased in patients with panic
attacks and in controls during lactate infusions in a study by Clow and colleagues [35].
Propranolol, a β-receptor blocking agent, does not block panic attacks or prolong
the time to panic during lactate infusions [62]. This ﬁnding casts doubt on a β-adrenergic
hypothesis of panic as an explanation for lactate-induced panic. Intravenous propranolol
reduces lactate-induced panic only negligibly, whereas intravenous diazepam is quite
effective [37,65]. Clonidine pretreatment did not lower prelactate anxiety, but blocked
lactate-induced panic in 4 of 10 subjects in a study by Coplan and colleagues [67].
Several studies focused on the response to lactate after successful treatment withvarious medications and its signiﬁcance for the etiology of panic anxiety. Rifkin [68]demonstrated blockade of lactate-induced panic with tricyclic antidepressants. In a study
by Fyer and colleagues [69], 7 of 13 patients panicked with lactate before treatment withtricyclic antidepressants, but none of them panicked with lactate while treated. This suggests that lactate vulnerability can exist in clinically well, unmedicated patients and may
be a trait characteristic. Successful alprazolam therapy also blocked lactate vulnerability
in studies by Liebowitz and colleagues [63] and Cowley and colleagues [70]. In anotherstudy, Liebowitz and colleagues [71] also reported that pretreatment with diazepam (5 mgi.v.) signiﬁcantly attenuated the effects of lactate-induced panic in panic disorder patients,
although it did not block the lactate-induced panic in a majority of patients. Gorman etal. [72] reported a detailed analysis of patients reinfused with lactate after treatment withvarious antipanic medications. They suggested that the nine symptoms that responded todrug therapy were associated with hyperventilation, and that antipanic drugs may have a
speciﬁc effect in blunting hyperventilation. Yeragani and colleagues [73] also reported
that tricyclic antidepressants appeared to increase the threshold for lactate-induced panic.
Pohl and colleagues [74] found that panic disorder patients treated with either imipramine
or diazepam had signiﬁcantly less lactate-induced anxiety than placebo-treated patients
when reinfused with lactate. Imipramine also decreased post-treatment panic attack frequency and diazepam decreased the perceived severity of post-treatment lactate-induced
panic. Interestingly, in a study by Keck and colleagues (75), valproate blocked reinductionof panic symptoms on lactate rechallenge in 83% of patients who initially experienced
panic symptoms on initial infusion. Thus, in summary, several studies demonstrated successful blockade of lactate-induced panic with various psychotropic drugs. However, noneof the above-mentioned treatment studies provide any deﬁnitive clues as to the etiologyof lactate-induced panic. The success of blockade can be explained by several mechanisms

708

Balon et al.

(e.g., a decrease in the respiratory rate and blockade, or downregulation of various receptors and decreased sensitivity to repeated lactate challenge).
The ﬁndings linking the mechanism of lactate-induced panic to noradrenergic systems are weak. Other provocative techniques seem to be better suited for addressing
the involvement of the α-adrenergic (yohimbine) or the β-adrenergic (isoproterenol) systemin the etiology of panic anxiety. The involvement of another neurotransmitter, serotonin,in the etiology of lactate-induced panic was suggested by Lingjaerde [76] and others.
Lingjaerde [76] theorized that lactate may stimulate serotonin reuptake in central serotonergic neurons and thereby induce anxiety by reducing the inhibitory serotonergic inﬂuence on the locus coeruleus.
2. Neuroendocrine Findings
Various endocrine organs are involved in central and peripheral neurotransmitter regulation. Abnormalities of the hypothalamic-pituitary-adrenal axis (HPA) during stress led
several authors to study the abnormalities of this axis during lactate-induced panic. Levinand colleagues [77] measured cortisol and corticotropin during lactate-induced panic anddid not ﬁnd elevation of either hormone. Plasma β-endorphin decreased slightly, but signiﬁcantly, during lactate infusions in panic disorder patients, depressed patients, and controls [78]. This ﬁndings suggests that the HPA axis is not activated by lactate-induced
panic, as ACTH and β-endorphin arise from the same precursor molecule in the anterior
pituitary gland. Appleby and colleagues [27] and Carr and colleagues [31] also did notﬁnd evidence for pituitary-adrenal activation during lactate-induced panic. Similarly,
Peskind and colleagues [79] reported that neither sodium lactate nor hypertonic sodium
chloride increased cortisol or ACTH in panic disorder patients and controls. However,plasma arginine vasopressin increased during both infusions, a response typical for acute
hypernatremia. Untreated and treated panic disorder patients have a plasma vasopressin
response to lactate similar to normal subjects [80], a ﬁnding suggesting intact posterior
pituitary function in these patients. Kellner and colleagues [81,82] suggested that the lackof pituitary-adrenocortical activation during lactate-induced panic is due to an immediaterise of atrial natriuretic hormone which suppresses both ACTH and cortisol release. Den
Boer et al. [66] also found no single neuroendocrine variable (cortisol, β-endorphin) tocorrelate with lactate-induced panic.
Thus, the neuroendocrine ﬁndings during lactate-induced panic do not clearly support any single hypothesis for induction of such panic.
3. Respiratory and Biochemical Findings
Shortness of breath and hyperventilation are frequent symptoms of spontaneous andlactate-induced panic attacks [83,84]. Lactate is metabolized to bicarbonate and subsequently to carbon dioxide and water. Carbon dioxide then easily passes the blood-brain
barrier. Centrally perceived hypercarbia may cause hyperventilation and panic [85]. However, D-lactate, which is poorly metabolized to carbon dioxide, does induce panic [86].
The role of carbon dioxide in the induction of anxiety and in the etiology of panic attacks
will be discussed in detail later.
Panicking patients have a lower PCO2 than nonpanicking patients during lactate
infusions [30]. Carbon dioxide pressure decreases during the lactate infusion [87] andlactate causes metabolic alkalosis. However, metabolic and respiratory alkalosis develops
in all subjects during lactate infusions, whereas only hyperventilation-induced hypocapnia
differentiates panickers and nonpanickers. Patients who had an acute panic attack during

Provocation and Pathogenesis of Anxiety Disorders709

lactate infusion had a greater increase in minute ventilation over baseline than nonpanicking patients or controls in a study by Gorman and colleagues [83].
Gaffney and colleagues [36] similarly described hyperventilation during lactateinduced panic, together with hypernatremia, hypocalcemia, and decreased bicarbonate levels. They suggested that sodium lactate produces panic by mimicking the physiology of
spontaneous panic. Gorman and colleagues [88], in a study addressing the proposed theory
of Grosz and Farmer [89], infused panic patients with lactate and with sodium bicarbonate,a sodium lactate metabolite. They reported a similar rate of panic during both infusions,although lactate appeared to be a stronger stimulus. Lactate induced a decrease in PCO2
in panickers and nonpanickers, whereas bicarbonate decreased PCO2 only in panickers.
D-Lactate also produced hypocapnia [14]. Venous PCO2 normalized after treatment withtricyclic antidepressants [90]. These ﬁndings suggest ventilatory dysregulation as a possible cause of panic anxiety. However, it is not clear whether this mechanism is peripheralor central. Maddock and colleagues [91] noted exaggerated increases in serum lactate inpanic disorder (PD) patients following hyperventilation during glucose infusion; however,the lactate response was not correlated with heart rate, PCO2, and other variables. Coplan
and colleagues [92] infused nonhuman primates with lactate and saline and measured
their cerebrospinal ﬂuid (CSF) and venous blood lactate, pH, PCO2, PO2, and bicarbonate.
Despite the development of characteristic peripheral biochemical effects of infused sodium
lactate (increased lactate and bicarbonate levels, metabolic alkalosis), no increase in central lactate or carbon dioxide were observed. However, according to Dager and colleagues[93], lactate appeared to cross the blood-brain barrier, and lactate concentrations in cisternal ﬂuid increased three times during the intravenous lactate infusions in baboons. In
another study, Dager and colleagues [94] observed signiﬁcantly higher brain lactate levels(using proton magnetic resonance spectroscopy) in panic disorder patients panicking during lactate infusion. The mechanism of the brain lactate rise was not clear. Hyperventilation may have a role in producing higher lactate levels in these subjects [94].
Data from several studies [30,85,95] did not support the role of lactate-induced
hypocalcemia initially suggested by Pitts and McClure [9] and Fink et al. [24]. Althougha signiﬁcant decrease in plasma inorganic phosphate during lactate infusions was observedby Liebowitz and colleagues [30], no consistent change in phosphate levels accompanied
lactate-induced panic. Inorganic phosphate also decreased during lactate infusions in studies by Gaffney and colleagues [36] and Aronson et al. [37], and during D-lactate infusions[86]. A signiﬁcantly lower inorganic phosphate level at baseline was found in patients who
panicked during subsequent lactate infusion when compared with nonpanicking patients in
two studies [86,96]. However, other authors [97] were not able to replicate this ﬁnding.
Hyperventilation is the most probable cause of phosphate decrease during the infusions.
Baseline hypophosphatemia suggests an abnormal metabolic state.
Other biochemical changes, such as an alteration in the body’s NAD⫹/NADH ratio,
are speculative and were discussed by other authors [30].
4. Cognitive Theories
Many authors [98,99] suggested that lactate produces panic through conditioning and cognitive mechanisms. According to this theory, the large volume of hyperosmolar ﬂuid infused produces various symptoms and cues panic. Peskind and colleagues [79] were able
to produce the same high incidence of panic and equivalent increases in panic symptoms
in panic disorder patients by infusing them with sodium lactate or hypertonic saline (3%NaCl). This suggests that a rapid increase in sodium or osmolality may be involved in710

Balon et al.

panic induction. Gorman and colleagues [86] infused patients with sodium D-lactate,
which is poorly metabolized. D-Lactate produced panic, hypocapnia, and alkalosis,
thereby indicating hyperventilation. Even though lactate metabolism may not be necessary
for panic induction, D-lactate may work through some other, as yet unknown, mechanism.
As discussed before [91–94], it is not clear whether lactate crosses the blood-brain barrier,although some studies [93,94] reported increased CNS or CSF lactate concentrations during intravenous lactate infusions. The perception of various cues may be inﬂuenced by
the severity of anxiety, especially before the infusion. Some authors, therefore, focusedon the role of baseline anxiety on subsequent response to lactate. Liebowitz and colleagues[30] found a greater baseline autonomic arousal in subsequent panickers. Cowley andcolleagues [100] reported that patients who had a typical panic attack with lactate hadhigher baseline symptom ratings, but these did not fully account for the differences in
response to lactate. They felt that baseline measures may inﬂuence how a patient reaches
the threshold for panic. Two other studies [37,101] reported similar ﬁndings. Yeragani etal. [102] studied the effects of infusion-induced panic anxiety on subsequent preinfusion
anxiety and infusion-induced panic attacks during repeated infusions. Although there wasa decrease of preinfusion anxiety from one infusion to the next, there was no evidenceof a signiﬁcant decrease or increase in the frequency of subsequent panic attacks. In a
study by Targum [39], patients with high frequency of panic attacks (at least one attack
a week) reacted positively to lactate infusions, whereas patients with low frequency ofpanic attacks (one or fewer a month) did not respond to lactate infusions. The author feltthat the current heightened anticipatory state (inﬂuenced by recent spontaneous attacks),
rather than a putative underlying trait, predominates in the provocation of panic. Interestingly, cognitive behavioral therapy decreased the vulnerability to subsequent lactate infusion in a study by Shear and colleagues [103]. It seems plausible that cognitive misperception may play a signiﬁcant role in triggering panic attacks during lactate infusions.
5. Miscellaneous
Many other hypotheses of panic etiology have been tested. Gorman and colleagues[104,105] addressed the popular idea that hypoglycemia causes panic attacks. They infused
two sets of panic disorder patients with 0.5 M sodium lactate, and they did not ﬁnd any
evidence of low blood sugar levels during lactate-induced panic attacks [104] nor signiﬁcant changes in insulin levels [105]. However, coadministration of glucose resulted in a
reduced sensitivity to the panicogenic effects of lactate in a study by George and colleagues[106], which could be explained by the effect of glucose on the adrenergic system, catastrophic misinterpretation, and other possibilities.
There is no support for the involvement of endogenous opiates in the pathogenesis
or control of panic attacks [107]. Cowley and Dunner [108] found a lack of signiﬁcantassociation between lactate response and presenting clinical variables. Patients with apanic response to lactate were more likely to report a deﬁnite history of panic attacks inat least one ﬁrst-degree relative in their study. Balon and colleagues [109] found a higher
prevalence of anxiety disorders among ﬁrst-degree relatives of controls who panicked
during lactate infusion than in those who did not panic. Two of these controls subsequently
developed panic attacks and, in one of them, panic attacks began soon after the infusion[110]. Both of these ﬁndings [108,109] suggest some genetic vulnerability to lactateinduced panic. George et al. [111] reported a marked reduction of parasympathetic nervous
activity (vagal tone) in six healthy volunteers during lactate administration and hyperventilation. They hypothesized that this reduction facilitates sympathetic activity (tachycardia).

Provocation and Pathogenesis of Anxiety Disorders

711

Several other studies focused on autonomic regulation in panic disorder patients duringlactate infusions. Yeragani and colleagues [112] suggested an exaggerated cardiac vagal
withdrawal in PD patients during lactate infusions. Panic disorder patients had a greater
cardiac and respiratory reactivity than healthy controls with lactate infusions during sleep
when the inﬂuence of cognitive factors is minimal or absent [113]. There were also substantial differences in autonomic regulation during lactate infusions between PD patientsand healthy controls in a study by Sloan and colleagues [114].
C. Summary
Sodium lactate is a speciﬁc (89%) and reliable provocative technique of panic attacks,
similar to naturally occurring panic attacks, and accompanied by similar physiologicalchanges. Lactate-induced panic is blocked by antipanic drug treatment. The presented
studies clearly demonstrate that the pathogenesis of lactate-induced panic is still unknown.
Various theories of lactate-induced panic, such as hypocalcemia, hypophosphatemia, hypoglycemia, hypersensitive β-adrenergic receptors, sudden shifts in pH, alkalosis, stimulation of central noradrenergic centers, decreased α1-adrenergic receptor density, endogenous opioid dysregulation, reduction of inhibitory serotonergic inﬂuence on the locus
coeruleus, hypothalamic-pituitary-adrenal axis stimulation, decrease in parasympathetic
activity (vagal tone), increase in tribulin, alteration of NAD⫹/NADH ratio, hyperventilation, chemoreceptor sensitivity, carbon dioxide sensitivity, ﬂuid expansion, and cognitive
theories (nonspeciﬁc stress, interceptive phobic cues) [115] have been entertained. Ventilatory dysregulation (stimulation of ventilation) and cognitive misinterpretation of peripheral cues may be the most plausible explanations at present. However, as Griez and
Schruers [2] pointed out, “In contrast to the growing body of data on the validity of lactate
infusion as a laboratory model of panic, no convincing progress has been made in answer
to the question of why patients panic from lactate.”
III. CARBON DIOXIDE
Shortness of breath is one of the prominent symptoms of panic attacks. Accompanying
hyperventilation leads to an increased exhalation of carbon dioxide and lowering of arterial
concentration of carbon dioxide (CO2). Therefore, one would assume that increased inhalation of CO2 would decrease anxiety. Carbon dioxide did actually reduce anxiety in somestudies. Griez and van den Hout [116] reported that double inhalation of a mixture of
35% CO2 and 65% oxygen reduced anxiety levels in 12 healthy volunteers. These authors
also used this technique, together with exposure, in the treatment of “phobophobia” [117].
Wolpe [118] strongly advocated the use of CO2 inhalation in the treatment of anxiety.
However, most studies report an anxiogenic effect of inhaled CO2. Cohen and White[8] found that the rebreathing technique, which increases CO2 levels, produced anxiety
attacks in anxiety neurosis patients. In another study [119], 7 of 12 (58%) panic disorderpatients panicked during increased ventilation stimulated by 5% CO2, and three of themalso during room–air hyperventilation. The rate of CO2-induced panic was similar to therate of lactate-induced panic in this study. Gorman et al. [84] later expanded their sample
to 31 patients and reported that 39% of them panicked with 5% CO2 and 23% with room–
air hyperventilation. They also administered 7% CO2 to some subjects who did not panic
during the 5% CO2 challenge. Most of the 5% CO2 nonpanickers panicked with 7% CO2.
These ﬁndings were replicated by the same group [120] in a methodologically improved

712

Balon et al.

study, which also conﬁrmed a better discrimination between patients and controls with
7% CO2. The 5% CO2 also provoked panic in 8 of 14 panic disorder patients in a study
by Woods et al. [121].
van den Hout and Griez [122] demonstrated that inhalation of 35% CO2 and 65%
oxygen resulted in autonomic symptoms highly reminiscent of natural or lactate-induced
panic in normal subjects. When CO2 inhalation was preceded by intake of a β-blocker(60 mg of propranolol), fewer symptoms occurred than when preceded by a placebo. The
same procedure provoked short-lived autonomic panic symptoms in both panic disorderpatients and normal controls [123], but high subjective anxiety was elicited only in patients. Other researchers [115,124–126] also reported that this procedure provoked higher
anxiety in panic patients than in controls. Zandbergen and colleagues [127] reported signiﬁcantly higher anxiety during 35% CO2 challenge in PD patients, when compared withthe response during this challenge in normal persons and during hyperventilation in bothpatients and normal subjects. They suggested that panic disorder patients are speciﬁcally
hypersensitive to an increase in CO2 pressure. Anxiety ratings increased markedly during
rebreathing both in patients and controls in a study by Woods and colleagues [128], andanxiety increases were signiﬁcantly greater in patients than in healthy subjects. Ventilatory
response to carbon dioxide was similar in patients and controls. On the other hand, Lousberg and associates [129] reported that panic patients showed signiﬁcantly higher ventilatory response than normal controls using the same rebreathing technique. A number ofother studies [130–134] conﬁrmed the anxiogenic effect of various concentrations of CO2.
The role of CO2 as a laboratory model for initiating panic has thus been clearly established.
A.

Studies Focused on Diagnostic Speciﬁcity

As with lactate, several studies tried to address the diagnostic speciﬁcity of CO2 challenge[14,84,135–145]. Patients with other anxiety disorders such as social phobia, generalized
anxiety disorder, and obsessive-compulsive disorder did not panic, whereas, in a study
by Gorman and colleagues [84], 39% of panic disorder patients panicked during 5% CO2
challenge.
Patients with social phobia were the most frequently studied group besides panic
disorder patients. All three patients with social phobia and 67% of panic disorder patientspanicked during subsequent challenge with 7% CO2 in the aforementioned study [84]. On
the other hand, 36% of social phobics compared with 50% of panic disorder patientspanicked during 35% CO2 challenge in another study by Gorman and colleagues [14].
The difference in the frequency of panic between patients with social phobia and panic
disorder patients was even larger (18.7% vs. 62.5%) during single inhalation of 50% CO2
in a study by Rapee and colleagues [135]. Papp and colleagues [136] reported panic rates
of 72% for PD patients and 30% for social phobia patients in a study with 35% CO2.
Interestingly, 5.5% CO2 did not differentiate well speciﬁc phobias and panic disorder ina study by Antony and colleagues [137]. In a study by Verburg and colleagues [140], a
comorbid depressive disorder appeared to increase the vulnerability of panic disorder patients to 35% CO2. In studies by Perna and colleagues [141,142], 35% CO2 challenge
differentiated well between panic disorder and generalized anxiety disorder [141] andbetween panic disorder and obsessive-compulsive disorder [142]. Patients with comorbid
panic and generalized anxiety or obsessive-compulsive disorder responded to 35% CO2
similarly as patients with panic disorder. Nine of 14 women with premenstrual dysphoria
without panic disorder panicked during 35% CO2 challenge, compared with none of 12

Provocation and Pathogenesis of Anxiety Disorders713

controls [143]. Interestingly, anxiety after 35% CO2 inhalation was signiﬁcantly stronger
in the early follicular phase than in the midluteal phase in patients with panic disorder[144]. Finally, Ware and colleagues [145] used the 35% CO2 challenge as a diagnostic
tool in the evaluation of suspected panic disorder. Carbon dioxide seems to be somewhat
less panic-disorder-speciﬁc than lactate. The sensitivity to CO2 in panic disorder patients
may be concentration-dependent, and Gorman and colleagues [14] suggested that increasing the concentration/dose of CO2 may compromise diagnostic speciﬁcity. Further studies
could help to better elucidate the sensitivity and speciﬁcity of this technique.
B. Studies Focused on Etiology
Results of animal studies present some theoretical basis for the mechanism of anxiety
induction with CO2. For instance, hypercapnia caused a rapid increase in the ﬁring rateof the locus coeruleus neurons of rats [146]. Gorman and colleagues [119] theorized thatthe similarity in response to lactate and CO2 in their patients was suggestive of the involvement of CO2 (lactate → bicarbonate → carbon dioxide) in triggering anxiety by stimulationof the locus coeruleus. CO2-induced panic was associated with an exaggerated ventilatory
response and increases in plasma norepinephrine and diastolic blood pressure [84], suggesting that patients may have hypersensitive CO2 receptors. On the other hand, the complex physiological and biochemical measurements (MHPG, plasma cortisol, prolactin,
growth hormone) obtained in a study by Woods and colleagues [120] did not elucidate
the anxiogenic effect of CO2, and Gorman and colleagues [14] were not able to ﬁnd asigniﬁcant group difference in anxiety level, physiological, or biochemical variables in
response to 35% CO2. However, 35% CO2 may be too high a concentration [14].
Various studies addressed biological changes during CO2 challenge and their relationship to possible etiology. Martinez and colleagues [147] observed signiﬁcantly greater
blood pressure reactivity in PD patients than in nonpanickers or controls, but they did notobserve any overall difference in hemodynamic responses between patients and controls.
Sinha and colleagues [148] noticed decreased cortisol levels after CO2 challenge. The
results of a study by Welkowitz and colleagues [149] suggested that CO2-induced panic
is a robust biological effect that occurs independent of cognitive set changes, thus theprobability of cognitive misperception seems to be small. Tryptophan depletion caused agreater anxiogenic response and an increased rate of panic attacks after 5% CO2 challengein PD patients [150]. This ﬁnding suggests involvement of the serotonin system in the
etiology of CO2-induced panic. Interestingly, premedication with cholecystokinin tetrapeptide (a panicogenic agent, see below) decreased panic symptoms upon 35% CO2 challenge
in healthy volunteers [151]. Dager and colleagues [152] reported that hyperventilation
disproportionately increased brain lactate in PD patients. Finally, two studies [153,154]
suggested increased hypersensitivity to 35% CO2 in ﬁrst-degree relatives of PD patients.
These ﬁndings suggest a degree of genetic vulnerability.
Several studies also reported on the effect of treatment on CO2-induced anxiety andits relation to etiology. Venous pH, venous PCO2, and bicarbonate were normalized inpanic patients after treatment with tricyclic antidepressants or clonidine [90]. Beckett andcolleagues [155] reported blockade of rebreathing-induced panic attack with clonazepam
in a patient with panic disorder. Alprazolam markedly attenuated anxiety increases during
rebreathing of 5% CO2 in eight panic disorder patients [128]. The authors hypothesizedthat alprazolam may antagonize CO2-induced anxiety by decreasing noradrenergic function through stimulation of benzodiazepine receptors located on noradrenergic neurons.

714

Balon et al.

Pretreatment with alprazolam, but not with clonidine, signiﬁcantly reduced the rebreathing-induced increase in anxiety [156]. The anxiogenic effect of rebreathing 5% CO2 wassigniﬁcantly reduced in six patients after long-term imipramine treatment [157], a ﬁnding
consistent with an increase of noradrenergic function in CO2-induced anxiety. Furthermore, alprazolam [158] and similarly clonazepam [159] blocked the 35% CO2-provokedpanic in PD patients. Various antidepressants (mostly imipramine) or cognitive-behavioral
therapy (CBT) reduced CO2 sensitivity in PD patients in a study by Gorman and colleagues[160]. Three other antidepressants, toloxatone (monoamine oxidase type A inhibitor)[161], ﬂuoxetine [162], and citalopram [163] also signiﬁcantly reduced 35% CO2 reactivity
in PD patients. CBT was successful in reducing the sensitivity to 35% CO2 in PD patientsin a study by Schmidt and colleagues [164]. Thus, treatments usually successful in thetreatment of PD are also successful in blocking the effect of CO2 in PD patients.
Other authors have suggested additional physiological, behavioral, and cognitive
explanations of CO2-induced panic. Griez and van den Hout [165] reported that CO2 produced largely sympathomimetic responses in the cardiovascular system of healthy subjects. van den Hout and Griez [166] indicated that the occurrence of peripheral panic
symptoms in healthy volunteers after CO2 inhalation in their study could be attributed tothe sudden decrease in arterial PCO2. These authors [167] also suggested that hypocarbia
alone is not sufﬁcient to provoke anxiety in patients. van den Hout and colleagues [115]observed a decrease in anxiety with the increased number of CO2 challenges and suggested
that their data support a behavioral explanation of the anxiogenic effect of CO2. Subjects
with panic attacks who were given no explanation reported a greater proportion of catastrophic cognition and greater panic than those with panic attacks who received a full
explanation [135]. Another possible contribution of psychological factors to the laboratory
induction of panic was presented in a study by Sanderson and coauthors [168]. Patients
who believed that they had control over CO2 administration reported a smaller amount ofanxiety and less intense anxiety than the patients who believed that they could not control
the CO2 administration.
The etiology of CO2-induced panic remains unknown. Hypersensitivity of carbon
dioxide receptors, increase in noradrenergic function, or cognitive misinterpretation of
peripheral symptoms induced by CO2 are the most plausible explanations. It is interestingthat benzodiazepines, respiratory depressants, and various breathing techniques are effective in treatment of panic.
C.

Summary

Carbon dioxide is a valid and relatively convenient model of panic anxiety. It provokes
anxiety similar to naturally occurring panic and its anxiogenic effect is successfully
blocked by antianxiety agents. The speciﬁcity of this model may be dose- or concentrationdependent. The etiology of CO2-induced panic anxiety remains unknown. The issue ofoversensitivity of chemoreceptive areas in PD subjects is still open to debate [2]. Klein’s
suffocation alarm theory of panic [169], according to which PD patients have a hypersensitive suffocation monitor that predisposes them to experiencing a panic attack under certain
conditions, provides an elegant explanation of CO2 and some other challenges, but not of
all anxiety provocation tests.
IV. YOHIMBINE
Yohimbine is an α2-adrenergic antagonist. It interacts with adrenoreceptors that are selectively stimulated by clonidine, but it can also interact with α1-receptors. It has been well

Provocation and Pathogenesis of Anxiety Disorders

715

established that α2-adrenoreceptors regulate sympathetic ﬂow in intact animals and humans. Increased noradrenergic function may play a pivotal role in the pathophysiologyof anxiety states [170]. The nucleus locus coeruleus (LC) is a collection of noradrenergic
neurons in the brain stem, and electric stimulation of this nucleus in monkeys results infearful behaviors, whereas destruction of this nucleus reduces such responses [171,172].
The same investigators have demonstrated that activation of LC by yohimbine produces
an increase in LC ﬁring and produces fearful behaviors.
In humans, yohimbine produces symptoms of anxiety and an increase in heart rate
and blood pressure [173]. Charney and colleagues [174] gave 30 mg of yohimbine to 10
healthy subjects, and this resulted in increases in subjective anxiety, blood pressure, andplasma MHPG. In this study, both diazepam and clonidine signiﬁcantly antagonizedyohimbine-induced anxiety. In another study, Charney and colleagues [175] administered
20 mg of yohimbine orally to 20 healthy controls and 39 drug-free patients with agoraphobia and panic attacks. This resulted in a signiﬁcantly greater anxiety and somatic symptoms, such as palpitations, hot and cold ﬂashes, restlessness, and tremors in patients compared with controls. Patients with frequent panic attacks also had a signiﬁcantly higher
plasma MHPG response to yohimbine than did normal persons. Gurguis and Uhde [176]and Gurguis and colleagues [177] reported that in their study panic disorder patients had
a greater anxiogenic response to 20 mg of yohimbine than controls.
Charney and Heninger [178] reported that alprazolam treatment of panic disorderpatients was associated with a decrease in baseline MHPG levels and blunting of theyohimbine-induced increase. They speculated that the antipanic mechanism of actionof alprazolam may be due to an interaction between benzodiazepine-sensitive andnoradrenergic neural systems. Charney and Heninger [179] also speculated that theregulation of noradrenergic activity is aberrant in some patients with PD. They [179]suggested that the increased dynamic range of noradrenergic activity observed as anincreased sensitivity to both yohimbine and clonidine may be due to abnormalities in regulatory input to noradrenergic neurons or dysfunction in the α2-adrenergic receptoreffector-coupling mechanism. Rasmussen and colleagues [180] found that yohimbine, administered to 12 drug-free patients with obsessive-compulsive disorder and 12 healthy
subjects, had no signiﬁcant effect on obsessive-compulsive symptoms. Southwick andcolleagues [181] studied administration of yohimbine in PTSD patients. Yohimbine induced signiﬁcant increases in core PTSD symptoms, and some of the patients experienced
yohimbine-induced ﬂashbacks and panic attacks (some patients had comorbid panic disorder). They speculated that uncontrollable stress produced substantial increases in noradrenergic neuronal function. Southwick and colleagues [182] also reported that 4 PTSD
subjects who took over-the-counter oral yohimbine experienced marked exacerbation ofanxiety/panic and PTSD-speciﬁc symptoms.
In summary, yohimbine appears to be an anxiogenic agent, and the yohimbine modelof anxiety has helped understand the pathophysiology of anxiety to a considerable extent.
However, it should also be noted that there are some inconsistencies with this model.
Some studies did not ﬁnd a baseline difference in MHPG levels between panic disorderpatients and controls [183]. Lactate-induced panic and caffeine-induced anxiety are notaccompanied by increases in plasma-free MHPG [64,80,184]. Although the yohimbine
model of anxiety is attractive, it is also possible that the increase in sympathetic ﬂow canresult in symptoms of anxiety through an additional β-adrenergic mechanism, as isoproterenol induces symptoms of panic anxiety in PD patients [19,185]. Last, but not least, aclinical caveat: yohimbine probably should not be used for treatment of sexual dysfunction
associated with medications in anxious patients.

716

V.

Balon et al.

CAFFEINE

Caffeine (1,3,7-trimethylxanthine) is a widely used psychotropic substance. Caffeine isassociated with an increase in self-rated symptoms of anxiety in several studies [186,187].
Caffeine in doses of 600 mg/day has been reported to result in caffeinism, characterized
by anxiety, sleep disturbances, and nervousness [188]. Caffeine is also known to produce
symptoms of panic anxiety in patients with anxiety disorders [189].
Boulenger and colleagues [186] found that PD patients, but not depressed patientsor normal controls, had levels of self-rated anxiety and depression that correlated with
their degree of caffeine consumption. They also found that panic disorder patients had
increased sensitivity to the effects of one cup of coffee. Furthermore, PD patients reported
more frequent discontinuation of coffee intake because of untoward side effects comparedwith controls. A proportion of PD patients reported reduction in panic attack frequency
after caffeine consumption reduction [190]. Eighty-four percent of anxious patients were
low-caffeine consumers, compared with 41% of medical inpatients in a study by Lee andcolleagues [187]. Uhde and colleagues [191] administered three different oral doses ofcaffeine (240, 480, and 720 mg) to eight normal controls and two panic patients. There
was a dose-related increase in measures of anxiety state in all subjects. Two normal controls developed unequivocal panic attacks after receiving 720 mg of caffeine. Charney
and associates [184] reported on the robust increases in subject-rated anxiety and nervousness in 11 healthy subjects after oral administration of 10 mg/kg of caffeine. They
[189] also found that PD patients had a signiﬁcantly greater anxiogenic response to caffeine (10 mg/kg), compared with controls, and the levels of anxiety were signiﬁcantly
correlated with plasma caffeine levels in patients. Caffeine increased plasma cortisol levels
equally in both groups. Mathew and Wilson [192] studied the effects of 250 mg of caffeine
in eight patients with generalized anxiety disorder, nine PD patients, and nine normal
controls. The anxiety disorder patients did not show any evidence of increased anxiety
and panic after caffeine. Both patients and controls who received caffeine had signiﬁcantdecreases in cerebral blood ﬂow. This study suggests that small doses of caffeine may
not induce symptoms of panic anxiety.
Several authors [193] proposed antagonism of adenosine effects as the mechanismof action of caffeine. Several other mechanisms may be involved in the anxiogenic response to caffeine. These include inhibition of phosphodiesterase, increased brain catecholamine activity [194], also consistent with ﬁndings in Charney and colleagues’ study[184], or antagonism of benzodiazepine and adenosine receptor function [195,196]. Caffeine’s anxiogenic effect may thus be related to several neurobiological systems, namely
noradrenergic, dopaminergic, adenosinergic, and even GABAergic. Alprazolam blocks
caffeine-induced anxiety [13]. Findings from a study by Orlikov and Ryzov [197] on
increased kynurenine (metabolite of tryptophan) during caffeine-induced anxiety in 15
male volunteers suggest the possibility of serotonergic system involvement.
The caffeine model of anxiety, although inconclusive as to the mechanism of its
anxiogenic effects, appears to be a useful research tool.

VI. ISOPROTERENOL
The role of catecholamines in the pathophysiology of anxiety has been studied for almosta century. In a study by Wearn and Sturgis [10] epinephrine reproduced the symptoms of“irritable heart,” a syndrome with functional cardiac symptoms and anxiety. In subsequentProvocation and Pathogenesis of Anxiety Disorders

717

studies, epinephrine provoked anxiety attacks in patients with anxiety disorders, but notin subjects with other psychiatric disorders [16,198]. Norepinephrine also induces anxiety
attacks in panic disorder patients [21].
Isoproterenol is a sympathomimetic amine, structurally very similar to epinephrine.
Unlike epinephrine, isoproterenol lacks α-adrenoceptor agonist effect and acts almost exclusively on β-adrenoceptors. In early uncontrolled studies, isoproterenol provoked intenseanxiety states in patients with a history of anxiety symptoms [199], and produced anxiety
attacks in subjects with a history of panic attacks [200]. In both studies, the anxiety states
quickly subsided after the intravenous injections of the β-blocker propranolol.
In a large double-blind study, Pohl and colleagues [185] found that PD patients
became much more anxious during isoproterenol infusions and were much more likely
to panic than normal controls (66% vs. 9%). In a follow-up experiment, 14 of the patientsin this study were reinfused with isoproterenol and placebo after treatment with tricyclic
antidepressants [201]. Thirteen of these 14 patients panicked before treatment, and only
two after treatment. The anxiogenic effects of isoproterenol in PD patients suggests thatβ-adrenoceptors may play a role in the pathophysiology of panic. One inconsistency inthe β-adrenergic model is that β-blockers are relatively ineffective for panic anxiety [202],
although they are effective for performance anxiety. However, this ﬁnding might be explained by the upregulation of β-receptors that occurs when β-blockers are given for an
extended time. Panic disorder patients may experience early improvement with propranolol that is not sustained [203]. Beta-blocker use for performance anxiety is generally
episodic, and since the drugs are only given before scheduled public performances, βreceptor upregulation would not occur.
The exact mechanism of isoproterenol-induced anxiety is not known, as isoproterenol (and epinephrine) does not readily cross the blood–brain barrier and some of thecentral effects may be mediated by isoproterenol’s peripheral effects. If isoproterenol exerts its anxiogenic effects outside the CNS, there are several possible explanations. One
is the possibility that, since provocative models of anxiety all have peripheral effects
and symptoms, drug-induced anxiety is a function of the psychological effects that occur
secondary to a provocative infusion (i.e., cognitive perception of the experience). Anotherpotential hypothesis is that PD is a peripheral disease of autonomic arousal, and that the
subjective symptoms of anxiety are a secondary phenomenon.
Isoproterenol is another reliable model of anxiety induction. As with the other provocation techniques, it induces anxiety similar to naturally occurring panic, and its effects
are blocked by antianxiety treatment. The relation of this model to CNS hypotheses ofanxiety is unknown.
VII. CHOLECYSTOKININ
Cholecystokinin is the most abundant neuropeptide in the CNS and also happens to be apanicogenic agent [15,204]. De Montigny [205] demonstrated that cholecystokinin tetrapeptide (CCK-4) can induce severe anxiety and brief panic attacks in healthy volunteers.
Cholecystokinin has been shown to induce panic attacks [206]. PD patients are moresensitive to the effects of CCK-4 than normal controls [207]. The panicogenic effect of
CCK-4 is dose-dependent [208,209].
The anxiety-provoking properties of CCK-4 are not limited to panic disorder only.
Women with premenstrual dysphoric disorder showed greater anxiety and panic response
to CCK-4 [210]. Similarly, though CCK-4 did not provoke ﬂashbacks in eight PTSD

718

Balon et al.

patients in a study by Kelner and colleagues [211], it induced panic in seven of thesepatients.
Infusion of CCK-4 did not activate the hypothalamic-pituitary adrenal axis and did
not increase plasma MHPG levels in one study [212]. However, CCK-4 increased thesecretion of ACTH, but not cortisol in another study with PD patients [213]. Interestingly,
CCK-B receptor agonist pentagastrin not only induced anxiety in healthy subjects, butalso signiﬁcantly increased ACTH and cortisol levels, blood pressure, and heart rate. The
effect of CCK-4 on respiration is not totally clear and may be dose dependent [214,215].
Bradwejn and colleagues [214] found that a fairly high dose of CCK-4 stimulates, among
other things, respiration in healthy volunteers. However, in a study by Schruers and colleagues [215], a lower dose of CCK-4 (10 µg) did not increase any of the respiratory
parameters in healthy volunteers. CCK challenge has similar behavioral effects as to theCO2 challenge [216].
The behavioral effects of CCK-4 in healthy volunteers were blocked by CI-988, a
CCK-B receptor antagonists [217]. However, this CCK-B receptor antagonist failed toblock the effects of CCK-4 in panic disorder patients [218]. Interestingly, clonidine also
failed to block the panicogenic effect of CCK-4 in PD patients [219]. However, CCK-B
receptor antagonists CI-998 and L-365,260 were not effective in the treatment of panic
disorder [220,221]. Interestingly, in a study by Bradwejn and Koszycki [222], PD patients
successfully treated with imipramine showed reduced sensitivity to the panicogenic effectof CCK-4. Similarly, ﬂuvoxamine [223] signiﬁcantly decreased the sensitivity of PD patients to CCK-4, while placebo was without effect.
Cholecystokinin tetrapeptide is an interesting anxiogenic agent. Its anxiogenic properties seem to be dose-dependent and not quite diagnosis-speciﬁc. The anxiogenic effectof CCK-4 could be blocked by various agents. Interestingly, its effect seems to be age
dependent [224]. The mechanism of action of CCK-4 is unclear. Rehfeld [225] outlined
some of the questions that need to be answered to elucidate the mechanism of action of
CCK-4 (e.g., whether endogenous CCK-4 exists, whether the panicogenic effect is mediated only through CCK-B receptors, and whether measurements of CSF CCK peptides
are useful).
VIII. SEROTONERGIC CHALLENGES—mCPP AND FENFLURAMINE
The involvement of serotonergic neurons in the pathophysiology of anxiety has been entertained especially after the ﬁnding of effectiveness of serotonergic antidepressants in various anxiety disorders. Meta-chlorophenylpiperazine (mCPP) was found to be anxiogenic
in panic disorder patients [226], obsessive-compulsive (OCD) patients [227–229], and in
higher doses in healthy volunteers [226]. However, mCPP has produced similar anxiety
increases and behavioral changes in PD patients and healthy controls in controlled studies[230,231]. Kahn and colleagues [232] also suggested that mCPP had pronounced side
effects that might induce anxiety as a cognitive side effect.
The ﬁnding of OC symptom exacerbation in OCD patients has also not always been
replicated [233,234] and may be dose-dependent [235]. Interestingly, mCPP increased infeeling calm and strange in schizophrenic patients and healthy volunteers in a study byMaes and Meltzer [236]. Methylphenidate, but not mCPP, produced psychotic symptoms
in ﬁrst-episode schizophrenia patients [237]. However, mCPP did decrease anxiety, hallucinations, and anger, and increased agitation, somatic concerns, and impaired understandability [237].

Provocation and Pathogenesis of Anxiety Disorders719

Fenﬂuramine, an indirect serotonin agonist, has been studied in anxiety [18] andother disorders. The anxiogenic effect of d-fenﬂuramine is unclear. It decreased simulated
public speaking anxiety in a study of healthy volunteers [238], and increased anxiety andconfusion in another study of healthy volunteers [239]. D-Fenﬂuramine caused anxiety
similar to generalized anxiety in PD patients, but reduced anxiety following 7% CO2 challenge [240]. In a study by McBride and colleagues [241], it did not signiﬁcantly exacerbate
OC symptoms in OCD patients.
The mCPP or fenﬂuramine challenges suggest possible involvement of the serotonergic system in the pathophysiology of anxiety. However, their exact mechanism ofaction remains unclear. These challenges are strictly a research and experimental tool.
One clinical caveat: mCPP provocation of anxiety in some sensitive patients may be themechanism of action of anxiety associated with some antidepressants, as mCPP is one of
their metabolites (e.g., nefazodone).

IX. BENZODIAZEPINE-RECEPTOR CHALLENGES
Several studies [17,242] reported provocation of panic anxiety with ﬂumazenil, a benzodiazepine antagonist, in some PD patients. However, in a study with lactate-sensitive PD
patients [243], ﬂumazenil did not induce panic attacks in PD patients. Flumazenil did not
provoke a high rate of panic attacks in social phobia (2 of 14 patients, none of 14 controls)[244]. In a study by Randall and colleagues [245], ﬂumazenil also did not produce anincrease of anxiety in PTSD patients. Flumazenil remains another experimental challenge
strategy. The mechanism of action is not clear. The theory of altered GABA-receptor
function in panic disorder needs to be further explored.

X.

CONCLUSION

Most of the provocative strategies discussed in this chapter have been replicated as
methods for inducing anxiety in panic disorder patients. Some of them, for instance, thebenzodiazepine-receptor or serotonergic challenges, are more controversial and their further use remains questionable. These challenges provoke anxiety that is similar to naturally
occurring panic anxiety, and they all have some threshold speciﬁcity. The methods vary,
but they share some possible common pathophysiology or mechanism: all may affect thenoradrenergic system and all could potentially be explained by cognitive misinterpretationof peripheral symptoms. Arguing against the latter is that many of the techniques occasionally provoke signs of anxiety in normal controls, and normal controls with a family historyof anxiety disorders may be at greater risk for this.
The provocative strategies are reversed by clinical treatment and, thus, clinicallyvalidated. As Woods et al. [128] pointed out, all provocation techniques appear to constitute useful neurobiological probes into the pathophysiology of panic anxiety. However,even though our knowledge of the biology of anxiety has increased enormously, the etiology of panic is still an enigma. These provocative techniques also seem to be an effectivemodel for conﬁrming the diagnosis of panic disorder [145] or the development and testing[103] of more speciﬁc and effective treatments. For instance, the CCK-B antagonist L365,260 failed to block lactate-induced panic [246] and was later found to be ineffectivein the treatment of panic disorder [221]. The results of provocation studies also tell usthat these substances should be used carefully in other situations in anxious patients (e.g.,

720

Balon et al.

cholecystokinin in GI tests; caffeine consumption in panic disorder; yohimbine in sexual
dysfunction associated with antidepressants).

REFERENCES
1. von Korff M, Eaton W, Keyl P. The epidemiology of panic attacks and panic disorder: resultsof three community surveys. Am J Epidemiol 1985; 122:970–981.
2. Griez E, Schruers K. Experimental pathophysiology of panic. J Psychosom Res 1998; 45:
493–503.
3. Freedman RR, Ianni P, Ettedgui E, Puthezhath N. Ambulatory monitoring of panic disorder.
Arch Gen Psychiatry 1985; 42:244–248.
4. Taylor CB, Sheik J, Agras WS, Roth WT, Margraf J, Ehlers A, Maddock RJ, Gossard D.
Ambulatory heart changes in patients with panic attacks. Am J Psychiatry 1986; 143:478–
482.
5. Balon R, Ortiz A, Pohl R, Yeragani VK. Heart rate and blood pressure during placebo associated panic attacks. Psychosom Med 1988; 50:434–438.
6. Jones M, Mellersh V. A comparison of the exercise response in anxiety states and normal
controls. Psychosom Med 1946; 8:180–187.
7. Cohen ME, Consolazio F, Johnson RE. Blood lactate response during moderate exercise inneurocirculatory asthenia, anxiety neurosis, or effort syndrome. J Clin Invest 1947; 26:339–
342.
8. Cohen ME, White PD. Life situations, emotions and neurocirculatory asthenia. (Anxiety neurosis, neurasthenia, effort syndrome). Psychosom Med 1951; 13:335–357.
9. Pitts FN, McClure JN. Lactate metabolism and anxiety neurosis. N Engl J Med 1967; 277:
1329–1336.
10. Wearn JT, Sturgis CC. Studies on epinephrine: effects of the injections of epinephrine insoldiers with “irritable heart.” Arch Intern Med 1919; 24:247–268.
11. Cowley DS, Arana GW. The diagnostic utility of lactate sensitivity in panic disorder. ArchGen Psychiatry 1990; 47:277–284.
12. Dorow R, Horowski R, Paschelke G, Amin M, Braestrup C. Severe anxiety induced by FG
7142, a beta-carboline ligand for benzodiazepine receptors. Lancet 1983; 2:98–99.
13. Uhde T. Caffeine provocation of panic: a focus on biological mechanisms. In: Ballenger JC,
ed. Neurobiology of Panic Disorder. New York: Wiley-Liss, 1990:219–242.
14. Gorman JM, Papp LA, Coplan JD, Martinez JM, Lennon S, Goetz RR, Ross D, Klein DF.
Anxiogenic effects of CO2 and hyperventilation in patients with panic disorder. Am J Psychiatry 1994; 151:547–553.
15. van Megen HJGM, Westenberg HGM, den Boer JA, Kahn RS. Cholecystokinin in anxiety.
Eur Neuropsychopharmacol 1996; 6:263–280.
16. Lindemann E, Finesinger J. The effect of adrenalin and mecholyl in states of anxiety inpsychoneurotic patients. Am J Psychiatry 1938; 95:353–370.
17. Nutt D, Glue P, Lawson CW, Wilson S. Flumazenil provocation of panic attacks: evidence
for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry 1990;
47:917–925.
18. Targum SD, Marshall LE. Fenﬂuramine provocation of anxiety in patients with panic disorder. Psychiatry Res 1989; 28:295–306.
19. Pohl R, Yeragani V, Balon R, Ortiz A, Aleem A. Isoproterenol-induced panic: a betaadrenergic model of panic anxiety. In: Ballenger JC, ed. Neurobiology of Panic Disorder.
New York: Wiley-Liss, 1990:107–120.
20. Charney DS, Woods SW, Goodman WK, Heninger GR. Serotonin function in anxiety.
II. Effects of the serotonin agonist MCPP in panic disorder patients and healthy subjects.
Psychopharmacology 1987; 92:14–24.

Provocation and Pathogenesis of Anxiety Disorders

721

21. Pyke RE, Greenberg HS. Norepinephrine challenges in panic patients. J Clin Psychopharmacol 1986; 6:279–285.
22. Charney DS, Woods SW, Price LH, Goodman WK, Glazer WM, Heninger GR. Noradrenergic dysregulation in panic disorder. In: Ballenger JC, ed. Neurobiology of Panic Disorder.
New York: Wiley-Liss, 1990:91–105.
23. Nutt D, Lawson C. Panic attacks. A neurochemical overview of models and mechanisms.
Br J Psychiatry 1992; 160:165–178.
24. Fink M, Taylor MA, Volavka J. Anxiety precipitated by lactate. N Engl J Med 1969; 281:1429.
25. Kelly D, Mitchell-Heggs N, Sherman D. Anxiety and the effects of sodium lactate assessedclinically and physiologically. Br J Psychiatry 1971; 119:129–141.
26. Bonn JA, Harrison J, Rees WL. Lactate-induced anxiety: therapeutic applications. Br J Psychiatry 1971; 119:468–471.
27. Appleby IL, Klein DF, Sachar EJ, Levitt M. Biochemical indices of lactate-induced panic:
Preliminary report. In: Klein DF, Rabkin JG, eds. Anxiety: New Research and Changing
Concepts. New York: Raven Press, 1981:411–423.
28. Rainey JM, Frohman CE, Freedman RR, Pohl RB, Ettedgui E, Williams M. Speciﬁcity oflactate infusion as a model of anxiety. Psychopharmacol Bull 1984; 20:45–49.
29. Liebowitz MR, Fyer AJ, Gorman JM, Dillon D, Appleby IL, Levy G, Anderson S, Levitt M,
Palij M, Davies SO, Klein DF. Lactate provocation of panic attacks. I. Clinical and behavioral
ﬁndings. Arch Gen Psychiatry 1984; 41:764–770.
30. Liebowitz MR, Gorman JM, Fyer AJ, Levitt M, Dillon D, Levy G, Appleby IL, Anderson
S, Palij M, Davies SO, Klein DF. Lactate provocation of panic attacks. II. Biochemical andphysiological ﬁndings. Arch Gen Psychiatry 1985; 42:709–719.
31. Carr DB, Sheehan DV, Susman OS, Coleman JH, Greenblatt DJ, Heninger GR, Jones KJ,
Levine PH, Watkins WD. Neuroendocrine correlates of lactate-induced anxiety and their
response to chronic alprazolam therapy. Am J Psychiatry 1986; 143:483–494.
32. Ehlers A, Margraf J, Roth WA, Taylor CB, Maddock RJ, Sheik J, Kopell ML, McClenahan
KL, Gossard D, Blowers GH, Agras WS, Kopell BS. Lactate infusions and panic attacks:
Do patients and controls respond differently? Psychiatry Res 1986; 17:295–308.
33. Knott VJ, Lapierre YD. Effects of lactate-induced panic attacks on brain stem auditory
evoked potentials. Neuropsychobiology 1986; 16:9–14.
34. Balon R, Pohl R, Yeragani VK, Rainey JM, Weinberg P. Lactate- and isoproterenol-induced
panic attacks in panic disorder patients and controls. Psychiatry Res 1988; 23:153–160.
35. Clow A, Glover V, Weg MW, Walker PL, Sheehan DV, Carr DB, Sandler M. Urinary catecholamine metabolite and tribulin output during lactate infusion. Br J Psychiatry 1988; 152:
122–126.
36. Gaffney FA, Fenton BJ, Lane LD, Lake CR. Hemodynamic, ventilatory, and biochemical
responses of panic patients and normal controls with sodium lactate infusion and spontaneous
panic attacks. Arch Gen Psychiatry 1988; 45:53–60.
37. Aronson TA, Whitaker-Azmitia P, Caraseti I. Differential reactivity to lactate infusions: therelative role of biological, psychological, and conditioning variables. Biol Psychiatry 1989;
25:469–481.
38. Cowley DS, Dager SR, Foster SI, Dunner DL. Clinical characteristics and response to sodium
lactate of patients with infrequent panic attacks. Am J Psychiatry 1987; 144:795–798.
39. Targum SD. Panic attack frequency and vulnerability to anxiogenic challenge studies. Psychiatry Res 1991; 28:75–83.
40. Balon R, Yeragani VK, Pohl R. Phenomenological comparison of dextrose, lactate, and isoproterenol associated panic attacks. Psychiatry Res 1988; 25:43–50.
41. Goetz RR, Klein DF, Gorman JM. Symptoms essential to the experience of sodium lactateinduced panic. Neuropsychopharmacology 1996; 14:355–366.
42. Gorman JM, Liebowitz MR, Fyer AJ, Dillon D, Davies SO, Stein J, Klein DF. Lactate infusions in obsessive-compulsive disorder. Am J Psychiatry 1985; 142:864–866.

722

Balon et al.

43. Liebowitz MR, Fyer AJ, Gorman JM, Dillon D, Davies S, Stein JM, Cohen BS, Klein DF.
Speciﬁcity of lactate infusions in social phobia versus panic disorder. Am J Psychiatry 1985;
142:947–950.
44. Rainey JM, Aleem A, Ortiz A, Yeragani V, Pohl R, Berchou R. A laboratory procedure forthe induction of ﬂashbacks. Am J Psychiatry 1987; 144:1317–1319.
45. Jensen CF, Keller TW, Peskind ER, McFall ME, Veith RC, Martin D, Wilkinson CW,
Raskind MA. Behavioral and neuroendocrine responses to sodium lactate infusion in subjects
with posttraumatic stress disorder. Am J Psychiatry 1997; 154:266–268.
46. Jensen CF, Peskind ER, Keller TW, McFall ME, Raskind MA. Comparison of sodium
lactate-induced panic symptoms between panic disorder and post-traumatic stress disorder.
Depress Anx 1998; 7:122–125.
47. Cowley DS, Dager SR, McClennan J, Roy-Byrne PP, Dunner DL. Response to lactate infusions in generalized anxiety disorder. Biol Psychiatry 1988; 24:409–414.
48. Liebowitz MR, Hollander E. Lactate-induced anxiety (editorial). Biol Psychiatry 1989; 25:
669–670.
49. George DT, Nutt DJ, Waxman PR, Linnoila M. Panic response to lactate administration inalcoholic and nonalcoholic patients with panic disorder. Am J Psychiatry 1989; 146:1161–
1165.
50. Cowley DS, Jensen CF, Johannessen D, Parker L, Dager SR, Walker RD. Response to sodium
lactate infusion in alcoholics with panic attacks. Am J Psychiatry 1989; 146:1479–1483.
51. George DT, Brewerton TD, Jimerson DC. Comparison of lactate-induced anxiety in bulimic
patients and healthy controls. Psychiatry Res 1987; 21:213–220.
52. Lindy DC, Walsh BT, Gorman JM, Roose SR, Gladis M, Devlin MJ, Glassman AH. Lactate
infusions in patients with bulimia. Psychiatry Res 1988; 26:287–292.
53. Pohl R, Yeragani VK, Balon R, Lycaki H. Lactate and isoproterenol infusions in bulimic
patients. Neuropsychobiology 1989; 22:225–230.
54. Cowley DS, Dager SR, Dunner DL. Lactate-induced panic in primary affective disorder. Am
J Psychiatry 1986; 143:646–648.
55. Cowley DS, Dager SR, Dunner DL. Lactate infusions in major depression wihout panic
attacks. J Psychiatr Res 1987; 21:243–248.
56. McGrath PJ, Stewart JW, Liebowitz MR, Markowitz JM, Quitkin FM, Klein DF, Gorman
JM. Lactate provocation of panic attacks in depressed outpatients. Psychiatry Res 1988; 25:
41–47.
57. Cowley DS, Dager SR, Dunner DL. Lactate response in patients with primary major depression. Psychiatry Res 1989; 27:357–358.
58. Buller R, von Bardeleben U, Maier W, Benkert O. Speciﬁcity of lactate response in panic
disorder, panic with concurrent depression and major depression. J Affect Disord 1989; 16:
109–113.
59. Targum SD. Differential response to anxiogenic challenge studies in patients with major
depressive disorder and panic disorder. Biol Psychiatry 1990; 28:21–34.
60. Sandberg D, Endicott J, Harrison W, Nee J, Gorman J. Sodium lactate infusion in late luteal
phase dysphoric disorder. Psychiatry Res 1993; 46:79–88.
61. George DT, Hibbeln JR, Ragan PW, Umhau JC, Phillips MJ, Doty L, Hommer D, Rawlings
RR. Lactate-induced rage and panic in a select group of subjects who perpetrate acts ofdomestic violence. Biol Psychiatry 2000; 47:804–812.
62. Gorman JM, Levy GF, Liebowitz MR, McGrath P, Appleby IL, Dillon DJ, Davies SO, Klein
DF. Effect of acute beta-adrenergic blockade on lactate-induced panic. Arch Gen Psychiatry
1983; 40:1079–1082.
63. Liebowitz MR, Gorman JM, Fyer A, Dillon D, Levitt M, Klein DF. Possible mechanisms
for lactate’s induction of panic. Am J Psychiatry 1986; 143:495–502.
64. Pohl R, Ettedgui E, Bridges M, Lycaki H, Jimerson D, Kopin I, Rainey JM. Plasma MHPG
levels in lactate and isoproterenol anxiety states. Biol Psychiatry 1987; 22:1127–1136.

Provocation and Pathogenesis of Anxiety Disorders

723

65. Aronson TA, Caraseti I, McBane D, Whitaker-Azmitia P. Biological correlates of lactatesensitivity in panic disorder. Biol Psychiatry 1989; 26:463–477.
66. den Boer JA, Westenberg HGM, Klompmakers AA, van Lint LEM. Behavioral biochemical
and neuroendocrine concomitants of lactate-induced panic anxiety. Biol Psychiatry 1989;
26:612–622.
67. Coplan JD, Liebowitz MR, Gorman JM, Fyer AJ, Dillon DJ, Campeas RB, Davies SO, Martinez J, Klein DF. Noradrenergic function in panic disorder. Effects of intravenous clonidine
pretreatment on lactate induced panic. Biol Psychiatry 1992; 31:135–146.
68. Rifkin A, Klein DF, Dillon D, Levitt M. Blockade by imipramine or desipramine of panic
induced by sodium lactate. Am J Psychiatry 1981; 138:676–677.
69. Fyer AJ, Liebowitz MR, Gorman JM, Davies SO, Klein DF. Lactate vulnerability of remitted
panic patients. Psychiatry Res 1985; 14:143–148.
70. Cowley DS, Dager SR, Roy-Byrne PP, Avery DH, Dunner DL. Lactate vulnerability after
alprazolam versus placebo treatment of panic disorder. Biol Psychiatry 1991; 30:49–56.
71. Liebowitz MR, Coplan JD, Martinez J, Fyer AJ, Dillon DJ, Campeas RB, Davies SO, Gorman
JM, Klein DF. Effects of intravenous diazepam pretreatment on lactate-induced panic. Psychiatry Res 1995; 58:127–138.
72. Gorman JM, Liebowitz MR, Dillon D, Fyer AJ, Cohen BS, Klein DF. Antipanic drug effects
during lactate infusion in lactate-refractory panic patients. Psychiatry Res 1987; 21:205–212.
73. Yeragani VK, Pohl R, Balon R, Rainey JM, Berchou R, Ortiz A. Sodium lactate infusions
after treatment with tricyclic antidepressants: behavioral and physiological ﬁndings. Biol Psychiatry 1988; 24:767–774.
74. Pohl R, Balon R, Berchou R, Lycaki H. Lactate-induced anxiety after imipramine and diazepam treatment. Anxiety 1994; 1:54–63.
75. Keck PE Jr, Taylor VE, Tugrul KC, McElroy SL, Bennett JA. Valproate treatment of panic
disorder and lactate-induced panic attacks. Biol Psychiatry 1993; 33:542–546.
76. Lingjaerde O. Lactate-induced panic attacks: possible involvement of serotonin reuptake
stimulation. Acta Psychiatr Scand 1985; 72:206–208.
77. Levin AP, Doran AR, Liebowitz MR, Fyer AJ, Gorman JM, Klein DF, Paul SM. Pituitaryadrenocortical unresponsiveness in lactate-induced panic. Psychiatry Res 1987; 21:23–32.
78. Dager SR, Cowley DS, Dorsa DM, Dunner DL. Plasma beta-endorphin response to lactate
infusion. Biol Psychiatry 1989; 25:243–245.
79. Peskind ER, Jensen CF, Pascualy M, Tsuang D, Cowley D, Martin DC, Wilkinson CW,
Raskind MA. Sodium lactate and hypertonic sodium chloride induce equivalent panic incidence, panic symptoms, and hypernatremia in panic disorder. Biol Psychiatry 1998; 44:1007–
1016.
80. Carr DB, Fishman SM, Kasting NW, Sheehan DV. Vasopressin response to lactate infusions
in normals and patients with panic disorder. Funct Neurol 1986; 1:123–127.
81. Kellner M, Herzog L, Yassouridis A, Holsboer F, Wiedemann K. Possible role of atrial
natriuretic hormone in pituitary-adrenocortical unresponsiveness in lactate-induced panic.
Am J Psychiatry 1995; 152:1365–1367.
82. Kellner M, Knaudt K, Jahn H, Holsboer F, Wiedemann K. Atrial natriuretic hormone inlactate-induced panic attacks: mode of release and endocrine and pathophysiological consequences. J Psych Res 1998; 32:37–48.
83. Gorman JM, Goetz RR, Uy J, Ross D, Martinez J, Fyer AJ, Liebowitz MR, Klein DF. Hyperventilation occurs during lactate-induced panic. J Anxiety Disord 1988; 2:193–202.
84. Gorman JM, Fyer MR, Goetz R, Askanazi J, Liebowitz MR, Fyer AJ, Kinney J, Klein DF.
Ventilatory physiology of patients with panic disorder. Arch Gen Psychiatry 1988; 45:31–
39.
85. Sandberg DP, Liebowitz MR. Potential mechanisms for sodium lactate’s induction of panic.
In: Ballenger JC, ed. Neurobiology of Anxiety, Frontiers of Clinical Neuroscience. Vol. 8.
New York: Alan R. Liss, 1990:155–172.

724

Balon et al.

86. Gorman JM, Goetz RR, Dillon D, Liebowitz MR, Fyer AJ, Davies S, Klein DF. Sodium Dlactate infusion of panic disorder patients. Neuropsychopharmacology 1990; 3:181–189.
87. Gorman JM, Cohen BS, Liebowitz MR, Fyer AJ, Ross D, Davies SO, Klein DF. Blood gaschanges and hypophosphatemia in lactate-induced panic. Arch Gen Psychiatry 1986; 43:
1067–1071.
88. Gorman JM, Battista D, Goetz RR, Dillon DJ, Liebowitz MR, Fyer AJ, Kahn JP, Sandberg
D, Klein DF. A comparison of sodium bicarbonate and sodium lactate infusion in the induction of panic attacks. Arch Gen Psychiatry 1989; 46:145–150.
89. Grosz HJ, Farmer BB. Pitts’ and McClure’s lactate-anxiety study revisited. Br J Psychiatry
1972; 120:415–418.
90. Gorman JM, Fyer AJ, Ross DC, Cohen BS, Martinez JM, Liebowitz MR, Klein DF. Normalization of venous pH, Pco2, and bicarbonate levels after blockade of panic attacks. Psychiatry
Res 1985; 14:57–65.
91. Maddock RJ, Carter CS, Gietzen DW. Elevated serum lactate associated with panic attacks
induced by hyperventilation. Psychiatry Res 1991; 38:301–311.
92. Coplan JD, Sharma T, Rosenblum LA, Friedman S, Bassoff TB, Barbour RL, Gorman JM.
Effects of sodium lactate infusion on cisternal lactate and carbon dioxide levels in nonhumanprimates. Am J Psychiatry 1992; 149:1369–1373.
93. Dager SR, Rainey JM, Kenny MA, Artu AA, Metzger GD, Bowden DW. Central nervous
system effects of lactate infusion in primates. Biol Psychiatry 1990; 27:193–204.
94. Dager SR, Marro KI, Richards TL, Metzger GD. Preliminary application of magnetic resonance spectroscopy to investigate lactate-induced panic. Am J Psychiatry 1994; 151:57–63.
95. Fyer AJ, Gorman JM, Liebowitz MR, Levitt M, Danielson E, Martinez J, Klein DF. Sodium
lactate infusion, panic attacks, and ionized calcium. Biol Psychiatry 1984; 19:1437–1447.
96. Balon R, Yeragani VK, Pohl R. Relative hypophosphatemia in patients with panic disorder.
Arch Gen Psychiatry 1988; 45:294–295.
97. Bass C, Gardner WN, Griez E, Pols H, Gorman JM. Blood gas changes and hypophosphatemia in lactate-induced panic [letter]. Arch Gen Psychiatry 1988; 45:95–96.
98. Ackerman SH, Sachar EJ. The lactate theory of anxiety: a review and reevaluation. Psychosom Med 1974; 36:69–81.
99. Margraf J, Ehlers A, Roth WT. Sodium lactate infusions and panic attacks: a review andcritique. Psychosom Med 1986; 48:23–51.
100. Cowley DS, Hyde TS, Dager SR, Dunner DL. Lactate infusions: the role of baseline anxiety.
Psychiatry Res 1987; 21:169–179.
101. Yeragani VK, Rainey JM, Pohl R, Balon R, Berchou R, Jolly S, Lycaki H. Preinfusion anxiety and laboratory-induced panic attacks in panic disorder patients. J Clin Psychiatry 1988;
49:302–306.
102. Yeragani VK, Balon R, Rainey JM, Ortiz A, Berchou R, Lycaki H, Pohl R. Effects oflaboratory-induced panic-anxiety on subsequent provocative infusion. Psychiatry Res 1988;
23:161–166.
103. Shear MK, Fyer AJ, Ball G, Josephson S, Fitzpatrick M, Gitlin B, Frances A, Gorman JM,
Liebowitz M, Klein DF. Vulnerability to sodium lactate in panic disorder patients given
cognitive-behavioral therapy. Am J Psychiatry 1991; 148:795–798.
104. Gorman JM, Martinez JM, Liebowitz MR, Fyer AJ, Klein DF. Hypoglycemia and panic
attacks. Am J Psychiatry 1984; 141:101–102.
105. Gorman JM, Liebowitz MR, Stein J, Fyer AJ, Klein DF. Insulin levels during lactate infusions. Am J Psychiatry 1984; 141:1621–1622.
106. George DT, Lindquist T, Nutt DJ, Ragan PW, Alim T, McFarlane V, Leviss J, Eckhardt
MJ, Linnoila M. Effect of chloride or glucose on the incidence of lactate-induced panic
attacks. Am J Psychiatry 1995; 152:692–697.
107. Liebowitz MR, Gorman JM, Fyer AJ, Dillon DJ, Klein DF. Effects of naloxone on patientswith panic attacks. Am J Psychiatry 1984; 141:995–997.

Provocation and Pathogenesis of Anxiety Disorders725

108. Cowley DS, Dunner DL. Response to sodium lactate in panic disorder: relationship to presenting clinical variables. Psychiatry Res 1988; 25:253–259.
109. Balon R, Jordan M, Pohl R, Yeragani VK. Family history of anxiety disorders in control
subjects with lactate-induced panic attacks. Am J Psychiatry 1989; 146:1304–1306.
110. Balon R, Pohl R, Yeragani VK, Rainey JM, Berchou R. Follow-up study of control subjects with lactate- and isoproterenol-induced panic attacks. Am J Psychiatry 1988; 145:238–
241.
111. George DT, Null DJ, Walker WV, Porges SW, Adinoff B, Linnoila M. Lactate and hyperventilation substantially attenuate vagal tone in normal volunteers. Possible mechanism of panic
provocation? Arch Gen Psychiatry 1989; 46:153–156.
112. Yeragani VK, Srinivasan K, Balon R, Ramesh C, Berchou R. Lactate sensitivity and cardiac
cholinergic function. Am J Psychiatry 1994; 151:1226–1228.
113. Koenigsberg HW, Pollak CP, Fine J, Kakuma T. Cardiac and respiratory activity in panic
disorder: Effects of sleep and sleep lactate infusions. Am J Psychiatry 1994; 151:1148–1152.
114. Sloan EP, Natarajan M, Baker B, Dorian P, Mironov S, Barr A, Newman DM, Shapiro CM.
Nocturnal and daytime panic attacks—comparison of sleep architecture, heart rate variability,
and response to sodium lactate challenge. Biol Psychiatry 1999; 45:1313–1320.
115. van den Hout MA, van der Molen GM, Griez E, Lousberg H, Nansen A. Reduction of CO2induced anxiety in patients with panic attacks after repeated CO2 exposure. Am J Psychiatry
1987; 144:788–791.
116. Griez E, van den Hout MA. Effects of carbon dioxide-oxygen inhalations on subjective anxiety and some neurovegetative parameters. J Behav Ther Exp Psychiatry 1982; 13:27–32.
117. Griez E, van den Hout MA. Treatment of photophobia by exposure to CO2-induced anxiety
symptoms. J Nerv Ment Dis 1983; 171:506–508.
118. Wolpe J. Carbon dioxide inhalation treatments of neurotic anxiety: an overview. J Nerv Ment
Dis 1987; 175:129–133.
119. Gorman JM, Askanazi J, Liebowitz MR, Fyer AJ, Stein J, Kinney JM, Klein DF. Response
to hyperventilation in a group of patients with panic disorder. Am J Psychiatry 1984; 141:
857–861.
120. Gorman JM, Papp LA, Coplan JD, Martinez JM, Lennon S, Goetz RR, Ross D, Klein DF.
Anxiogenic effects of CO2 and hyperventilation in patients with panic disorder. Am J Psychiatry 1994; 151:547–553.
121. Woods SW, Charney DS, Goodman WK, Heninger GR. Carbon dioxide-induced anxiety:behavioral, physiologic, and biochemical effects of carbon dioxide in patients with panic
disorder and healthy subjects. Arch Gen Psychiatry 1988; 45:43–52.
122. van den Hout MA, Griez E. Panic symptoms after inhalation of carbon dioxide. Br J Psychiatry 1984; 144:503–507.
123. Griez EJL, Lousberg H, van den Hout MA, van der Molen GM. CO2 vulnerability in panic
disorder. Psychiatry Res 1987; 20:87–95.
124. Fyer MR, Uy J, Martinez J, Goetz R, Klein DF, Fyer AJ, Liebowitz MR, Gorman JM. CO2
challenge of patients with panic disorder. Am J Psychiatry 1987; 144:1080–1082.
125. Ichiro S, Akiyoshi J, Sakurai R, Tsutsumi T, Ono H, Yamada K, Fujii I. Carbon dioxide
induced panic attack in panic disorder in Japan. Prog Neuro-Psychopharmacol Biol Psychiatry 1996; 20:1145–1157.
126. Bystritsky A, Craske M, Maidenberg E, Vapnik T, Shapiro D. Autonomic reactivity of panic
patients during a CO2 inhalation procedure. Depress Anx 2000; 11:15–26.
127. Zandbergen J, Lousberg HHA, Pols H, de Loof C, Griez EJL. Hypercarbia versus hypocarbia
in panic disorder. J Affect Disord 1990; 18:75–81.
128. Woods SW, Charney DS, Loke J, Goodman WK, Redmond DE, Heninger GR. Carbon dioxide sensitivity in panic anxiety. Ventilatory and anxiogenic response to carbon dioxide in
healthy subjects and patients with panic anxiety before and after alprazolam treatment. ArchGen Psychiatry 1986; 43:900–909.

726

Balon et al.

129. Lousberg H, Griez E, van den Hout MA. Carbon dioxide chemosensitivity in panic disorder.
Acta Psychiatr Scand 1988; 77:214–218.
130. Papp LA, Martinez JM, Klein DF, Coplan JD, Norman RG, Cole R, de Jesus MJ, Ross D,
Goetz R, Gorman JM. Respiratory psychophysiology of panic disorder: three respiratory
challenges in 98 subjects. Am J Psychiatry 1997; 154:1557–1565.
131. Zvolensky MJ, Eifert GH, Lejuez CW, McNeil DW. The effects of offset control over 20%
carbon-dioxide-enriched air on anxious responding. J Abnorm Psychol 1999; 108:624–632.
132. Perna G, Battaglia M, Garberi A, Arancio C, Bertani A, Bellodi L. Carbon dioxide/oxygen
challenge test in panic disorder. Psychiatry Res 1994; 52:159–171.
133. Perna G, Gabriele A, Caldirola D, Bellodi L. Hypersensitivity to inhalation of carbon dioxideand panic attacks. Psychiatry Res 1995; 57:267–273.
134. Forsyth JP, Eifert GH, Canna MA. Evoking analogue subtypes of panic attacks in a nonclinical population using carbon dioxide-enriched air. Behav Res Therapy 2000; 38:559–572.
135. Rapee R, Mattick R, Murrell E. Cognitive mediation in the affective component of spontaneous panic attacks. J Behav Ther Exp Psychiatry 1986; 17:245–253.
136. Papp LA, Klein DF, Martinez J, Schneier F, Cole R, Liebowitz MR, Hollander E, Fyer AJ,
Jordan F, Gorman JM. Diagnostic and substance speciﬁcity of carbon-dioxide-induced panic.
Am J Psychiatry 1993; 150:250–257.
137. Antony MM, Brown TA, Barlow DH. Response to hyperventilation and 5.5% CO2 inhalationof subjects with types of speciﬁc phobia, panic disorder, or no mental disorder. Am J Psychiatry 1997; 154:1098–1095.
138. Biber B, Alkin T. Panic response subtypes: differential response to CO2 challenge. Am J
Psychiatry 1999; 156:739–744.
139. Coryell W. Hypersensitivity to carbon dioxide as a disease-speciﬁc trait marker. Biol Psychiatry 1997; 41:259–263.
140. Verburg K, Klaassen T, Pols H, Griez E. Comorbid depressive disorder increases vulnerability to the 35% carbon dioxide (CO2) challenge in panic disorder patients. J Affect Disord
1998; 49:195–201.
141. Perna G, Bussi R, Allevi L, Bellodi L. Sensitivity to 35% carbon dioxide in patients withgeneralized anxiety disorder. J Clin Psychiatry 1999; 60:379–384.
142. Perna G, Bertani A, Arancio C, Ronchi P, Bellodi L. Laboratory response of patients withpanic and obsessive-compulsive disorders to 35% CO2 challenges. Am J Psychiatry 1995;
152:85–89.
143. Harrison WM, Sandberg D, Gorman JM, Fyer M, Nee J, Uy J, Endicott J. Provocation ofpanic with carbon dioxide inhalation in patients with premenstrual dysphoria. Psychiatry Res
1989; 27:183–192.
144. Perna G, Brambilla F, Arancio C, Bellodi L. Menstrual cycle-related sensitivity to 35% CO2
in panic patients. Biol Psychiatry 1995; 37:528–532.
145. Ware MR, Caton D, DeVane CL. The practical use of carbon dioxide-induced anxiety inthe diagnosis and care of patients with panic disorder. Ann Clin Psychiatry 1996; 8:199–
202.
146. Elam M, Yao T, Thoren P, Svensson TH. Hypercapnia and hypoxia: chemoreceptormediated control of locus coeruleus neurons and splanchnic, sympathetic nerves. Brain Res
1981; 222:373–381.
147. Martinez JM, Coplan JD, Browne ST, Goetz R, Welkowitz LA, Papp LA, Klein DF, Gorman
JM. Hemodynamic response to respiratory challenges in panic disorder. J Psychosomat Res
1998; 44:153–161.
148. Sinha SS, Coplan JD, Pine DS, Martinez JA, Klein DF, Gorman JM. Panic induced by carbon
dioxide inhalation and lack of hypothalamic-pituitary-adrenal axis activation. Psychiatry Res
1999; 86:93–98.
149. Welkowitz LA, Papp L, Martinez J, Browne S, Gorman JM. Instructional set and physiological response to CO2 inhalation. Am J Psychiatry 1999; 156:745–748.

Provocation and Pathogenesis of Anxiety Disorders727

150. Miller HEJ, Deakin JFW, Anderson IM. Effects of acute tryptophan depletion on CO2induced anxiety in patients with panic disorder and normal volunteers. Br J Psychiatry
2000; 176:182–188.
151. Pols H, Griez E, Bourin M, Schruers K. Effect of CCK-4 on a 35% carbon dioxide challenge
in healthy volunteers. Prog Neuropsychopharmacol Biol Psychiatry 1999; 23:1345–1350.
152. Dager SR, Strauss WL, Marro KI, Richards TL, Metzger GD, Artru AA. Proton magnetic
resonance spectroscopy investigation of hyperventilation in subjects with panic disorder andcomparison subjects. Am J Psychiatry 1995; 152:666–672.
153. Perna G, Cocchi S, Bertani A, Arancio C, Bellodi L. Sensitivity to 35% CO2 in healthy ﬁrst
degree relatives of patients with panic disorder. Am J Psychiatry 1995; 152:623–625.
154. van Beek N, Griez E. Reactivity to a 35% CO2 challenge in healthy ﬁrst-degree relatives ofpatients with panic disorder. Biol Psychiatry 2000; 47:830–835.
155. Beckett A, Fishman SM, Rosenbaum J. Clonazepam blockade of spontaneous and CO2
inhalation-provoked panic in a patient with panic disorder. J Clin Psychiatry 1986; 47:475–
476.
156. Woods SW, Krystal JH, Heninger GR, Charney DS. Effects of alprazolam and clonidine on
carbon dioxide-induced increases in anxiety ratings in healthy human subjects. Life Sci 1989;
45:233–242.
157. Woods SW, Charney DS, Delgado PL, Heninger GR. The effect of long-term imipramine
treatment on carbon dioxide-induced anxiety in panic disorder patients. J Clin Psychiatry
1990; 51:505–507.
158. Sanderson WC, Wetzler S, Asnis GM. Alprazolam blockade of CO2-provoked panic in patients with panic disorder. Am J Psychiatry 1994; 151:1220–1222.
159. Nardi AE, Valenca AM, Zin W, Nascimento I. Carbon dioxide induced panic attacks andshort term clonazepam treatment. Neuropsiquiatr 1999; 57:361–365.
160. Gorman JM, Browne ST, Papp LA, Martinez J, Welkowitz L, Coplan JD, Goetz RR, Kent
J, Klein DF. Effect of antipanic treatment on response to carbon dioxide. Biol Psychiatry
1997; 42:982–991.
161. Perna G, Cocchi S, Bertani A, Arancio C, Bellodi L. Pharmacologic effect of toloxatone onreactivity to the 35% carbon dioxide challenge: a single-blind, random, placebo-controlled
study. J Clin Psychopharmacol 1994; 14:414–418.
162. Bocola V, Trecco MD, Fabbrini G, Paladini C, Sollecito A, Martucci N. Antipanic effect of
ﬂuoxetine measured by CO2 challenge test. Biol Psychiatry 1998; 43:612–615.
163. Bertani A, Caldirola D, Bussi R, Bellodi L, Perna G. The 35% CO2 hyperreactivity andclinical symptomatology in patients with panic disorder after 1 week of treatment with citalopram: an open study. J Clin Psychopharmacol 2001; 21:262–267.
164. Schmidt NB, Trakowski JH, Staab JP. Extinction of panicogenic effects of a 35% CO2 challenge in patients with panic disorder. J Abnorm Psychol 1997; 106:630–638.
165. Griez E, van den Hout MA. Carbon dioxide and anxiety: cardiovascular effects of a single
inhalation. J Behav Ther Exp Psychiatry 1983; 14:297–304.
166. van den Hout MA, Griez E. Peripheral panic symptoms occur during changes in alveolar
carbon dioxide. Compr Psychiatry 1985; 26:381–387.
167. Griez E, Zandbergen J, Lousberg H, van den Hout M. Effects of low pulmonary CO2 on
panic anxiety. Compr Psychiatry 1988; 29:490–497.
168. Sanderson WC, Rapee RM, Barlow DH. The inﬂuence of an illusion of control on panic
attacks induced via inhalation of 5.5% carbon dioxide-enriched air. Arch Gen Psychiatry
1989; 46:157–162.
169. Klein DF. False suffocation alarms, spontaneous panics, and related conditions: an integrative
hypothesis. Arch Gen Psychiatry 1993; 50:306–317.
170. Tanaka M, Yoshida M, Emoto H, Ishii H. Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies. Eur J
Pharmacol 2000; 405:397–406.

728

Balon et al.

171. Redmond DE Jr, Huang YH, Snyder DR, Maas JW, Baulu J. Behavioral changes following
lesions of the nucleus locus ceruleus in macaca arctoides. Neurosci Abstr 1976; 1:472.
172. Redmond DE Jr, Huang YH, Snyder DR, Maas JW. Behavioral effects of stimulation of thenucleus locus ceruleus in the stump-tailed monkey (Macaca arctoides). Brain Res 1976; 116:
502–510.
173. Holmberg G, Gershon S. Autonomic and psychic effects of yohimbine hydrochloride. Psychopharmacologia 1961; 2:93–106.
174. Charney DS, Heninger GR, Redmond DE. Yohimbine induced anxiety and increased noradrenergic function in humans. Effects of diazepam and clonidine. Life Sci 1983; 33:19–29.
175. Charney DS, Heninger GR, Breier A. Noradrenergic function in panic anxiety. Effects ofyohimbine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen
Psychiatry 1984;41:751–763.
176. Gurguis GNM, Uhde TW. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) andgrowth hormone responses to yohimbine in panic disorder patients and normal controls. Psychoneuroendocrinology 1990; 15:217–224.
177. Gurguis GNM, Vitton BJ, Uhde TW. Behavioral, sympathetic and adrenocortical responses
to yohimbine in panic disorder patients and normal controls. Psychiatry Res 1997; 71:27–
39.
178. Charney DS, Heninger GR. Noradrenergic function and the mechanism of action of antianxiety treatment. I. The effect of long-term alprazolam treatment. Arch Gen Psychiatry
1985; 42:458–467.
179. Charney DS, Heninger GR. Abnormal regulation of noradrenergic function in panic disorders. Effects of clonidine in healthy subjects and patients with agoraphobia and panic disorder. Arch Gen Psychiatry 1986; 43:1042–1054.
180. Rasmussen SA, Goodman WK, Woods SW, Heninger GR, Charney DS. Effects of yohimbine
in obsessive compulsive disorder. Psychopharmacology 1987; 93:308–313.
181. Southwick SM, Krystal JH, Morgan CA, Johnson D, Nagy LM, Nicolaou A, Heninger GR,
Charney DS. Abnormal noradrenergic function in posttraumatic stress disorder. Arch Gen
Psychiatry 1993; 50:266–274.
182. Southwick SM, Morgan CA III, Charney DS, High JR. Yohimbine use in natural setting:effects on posttraumatic stress disorder. Biol Psychiatry 1999; 46:442–444.
183. Hamlin CL, Lydiard RB, Martin D, Dackis CA, Pottash AC, Sweeney D, Gold MS. Urinary
excretion of noradrenaline metabolite decreased in panic disorder. Lancet 1983; 2:740–741.
184. Charney DS, Galloway MP, Heninger GR. The effects of caffeine on plasma MHPG, subjective anxiety, autonomic symptoms and blood pressure in healthy humans. Life Sci 1984; 35:
135–144.
185. Pohl R, Yeragani VK, Balon R, Rainey JM, Lycaki H, Ortiz A, Berchou R, Weinberg P.
Isoproterenol induced panic attacks. Biol Psychiatry 1988; 24:89–92.
186. Boulenger J, Uhde TW, Wolff EA, Post RM. Increased sensitivity to caffeine in patientswith panic disorders. Arch Gen Psychiatry 1984; 41:1067–1071.
187. Lee MA, Cameron OG, Greden JF. Anxiety and caffeine consumption in people with anxiety
disorders. Psychiatry Res 1985; 15:211–217.
188. Greden JF. Anxiety or caffeinism: a diagnostic dilemma. Am J Psychiatry 1974; 131:1089–
1092.
189. Charney DS, Heninger GR, Jatlow I. Increased anxiogenic effects of caffeine in panic disorders. Arch Gen Psychiatry 1985; 42:233–243.
190. Bruce MS, Lader M. Caffeine abstention in the management of anxiety disorders. Psychol
Med 1989; 19:211–214.
191. Uhde TW, Boulenger JP, Jimerson DC, Post RM. Caffeine: relationship to human anxiety,plasma MHPG and cortisol. Psychopharmacol Bull 1984; 20:426–430.
192. Mathew RJ, Wilson WH. Cerebral blood ﬂow in anxiety and panic. In: Ballenger JC, ed.
Neurobiology of Panic Disorder. New York: Alan R Liss, 1990:281–309.

Provocation and Pathogenesis of Anxiety Disorders729

193. DeMet E, Stein MK, Tran C, Chicz-DeMet A, Sangdal C, Nelson J. Caffeine taste test forpanic disorder. Psychiatry Res 1989; 30:231–242.
194. Berkowitz BA, Tarver JH, Spector S. Release of norepinephrine in the central nervous systemby theophylline and caffeine. Eur J Pharmacol 1970; 10:64–71.
195. Marangos PJ, Paul SM, Parma AM, Goodwin FK, Syapin P, Skolnick P. Purinergic inhibitionof diazepam binding to rat brain (in vitro). Life Sci 1979; 2:851–858.
196. Snyder S, Sklar P. Behavioral and molecular actions of caffeine. Focus on adenosine. J Psychiatr Res 1984; 18:91–106.
197. Orlikov A, Ryzov I. Caffeine-induced anxiety and increase of kynurenine in plasma of
healthy subjects. A pilot study. Biol Psychiatry 1991; 29:391–396.
198. Lindemann E. The psychopathological effect of drugs affecting the vegetative system. Am
J Psychiatry 1935; 91:983–1008.
199. Frolich ED, Tarazi RC, Dustan HP. Hyperdynamic beta adrenergic circulatory state. Arch
Intern Med 1969; 123:1–7.
200. Easton JD, Sherman DG. Somatic anxiety attacks and propranolol. Arch Neurol 1976; 33:
689–691.
201. Pohl R, Yeragani VK, Balon R. Effects of isoproterenol in panic disorder patients after antidepressant treatment. Biol Psychiatry 1990; 28:203–214.
202. Noyes R Jr. Beta-blocking drugs and anxiety. Psychosomatics 1982; 23:155–170.
203. Noyes R Jr, Anderson DJ, Clancy J, Crowe RR, Slymen DJ, Ghoneim MM, Hinrichs JV.
Diazepam and propranolol in panic disorder and agoraphobia. Arch Gen Psychiatry 1984;
41:287–292.
204. Abelson JL. Cholecystokinin in psychiatric research: a time for cautious excitement. J Psychiatr Res 1995; 29:389–396.
205. De Montigny C. Cholecystokinin tetrapeptide induces panic like attacks in healthy volunteers. Arch Gen Psychiatry 1989; 46:511–517.
206. Bradwejn J, Koszycki D, Shriqui C. Enhanced sensitivity to cholecystokinin-tetrapeptide inpanic disorder: clinical and behavioral ﬁndings. Arch Gen Psychiatry 1991; 48:603–607.
207. Bradwejn J, Koszycki D, Payeur R, Bourin M, Borthwick H. Replication of action of cholecystokinin tetrapeptide in panic disorder: clinical and behavioral ﬁndings. Am J Psychiatry
1992; 149:962–964.
208. Bradwejn J, Koszycki D, Annable L, Couetoux du Tertre A, Reines S, Karkanias C. A doseranging study of the behavioral and cardiovascular effects of CCK-tetrapeptide in panic disorder. Biol Psychiatry 1992; 32:903–912.
209. van Megen HJGM, Westenberg HGM, den Boer JA, Kahn RS. The panic-inducing propertiesof the cholecystokinin tetrapeptide CCK4 in patients with panic disorder. Eur Neuropsychopharmacol 1996; 6:187–194.
210. Le Melledo J-M, Merani S, Koszycki D, Bellavance F, Palmour R, Gutkowska J, Steinberg
S, Bichet DG, Bradwejn J. Sensitivity to CCK-4 in women with and without premenstrual
dysphoric disorder (PMDD) during their follicular and luteal phases. Neuropsychopharmacology 1999; 20:81–91.
211. Kellner M, Wiedemann K, Yassouridis A, Levengood R, Guo LS, Holsboer F, Yehuda R.
Behavioral and endocrine response to cholecystokinin tetrapeptide in patients with posttraumatic stress disorder. Biol Psychiatry 2000; 47:107–111.
212. Strohle A, Holsboer F, Rupprecht R. Increased ACTH concentrations associated with cholecystokinin tetrapeptide-induced panic attacks in patients with panic disorder. Neuropsychopharmacology 2000; 22:251–256.
213. Abelson JL, Liberzon I. Dose response of adrenocorticotropin and cortisol to the CCK-B
agonist pentagastrin. Neuropsychopharmacology 1999; 21:485–494.
214. Bradwejn J, Koszycki D, Bourin M. Dose ranging study of the effects of cholecystokininin healthy volunteers. J Psychiatry Neurosci 1991; 16:91–95.
215. Schruers H, Caycedo N, Overbeek T, Buchold H, Bourin M, Griez E. Effects of low-dose

730

216.

217.

218.

219.

220.
221.

222.
223.

224.
225.
226.

227.
228.

229.

230.

231.
232.
233.

234.

Balon et al.
cholecystokinin on respiratory function in healthy volunteers. Eur Neuropsychopharmacol
2000; 10:419–421.
Bradwejn J, Koszycki D. Comparison of the panicogenic effect of cholecystokinin 30–33
and carbon dioxide in panic disorder. Progr Neuropsychopharmacol Biol Psychiatry 1991;
15:237–239.
Bradwejn J, Koszycki D, Paradis M, Reece P, Hinton J, Sedman A. Effects of Cl-988 oncholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers. Biol Psychiatry
1995; 38:742–746.
van Megen HJGM, Westenberg HGM, den Boer JA, Slaap B, van Radhakishun F, Pande
AC. The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients. Psychopharmacology 1997; 129:243–248.
Kellner M, Yassouridis A, Jahn H, Wiedemann K. Inﬂuence of clonidine on psychopathological, endocrine and respiratory effects of cholecystokinin tetrapeptide in patients with panic
disorder. Psychopharmacology 1997; 133:55–61.
Pande AC, Greiner M, Bammert Adams J, Lydiard RB, Pierce MW. Placebo-controlled trialof the CCK-B antagonist, CI-988, in panic disorder. Biol Psychiatry 1999; 46:860–862.
Kramer MS, Cutler NR, Ballenger JC, Patterson WM, Mendels J, Chenault A, Shrivastava
R, Matzura-Wolfe D, Lines C, Reines S. A placebo-controlled trial of L-365, 260, a CCKB
antagonist, in panic disorder. Biol Psychiatry 1995; 37:462–466.
Bradwejn J, Koszycki D. Imipramine antagonism of the panicogenic effects of cholecystokinin tetrapeptide in panic disorder patients. Am J Psychiatry 1994; 151:261–263.
van Megen HJGM, Westenberg HGM, den Boer JA, Slaap B, Scheepmakers A. Effect of
the selective serotonin reuptake inhibitor ﬂuvoxamine on CCK-4 induced panic attacks. Psychopharmacology 1997; 129:357–364.
Flint AJ, Koszycki D, Vaccarino FJ, Cadieux A, Boulenger J-P, Bradwejn J. Effect of aging
on cholecystokinin-induced panic. Am J Psychiatry 1998; 155:283–285.
Rehfeld JF. Cholecystokinin and panic disorder p three unsettled questions. Reg Peptides
2000; 93:79–83.
Charney DS, Woods SW, Goodman WK, Heninger GR. Serotonin function in anxiety: II.
Effects of the serotonin agonist MCPP in panic disorder and healthy subjects. Psychopharmacology 1987; 92:14–24.
Zohar J, Mueller EA, Insel TR, Zohar-Kadouch RC, Murphy DL. Serotonergic responsivity
in obsessive-compulsive disorder. Arch Gen Psychiatry 1987; 44:946–951.
Pigott TA, Hill JL, Grady TA, L’Heureux F, Bernstein S, Rubenstein CS, Murphy DL. A
comparison of the behavioral effects of oral versus intravenous CPP administration in OCD
patients and the effect of metergoline prior to IV mCPP. Biol Psychiatry 1993; 33:3–14.
Hollander E, DeCaria CM, Nitescu A, Gully R, Suckow RF, Cooper TUB, Gorman JM, Klein
DF, Liebowitz MR. Serotonergic function in obsessive-compulsive disorder. Behavioral andneuroendocrine responses to oral m-chlorophenylpiperazine and fenﬂuramine in patients andhealthy controls. Arch Gen Psychiatry 1992; 49:21–28.
Germine M, Goddard AW, Sholomskas DE, Woods SW, Charney DS, Heninger GR. Response to meta-chlorophenylpiperazine in panic disorder patients and healthy subjects: inﬂuence of reduction in intravenous dosage. Psychiatry Res 1994; 54:115–133.
Wetzler S, Asnis GM, DeLecuona JM, Kalus O. Serotonin function in panic disorder: intravenous administration of meta-chlorophenylpiperazine. Psychiatry Res 1996; 64:77–82.
Kahn RS, Asnis GM, Wetzler S, van Praag HM. Neuroendocrine evidence for a serotoninreceptor supersensitivity in panic disorder. Psychopharmacology 1988; 96:360–364.
Charney DS, Goodman WK, Price LH, Woods SW, Rasmussen SA, Heninger GR. Serotoninfunction in obsessive-compulsive disorder. A comparison of the effects of tryptophan andm-chlorophenylpiperazine in patients and healthy subjects. Arch Gen Psychiatry 1988; 45:
177–185.
Goodman WK, McDougle CJ, Price LH, Barr LC, Hills OF, Caplik JF, Charney DS, Hen-Provocation and Pathogenesis of Anxiety Disorders

235.
236.

237.

238.
239.

240.
241.

242.

243.
244.
245.

246.

731

inger GH. m-Chlorophenylpiperazine in patients with obsessive-compulsive disorder: absence of symptom exacerbation. Biol Psychiatry 1995; 38:139–149.
Erzegovesi S, Martucci L, Henin M, Bellodi L. Low versus standard dose mCPP challenge
in obsessive-compulsive patients. Neuropsychopharmacology 2000; 24:31–36.
Maes M, Meltzer HY. Effects of meta-chlorophenylpiperazine on neuroendocrine and behavioral responses in male schizophrenic patients and normal volunteers. Psychiatry Res 1996;
64:147–159.
Koreen AR, Lieberman JA, Alvir J, Chakos M. The behavioral effect of m-Chlorophenylpiperazine (mCPP) and methylphenidate in ﬁrst-episode schizophrenia and normal controls.
Neuropsychopharmacology 1997; 16:61–68.
Hetem LAB, de Souza CJ, Guimaraes FS, Zuardi AW, Graeff FG. Effect of d-fenﬂuramine
on human experimental anxiety. Psychopharmacology 1996; 127:276–282.
Brauer LH, Johanson C-E, Schuster CR, Rothman RB, de Wit H. Evaluation of phentermine
and fenﬂuramine, alone and in combination, in normal, healthy volunteers. Neuropsychopharmacology 1996; 14:233–241.
Mortimore C, Anderson IM. d-Fenﬂuramine in panic disorder: a dual role for 5-hydroxytryptamine. Psychopharmacology 2000; 149:251–258.
McBride PA, DeMeo MD, Sweeney JA, Halper J, Mann JJ, Shear KM. Neuroendocrine andbehavioral responses to challenge with the indirect serotonin agonist dl-fenﬂuramine in adults
with obsessive-compulsive disorder. Biol Psychiatry. 1992; 31:19–34.
Woods SW, Charney DS, Silver JM, Krystal JH, Heninger GR. Behavioral, biochemical,
and cardiovascular responses to the benzodiazepine receptor antagonist ﬂumazenil in panic
disorder. Psychiatry Res 1991; 36:115–127.
Strohle A, Kellner M, Yassouridis A, Holsboer F, Wiedermann K. Effect of ﬂumazenil in
lactate-sensitive patients with panic disorder. Am J Psychiatry 1998; 155:610–612.
Coupland NJ, Bell C, Potokar JP, Dorkins E, Nutt DJ. Flumazenil challenge in social phobia.
Depress Anxiety 2000; 11:27–30.
Randall PK, Bremner JD, Krystal JH, Nagy LM, Heninger GR, Nicolaou AL, Charney DS.
Effects of the benzodiazepine antagonist ﬂumazenil in PTSD. Biol Psychiatry 1995; 38:319–
324.
van Megen HJGM, Westenberg HGM, den Boer JA. Effect of the cholecystokinin-B receptor
antagonist L-365,260 on lactate-induced panic attacks in panic disorder patients. Biol Psychiatry 1996; 40:804–806.

31
Pharmacotherapy of Anxiety Disorders
DAVID S. BALDWIN
Royal South Hants Hospital
University of Southampton
Southampton, England
DAVID BRIDLE and ANDERS EKELUNDRoyal South Hants HospitalSouthampton, England

I.

INTRODUCTION

Many treatments for patients with anxiety disorders have become available in the last
decade. The ﬁndings of randomized controlled trials and the advent of better tolerated
and safer drugs together have led to considerable changes in prescribing practice. Newerclasses of drug such as the selective serotonin reuptake inhibitors (SSRI) have largely
replaced traditional treatment approaches with monoamine oxidase inhibitors (MAOI) or
tricyclic antidepressants (TCA). This chapter reviews the pharmacological treatment ofpanic disorder, social anxiety disorder, generalized anxiety disorder, and post-traumaticstress disorder. It gives greatest emphasis to the ﬁndings of double-blind placebo-controlled studies, and reﬂects changes in practice by focusing on treatments that are effective
and acceptable in clinical practice.
II. PANIC DISORDER
A. Selective Serotonin Reuptake Inhibitors
Two recent reviews have examined the efﬁcacy and tolerability of SSRIs in the management of patients with panic disorder [1,2]. In many countries, prescription of an SSRI is
regarded as the most appropriate ﬁrst-line treatment: in others, cognitive therapy may berecommended, despite the limited availability of trained cognitive therapists. Typically,
about 60% of patients will become free of panic attacks after short-term treatment withan SSRI, continuation treatment being associated with further improvement. The sideeffect proﬁle of SSRIs in anxiety disorders is similar to that seen in patients with depression, the more common side effects being nausea, sweating, diarrhea, and delayed ejacula733

734

Baldwin et al.

tion or anorgasmia. The sexual side effects of SSRIs and other antidepressants have beenreviewed elsewhere [3].
1. Zimelidine
In the ﬁrst randomized controlled trial (n ⫽ 44) of an SSRI in panic disorder, zimelidine
was found to be more efﬁcacious than either placebo or imipramine [4]. Unfortunately,
zimelidine was later associated with the development of a disorder similar to Guillain–
Barre syndrome, and was withdrawn from clinical use [5].
2. Citalopram
There are few placebo-controlled studies of citalopram, although it has been available insome European countries for many years. An 8-week treatment study (n ⫽ 475) compared
three dose’s of citalopram to placebo and clomipramine, and found that the lowest daily
dose of citalopram (10–15 mg) was not different from placebo, but higher doses (20–30
mg and 40–60 mg) were associated with signiﬁcantly greater reductions in panic attack
frequency and measures of anxiety and depressive symptoms [6]. Patients who completed
the acute study and were expected to beneﬁt from longer term treatment could then be
included in a further 1-year double-blind continuation study [7]. In the 279 patients whoentered this treatment phase, there were again no differences in efﬁcacy between the lowest
dose of citalopram and placebo, but patients who received higher doses of citalopram or
who continued with clomipramine had the best chances of responding. There were few
differences in tolerability between citalopram and clomipramine. Although patients who
received higher doses of citalopram made similar improvements to those with clomipramine, the daily dose of clomipramine in both treatment phases was low (60–90 mg) andfurther studies are needed to establish the relative efﬁcacy of the two drugs.
3. Fluoxetine
Fluoxetine is used widely as a treatment for depression, but has been studied only infrequently in panic disorder. The ﬁrst evaluation involved both acute and continuation treatment phases [8,9]; a second study examined the effect of dose increase in early nonrespondents [10].
In the acute phase of the placebo-controlled study (n ⫽ 243) patients were randomized to receive either placebo or one of two daily doses (10 or 20 mg) of ﬂuoxetine for
10 weeks [11]. Fluoxetine was associated with greater reductions in panic attack frequency, phobic symptoms, and functional impairment. These changes were most noticeable with the higher dose; the 10-mg daily dose was linked to a signiﬁcant reduction inpanic attack frequency, but did not differ from placebo on measures of anxiety symptoms,
work impairment, anticipatory anxiety, or overall functioning. In the continuation phase(n ⫽ 88), patients who had responded to ﬂuoxetine were randomly allocated either tocontinue with ﬂuoxetine or to switch to placebo, both groups being followed up for 24
weeks. Patients continuing with active treatment showed signiﬁcant reductions in panic
attack frequency and phobic avoidance, but switching to placebo signiﬁcantly worsened
anxiety and depressive symptoms [9].
In the second placebo-controlled study (n ⫽ 180), patients who had not responded
after 6 weeks of treatment had the dose increased (to a maximum of 60 mg per day inthe ﬂuoxetine group) [10]. The proportion of patients who became panic-free increased
in both groups (from 29% at 6 weeks to 42% at endpoint with ﬂuoxetine, from 16 to 28%
with placebo), suggesting that dose increases may be useful in some patients.

Pharmacotherapy of Anxiety Disorders

735

The relative efﬁcacy of ﬂuoxetine and moclobemide (a reversible inhibitor of monoamine oxidase type A) has been evaluated in an 8-week treatment study involving 399
patients: at study endpoint 70% of ﬂuoxetine-treated patients were panic-free, compared
to 63% with moclobemide, there being no difference in overall response assessed by theClinical Global Impression Scale (CGI) [11].
4. Fluvoxamine
This has been evaluated in a number of placebo-controlled and comparator-controlled
treatment studies. In the ﬁrst (n ⫽ 50), both ﬂuvoxamine and clomipramine were efﬁcacious, 15 of 26 clomipramine-treated and 14 of 24 ﬂuvoxamine-treated patients being freefrom symptoms at study endpoint [12]. In a second randomized, controlled trial comparing
ﬂuvoxamine with the noradrenaline reuptake inhibitor maprotiline, ﬂuvoxamine was associated with a reduction in anxiety and depressive symptoms and a decrease in the numberof panic attacks, whereas maprotiline had little effect. At study endpoint, 10 of 20 patientstreated with ﬂuvoxamine had improved substantially, compared to only 5 of 24 patients
who received maprotiline [13]. A third placebo-controlled study compared ﬂuvoxaminewith ritanserin (a postsynaptic 5HT2-receptor blocker), but only ﬂuvoxamine was efﬁcacious, with a signiﬁcant reduction in panic attacks and improvements in anxiety and depressive symptoms and avoidance behavior [14].
Further placebo-controlled studies have conﬁrmed the efﬁcacy of ﬂuvoxamine. In
an 8-week study (n ⫽ 50), treatment with ﬂuvoxamine (mean daily dose at endpoint,
206.8 mg) was associated with reductions in panic attacks from week 3, and anxiety anddepressive symptoms from the sixth week. At study endpoint, 61% of the ﬂuvoxaminegroup were free of panic attacks, compared to 22% of those receiving placebo, but the
panic attacks that remained were no less severe [15]. In another placebo-controlled trial(n ⫽ 188) ﬂuvoxamine was also signiﬁcantly more efﬁcacious than placebo, with greater
reductions in panic attack frequency and Clinical Anxiety Scale scores, from the second
week of treatment [16]. These studies are partly supported by the ﬁndings of a third placebo-controlled investigation (n ⫽ 46) in which ﬂuvoxamine produced a signiﬁcantly
greater reduction in the number of limited symptom attacks, but not full panic attacks[17].
The relative efﬁcacy of ﬂuvoxamine in panic disorder has been evaluated throughcomparisons with imipramine [18,19], brofaromine [20], and cognitive therapy [21,22].
An 8-week multicenter double-blind placebo-controlled study (n ⫽ 148) found that ﬂuvoxamine (mean daily dose at endpoint, 171.4 mg) was less efﬁcacious than imipramine(164.7 mg) [18]. However, patients in the placebo group had signiﬁcantly fewer panic
attacks at baseline than those in the two active treatment groups, and further analysis using
data from only one center found evidence for efﬁcacy of both imipramine and ﬂuvoxamine[19]. In a small study (n ⫽ 30) comparing ﬂuvoxamine (daily dose, 150 mg) with thereversible monoamine oxidase inhibitor brofaromine, both treatments were efﬁcacious.
Ninety-three percent of brofaromine-treated patients were much or very much improved,
compared to 87% in the ﬂuvoxamine group, but only a minority had reductions of 50%
or more on the Hamilton Anxiety Scale [20].
The ﬁrst comparison of ﬂuvoxamine (n ⫽ 75) with cognitive therapy found that it
was superior to both cognitive therapy and placebo: at the end of the 8-week study, 90%of the ﬂuvoxamine group had achieved moderate to marked improvement, compared to
50% with cognitive therapy and 39% with placebo [21]. In the ﬂuvoxamine group, 81%
became free of panic attacks, this ﬁgure being less with cognitive therapy (53%) or placebo

736

Baldwin et al.

(29%); depressive symptoms improved in parallel with changes in panic attacks and anxiety symptoms [23]. However treatment with cognitive therapy produced more beneﬁcialchanges in “abnormal personality traits,” which were relatively resistant to ﬂuvoxamineor placebo [24]. By contrast, a placebo-controlled 13-week study (n ⫽ 190) in primary carefound that cognitive behavior therapy was more effective than ﬂuvoxamine; the greatest
improvements were seen with cognitive behavior therapy and ﬂuvoxamine in combination[22,25].
5. Paroxetine
The efﬁcacy of paroxetine in short- and long-term treatment has been investigated in aseries of placebo-controlled multi-center trials, some of which have also included an active
comparator drug. In the ﬁrst study (n ⫽ 120) [26], patients received either a ﬂexible dose
(10–60 mg/day) of paroxetine or placebo in addition to cognitive behavior therapy. There
was a signiﬁcantly greater reduction in panic attack frequency in patients receiving
paroxetine, compared to those taking placebo, from the sixth week of treatment: however,
the majority (64%) of patients who responded to paroxetine were still experiencing panic
attacks at the end of the study. The optimal dosage of paroxetine in the acute treatment ofpanic disorder is around 40 mg/day, this having been established in two placebo-controlled
studies [29]. In the ﬁrst of these, 425 patients received either placebo or 10, 20, or 40
mg/day of paroxetine; only the 40 mg daily dose was signiﬁcantly more efﬁcacious, with
86% of paroxetine treated patients becoming free of panic attacks compared with 50%
on placebo [27].
The relative efﬁcacy of paroxetine has been examined in three studies. In one investigation [28], 367 patients were randomized to receive placebo, paroxetine (daily dose, 20–60 mg), or clomipramine (daily dose, 50–150 mg). More patients in the paroxetine groupexperienced a complete resolution of panic attacks by the end of the 12-week study, andparoxetine treatment showed a signiﬁcantly earlier onset of action than clomipramine.
Patients who completed acute-phase treatment could then continue with treatment for afurther 36 weeks. Panic attacks in the active treatment groups continued to decrease during
the maintenance study: at the study endpoint, 85% of paroxetine-treated patients were freefrom panic attacks, compared to 72% with clomipramine and 59% with placebo [29]. A
further placebo-controlled comparison (n ⫽ 131) has evaluated the relative efﬁcacy ofparoxetine, clomipramine, and cognitive therapy. After 12-weeks, both drug treatments
were superior to cognitive therapy or placebo in reducing anticipatory anxiety agoraphobia
avoidance, and associated disability: furthermore, signiﬁcantly more paroxetine-treatedpatients were panic-free (65%) than with cognitive therapy (40%) or placebo (34%) [30].
However, another comparator-controlled study produced less encouraging results: whencompared to treatment with placebo or alprazolam there was no advantage for paroxetine,
probably because of unusually high response rates among patients receiving placebo (dataon ﬁle, SmithKline Beecham Pharmaceuticals).
Further evidence for long-term efﬁcacy comes from an investigation that employeda “relapse prevention” design. In this study (n ⫽ 175), patients who responded to acutetreatment were allocated randomly either to continue with paroxetine or to switch to placebo: only 5% of patients who continued with paroxetine relapsed, compared to 30% inpatients who switched to placebo [31].
6. Sertraline
The results of several large double-blind placebo-controlled studies of sertraline have been
published [32–34]. In two studies of identical design, which together included 342 patientPharmacotherapy of Anxiety Disorders

737

Figure 1 Efﬁcacy of paroxetine and clomipramine in long-term treatment of panic disorder (p ⫽ 0.004, paroxetine vs. placebo at week 36). (From Ref. 28).

[32,33], sertraline (50–200 mg/day) was signiﬁcantly more efﬁcacious than placebo in
reducing the “panic attack burden” (a product of the number and severity of panic attacks),
from the second week of treatment. Signiﬁcantly more patients became free of panic attacks with sertraline (59.3%) than with placebo (46.3%). In addition, there were greater
improvements with sertraline in quality-of-life measures, including items relating to mood,work, social, family and leisure activities, and in overall satisfaction with life. In one
study [33], adverse events were as frequent with sertraline and placebo; in the other [32],signiﬁcantly more patients stopped treatment with sertraline because of adverse experiences.
In a third double-blind, placebo-controlled 12-week study (n ⫽ 178) that compared
three ﬁxed daily doses (50, 100, or 200 mg) [34], sertraline was superior in reducing thenumber of panic attacks and limited symptom attacks, and in improving anxiety symptoms.
Although there were advantages for sertraline on scores on the CGI scale earlier in the
study, there was no difference from placebo at the end of treatment. The number of patients
dropping out from the study were similar for active and placebo treatment, but signiﬁcantly
more patients discontinued sertraline because of adverse events (mainly dry mouth anddelayed ejaculation). The authors concluded that there was no advantage in increasing thedose of sertraline above 50 mg per day [34].
The relative efﬁcacy of sertraline, compared to other treatments for panic disorder,
is uncertain. A double-blind placebo-controlled study that compared sertraline to imipramine, yet to be published, found some advantages for sertraline over placebo, but none
for imipramine, probably because of high placebo response rate [35].
7. Summary
Most double-blind placebo-controlled studies of SSRIs in acute and continuation treatmentof patients with panic disorder have found evidence for efﬁcacy. However, the magnitudeof improvement during treatment is variable—the proportion of patients becoming freefrom panic attacks ranges from 36 [26] to 86% [27], highest response rates with SSRIs
being seen in those studies that also show greater improvements on placebo [36]. Similarvariation is seen in measures of global anxiety [36]. Differences in study design do notallow exact comparison of the efﬁcacy of different SSRIs, and there is still a need forhead-to-head comparisons. Although a meta-analysis of 27 placebo-controlled, random-

738

Baldwin et al.

ized trials concluded that SSRI treatment was more effective than treatment with either
imipramine or alprazolam [37]; this was published in 1995 and therefore is out of date.
The relative side-effect burden with differing treatments is also unclear, although a recent
review suggests SSRIs are better tolerated than other pharmacological treatments in panic
disorder [38]. The relative efﬁcacy of SSRIs and psychological approaches remains unclear, but combination treatment may produce optimal results [22].
B.

Benzodiazepines

The efﬁcacy and tolerability of benzodiazepine anxiolytics in the treatment of panic disorder have been reviewed elsewhere [2]. The efﬁcacy of alprazolam has been establishedin both short- and long-term treatment, whereas clonazepam, lorazepam, and diazepam
have been evaluated only in short-term treatment studies.
1. Alprazolam
The short-term efﬁcacy of alprazolam (6–10 mg/day) was established in the ﬁrst phase(n ⫽ 526) of the Cross-National Collaborative Panic Study. After 8 weeks of treatment,
signiﬁcantly more alprazolam-treated patients (55%) were panic attack–free than among
those receiving placebo (32%): there were also signiﬁcant advantages for alprazolam overplacebo in reducing anticipatory anxiety and associated disability [39]. In the second phaseof the study (n ⫽ 168), patients were allocated randomly to receive alprazolam (6–10
mg/day), imipramine (150–250 mg/day), or placebo for 8 weeks. At study endpoint, bothactive treatments (70% panic-free) were signiﬁcantly more efﬁcacious than placebo (50%):
alprazolam had an earlier onset of action than imipramine [40]. Two subsequent placebocontrolled studies have conﬁrmed the efﬁcacy of alprazolam in short-term treatment[41,42].
Alprazolam may also be efﬁcacious in continuation treatment. In an extension of
the Cross-National Study in which patients who completed phase II (n ⫽ 181) could
continue with treatment for a further 6 months, the efﬁcacy of all three treatments wasmaintained [43]. An 8-month treatment study (n ⫽ 106) also found that alprazolam, imipramine, or placebo were helping patients become free of panic attacks [44].
2. Clonazepam
The short-term efﬁcacy of clonazepam has been conﬁrmed by the ﬁndings of three placebo-controlled treatment studies. In a 6-week study (n ⫽ 71), both clonazepam (0.5–5.0
mg/day) and alprazolam (1–10 mg/day) were signiﬁcantly more efﬁcacious than placebo:at endpoint the proportion of patients who were panic-free was 50%, 46%, and 14%,respectively [45]. The second investigation (n ⫽ 32) conﬁrmed the efﬁcacy of clonazepam
over 4 weeks of treatment [46]. A subsequent ﬁxed-dose treatment study (n ⫽ 413) foundthat higher daily doses of clonazepam were all more efﬁcacious than placebo in reducing
phobic avoidance and anticipatory anxiety; at study endpoint 73% of the group who received 1.0 mg per day were panic-free compared to 55% of those receiving placebo [47].
3. Other Benzodiazepines
Both diazepam and lorazepam have been efﬁcacious in short-term controlled studies. In
a placebo-controlled comparison (n ⫽ 241) of diazepam (60–100 mg/day) and alprazolam(6–10 mg), both active treatments were signiﬁcantly more efﬁcacious in reducing panic
attack frequency, anticipatory anxiety, agoraphobic avoidance, and overall disability [48].

Pharmacotherapy of Anxiety Disorders

739

Finally, a 6-week treatment study showed that lorazepam had similar efﬁcacy to alprazolam [49].
4. Summary
Benzodiazepines are efﬁcacious in short-term treatment of panic disorder. Treatment studies indicate that the treatment effect for benzodiazepines (i.e., the difference between active treatment and placebo groups) is 20 to 32% for alprazolam and 22 to 36% for clonazepam. There is much less evidence that benzodiazepines are efﬁcacious in longer term
treatment. Side effects are common and can be troublesome. About 80% of patients will
experience sedation or drowsiness, and ataxia, fatigue, slurred speech, memory disturbances, and sexual problems are not uncommon [2]. Approximately one-third of patients
undergoing long-term treatment develop dependence, and discontinuation symptoms canbe most distressing. As such, benzodiazepines are best reserved for short-term treatment
when other approaches have not proved unhelpful.

III. SOCIAL ANXIETY DISORDER
The treatment of patients with social phobia has received much attention in recent years,
possibly because of increasing awareness of the burden imposed by this potentially lifelong
condition. The effects of most treatments have been evaluated in short-term placebo-controlled, randomized trials, so there is little information on the potential value of continuation treatment.
A. Selective Serotonin Reuptake Inhibitors
1. Citalopram
There are no published studies with citalopram, but the efﬁcacy of other SSRIs in thiscondition suggests that citalopram is likely to be efﬁcacious. Studies with the enantiomer
escitalopram are believed to be underway.

Figure 2 Social anxiety disorder: controlled treatment studies of SSRIs. (From Refs. 51–
57,67.)

740

Baldwin et al.

2. Fluoxetine
No placebo-controlled or comparator-controlled studies of ﬂuoxetine have been published.
There has been one double-blind, placebo-controlled study of ﬂuoxetine in children withelective mutism, which has some similarities to social phobia [50]. Children who had not
responded to placebo treatment were randomly allocated to either continue with placebo
or switch to ﬂuoxetine at a dose of 0.6 mg/kg/day. There were signiﬁcant advantages forﬂuoxetine on parents’ ratings of mutism and global change, but not on ratings made byteachers or health professionals, and most children remained substantially impaired at theend of the treatment period.
3. Fluvoxamine
The effects of ﬂuvoxamine have been investigated in two double-blind, placebo-controlled
studies. In the ﬁrst, single-center, study (n ⫽ 30) patients received either a ﬁxed daily
dose of ﬂuvoxamine (150 mg) or placebo for 12 weeks: a substantial improvement wasseen in 7 (46%) of the 15 patients who received ﬂuvoxamine, but in only one patient(7%) who received placebo. Fluvoxamine treatment had signiﬁcant advantages on measures of social and anticipatory anxiety, but did not differ from placebo in phobic avoidance [51]. In a subsequent multicenter, 12-week ﬂexible-dose placebo-controlled study(n ⫽ 92), there were signiﬁcant advantages for ﬂuvoxamine (mean daily dose at endpoint, 202 mg) on all social phobia rating scales from week 8 and at endpoint there
were signiﬁcantly more responders with ﬂuvoxamine (42.9%) than with placebo (22.7%)[52].
4. Paroxetine
Three large double-blind, placebo-controlled multicenter studies have evaluated efﬁcacy
in short-term treatment [53,54] (data on ﬁle, SmithKline Beecham Pharmaceuticals). In
the ﬁrst, conducted in North America (n ⫽ 187), patients were randomly allocated toreceive placebo or ﬂexible daily doses (10–50 mg) of paroxetine for 12 weeks. At theend of the study, signiﬁcantly more paroxetine-treated patients were rated as much or verymuch improved (paroxetine 55%, placebo 23.9%): there were also signiﬁcant advantages
for paroxetine in measures of social anxiety symptoms and phobic avoidance [53].
A second multicenter double-blind treatment study (n ⫽ 290) conducted in Europe
and South Africa produced similar ﬁndings. Patients were assigned randomly to receive
placebo or ﬂexible doses of paroxetine (mean daily dose at endpoint, 34.7 mg) over 12
weeks. Signiﬁcantly more patients who received paroxetine responded to treatment (65.7%
vs. 32.4%), and paroxetine was associated with signiﬁcantly greater reductions in social
anxiety symptoms and phobic avoidance and greater improvements in work, social, andfamily life [54]. A third, placebo-controlled study, which employed ﬁxed daily doses ofparoxetine (20, 40, or 60 mg), found that there was little to be gained in increasing thedose of paroxetine above 40 mg per day, because higher doses were not associated withgreater improvement, but rather linked to a greater side-effect burden (data on ﬁle,SmithKline Beecham Pharmaceuticals).
There are at present no published large-scale studies of paroxetine in long-term
treatment but an investigation of open-label acute treatment, followed by double-blind
placebo-controlled discontinuation, found that paroxetine was efﬁcacious in preventing
relapse of illness [55].

Pharmacotherapy of Anxiety Disorders

741

Figure 3 Paroxetine in generalized social anxiety disorder (p ⬍ 0.001 vs. placebo). (FromRef. 54).

5. Sertraline
Three placebo-controlled studies have examined the effects of sertraline in the acute treatment of patients with social phobia [56–58]. A preliminary, small, double-blind crossover study (n ⫽ 12) of treatment with ﬂexible daily doses of sertraline (50–200 mg) founda signiﬁcant improvement in social anxiety symptoms with sertraline, but not with placebo[56]. In a larger (n ⫽ 233) placebo-controlled parallel-group ﬂexible-dose 12-week treatment study, there were signiﬁcant advantages for sertraline in measures of social anxiety
symptoms and phobic avoidance, and in the proportion of patients who responded to treatment (sertraline, 52%; placebo 29%) [57]. The investigation of sertraline in social phobia
is a 24-week double-blind placebo-controlled treatment study in primary care, in which
patients were allocated randomly to receive sertraline alone, exposure therapy alone, acombination of sertraline plus exposure, or placebo: the greatest response rate (46%) was
seen with combination treatment [58].
6. Venlafaxine
There is at present little evidence for the efﬁcacy of venlafaxine in social phobia. In a
12-week open-label study, 8 out of 17 patients (47%) showed clinically relevant improvement during venlafaxine treatment [59].
B. Tricyclic Antidepressants
Tricyclic antidepressants have not been studied extensively in patients with social phobia
there is little evidence to suggest they may be valuable. While early open-label studies
suggested that treatment with clomipramine could be efﬁcacious, these studies were uncontrolled and included patients with a variety of anxiety disorders [60–62]. A more recent
8-week open study of imipramine in 15 patients showed a response rate on the CGI scaleof only 20% [63].
C. Monoamine Oxidase Inhibitors
Randomized controlled trials have shown the irreversible MAOI phenelzine to be efﬁcacious in social anxiety disorder. Its efﬁcacy has been evaluated in double-blind, placebo-

742

Baldwin et al.

Figure 4 Social anxiety disorder: controlled treatment studies of MAOIs.
controlled studies involving over 200 patients [64–66]. In these studies, phenelzine wasconsistently more effective than placebo. However, phenelzine has a rather poor sideeffect proﬁle, causing weight gain and hypotension; the need for a restricted diet becauseof the interaction of the drug with tyramine-containing foodstuffs and sympathomimetic
medicines precludes phenelzine from being a ﬁrst-line treatment [67].
There are inconsistent efﬁcacy data for the selective and reversible MAOI moclobemide. Early placebo-controlled studies found it to be more efﬁcacious than placebo[66,68], particularly at higher doses, but later studies suggest that moclobemide treatment
conveys little beneﬁt [69,70]. In a large (n ⫽ 523), 12-week controlled study of moclobemide, with doses ranging from 75 to 900 mg/day, response rates using the CGI scale
were only 32 to 38% for moclobemide, compared with 33% for placebo [69]. Althoughmoclobemide is licensed for the treatment of social phobia in some countries, the overall
evidence for clinical efﬁcacy of moclobemide does not support its use as a ﬁrst-line treatment. Furthermore, at higher doses it behaves more like an irreversible MAOI, and patients
must observe similar dietary restrictions to those needed when taking phenelzine.
Three 12-week placebo-controlled treatment studies with the reversible MAOI brofaromine have produced encouraging results, although the development of the drug has
been curtailed. In the ﬁrst study, there was a response rate (a score of 10 or less on the
Hamilton Anxiety Scale) of 73% with brofaromine, compared to 0% with placebo [71].
In a second study, response rates (“very much” or “much” improved on the CGI item)
were 78% for brofaromine and 23% for placebo [72]. In the third investigation (n ⫽ 102),
the response rates were 50% for those receiving brofaromine and 19% in those allocatedto placebo [73].
D.

Benzodiazepines

There are few data on the efﬁcacy of benzodiazepines in the treatment of social phobia,
but two short-term, placebo-controlled studies have evaluated alprazolam and clonazepam.
For alprazolam, there was only modest efﬁcacy (evaluated by the fear questionnaire) overa 12-week treatment period in a study of 65 patients (38% response rate vs. 20% forplacebo [64]. In a study of 75 patients, clonazepam was signiﬁcantly superior to placeboPharmacotherapy of Anxiety Disorders743

on the basis of the CGI scale, over a treatment period of 10 weeks (78% response rate
vs. 20% for placebo [74]. Benzodiazepines are probably best reserved for patients who
do not respond to other treatment approaches. They have marked sedative effects and are
not recommended in patients with comorbid alcohol abuse or dependence. Furthermore,they are largely ineffective in treating depression, which is a disadvantage in the management of patients with social phobia, who often have signiﬁcant comorbid depressive symptoms.
E.

Buspirone

The azapirone anxiolytic drug buspirone produces only a modest improvement in patientswith social phobia [75,76]. A small (n ⫽ 30) placebo-controlled, double-blind treatment
study showed no signiﬁcant differences between placebo and buspirone at an average doseof 30 mg/day [77]. However, it may be a useful adjuvant treatment in some patients who
have made a partial response to an SSRI [78].
F.

Beta-Blockers

Beta-blockers are often prescribed to professional performers in an attempt to control
performance-related anxiety manifest by autonomic symptoms such as tachycardia,
tremor, and sweating [79]. However, placebo-controlled trials with atenolol have found
it not to be helpful in the treatment of generalized social phobia [65,80,81]. Beta-blockers
should be avoided in patients with asthma and, because of the limited evidence for efﬁcacy,
are not an appropriate treatment [82].
G.

Gabapentin and Prebagalin

A double-blind placebo-controlled treatment study with the anticonvulsant drug gabapentin suggests that it could be helpful in the overall management of patients with social
phobia [83]. After 7 days of single-blind placebo treatment, patients were allocated randomly to receive either placebo or ﬂexible doses (300–360 mg/day) of gabapentin. Outcome measures included the LSAS, Fear Questionnaire (FQ), Brief Social Phobia Scale(BSPS), and CGI. A total of 82 patients were enrolled: 69 entered double-blind treatment,but only 39 completed the study. There were signiﬁcant advantages for gabapentin overplacebo on the LSAS, FQ, BSPS, and CGI, especially in patients with more severe symptoms at baseline. There were more withdrawals because of adverse events with gabapentin
than with placebo, the more common events being nausea, dizziness, somnolence, insomnia, nervousness, and facial edema [83]. A recent ﬁxed-dose (150 mg or 600 mg/day)placebo-controlled study (n ⫽ 135) indicates that at the higher dose pregabalin is efﬁcacious in generalized social phobia, but more research into its efﬁcacy and tolerability isrequired before its potential value in treatment can be assumed [84].
H. Summary
SSRIs are efﬁcacious in short-term treatment of patients with social phobia. Their efﬁcacy
in long-term treatment is not yet established fully nor is their relative efﬁcacy comparedto other treatment approaches, including drug treatment with phenelzine and psychologicaltreatment with cognitive behavior therapy. Monoamine oxidase inhibitor drugs are usefulin many patients, but the tolerability of phenelzine is poor and stringent dietary restrictions
restrict its use in clinical practice: it is probably best reserved for second-line or third-

744

Baldwin et al.

line treatment in patients who have not responded to an SSRI. Moclobemide has provenefﬁcacy, although the evidence is somewhat conﬂicting: higher doses are needed, and it
is best to follow a traditional MAOI exclusion diet. Benzodiazepines may be useful inthe early phases of treatment while waiting for an SSRI to become efﬁcacious, or possibly
as an adjuvant approach in partial responders. Finally, the evidence for gabapentin andpregabalin suggests these compounds are efﬁcacious in social phobia, but the relative
efﬁcacy and tolerability of these compounds compared to an SSRI has not been established.
IV. GENERALIZED ANXIETY DISORDER
A.

Selective Serotonin Reuptake Inhibitors

As has been demonstrated, selective serotonin reuptake inhibitors have proven efﬁcacy
in panic disorder and social anxiety disorder. Accumulating data, most relating toparoxetine, show that SSRI treatment can also be efﬁcacious in patients with generalized
anxiety disorder(GAD).
1. Citalopram
No controlled trials with citalopram have yet been presented or published. An early randomized controlled trial comparing two dose ranges of citalopram and imipramine in 472
primary care depressed patients found that both treatments produced reduced mean scoreson the HAMD anxiety factor [85]. A more recent study comparing citalopram and paroxetine in 104 patients with DSM-IV major depression or mixed anxiety-depressive disorderfound that both treatments were associated with signiﬁcant reductions in the HAM-A total
scorce [86]. By contrast, the results of a 24-week double-blind placebo-controlled treatment study comparing citalopram and sertraline in 323 patients with DSM-IV major depressive disorder indicate that citalopram was more efﬁcacious than placebo in reducing
mean scores on the HAMD anxiety cluster ( p ⬍ 0.01), there being no signiﬁcant difference
on this measure between sertraline treatment and placebo [87].
2. Fluoxetine
There are no published treatment studies in adults with DSM-IV GAD. An open pilot
treatment study in 16 children and adolescents (9–18 years) with mixed anxiety disorders
showed that ﬂuoxetine might be of only limited beneﬁt [88]. Double-blind treatment studies of depressed patients indicate that ﬂuoxetine is as efﬁcacious as imipramine, clomipramine, or amitriptyline in relieving anxiety symptoms in depression, but the efﬁcacy of
ﬂuoxetine in comorbid depression and GAD is not proven [89].
3. Fluvoxamine
The efﬁcacy of ﬂuvoxamine as a treatment for GAD has not been established. However,in a small (n ⫽ 30) open study of patients with comorbid major depression and GAD,
ﬂuvoxamine showed signiﬁcant improvement in both anxiety and depressive symptoms[90]. This ﬁnding requires replication in patients with GAD before the efﬁcacy of ﬂuvoxamine can be assumed.
4. Paroxetine
The efﬁcacy of paroxetine in short-term treatment of GAD has been evaluated in four
randomized double-blind controlled studies [91]. The ﬁrst evaluation of paroxetine wasPharmacotherapy of Anxiety Disorders745

in a comparator-controlled trial involving 81 patients with a DSM-IV diagnosis of GAD,
paroxetine being compared to imipramine and 2′-chlorodesmethyl-diazepam in an 8-weektreatment study [92]. Paroxetine showed superior efﬁcacy to 2′-chlorodesmethyldiazepam
and similar efﬁcacy to imipramine. Paroxetine treatment differed signiﬁcantly ( p ⬍ 0.05)
from 2′-chlorodesmethyl-diazepam from week 4 onward, while imipramine only did so
at study endpoint. The second investigation was an 8-week, dose-ﬁnding study involving
566 patients, performed in the United States. In this study, paroxetine treatment (20 or
40 mg/day) was signiﬁcantly superior to placebo ( p ⬍ 0.001) in reducing both the mean
HAM-A total score and the mean scores on HAM-A items 1 (anxious mood) and 2 (tension). Response rates were 68 and 81% with paroxetine 20 mg and 40 mg/day, respectively, compared with 52% of patients in the placebo group (observed case data). By
the end of the study, the mean change from baseline on a health-related quality-of-lifequestionnaire (EuroQoL-5D) and visual analog scale was signiﬁcantly greater for bothparoxetine-treatment groups, indicating a signiﬁcant improvement in quality of life. The
third treatment study was an 8-week, ﬂexible-dose study conducted in 326 U.S. patientswith GAD. Paroxetine (20–50 mg/day) was signiﬁcantly superior to placebo ( p ⬍ 0.05)
in reducing mean HAM-A total score and mean scores on HAM-A items 1 and 2 andwas generally well tolerated. A fourth study of similar design conducted in 372 patientsin Europe has revealed similar reductions in HAM-A total score and HAM-A items 1
and 2.
The effects of treatment may extend beyond symptom reduction and improved quality of life. A small (n ⫽ 29) uncontrolled pilot study showed paroxetine treatment was
associated with a reduction in maladaptive personality traits [93] with signiﬁcant decreases
in harm avoidance (p ⫽ 0.0001) and novelty seeking ( p ⫽ 0.006), and a signiﬁcant increase in self-directedness ( p ⫽ 0.0004) The placebo-controlled paroxetine treatment studies also showed that as symptoms of GAD resolve there is an associated improvement insymptom-related disability, assessed using the patient-rated Sheehan Disability Scale(SDS) which covers impairment in social, work, and family life. At endpoint in all threestudies, a statistically signiﬁcant difference between paroxetine and placebo was seen in
the SDS total score (ﬂexible-dose study 1 difference ⫽ ⫺1.8; p ⫽ 0.037; study 2 difference⫽ ⫺2.4; p ⫽ 0.001; ﬁxed-dose study for 20 mg/day regimen, difference ⫽ ⫺3.1; p ⬍0.001; for 40 mg/day regimen, difference ⫽ ⫺3.6; p ⬍ 0.001) [94].
Paroxetine has recently been found efﬁcacious in long-term treatment, there being
signiﬁcantly fewer relapses with paroxetine (11%) than with placebo (40%) in a 6-month
relapse-prevention study [95].
5. Sertraline
No clinical trials of sertraline in the treatment of GAD have been reported. Double-blind
treatment studies indicate that sertraline is efﬁcacious in relieving anxiety symptoms
within depression and the symptoms and impairment associated with panic disorder, social
phobia, post-traumatic stress disorder, and obsessive-compulsive disorder, but its efﬁcacy
in GAD cannot be assumed.
The ﬁndings of the randomized controlled trials with paroxetine indicate that SSRI
treatment can be efﬁcacious in GAD. There are many further research needs, such as
establishing the comparative efﬁcacy and acceptability of differing treatments, in both
short- and long-term treatment; examining the effects of combining SSRI treatment withpsychological approaches such as cognitive-behavioral therapy; and evaluating the effectiveness of treatment in wider clinical practice.

746

Baldwin et al.

Figure 5 Fixed-dose study of paroxetine in generalized anxiety disorder (*p ⬍ 0.027 vs.
placebo for pairwise comparisons; **p ⬍ 0.001 vs. placebo, ⫹adjusted for treatment and
site.
B.

Other Antidepressant Drugs

1. Nefazodone
Nefazodone inhibits the reuptake of both serotonin and noradrenaline, although its strongest action is antagonism of the 5HT2a receptor. Studies in patients with major depression
and associated anxiety indicate that nefazodone can signiﬁcantly reduce anxiety symptoms[96], and a small open-label evaluation suggests that it can improve the symptoms of
GAD [97].
2. Venlafaxine
This serotonin-noradrenaline reuptake inhibitor has proven efﬁcacy in the treatment ofdepression and GAD. A preliminary study [98] in depressed outpatients indicated thatonce-daily venlafaxine was efﬁcacious in relieving anxiety symptoms, and suggested it
might therefore have a role in the management of patients with GAD. This supposition was
conﬁrmed by the ﬁndings of two studies of short-term treatment of GAD with venlafaxine[99,100]. In one study, venlafaxine was signiﬁcantly superior to the active comparator
buspirone in reducing anxiety symptoms, and there was some evidence that venlafaxine
had an earlier onset of action [99]. Three other placebo-controlled studies of venlafaxine
in the short-term treatment of GAD have been presented [101,102]. Efﬁcacy is reported
in two of the three studies of venlafaxine compared to placebo, but until these studies are
published fully it is difﬁcult to make a detailed assessment.
The long-term efﬁcacy of venlafaxine extended-release capsules has been shown
through the results of a 6-month randomized, double-blind, placebo-controlled, parallelgroup study [103]. These 6-month results were replicated in a second placebo-controlled
study [104]. The single relapse-prevention study, over a period of 4 months did not show
efﬁcacy for venlafaxine compared to placebo. Evidence supporting a dose-response relationship for venlafaxine is reported in the 6-month studies, with higher doses associatedwith a better response.
3. Mirtazapine
The primary mechanism of action of mirtazapine is through antagonism of presynapticalpha-2 receptors and heteroceptors. No studies of mirtazapine in GAD have been reported,Pharmacotherapy of Anxiety Disorders

747

although a small placebo-controlled study of outpatients with primary anxiety disorders
indicated that it could reduce anxiety symptoms and improve overall functioning [105].
A meta-analysis of eight double-blind controlled treatment studies in patients with major
depression suggests that mirtazapine is efﬁcacious in reducing anxiety-related items of
the Hamilton Rating Scale for Depression [106].
4. Buspirone
Buspirone is a azapirone anxiolytic drug, with partial agonist properties at 5HT1a receptors,
which has proven efﬁcacy in the treatment of patients with GAD [107]. An early study[108] established that buspirone had comparable efﬁcacy to diazepam in patients withgeneralized anxiety, and a meta-analysis of eight controlled treatment studies indicatesthat buspirone has comparable efﬁcacy to benzodiazepines in the management of GAD[109]. It also appears efﬁcacious in reducing associated depressive symptoms in patientswith GAD, but is not an accepted treatment for patients with major depression [110].
However, not all studies with buspirone have been positive [111,112].
5. Benzodiazepines
A systematic review of randomized controlled trials has established that benzodiazepines
are an effective and rapid treatment for many patients with GAD [113]. However, thebenzodiazepines are far from ideal anxiolytic drugs. The untoward effects of benzodiazepines include sedation, memory disruption, and psychomotor impairment, with an associated increased risk of trafﬁc accidents. Other problems include the development of tolerance, abuse, and dependence, and withdrawal symptoms on stopping the drug. As such,many authorities counsel that benzodiazepines should be reserved for short-term use (upto 4 weeks), and prescribed at low dosage [114]. Others have argued that benzodiazepines
are clearly efﬁcacious, and withholding treatment on the basis of potential risk of dependence is unjustiﬁed and detrimental to overall well-being [115].

V.

POST-TRAUMATIC STRESS DISORDER

A. Selective Serotonin Reuptake Inhibitors
The number of published or presented placebo-controlled or comparator-controlled studies
of SSRIs in the treatment of post-traumatic stress disorder (PTSD) has increased rapidly
in recent years.
1. Fluoxetine
Three double-blind placebo-controlled studies with ﬂuoxetine have been performed. In
the ﬁrst study [116], 64 patients (31 combat veterans and 33 civilian patients) with PTSD
were randomly allocated to receive placebo or ﬂuoxetine, up to a maximum daily doseof 60 mg, for 5 weeks. By the end of the study there were signiﬁcant advantages forﬂuoxetine over placebo, in terms of overall PTSD psychopathology, largely in the civilianpatients. Certain symptom clusters, such as hyperarousal and hostility, showed littlechange with ﬂuoxetine treatment. In a second placebo-controlled ﬂexible-dose 12-weektreatment study of ﬂuoxetine in civilian patients (n ⫽ 53), ﬂuoxetine was associated withsigniﬁcantly greater reductions in overall PTSD psychopathology, and with a greater likelihood of response (ﬂuoxetine, 85%; placebo, 62%) [117]. A parallel investigation in combat

748

Baldwin et al.

Figure 6 Sertraline in short-term treatment of PTSD. (a Responder ⫽ CAPS-2 30% decrease and CGI ⫽ 1 or 2 at endpoint.

veterans using an identical protocol found no difference between ﬂuoxetine and placebo,indicating that patient background is an important treatment consideration in PTSD [118].
2. Paroxetine
Three large multicenter placebo-controlled treatment studies, together involving about1200 patients, have been undertaken. The ﬁndings of the two ﬂexible-dose studies (20–50 mg/day) and one ﬁxed-dose study (20 or 40 mg/day) together show that paroxetine
is efﬁcacious in reducing PTSD symptoms, with signiﬁcant advantages over placebo on
the reexperiencing/intrusion, avoidance/numbing and increased arousal symptom clusters.
Treatment was efﬁcacious in all patient groups regardless of trauma type or gender [119].
3. Sertraline
Two double-blind, ﬂexible-dose, placebo-controlled, 12-week treatment studies with sertraline have been performed [120,121]. In the ﬁrst study (n ⫽ 208) (mean sertraline daily
dose at endpoint, 125 mg), there were advantages for sertraline in three measures of overall
psychopathology, and no signiﬁcant differences in the rate of discontinuation from treatment because of adverse experiences [120]. In the second study (n ⫽ 187), there weresigniﬁcantly greater improvements with sertraline in three and four primary efﬁcacy measures (CAPS-2 severity score, CGI-S, and CGI-I) and on all secondary measures, andagain the rate of discontinuation because of side effects was similar in the two groups[121]. Preliminary data suggest that continuation of sertraline treatment is efﬁcacious inpreventing symptomatic relapse.
B.

Tricyclic AntidepressantsTwo placebo-controlled studies have evaluated the efﬁcacy of TCA treatment in combat
veteran patients with PTSD. The ﬁrst was an 8-week study (n ⫽ 46) of amitriptyline, whichfound it to be efﬁcacious, with signiﬁcant advantages over placebo on global measures of
PTSD symptoms, anxiety, and depression: the presence of comorbid depression, panic
disorder, or alcohol abuse reduced the chance of response [122]. A further analysis showedPharmacotherapy of Anxiety Disorders

749

that response was greater with less severe degrees of trauma, with less severe symptoms,
and when there was no premorbid neuroticism [123]. The second placebo-controlled 8week treatment study (n ⫽ 60) of a TCA involved imipramine (up to 300 mg/day), withphenelzine (up to 75 mg/day) as an active comparator. Imipramine was marginally less
efﬁcacious than phenelzine (global response 65% and 68%, respectively), the MAOI
showing greater efﬁcacy in reducing intrusive and avoidant symptoms [124].
C. Other AntidepressantsTwo placebo-controlled treatment studies with brofaromine have been published. A small(n ⫽ 45) ﬂexible-dose European study found that brofaromine was efﬁcacious in a predominantly civilian group of patients, greater efﬁcacy being seen in those whose symptoms
had lasted more than 12 months. At study endpoint, 55% of brofaromine-treated patientsno longer fulﬁlled diagnostic criteria for PTSD, compared to 26% of those who had received placebo; insomnia was the most troublesome side effect [125]. A larger (n ⫽ 118)
U.S. study found some evidence for efﬁcacy of brofaromine: although there were no signiﬁcant drug–placebo differences on measures of PTSD symptoms, overall response rates
were greater with drug treatment (60%) than with placebo (39%) [126].
The potential efﬁcacy of trazodone or nefazodone in PTSD has been assessed inopen-label treatment. In a small case series (n ⫽ 6), trazodone treatment (up to 400 mg/day) produced only marginal beneﬁt in reducing PTSD symptoms, with no associatedimprovement in social or occupational functioning [127]. Nefazodone has been evaluatedin two case series. In the ﬁrst, there were considerable improvements in most measuresin 10 combat veterans treated with doses up to 600 mg per day for 12 weeks [128]. These
promising ﬁndings are supported by a second report, in which 36 combat veterans showed
improvements in measures of PTSD symptoms, anxiety, and depression, over 8 weeks[129].
D. Summary
Placebo-controlled treatment studies indicate that SSRIs, amitriptyline, imipramine, phenelzine, and brofaromine are efﬁcacious in PTSD. The evidence for differing SSRI treatment varies; only paroxetine has been found efﬁcacious in both genders, regardless of
trauma type, across all key symptom clusters. More research is needed into the effects oflong-term treatment, and into the relative efﬁcacy and tolerability of different treatment
approaches.
VI. CONCLUSIONS
Modern management of patients with anxiety disorders will focus on better-tolerated treatments, with efﬁcacy that has been proven in both short- and long-term treatment studies.
Although numerous double blind placebo-controlled trials have shown that the SSRIs are
efﬁcacious in a range of anxiety disorders, many patients do not respond to treatment.
The magnitude of improvement in those who do respond is often disappointing, so there
is still a need to develop novel psychopharmacological approaches with greater efﬁcacy
than SSRI treatment. In addition, many patients with anxiety disorders are exquisitely
sensitive to the side effects of psychotropic drugs, and new treatments with a more acceptable side-effect proﬁle are needed. Finally, many patients prefer psychological treatment
approaches, fearing possible side effects of drug treatment or the risk of becoming depen-

750

Baldwin et al.

dent. There have been few well-designed controlled studies where the effects of drug andpsychological treatments are compared. This is a substantial deﬁcit, as clinicians cannot
obtain a full picture of the relative strengths and weaknesses of different treatment approaches in these chronic and severe disorders.

REFERENCES
1. Baldwin DS, Birtwistle J. Selective serotonin reuptake inhibitors in anxiety disorders: room
for improvement. In: Briley M, Nutt D, eds. Anxiolytics. Basel: Birkhauser, 2000; 55–75.
2. Kasper S, Resinger E. Panic disorder: the place of benzodiazepines and selective serotonin
reuptake inhibitors. Eur Neuropsychopharmacol 2001; 11:307–321.
3. Baldwin DS. Depression and sexual function. Br Med Bull 2001; 57:81–99.
4. Evans L, Kennardy J, Schneider P, Hoey H. Effect of a selective serotonin uptake inhibitorin agoraphobia with panic attacks: a double blind comparison of zimelidine, imipramine andplacebo. Acta Psychiatr Scand 1986; 73:49–53.
5. Nilsson BS. Adverse reactions in connection with zimelidine treatment: a review. Acta Psychiatr Scand 1983; 308(suppl):115–119.
6. Wade AG, Lepola U, Koponen HJ, Pedersen V, Pedersen T. The effect of citalopram inpanic disorder. Br J Psychiatry 1997; 179:549–553.
7. Lepola UM, Wade AG, Leinonen EV, Koponen HJ, Frazer J, Sjodin I, Pettinen JTT, Pedersen
T, Lehto HJ. A controlled, prospective 1-year trial of citalopram in the treatment of panic
disorder. J Clin Psychiatry 1998; 59:528–534.
8. Michelson D, Lydiard RB Pollack MH, Tamura RN, Hoog SL, Tepner R, Demitrack MA,
Tollefson GD and the Fluoxetine Panic Disorder Study Group. Am J Psychiatry 1998; 155:
1570–1577.
9. Michelson D, Pollack M, Lydiard RB, Tamura R, Tepner R, Tollefson and the Fluoxetine
Panic Disorder Study Group. Continuing treatment of panic disorder after acute response:
randomized, placebo-controlled trial with ﬂuoxetine. Br J Psychiatry 1999; 174:213–218.
10. Michelson D, Allgulander C, Dantendorfer K, et al. Efﬁcacy of usual antidepressant dosing
regimens of ﬂuoxetine in panic disorder. Randomised, placebo-controlled trial. Br J Psychiatry 2001; 179:514–518.
11. Tiller JWG, Bouwer C. Moclobemide and ﬂuoxetine for panic disorder. Eur Arch Psychiatry
Clin Neurosci 1999; 249(suppl 1):S7-S10.
12. den Boer JA, Westenberg HG, Kamerbeek WD, Verhoeven WM, Kahn RS. Effect of serotonin uptake inhibitors in anxiety disorders; a double-blind comparison of clomipramine andﬂuvoxamine. Int Clin Psychopharmacol 1987; 2:21–32.
13. den Boer JA, Westenberg HG. Effect of a serotonin and noradrenaline uptake inhibitor inpanic disorder: a double-blind comparative study with ﬂuvoxamine and maprotiline. Int Clin
Psychopharmacol 1988; 3:59–74.
14. den Boer JA, Westenberg HG. Serotonin function in panic disorder: a double blind placebo
controlled study with ﬂuvoxamine and ritanserin. Psychopharmacology (Berl) 1990; 102:
85–94.
15. Hoehn-Saric R, McLeod DR, Hipsley PA. Effect of ﬂuvoxamine on panic disorder. J Cli
Psychopharmacol 1993; 13:321–326.
16. Woods S, Black D, Brown S et al. Fluvoxamine in the treatment of panic disorder in outpatients: a double-blind, placebo-controlled study. Presented at the Annual Meeting of the College of International Neuropsychopharmacology, Washington DC, 1994.
17. Sandmann J, Lorch B, Bandelow B, Hartter S, Winter P, Hiemke C, Benkert 0. Fluvoxamineor placebo in the treatment of panic disorder and relationship to blood concentrations of
ﬂuvoxamine. Pharmacopsychiatry 1988; 31:117–121.
18 Nair NP, Bakish D, Saxena B, Amin M, Schwartz G, West TE. Comparison of ﬂuvoxamine

Pharmacotherapy of Anxiety Disorders

19.

20.

21.
22.

23.

24.

25.

26.

27.

28.

29.

30.
31.

32.
33.

34.

35.

751

imipramine, and placebo in the treatment of outpatients with panic disorder. Anxiety 1996;
2:192–198.
Bakish D, Hooper CL, Filteau MJ, Charbonneau Y, Fraser G, West DL, Thibaudeau C, Raine
D. A double-blind placebo-controlled trial comparing ﬂuvoxamine and imipramine in thetreatment of panic disorder with or without agoraphobia. Psychopharmacol Bull 1996; 32:
135–141.
Van Vliet IM, Den Boer, Westenberg HG, Slaap BR. A double-blind comparative study of
brofaromine and ﬂuvoxamine in outpatients with panic disorder. J Clin Psychopharmacol
1996; 16:299–306.
Black DW, Wesner R, Bowers W, Gael J. A comparison of ﬂuvoxamine, cognitive therapy,
and placebo in the treatment of panic disorder. Arch Gen Psychiatry 1993; 50:44–50.
Sharp DM, Power KG, Simpson RJ, Swanson V, Moodie E, Anstee JA, Ashford JJ. Fluvoxamine, placebo and cognitive behaviour therapy used alone and in combination in the treatment of panic disorder and agoraphobia in primary care. Br J Gen Pract 1997; 47:150–155.
Black DW, Wesner R, Bowers W, Monahan P, Gabel J. Acute treatment response in outpatients with panic disorder: high versus low depressive symptoms. Ann Clin Psychiatry 1995;
7:181–188.
Black DW, Monahan P, Wesner R, Gabel J, Bowers W. The effect of ﬂuvoxamine, cognitive
therapy, and placebo on abnormal personality traits in 44 patients with panic disorder. J
Person Disord 1996; 10:185–194.
Sharp DM, Power KG, Simpson RJ, Swanson V, Anstee JA. Global measures of outcome
in a controlled comparison of pharmacological and psychological treatment of panic disorderand agoraphobia in primary care. Br J Gen Pract 1997; 47:150–155.
Oehrberg S, Christiansen PE, Behnke E, Borup AL, Sverin B, Soegaard J, Callberg H, Judge
R, Ohrstrom JK, Manniche PM. Paroxetine in the treatment of panic disorder. A randomised
double-blind, placebo-controlled study. Br J Psychiatry 1995; 167:374–379.
Ballenger JC, Wheadon DE, Steiner M, Bushnell W, Gergel IP. Double-blind, ﬁxed dose,placebo-controlled study of paroxetine in the treatment of panic disorder. Am J Psychiatry
1998; 155:36-42.
Lecrubier Y, Bakker A, Dunbar G, Judge R. A comparison of paroxetine, clomipramine andplacebo in the treatment of panic disorder. Collaborative Paroxetine Panic Study Investigators. Acta Psychiatr Scand 1997; 95:145–152.
Lecrubier Y, Judge R. Long-term evaluation of paroxetine, clomipramine and placebo inpanic disorder. Collaborative Paroxetine Panic Study Investigators. Acta Psychiatr Scand
1997; 95:153–160.
Bakker A, van Dyck R, Spinhoven P, et al. Paroxetine, clomipramine, and cognitive therapy
in the treatment of panic disorder. J Clin Psychiatry 1999; 60:831–838.
Burnham DB, Steiner MX, Gergle IP et al. Paroxetine long-term safety and efﬁcacy in panic
disorder and prevention of relapse: a double-blind study. Presented in poster session at theannual meeting of the American College of Neuropsychopharmacology, San Juan, Puerto
Rico, 1995.
Pohl RB, Wolkow RM, Clary CM. Sertraline in the treatment of panic disorder: a double
blind multicenter trial. Am J Psychiatry 1998; 155:1189–1195.
Pollack MH, Otto MW, Worthington JJ, Manfro GG, Wolkow R. Sertraline in the treatmentof panic disorder: a ﬂexible-dose multicenter trial. Arch Gen Psychiatry 1998; 55:1010–
1016.
Londborg PD, Wolkow R, Smith WT, DuBoff E, England D, Ferguson J, Rosenthal M,
Weise C. Sertraline in the treatment of panic disorder. A multi-site, double-blind, placebocontrolled, ﬁxed-dose investigation. Br J Psychiatry 1998; 173:54–60.
Baldwin DS Baldwin DS, Cookson JC, Nutt DJ. Multi-centre double-blind placebo-controlled study of sertraline and imipramine in the treatment of panic disorder. J Psychopharmacol 2001; 13(suppl):A21.

752

Baldwin et al.

36. den Boer JA. Pharmacotherapy of panic disorder: differential efﬁcacy from a clinical viewpoint. J Clin Psychiatry 1998; 59(suppl 8):30–36.
37. Boyer W. Serotonin uptake inhibitors are superior to imipramine and alprazolam in alleviating panic attacks: a meta analysis. Int Clin Psychopharmacol 1995; 10:45–49.
38. Baldwin DS, Birtwistle J. The side effect burden associated with drug treatment of panic
disorder. J Clin Psychiatry 1998; 59(suppl 8):39–44.
39. Ballenger JC, Burrows GD, DuPont Jr RL, et al. Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efﬁcacy in short-term treatment. Arch Gen Psychiatry
1988; 45:413–422.
40. Cross-National Study Collaborative Panic Study, Second Phase Investigators. Drug treatmentof panic disorder: comparative efﬁcacy of alprazolam, imipramine and placebo. Br J Psychiatry 1992; 160:191–202.
41. Schweizer E, Patterson W, Rickels K, et al. Double-blind, plaeco-controlled study of a oncea-day, sustained-release preparation of alprazolam for the treatment of panic disorder. Am
J Psychiatry 1993; 150:210–215.
42. Pecknold J, Luthe L, Munjack D, et al. A double-blind, placebo-controlled, multicentre study
with alprazolam and extended-release alprazolam in the treatment of panic disorder. J Clin
Psychopharmacol 1994; 14:314–321.
43. Curtis GC, Massana J, Udina C, et al. Maintenance therapy of panic disorder. J Psychiatr
Res 1993; 27(suppl 1):127–142.
44. Schweizer E, Rickels K, Weiss S, et al. Maintenance drug treatment of panic disorder. I.
Results of a prospective, placebo-controlled, comparison of alprazolam and imipramine. ArchGen Psychiatry 1993; 50:51–60.
45. Tesar GE, Rosenbaum KF, Pollack MH, et al. Double-blind, placebo-controlled comparisonof clonazepam and alprazolam for panic disorder. J Clin Psychiatry 1991; 52:69–76.
46. Beauclair L, Fontaine R, Annable L, et al. Clonazepam in the treatment of panic disorder:
a double-blind, placebo-controlled trial investigating the correlation between clonazepam
concentrations in plasma and clinical response. J Clin Psychiatry 1994; 14:111–118.
47. Rosenbaum JF, Moroz G, Bowden CL. Clonazepam in the treatment of panic disorder withor without agoraphobia: a dose response study of efﬁcacy, safety and discontinuance. J Clin
Psychopharmacol 1997; 17:390–400.
48. Noyes Jr R, Burrows GD, Reich JH, et al. Diazepam versus alprazolam for the treatment ofpanic disorder. J Clin Psychiatry 1996; 57:349–355.
49. Schweizer E, Pohl R, Balon R, et al. Lorazepam vs. alprazolam in the treatment of panic
disorder. Pharmacopsychiatry 1990; 23:90–93.
50. Black B, Uhde TW. Treatment of elective mutism with ﬂuoxetine: a double-blind, placebo
controlled study. J Am Acad Child Adolesc Psychiatry 1994; 33:701–703.
51. van Vliet IM, den Boer JA, Westenberg HG. Psychopharmacological treatment of social
phobia: a double blind placebo controlled study with ﬂuvoxamine. Psychopharmacology(Berl) 1994; 115:128–134.
52. Stein MB, Fyer AJ, Davidson JR, Pollack MH, Wiita B. Fluvoxamine treatment of social
phobia [social anxiety disorder]: a double-blind, placebo-controlled study. Am J Psychiatry
1999; 156:756–760.
53. Stein MB, Liebowitz, Lydiard RB, Pitts CD, Bushnell W, Gergel I. Paroxetine treatment ofgeneralized social phobia [social anxiety disorder]: a randomized controlled trial. J Am Med
Assoc 1998; 280:708–713.
54. Baldwin DS, Bobes J, Stein DJ, Scharwachter I, Faure M. Paroxetine in social phobia/social
anxiety disorder. Randomised, double-blind, placebo-controlled study. Br J Psychiaty 1999;
175:120–126.
55. Stein MB, Chartier MJ, Hazen AL, Kroft CD, Chale RA, Cote D, Walker JR. Paroxetine in
the treatment of generalized social phobia: open-label treatment and double-blind placebocontrolled discontinuation. J Clin Psychopharmacol 1996; 16:218–222.

Pharmacotherapy of Anxiety Disorders753

56. Katzelnick DJ, Kobak KA, Greist JH, Jefferson W, Mantle JM, Serlin RC. Sertraline forsocial phobia: a double-blind placebo-controlled crossover study. Am J Psychiatry 1995;
152:1368-1371.
57. Van Ameringen MA, Swinson R, Walker JR, et al. A placebo-controlled study of sertraline
in generalised social phobia. Eur Neuropsychopharmacol 2000; 10(suppl 4):S335.
58. Blomhoff S, Haug TT, Hellstrom K, et al. Randomised controlled general practice trial ofsertraline, exposure therapy and combined treatment in generalised social phobia. Br J Psychiatry 2001; 179:223–230.
59. van Vliet IM, Westenberg HGM, van Megen H. Clinical effects of venlafaxine in social
phobia. Eur Neuropsychopharmacol 1997; 8(suppl 2):S258.
60. Beaumont G (1977) A large open multicentre trial of clomipramine (Anafranil) in the management of phobic disorders. J Int Med Res 19xx; 5:(suppl 5): 116–123.
61. Gringras M (1977) An uncontrolled trial of clomipramine (Anafranil) in the treatmentof phobic and obsessional states in general practice. J Int Med Res 19xx; 5:(suppl 5):111–
115.
62. Allsopp LF, Cooper GL, Poole PH. Clomipramine and diazepam in the treatment of agoraphobia and social phobia in general practice. Curr Med Res Opin 1984; 9:64–70.
63. Simpson HB, Schneier FR, Campeas RB et al. Imipramine in the treatment of social phobia.
J Clin Psychopharmacol 1998; 18:132–135.
64. Gelernter CS, Uhde TW, Cimbolic P et al. Cognitive-behavioural and pharmacological treatments of social phobia: a controlled study. Arch Gen Psychiatry 1991; 48:938–945.
65. Liebowitz MR, Schneier F, Campeas R et al. Phenelzine vs atenolol in social phobia: aplacebo-controlled comparison. Arch Gen Psychiatry 1992; 49:290–300.
66. Versiani M, Nardi AE, Mundim FD et al. Pharmacotherapy of social phobia: a controlled
study with moclobemide and phenelzine. Br J Psychiatry 1992; 161:353–360.
67. Davidson JRT. Pharmacotherapy of social anxiety disorder. J Clin Psychiatry 1998; 59(suppl
17):47–51.
68. The International Multicentre Clinical Trial Group on Moclobemide in Social Phobia. Moclobemide in social phobia. A double-blind, placebo-controlled clinical study. Eur Arch Psychiatry Clin Neurosci 1997; 247:71–80.
69. Noyes R Jr, Moroz G, Davidson JRT et al. Moclobemide in social phobia: a controlled doseresponse trial. J Clin Psychopharmacol 1997; 17:247–254.
70. Schneier FR, Goetz D, Campeas R et al. Placebo-controlled trial of moclobemide in social
phobia. Br J Psychiatry 1998; 172:70–77.
71. van Vliet IM, den Boer JA, Westenberg HGM. Psychopharmacological treatment of social
phobia: clinical and biochemical effects of brofaromine, a selective MAO-A inhibitor. Eur
Neuropsychopharmacol 1992; 2:21–29.
72. Fahlen T, Nilsson HL, Borg K, et al. Social phobia: the clinical efﬁcacy and tolerability of themonoamine oxidase A and serotonin uptake inhibitor brofaromine. A double-blind placebocontrolled study. Acta Psychiatrica Scand 1995; 92:351–358
73. Lott M, Greist JH, Jefferson JW et al. Brofaromine for social phobia: a multicenter, placebocontrolled, double-blind study. J Clin Psychopharmacol 1997; 17:255–260.
74. Davidson JRT, Potts N, Richichi E et al. Treatment of social phobia with clonazepam andplacebo. J Clin Psychopharmacol 1993; 13:423–428.
75. Munjack DJ, Bruns J, Baltazar PL et al. A pilot study of buspirone in the treatment of social
phobia. J Anxiety Disord 1991; 5:87–98.
76. Schneier FR, Saoud JB, Campeas R et al. Buspirone in social phobia. J Clin Psychopharmacol
1993; 13:251–256.
77. Van Vliet IM, den Boer JA, Westenberg HGM, et al. Clinical effects of buspirone in social
phobia: a double-blind, placebo-controlled study. J Clin Psychiatry 1997; 58:164–168.
78. van Ameringen M, Mancini C, Wilson C. Buspirone augmentation of selective serotonin
reuptake inhibitors (SSRIs) in social phobia. J Affect Disord 1996; 39:115–121.

754

Baldwin et al.

79. James IM, Grifﬁth DN, Pearson RM et al. Effect of oxprenolol on stage-fright in musicians.
Lancet 1997; 2:952–954.
80. Falloon IRH, Lloyd GG, Harpin RE. The treatment of social phobia. Real-life rehearsal with
nonprofessional therapists. J Nerv Ment Dis 1981; 169:180–184.
81. Turner SM, Beidel DC, Jacob RG. Social phobia: a comparison of behaviour therapy andatenolol. J Consult Clin Psychol 1994; 62:350–358.
82. Ballenger JC, Davidson JRT, Lecrubier Y et al. Consensus statement on social anxiety disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry
1998; 59(suppl 17):54–60.
83. Pande AC, Davidson JRT, Jefferson JW, Janney CA, Katzelnick DJ, Weisler RH, Greist JH,
Sutherland SM. Treatment of social phobia with gabapentin: a placebo-controlled study. J
Clin Psychopharmacol 1999; 19:341–348.
84. Feltner DE, Pollack MH, Davidson JRT et al. A placebo-controlled double-blind study ofpregabalin treatment of social phobia: outcome and predictors. Eur Neuropsychopharmacol
2000; 10(suppl 4):S345–S345.
85. Rosenberg C, Damsbo N Fuglum E et al. Citalopram and imipramine in the treatment ofdepressive patients in general practice. A Nordic multicentre clinical study. Int Clin Psychopharmacol 1994; 9(suppl 1):41–48.
86. Jefferson J, Greist J. A double-blind comparison of citalopram and paroxetine in the treatmentof patients with depression and anxiety. Presented at ACNP, December 2000.
87. Stahl S. Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline. Biol Psychiatry 2000; 48:894–201.
88. Fairbanks JM, Pine DS, Tancer NK, et al. Open ﬂuoxetine treatment of mixed anxiety disorders in children and adolescents. J Child Adolesc Psychopharmacol 1997; 7(1):17–29.
89. Hurst M, Lamb HM. Fluoxetine: a review of its use in anxiety disorders and mixed anxiety
and depression. CNS Drugs 2000; 14:51–80.
90. Sonawalla SB, Spillmann MK, Kolsky AR, et al. Efﬁcacy of ﬂuvoxamine in the treatmentof major depression with comorbid anxiety disorders. J Clin Psychiatry 1999; 60(9):580–
583.
91. Baldwin DS. SSRIs in the treatment of generalised anxiety disorder. In: Montgomery
SA, den Boer JA, eds. SSRIs in Depression and Anxiety. Chichester: Wiley, 2001:193–
209.
92. Rocca P, Fonzo V, Scotta M, et al. Paroxetine efﬁcacy in the treatment of generalized anxiety
disorder. Acta Psychiatr Scand 1997; 95:444–450.
93. Allgulander C, et al. Changes on the temperament and character inventory after paroxetine
treatment in volunteers with generalized anxiety disorder. Psychopharmacol Bull 1998; 34:
165–166.
94. Baldwin DS, McCafferty J, Bellew K, et al. Improving the disability associated with generalised anxiety disorder with paroxetine treatment. Eur Neuropsychopharmacol 2001; 11(suppl).
95. Montgomery SA. Long term treatment of GAD. First International Forum on Mood andAnxiety Disorders, Monte Carlo, December, 2000.
96. Fontaine R, Ontiveros A, Elie R, et al. Double-blind comparison of nefazodone, imipramine,and placebo in major depression. J Clin Psychiatry 1994; 55:234–241.
97. Hedges DW, Reimherr FW, Strong RE, et al. An open trial of nefazodone in adult patientswith generalised anxiety disorder. Psychopharmacol Bull 1996; 32:671–676.
98. Feighner JP, Entsuah AR, McPherson MK. Efﬁcacy of once-daily venlafaxine extended release (XR) for symptoms of anxiety in depressed outpatients. J Affect Disord 1998; 47:55–
62.
99. Davidson JR, DuPont RL, Hedges D, et al. Efﬁcacy, safety, and tolerability of venlafaxine
extended release and buspirone in outpatients with generalised anxiety disorder. J Clin Psychiatry 1999; 60:528–530.
100. Rickels K, Pollack M, Sheehan D, et al. Efﬁcacy of venlafaxine extended-release (XR) cap-Pharmacotherapy of Anxiety Disorders

101.
102.

103.

104.

105.
106.
107.
108.
109.

110.
111.
112.
113.

114.
115.
116.
117.

118.
119.

120.

121.

755

sules in nondepressed outpatients with generalised anxiety disorder. Am J Psychiatry 2000;
157:968–974.
Salinas E. Placebo-controlled evidence for the use of antidepressants in generalised anxiety
disorder. Eur Neuropsychopharmacol 1999; 9(suppl 5):S176.
Hackett D, Meoni P, White C, et al. Efﬁcacy of short and long-term venlafaxine ER treatment
for somatic and psychic symptoms of GAD. Eur Neuropsychopharmacol 2000; 10(suppl 10):
S337.
Gelenberg AJ, Lydiard RB, Rudolph RL, et al. Efﬁcacy of venlafaxine extended-releasecapsules in nondepressed outpatients with generalised anxiety disorder. JAMA 2000; 283:
3082–3088.
Allgulander C, Hackett D, Salinas E. Venlafaxine extended release (ERI in the treatment ofgeneralised anxiety disorder: twenty-four-week placebo-controlled dose-ranging study. Br J
Psychiatry 2001; 179:15–22.
Sitsen JMA, Moors J. Mirtazapine, a novel antidepressant, in the treatment of anxiety symptoms: results from a placebo-controlled trial. Drug Invest 1994; 8:339–344.
Fawcett J, Barkin RL. Meta-analysis of eight randomised, double-blind, controlled trials of
mirtazapine, a novel antidepressant drug. J Clin Psychiatry 1998; 59:123–127.
Goa KL, Ward A. Buspirone: a preliminary review of its pharmacological properties andtherapeutic efﬁcacy as an anxiolytic. Drugs 1986; 32:114–129.
Goldberg HL, Finnerty RJ. The comparative efﬁcacy of buspirone and diazepam in the treatment of anxiety. Am J Psychiatr 1979; 136:1184–1187.
Gammans RE, Stringfellow JC, Hvidzos AJ, et al. Use of buspirone in patients with generalized anxiety disorder and coexisting depressive symptoms: a meta-analysis of eight randomized controlled trials. Neuropsychobiol 1992; 25:193–201.
Sramek JJ, Tansman M, Suri, et al. Efﬁcacy of buspirone in generalised anxiety disorderwith coexisting mild depressive symptoms. J Clin Psychiatry 1996; 57:287–291.
Ansseau M, Paprt P, Gerard MAA, et al. Controlled comparison of buspirone and oxazepam
in generalised anxiety. Neuropsychobiol 1990; 24:74–78.
Rickels K, Schweizer E. The spectrum of generalised anxiety in clinical practice: the roleof short-term, intermittent treatment. Br J Psychiatry 1998; 173(suppl 34):49–54.
Gould RA, Otto MW, Pollack MH, et al. Cognitive behavioural and pharmacological treatment of generalised anxiety disorder: a preliminary meta-analysis. Behav Ther 1997; 28:
285–305.
Lader MH. Limitations on the use of benzodiazepines in anxiety and insomnia: are theyjustiﬁed? Eur Neuropsychopharmacol 1999; 9(suppl 9):S399–S405.
Argyropoulos SV, Nutt DJ. The use of benzodiazepines in anxiety and other disorders. Eur
Neuropsychopharmacol 1999; 9(suppl 9):S407–S412.
van der Kolk BA, Dreyfus D, Michaels M, Shera D, Berkowitz R, Fisler R, Saxe G. Fluoxetine in posttraumatic stress disorder. J Clin Psychiatry 1994; 55:517–522.
Connor KM. Sutherland SM, Tupler LA, Malik ML, Davidson JRT. Fluoxetine in posttraumatic stress disorder. A randomised double-blind study. Br J Psychiatry 1999; 175:17–
22.
Hertzberg MA, Feldman ME, Beckham JC, et al. Lack of efﬁcacy for ﬂuoxetine in PTSD:
a placebo-controlled trial in combat veterans. Ann Clin Psychiatry 2000; 12:101–105.
Davidson JRT, Connor KM. Serotonin and serotonergic drugs in post-traumatic stress disorder. In: Montgomery SA, den Boer JA, eds. SSRIs in Depression and Anxiety. Chichester:
Wiley, 2001: 175–191.
Davidson J, Rothbaum BO, van der Kolk BA, et al. Multicenter, double-blind comparisonof sertraline and placebo in the treatment of posttraumatic stress disorder. Arch Gen Psychiatry 2001; 58:485–492.
Brady K, Pearlstein T, Asnis GM, et al. Efﬁcacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA 2000; 283:1837–1844.

756

Baldwin et al.

122. Davidson JRT, Kudler H, Smith R, et al. Treatment of post-traumatic stress disorder withamitriptyline and placebo. Arch Gen Psychiatry 1990; 47:259–266.
123. Davidson JRT, Kudler HS, Saunders WB, et al. Predicting response to amitriptyline in posttraumatic stress disorder. Am J Psychiatry 1993; 150:1024–1029.
124. Kosten TR, Frank JB, Dan E. Pharmacotherapy for post-traumatic stress disorder using phenelzine or imipramine. J Nerv Men Dis 1991; 1179:366–370.
125. Katz RJ, Lott MH, Arbus P, et al. Pharmacotherapy of post-traumatic stress disorder witha novel psychotropic. Anxiety 1995; 1:169–174.
126. Baker DG, Diamond BI, Gillette G, et al. A double-blind randomized, placebo-controlled,
multi-center study of brofaromine in the treatment of post-traumatic stress disorder. Psychopharmacol 1996; 122:3386–3389.
127. Hertzberg MA, Feldman ME, Beckham JC, et al. Trial of trazodone for post-traumatic stressdisorder using a multiple baseline group design. J Clin Psychopharmacol 1996; 59:460–464
128. Hertzberg MA, Feldman ME, Beckham JC, et al. Open trial of nefazodone for combat-related
posttraumatic stress disorder. J Clin Psychiatry 1998; 59:460–464.
129. Davis LL, Nugent AL, Murray J, et al. Nefazodone treatment for chronic posttraumatic stressdisorder: an open trial. J Clin Psychopharmacol 2000; 20:159–164.

32
Pharmacotherapy of Mixed
Anxiety/Depression Disorders
A. CARLO ALTAMURA, ROBERTA BASSETTI, SARA FUMAGALLI,DONATO MADARO, DANIELE SALVADORI, and EMANUELA MUNDO
University of Milan
Milan, Italy

I.

INTRODUCTION

The choice and the clinical management of the pharmacological treatment of psychiatricconditions characterized by the co-occurrence of anxiety and depression is mostly inﬂuenced by the model adopted to explain the co-occurrence of symptoms that appear tobelong to different diagnostic domains. The two models currently accepted to explain
the occurrence of psychiatric comorbidity are the categorical and the dimensional one.
According to the categorical model, as ﬁrst described by Roth et al. in the 1960s [1],anxiety and depression are discrete syndromes that may co-occur in the same patient at
a certain time. Actually, anxiety may occur either as a “subthreshold” or subsyndromal
condition (i.e., few or isolated symptoms not structured in a full syndrome) or as full
syndrome with all the clinical features that characterized the speciﬁc clinical diagnosis(e.g., panic disorder, obsessive-compulsive disorder, generalized anxiety disorder). Morethan 30% of anxiety disorder patients receive an additional diagnosis of depression (major
depression or dysthymia) [2], 20% had generalized anxiety disorder (GAD) [3], and 20
to 30% of this group experience panic attacks [4]. Similarly, depression may be present
as a full syndrome or as a subthreshold condition.
The clinical observation that anxiety and depression frequently co-occur at a subsyndromal level, together with data derived from genetic and pharmacological studies onthese comorbid conditions, have stimulated the popularity, in recent years, of the dimensional model as opposed to the categorical one.

757

758

Altamura et al.

According to the dimensional model, the different clinical conditions (e.g., anxiety
and depression) are not discrete entities but a “spectrum” of syndromes characterized byanxiety and depressive symptoms in different combinations and with different degrees ofseverity [5].
The concept of spectrum, as opposed to that of full syndromal discrete diagnoses,
implies the consideration of clinical conditions that are not severe or deﬁnite enough to
fulﬁll the diagnostic criteria but that may be relevant in terms of prevalence in the population and challenging in terms of clinical management. It has been estimated that the prevalence of subthreshold depression and anxiety in psychiatric populations is about 7% and22%, respectively [6]. Furthermore, the co-occurrence of depression and anxiety symptoms (even though at a subsyndromal level) has been associated with greater severity ofillness, higher levels of functional impairment [7], chronicity [8], and delayed [9] or poor
[10] response to antidepressants.
The International Classiﬁcation of Diseases (ICD-10) [11] provides a code for mixed
anxiety and depression disorder. In the DSM-IV [12], the diagnostic category of mixed
anxiety depressive disorder (MAD) and of minor depressive disorder have been proposed
as research diagnostic criteria, suggesting the need for a more dimensional approach to
explain the presence of comorbid conditions. The essential feature of MAD is a persistentor recurrent dysphoric mood lasting at least 1 month. The dysphoric mood is accompanied
by additional symptoms that also must persist for at least 1 month and include at least
four of the following: (1) concentration or memory difﬁculties; (2) sleep disturbance; (3)fatigue or low energy; (4) worry—being easily moved to tears; (5) hypervigilance inanticipating the worst; (6) hopelessness or pessimism about the future; (7) low self-esteem
or feelings of worthlessness. Actually, many questions about this diagnostic category remain unanswered. The prevalence of MAD in the general population, the etiopathogenetic
mechanisms underlying this illness, its natural course, and the response to treatment are
still uncertain. In addition, the clinical characteristics that may allow discrimination between MAD, major depressive disorder (MDD), or anxiety disorders are not clearly deﬁned yet [13]. Furthermore, the matter appears to be complicated by methodological andassessment issues. As an example, it cannot be ruled out that the frequently observed
overlap of depressive and anxiety symptoms could be due to the use of nonspeciﬁc assessment instruments (e.g., the Hamilton Depression Rating Scales for Anxiety and for Depression). In addition, general practitioners sometimes are not able to distinguish between
anxiety and depressive disorders because this diagnosis requires psychiatric training. This
has led to the assumption, quite common in the general practice, that psychiatric patientsusually experience an admixture of symptoms instead of speciﬁc conditions [14].
However, the traditional view that anxiety and depression are discrete clinical conditions has been dramatically challenged in the last few years, particularly when the dichotomy between antidepressant and anxiolytic compounds has been surpassed. The ﬁndingthat some antidepressants show speciﬁc antianxiety properties and are effective in thetreatment of anxiety disorders even when not complicated by the occurrence of depressive
symptoms dates back to the early 1980s, when tricyclic antidepressants (TCAs) in monotherapy were found to be effective in the treatment of speciﬁc anxiety disorders [15–17].
In the last decade, it has become clearer that the boundaries between antidepressant andantianxiety activities were fallacious, as serotonergic antidepressants showed efﬁcacy inanxiety disorders where benzodiazepines (BDZs) were not equally effective [18].
From a clinical perspective, compared with depressed patients without anxiety
symptoms, those with symptoms of both disorders (either at subsyndromal or at full-Pharmacotherapy of Mixed Disorders759

syndromal level) have more severe depressive symptoms, higher levels of psychosocial
impairment, higher health-care costs, and are less likely to respond well to treatment[19,20]. Prospective studies on depressive patients have shown that the co-occurrence of
panic attacks was correlated with a poor outcome [21,22], and patients with depression
and comorbid obsessive-compulsive disorder (OCD) have been found to be more frequently resistant to treatment, even when selective serotonin reuptake inhibitors (SSRIs)
are used [23]. Moreover, depressed patients with a baseline high level of anxiety wereless likely to respond to the treatment with tricyclic antidepressants (TCAs) than patientswith no anxiety symptoms [7]. In addition, in a post-hoc analysis of more than 250 casesof “anxious-depression,” Filteau et al. [24] found that patient responders to SSRIs had
higher baseline anxiety/agitation levels than those responders to norepinephrine reuptake
inhibitors (NRI). On the other hand, high baseline levels of anxiety did not appear to
reduce the overall antidepressant response but rather to delay the onset of the clinicalresponse to sertraline or imipramine in patients with MDD [25]. It is likely that a longer
duration of antidepressant treatment is necessary to obtain remission of symptoms in patients with higher levels of anxiety [26]. A meta-analytic study comparing ﬂuoxetine,
placebo, and TCAs failed to demonstrate that high levels of anxiety during the course ofa major depressive episode affect the response to antidepressants, suggesting that the
choice of the antidepressant to be administered for the treatment of major depression
should not be based on the presence or absence of anxiety [27,28]. In a recent multicenter
study on patients with recurrent MDD, baseline anxiety levels were not related to theantidepressant response to two antidepressants with different pharmacodynamic proﬁle(bupropion or sertraline), thus conﬁrming that the baseline anxiety levels are not a clinicalvariable on which the choice of an antidepressant should be based [26].
In general, the most commonly used antidepressants [TCAs, SSRIs, and monoamineoxidase inhibitors (MAOIs-)] also exert anxiolytic properties, and there is evidence indicating that these agents are more effective in the treatment of patients with symptoms ofboth depression and anxiety then classical anxiolytic compounds [29].
The decision process for the choice of an antidepressant for the treatment of depression complicated by anxiety symptoms should include several clinical considerations. First, the ideal compound should induce a rapid improvement of anxiety symptoms,
minimal side effects, and minimal risk of developing abuse or dependence. The antidepressants currently used, despite the different degrees of selectivity, act on different neurotransmission systems, producing both clinically beneﬁcial and adverse effects [30]. Furthermore, the fact that the symptoms related to mixed anxiety/depressive syndromes usually
have a chronic course suggests that a monotherapy (with a compound exerting both antidepressant and anxiolytic activity) will be better tolerated than combination therapy[31].
In this chapter we will review the main literature on the pharmacological treatmentof comorbid anxiety and depression (either at syndromal or at subsyndromal level). In
the last few decades, many studies have been published on this issue. However, the main
limitation of these studies is that the diagnosis, in many cases, is not clearly assessed(according to DSM or ICD). Co-occurring syndromal conditions are often confused withisolated anxious or depressive symptoms, and the diagnosis of MAD according to DSMIV research criteria is not usually considered.
We will focus our attention primarily on the research that considered full syndromalor subthreshold anxiety–depression comorbidity. The pharmacodynamic proﬁle and clinical differences among the different antidepressant compounds currently used in the treat-

760

Altamura et al.

ment of depression and anxiety conditions will be brieﬂy reviewed, and practical guidelines for the treatment of these conditions will be derived from the studies available todate on adult and elderly populations.
Pharmacokinetic aspects in the case of combination treatments are rarely considered,
whereas they appear to be critical for the assessment of the efﬁcacy and tolerability ofpharmacotherapy in complex comorbid conditions.

II. TREATMENT IN THE ADULT POPULATIONA.

Benzodiazepines

Benzodiazepines (BDZs) in combination with antidepressants are often used in the generalpractice for the treatment of anxious/depressive syndromes at subsyndromal levels. BDZs
are effective, at least in the short-term, for the treatment of anxiety and panic attacks,
with rapid resolution of the anxiety symptoms, but with the risk of developing psychological and physical dependence. This potential complication, among other efﬁcacy considerations, prevents us from using these compounds as ﬁrst-choice therapy in mixed anxiety/depression conditions. Furthermore, their antidepressant activity is controversial [32]. On
the other hand, there is some evidence that BDZs, in particular clonazepam, may induce
depressive symptoms [33,34]. They may also induce sedation and, when administered athigh doses, may be associated with the development of dependence, with the occurrenceof withdrawal symptoms when the treatment is discontinued. Moreover, multiple daily
dosing with some short-acting BDZs may affect patient compliance, and missed doses
may lead to a worsening of anxiety [29]. Given all these potential implications, the useof BDZs in patients with depression and comorbid anxiety is not advised, except as shortterm adjunctive treatment to an antidepressant [35]. The rapid action of BDZs in relieving
anxiety symptoms may improve patient compliance and thus continue therapy long enoughto experience antidepressant treatment effects. After 3 to 6 weeks, when the antidepressantaction is fully reached, BDZ therapy should be slowly tapered, in order to prevent reboundanxiety or withdrawal symptoms [36]. In a recent meta-analytic study involving 9 clinical
trials on a total of 679 major depressives, the combination therapy group (antidepressants
plus BDZs) was 37% less likely to drop out than the antidepressant group alone, and more
likely to show a clinical response (deﬁned as 50% or greater reduction in the depression
scales from baseline) after 4 weeks of treatment [37].
In fact, during antidepressant treatment (with venlafaxine or SSRIs) [38] for anxiety
disorders or mixed anxiety-depression syndromes, patients may discontinue the treatment
or show unstable compliance because the latency of the clinical efﬁcacy is 2 or more
weeks. In these cases, the addition of BDZs at the early stages of the treatment together
with an appropriate clinical intervention (i.e., explaining to the patient that the clinicaleffect of the treatment will require a few weeks) will improve compliance signiﬁcantly
and thus the success of the treatment.
B.

Tricyclic Antidepressants and Monoamine Oxidase Inhibitors

1. Tricyclic Antidepressants
Tricyclic antidepressants (TCAs) are compounds with a relatively broad spectrum of pharmacodynamic proﬁles and clinical activities, and are effective in a wide range of de-Pharmacotherapy of Mixed Disorders

761

pressive pictures. Rather than being selective drugs limited in their efﬁcacy strictly todepressive symptoms, TCAs exert their efﬁcacy also in anxious depression [39].
TCAs appear to be at least equivalent to the BDZs in the short term and more
effective in the long-term treatment of MAD, with particular efﬁcacy in improving the
cognitive symptoms of anxiety [19,32]. However, they may induce psychomotor activation[40]. Amitriptyline appeared to be superior to placebo and diazepam in the treatment of
mixed anxiety/depression conditions [41]; similar ﬁndings were found for imipramine
versus chlordiazepoxide and placebo [42]. Imipramine and clomipramine have been suggested to be more useful in case of panic disorder (PD) complicated by comorbid depression. In these cases, the treatment should be started with low doses and gradually titrated
upward in order to avoid the risk of exacerbating panic attacks during the early phasesof treatment [20].
Clomipramine is particularly indicated in depressed patients with comorbid OCD[43]. In general, OCD patients require longer periods of treatment and higher doses incomparison to what is required by other clinical conditions.
Although TCAs have quite good antianxiety properties, their use is sometimes restricted by the fact that they may induce serious side effects, and because of the potentially
dangerous interaction with other compounds, such as MAOIs, ethanol, SSRIs, antipsychotics, oral contraceptives, and anticholinergic drugs [44]. For all these reasons, TCAs are
no longer considered a ﬁrst-choice treatment in MAD.
2. Monoamine Oxidase Inhibitors
Monoamine oxidase inhibitors (MAOIs) are often used for the treatment of more severe
and/or atypical forms of MDD, for major depressive episodes complicated by the presenceof clinically signiﬁcant anxiety symptoms, and for treatment-resistant depression [45].
Phenelzine was clearly found superior to placebo and to amitryptiline in depressed patientswith anxiety features [46]. At least one study has reported that MAOIs are more effective
than TCAs in treating patients with atypical depression who also suffer from panic attacks[45]. A within-treatment analysis indicated that depressed patients responded better to
MAOIs than did those with prevalent anxiety symptoms [47]. However, the use of MAOIs
is limited by their side-effect proﬁle and by the high potential for adverse drug–druginteractions [44]. Moclobemide, a reversible inhibitor of monoamine oxidase-A, provides
an alternative to the traditional irreversible MAOIs. This compound appears to be quite
effective in treating both agitated and retarded forms of depression [48], but more evidenceis needed to establish its efﬁcacy in mixed anxiety/depressive syndromes [31].
C. Selective Serotonin Reuptake Inhibitors
Several studies have shown that selective serotonin reuptake inhibitors (SSRIs) are aseffective as TCAs in treating depression and anxiety, although traditionally TCAs havebeen favored over SSRIs in patients with mixed syndromes. According to the results ofthree large meta-analytic studies, ﬂuoxetine [27,49] and paroxetine [50] are as effective
as TCAs in reducing anxiety and agitation in depression, and another study has shownthat sertraline is as effective as clomipramine in anxious depression [51]. When comparedto TCAs, SSRIs show a better tolerability proﬁle [27,52] and a good efﬁcacy in major
depression with severe anxiety symptoms. Furthermore, these compounds are effective
in anxiety disorders without depression, with a speciﬁc activity on anxiety symptoms,
compulsions, and avoidance behaviors. The dual (i.e., antianxiety and antidepressant) ef-

762

Altamura et al.

fect of these compounds, together with data derived from biological studies, have supported the hypothesis that serotonin (5HT) dysfunctions play a central role in the pathogenesis of mixed anxiety/depression syndromes. Given their pharmacokinetic characteristics,
SSRIs are suitable for once-daily dosing, are generally well tolerated even in the longterm, and have the compelling beneﬁt of being safe in overdose [53].
1. Fluoxetine
Results from two meta-analytic studies (involving 19 trials and 3183 patients and 31 trials
and 4737 patients) [54] showed that ﬂuoxetine and TCAs have comparable efﬁcacy interms of antidepressant response and induce psychomotor agitation at the same rate. Fluoxetine represents a good treatment for PD patients with depression and for patients withmedical conditions and comorbid anxiety and depression [55].
In randomized, double-blind studies [56,57], ﬂuoxetine (20–60 mg/day) showed asimilar efﬁcacy to that of imipramine and amitriptyline in the treatment of patients withmajor depression and anxiety symptoms (as evidenced by the scores of HRDS items psychic anxiety, somatic anxiety, agitation). Data from a 10-week double-blind trial on 284
patients with major depression indicate that ﬂuoxetine (20 mg/day), is as effective as other
SSRIs in patients with both high or low baseline anxiety [58]. These data conﬁrm previous
evidence showing that 20 mg/day of ﬂuoxetine is the optimal dose in the treatment ofdepression, with or without prominent anxiety features [59].
2. Sertraline
Some studies have shown the efﬁcacy and safety of sertraline in the treatment of mixed
anxiety and depression syndromes. In a sample of 38 patients suffering from mixed anxiety
depressive disorders (diagnosed according to ICD-10), during the ﬁrst week of treatment
there was a 40% decrease in anxiety symptoms (as measured by the HAM-A), while thedecrease in depression symptoms was 20% at week 2 and 50% at week 3. These results
conﬁrm the clinical observation that the efﬁcacy on depressive symptoms has a longer
latency than the efﬁcacy on anxiety [60].
Considering the three symptom clusters [using the Inventory of Depressive Symptomatology-Clinician rated (IDS-C)] of anxiety, depression, and anhedonia in a sample
of 140 patients with MDD, sertraline showed a “sequential” therapeutic effect acting ﬁrst
on anxiety, then on depression, and later on anhedonia [61].
A controlled, double-blind, randomized study did not show any statistically signiﬁcant difference in efﬁcacy and onset of action of ﬂuoxetine, sertraline, and paroxetine
during acute treatment of MDD with severe anxiety symptoms (with the exception of astatistically signiﬁcant greater improvement in the anxiety/somatization factor score forboth ﬂuoxetine- and sertraline-compared to paroxetine-treated patients) [62]. In addition,
this study did not support the assumption derived from previous reports [58,63] of a better
tolerability for one agent over the other. However a ﬁxed-dose study on 363 depressed
patients suggested that ﬂuoxetine 60 mg/day, when compared to placebo, may increaseagitation, anxiety, and insomnia [64].
3. Fluvoxamine
As far as the control of anxiety symptoms in general is concerned, a meta-analysis showed
an advantage of ﬂuvoxamine over TCAs [65], while in head-to-head comparisons withother SSRIs, ﬂuvoxamine was equivalent to ﬂuoxetine [66], sertraline [67], and citalopram[68], and slightly superior to paroxetine [69] in reducing anxiety in patients with MDD.

Pharmacotherapy of Mixed Disorders763

In an 8-week, open-label trial on 30 patients with MAD, ﬂuvoxamine showed moderately strong effectiveness in improving anxiety and depression with a greater efﬁcacy
on depressive patterns [70]. Fluvoxamine also showed a good efﬁcacy proﬁle in cases ofcomorbid OCD and MDD [71].
In a 12-week open trial on 30 patients, ﬂuvoxamine, showed a positive effect on
both depressive and anxiety symptoms in MDD subjects with one or more co-occurring
anxiety disorders [72], and in a 8-week, open trial on 70 patients, ﬂuvoxamine improved
both PD and depressive symptoms [73].
4. Paroxetine
Paroxetine showed similar efﬁcacy to maprotiline in depressed outpatients [74]. This SSRI
provides effective and well-tolerated monotherapy for depression, PD, OCD, social phobia(SPh) [75], and GAD [76].
According to the results of a 12-week, double-blind parallel group trial on 1002
patients with a primary diagnosis of depression who also experienced symptoms of anxiety, this compound has shown similar efﬁcacy to that of clomipramine, but a lower incidence of anticholinergic side effects [77]. A 6-week randomized, double-blind, placebocontrolled study in outpatients with anxious depression showed that the clinical efﬁcacy
of paroxetine and imipramine was similar at week 6, although paroxetine appeared tohave an earlier onset of action on anxiety symptoms [78].
A 6-week study on 275 patients comparing mirtazapine and paroxetine in MDD
showed a similar efﬁcacy (although mirtazapine showed a faster onset of action in anxiety,as evidenced by a reduction at HAM-A total scores) and good tolerability. However, paroxetine-treated patients reported more frequently the occurrence of nausea, vomiting, andtremor, while mirtazapine-treated patients reported more weight gain and ﬂulike symptoms[79].
5. Citalopram
Citalopram appears to exert good efﬁcacy on depression and anxiety with a low incidenceof side effects [80]. A comparison with sertraline, in a double-blind, randomized study
on 323 patients with MDD showed that citalopram has a faster antidepressant activity,that this clinical effect is signiﬁcantly related to a more pronounced antianxiety effect,
and that the compound has a better tolerability proﬁle leading to a signiﬁcant improvement
in compliance [81].
D. Miscellaneous Agents
1. Venlafaxine
Venlafaxine is an antidepressant classiﬁed as serotonin norepinephrine reuptake inhibitor(SNRI). Its mechanism of action consists of the inhibition of both norepinephrine (NE)and 5HT reuptake [82]. This compound has recently been approved for the treatment of
GAD [83].
Venlafaxine has shown considerable efﬁcacy in alleviating anxiety (as showed bya reduction in anxiety/somatization cluster scores at HAM-D) in patients with MDD ina randomized, placebo-controlled trial [84]. A meta-analytic study on 358 patients suffering from MDD with severe anxiety symptoms at baseline showed that venlafaxine, incomparison to placebo, induced a highly signiﬁcant improvement in both depression and764

Altamura et al.

anxiety symptoms (anxiety/somatization factor and anxiety psychic item score on
HAM-D) [85].
The slow-release preparation of this compound appears to have a faster onset ofaction, especially at higher doses. In addition, venlafaxine has been shown to improvesigniﬁcantly both the psychic and somatic manifestations of anxiety in 359 MDD patients[86].
As previously stated, the combination with a BDZ may prove useful in the earlyphases of treatment because the venlafaxine antianxiety clinical effect requires days toweeks to become evident.
2. Mirtazapine
Mirtazapine is a noradrenergic and speciﬁc serotonergic antidepressant (NaSSA) whose
direct enhancement of NE and 5HT1A-receptor-mediated 5HT neurotransmission is thought
to be responsible for its antidepressant activity, whereas the 5HT2 and 5HT3 blockade may
account for the low incidence of anxiety and agitation [87]. Clinical trials have shownthat mirtazapine is similar to TCAs in both its pharmacodynamic properties (interaction
with NE and 5HT transmission) and overall clinical efﬁcacy [88]. In three double-blind,randomized, controlled studies on patients with MDD and severe anxiety symptoms, comparing mirtazapine with citalopram (Mir: n⫽136; Cit: n⫽133), paroxetine (Mir: n⫽127;
Par: n⫽123), and ﬂuoxetine (Mir: n⫽60; Flu: n⫽63), mirtazapine consistently appeared
to reduce anxiety symptoms more than any of the other antidepressants, with a faster onsetof the effect on anxiety symptoms and a sustained activity throughout the course of treatment [89]. The results from a meta-analysis of eight randomized, double-blind, placebocontrolled clinical trials showed that the rapid improvement in anxiety symptoms seen in
161 depressed patients treated with mirtazapine could have important implications whenchoosing antidepressant therapy for depressed patients with prominent anxiety symptoms[30].
More than 700 patients with moderate-to-severe symptoms of depression have also
been tested to estimate the antianxiety effects of mirtazapine versus amitriptyline [90].
Both drugs proved to be equally effective, as shown by the variations on anxiety andsomatization factor scores of the HAM-D scale (items 10–13, 15, and 17). However,mirtazapine induced fewer side effects and adverse reactions in comparison to imipramine(76% vs. 87%), and a lower dropout rate (4.9% vs. 9.1%).
In an 8-week open-label study, a sample of 10 patients suffering from MDD withcomorbid GAD showed a signiﬁcant improvement on both HAM-D and HAM-A total
scores [91]. Excessive drowsiness and weight gain are sometimes limitations of the tolerability proﬁle for this compound. In the event of the occurrence of these undesirable effects,
administration at night and at lower dosage is advisable.
In conclusion, the clinical antidepressant efﬁcacy of mirtazapine appears to be similar to that of classical antidepressants with a more speciﬁc effect on anxiety and somatization symptoms and a better tolerability proﬁle.
3. Buspirone and Gepirone
These two 5HT1A agonists share some efﬁcacy in the treatment of comorbid anxiety anddepression [92]. Buspirone has been reported to have a signiﬁcant effect on the treatmentof GAD with co-occurring depressive symptoms [93], a situation that occurs in almost
50% of patients with a primary diagnosis of GAD [32]. More recently, it has been suggested that buspirone may have a signiﬁcant clinical effect in other anxiety disorders

Pharmacotherapy of Mixed Disorders

765

and comorbid conditions, even though more controlled trials are needed to conﬁrm thisobservation [94]. The idea that buspirone could be useful in the treatment of GAD patients
when discontinuing benzodiazepines is still controversial [95].
Gepirone has also been shown to be effective in the treatment of GAD with [92]and without [96] comorbid depression. However, the observation that SSRIs and venlafaxine may show a better efﬁcacy proﬁle than 5HT1A agonists makes the role of buspirone
and gepirone uncertain in the treatment of comorbid anxiety–depression conditions.
4. Nefazodone
Nefazodone acts as a weak inhibitor of NE and 5HT reuptake, while it is a potent 5-HT2
antagonist. In a meta-analysis of six randomized, placebo-controlled, double-blind trials
on patients suffering with MDD with high levels of anxiety, nefazodone showed a signiﬁcantly faster effect (within the ﬁrst week of treatment) on agitation than imipramine orplacebo [97].
In an open 8-week trial on 40 patients with PD and comorbid MDD or dysthymia,
nefazodone showed efﬁcacy in reducing both acute anxiety symptoms and depressive
symptoms [98].
E.

Antipsychotics

Severely depressed patients who responded poorly to antidepressant treatment or withhigh levels of anxiety and agitation may be treated with antipsychotics. Three patients
suffering from unipolar recurrent depression complicated by high levels of anxiety havebeen treated with atypical antipsychotics (quetiapine, risperidone, and olanzapine) withgood response [99]. This observation appears to conﬁrm the hypothesis that in patientswith recurrent chronic depression and high levels of anxiety, low doses of atypical antipsychotics may improve function through an antianxiety or antidepressant effect that is independent from their antipsychotic efﬁcacy [100]. This effect may occur with typical antipsychotics as well, but concern about the induction of tardive dyskinesia has limited theusefulness of these compounds [101].
Given their lower risk for tardive dyskinesia and extrapyramidal side effects (EPS),
atypical antipsychotics (e.g., risperidone, olanzapine), devoid or with few EPS, have beensuccessfully employed in the treatment of refractory obsessive-compulsive disorder, withpromising results [102,103].
III. TREATMENTS IN THE ELDERLY POPULATIONIn the elderly, as in adults, the co-occurence of depression and anxiety is often at a subsyndromal level (MAD). Risk and morbidity factors for comorbid depression and anxiety inlate life may be different from those for depression without anxiety and from those inyounger adults. Elderly depressives with comorbid anxiety disorders or symptoms present
with more severe psychopathology, higher impairment of the global functioning, a more
difﬁcult course of illness, and a decreased or delayed treatment response [104]. In addition,some anxiety disorders show an increased prevalence rate in the elderly. The 12-monthprevalence rate for GAD has been estimated from 7 to 9%, and this disorder has been
considered the most prevalent anxiety disorder in patients over 65 years of age [105]. On
the other hand, 91% of elderly with GAD show depression [106], which usually has an
earlier onset [107]. In a recent study, van Balkom et al. [108] showed that not only MDD,

766

Altamura et al.

but also BDZ use and chronic somatic diseases are signiﬁcantly more prevalent in elderly
patients with an anxiety disorder than in patients without comorbid conditions.
The ideal treatment in these situations should take the form of a monotherapy witha compound effective in the treatment of both anxiety and depression. An effective dosageof the drug should be achievable through once-daily administration to improve compliance. The compound should have a good tolerability proﬁle and should be safe in caseof overdose, since the risk of suicide is higher in depressed patients with anxiety than inthose without prominent anxiety [35].
The main problems faced in the management of the pharmacological treatment of
mixed anxiety–depressive syndromes in the elderly are related to the clinical, biologicalpharmacodynamic, and pharmacokinetic peculiarities of this population [109,110] (Table 1).
In the elderly, symptoms of depression and anxiety are often accompanied by somatic complaints, which may dominate the clinical picture, sometimes masking the mood
symptoms. In general, symptoms may be atypical in comparison to those encounteredin adults and may include multiple somatic complaints, persistent insomnia, irritability,
cognitive impairment, and hypochondriac ideation [111].
The frequent co-occurrence of neurological or medical conditions may cause difﬁculties in the recognition and diagnosis of depressive and anxiety symptoms [112,113].
A further complication is represented by the fact that in the elderly population there is aconsiderable overlap among symptoms of depression and anxiety, cognitive decline, andmedical syndromes. However, given that the risk of not recognizing and treating depression and anxiety in the elderly is very high in terms of morbidity and increased mortality,
clinicians are urged to appreciate anxiety and depressive syndromes in their different andvariable forms and combinations so that the pharmacological intervention can be initiatedin a timely manner and properly targeted.
In late life there are physiological changes associated with aging, namely, a higher
sensitivity to side effects, higher risks for drug–drug interaction phenomena, and compliance problems. All these factors need to be carefully taken into account when selecting
a pharmacological treatment [114,115]. For any new medication prescribed, it is important
to do a careful physical and laboratory assessment and to consider the pharmacodynamic
proﬁle of the compound prescribed, with particular respect to the potential side effects
on the central nervous system, including depressogenic or anxiogenic effects.
With respect to pharmacokinetic aspects, differences in the absorption, distribution,
metabolism, and excretion for most of the antidepressants and anxiolytics between elderly
and younger subjects have been described. Pharmacokinetic parameters are inﬂuenced by
Table 1 Clinical–Pharmacological Problems
Encountered in the Diagnosis and Treatment of
Mixed Anxiety/Depression Disorders in the Elderly
1. Atypical features
2. Cognitive impairment
3. Compliance problems
4. Concomitant medical disorders
5. Environmental factors (interfering with drug response)
6. Bioavailability/metabolic peculiarities
7. Reduced drug tolerability

Pharmacotherapy of Mixed Disorders

767

changes in gastrointestinal motility, renal function, atherosclerosis, muscular mass reduction, and increased body fats. All these factors contribute to determine the bioavailabilityof the drugs administered and thus they need to be considered carefully when prescribing
medication to elderly patients.
From a clinical point of view, TCAs are as effective as SSRIs in elderly anxietydepressive syndromes [114]. However, imipramine, amitriptyline [116], desimipramine[117], and nortriptyline [118,119] may cause cardiotoxicity and have an increased bioavailability, which leads to higher steady-state plasma concentrations. In addition, theoccurrence of anticholinergic effects is particularly dangerous in the elderly because of
the higher risk of induction of cognitive dysfunctions and deterioration. TCAs have beenreported to cause delirium in 11 to 30% of elderly patients [120]. These side effects may
have a signiﬁcant negative impact on clinical outcome and thus the use of TCAs in subjects
with concomitant medical or neurological conditions is discouraged [121].
Clinical evidence suggests the initial use of low doses of nortriptyline and desimipramine (10 mg/day) with a gradual titration upward to 75 mg/day. The dose indicatedfor other TCAs with more of a sedative effect (such as amitriptyline and dotiepin) is 30
to 100 mg/day. However, the possible occurrence of anticholinergic side effects should
be monitored very carefully [122].
SSRIs are at least as effective as TCAs, but have a more favorable tolerability proﬁle[123]. These characteristics make SSRIs more suitable for the treatment of depression andanxiety in the elderly [124]. Potential disadvantages of the SSRIs include the inductionof agitation and insomnia (occurring mostly with high doses of ﬂuoxetine), gastrointestinalside effects, and headache. The risk of the induction of adverse events, particularly in theelderly, is usually dose dependent. For this reason, a search for the minimal effective doseof the compound to be administered should be encouraged.
The choice of a TCA versus SSRI in mixed anxiety–depressive syndromes should
be based on their anxiolytic proﬁle and on the potential drug–drug interactions. Cytochrome P450 enzymes are the sites of metabolism for SSRIs and their activity is reducedin the elderly. This should always be considered when prescribing more than one compound to an elderly patient. Pharmacokinetic studies suggest that lower doses should be
used for citaprolam, paroxetine, and probably sertraline [123,124], particularly in case ofrenal or hepatic dysfunctions. On the other hand, no clear evidence was found for ﬂuoxetine and ﬂuvoxamine regarding age-dependent pharmacokinetic variations [125].
With respect to efﬁcacy issues, clinical studies revealed that some of the SSRIs are
particularly effective in treating comorbid anxiety in depressed patients [126]. The largest
clinical database relating to SSRI treatment of patients with depression/anxiety exists forparoxetine [77,127] but other SSRIs have also been shown to be effective.
Fluoxetine (20 mg/day) administered to elderly patients with a diagnosis of MDD
appeared to be particularly effective on early awakenings, sexual disturbances, guilt andsuicidal thoughts, and psychomotor inhibition [128], but less effective than TCAs on anxiety and insomnia.
In elderly patients with more severe anxiety symptoms, SSRIs with a more sedative
proﬁle, such as sertraline or ﬂuvoxamine, should be preferred [129].
Regarding SNRIs, there are data showing that venlafaxine (150 mg/day) and venlafaxine–XR are both effective in reducing anxiety in patients with depression [86,130].
Moreover, venlafaxine has a good tolerability proﬁle, which makes the compound an
attractive choice for geriatric patients, where the induction of hypotension is one of themain causes of hip fractures [131]. Venlafaxine has a low plasma protein binding rate

768

Altamura et al.

and slightly inhibits the cytochrome P450 system. These two characteristics indicate thatthe potential for dangerous interactions with other compounds is quite low. However,venlafaxine dosage should be adjusted in elderly patients [132] because of reduced metabolism rate in these subjects [133].
For mirtazapine, data suggest a reduced dose in the elderly because the pharmacokinetic proﬁle of this compound is gender- and age-dependent [134,135]. Females and elderly patients show higher plasma concentrations compared to those of males and adults.
The elimination half-life of mirtazapine ranges from 20 to 40 h, with a time to reach thesteady state of approximately 1 week [136]. Liver and renal dysfunctions cause a 30–
50% decrease in the drug clearance [136].
Some “atypical” antidepressants such as mianserin [122], viloxazine [137], and trazodone [138] have been successfully used in mixed anxiety-depressive syndromes. They
induced a signiﬁcant improvement of several core symptoms of depression and anxiety,as well as an improvement in somatic complaints and sleep disturbances. Overall, theside-effect proﬁle of these compounds is better than that of TCAs, even though mianserin
and trazodone may induce orthostatic hypotension.
BDZs in the elderly should be used with caution. They are the most commonly usedpsychotropic drugs among older people [139,140], but their adverse effects, which appear
to increase with age [141,142], limit their beneﬁt in this population. As a consequence,
BDZ prescription should be considered only in case of severe insomnia, agitation, anxiety,and somatoform symptoms, and when these symptoms have a central role in the overall
depressive picture [111]. The disadvantages associated with BDZ use in elderly patients
include daytime sedation or disinhibition (as paradoxical effect), cognitive and psychomotor impairment, dependency, withdrawal and rebound symptoms, ataxia, dysarthria vertigo, and cognitive toxicity in patients with preexisting cognitive decline [143]. Studies
on elderly inpatients showed that long-term treatments with BDZs represent one of themost common causes of exacerbation of dementia symptoms. Moreover, the use of BDZs,
even at low doses, appears to increase the risk of hip fracture [131]. All these side effects,
in particular the psychomotor ones, appear to be particularly evident at the beginning of
the treatment and in the ﬁrst month of continuous use [131,144,145]. BDZs with shorter
half-lives are no safer than agents with longer half-life, and are associated with the development of more severe cognitive impairment (e.g., memory deﬁcits), more rapid tolerance,or more severe withdrawal symptoms than those experienced with long-acting compounds[146,147].
Clinicians should consider these risks against potential beneﬁts when prescribing
BDZs for elderly patients. These cautions should not be interpreted as if the safest courseof action is always to avoid the use of BDZs, but rather suggest careful appraisal of therisks associated with their administration. It is necessary to weigh the hazards of not treating the clinical conditions (e.g., anxiety symptoms, agitation, or insomnia), which areoften substantial. In any case, the prescription of BDZs should be kept at low doses, forless than 4 months, and should be strictly monitored. Typical geriatric dosages of shortacting BDZs are the following: oxazepam, 15 to 30 mg/day; lorazepam, 0.5 to 3 mg/day;temazepam, 7.5 to 15 mg/day; alprazolam, 0.25 to 1.5 mg/day; triazolam, 0.125 to 0.250
mg/day. BDZs without active metabolites and with a short or ultrashort life (oxazepam,
triazolam) are preferable given the potential risk of accumulation phenomena due to the
reduced liver metabolic activity.
The so-called high-potency benzodiazepines (i.e., alprazolam and adinazolam) appear to be quite promising in the treament of comorbid anxiety–depression conditions,Pharmacotherapy of Mixed Disorders

769

since they have been shown to have both an anxiolytic and an antidepressant activity. The
mechanisms underlying this complex clinical proﬁle are not completely known. Alprazolam has been reported to have an effect on corticotropin-releasing hormone (CRH) [148]
as well as noradrenergic properties [149], and both these parmacodynamic properties may
well account for its antidepressant activity.
However, the limit to their use is related to the risk, in some cases, of exacerbating
somatization symptoms, and are not indicated in cases where these features are predominant in the clinical picture. In addition, the risk of the development of abuse or dependence
in patients treated with BDZs should be always considered and evaluated in the context
of global clinical management. The risk of developing abuse and dependence may be
increased in the elderly for pharmacokinetic changes occurring with aging. However, thissuggestion has not been conﬁrmed by controlled studies and still remains controversial[150], and recent data support the hypothesis that the development of BDZ abuse anddependence is mostly accounted for by interindividual differences including clinical andpersonality characteristics of the patients [151].
Many clinicians prefer the use of buspirone for the treatment of chronic anxiety inthe elderly [152]. Buspirone does not induce a worsening of depressive symptoms; however, it is not useful for as-needed prescription in the treatment of insomnia or acuteanxiety because its clinical effect has some latency. On the other hand, as opposed towhat has been described for BDZs, there are few drug–drug interactions and no discernible
drug–alcohol interactions, no potential for tolerance, withdrawal, or serious overdose toxicity with buspirone [153].
In conclusion, in the case of mixed anxiety–depressive syndromes occurring in elderly patients, it is of critical importance to differentiate between co-occurrence of depression and anxiety as isolated symptoms (MAD) or full syndromal patterns in order to envisage a more rational and targeted treatment. SSRIs, SNRIs, and NASSAs are preferable
to TCAs for efﬁcacy and tolerability proﬁles both in cases of subsyndromal or syndromal
coexistence of anxiety and depression. TCAs can be chosen in cases with melancholicfeatures. However, their use should be carefully monitored, particularly when administeredin combination with other compounds, because of the risk of adverse events due to drug–
drug interactions. Moreover, their dosage should be adjusted because their pharmacokinetic characteristics are signiﬁcantly affected by aging.
The use of BDZs should be discouraged in elderly subjects because of the risk ofdeveloping confusion and or agitation. Buspirone may be a suitable alternative. In general,a rational management of pharmacotherapy in complex comorbid conditions in the elderly
should imply careful attention to the occurrence of drug–drug interaction phenomena (pharmacodynamic and pharmacokinetic interactions with neuroleptics, neurotropics, or drugs
for other medical conditions) [111,115]. In case of combination treatment with more than
one compound, some side effects may occur despite a good tolerability proﬁle for eachindividual medication, particularly in case of long-term treatments.
IV. CONCLUSIONS
A critical review of the literature on the treatment of anxiety–depression syndromes led
to some theoretical and methodological considerations. First of all, there are some controversial issues: for example, whether high baseline levels of anxiety associated with depression could inﬂuence or not the overall clinical outcome [26,35], or whether some compounds with a more speciﬁc and selective pharmacodynamic proﬁle (e.g., serotonergic

770

Altamura et al.

vs. noradrenergic) could be more useful than others in treating both anxiety and depressive
symptoms [24]. From a methodological point of view, in many studies published to datethe quality of the association between anxiety and depressive symptoms (full-syndromalor subsyndromal) has not been speciﬁed. The new diagnostic category of MAD as proposed by the DSM-IV opens some questions about incidence, etiology, natural course,
and treatment response. These issues need to be addressed in order to validate this novel
category. Another methodological problem is that most of the studies have been done
according to a cross-sectional design, without adequate follow-up periods. Consequently,
very little is known about the course of the clinical picture and the long-term effect of
the treatments employed. Are SSRIs or other antidepressant compounds actually able tomodify the course of mixed anxiety–depression syndromes over time?
Another important issue is relative to the use of BDZs. These compounds are stillprescribed for anxiety–depression conditions, even though only some of them have shown
some antidepressant activity (e.g., alprazolam) and most of them may exert undesirable
side effects (e.g., depressogenic effects). The role of BDZs in the management of neurovegetative symptoms and insomnia in monotherapy or in combination with antidepressantsis arguable, and the clinician should always evaluate carefully the risk/beneﬁt ratio of a
combined therapy. In some cases, the anxiolytic effect of the antidepressants takes longer
to develop and this may hinder treatment compliance in anxious depression and othercomorbid conditions. In these cases, the use of BDZs may be advisable for the early stagesof the treatment until the clinical effect of the antidepressant compound has been reached[35]. A meta-analytic study showed some superiority of the combination antidepressant–BDZ in terms of drop-out rates and clinical response [37]. However, this study did not
elucidate whether the observed advantage of the combination treatment on the global
clinical outcome was only due to its effect on sleep and anxiety, or rather to some synergic
effects on core depressive symptoms. Moreover, none of the trials included in the metaanalysis lasted more than 8 weeks. Thus, whether a drug combination is more useful thanmonotherapy in the treatment of comorbid conditions is still unknown. The monotherapy
with a drug effective in the treatment of both anxiety and depression (as the SSRIs, SNRIs,
and NaSSAs) is generally preferable. The use of one compound as opposed to the use of
combination therapies allows the avoidance of drug–drug interaction phenomena, which
are particularly risky in the elderly.
The fact that the dichotomy between anxiolytic and antidepressant pharmacologicalcompounds has been deﬁnitively overcome appears to be conﬁrmed by the observationthat not only TCAs but also the new antidepressants (SSRIs, SNRIs, and NaSSAs) havea signiﬁcant clinical effect on both anxiety and depressive symptoms and syndromes.
A clear advantage of these new compounds in comparison to BDZs is that they
appear to exert an effect on the “core” features of anxiety (the cognitive symptoms andthe behavioral changes), while BDZs have a better effect on neurovegetative and somatic
symptoms. Thus, these new classes of antidepressants represent a critical step forward in
the treatment of co-occurring anxiety/depression compared to TCAs or MAOIs. Furthermore, their pharmacodynamic proﬁle, which implies different degrees of selectivity on
the 5HT neurotransmission systems, points out the critical role of this monoamine in thepathophysiology of these clinical conditions. Given higher acquisition costs for these newcompounds, formulary directors and pharmacy beneﬁt managers have questioned whether
they produced sufﬁciently superior clinical outcomes to justify their added expense. Somestudies estimated the overall treatment costs for SSRIs to be no greater (or even lower)Pharmacotherapy of Mixed Disorders

771

than those for TCAs, given their better tolerability proﬁle and the consequent improved
compliance [154].
Unfortunately, there are more data available on the pharmacological treatment offull-syndromal comorbid conditions (e.g., MDD and GAD, OCD, or PD) than on thetreatment of MAD. In our opinion, when treating MAD with antidepressants, a conservative attitude should be kept, particularly when there is no familial loading for anxiety anddepressive disorders, and limited impairment in everyday life functioning.
Low doses of SSRIs, SNRIs, and NaSSAs for 4 to 6 weeks could be effective inmild and moderate depressive subthreshold situations. On the other hand, when anxiety
and depression are present as full-syndromal disorders, the choice of compound to beadministered, the doses, and the duration of treatment should be based on the assessmentof the most prevalent symptoms. As an example, in case of OCD with a severe secondary
depressive disorder, clomipramine or SSRIs should be preferred to other compounds,
despite the observation that in severe depression a TCA should be preferred to a SSRI
[155].
In conclusion, the association of anxiety with depression is a common clinical experience in everyday practice. A dimensional approach appears to be more appropriate to
explain the clinical and pathophysiological characteristics of these conditions even though
there are not univocal models to explain the co-occurrence of anxiety and depression in
the same subject. Future studies should focus on a better assessment of the time courseof these conditions, including the long-term response to medication. These observations
will help the understanding of the biological bases of the occurrence of admixture of
symptoms in some clinical situations (e.g., in MAD), and will eventually improve treatment and prevention strategies.
REFERENCES
1. Roth M, Gurney C, Garside RF. Studies in the classiﬁcation of affective disorders. The relationship between anxiety states and depressive illnesses. Br J Psychiatry 1972; 121(561):
147–161.
2. Sanderson WC, di Nardo PA, Rapee RM. Syndrome comorbidity in patients diagnosed witha DSM-III-R anxiety disorder. J Abnorm Psychol 1990; 99(3):308–312.
3. Sanderson WC, Barlow DH. A description of patients diagnosed with DSM-III-R generalized
anxiety disorder. J Nerv Ment Dis 1990; 178(9):588–591.
4. Fawcett J. The detection and consequences of anxiety in clinical depression. J Clin Psychiatry
1997; 58 (suppl 8):35-40.
5. Goldberg RJ. Diagnostic dilemmas presented by patients with anxiety and depression. Am
J Med 1995; 98(3):278–284.
6. Wittchen HU, Essau CA. Comorbidity and mixed anxiety-depressive disorders: is epidemiologic evidence? J Clin Psychiatry 1993; 54:9–15.
7. Joffe RT, Bagby RM, Levitt A. Anxious and non anxious depression. Am J Psychiatry 1993;
150(8):1257–1258.
8. Van Valkenburg C, Akisal HS, Puzantian V et al. Anxious depression: clinical, family history
and naturalistic outcome-comparison with panic and major depression disorders. J Affect
Disord 1984; 6:67–82.
9. Clayton PJ, Grove WM, Coryell W et al. Follow-up and family of anxious depression. Am
J Psychiatry 1991; 148(11):1512-1517.
10. Flint AJ, Rifat SL. Anxious depression in elderly patients: response to antidepressant treatment. Am J Geriatr Psych 1997; 5:107–115.

772

Altamura et al.

11. World Health Organization. International Classiﬁcation of Mental and Behavioral disorders,
10th ed., Geneva, Switzerland: World Health Organization, 1992.
12. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
4th ed. Washington, D.C.: American Psychiatric Press, 1994.
13. Boulanger JP, Levallèe. Mixed anxiety and depression. Diagnostic issue. J Clin Psychiatry
1993; 54 (suppl 1):3–8.
14. Janicak PC, Davis JM, Preskorn SH. Indications for antidepressant therapy. In: Principle andPractice of Psychopharmacotherapy. Baltimore: William & Wilkins, 1997:219-242.
15. Garakani H, Zitrin CM, Klein DF. Treatment of panic disorder with imipramine alone. Am
J Psychiatry 1984; 141(3):446–448.
16. Ananth J, Solyom L, Bryntwick S, Krisjhnappa U. Clomipramine therapy for obsessivecompulsive neurosis. Am J Psychiatry 1979; 136(5):700–701.
17. Ananth J. Clomipramine: an antiobsessive drug. Can J Psychiatry, 1986; 31(3):253–258.
18. Berk M. Selective serotonin reuptake inhibitors in mixed anxiety-depression. Int Clin Psychopharmacol 2000; 15 (suppl 2):S41-S45.
19. Keller MB, Hanks DL. Anxiety symptom relief in depression treatment outcomes. J Clin
Psychiatry 1995; 56 (suppl 6):22-29.
20. Zajecka JM, Ross JS. Management of comorbid anxiety and depression. J Clin Psychiatry
1995; 56 (suppl 2):10–13.
21. Coryell W, Endicott J, Andreasen NC. Depression and panic attacks: the signiﬁcance ofoverlap as reﬂected in follow up and family study data. Am J Psychiatry 1988; 145(3):293–300.
22. Albus M, Scheibe G. Outcome of panic disorder with or without concomitant depression: a
2 year prospective follow-up study. Am J Psychiatry 1993; 150(12):1878–1880.
23. Hollander E, Mullen L, De Caria CM, Skodol A, Schneider FR, Liebowitz MR, Klein DK.
Obsessive compulsive disorder, depression and ﬂuoxetine. J Clin Psychiatry 1991; 52(10):418–422.
24. Filteau MJ, Baruch P, Lapierre YD, Bakish D, Blanchard A. SSRIs in anxious-agitateddepression: a post hoc analysis on 279 patients. Int Clin Psychopharmacol 1995; 10:51–
54.
25. Russell JM, Koran LM, Rush J. Effects of concurrent anxiety on response to sertraline andimipramine in patients with chronic depression. Depress Anxiety 2001; 13(1):18–27.
26. Rush J, Batey S, Donahue R, Camody T, Metz A. Does pretreatment anxiety predict response
to either bupropion SR or sertraline? J Affect Disord 2001; 64:81–87.
27. Tollefson GD, Holman SL, Sayler ME, Potvin JH. Fluoxetine, placebo and tryciclic antidepressants in major depression with and without anxious features. J Clin Psychiatry 1994; 55:
50-59.
28. Tyrer PJ, Lee I, Edwards JG, Steinberg B, Elliot EJ, Nightingale JH. Prognostic factors
determining response to antidepressant drugs in psychiatric out-patients and general practice.
J Affect Disord 1980; 2:149–156.
29. Lenox RH, Shipley JE, Peyer JM. Double-blind comparison of alprazolam versus imipramine
in panic disorder. Psychopharmacol Bull 1984; 20:79–82.
30. Fawcett J, Barkin RL. Meta-analysis of eight randomized, double-blind, controlled clinical
trials of mirtazapine for the treatment of patients with major depression and symptoms ofanxiety. J Clin Psychiatry 1998; 59:123–127.
31. Bakish D, Habib R, Hooper C. Mixed anxiety and depression. Diagnosis and treatment options. CNS Drugs 1998; 9(4):271-280.
32. Rickels K, Schweizer E. The treatment of generalized anxiety disorder in patients with depressive symptomatology. J Clin Psychiatry 1993; 54:20–23.
33. Liebowitz MR. Treating the patient with depression and associated anxiety. In Serotoninreshaping the treatment of depression. Medicine Publishing Foundation Symposium Series.
32. Toronto: The Medicine Group (Canada), 1992:31–41.

Pharmacotherapy of Mixed Disorders773

34. Lydiard RB, Larnia MT, Ballenger JC et al. Emergence of depressive symptoms in patients
receiving aiprazolam for panic disorder. Am J Psychiatry 1987; 144:664–665.
35. Nutt D. Treatment of depression and concomitant anxiety. Eur Neuropsychopharmacol 2000;
10 (suppl 4).
36. Fawcett J. Targeting treatment in patients with mixed symptoms of anxiety and depression.
J Clin Psychiatry 1990; 51 (suppl 11):40–43.
37. Furukawa AT, Streiner DL, Young LT. Is antidepressant-benzodiazepine combination therapy clinically more useful? A meta-analytic study. J Affect Disord 2001; 65:173–177.
38. Altamura AC, Pioli R, Vitto M, Mannu P. Venlafaxine in social phobia: a study in selective
serotonin reuptake inhibitors non-responders. Int Clin Psychopharmacol 1999; 14(4):239245.
39. Paykel ES. Predictors of treatment response. In Paykel ES, Coppen A, eds. Psychopharmacology of Affective Disorders. Oxford: Oxford University Press, 1979:193–220.
40. Noyes R, Perry P. Maintenance treatment with antidepressants in panic disorder. J Clin Psychiatry 1990; 51 (suppl 12):24–30.
41. Johnstone EC, Cunningham Owens D, Frith CD et al. Neurotic illness and its response toanxiolytic and antidepressant treatment. Psychol Med 1980; 10:321–328.
42. Khan RJ, McNair D, Lipman R et al. Imipramine and chlordiazepoxide in depressive andanxiety disorders. Arch Gen Psychiatry 1986; 43:79–85.
43. De Veaugh-Geiss J, Landaw P, Katz R. Treatment of obsessive-compulsive disorder withclomipramine. Psychiatr Ann 1989; 19:97–101.
44. Lydiard RB, Brawman O, Ballenger JC. Recent developments in the psychopharmacologyof anxiety disorders. J Consult Clin Psychol 1996; 64:660–668.
45. Liebowitz MR, Quitkin F, Stewart J. Antidepressant speciﬁcity in atypical depression. ArchGen Psychiatry 1988; 45:129–137.
46. Paykel ES, Rowan PR, Parker RR et al. Response to phenelzine and amitriptyline in subtype of neurotic depression. Arch Gen Psychiatry 1982; 39:1041–1049.
47. Davidson J, Pelton S, Krishnan R, Allf B. The Newcastle Anxiety Depression Diagnostic
Index in relationship to the effects of monoamine oxidase inhibitors and tricyclic antidepressant. J Affect Disord 1986; 11(1):51–58.
48. Angst J, Stahl M. Efﬁcacy of moclobemide in different patient groups: a meta-analysis ofstudies. Psychopharmacology 1992; 106:109–113.
49. Montgomery SA. The efﬁcacy of ﬂuoxetine as an antidepressant in the short and long term.
Int Clin Pharmacol 1989; 4:S113–119.
50. Sheehan D, Dunbar GC, Fuell DL. The effect of paroxetine on anxiety and agitation associated with depression. Psychopharmacol Bull 1992; 28:139–143.
51. Moon CA, Jago W, Wood K, Doogan DP. A double blind comparison of sertraline andclomipramine in the treatment of major depressive disorders and associated anxiety in generalpractice. J Psychopharmacol 1994; 8:171–176.
52. Simon GE, Heiligenstein JH, Grothaus L, Katon W, Revicki D. Should anxiety and insomnia
inﬂuence antidepressant selection: a randomized comparison of ﬂuoxetine and imipramine.
J Clin Psychiatry 1998; 59(2):49–55.
53. Lecrubier Y, Judge R. Long-term evaluation of paroxetine, clomipramine and placebo inpanic disorder. Acta Psychiatr Scand 1997; 95 (2):153–160.
54. Tollefson GD, Sayler ME. Course of psychomotor agitation during pharmacoterapy of depression: analysis from double-blind controlled trials with ﬂuoxetine. Depression Anxiety
1996; 4(6):294–311.
55. Schatzberg A. Fluoxetine in the treatment of comorbid anxiety and depression. J Clin Psychiatry Monogr 1995; 13(2):2–12.
56. Marchesi C, Ceccherininelli A, Rossi A, Maggini C. Is anxious-agitated major depression
responsive to ﬂuoxetine? Is anxious-agitated major depression responsive to ﬂuoxetine? A
double blind comparison with amitriptyline. Pharmacopsychiatry 1998; 31:216–221.

774

Altamura et al.

57. Versiani M, Plewers J, Ontivieros A. Fluoxetine and amitriptyline in the treatment of major
depression with associated anxiety. Eur Neuropsychopharmacol 1999; 2 (S187).
58. Fava M, Rosenbaum JF, Hoog S. Fluoxetine versus sertraline and paroxetine with and without anxious features: safety and efﬁcacy in anxious and non anxious subgroups. Biol Psychiatry 1998; 15(43):103 S.
59. Altamura AC, Montgomery SA, Wernicke JF. The evidence for 20 mg a day of ﬂuoxetine
as the optimal dose in the treatment of depression. Br J Psychiatry 1988; 153(3):108–111.
60. Carrasco JL, Diaz-Marsa M, Saiz-Ruiz J. Sertraline in the treatment of mixed anxiety anddepression disorder. J Affecti Disord 2000; 59:67–69.
61. Boyer P, Tassin JP, Fallisart B, Troy S. Sequential improvement of anxiety, depression andanhedonia with sertraline treatment in patients with major depression. J Clin Pharm Ther
2000; 25(5):363–371.
62. Fava M, Rosenbaum JF, Hoog SL, Tepner RG, Koop JB, Nilsson ME. Fluoxetine versus
sertraline and paroxetine in major depression: tolerability and efﬁcacy in anxious depression.
J Affect Disord 2000; 59:119–126.
63. Bennie EH, Mullin JM, Martindale JJ. A double blind multicenter trial comparing sertraline
and ﬂuoxetine in outpatients with major depression. J Clin Psychiatry 1995; 56(6):229–
237.
64. Beasley CM, Potvin JH. Fluoxetine: activating and sedating effects. Int Clin Psychopharmacol 1993; 8(4):271–275.
65. Montgomery SA. Selective serotonin reuptake inhibitors in the acute treatment of depression.
In: Bloom FE, Kupfer DJ, eds. Psychopharmacology: The Fourth Generation of Progress.
New York: Raven Press, Ltd, 1995:1043–1051.
66. Rapaport M, Coccaro E, Sheline Y et al. A comparison of ﬂuvoxamine and ﬂuoxetine in
the treatment of major depression. J Clin Psychopharmacol 1996; 16:373–378.
67. Nemeroff CB, Ninan PT, Ballanger J. Double-blind multicenter comparison of ﬂuvoxamine versus sertraline in the treatment of depressed outpatients. Depression 1995; 3:163–
169.
68. Haffman PM, Timmerman L, CA Hoogduin. Efﬁcacy and tolerability of citalopram in comparison with ﬂuvoxamine in depressed outpatients: a double blind, multicenter study. Int Clin
Psychopharmacol 1996; 11:157–164.
69. Kiev A, Feiger A. A double-blind comparison of ﬂuvoxamine and paroxetine in the treatment
of depressed outpatients. J Clin Psychiatry 1997; 58:146–152.
70. Houck C. An open-label pilot study of ﬂuvoxamine for mixed anxiety-depression. Psychopharmacol Bull 1998; 34 (2):225–227.
71. den Boer JA. Psychopharmacology of comorbid obsessive-compulsive disorder and depression. J Clin Psychiatry 1997; 58 (suppl 8):17–19.
72. Sonawalla SB, Spillman MK, Kolsky AR, Alpert JE, Nieremberg AA, Rosembaum JF, Fava
M. Efﬁcacy of ﬂuvoxamine in the treatment of major depression with comorbidity anxiety
disorders. J Clin Psychiatry 1999; 60:580–583.
73. Spiegel DA, Saeed SA, Bruce TJ. An open trial of ﬂuvoxamine in therapy for panic disordercomplicated by depression. J Clin Psychiatry 1996; 57(suppl 8):37–40.
74. Szegedi A, Wetzel H, Angersbach D, Dunbar GC, Schwarze H, Phil M, Benkert O. A doubleblind study comparing paroxetine and maprotilin depressed outpatients. Pharmacopsychiatry
1997; 30(3):97–105.
75. Rouillon F. Depression comorbid with anxiety or medical illness: the role of paroxetine. Int
J Psych Clin Pract 2001; 5:3–10.
76. Pollack MH, Zaninelli R, Goddard A, Mc Cafferty J, Bellew K, Burnham D, Iyengar M.
Paroxetine in the treatment of generalized anxiety disorder: results of a placebo controlled
ﬂexible dosage trial. J Clin Psychiatry 2001; 62:5.
77. Ravindran AV, Judge R, Hunter BN, Bray J, Morton NH. A double-blind multicenter study

Pharmacotherapy of Mixed Disorders

78.
79.
80.
81.
82.
83.
84.

85.
86.
87.
88.
89.
90.
91.
92.

93.
94.
95.

96.

97.

98.
99.

775

in primary care comparing paroxetine an clomipramine in patients with depression and associated anxiety. J Clin Psychiatry 1997; 58(3):112–118.
Feighner JP, Cohn JB, Fabre LB, Mendels J, Dumbar JC. A study comparing paroxetine
placebo and imipramine in depressed patients. J Affect Disord 1993; 28:71–79.
Benkert O, Szegedi A, Kohnen R. Mirtazapine compared with paroxetine in major depression. J Clin Psychiatry 2000; 61(9):656–663.
Feighner JP, Overo K. Multicenter, placebo-controlled, ﬁxed-dose study of citalopram inmoderate to severe depression. J Clin Psychiatry 1999; 60(12):824–830.
Stahl SM. Placebo-controlled comparison of the selective serotonin reuptake inhibitors citalopram and sertraline. Biol Psychiatry 2000; 48(9):894–901.
Preskorn SH. Antidepressant drug selection: criteria and options. J Clin Psychiatry 1994; 55:
6–22.
Sheehan D. Venlafaxine extended release in the treatment of generalized anxiety disorder.
J Clin Psychiatry 1999; 60 (suppl 22):23–28.
Feighner JP, Entsuah AR, McPherson MK. Efﬁcacy of once-daily venlafaxine extended release (XR) for symptoms of anxiety in depressed outpatients. J Affect Disord 1998; 47:55–
62.
Rudolph RL, Entsuah R, Chitra R. A meta-analysis of the effect of Venlafaxine on anxiety
associated with depression. J Clin Psychopharmacol 1998; 18:136–144.
Silverstone H, Ravindran A. Once-daily venlafaxine extended release compared with ﬂuoxetine in outpatients with depression and anxiety. J Clin Psychiatry 1999; 60(1):22–28.
De Boer T. The effects of mirtazapine on central noradrenergic and serotonergic neurotrasmission. Int Clin Psychopharmacol 1995; 10(4):19–23.
Kasper S. Clinical efﬁcacy of mirtazapine: a review of meta-analyses of pooled data. Int
Clin Psychopharmacol 1995; 10 (suppl 4):25–35.
Van Hensbeek I, Schutte AJ, Reimitz P. Onset of mirtazapine on anxiety symptoms related
to depression. Int J Neuropsychopharmacol 2000; 3 (suppl 1):S227, P03, 176.
Bremmer JD. A double blind comparison of Org 3770, amitriptyline and placebo in major
depression. J Clin Psychiatry 1995; 56:519–526.
Goodnick PJ, Puig A, DeVane CL et al. Mirtazapine in major depression with comorbid
generalized anxiety disorder. J Clin Psychiatry 1999; 60(7):446–448.
Cascalenda N, Boulenger JP. Pharmacological treatments effective in both GAD and major
depressive disorder: clinical and theoretical implications. Can J Psychiatry 1998; 43(7):722–
730.
Sramek JJ, Tansman M, Suri A et al. Efﬁcacy of Buspirone in generalized anxiety disorderwith coexisting mild depressive symptoms. J Clin Psychiatry 1996; 57(7):287–291.
Apter JT, Allen LA. Buspirone: future directions. J Clin Psychopharmacol 1999; 19(1):86–
93.
Rickels K, DeMartinis N, Garcia-Espana F, Greenblatt DJ, Mandos LA, Rynn M. Imipramineand buspirone in treatment of patients with generalized anxiety disorder who are discontinuing long-term benzodiazepine therapy. Am J Psychiatry 2000; 157(12):1973–1979.
Rickels K, Schweizer E, De Martinis N, Mandos L, Merces C. Gepirone and diazepam ingeneralized anxiety disorder: a placebo-controlled trial. J Clin Psychopharmacol 1997; 17(4):272-277.
Fawcett J, Marcus RN, Anton SF, O’Brien K, Scwiderski U. Response of anxiety and agitation symptoms during nefazodone treatment of major depression. J Clin Psychiatry 1995;
56 (suppl 6):37–42.
DeMartinis NA, Schweizer E, Rickels K. An open-label trial of nefazodone in high comorbidity panic disorder. J Clin Psychiatry 1996; 57(6):245–248.
Kaplan M. Atypical antipsychotics for treatment of mixed depression and anxiety. J Clin
Psychiatry 2000; 61(5):386-387.

776

Altamura et al.

100. Jacobsen FM. Risperidone in the treatment of affective illness and obsessive-compulsive
disorder. J Clin Psychiatry 1995; 56:423–429.
101. Robertson MM, Trimble MR. Major tranquillizers used as antidepressants: a review. J Affect
Disord 1982; 4:173–193.
102. McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH. A double-blind placebocontrolled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessivecompulsive disorder. Arch Gen Psychiatry 2000; 57(8):794–801.
103. Koran LM, Ringold AL, Elliot MA. Olanzapine augmentation for treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry 2000; 61(7):514–517.
104. Lenze EJ, Mulsant BH, Shear MK, Alexopoulos GS, Frank E, Reynolds CF. Depress Anxiety
2001; 14(2):86–93.
105. Krasuki C, Howard R, Mann A. The relationship between anxiety disorders and age. Int J
Geriatr Psychiatry 1998; 13:79-99.
106. Lindesay J, Briggs K, Murphy E. The Guy’s/Age Concern Survey: prevalence rates of cognitive impairment, depression and anxiety in an urban elderly community. Br J Psychiatry
1989; 155: 317–329.
107. Parmelee PA, Lawton MP, Kats IR. The structure of depression among elderly institution
residents: affective and somatic correlates of physical frailty. J Gerontol A Biol Sci Med Sci
1998; 53(2):M155–162.
108. van Balkom AJLM, Beckman ATF, de Beurs E, Deeg DJH, van Dyck R, van Tilburg W.
Comorbidity of anxiety disorders in a community-based older population in The Netherlands.
Acta Psychiatr Scand 2000; 101:37–45.
109. Fernandez F, Levy JK, Lachar BL, Small GW. The management of depression and anxiety
in the elderly. J Clin Psychiatry 1995; 56 (suppl 2):20–29. Review.
110. Kenneth J, Weiss MD. Management of anxiety and depression syndromes in the elderly. J
Clin Psychiatry 1994; 55 (suppl 2):5–12.
111. Altamura AC. Anxious-depressive syndromes in the elderly. Assessment, clinical course andtreatment. In: Racagni G, Smeraldi R, ed. Anxious Depression: Assessment and Treatment.
New York: Raven Press, 1987:209–216.
112. Katona C. Managing depression and anxiety in the elderly patient. Eur Neuropsychopharmacol 2000; 10 (suppl 4):S427–S432.
113. Small GW, Hamilton SH, Bystritsky A, Meyers BS, Nemeroff CB. Clinical response predictors in a double- blind, placebo-controlled trial of ﬂuoxetine for geriatric major depression.
Fluoxetine Collaborative Study Group. Int Psychogeriatr 1995; 7 (suppl):41–53.
114. Montgomery SA, Judge R. Treatment of depression with associated anxiety: comparisonsof tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta Psychiatr Scand
2000; 403(suppl):9–16.
115. Altamura AC, Bassetti R. Dosage and treatment interactions in the elderly. Presented at FirstInternational Forum on Mood and Anxiety Disorders, Montecarlo, November 29- December
2, 2000.
116. Altamura AC, Henry JF, Gomeni R, Hervy MP, Forette F, Morselli PL. Pharmacokinetics
of amitriptyline in the elderly. Int J Clin Pharmacol 1981; 19(1):1–5.
117. Abernethy DR, Greenblatt DJ, Shader RI. Imipramine and desipramine disposition in theelderly. J Pharmacol Exp Ther 1985; 232 (1):183–188.
118. Bump GM, Mulsant BH, Pollock BG, Mazumdar S, Beglev AE, Dew MA, Reynolds CF.
Paroxetine versus nortriptyline in the continuation and maintenance treatment of depression
in the elderly. Depress Anxiety 2001; 13(1):38–44.
119. Finkel SI, Richter EM, Clarly CM. Comparative efﬁcacy and safety of Sertraline versus
Nortriptyline in major depression in patients 70 and older. Int Psychogeriatr 1999; 11(1):85–99.
120. Moore AR, O’Keeffe ST. Drug-induced cognitive impairment in the elderly. Drugs Aging
1999; 15(1):15–28.

Pharmacotherapy of Mixed Disorders

777

121. Altamura AC. Efﬁcacy and tolerability of ﬂuoxetine in the elderly: a double blind study
versus amitriptyline. Int Clin Psychopharmacol 1989; 4(S1):103–106.
122. Altamura AC, Mauri MC, Rudas N, et al. Clinical activity and tolerability of trazodone,mianserin and amitriptyline in the elderly subjects with major depression: a controlled
multicenter trial. Clin Neuropharmacol 1989; 12(S1):25–33.
123. Montgomery SA. Efﬁcacy and safety of the selective serotonin reuptake inhibitors in treating
depression in elderly patients. Int Clin Psychopharmacol 1998; 13 (suppl 5):S49–S54.
124. Baumann P. Care of depression in the elderly: comparative pharmacokinetics of SSRIs. Int
Clin Psychopharmacol 1998; 13 (suppl 5):S35–S43.
125. Altamura AC, Percudani M. The use of antidepressants for long-term treatment of recurrent
depression: rationale, current methodologies, and future directions. J Clin Psychiatry 1993;
54 (suppl 8):29–37.
126. Flint AJ. Management of anxiety in late life. J Geriatr Psychiatry Neurol 1998; 11(4):194–200.
127. Walters G, Reynolds CF, Mulsant BH, Pollock BG. Continuation and maintenance pharmacotherapy in geriatric depression: an open-trial comparison of Paroxetine and Nortriptyline
in patients older than 70 years. J Clin Psychiatry 1999; 60 (suppl 20):21–25.
128. Altamura AC, Percudani M, Guercetti G, Invernizzi G. Efﬁcacy and tolerability of ﬂuoxetinein the elderly: a double blind study versus amitriptyline. Int Clin Psychopharmacol 1989;
4(S1):103–106.
129. Wylie ME, Miller MD, Shear MK, Little JT, Mulsant BH, Pollock BG, Reynolds CF. Fluvoxamine pharmacotherapy of anxiety disorders in later life: preliminary open-trial data. J Geriatr
Psychiatry Neurol 2000; 13(1):43–48.
130. Gorman JM, Papp LA. Efﬁcacy of venlafaxine in mixed depression-anxiety states. Depress
Anxiety 2000; 12 (suppl 1):77–80.
131. Wang PS, Bohn RL, Glynn RJ, Mogun H, Avorn J. Hazardous benzodiazepine regimens in
the elderly: effect of half-life, dosage, and duration on risk of hip fracture. Am J Psychiatry
2001; 158:892–898.
132. Staab JP, Evans DL. Efﬁcacy of venlafaxine in geriatric depression. Depress Anxiety 2000;
12 (suppl 1):63–68.
133. Klamerus KJ, Parker VD, Rudolph RL, Derivan AT, Chiang ST. Effects of age and genderon venlafaxine and O- desmethylvenlafaxine pharmacokinetics. Pharmacother 1996; 16(5):915–923.
134. Gorman JM. Mirtazapine: clinical overview. J Clin Psychiatry 1999; 60 (suppl 17):9–13;
discussion 46–48.
135. Hoyberg OJ, Maragakis B, Mullin J, Norum D, Stordall E, Ekdahl P, Ose E, Moksnes KM,
Sennef CA. Double-blind multicentre comparison of mirtazapine and amitriptyline in elderly
depressed patients. Acta Psychiatr Scand 1996; 93 (3):184–190.
136. Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet 2000; 38(6):461–474. Review.
137. Altamura AC, Melorio T, Invernizzi G, Colacurcio F, Gomeni R. Age related differences inkinetics and side-effects of viloxazine in man and their clinical implications. Psychopharmacol 1983; 81:281–285.
138. Altamura AC, Mauri MC, Colacurcio F. Trazodone in late life depressive states: a doubleblind multicenter study versus amitriptyline and mianserin. Psychopharmacol 1988; 95S:
534–536.
139. Skoog I, Nilsson L, Landahl S, Steen B. Mental Disorders and the use of psychotropic drugsin 85-year-old urban population. Int Psychogeriatr 1993; 5:33–48.
140. Fichter MM, Witzke W, Liebl K, Hippius H. Psychotropic drug use in representative community sample: the Upper Bavarian study. Acta Psychiatr Scand 1989; 80:68–77.
141. Ray W, Fought R, Decker M. Psychoactive drugs and the risk of injurious motor vehicle
crashes in elderly drivers. Am J Epidemiol 1992; 136:873–883.

778

Altamura et al.

142. Greenblatt DJ, Harmatz JS, Shapiro L, Englehardt N, Guthro T, Shador RJ. Sensitivity totriazolam in the elderly. N Engl J Med 1991; 324:1691–1698.
143. Benzodiazepine Dependence, Toxicity and Abuse: A Task Force Report of the American
Psychiatric Association, Washington, DC, 1990.
144. Hemmelgarn B, Suissa S, Huang A, Bolvin JF, Pinard J. Benzodiazepine use and the riskof motor vehicle crash in the elderly. JAMA 1994; 272:1518–1522.
145. Sumner DD. Benzodiazepine-induced persisting amnestic disorder: are older adults at risk?
Arch Psychiat Nurs 1998; 12(2):119–125.
146. Rohers T, Merlotti L, Zorich F, Roth T. Sedative, memory, and performance effects of hypnotics. Psychopharmacology (Berl) 1994; 116:130–134.
147. Hallfors OD, Saxe L. The dependence potential of short half-life benzodiazepines: a metaanalysis. Am J Publ Health 1993; 83:1300–1304.
148. Curtis GC, Abelson JL, Gold PW. Adenocorticotropic hormone and cortisol response tocorticotropin-releasing hormone: changes in panic disorder and effects of alprazolam treatment. Biol Psychiatry 1997; 41(1):76–85.
149. Mooney JJ, Schatzberg AF, Cole JO, Kizuka PP, Salomon M, Lerbinger J, Pappalardo KM,
Gerson B, Schildkraut JJ. Rapid antidepressant response to alprazolam in depressed patientswith high catecolamine output and heterologous desensitisation of platelet adeniylate cyclase.
Biol Psychiatry 1988; 23(6):543-559.
150. Ozdemir V, Fourie J, Busto U, Naranjo CA. Pharmacokinetic changes in the elderly. Do
they contribute to drug abuse and dependence? Clin Pharmacokinet 1996; 31(5):372–385.
151. Oswald LM, Roache JD, Rhoades HM. Predictors of individual differences in alprazolam
self-medication. Exp Clin Psychopharmacol 1999; 7(4):379–390.
152. Rickels K, De Martinis N, Garcia-Espana F, Greenblatt DJ, Mandos LA, Rynn M. Imipramine and buspirone in treatment of patients with generalized anxiety disorder who are discontinuing long-term benzodiazepine therapy. Am J Psychiatry 2000; 157(12):1973–1979.
153. Schweizer E, Rickels K, Hassman H, Garcia-Espana F. Buspirone and imipramine for thetreatment of major depression in the elderly. J Clin Psychiatry 1998; 59(4):175–183.
154. Schulberg HC, Katon W, Simon GE, Rush AJ. Treating major depression in primary carepractice. Arch Gen Psychiatry 1998; 55:1121–1127.
155. Danish University Antidepressant Group (DUAG). Citalopram: clinical effect proﬁle in comparison with clomipramine: a controlled multicenter study. Psychopharmacology 1986; 90:
131–138.

33
New and Emerging Therapies
for Anxiety
DAVID J. NUTT and SPILIOS V. ARGYROPOULOS
University of Bristol
Bristol, England

I.

INTRODUCTION

Despite the major progress in the treatment of anxiety disorders in the past decade, there
is still a long way to go. For some of the anxiety disorders, prognosis is still moderateor even poor. Moreover, even with the current best treatments in practice many patients
recover only partially (i.e., they do not enter remission). A further issue is that all usedtreatments have side effects that, although not pronounced, in many cases can limit compliance in a signiﬁcant proportion of patients. For these reasons, the search for the next
generation of anxiety therapies is currently quite vigorous, especially as now companies
can be reassured that successful treatment for the anxiety disorders will be reimbursed in
all countries in the western world.

II. NEW SEROTONIN-TARGETED APPROACHES TO REDUCINGANXIETY
The most direct and, some would argue, safest way of designing new anxiolytics is tobuild on the ﬁnding that serotonin (5HT)-acting drugs are effective anxiolytics. There is
growing and perhaps surprising evidence for the efﬁcacy of the selective serotonin reuptake inhibitors (SSRIs) on the broad spectrum of the anxiety disorders. However, it should
be remembered that the role of 5HT in anxiety is complex and possibly biphasic [4]. It
is conceivable that drugs that either increase or decrease the effects of 5HT are anxiolytic.
As yet, there are only limited data pertaining to this issue, but one of the more exciting
779

780

Nutt and Argyropoulos

recent ﬁndings is that the anxiolytic actions of the SSRIs are reversed when 5HT synaptic
concentrations are reduced using the tryptophan depletion paradigm. The procedure andtheory behind tryptophan depletion is discussed in detail in Bell et al. [5]. The technique
has been used to demonstrate that the actions of SSRIs and other 5HT-acting antidepressants are dependent on the presence of 5HT in the synaptic cleft, as relapse is producedby tryptophan depletion [12].
Interestingly, the next group of patients to be studied with tryptophan depletion were
those with OCD and it was found that the technique did not produce a relapse [31]. We
have just completed a tryptophan depletion study of panic disorder patients who had responded to SSRI treatment and found that tryptophan depletion led to a relapse, as indicated by increased vulnerability to the panicogenic actions of ﬂumazenil [6]. Preliminary
data suggest that the same is true in social anxiety disorder. Our ongoing studies showthat the anxiogenic response to a social phobic challenge is enhanced after tryptophan
depletion in patients successfully treated with SSRIs.
Taken together, it would appear that the anxiolytic action of the SSRIs in someanxiety disorders is similar to that in depression in that an elevation in 5HT concentrationsin the synaptic cleft is critical to their therapeutic effect. This ﬁts with the theory of Deakin
and Graeff [11] that 5HT acts to inhibit unconditioned anxiety and suggests that otherways of increasing 5HT postsynaptic function might also be anxiolytic. To some extent
this is supported by the animal work that found 5HT2C agonists to be antipanic in rats[26]. Why OCD should be different is not yet known. It may be that the OCD experiments
were not as robust as they could have been, since they did not use anxiety-provoking
challenges during the tryptophan depletion. However, if the ﬁnding were to remain true,
one could then argue that downstream postsynaptic mechanisms underlie activity in OCD
and that if these were identiﬁed they could give rise to new drug targets.
Another important conceptual issue relates to the mode of action of buspirone. Thisis a relatively selective 5HT1A partial agonist that in animal studies acutely inhibits 5HT
neuronal ﬁring. If anxiety is due to excess ﬁring of the 5HT neuronal system, then shutting
down the ﬁring rate would be directly anxiolytic in conditions such as generalized anxiety
disorder (GAD), but it would worsen anxiety in other conditions such as panic disorder[11]. Interestingly, buspirone itself does not appear to worsen panic disorder but newer
analogs such as ﬂesinoxan, which is a full agonist of this receptor, does increase anxiety
in these patients [60].
However, the inhibiting action of buspirone at the raphe nuclei is seen after a single
dose of the drug whereas, similar to the antidepressants, the therapeutic effects of buspirone take a few weeks to emerge. This suggests that other factors may play an importantrole. Perhaps, the most obvious target is the postsynaptic 5HT1A receptor, which is foundin high densities in forebrain areas implicated in anxiety such as the hippocampus, septum,
and temporal cortex [49]. Stimulation of these receptors is thought to be responsible forthe therapeutic actions of many antidepressants. It may be that some anxiety disorders
respond in a similar way. There is provisional evidence that in panic disorder these receptors are downregulated as in depression [50]. It is conceivable then that stimulation ofthese receptors by an agonist could increase 5HT function and be anxiolytic. The datawith ﬂesinoxan mentioned earlier rather go against this theory but the area is still relatively
young.
Are there any other ways of improving the clinical value of buspirone? One limiting
factor with all the 5HT1A-agonist drugs is that they have a marked ﬁrst-pass metabolism

New and Emerging Therapies for Anxiety

781

so that poor metabolizers can experience high plasma concentrations that produce unacceptable side effects. One way to overcome this problem is to change the delivery system
and a buspirone patch has been reported in children and is being evaluated in adults [9].
Buspirone may also have a role as an augmentation treatment of SSRI partial responders. This has been tried in PTSD with some beneﬁcial effect in 11 of 14 patients[21]. The idea of combining a 5HT1A agonist with an SSRI in the same molecule has also
been explored [33].
Gepirone is an analog of buspirone that is also a partial 5HT1A agonist. It has shown
some efﬁcacy in GAD [47] and panic disorder [44]. The trial by Rickels et al. included
198 patients with GAD and showed that the anxiolytic effect was delayed and more adverse effects were noted compared with diazepam. In contrast, rebound anxiety was notexperienced upon ceasing gepirone, but it was seen in withdrawal from the benzodiazepine. Of interest is the fact that gepirone is also developed for atypical depression, acondition that is often associated with anxiety.
Flesinoxan was discovered to have a high afﬁnity for 5HT1A receptors during initialdevelopment as a centrally acting antihypertensive. Phase III pilot trials in patients withpanic disorder have shown it to be ineffective. They also show a dose-dependent panicogenic effect [60]. Preclinical studies of the buspirone analogue MM199 have revealed
anxiolytic properties [15]. Other 5HT1A agonists still in discovery are lesopitron andeptapirone.
If stimulating 5HT1A receptors leaves something to be desired in the treatment ofanxiety, what about other 5HT receptors as targets (Table 1)?
5HT1A antagonists also have anxiolytic action in rats. A compound, robisartan, isin trials for depression so it may yet be tested in anxiety disorders. It presumably works
by disinhibiting the cell body and terminal autoreceptors, therefore increasing 5HT in thesynaptic cleft. 5HT1B antagonists would also have the same effect on 5HT transmission.
Since a number of such compounds have been discovered, we may well have clinical trial
data in the next decade.
Deramciclane is a 5HT2C antagonist with anxiolytic properties that is now in phase
III trials. Animal data show that it does not potentiate the effects of alcohol, yet it improves
sleep [7,16]. Another 5HT2C antagonist in development for depression, and possibly foranxiety, is agomelatine [61]. This compound has both melatonin agonist and 5HT2C antagonist properties in the same molecule and shows anxiolytic properties in animal models.

Table 1 5HT Targets for Novel Anxiolytic Treatments
Type of approach

ExamplesComments

5HT1-receptor antagonists

Modify SSRIs (e.g., adding
5HT1A /5HT2 blocking)
5HT1A and 5HT1B blockers

5HT2-receptor antagonists

Deramciclane (5HT2C)

Agomelatine

5HT2C antagonist ⫹ melatoninagonist

Questionable efﬁcacy, better tolerability
In depression trials, anxiolytic inanimal tests
In phase II for depression 2C antagonists; anxiolytic in animal
tests
In clinical trials for anxiety;works in animal models

Modify current treatments

782

Nutt and Argyropoulos

Why the melatonin component should contribute to either the antidepressant or the anxiolytic actions is rather unclear, but studies show that the combination of these two actions
produces potentiation of effects.
If the stimulation of postsynaptic 5HT receptors is critical in the action of the SSRIs
in the treatment of OCD, then it is likely that the 5HT2 rather than the 5HT1A subtype is
responsible, given the lack of efﬁcacy of the latter agonists in this disorder. There are no
selective 5HT2 agonists available yet, and indeed such drugs could be hallucinogenic.
However, a beneﬁcial effect has been reported in OCD with the hallucinogen psilocybin,
which has 5HT2-agonist properties [22].
Double-blind reports of trials of the 5HT3 antagonist ondansetron have proved rather
ineffective in GAD [17] and in panic disorder [14,51]. It remains to be seen if another
5HT3 antagonist (zatosetron) may fare better [53].
Finally, we should consider the feasibility of improving on the actions of the SSRIs
in the anxiety disorders. One way would be to remove some of the anxiogenic effects
apparent early in treatment that are particularly problematic in panic disorder. This may
be possible by adding some 5HT2-receptor antagonist activity such as is found in nefazodone and mirtazapine. Although neither of these new antidepressants has been extensively
tested in anxiety, they are more beneﬁcial than the SSRIs on anxiety symptoms in depression, especially in the early phase of treatment [35,36].

III. NEW GABA-TARGETED APPROACHESNew GABA-targeted approaches are listed in Table 2, where a number of different approaches are considered. Perhaps the most exciting are the GABA-A-receptor subtype
agonists, which are predicted to have very focal actions in the brain and, at least in preclinical tests, show excellent separation of anxiolytic and sedative actions [32,39]. There is
still some debate as to whether the alpha 2 or the alpha 3 GABA-A-receptor subtype
mediates anxiety and it may be that both are involved to differing extents in various formsof anxiety.
Another potential development is that of making partial agonists at one or both ofthese receptors given the emerging utility of partial agonists in many disorders. Support
for the potential utility of GABA-A-receptor partial agonists comes from the early studies

Table 2 GABA and Glutamate Drugs as Potential Anxiolytic Therapies
Type of approach

ExamplesComments

Subtype selective
GABA-A-receptor
agonists/partial agonists
Novel GABA modulators

Pagoclone, α2 and α3 subtype agonists

Some positive data in panic disorder; less side effects than traditional benzodiazepines

Gabapentin Pregabalin

Neurosteroids
Glutamate antagonists

Pregnenalones, DHEA
NMDA antagonists

Reduce glutamate release

MGLUrl agonists

Some clinical data; may work on
Ca channels? Development in anxiety stopped
Block conditioned anxiety (e.g.
PTSD in animals)
Work in animal models; broad
range of therapeutic indications

New and Emerging Therapies for Anxiety

783

with abecarnil and later ones with pagoclone. Abecarnil was the ﬁrst new nonbenzodiazepine partial agonist to be tested. It had equivalent efﬁcacy to a benzodiazepine full agonist
in a GAD trial and appeared to have fewer side effects and withdrawal problems [45].
However, the development of this drug was ceased.
Pagoclone is a partial agonist in the same series as zopiclone [24], and has similar
but less pronounced action on sleep to this full agonist [62]. A recent 11C-ﬂumazenil PET
study by our group has conﬁrmed that in humans pagoclone does behave like a partial
agonist because it produces less pharmacodynamic action than lorazepam, despite occupying more brain receptors [30]. We have also shown that pagoclone has some efﬁcacy
in panic disorder [48].
Other GABA approaches include the use of drugs such as gabapentin and pregabalin,
which were developed to be GABA modulators but have since been shown to act on othersystems such as calcium channels. Gabapentin is the earlier drug and has been used as
an anticonvulsant for many years now. There have been positive trials for this in panic
disorder and social anxiety disorder [41,42]. For reasons of potency, pregabalin is now
being studied in these disorders and there is already one positive study in social anxiety
disorder where the higher dose used was effective [25].
One area of new research that peaked in the 1990s was that of neurosteroids. These
are compounds that act at the GABA-A-receptor complex to increase the effects of thenatural transmitter GABA. They are effective anxiolytics in animal models as well as
being anticonvulsant and hypnotic (for a review, see Ref. 18). However, it appears thatthe development of the leading compound for anxiety treatment has now ceased and only
an anticonvulsant is currently in clinical trials. Why this should be the case is not immediately clear, but it may reﬂect the fact that the broad action of these agents to promote
GABA-A function gives a range of sedative and other side effects.
The potential of glutamate as a target has become obvious in recent years. Glutamateis the major excitatory transmitter in the human brain and so it is critically involved inlearning and memory, as well as perception and performance. There is evidence that glutamate contributes to the laying down of traumatic memories [38]. Therefore, it may havea particular involvement in PTSD [40], although it is also likely to be relevant to thelearning of avoidance behavior as seen in panic attacks and social anxiety disorder.
In essence, the glutamate theory of anxiety suggests that the embedding of anxiety
is a consequence of glutamate-mediated learning. In addition, some authorities believethat simply increasing brain glutamate concentrations will cause anxiety [1]. It is possible
to block glutamate transmission at the key receptor involved in learning and memory (theNMDA receptor) by postsynaptic antagonists such as dizocilpine (MK801). These drugs,
though, tend to produce problematic alterations in consciousness so they cannot be used
as long-term therapy but they can be contemplated as a short-term/immediate intervention.
Other antagonists with less problematic side effects have now been discovered and one,memantine, has been used in humans for other indications. It could perhaps be used totest the glutamate theory of anxiety [43].
The multiple groups of metabotropic G-protein glutamate receptors (mGluR) havealso been explored recently. Animal studies indicate that mGlu5 antagonists, such as 2methyl-6-(phenylethynyl)pyridine (MPEP), possess anxiolytic properties [54,56]. Intriguingly, it is also possible to reduce glutamate function by decreasing release through inhibition of presynaptic cell activity. One possible way of achieving this would be with a
speciﬁc presynaptic glutamate agonist that acts on the glutamate autoreceptor. One suchcompound appears to be the mGlu2/3 receptor ligand LY354740. It has shown to have

784

Nutt and Argyropoulos

Table 3 Peptides
Type of approach

ExamplesComments

CCK 4 antagonist
Antistress agents

PD9
CRF antagonist

Substance P antagonists (NK1receptor antagonists)
NPY agonist is anxiolytic

MK 869? Clinically effective
Animal tests positive; under trials for depression
Reduced anxiety in depression trials

None as yet

Hard to make orally active drug

activity in a number of animal models in which anxiety is prominent, including drug andalcohol withdrawal and conﬂict tests [27,52]. As there are many other potential indications
for this sort of compound, including schizophrenia, the ﬁeld is one that is likely to growand it may soon be possible for clinical trials in anxiety to start.
IV. PEPTIDE ANTAGONIST TREATMENTS
A number of peptides have been involved in the brain mechanisms of anxiety (Table 3).
The best-studied neuropeptide in anxiety is cholecystokinin (CCK). The tetrapeptide CCK4 and the synthetic pentapeptide pentagastrin can be used to provoke anxiety in humanvolunteers and, in lower doses, in patients with panic disorder. Patients with social anxiety
disorder show an intermediate sensitivity [13,57]. These actions of CCK-4 are attenuatedin patients treated with effective antipanic medications [58]. Taken together, these data
were very exciting and suggested that the CCK receptor or endogenous CCK might havea causal role in panic disorder. Based on these theories, several companies made highafﬁnity antagonists but unfortunately none of the ﬁrst-generation CCK antagonists, suchas CI 988, proved to be effective in panic disorder [59], although they were able to block
the anxiogenic actions of CCK-4 itself. There was also a negative trial in GAD [2]. It is
possible that pharmacokinetic problems, especially poor brain entry, might have contributed to the poor therapeutic response. Until a compound with good brain entry is discovered and tested, the value of this approach in treating anxiety should remain open.
One of the more exciting areas of research in depression is the search for peptide
therapeutics that will attack depression at its presumed source—the central and peripheral
stress axis. Corticotropin-release factor (CRF) is one, if not the main, hormone-mediatingstress in the brain. CRF production in the nervous system is increased by stress and if
CRF is injected into the ventricles of animals it produces many of the behavioral effectsof stress. For nearly a decade now, we have known that blocking central CRF receptors
could reduce stress-related behavior in animals, although these experiments initially relied
on directly injecting a peptide analog of CRF (α-helical CRF) or antisense to CRF directly
into the brain [29]. More recently, stable small-molecule antagonists have been discoveredand studies with these have conﬁrmed that central CRF mediates many of the behavioral
responses to stress in animals (for review, see Ref.20).
One CRF antagonist, the R121919 compound, has been put into pilot trials of humandepression with initial promising results [63]. The trials were, however, terminated due
to safety concerns, not related to the hormonal actions of the drug. New compounds arein the pipelines of many drug companies so this ﬁnding may soon be replicated. AlthoughNew and Emerging Therapies for Anxiety

785

depression is the primary target of these new compounds, it seems that the anxiety disorders, especially those with established cortisol abnormalities, such as PTSD, might also
be potential targets.
Other peptide antagonists, especially the substance P (NK1 receptor) blockers, havecaused a lot of excitement in recent years with the ﬁnding that MK869 was effective in
depression [3,28,37]. Animal data have revealed substance P to play a role in anxietylike behavior, depending upon dose and brain region [23]. In the MK 869 depression trial,
which was a randomized, placebo-controlled, double-blind comparison with paroxetine
in patients with major depression and moderately high anxiety, both drugs signiﬁcantly
improved depression compared with placebo. From week 4 onward, both agents also reduced anxiety, as measured on the Hamilton anxiety scale (HAMA), signiﬁcantly morethan placebo [28]. It appears that the pharmacokinetic properties of this drug mean that
it is not an ideal medication. That this research program has not yet come to fruition asa more potent homolog is being tested currently. Therefore, with this compound, resolving
the issue of whether NK1-receptor antagonists will prove to be a new class of anxiolytic
is still some time away.
However, in light of the exciting ﬁndings with MK869, many pharmaceutical companies have produced high-afﬁnity antagonists with high selectivity for the NK1 receptor.
Some of these have been tested in anxiety disorders such as social anxiety disorder aswell as in depression, but as yet there are no data in the public domain.
Neuropeptide Y (NPY) is colocalized in the central nervous system (CNS) with
norepinephrine and it may act in part to modulate the actions of this neurotransmitter.
There are a great deal of data linking norepinephrine to anxiety [10,34], but little interestin the development of new direct-acting antinorepinephrine agents. For this reason, NPY
might offer a novel way to indirectly downregulate noradrenaline transmission and thus
reduce human anxiety [19]. There are three subtypes of NPY receptors the Y-1, 2 and 3,
with Y1 being the one most likely related to anxiety. There have been attempts to evaluate
NPY function in humans using plasma levels as a proxy for those in the brain. Thesestudies of NPY levels in anxiety disorders have yielded conﬂicting results [8,55], but alink with norepinephrine has been found in that an increase in norepinephrine release also
increases NPY levels in plasma [46]. Making a NPY agonist that is orally active is achallenge, which may explain why there are no reported NPY drugs yet in development.
V.

CONCLUSION

The quest for new improved anxiolytics has gathered pace in recent years. Various approaches have been employed in the attempt to produce effective and better-tolerated
drugs. Researchers and the industry have tried to capitalize on the success of the SSRIs.
The insights that this group of compounds provided into the nature of anxiety have allowed
for theorization and design of drugs acting on speciﬁc 5HT-receptor types. The successhas been limited so far, but a number of promising drugs are currently undergoing trials.
Further, better understanding of the neurobiology of the inhibitory neurotransmission in
the brain through GABA prompted the research into compounds acting either on speciﬁc
subunits of the GABA-benzodiazepine receptor complex or as partial agonists to this receptor. These drugs promise to be devoid of the dependence and abuse potential of theclassical benzodiazepines, but this is yet to be fulﬁlled.
New approaches have also ﬂourished. Drugs affecting the excitatory glutamate neurotransmission have shown great promise in animal studies. Finally, drugs interacting with

786

Nutt and Argyropoulos

a variety of neuropeptide receptors, notably those of cholecystokinin, CRF, and substanceP, are extensively investigated. It is hoped that at least one of the above approaches will
be fruitful and eventually lead to the new generation of anxiolytics.
REFERENCES
1. Adamec RE, Burton P, Shallow T, et al. NMDA receptors mediate lasting increases in anxietylike behaviour produced by the stress of predator exposure—implications for anxiety associated with posttraumatic stress disorder. Physiol Behav 1999; 65:723–737.
2. Adams JB, Pyke RE, Costa J, et al. A double-blind, placebo-controlled study of a CCK-B
receptor antagonist, CI-988, in patients with generalized anxiety disorder. J Clin Psychopharmacology 1995; 15:428–434.
3. Argyropoulos SV, Nutt DJ. Substance P antagonists: novel agents in the treatment of depression. Exp Op Inv Drugs 2000; 9:1871–1875.
4. Bell CJ, Nutt DJ. Serotonin and panic. Br J Psychiatry 1998; 172:465–471.
5. Bell CJ, Abrams J, Nutt DJ. Tryptophan depletion and its implications for psychiatry. Br J
Psychiatry 2001; 178:399–405.
6. Bell CJ, Forshall S, Adrover M, et al. Tryptophan depletion in patients with panic disorder who
have responded to treatment with the SSRI paroxetine: implications for the role of serotonin in
the mechanism of action. J Psychopharmacol 2002; in press.
7. Berenyi E, Blasko G, Fekete M, et al. EGYT-3886. Drugs of Future, 1990; 15:1174–1175.
8. Boulenger JP, Jerabek I, Jolicoeur FB, et al. Elevated plasma levels of neuropeptide Y inpatients with panic disorder. Am J Psychiatry 1996; 153:114–116.
9. Conners CK, Jackson DL, Silva D, et al. Transdermal buspirone in the treatment of childhood
ADHD. Psychopharmacol Bull 1997; 33:507.
10. Coupland NJ, Nutt DJ. The neurobiology of anxiety and panic. In: Bradwejn J, Vasar E, eds.
Cholecystokinin and anxiety, from neuron to behaviour. Austin, TX: R.G. Landes Company
Biomedical Publishers, 1995:1–32.
11. Deakin JFW, Graeff FG. 5-HT and mechanisms of defense. J Psychopharmacol 1991; 5:305–315.
12. Delgado PL, Chamey DS, Price LH et al. Serotonin function and the mechanism of antidepressant action: reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry 1990; 47:411–419.
13. De Montigny C. Cholecystokinin tetrapeptide induces panic-like attacks in healthy volunteers.
Preliminary ﬁndings. Arch Gen Psychiatry 1989; 46:511–517.
14. Depot M, Merani S, Bradwejn J et al. Effect of oral ondansetron on total cholecystokinin
plasma levels following CCK-4 panic challenge procedure in healthy men. J Psychiat Neurosci
1998; 23:298–304.
15. Deren-Wesolek A, Tatarczynska E, Chojnacka-Wojcik E. The novel buspirone analogue, 8(4-(2-(1,2,3,4-tetrahydroisoquinolinyl)(butyl)-8-azaspiro(4.5)decane-7,9-dione, with anxiolytic-like and antidepressant-like effects in rats. J Psychopharmacol 1998; 12:380–384.
16. Detari L, Szentgyorgyi V, Hajnik T et al. Differential EEG effects of the anxiolytic drugs,
deramciclane (EGIS-3886), ritanserin and chlordiazepoxide in rats. Psychopharmacology
1999; 142:318–326.
17. Freeman AM, Westphal JR, Norris GT et al. The efﬁcacy of ondansetron in the treatment ofgeneralised anxiety disorder. Depress Anxiety 1997; 5:140–141.
18. Gasior M, Carter RB, Witkin JM. Neuroactive steroids: potential therapeutic use in neurological and psychiatric disorders. Tr Pharmacol Sci 1999; 20:107–112.
19. Grundemar L, Håkanson R. Neuropeptide Y effector systems: perspectives for drug development. Tr Pharmacol Sci 1994; 15:153–159.
20. Gutman DA, Owens MJ, Nemeroff CB. CRF receptor antagonists: a new approach to thetreatment of depression. Pharmaceut News 2001; 8:18–25.

New and Emerging Therapies for Anxiety

787

21. Hammer M, Ulmer H, Horne D. Buspirone potentiation of antidepressants in the treatment
of PTSD. Depress Anxiety 1997; 5:137–139.
22. Hanes KR. Serotonin, psilocybin, and body dysmorphic disorder: A case report. J Clin, Psychopharmacol 1996; 16:188-189.
23. Hasenohrl RU, Jentjens O, De-Souza-Silva MA et al. Anxiolytic-like action of neurokinin
substance P administered systemically or into the nucleus basalis magnocellularis region. Eur
J Pharmacol 1998; 354:123–133.
24. Jackson HC, Nutt DJ. Body temperature discriminates between full and partial benzodiazepine
receptor agonists. Eur J Pharmacol 1990; 185:243–246.
25. Jefferson JW. Benzodiazepines and anticonvulsants for social phobia (social anxiety disorder).
J Clin Psychiatry 2001; 62(suppl):150–153.
26. Jenck F, Martin JR, Moreau JL. Animal models of panic disorder–emphasis on face and predictive validity. Eur Neuropsychopharmacol 1996; 6 (suppl 4):s22.01
27. Klodzinska A, Chojnacka-Wojcik E, Palucha A et al. Potential antianxiety, anti-addictive effects of LY354740, a selective group II glutamate metabotropic receptors agonist in animalmodels. Neuropharmacology 1999; 38:1831–1839.
28. Kramer MS, Cutler N, Feighner J, et al. Distinct mechanism for antidepressant activity byblockade of central substance P receptors. Science 1998; 281:1640–1645.
29. Liebsch G, Landgraf R, Engelmann M et al. Differential behavioural effects of chronic infusionof CRH 1 and CRH 2 receptor antisense oligonucleotides into the rat brain. J Psychiat Res
1999; 33:153–163.
30. Lingford-Hughes AR, Uhl N, Feeney AJ et al. Is pagoclone a partial agonist at the central
GABA-benzodiazepine receptor? A [11C]-ﬂumazenil positron emission tomography study. Int
J Neuropsychopharmacol 2000; 3:S288.
31. McDougle CJ, Goodman WK, Price LH. The pharmacotherapy of obsessive-compulsive disorder. Pharmacopsychiatry 1993; 26 (suppl 1):24–29.
32. McKernan RM, Rosahl TW, Reynolds DS et al. Sedative but not anxiolytic properties ofbenzodiazepines are mediated by the GABA(A) receptor alpha 1 subtype. Nat Neurosci 2000;
3:587–592.
33. Murck H, Frieboes RM, Antonijevic LA et al. Distinct temporal pattern of the effects of the
combined serotonin-reuptake inhibitor and 5-HT1A agonist EMD 68843 on the sleep EEG in
healthy men. Psychopharmacology 2001; 155:187–192.
34. Nutt DJ, Lawson CW. Panic attacks: a neurochemical overview of models and mechanisms.
Br J Psychiatry 1992; 160:165–178.
35. Nutt DJ. Early action of nefazodone in anxiety associated with depression. J Psychopharmacol
1996; 10 (suppl):18–21.
36. Nutt DJ. Efﬁcacy of mirtazapine in clinically relevant subgroups of depressed patients. Depress
Anxiety 1998; 7:7–10.
37. Nutt DJ. Substance-P antagonists: a new treatment for depression? Lancet 1998; 352:1644–
1646.
38. Nutt DJ. The psychobiology of posttraumatic stress disorder. J Clin Psychiatry 2000; 61:24–32.
39. Nutt DJ, Malizia AL. New insights into the role of the GABA-A benzodiazepine receptor. Br
J Psychiatry 2001; 179:390–396.
40. O’Brien M, Null DJ. Loss of consciousness and PTSD: a clue to aetiology and treatment? Br
J Psychiatry 1998; 173:102–104.
41. Pande AC, Davidson JRT, Jefferson JW et al. Treatment of social phobia with gabapentin: aplacebo-controlled study. J Clin Psychopharmacol 1999; 19:341–348.
42. Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of gabapentin treatment
in panic disorder. J Clin Psychopharmacol 1999; 20:467–471.
43. Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist. A review of preclinical data. Neuropharmacology 1999; 38:735–767.

788

Nutt and Argyropoulos

44. Pecknold JC, Luthe L, Scott-Fleury MH et al. Gepirone and the treatment of panic disorder:
an open study. J Clin Psychopharmacol 1993; 13:145–149.
45. Potokar JP, Nutt DJ. Anxiolytic potential of benzodiazepine receptor partial agonists. CNS
Drugs 1994; 1:305–315.
46. Rasmusson AM, Southwick SM, Hauger RL et al. Plasma neuropeptide Y (NPY) increases
in humans in response to the alpha 2 antagonist yohimbine. Neuropsychopharmacology 1998;
19:95–98.
47. Rickels K, Schweiser E, De Martinis M et al. Gepirone and diazepam in generalised anxiety
disorders: a placebo-controlled trial. J Clin Psychopharamcol 1997; 17:272–277.
48. Sandford JJ, Forshall S, Bell C et al. Crossover trial of pagoclone and placebo in patientswith DSM-IV panic disorder. J Psychopharmacol 2001; 15:205–208.
49. Sargent PA, Kjaer KH, Bench CJ et al. Brain serotonin 1A receptor binding measured bypositron emission tomography with [11C]WAY-100635: effects of depression and antidepressant treatment. Arch Gen Psychiatry 2000; 57:174–180.
50. Sargent PA, Nash J, Hood S, et al. 5-HT1A receptor binding in panic disorder; comparison
with depressive disorder and healthy volunteers using PET and [11C]WAY-100635. Neuroimage 2000; 11:189.
51. Schneier FR, Garﬁnkel R, Kennedy B, et al. Ondansetron in the treatment of panic disorder.
Anxiety 1996; 2:199–202.
52. Shekhar A, Keim SR. LY354740, a potent group II metabotropic glutamate receptor agonist
prevents lactate-induced panic-like response in panic-prone rats. Neuropharmacology 2000;
39:1139–1146.
53. Smith WT, Londborg PD, Blomgren SL et al. Pilot study of zotosetron (LY277359) maleate,a 5-hydroxytryptamine-3 antagonist, in the treatment of anxiety. J Clin Psychopharmacol 1999;
19:125–131.
54. Spooren WP, Gasparini F, Salt TE et al. Novel allosteric antagonists shed light on mglu(5)receptrs and CNS disorders. Tr Pharm Sci 2001; 22; 331–337.
55. Stein MB, Hauger RL, Dhalla KS et al. Plasma neuropeptide Y in anxiety disorders: ﬁndings
in panic disorder and social phobia. Psychiatr Res 1996; 59:183–188.
56. Tatarczynska E, Klodzinska A, Chojnacka-Wojcik E et al. Potential anxiolytic- and antidepressant-like effects of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist. Br J Pharamacol 2001; 132:1423–1430.
57. van Megen HJ, Westenberg HG, den Boer JA et al. The panic-inducing properties of thecholecystokinin tetrapeptide CCK4 in patients with panic disorder. Eur Neuropsychopharmacol 1996; 6:187–194.
58. van Megen HJ, Westenberg HG, den Boer JA et al. Effect of the selective serotonin reuptake
inhibitor ﬂuvoxamine on CCK-4 induced panic attacks. Psychopharmacology 1997; 129:357–
364.
59. van Megen HJ, Westenberg HG, den Boer JA et al. The cholecystokinin-B receptor antagonist
CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients. Psychopharmacology 1997; 129:243–248.
60. van Vliet IM, Westenberg HGM, den Boer JA. Effects of the 5-HT1A receptor agonist ﬂesinoxan in panic disorder. Psychopharmacology 1996; 127:174–180.
61. Wiley JL, Dance ME, Balster RL. Preclinical evaluation of the reinforcing and discriminative
stimulus effects of agomelatine (S-20098), a melatonin agonist. Psychopharmacology 1998;
140:503–509.
62. Wilson SJ, Birnie A, Sheridan B et al. Sleep effects of pagoclone, a new benzodiazepine partial
agonist. J Psychopharmacol 1997; 11(suppl 3):A55.
63. Zobel AW, Nickel T, Kunzel HE et al. Effects of the high afﬁnity corticotropin-releasing
hormone receptor 1 antagonist R121919 in major depression: the ﬁrst 20 patients treated. J
Psychiatr Res 2000; 34:171–181.

34
Scales Used in Depression
and Anxiety Research
HANS-JÜRGEN MÖLLER
Ludwig Maximilian University
Munich, Germany

I.

AIMS AND METHODSStandardized methods of examination are used in psychiatry to assess objectively and, insome cases, quantify psychopathological phenomena and other clinically relevant domains, making it easier to communicate, verify their status, and analyze statistically [1,2].
They are essential to develop models of psychopathology.
Major areas in which standardized procedures are applied in psychiatry include thefollowing:
Cross-sectional quantitative description of psychopathological abnormalities.
Assignment by a standardized method of individual cases to diagnostic categories.
Quantitative assessment of change over time in psychopathological abnormalities(with or without therapeutic interventions).
Standardized measurement procedures can be categorized on the basis of their methodologies into standardized assessment instruments, systematic behavioral analysis, and objective tests in the narrower sense of the word [3]. The terms standardized assessment instrument or rating scale are applied to structured methods of assessing current and/or past
behavior and/or experience, based on lists of characteristics and, in some cases, descriptions of these characteristics. The extent of standardization varies from a simple list of
symptoms ﬁlled in on the basis of a freely structured exploratory interview to semi- or fully
structured interview schedules. These standardized assessment procedures are especiallysuitable to examine the full spectrum of psychiatric symptomatology; in addition, as they
789

790

Möllerare less restrictive than other procedures, they are particularly practicable. A variety ofinterview schedules are available and in general use.
Because they are very practicable, rating scales are often preferred to other methods
if the results of patient examinations are to be documented in the context of routine professional care. They are also frequently applied in clinical psychiatric research, such as clinical trials of drugs, studies of longitudinal course, in routine clinical documentation, or in
epidemiological studies [4,5], even though, in terms of their level of precision, standardized assessment measures are methodologically inferior to objective tests and systematic
behavioral analysis.
II. SCALE CONSTRUCTION, SCORING METHODSAND QUALITY CRITERIAStandardized methods of assessment, or rating scales, allow description in terms of numerical values of psychological abnormalities of various characteristic forms [6]. Different
measurement scales allow the degree of abnormality to be quantiﬁed to varying extents.
In the simplest instances, such as symptom checklists, scales simply allow for a rating of
0 or 1 to be made for each symptom or complex of symptoms, indicating whether or not
it is present. More precise assessment becomes possible if the construction of the scale
allows the severity of phenomena to be described using a scale consisting of a series oflevels. As there is a danger that different assessors will base their evaluations on different
standards, it is important to establish a framework for the assessment by providing anchor
points (e.g., by giving examples of situations that would be characteristic for each pointon the scale). Overly detailed assessment using an excessively broad scale is not meaningful, as differences at the extreme end of the scale cease to reﬂect real and signiﬁcantvariations in the phenomena being examined, so that the differentiations being made are
not real ones.
In some assessment instruments, the values at which points on the scale are ﬁxed
may be varied as required, so that a scale may be constructed that is as ﬁnely differentiatedas required; examples include visual analog methods of assessing subjective well being[7]. As the measurement of psychological phenomena is essentially imprecise, a relatively
coarse scale is usually adequate, especially for comparisons between individuals (Fig. 1).

Figure 1 Correlations of different scales during the course of antidepressant treatment(n ⫽ 25). (From Ref. 9.)

Scales791

A ﬁne scale may have advantages for intraindividual comparisons. However, any improvement in measurement precision will generally be achieved not by reﬁning the constructionof the scale, but rather by improving methods of measurement [8].
The values for characteristics that belong together (e.g., individual symptoms within
a syndrome) can be combined to produce a summary score. The extent to which characteristics belong together to make up a syndrome is determined during the process of test
construction (see below) by applying multivariate statistical procedures such as factor andcluster analysis. In some cases, before adding together the ﬁgures for each characteristic
to produce a summary score, these ﬁgures will be weighted to indicate the relative importance of each characteristic within the syndrome. However, if the characteristics have beenshown to be relatively independent, theoretical or practical justiﬁcation is required for any
such summation [10].
Measures of psychopathology obtained from standard rating scales generally havethe level of measurement of ordinal scales (i.e., they give only a rank order and do notpossess the measurement level of an interval scale in which there are equal intervals between points on the scale). A fundamental problem in measurement is that measurement
instruments with more detailed scales and higher levels of precision tend to bring withthem greater restrictions regarding the phenomena that can be measured. This normallymeans that increasing quality of measurement is accompanied by increasing abstraction
from the theoretical or conventional understanding of the characteristic that is the starting
point (the reliability/validity dilemma).
Standardized assessment instruments should meet as far as possible the following
quality criteria derived from test theory [11–13]:
1. Objectivity: The results should not depend on who carries out the assessment
and analyzes the results. Procedure, analysis, and interpretation should be standardized so that, as far as possible, the same results are obtained regardless of
who administers, analyzes, or interprets the instrument.
2. Reliability: This refers to the reliability with which a standardized assessment
instrument records a characteristic. When the measurement is repeated, the same
result should be obtained.
3. Validity: This is the extent to which the instrument records what it is intended
to record. The connection between the results of measurement and any external
criteria available for assessing what is to be measured should be as close as
possible.
4. Establishment of norms: Reference values for different clinical groups and varying groups of normal probands and, where applicable, a representative sampleof the general population should be available.
5. Practicability: The amount of resources required for administering standardized
assessment instruments in terms of time, staff, and material should be as low
as possible.
While for psychometric tests in the narrower sense the availability of norms islargely taken for granted, this has been approached with a great deal less rigor for clinicalrating scales. Thus, there are only a few psychopathological scales that include norms
from representative samples of the general population. Most of the clinical evaluation
scales are limited to reference values available for particular diagnostic groups. Referring
to such norms or, more precisely, reference values has a substantial impact on the interpretation of results. For example, moderately high scores for the domain of paranoid syn-

792

Möllerdromes have quite a different signiﬁcance from moderately high scores for depressive
symptoms or anxiety symptoms in that depressive and anxiety symptoms are common in
the general population, whereas paranoid symptoms are not.
In producing norms for a standardized assessment instrument, the usual starting
point is the normal distribution of values. There has to be a relation to the normal distribution in order for it to be possible to derive conﬁdence intervals (see below) and to apply
particular statistical tests, such as Pearson’s product moment correlation. Two values need
to be known to characterize a particular normal distribution: (1) the mean of all scoresobtained for the test and (2) a measure of the extent of dispersion of these values, generally
expressed in the form of standard deviation. Once these values are known, the standard
properties of the Gaussian (normal) distribution allow the proportion of subjects who will
have a particular test score to be calculated. Thus, for example, 68% of patients will havea test value that falls within 1 standard deviation either side of the mean, and around 95%
a value that is no more than two standard deviations from the mean. On the basis of thenorm values, it will therefore be possible to calculate where a proband’s score lies inrelation to a reference population (Fig. 2).
Norm values for a particular test can be straightforwardly expressed by giving themean and standard deviation. Once this information is available, a statement may be madeabout the position of the proband in relation to the reference population. However, adisadvantage of referring to the numerical value of the standard deviation for a particular
test is that it is difﬁcult to compare the results obtained by a particular proband for several
different tests. To allow comparisons of this sort to be made, a z-value can be calculated;
this is the result obtained on a particular test expressed in terms of units of the standard
deviation for that test. Results obtained by a particular proband in different tests may also

Figure 2 Relationship between some frequently used standardized scales and the normal distribution curve. (From Ref. 6.)

Scales793

be compared using percentage rankings, by specifying for each test what proportion of areference population has higher or lower scores for the test.
Various empirical methods may be used to test whether the test quality criteria
speciﬁed above have been met. Appropriate ways of examining the reliability of a test
include test–retest reliability, inter-rater reliability, the split-half correlation coefﬁcient,and internal consistency. To determine test–retest reliability, the same test is given to thesame group of people at two different time points. The time between the two applicationsof the test depends on the interval to which the test is intended to apply. For tests in which
the aim is to record enduring personality traits, an interval between applications of thetest of between 14 days and 1 year is recommended. For tests where the aim is to record
rapidly ﬂuctuating characteristics (such as mood or subjective well-being), a time span
between several minutes and a few hours is appropriate. Ideally, identical results should
be obtained for each measurement, but of course this is not the case in practice, as measurement errors necessarily occur (related to strong inﬂuences caused by the test situation,practice effects, etc.). The correlation between the two values gives the test–retest reliability coefﬁcient. Deciding whether the reliability of a test is sufﬁciently high depends verymuch on the purpose of administering the test [11,14,15]. As a rule, a reliability coefﬁcientin excess of 0.8 is required. Methods for which the test–retest reliability is below 0.5 are
not generally useful. The measurement accuracy of a test may be different for different
diagnostic groups (differential reliability).
Several different procedures also exist for determining the validity of a test (e.g.,
examination of consensual validity, predictive validity, construct validity, and content
validity). Consensual validity is determined by correlating the results of applying the tests
to a sample of probands with comparable data obtained by methods other than the application of the test (external criteria). For example, results for the test may be correlated withcorresponding scores obtained for the same subjects for another test examining the same
psychological characteristics. Whereas with consensual validity test values and external
criteria are measured at the same time, predictive validity is determined by investigating
whether events predicted on the basis of the test results have actually happened. A classic
example is the correlation of test results from an intelligence test with assessment at alater date of actual success at school.
A requirement that needs to be emphasized is that following translation of a scalefrom one language into another, new validity tests must be carried out with the translated
version. This is also true if the scale is modiﬁed in any way.

III. STANDARDIZED RATING SCALES FOR THE DESCRIPTION
OF DEPRESSION AND ANXIETY
Anxiety and depression scales represent one of the central methodological approaches inclinical research of depression and anxiety (Fig. 3).
Standardized assessment scales relate to past or current behavior and experience.
The extent of psychological abnormalities is rated using ﬁxed scales. These rating scales
may focus on a single aspect (e.g., anxiety—unidimensional scales) or on several aspects—multidimensional scales) of psychopathology. For each aspect of psychopathology, assessment may be based on a global rating or on different elements within the aspect
being assessed (e.g., on individual symptoms of the depressive syndrome). In this latter

794

Möller

Figure 3 Mean values and standard deviations of the total scores of HAM-D. (a) 21 items
and AMS (b) von Zerssen self-rating scale for two treatment groups over an 8-week doubleblind period. (From Ref. 16, courtesy of Elsevier Science.)

case, the overall score on the instrument is obtained by adding together values for thesedifferent elements.
The level of standardization of standardized assessment scales falls between that of
unstructured clinical assessment and that of objective tests. In some of these instruments,
standardization is limited to providing guidelines describing items and the categories used

Scales795

for assessing them and to specifying a method of analysis (generally one or more summaryscores are calculated). In other scales, a time frame is also stipulated for the assessment,
and in some the framework in which observation takes place is also ﬁxed. In the latter
case, the instrument is referred to as a fully structured or standardized interview. Generally,
the more extensive the standardization procedures, the greater the reliability of an assessment instrument. However, a highly standardized instrument tends to become less practicable.
Particularly for the simpler rating scales, inter-rater reliability for observer-rated
instruments can be improved by systematic joint training of the raters [17]. In principle,
fully structured interview methods with extensive individual interviewing ought to produce
high inter-rater reliability and, therefore, they have particular advantages in multicenter,
multinational studies in which great discrepancies need to be taken into account not onlyin terms of how mental states are assessed, but also in the psychiatric interview techniques
used.
Standardized assessment instruments may be classiﬁed on the basis of who carries
out the assessment into self-rated and observer-rated instruments. In observer-rated instruments, psychopathological abnormalities are identiﬁed by trained assessors (e.g., doctors,
psychologists, care staff, lay people trained to administer the instrument) or by signiﬁcantothers (e.g., partner, relatives, friends). The assessment concerns the behavior and/or experience of the patient and is based on the assessor’s own observations and/or information
given by the patient. Observer-rated scales need to be constructed so that they are appropriate to the level of training of the particular types of interviewer to be involved in theiradministration.
On the basis of multivariate statistical analysis (factor and cluster analysis), the dataobtained from administering rating scales may be used to derive factors. These factors
identify groups of individual symptoms that tend to occur together. If we consider thatthe term “clinical syndrome” generally refers to a group of symptoms that frequently occur
in combination, it then becomes apparent that the factors extracted from rating scales
relating to mental state are conceptually identical to clinical syndromes.
For some well-developed observer-rated scales, it has been shown that the factor
structure also remains relatively stable across different studies, and for many of the factors
this is true even with repeated measurements in the course of treatment [18–20]. Thisinvariability of the structure of factors across different samples and time points is an
important aspect of the validity of a scale (factorial validity). Different psychiatric diagnostic groups are reﬂected in different characteristic syndrome proﬁles when rating scales
are applied [21].
It is important to bear in mind that identically named syndromes from different
scales may vary greatly in terms of the items included, and the correlation between analogous syndrome scores is not always very great. As scales that measure the same domain(e.g., depressive symptoms) sometimes focus on different aspects of this domain [22],certain questions may be best addressed by using a combination of them.
When observer-rated instruments are administered by professionally trained observers, it is usually assumed that, in making the rating, the observer decides how much weightto put on the information the patient gives (e.g., an observable improvement in generalbehavior and demeanor is taken into account in the rating even if the patient gives noclear report of this improvement). An advantage of this expert assessment is that it reduces
the scope for inaccurate assessments resulting from the distortions in patients’ perceptionof themselves; on the other hand, it introduces the danger of distortions that are related

796

Möllerto the assessment (rater bias). Systematic distortion in the assessor’s observations [23]can result from the following factors in particular:
1.
2.
3.

4.

Rosenthal effect: The assessor’s expectations inﬂuence the result of the assessment.
Tendency on the rater’s part to systematically over- or under-rate the degreeof disturbance.
Halo effect: The result of assessment of one characteristic is inﬂuenced by therater’s knowledge of the subject’s other characteristics or by the overall impression made by the subject.
Logical errors: The result of the assessment is inﬂuenced by the assessors reporting only those detailed observations that make sense to them in the context
of their theoretical and logical preconceptions.

These errors may be partially compensated for by combining observer-rated scaleswith self-rated scales [3,9,24]. In self-rated instruments, patients can themselves classify
past or current behavior and experience on the basis of ﬁxed rating scales. Self-rated scales
have the further advantage that their use is very economical for the assessor and eliminatesobserver bias. However, their use also introduces the disadvantage that conscious or unconscious tendencies to falsify responses (e.g., tendencies to exaggerate or conceal symptoms, the positive response bias, social desirability effects) will have a greater impact onpatients and are only partially detectable through use of control scales (so-called lie detector scales).
Apart from a few scales measuring current mental state which, as with the SelfReport Symptom Inventory (SCL-90), record a very broad spectrum of psychopathologicalsymptoms, most self-rated scales focus on speciﬁc aspects of disturbance of subjective
experience (Table 1). Examples are inventories of physical and systemic complaints[25,26], depressive symptom scales [26–28], or measures of general subjective well-being
Table 1 Examples of Clinical Self-Rated Procedures
Domains

Procedure

Abbreviation

Global psychopathology

Self-Report Symptom Inventory

Depression

Depressivitäts-Skala (Depressive Symptom Scale)Beﬁndlichkeits-Skala (Mental
State Scale)
Beck Depression InventorySelf-Rating Anxiety Scale
State-Trait Angst-Inventar(State-Trait Anxiety Inventory)
Hamburger Zwangsinventar(Hamburg Compulsive Inventory)Münchner Alkoholismustest(Munich Alcoholism Test)

SCL-90SCL-90R
DS

30
31
26

Bf-S

26

BDI
SAS
STAI

32
33, 3134

HZI35, 36MALT

37Anxiety disorders

Obsessive-compulsive
symptoms
Alcoholism
Source: Ref. 6.

Refs.

Scales

797[26,29]. One of the advantages of this approach is that the quantity of items is limited, aparticular strength where severely disturbed psychiatric patients are concerned.
However, very precise differentiation between different aspects of “subjective state”
probably is not generally meaningful [38] in contrast to the detailed measurement of psychological disturbances that may be made by observer assessment. In fact, where resultsfrom clinical self-rated scales are compared with observer-rated scales administered by
specialists, it seems that the various dimensions of the subjective state that self-rated instruments describe are more similar to one another than the different aspects of psychopathology delineated by clinical observer-rated assessments.
The level of agreement between self-assessment and observer assessment is variableand depends, among other things, on the type of disturbance and on symptom severity[39–42]. Thus, for example, where depressive symptomatology is severe, as at the timeof inpatient admission, agreement is substantially more limited than after partial remission of symptoms at the time of discharge. This is probably connected with greater limitation of the capacity for self-observation among the severely depressed, and probably
also with the fact that observers tend to recognize very severe depressive symptoms on
the basis of nonverbal evidence to a greater extent than with less severe depressive symptoms, where the patient’s verbal reports are more important. Compared with patients withendogenous depression, those with neurotic depression show a greater tendency to overstate their symptoms. Degree of agreement between self-rating and observer rating is substantially greater for the amount of change, as measured in longitudinal studies (e.g., in
the context of treatment studies), than when psychopathological phenomena are recorded
at a single cross-sectional time point [24,43] (Fig. 4).
Multi-methodological diagnostic procedures in which a combination of self-rated
and observer-rated scales is applied [5,44] offer the best guarantee of satisfactory description of both subjective and objective psychopathological state.
Measures of subjective well being are of particular interest in the area of treatment
assessment, particularly visual analog scales that measure current disturbances of psychological well being and lend themselves especially well to repeated measurement. Thesemethods allow a very good description at the self-assessment level of response to a therapeutic intervention. Modern methods of statistical analysis, such as some of the procedures
developed for time series analysis, allow satisfactory analysis of such data [9,24,45,46].
A full discussion of such approaches is presented by Morley [47].

IV. SOME FREQUENTLY USED OBSERVER RATING SCALESFOR DEPRESSION AND ANXIETY
A. Hamilton Depression Scale
The Hamilton Depression Scale (HAM-D) [48,49] became one of the ﬁrst observer rating
scales for depression to gain worldwide acceptance, although its weaknesses are increasingly criticized (see below). The original version of this scale contains 17 items, later
versions 21 or even 24. The formulation of the items is not always precise enough, andis considerably worse than in the Montgomery-Asberg Depression Rating Scale [50], forexample. Additional information from relatives and friends, etc., can be considered in therating. In addition to the possibility of calculating a total score, it is also possible tocalculate factor scores during the ﬁnal analysis [48]. However, there is no uniform solution
since the results of factor analytical evaluations resulted in solutions of two to six factors

798

Möller

Figure 4 Two responders (a, b) and two nonresponders (c, d) under antidepressant therapy as assessed by psychiatrist ratings (HAM-D) and self-ratings (AMS). (From Ref. 9.)[48,49,51]. The inter-rater reliability can be seen as very high, at least on the level of thetotal score [48,52]. The correlation with the Clinical Global Impression of the depressivity indicates the validity of the scale [53], as does the sensitivity for the recording ofantidepressant-induced changes, which has been demonstrated in numerous antidepressantstudies. Reference values for various clinical samples are available.
However, some further problems of the scale still remain unsolved, for example,
concerning the content. The scale does not record certain diagnostically speciﬁc areas thatare partially depicted in other depression scales and therefore proves to be unsatisfactory

Scales799

Figure 4 Continued

for a differentiated diagnosis of depressive disorders, particularly under the aspect of adifferential diagnosis. As concerns the content, it is questionable whether the characteristic“daytime ﬂuctuations” makes a difference in the sense of a higher depression score. Thiscan lead to contradictions in the diagnosis of the course of the disease in view of theclinical experience that the most severe endogenous depressions often show no daytime
ﬂuctuations at ﬁrst and that these only occur upon improvement of the severe depressive
mood. The fact that sleep disorders are depicted with eight items leads to an efﬁcacy bias
in favor of sedating/sleep-inducing antidepressants in antidepressant studies.
The scale was subjected to a critical test-theoretical analysis in order to investigate

800

Möller

its homogeneity and the stability of the factor structure in repeated measurements during
treatment [20,54,55]. On the basis of this analysis, it was modiﬁed to the Bech-Rafaelsen
Melancholia Scale (BRMES) [54,56], which consists of 11 items, six of which are fromthe original scale.
B.

Bech-Rafaelsen Melancholia Scale

As mentioned above, the Bech-Rafaelsen Melancholia Scale was constructed on the basisof an analysis of the HAM-D. The analysis used Rasch’s Probabilistic Test Theory [54],which showed six items of the HAM-D to be suitable. In addition, another ﬁve items fromthe Cronholm-Ottosan Depression Scale [57], which also cover the aspect of “depressive
retardation,” were incorporated. The BRMAS Mania Scale by the same authors was similarly constructed for use in mania.
The scale consists of the following 11 items: decreased motor activity; decreased
verbal activity; retardation (intellectual); anxiety (psychic); suicidal impulses; lowered
mood; self-deprecation; retardation (emotional); sleep disturbances; tiredness and pains;
work and interests. Unrotated factor analysis performed by Chambon et al. [58] showedthat the ﬁrst factor was a general factor. After varimax rotation, the following structure
emerged: aspects of retardation, asthenia, anxiety, depression, and suicidal thoughts. Using
Rasch models for testing whether the BRMES measures a dimension of severity of depressive states, it was found [59–62] that the sum total of the 11 items is a sufﬁcient
statistic. A BRMES score of 0–5 means no depression; 6–14 minor; and of 15 or more
major depression [63]. A score of 15 or more on BRMES corresponded to DSM-III major
depression [64]. The comparison to the HAM-D has shown correlation coefﬁcients around0.90 [65,66]. When comparing the HAM-D, the Montgomery-Asberg Depression Rating
Scale (see below), and the BRMES, it was found that the BRMES was superior to theother scales in measuring sensitivity to change during antidepressive therapy [60,61]. In
terms of Spearman correlation coefﬁcients, the range of inter-observer reliability of the
BRMES total score varied from 0.80 to 0.90 when several Scandinavian raters participatedin joint rating sessions [65].
A substantial advantage that is offered by the BRMES in comparison to other depression scales is that it can be employed in conjunction with the BRMAS in long-term studiesof bipolar disorder, and thus permits comparable evaluation of both manic and depressive
episodes.
C.

Montgomery-Asberg Depression Rating Scale

Although the HAM-D is still widely accepted, the Montgomery-Asberg Depression Rating
Scale (MADRS) [67] is becoming increasingly important thanks to its conciseness andparticularly to its better deﬁnition of characteristics. The aspect that the scale was constructed according to the principle “sensitivity to change” is of advantage for treatmentrelated studies.
The scale includes the following 10 items: apparent sadness; reported sadness; innertension; reduced sleep; reduced appetite; concentration difﬁculties; lassitude; inability tofeel; pessimistic thoughts; suicidal thoughts. The scale is supposed to include the main
symptoms of depressive illnesses, even if certain important areas (e.g., psychomotor retardation, tendency to somatize) have been omitted as a result of the method of item selection[68]. Overall, the factor analyses and correlations with the Hamilton scale (in particularScales801

with the various subscales) show that the MADRS covers more purely psychologicalsymptoms than the HAM-D (see also Refs. 67,68).
Schmidtke et al. [50] used a heuristic procedure in which they subjected the correlations between individual item scores (calculated from the raw scores after dichotomizationof the items according to various criteria such as less than the mean ⫽ 0/ ⫽ ⬎ mean ⫽1; 0 and 1 ⫽ 0, 2 and 2 ⫽ 1; (see Ref. 59) for 57 different patient ratings by MADRS
and the HAM-D conducted by the same physician to a main axis factor analysis withvarimax rotation. The analyses all show that, despite the methodological limitation thatstill pertains because of the similar calculations of the various factor analyses, the MADRS
items do not represent a unidimensional scale. Four-factor solutions accounting for 51 to
54% of the total variance in all analyses proved relatively stable. In these analyses, theaspects covered by the MADRS items were classiﬁed under the headings sadness/pessimistic thoughts, inner tension, inability to feel, and reduced appetite.
In the construction studies, the sensitivity to change was claimed to be better thanthat of other procedures used simultaneously (e.g., Refs. 69,70). In later studies, the sensitivity of the MADRS for differences in the severity of depression [68] and changes in thesymptoms of depression was again shown to be good [50,71,72].
Reference values of several clinical samples are available [50,59]. The inter-rater
reliability has been given for different samples as 0.89 to 0.97 [67,69].
D. Hamilton Anxiety Scale
A number of symptoms that can be observed in association with anxiety states have beencollected for the Hamilton Anxiety Scale (HAM-A) [73–76]. Thirteen symptom groups
have been put together, and complemented by a fourteenth variable, namely the patient’s
observable behavior during the interview. The 14 groups of symptoms measure either
psychic or somatic effects of anxiety and are as follows: anxious mood; tension; fears;
insomnia; intellectual; depressed mood; somatic (muscular); somatic (sensory); cardiovascular symptoms; respiratory symptoms; gastrointestinal symptoms; genitourinary symptoms; autonomic symptoms; behavior at interview.
A factor score is calculated for both the symptom groups assessing somatic anxiety
and the symptom groups assessing psychic anxiety (scores 1 and 2, respectively). The
total raw score (score 3) can be taken as a measure of the patient’s anxiety and makes it
possible to compare groups receiving different treatments. Hamilton gave a very highcoefﬁcient of correlation for the inter-rater reliability, namely, 0.89 (following z transformation of the mean of the correlations between three raters).
E.

Anxiety Status Inventory

The Anxiety Status Inventory (ASI) [77–79] records anxiety as a common symptom ofvarious psychiatric disorders. The inventory includes 20 items, whereby items 1 to 5 and
20 refer to affective and items 6 to 19 to somatic symptoms of anxiety. The observer
rating scale ASI was developed to supplement the Self-Rating Anxiety Scale (SAS) toassist the clinical evaluation of pathological anxiety conditions.
In a study by Zung [78], 22 patients with a diagnosis of anxiety disorder demonstrated a signiﬁcantly higher (p ⬍ 0.05) average ASI score than 187 patients with otherpsychiatric diagnoses (schizophrenia, depressive disorders, personality disorders, transient
situational disturbances), whereas the Taylor Anxiety Scale [77] could not show any signiﬁcant difference.

802

F.

Möller

Liebowitz Social Anxiety Scale

The ﬁrst clinician-administered scale developed for the assessment of fear and avoidanceassociated with social phobia was the Liebowitz Social Anxiety Scale (LSAS) [80]. The
LSAS assesses a wide range of both social interaction and performance/observation situations that are rated for degree of fear/anxiety and frequency of avoidance. It has been
widely used in studies of the pharmacotherapy of social phobia. The LSAS shows a highdegree of convergent validity with other measures of social phobia, such as the Social
Interaction Anxiety Scale [81], the Social Phobia Scale [81], etc. Also other psychometricvariables related to validity and reliability are satisfactory.
G.

The Panic and Agoraphobia Scale

The Panic and Agoraphobia Scale (PAS) [82] was developed to determine the severityof panic disorder with or without agoraphobia and to monitor treatment efﬁcacy in psychotherapy and drug treatments. The scale has 13 items and is divided into ﬁve subscores(panic attacks, agoraphobic avoidance, anticipatory anxiety, restriction of activities andquality of life, and worries about health). The scale is also available as a self-rating version,
which consists of identical questions. The test–retest reliability of the observer-rated version is r ⫽ 0.73. Both the observer-rated and self-rated version have satisfactory validity.
V.

SOME FREQUENTLY USED SELF-RATING SCALESFOR ANXIETY AND DEPRESSIONA.

Paranoid Depression Scale

The Paranoid Depression Scale [26,83,84], which is available in two parallel forms, iscomposed of 43 items. It records the degree of subjective impairment by emotional reduction of the type anxious-depressive mood—these items are also on a separate depression
scale—as well as a distinct cognitive dimension to determine a distrusting attitude andwhether the subject is out of touch with reality. In addition, there are eight control items
to measure disease denial and three items to assess motivation.
The values of the individual items are summarized as factor values. Among others,
correlations of the paranoid scale with the criterion of the afﬁliation to a group of schizophrenic patients, correlations of the depression scale with the criterion of afﬁliation to agroup of patients with depressive mood, correlations with relevant factors of other scales,and sensitivity in the recording of therapy-induced changes indicate the validity. The depression scale is also available as a separate scale, with 16 items, without the items of
the paranoid scale. Norm values are available for a representative sample of the general
population in the former West Germany, as well as reference values for various clinicalgroups (physically ill, mixed psychiatric groups, individual psychiatric diagnosis groups).
B.

Beck Depression Inventory

Another frequently used self-rating scale is the Beck Depression Inventory [27,85], which
was originally developed as an observer rating scale. It has 21 items and is still widelyused. It has a special focus on cognitive aspects of depression, which might explain thefact that it is preferentially used in the context of psychological treatments, while theapplication in psychopharmacological studies is seldom. The psychometric criteria withrespect to reliability and validity are satisfactory [86].

Scales803

C. State-Trait Anxiety Inventory
The State-Trait Anxiety Inventory (STAI) is an inventory for evaluating two different
components of anxiety [34,87,88]. One scale (scale 1) is designed to measure state anxiety
and the other (scale 2) to measure generalized (trait) anxiety. Depending on the purpose
to which they are being put, both scales can be used on their own or together. Scale 1
assesses a relatively stable personality trait and is thus neither time nor situation dependent.
It provides an evaluation of the person’s state at the time of testing. However, if the
instructions are altered, scale 1 can also be used to assess state anxiety in any speciﬁcsituation provided that the subject can bring to mind the situation in question and is willingto cooperate with the tester.
The total scores for scales 1 and 2 are calculated for each subject as measures ofstate and trait anxiety, respectively. The correlations with the IPAT anxiety scale, theTaylor Manifest Anxiety Scale (TMAS), and the Zuckerman Affect Adjective Checklist(AACL) are high (between 0.75 and 0.84). Studies on construct validity in which thescale was administered repeatedly under different conditions have shown point-biserial
correlations of r ⫽ 0.60 and r ⫽ 0.73. Test–retest reliability is reported for trait as r ⫽0.84 and state r ⫽ 0.34 (men, interval 1 h). Alpha coefﬁcients of r ⫽ 0.83 and 0.92 havebeen found for internal consistency. Norm values are available [83,84].
D. Adjective Mood Scale
The Adjective Mood Scale contains 28 items [26,83,84] and is available in two parallelversions. It records the degree of current impairment of subjective well being. The scaleis especially indicated for course descriptions when tests are frequently repeated. It is
suitable for healthy subjects, and physically or psychically ill patients, particularly for
psychically ill patients with affective disorders.
The values of the individual items are summed to give a total score, which gives
the impairment of the subjective well being. High inter- and intra-individual correlations
with global assessments of the depressive mood as well as the sensitivity for the recordingof therapy-induced changes prove the validity. There are norm values for a representative
sample of the general population of the former West Germany and reference values forvarious clinical groups.
E.

Self-Rating Anxiety Scale

The Self-Rating Anxiety Scale (SAS) is the self-rating version of the observer rating scale
Anxiety Status Inventory developed by the same author [78]. The SAS contains 20 anxiety
symptoms, ﬁve of which are affective and 15 somatic. Some of the items are formulated
positively with respect to symptoms, other negatively.
With respect to content validity, items were selected using psychiatric diagnosis
criteria of different psychiatric disorders that are associated with anxiety. And with respect
to criteria-related validity, patients with the diagnosis of “anxiety symptoms” have a signiﬁcantly higher mean index (p ⬍ 0.05) than patients with the diagnoses of “schizophrenia,” “depressive symptoms,” “personality disorder,” or “situative transitional symptoms.”
The Taylor Manifest Anxiety Scale [77] could not show this difference. A group of 100
controls (57 men, 43 women, aged 18–62 years, mean 34 years) had a signiﬁcantly lower
mean index than the diagnosis groups listed above. Correlations with other tests are as

804

Möller

Figure 5 Course of the median values in the SCL-90-R anxiety subscale; median values
dependent on drug and treatment duration (n ⫽ 218). (From Ref. 94.)

follows: r ⫽ 0.66 with the observer rating form ASI (r ⫽ 0.74 only in patients with adiagnosis of anxiety), r ⫽ 0.30 with the Taylor Manifest Anxiety Scale.
F.

Self-Report Symptom Inventory

The Self-Report Symptom Inventory 90 items (SCL-90) [89–91] is the revised versionof the Hopkins Symptom Check List. The scale is used for the self-rating of patients withrespect to various burdening symptoms. It allows nine ranges of syndromes to be recorded
and was specially constructed to register of effects of drug treatment (Fig. 5). It has alreadyproved itself in this respect in various clinical studies with neuroleptics, tranquilizers, andantidepressants [92,93].
G.

Complaint List

The Complaint List consists of 24 items [83,84] and is available in two parallel forms,
the content of which can be supplemented with an additional form with 17 items.
The Complaint List records the degree of subjective impairment due to physical andgeneral complaints. It is indicated to record those kinds of complaints in depression oranxiety disorders, among others.
For the analysis, the values of the individual items are summed to give a total score.
Good correlations with the criterion of the afﬁliation to a corresponding clinical group,
correlations with analog test scales, and the sensitivity for the recording of treatmentinduced changes all speak for the validity. Norm values from a representative sample of
the general population in the former West Germany are available, together with reference
values for various clinical groups (physically ill, mixed psychiatric groups, individual
psychiatric disorders).

Scales805

REFERENCES
1. Stieglitz RD, Baumann U. Psychodiagnostik psychischer Störungen. Stuttgart: Enke, 1994.
2. Möller HJ, Engel RR, Hoff P. Befunderhebung in der Psychiatrie: Lebensqualität, Negativsymptomatik und andere aktuelle Entwicklungen. New York: Springer, 1996.
3. von Zerssen D, Möller HJ. Psychopathometrische Verfahren in der psychiatrischen Therapieforschung. In: Biefang S, ed. Evaluationsforschung in der Psychiatrie. Fragestellungen und
Methoden. Stuttgart: Enke, 1980:129–166.
4. Cronholm B, Daly RJ. Evaluation of psychiatric treatment. In: Helgason T, ed. Methodology
in Evaluation of Psychiatric Treatment. Cambridge: Cambridge University Press, 1982:183–
204.
5. Möller HJ, Barthelmes H, von Zerssen D. Forschungsmöglichkeiten auf der Grundlage einer
routinemässig durchgeführten psychiatrischen Basis- und Befunddokumentation. Psychiatr
Clin Base 1983; 16:45–61.
6. Möller HJ, Engel R, Hemsley D. Standardised measurement instruments in psychiatry. In:
Henn F, Sartorius N, Helmchen H, Lauter H, eds. Contemporary Psychiatry. New York:
Springer, 2001:114–133.
7. Luria RE. The validity and reliability of the visual analogue mood scale. J Psychiatr Res 1975;
12:51–57.
8. von Zerssen D. Konstitutionstypologische Forschung. In: Strube G, ed. Die Psychologie des20. Jahrhunderts, Vol 5. Zurich: Kindler, 1977:545–616.
9. Möller HJ. Outcome criteria in antidepressant drug trials: self-rating versus observer-rating
scales. Pharmacopsychiatry 1991; 24:71–75.
10. Garety PA, Hemsley DR. Characteristics of delusional experience. Eur Arch Psychiatry Neurol
Sci 1987; 236:294–298.
11. Lienert GA. Testaufbau und Testanalyse. Weinheim: Beltz, 1969.
12. Fischer G. Einführung in die Theorie psychologischer Tests. Bern: Huber, 1974.
13. Sarris V, Rey ER. Allgemeine Grundlagen von klinisch-psychologischen Testfaktoren. In: Rey
ER, ed. Klinische Psychologie. Stuttgart: Fischer, 1981:11–28.
14. Hofstätter PR. Psychologie. Frankfurt: Fischer, 1957.
15. Meili R. Lehrbuch der psychologischen Diagnostik. Bern: Huber, 1961.
16. Möller HJ, Volz HP. Brofaromine in major depressed patients: a controlled clinical trial versus
imipramine and open follow-up of up to one year. J Affect Disord 1992; 26:163–172.
17. Heimann H, Obermair W, Boller W, Stoll KD. Videotape training in psychiatric practice. Prog
Neuropsychopharmacol 1977; 1:141–145.
18. Baumann U, Stieglitz RD. Testmanual zum AMDP-System. Empirische Studien zur Psychopathologie. New York: Springer, 1983.
19. Möller HJ, Hacker H. Study concerning the sample dependency and temporal variance of thefactor structure in the Inpatient Multidimensional Psychiatric Scale. Psychopathology 1988;
21:281–290.
20. Steinmeyer EM, Möller HJ. Facet theoretic analysis of the Hamilton-D scale. J Affect Disord
1992; 25:53–61.
21. Möller HJ, von Zerssen D. Probleme und Verbesserungsmöglichkeiten der psychiatrischen
Diagnostik. In: Biefang S, ed. Evaluationsforschung in der Psychiatrie. Fragestellungen und
Methoden. Stuttgart: Enke, 1980:167–207.
22. Mombour W. Systematik psychischer Störungen. In: Pongratz LJ, ed. Handbuch der Psychologie, Vol 8/1. Göttingen: Hogrefe, 1976:116–153.
23. Hasemann K. Verhaltensbeobachtung. In: Heiss R, ed. Handbuch der Psychologie, 3rd ed.,vol 6. Göttingen: Hogrefe, 1971:807–836.
24. Möller HJ, von Zerssen D. Self-rating procedures in the evaluation of antidepressants. Reviewof the literature and results of our studies. Psychopathology 1995; 28:291–306.
25. Fahrenberg J. Die Freiburger Beschwerdenliste FBL. Z Klin Psychol 1975; 4:79–106.

806

Möller

26. von Zerssen D. Klinische Selbstbeurteilungs-Skalen (KSbS) aus dem Münchener Psychiatrischen Informationssystem (PSYCHIS München). Manuale: a) allgemeiner Teil, b) ParanoidDepressivitäts-Skala, c) Beﬁndlichkeits-Skala, d) Beschwerden-Liste. Weinheim: Beltz, 1976.
27. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561–571.
28. Zung WWK. A self-rating depression scale. Arch Gen Psychiatry 1965; 12:63–67.
29. Janke W, Debus G. Die Eigenschaftswörterliste EWLK. Ein Verfahren zur Messung der Beﬁndlichkeit. Göttingen: Hogrefe, 1977.
30. Derogatis LR, Lipman RS, Covi L. SCL-90. Self-Report Symptom Inventory. In: Guy W, ed.
ECDEU assessment manual for psychopharmacology. Rockville: National Institute of Mental
Health, 1976:313–331.
31. CIPS/Collegium Internationale Psychiatriae Scalarum. Internationale Skalen für Psychiatrie,
4th ed. Weinheim: Beltz, 1996.
32. Beck AT, Rush AJ, Shaw BF, Emery G. Kognitive Therapie der Depression. 2nd ed. Munich:
Psychologie Verlags Union, 1986.
33. Zung WWK. SAS. Self-rating Anxiety Scale. In: Guy W, ed. ECDEU assessment manual for
psychopharmacology. Rockville, MD: National Institute of Mental Health, 1976:337–340.
34. Laux L, Glanzmann P, Schaffner P, Spielberger CD. Das State-Trait-Angstinventar (STAI).
Weinheim: Beltz Test GmbH, 1981.
35. Zaworka W, Hand I, Jauernig G, Lünenschloss K. Hamburger Zwangsinventar. Weinheim:
Beltz, 1983.
36. Klepsch R. Entwicklung computerdialogfähiger Kurzformen des Hamburger Zwangsinventars.
Weinheim: Deutscher Studienverlag, 1989.
37. Feuerlein W, Küfner H, Ringer C, Antons K. Münchner Alkoholismus-Test. Manual. Weinheim: Beltz, 1979.
38. von Zerssen D. Klinisch-psychiatrische Selbstbeurteilungs-Fragebögen. In: Baumann U, Berbalk H, Seidenstücker G, eds. Klinische Psychologie. Trends in Forschung und Praxis, Vol
2. Bern: Huber, 1979:130–159.
39. Heimann H, Schmocker A. Zur Problematik der Beurteilung des Schweregrades psychiatrischer Zustandsbilder. Arzneimittelforsch 1974; 24:1004–1006.
40. Prusoff BA, Klerman GL, Paykel ES. Concordance between clinical assessments and patients’
self-report in depression. Arch Gen Psychiatry 1972; 26:546–552.
41. Prusoff BA, Klerman GL, Paykel ES. Pitfalls in the self-report assessment of depression. Can
Psychiatr Assoc J 1972; 17:Suppl.
42. White J, White K, Razani J. Effects of endogenicity and severity on consistancy of standard
depression rating scales. J Clin Psychiatry 1984; 45:260–261.
43. von Zerssen D. Clinical Self-Rating Scales (CSRS) of the Munich Psychiatric Information
System (PSYCHIS München). In: Sartorius N, Ban TA, eds. Assessment of Depression. New
York: Springer, 1986:270–303.
44. Seidenstücker G, Baumann U. Multimethodale Diagnostik. In: Baumann U, Berbalk H, Seidenstücker G, eds. Klinische Psychologie. Trends in Forschung und Praxis, Vol 1. Bern: Huber,
1978:134–183.
45. Möller HJ, Leitner M, Dietzfelbinger T. A linear mathematical model for computerized analyses of mood curves. An empirical investigation on mood courses in depressive and schizophrenic inpatients. Eur Arch Psychiatry Neurol Sci 1987; 236:260–268.
46. Möller HJ, Blank R, Steinmeyer EM. Single-case evaluation of sleep-deprivation effects bymeans of nonparametric time-series analysis (according to the HTAKA model). Eur Arch
Psychiatry Neurol Sci 1989; 239:133–139.
47. Morley SJ. Single case methodology in psychological therapy. In: Lindsay SJ, Powell GE,
eds. Handbook of Clinical Adult Psychology, 2nd ed. London: Routledge, 1994:723–745.
48. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56–62.
49. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin
Psychol 1967; 6:278–296.

Scales807

50. Schmidtke A, Fleckenstein P, Moises W, Beckmann H. Untersuchungen zur Reliabilitat und
Validitat einer deutschen Version der Montgomery-Asberg Depression-Rating Scale (MADRS).
[Studies of the reliability and validity of the German version of the Montgomery-Asberg Depression Rating Scale (MADRS)]. Schweiz Arch Neurol Psychiatr 1988; 139:51–65.
51. Baumann U. Methodische Untersuchungen zur Hamilton-Depression-Skala [Methodologic
studies of the Hamilton rating scale for depression]. Arch Psychiatr Nervenkr 1976; 222:359–
375.
52. Waldron J, Bates TJN. The management of depression in hospital: a comparative trial of desipramine and imipramin. Br J Psychiatry 1965; 111:511–516.
53. Welner J. Eine internationale multizentrische Doppelblind-Prüfung eines neuen Antidepressivums. In: Kielholz P, ed. Depressive Zustände. Vienna: Huber, 1972:209–219.
54. Bech P. Rating scales for affective disorders: their validity and consistency. Acta Psychiatr
Scand Suppl 1981; 295:11–101.
55. Maier W, Philipp M, Gerken A. Dimensionen der Hamilton-Depressionsskala (HAMD).
Faktorenanalytische Untersuchungen. [Dimensions of the Hamilton Depression Scale. Factor
analysis studies]. Eur Arch Psychiatry Neurol Sci 1985; 234:417–422.
56. Bech P. The instrumental use of rating scales for depression. Pharmacopsychiatry 1984; 17:
22–28.
57. Cronholm B, Ottoson JO. Experimental studies of the therapeutic action of electroconvulsive
therapy in endogenous depression. Acta Psychiatr Scand 1960; 35 (suppl 145):69–97.
58. Chambon O, Poncet F, Kiss L, Milani D, Cottraux J. Adaptation Française, validation concurrente et analyse factorielle de l’echelle de melancolie de Bech et Rafaelsen. [French adaptation,
concurrent validation and factorial analysis of the Bech and Rafaelsen melancholia scale.]
Encephale 1988; 14:443–448.
59. Maier W, Philipp M. Comparative analysis of observer depression scales. Acta Psychiatr Scand
1985; 72:239–245.
60. Maier W, Heuser I, Philipp M, Frommberger U, Demuth W. Improving depression severity
assessment—II. Content, concurrent and external validity of three observer depression scales.
J Psychiatr Res 1988; 22:13–19.
61. Maier W, Philipp M, Heuser I, Schlegel S, Buller R, Wetzel H. Improving depression severity
assessment—I. Reliability, internal validity and sensitivity to change of three observer depression scales. J Psychiatr Res 1988; 22:3–12.
62. Chambon O, Cialdella P, Kiss L. Study of the unidimensionality of the Bech-Rafaelsen Melancholia Scale using Rasch analysis. Paper presented at the ECNP congress, Gothenborg, 1989.
63. Bech P. Rating scales for mood disorders: applicability, consistency and construct validity.
Acta Psychiatr Scand 1988; 345; 78(suppl):45–55.
64. Bech P, Gjerris A, Andersen J, Bojholm S, Kramp P, Bolwig TG, Kastrup M, Clemmesen L,
Rafaelsen OJ. The Melancholia Scale and the Newcastle Scales. Item-combinations and interobserver reliability. Br J Psychiatry 1983; 143:58–63.
65. Rafaelsen OJ, Bech P, Bolwig TG, Kramp P, Gjerris A. The Bech-Rafaelsen combined rating
scale for mania and melancholia. In: Acht’e K, Aalberg V, Lonnqvist J, eds. Psychopathology
of Depression. Psychiatrica Fennica Suppl. Helsinki: World Psychiatric Association, 1980:
327–331.
66. Ballus C, Marcos T. The “Melancholia Rating Scale”: a useful instrument for the assessmentof affective disorders. Validity and reliability of the Spanish adaptation. Pharmacopsychiatry
1986; 19:48–51.
67. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br
J Psychiatry 1979; 134:382–389.
68. Kearns NP, Cruickshank CA, McGuigan KJ, Riley SA, Shaw SP, Snaith RP. A comparisonof depression rating scales. Br J Psychiatry 1982; 141:45–49.
69. Montgomery S, Asberg M, Jörnestedt L, Thoren P, Träskman L, McAuley R, Montgomery
D, Shaw P. Reliability of the CPRS between the disciplines of psychiatry, general practice,nursing and psychology. Acta Psychiatr Scand Suppl 1978; 272:29–32.

808

Möller

70. Montgomery SA, Montgomery DB. Measurement of change in psychiatric illness: new obsessional, schizophrenia and depression scales. Postgrad Med J 1980; 56(suppl 1):50–52.
71. Deloch E. Vortrag auf dem Idom-Expertengespräch in Estoril. G. Selecta Bericht 1986; 42:3068–3070.
72. Gutzmann H. Vortrag auf dem ldom-Expertengespräch in Estoril. G. Selecta 1986; 42:3068–
3070.
73. Hamilton M. The assessment of anxiety states by rating. Br J Psychiatry 1959; 32:50–55.
74. Hamilton M. Diagnosis and rating of anxiety. In: MH Lader, ed. Studies of anxiety. Br J
Psychiatry Spec Pub 3. Ashford, Kent: Headley Brothers Ltd, 1969:76–79.
75. Lader MH, Marks IM. The rating of clinical anxiety. Acta Psychiatr Scand 1974; 50:112–137.
76. Beneke M. Methodological investigations of the Hamilton Anxiety Scale. Pharmacopsychiatry
1987; 20:249–255.
77. Taylor JA. A personality scale of manifest anxiety. J Abnorm Soc Psychol 1953; 48:285–
290.
78. Zung WW. A rating instrument for anxiety disorders. Psychosomatics 1971; 12:371–379.
79. Zung WW. The measurement of affects: depression and anxiety. Mod Probl Pharmacopsychiatry 1974; 7:170–188.
80. Liebowitz MR. Social phobia. Mod Probl Pharmacopsychiatry 1987; 22:141–173.
81. Mattick RP, Clarke JC. Development and validation of measures of social phobia scrutiny
fear and social interaction anxiety. Behav Res Ther 1998; 36:455–470.
82. Bandelow B. Assessing the efﬁcacy of treatments for panic disorder and agoraphobia. II. The
Panic and Agoraphobia Scale. Int Clin Psychopharmacol 1995; 10:73–81.
83. CIPS/Collegium Internationale Psychiatriae Scalarum. Rating scales for psychiatry. Weinheim: Beltz, 1990.
84. AMDP/Association for Methodology and Documentation in Psychiatry. Das AMDP-System.
Manual zur Dokumentation psychiatrischer Befunde. Göttingen Bern Toronto: Hogrefe, 1995.
85. Beck AT, Beamesderfer A. Assessment of depression: The depression inventory. In: Pichot
P, ed. Psychological measurements in psychopharmacology. Modern problems in pharmacopsychiatry. Vol 7. Basel: Karger, 1974:151–169.
86. Steer RA, Beck AT, Garrison B. Applications of the Beck Depression Inventory. In: Sartorius
N, Ban TA, eds. Assessment of depression. New York: Springer Verlag, 1986:123–142.
87. Spielberger CD, Gorsuch RL, Lushene RE. State-Trait-Anxiety-Inventory. Palo Alto: Consulting Psychologists Press, 1970.
88. Johnson DT. Effects of interview stress on measures of state- and trait-anxiety. J Abnorm
Psychol 1968; 73:245–251.
89. Derogatis LR, Lipman RS, Covi L. SCL-90: an outpatient psychiatric rating scale—preliminary report. Psychopharmacol Bull 1973; 9:13–28.
90. Derogatis LR, Lipman RS, Rickels K, Uhlenhuth EH, Covi L. The Hopkins Symptom Checklist (HSCL): a self-report symptom inventory. Behav Sci 1974; 19:1–15, 1974.
91. Derogatis LR. SCL-90. Administration, scoring and procedures. Manual-I for the R(evised)version and other instruments of the psychopathology rating scale series. Baltimore: Johns
Hopkins University School of Medicine, 1977.
92. Möller HJ, Volz HP, Reimann I, Stoll KD. Opipramol for the treatment of generalized anxiety
disorder: a placebo-controlled trial including an alprazolam-treated group. J Clin Psychopharmacol 2001; 21:59–65.
93. Volz HP, Möller HJ, Reimann I, Stoll KD. Opipramol for the treatment of somatoform disorders results from a placebo-controlled trial. Eur Neuropsychopharmacol 2000; 10:211–217.
94. Möller HJ, Volz HP. Konﬁrmatorische Drei-Arm-Studie mit Opipramol und Alprazolam versus Placebo bei Generalisierter Angst. In: Müller WE, Möller HJ, eds. Opipramol, Sigmaligand
und stimmungsaufhellendes Anxiolytikum. Neu-Isenburg: LinguaMed-Verl, 2001:93–108.

Index

AACL, 803
Abecarnil, 427
Acetylcholine, 470–471
ACTH, 232
Acute depression (see Major depression)Acute phase proteins, major depression,
274–275
Acute stress, 511–513
Adaptive immunity, 271–272
Addison’s disease, 230
ADH (see Arginine-vasopressin)
Adinazolam, mixed anxiety/depression disorders, 768
ADIS-R, 132
Adjective Mood Scale, 803
Adjustment disorders, 72
comorbidity, 72
Adrenal hypertrophy, 567
Adrenergic condition, 25
Adrenergic receptor antagonists, 401
Adrenergic receptors, 460–464
Adrenocorticotropin (ACTH), 232
Adult isolation, 525
Affect Adjective Checklist (AACL), 803
Affective disorders, 16
brain imaging, 292–303
familial relationship, 171
genes and environment, 173
neurobiology, 479–482
neuropeptides, rationale, 230–231
with psychotic symptoms, 171
serotonin hypothesis, 465
subtypes, genetics, 170–171

Age,anxiety risk-modifying factor, 192
plasticity reduction, 374
Agency for Health Care Policy and Research, 629
Aggression, serotonin link, 565
Agomelatin,
animal studies, 622
depression, 622
Agoraphobia, 22–23, 31, 36, 152, 155, 192–
193, 333, 397
anxious attachment, 660
epidemiology, 56–58
life events, 661
personality disturbances, 662
Akt-1, function, 360
Alcohol,dependence, 394
hallucinosis, 25
Alcoholism, 195
early-onset, 430
late-onset, 430
mood disorders, 172
serotonin link, 565
Allopregnanolone, 431
Allotetrahydrodeoxycorticosterone, 431
Alprazolam,mixed anxiety/depression disorders, 768–769
panic disorder, 79, 738
Alzheimer’s disease, 370, 372, 373
AMDP-System, 136
α-methyl-para-tyrosine (AMPT), 395–396
depression, 546, 548–549
809

810
Amine hypothesis, limitations, 569–576
Amino acids, tryptophan depletion, 547
Amitriptyline, 153, 401
depression, 237
mixed anxiety/depression disorders, 767
AMPT, 395–396
depression, 546, 548–549
Amygdala,anxiety, 666–668
corticotropin-releasing factor, 118
fear and anxiety, 338
related structures, 117
Anesthetics, GABAA receptors, 428
Anhedonia, 509–510, 517
Animal models,anxiety and drug action, 681–690
classic anxiolytic agents, 682
class-speciﬁc models, 682
cyclic antidepressants, 687
standard anxiolytic agents, 686
bipolar disorder, 524
chronic mild stress,
behavioral changes, 516–517
behavioral deﬁcit reversal, 516
induced anhedonia, 517
induction and maintenance, 518
severe life events, 518
chronic stress, 515–518
conﬂict tests, 687–688
construct validity, 508–510
anhedonia, 509–510
behavioral despair test, 510
CMS, 509–510
etiology, 508–509
correlation model, 681
delusional depression, 523–524
depression subtypes, 505–529
elevated plus maze, 684–685
face validity, 507–508
DSM-IV symptoms diagnosis, 507
subsidiary symptoms, 507–508
fear-potentiated startle, 687
forced-swim test, 513–515
effective treatments, 513–514
predictive validity, 514
theoretical rationale, 514
genomic models, 526–528
CRH receptor subtype knockouts, 527
HPA transgenic, 527
5HT transporter knockout, 527
tachykinin receptor knockout, 527–528
homology, 681–682

Index[Animal models]
isomorphism, 681–682
learned helplessness, 511–513
cLH, 512–513
ICSS, 512shock, 512
stress-induced motor inactivation, 513
light-dark exploration test, 682–683
melancholia, 510–511
muscarinic hypersensitivity breeding, 522–
523
neonatal antidepressants, 521–522
nonmelancholic depression, 523
nonpainful stressors reactions, 682–685
olfactory bulbectomy, 525
painful stressors reactions, 686–689
perinatal stress, 522
predictive validity, 506–507
ineffective antidepressants, 507
new compounds, 506–507
psychomotor stimulants withdrawal, 518–
519
resident-intruder test, 521
impulsive aggression, 521
separation-induced ultrasonic distress vocalization, 685
shock-induced ultrasonic vocalization,
688–689shock-probe burying, 686–687
social defeat, 519–520
social dominance, 519–521
social hierarchy, 520–521
social interactions, 683–684
social separation, 524–525
adult, 525
neonatal, 524–525
tail-suspension test, 515
waiting behavior, 526
Animal studies,
anticonﬂict tests, 418
elevated plusmaze test, 434
GABAA receptors gene encoding, 433–434
light-dark choice test, 434
social interaction test, 418
steroids, 431
Anorexia, affective disorders, 172
ANP, 210
Anticonﬂict tests, animal studies, 418
Antidepressants, 152–156, 216–218
action mode, 350
animal studies, 216–217
BDNF, 216

Index[Antidepressants]
clinical pharmacology, 118–119
clinical response, 444–447
clinical trial,
efﬁcacy, 568–569
limitation, 569
cytokines, 276–278
depression, 444–445
and anxiety disorders, 443–451
dual and receptor-speciﬁc, 617–618
efﬁcacy, 350, 568–569
ﬁrst generation, 616–617
MDD, 336
mechanism of action, 447–451
monamine oxidase inhibitors, 616
monoaminergic system and speciﬁcity
link, 573–574
neonatal, 521–522
neurotransmitters, 561–577
newer, 617–619
nonaminergic neurotransmitters, 571–573
novel, 620–622
OCD, 445–446, 449
panic disorder, 446–447, 449–450
personality disorders, 101
pharmacodynamic properties, 619, 647–649
proinﬂammatory cytokines, 574–576
PTSD, 447, 450–451
randomized controlled trials, 616–617
selectivity, 350
serotonergic, 461
side effects, 568–569
stress, 368–369
subcellular process action, 570–571
target genes activation, 570–571
therapeutic effect delayed onset, 350
Antidiuretic hormone (ADH) (see Argininevasopressin)
Antipsychotics, mixed anxiety/depression disorders, 765
Anxiety (see also Anxiety and depression;
Anxiety disorders)animal models, 681–690
animal studies, 665, 667
anxious attachment, 660
attacks, 31
clinical studies, 33–35
bodily perceptions role, 33–34
vs. fear, 33–35
cognitive and behavioral theories, 663–664
comorbidity, with depressive disorders,
332–333

811[Anxiety]demarcation, 36
developmental theories, 659–660
dimensional assessment, 132–136
endocrine and immune system changes,279
etiology theories, 657–673
existential, 664–665
free-ﬂoating, 659, 663
Freud’s neurosis views, 658–659
general psychopathology scales, 132–134
genetics, 189–200
animal models, 198–200
epidemiology, 189–192
family and twin studies, 189–195
risk factors modiﬁers, 192
hetero-evaluation scales, 135–136
immune function, 278–280
inner threat, 32
instruments assessing speciﬁc dimensions,
135
life events and development, 660–661
neuroanatomical substrates, 665–668
neurochemical basis, 668–669
neurosis, 31–32
abortiv, 31
larvit, 31
libido, 31
psyche, 31
new and emerging therapies, 779–786
objectivation, 27
personality disorders, 103–104
posttraumatic stress disorder, 215
predisposing genes, 196–199
candidate genes, 198–199
genome-wide linkage, 197–198
provocation and pathogenesis, 703–720
psychodynamic theories, 658–659
psychosis, agitated melancholia, 25
research scales, 789–804
scales assessing general anxiety, 134–135
self-assessment scales, 132
separation, 660
stress paradigm, 278–279
threat link, 35transmission modes, 192–200transmitted phenotype,continuum, 193
diagnostic speciﬁcity, 193–194
neurobiological indicators, 195–196
relationships, 194–195
under war circumstances, 23–25

812
Anxiety and depression,
AVP, 241
brain imaging, 289–311
clinical and epidemiological studies, 113
family studies, 114–115
longitudinal, 113–115
comorbidity, 69–86
conceptual history, 1–38
Ancient Greece and Rome, 3–7
Middle Ages, 7–10
Renaissance, 17th and 18th Centuries,
11–14
19th Century, 14–16
etiology, 111–145
imaging studies, 115–116
immunology, 267–281
neurobiology, 331–341, 457–484
acetylcholine, 470–471
affective disorder HPA axis, 479–482
anatomical circuits, 478
CT and MRI studies, 475–476
diagnostic conundrum, 331–333
dopamine, 468–470
functional anatomy, 337–338
molecular studies, 340–341
neurochemistry, 333–337
neuroimaging studies, 338–340
OCD etiopathogenic studies, 340
neuroendocrine mechanisms, 117–118
challenge studies, 117–118
neuropeptide alterations, 229–250
nomenclature, 2–3
normal and abnormal, 111–113
personality, 91–106
psychophysical studies, 116–117
autonomic nervous system arousal measures, 117
cardiovascular activity, 117
electrodermal activity, 116
panic provocation, 116–117
quantitative encephalographic asymmetry, 116
sleep encephalographic, 116
psychotherapy and pharmacotherapy combined, 151–157
reasons, 152–153
stress response, 208–212
stress-responsive neurohormones, 207–
221
treatment, stress-responsive neurohormones, 215–220
Anxiety diathesis, 196

IndexAnxiety disorders, 155–156, 197
antidepressants, 443–451
brain imaging, 303–310
cognitive and behavioral abnormalities,
663
corticotropin releasing factor, 237–238
epidemiology, 54–61
genetic etiology, 672–673
life events, 661
neuropeptides, rationale, 230–231
personality, 661–663
pharmacotherapy, 733–750
prevalence, 54–58
psychotherapy and pharmacotherapy, combined efﬁcacy, 155–156
TRH alterations, 240
twin and family studies, 673
Anxiety Disorders Interview Schedule(ADIS-R), 132
Anxiety neurosis, 24, 112, 114
Anxiety provocation, 703–720
benzodiazepine receptor challenges, 719
caffeine, 716
carbon dioxide, 711–714
cholecystokinin, 717–718
isoproterenol, 716–717
lactate-induced vs. natural, 705
noradrenergic mechanism, 706–708
serotonergic challenges, 718–719
sodium lactate, 704–711
yohimbine, 714–715
Anxiety psychosis, 25–27
Anxiety rating scales, 112
Anxiety Sensitivity Index, 137
Anxiety Status Inventory, 801
Anxiolytic drugs, 199
Arachidonic acid, 432
Arginine-vasopressin (AVP), 208, 240–241
Association for Methodology and Documentation in Psychiatry (AMDP-System),
136
Astrocytes, immune function, 269–270
Atenolol, 401
Atrial natriuretic peptide (ANP), 210
Attention deﬁcit hyperactivity disorder, 400
Atypical neuroleptics, bipolar disorder, 600–
602
Aversive experience avoidance, 338
Avoidance behavior, 22
AVP, 208, 240–241
Axis I disorders, 128
adult, 131Index
BAI, 103, 132, 134–135
Barbiturates, action on GABAA receptors,
428
Bcl-2, function, 360
BDI (see Beck Depression Inventory)
BDNF (see Brain-derived neurotropic factor)
BDNF/MAPK cascade, 367
Bech-Rafaelsen Melancholia Scale, 143, 800
Beck Anxiety Inventory (BAI), 103, 132,
134–135
Beck Depression Inventory (BDI), 103, 141,
630, 632, 636, 802
Bedford College Interview Schedule, 661
Beﬁndlichkeits-Skala (BFS), 142
Behavioral therapy, 152
Benzamides, dysthymia, 81
Benzodiazepine-like compounds, endogenous
ligands, 429
Benzodiazepine receptors, 421–422
Benzodiazepines, 119, 199, 415–435
addiction, 421
adverse effects, 417, 418, 419
anxiety, 35
central muscle relaxation, 419–420
commercially available, 416
dependence, 421
depression and anxiety, 80, 83, 215–216
GABAA receptors, 422–428
generalized anxiety disorder, 747
mixed anxiety/depression disorders, 760,
768–769
panic disorder, 738–739
pharmacological and clinical actions, 415–
421
plasma levels and pharmacokinetic-pharmacodynamic relationship, 420–421
receptor, 719
sedative-hypnotic actions, 418–419
social anxiety disorder, 742–743
societal costs, 417
tolerance development, 421
toxic actions, 420
withdrawal, 421
Beta-adrenergic receptor antagonists, 401
Beta-blockers, social anxiety disorder, 743
Beta-endorphin, 242
BFS, 142
Biological function, 112
Biological markers, depression, 562–568
Bipolar depression,acute treatment, 602–603
comorbidity, 76–77

813[Bipolar depression]
obsessive-compulsive disorder, 76–77
probands, affective disorders among relatives, 166
serotonin transporter gene study, 649
Bipolar disorder (BPD), 17, 21–22, 115,
154, 194, 300–303
animal models, 524
blood ﬂow and glucose metabolism studies, 302
emerging mood stabilizers, 622
epidemiology, 53
fMRI, 301–302
genetics, 170
HPT abnormalities, 240
MRI, 300–301
MRS, 301
neurobiology, 478
pharmacotherapy, 599–610, 649–650
pregnancy and breast feeding, 607–
609
radioligand studies, 302–303
rapid cycling, 603–604
therapy-refractory depression, 603
twin studies, 168
Bipolar I depression, treatment, 602
Bipolar I disorder, 170–171
long-term maintenance strategies, 604
serotonin transporter gene study, 648
Bipolar II depression, treatment, 602
Bipolar II disorder, 170–171
long-term maintenance strategies, 604–
605
serotonin transporter gene study, 648
Blood, cytokines, 270–271
Blood ﬂow, 296
bipolar disorder, 302
Blood oxygenation level detection (BOLD),
290
BOLD, 290
BPD (see Bipolar disorder)
Brain,
plasticity, 353–355
structure and function, stress, 353–355
Brain-derived neurotropic factor (BDNF),
353, 359, 473, 570–571
antidepressants, 216
brain plasticity, 367
replacement therapy, 370
stress, 473
Brain-derived neurotropic factor (BDNF)/
MAPK cascade, 367

814
Brain imaging, 289–311
affective disorders, 292–293
anxiety disorders, 303–310
healthy subjects, 303
bipolar disorder, blood ﬂow and glucose
metabolism, 302
fMRI, 290, 301–302
GAD, 303–304
MDD, 292–300
modalities, 290–292
MRI, 290, 292–294, 300–301
MRS, 290–291, 294–296, 301
OCD, 306–308
panic disorder, 304
PET, 290
phobias, 305–306
social, 305–306
speciﬁc, 305
PTSD, 308–310
functional imaging studies, 309
neurochemical studies, 309
radioligand studies, 302–303
radionuclide imaging, 291–292
SPECT, 290
structural and functional integration, 292
Brain injury, recovery, 372
Brain overload, stress, 363–368
Breast feeding, bipolar disorder, 607–609
Brief Social Phobia Scale (BSPS), 138, 743
Brief Symptom Inventory (BSI), 132–134
Bright light therapy, SAD, 105
BRMAS Mania Scale, 800
Brofaromine, posttraumatic stress disorder,
749
BSI, 132–134
BSPS, 138, 743
Bulimia, affective disorders, 172
Bupropion, 119, 398
depression, 618
smoking cessation, 618
Buspirone,
generalized anxiety disorder, 747
mixed anxiety/depression disorders, 764–
765
new anxiety therapies, 780–781
social anxiety disorder, 743
Caffeine, 199
Calcium channel blockers, bipolar disorder,
600–602
Calcium response element-binding protein(CREB), 353, 355–357, 359, 570

Index
Calgary Depression Scale for Schizophrenia(CDSS), 144
CAMP-responsive element (CRE), 357
CAMP signal transduction cascade, 353, 359
Candidate genes, 174, 176, 198–199, 645
Candidate regions, 176
CAPS, 141
Carbamazepine, bipolar disorder, 600–602,
622
Carbon dioxide,
animal studies, 713
anxiety provocation, 711–714
additional response explanations, 714
autonomic symptoms, 712
biological changes, 713
diagnostic speciﬁcity, 712–713
etiology, 713–714
hyperventilation, 711
photophobia, 711
rebreathing technique, 711
Cardiovascular abnormalities, stress, 369
Catecholamine anxiety hypothesis, 668
Catecholamines,
depletion studies, 546, 548–549
depression, 548–549
healthy subjects, 548
PTSD, 335
Cattel 16 Personality Factor Questionnaire,
662
CBASP, 154
CCK (see Cholecystokinin)
CDS, 587
NIMH, 75
CDSS, 144
Center for Epidemiologic Studies Depression
Scale (CES-D), 141–142
Center-periphery model, 21
Central nervous system,
cytokines, 269, 270–271
estrogen, 373–374
immune function, 269–270
NA, 388
regional, 355
Cerebrospinal ﬂuid, 231, 387
NA, 392
CES-D, 141–142
C-fos, 355–357
CGI, 643, 798
CGI-I, 631, 633
CGI-S, 631
Change points, 584–585
Chemical neurotransmission theory, 389

IndexCholecystokinin (CCK), 231anxiety provocation, 717–718
behavioral effects, 718
biology, 247–248
panic disorders, 248
Cholinergic hypothesis, depression, 572
Cholinesterase inhibitors, bipolar disorder,
600–602
Chronic depression, 586
Chronic fatigue syndrome, psychasthenia, 29
Chronic mild stress (CMS), 509–510
Chronic stress, 515–518
CIDI, 51, 131
Citalopram, 399
depression, 617
generalized anxiety disorder, 744
mixed anxiety/depression disorders, 763,
767
panic disorder, 734
personality disorder, 102
social anxiety disorder, 739–744
Civilian Mississippi Posttraumatic Stress Disorder Scale, 140–141
Claustrophobia, 22
CLH, 512–513
Clinical Evaluation Guide, 130
Clinical Global Impression (CGI), 643, 798
Clinical Global Impression Scales for Improvement (CGI-I), 631, 633
Clinical Global Impression Scales for Severity (CGI-S), 631
Clinician-Administered PTSD Scale (CAPS),141
Clomipramine, 398, 401
anxiety disorders, 155
depression, 83, 277
OCD, 445, 447
Clonazepam, panic disorder, 738
Clonidine, 118, 119, 401
growth hormone response, 394
Cloninger’s psychobiological theory, 92
Clozapine, bipolar disorder, 600–601
CMS, 509–510
CNP, 210
Cognitions Questionnaire (CQ), 636
Cognitive behavioral analysis system of psychotherapy (CBASP), 154
Cognitive behavioral therapy, 152, 153–156,663
CO2 inhalation, 195–196
Collaborative Depression Study (CDS), 587
NIMH, 75

815
Collaborative Study on Psychological Problems in General Health Care
WHO, 74
Coma, 419
Comorbidity, 113–114
anxiety risk-modifying factor, 192
bipolar depression, 76–77
bipolar disorder, 601
classiﬁcation approaches, 70–71
clinical descriptions and symptom clusters,
74–84
clinical samples, 77–79
concepts and deﬁnitions, 69–71
depression,and alcoholism, 172
and anxiety, 62, 332–333
clinical samples, 77–79
and panic disorder, 61–62
dysthymic disorder, 80–81
epidemiology, 61–63
generalized anxiety disorder, 77
general neurotic syndrome, 62
implications and guidelines, 84–85
spectrum model, 73–74
substance abuse, 601
syndromal and subsyndromal, 71–74
theoretical models, 71
treatment response, 79–80
types, 70
Complaint List, 804
Composite International Diagnostic Interview(CIDI), 51, 131
Comprehensive Psychopathological Rating
Scale (CPRS), 136
Compulsive gambling, 565
Computed tomography (CT), 475–476
Conditioned fear, 338
Conditioning theory, 663
Conﬂict tests, animal models, 687–688
Congenital learned helplessness (cLH), 512–
513
Construct validity, animal models, 508–
510
Contextual fear, 338
Continuation period, relapse, 587–588
Continuation treatment, 584, 587–588
bipolar disorder, 604
Continuum model, 21
Convulsants, action on GABAA receptors,
428
CORE system, 143
Correlation model, animal models, 681

816
Corticotropin releasing factor (CRF), 117,
118, 232, 479–480
anxiety disorder, 237–238
depression, 562–564
extrahypothalamic, depression, 236–237
mood and anxiety disorders, 232–238
stimulation test, 235–236
Corticotropin releasing hormone (CRH),
208–210, 232, 527
depression, 620–621
receptors, 208–210
subtypes, 234
Cortisol, 117–118
CPRS, 136
CQ, 636
CRE, 357
CREB, 353, 355–357, 359, 570
CRF (see Corticotropin releasing factor)
CRH (see Corticotropin releasing hormone)
Cronholm-Ottoson Depression Scale, 143,
800
Cross-National Collaborative Panic Study,
738
CT, 475–476
C-type natriuretic peptide (CNP), 210
Cushing’s disease, 567, 571
Cushing’s syndrome, 230
Cyclical mood swings, 15
Cyclothymia, 22, 170
CYP2 enzymes, drug metabolism, 646
Cytochrome P450 (CYP2) enzymes, drug
metabolism, 646
Cytogenetic techniques, 177
Cytokines,
antidepressant, 276–278
antidepressants, 574–576
blood, 270–271
CNS, 269, 270–271
depression, 575
etiological role in depression, 575
major depression, cellular immune system,
274–275
Da Costa syndrome, 23
Darier’s disease, 176
DAS, 636
DBI, endogenous ligands, 429
DCR, 129
Delusional depression, 523
Dementia praecox, 15, 17, 26
Demethylated epinephrine (see Norepinephrine)

Index
Deoxycorticosterone (DOC), anxiety, 211
Depression, 584–585 (see also Anxiety anddepression; Depressive disorders)assessment instruments, 141–145
biological markers, 562–568
change points, 584–585
cholinergic hypothesis, 572
classiﬁcation debate, 21–22
clinical and economic impact, 561
course, 53, 586–593
delusional animal models, 523–524
early-onset, 169–170
endogenous opioid peptides, 242–243
epidemiology, 53
extrahypothalamic CFR, 236–237
forced-swim model, 571
full remission and recovery, 634–637
genetics, 165–179, 351–352
growth hormone, 245–246
HPA axis abnormalities, 235–236
immune function disorder, 574–576
immune pathologies, 275–276
intracellular signaling transduction dysregulation, 349–375
monoamine hypothesis, 349–351
stress-BDNF hypothesis, 357–363
stress-induced brain overload, 363–368
intracellular signal transduction pathways,
473–475
late-onset, 169
learned helplessness model, 571
longitudinal course modiﬁers, 585–586
macrophage hypothesis, 575
neurobiology studies, 457–484
neuroendocrine axis changes, 562–568
neurotrophic factors, 475
neurotrophic hypothesis, 571
panic disorders, 61–62
pathogenesis, 545–555
personality disorders, 102–103
pharmacotherapy, 216–218, 443–451,
583–595
prevalence, 53
proinﬂammatory cytokines, 575
recurrent, 586
research scales, 789–804
stress, 351–352, 473–475
subthreshold form treatments, 593
subtypes, animal models, 505–529
thyroid axis, 238–240
thyroid dysfunction, 239
thyrotropin-releasing factor, 238–240

Index[Depression]
treatment, 586–593
future, 368–374
new options, 621–623
pharmacotherapy, 213, 246–247, 583–
595, 617, 618, 622
Depression rating scales, 112
Depressive disorders, 153–155
life events, 661
psychotherapy and pharmacotherapy, combined efﬁcacy, 153–155
Depressive neurosis, 36, 112
Depressive personality disorders, 170
Deramciclane,
depression, 622
new anxiety therapies, 781
Desipramine,
clinical efﬁcacy proﬁle, 397–398
depression, 237
OCD, 445
PTSD, 447
Dexamethasone,
depression, 213
major depression, 217
Dexamethasone/corticotropin releasing factor(CRF) test, HPA, 236
Dexamethasone suppression test (DST),
117–118, 213, 450
DHPG, 460–462
Diagnosis Interview Schedule (DIS), 131
Diagnostic and Statistical Manual of Mental
Disorders (DSM), 51, 113, 131
Diagnostic and Statistical Manual of Mental
Disorders-III (DSM-III), 131
personality disorder, 662
Diagnostic and Statistical Manual of Mental
Disorders-IV (DSM-IV), 585
melancholia, models, 510–511
Diagnostic Criteria for Research (ICD-10DCR), 129
Diagnostic Interview for Genetic Studies(DIGS), 132
Diazepam, 434
Diazepam binding inhibitor (DBI), endogenous ligands, 429
DIGS, 132
Dihydroxyphenylglycol (DHPG), 460–
462
Direct kinase activity targeting, 370–371
DIS, 131
Dizocilpine, 783
DOC, anxiety, 211

817
Dopamine, 299–300, 387, 468–470
deﬁciency, 469
ECS, 469
major depressive disorder, 299–300
neuroimaging studies, 470
preclinical studies, 469
Dopamine 3 receptor (DRD3), 95
Dopamine 4 receptor (DRD4), 94
Double depression, 592
Doxepin, depression, 401
DRD3, 95
DRD4, 94
Drug metabolism,
cytochrome P450 enzymes, 646
genetic variation in enzymes, 645–646
pharmacokinetic variability, 646
DSM, 51, 113, 131, 132
DSM-III, 131
personality disorder, 662
DSM-IV, 585
melancholia, models, 510–511
DST, 117–118, 213, 450
Dysfunctional Attitude Scale (DAS), 636
Dysthymia, 22, 36, 170, 332, 585–586, 595
epidemiology, 53–54
pharmacotherapy, 594
prevalence, 53–54
Dysthymic disorder, 153 (see also Minor depression)
comorbidity, 80–81
Early-onset bipolar disorders, genes and environment, 173
Early-onset depression, MRI, 293–294
Eating disorders, affective disorders, 172
ECA, 51, 75, 76, 332–333
ECS, 363, 506
dopamine, 469
ECT, 237
depression, 20
neurotrophin signaling pathway, 362–363
Edinburgh Postnatal Depression Scale, 143
Effectiveness, vs. efﬁcacy, 568
Efﬁcacy,
antidepressants, 568–569
clinical trial limitations, 568
vs. effectiveness, 568
real world, 568
Effort phobia, 25
Effort syndrome, 24Electroconvulsive shock (ECS), 363, 506
dopamine, 469

818Electroconvulsive therapy (ECT), 237
depression, 20
neurotrophin signaling pathway, 362–363
Elevated plus maze, 684–685
animal studies, 434
Emerging mood stabilizers, bipolar disorder,
622
Emotional response, 112
Encephalopathy, 602
Endocrine studies, 479–482
Endogenous depression, genetic factor study,
644
Endogenous ligands, 428–432
acting via benzodiazepine binding site,
428–429
acting via GABAA receptor sites, 420–432
increase in neuropsychiatric diseases,
429–430
Endogenous neuroactive steroids, 430–432
Endogenous opioid peptides, 242–243
biology, 242
depression, 242–243
Endorphin, 242
Enzyme monoamine oxidase (MAO),GABAA receptors, 432
Epidemiological Catchment Area (ECA), 51,
75, 76, 332–333
Epidemiological study methodology, 49–53
diagnostic and interview technique, 51–53
health-care utilization, 63–64
interview manuals, 50–51
discrepancies, 52–53
exaggerations, 52
prevalence rates, 49–50
animal prevalence, 50
lifetime prevalence, 49
point prevalence, 50
representativity, 50–51
door-knock survey, 50
Epilepsy, 7, 417
Episode, deﬁnition, 584
EPS, 765
ER, 373
ERK, 371
function, 360
neuronal plasticity and survival, 371
ERKs, 358–359
ERT, depression, 373–374
Escitalopram, depression, 617
Estrogen,
CNS function, 373–374
neural plasticity, 372–373

Index
Estrogen receptors (ER), 373
Estrogen replacement therapy (ERT), depression, 373–374
Ethanol, action on GABAA receptors, 428
Existential anxiety, 664–665
Existentialism, 664–665
Exposure therapy, 155–156
Extrapyramidal side effects (EPS), 765
Face validity, animal models, 507–508
Familial clustering, mood disorders, 165–167
Familial genetic inﬂuences, unipolar depression, 169–170
Family studies, 114
Fatigue syndrome, 25
Fear,conditioned, 338
contextual, 338
public speaking, 22
Fear of anxiety, 23
Fear-potentiated startle, 687
Fear Questionnaire, 132, 135, 743
Feighner Criteria, 36
Fenﬂuramine,anxiety provocation, 719
panic disorder, 449
Fiske Big Five personality factors model, 92
5HT (see Serotonin)
Flesinoxan,
depression, 618
new anxiety therapies, 781
Flinders Sensitive Line (FSL) rat, 522–523
Floppy infant syndrome, 609
Flumazenil, 432
Fluoxetine,
depression, 79, 80, 237, 277, 444, 446, 617
dysthymia with depression, 81
generalized anxiety disorder, 744
major depression, 218, 635
MDE, OCD, and panic disorder, 399
mixed anxiety/depression disorders, 762,
767
panic disorder, 734–735
personality disorders, 98, 102
posttraumatic stress disorder, 747–748
social anxiety disorder, 740
unipolar major depression, 643
Fluvoxamine,anxiety disorders, 155
depression, 79, 617
generalized anxiety disorder, 744
major depression, 648

Index[Fluvoxamine]
MDE, OCD, and panic disorder, 399
mixed anxiety/depression disorders, 762–
763
OCD, 445
panic disorder, 735–736
pindolol combination study, 647
social anxiety disorder, 740
FMRI, 290
bipolar disorder, 301–302
PTSD, 309
Forced-swim model, depression, 571
Forced-swim test, 513–515
Four humors theory, 3–6
Free-ﬂoating anxiety, 31, 659, 663
FSL rat, 522–523
Full remission, 584
Functional magnetic resonance imaging(fMRI), 290
bipolar disorder, 301–302
PTSD, 309
GABA (see γ-aminobutyric acid)
Gabapentin, social anxiety disorder, 743
GAD (see Generalized anxiety disorder)
Galen, melancholia, 5–6
Gambling, compulsive, 565
γ-aminobutyric acid (GABA), 119, 471
depression, 572–573
inhibitory synaptic transmission, 471
new anxiety therapies, 782–785
γ-aminobutyric acid (GABA)A receptors,
anesthetics, 428
barbiturates, 428
benzodiazepine, 422–428
convulsants, 428
endogenous ligands, 420–433
enzyme monoamine oxidase, 432
GABA, 424
imidazoleacetic acid, 432
melatonin, 431
model, 423
neuroactive steroids, 428
neuronal growth factors, 431
platelet-derived growth factor, 431
polyamines, 432
somatostatin, 431
stoichiometry and subunit arrangement,
424
subtypes, 432–434
animal studies, 433–435
thyroid hormones, 431

819
γ-aminobutyric acid (GABA)-benzodiazepine
system, anxiety, 670–672
GAS, 636
GDS, 144
Gender,anxiety risk-modifying factor, 192
frontal lobe RCAF, 364–365
genetic factors, 167
higher limbic regions, animal studies,
363–368
overload threshold hypothesis, 365
Gene-dose effect, 192
Gene expression regulation, stress, 355–357
Gene knockout strategies, 671
General Health Questionnaire (GHQ), 132–
133
General Health Questionnaire-12 (GHQ-12),
133
General Health Questionnaire-28 (GHQ-28),
133
Generalized anxiety disorder (GAD), 36,
114, 118, 119, 152, 394
brain imaging, 303–304
combined therapy, 155comorbidity, 77
epidemiology, 60–61
immune function, 279–280
neurochemistry, 333–334
new therapies, 780
pharmacotherapy, 744–747
symptoms, 332
General Neurotic Syndrome, 673
Genetic association studies, 176–177
Genetic imprinting, 178
Genetic risk factors,
additive model, 352
depression, 351–352
sensitivity to environment model, 352
Genetics, 114
affective disorder subtypes, 170–171
anxiety, 189–200
depression, 165–179
mood disorders, 167–169, 458–459
Genome-wide linkage, 174–175, 197–198
Gepirone,depression, 618
mixed anxiety/depression disorders, 765
new anxiety therapies, 781
Geriatric Depression Scale (GDS), 144
GHQ, 132–133
GHQ-12, 133
GHQ-28, 133

820
GHRH, 394
Gilles de la Tourette syndrome, 394
Global Assessment Scale (GAS), 636
Global Burden of Disease Study, 458
Glucocorticoid receptors, 211–212
blockade, 219
Glucocorticoids, 211–212
Glucose metabolism, bipolar disorder, 302
Glutamate, 471–473
excitotoxicity, 471–472
functional imaging, 472
MNDA, 472–473
new anxiety therapies, 782–783
post-mortem studies, 472
Group psychoeducation, 25
Growth hormone, 244–247
biology, 244–245
depression, 245–246
Growth hormone releasing hormone(GHRH), 394
GSK-3, function, 360
HADS, 132, 134
Halo effect, 796
HAM-A, 398, 735, 784, 801
HAM-D, 79, 105, 142, 398, 643, 797–802
Hamilton and Montgomery-Asberg rating
scales, 132
Hamilton Anxiety Rating Scale (HARS),
135, 620
Hamilton Anxiety Scale (HAM-A), 398, 735,
784, 801
Hamilton Depression Rating Scale (HDRS),
620, 630, 632, 633–634, 636,
758
Hamilton Depression Scale (HAM-D), 105,
398, 643, 797–802
Hamilton -17 item scale, 143
Hamilton Rating Scale for Depression(HAM-D), 79, 142
Haplotype analysis, 175
Haplotype relative risk (HRR) method, 651
HARS, 135, 620
HDRS, 620, 630, 632, 633–634, 636, 758
Heart neurosis, 24
Hepatic encephalopathy, 429
5-HIAA, 466
Hippocampus, stress, 475
Homology, 681–682
Hopkins Symptom Check List, 804
Hospital Anxiety and Depression Scale(HADS), 132, 134

Index
HPA axis, 117, 233, 450, 479–482, 527, 708
animal models, 117
axis abnormalities, 235–236
combined dexamethasone/CRF test, 236
PTSD, 336
stress abnormalities, 369–370
HPO axis, 482
HPT axis, 482
stress abnormalities, 369
HRR method, 651
5HT (see Serotonin)
Human gene sequence, 641–642
Huntington’s disease, 370
Hydroxybupropion, 398
5-hydroxyindolacetic acid (5-HIAA), 466
Hypercortisolemia, 369, 479, 574
major depression association, 564
Hyperdynamic beta-adrenergic condition, 25
Hyperforin (see St. John’s Wort)
Hypericum perforatum, 511, 618–619
depression, 618–619
Hyperkinetic heart syndrome, 25Hyperosmolar ﬂuid, 709
Hyperventilation, 195–196
carbon dioxide, 711
Hypocampus, 355
atrophy, 362
Hypoglycemia, 710
Hypomanic episodes
acute treatment, 600–602
Hypothalamic-pituitary-adrenal (HPA) axis,
117, 233, 450, 479–482, 527, 708
animal models, 117
axis abnormalities, 235–236
combined dexamethasone/CRF test, 236
PTSD, 336
stress abnormalities, 369–370
Hypothalamic-pituitary-ovarian (HPO) axis,
482
Hypothalamic-pituitary-thyroid (HPT) axis, 482
stress abnormalities, 369
Iatrochemistry, melancholia, 11, 13
Iatromechanics, melancholia, 12, 13
ICD-10, 51, 758
ICD-10-DCR, 129
ICSS, 512, 518–519
Idiopathic recurrent stupor, 430
IDS-C, 762
IEGs, 355–357
IES, 140
IL-1, 281

IndexIL-6, 281
major depression, 274–275
Imidazenil, 427
Imidazoleacetic acid, 432
Imipramine, 199
agoraphobia, 35
depression, 83, 154, 155
dysthymia, 81
genetic factor study, 644
mixed anxiety/depression disorders, 767
OCD, 445
panic disorder, 79, 83, 444, 446–447
Immediate early genes (IEGs), 355–357
Immune function, 483–484
anxiety, 278–280
GAD, 279–280
innate and adaptive, 270–272
panic disorder, 280
Immune function disorder, 574–576
Immune system,components, 272
helper cells, 272
Immunology, 267–281
Impact of Event Scales (IES), 140
Impulsivity, suicide, 105–106
Innate immunity, 271–272
Intercranial self-stimulation (ICSS), 512,518–519
International Classiﬁcation of Diseases (ICD10), 51, 758
Interpersonal psychotherapy (ITP), 152–154
Intracellular signaling transduction dysregulation,
depression, 349–375
monoamine hypothesis, 349–351
stress-BDNF hypothesis, 357–363
stress-induced brain overload, 363–368
future treatment opportunities, 368–374
stress and brain dysfunctions, 351–357
stress-BDNF hypothesis, 357–363
stress-induced brain overload, 363–368
Intracellular signal transduction pathways,
473–475
brain-derived neurotropic factor, 473
depression, 473–475
morphometric neuroimaging studies, 474–
475
morphometric studies, 474
post-mortem studies, 473–474
stress and depression, 473–475
Inventory of Depressive SymptomatologyClinician rated (IDS-C), 762

821
Ipsapirone, depression, 618
Irritable heart, 23, 28, 716
Isomorphism, 681–682
Isoproterenol,
anxiety attacks, 669
anxiety provocation, 716–717
irritable heart syndrome, 716
ITP, 152–154
James-Lange anxiety theory, 658, 663
James-Lange emotions theory, 33, 35
James Lange peripheral anxiety model, 669
Karolinska scales of personality, 95
Ketamine, major depression, 572
Kindling hypothesis, 600, 622
Klein’s suffocation theory in panic disorder,
659
Kluver-Bucy syndrome, 667
Kraepelin, Emil, 16–18
Kynurenine (see Serotonin)
L-838.417, 427
Lactate infusion, 195–196
Lactate infusion and CO2 inhalation challenge studies,
GAD, 333
panic disorder, 334
SAD, 335
Lamotrigine, bipolar disorder, 622
Late-onset depression, MRI, 293
LC,anatomy, 388
function, 390–391
neurons, 388
LD, 645
L-dihydroxy-phenylalanine (L-DOPA), 389
Learned helplessness model, 511–512
depression, 571
Leyton Obsessional Inventory, 139–140
LHRH, 243
Liebowitz Social Anxiety Scale (LSAS),
138, 802
Ligands,
action on GABAA receptors, 424–428
endogenous, 428–432
Light-dark choice test, animal studies, 434
Light-dark exploration test, 682–683
Light therapy, 554–555
Limbic-thalamo-cortical (LTC) activity,
478–479
Linkage disequilibrium (LD), 645

822
Lithium, 178bipolar disorder, 599–602, 622, 649–650
depression, 20
neurotrophin signaling pathway, 360–361
responsiveness, 649–650
Locus coeruleus (LC),anatomy, 388
function, 390–391
neurons, 388
Lofepramine, panic disorder, 444, 446
Long-term maintenance strategies,
bipolar I disorder, 604
bipolar II disorder, 604–605
LSAS, 138, 802
LTC activity, 478–479
Luteinizing hormone-releasing hormone(LHRH), 243
Lymphocytes, NA, 392–393
MacArthur Foundation task force, 584
Macrophage hypothesis, 575
depression, 575
MADRS, 143, 632, 800–801
Magnetic resonance imaging (MRI), 290,
475–476bipolar disorder, 300–301
GAD, 303–304
OCD, 307, 339
panic disorders, 304
PTSD, 308, 339, 340
social anxiety disorder, 305
Magnetic resonance spectroscopy (MRS),
290–291, 294–296
bipolar disorder, 301
OCD, 307
panic disorders, 304
phosphorus, 291
proton, 291
SAD, 338–339
Maintenance treatment, deﬁnition, 584
Major depressive disorder (MDD), 194,
292–300, 355, 400, 478, 585–586
acute episode treatment, 587
acute phase proteins, 274–275
antidepressants, 635
blood ﬂow and metabolism, 296–297
brain imaging, 292–300
blood ﬂow and metabolism, 296–297
dopamine transmission, 299–300
early-onset, 293–294
late-onset, 293
neuroceptor studies, 297–300
serotonin transmission, 297–299

Index[Major depressive disorder (MDD)]
change points,
deﬁnitions, 630
operational criteria, 631
response, 632–633
chronic, 590–592
risk, 590
treatment, 590–592
comorbidity, 77–80
dopamine transmission, 299–300
full remission and recovery, 634–637
genetic factor study, 644
helper cells and suicidality, 272–273
IL-6, 274–275
morbidity and mortality, 586–587
MRI, 292–294
MRS, 294–296
neuroceptor studies, 297–300
neurochemistry, 336–337
outcome deﬁnitions, 630–632
partial remission, 633–634
probands, affective disorders among relatives, 166
reboxetine, 398–399
recurrent, 588–590
risk, 588
treatment, 588
regional blood ﬂow and metabolism, 296–297
serotonin transmission, 297–299
serotonin transporter gene study, 647
stress-responsive neurohormones, 213–214
symptomatic overlap, 332
symptoms, 332, 637
TH-1 cytokines, 273–274
TH1/TH2 responses, 276
treatment outcome, 629–638
Mania, 649
acute treatment, 600–602
antidepressant-induced, 649
melancholia, 6–7
Manic depressive disorder, 15, 17, 18, 26,
114, 355
MAO, 432
MAOIs (see Monoamine oxidase inhibitors)
Maprotiline, panic disorder, 446
Mastery of your Anxiety and Panic II, 137
Maudsley Obsessional Compulsive Inventory(MOCI), 140
Maudsley Personality Scale, 662
MBTI, 96
M-chlorophenylpiperazine (mCPP), 118
mCPP, 118
anxiety provocation, 718

Index
MDD (see Major depressive disorder)
Measurements, 127–145
Medical Research Council of the United
Kingdom, 444
MEK1, 358–359
function, 360
Melancholia, 3–22, 170affective reaction type, 18–19
alchemy, 11astrology, 10–11
empirical school, 10
endogeny and exogeny dichotomy, 19
Galen’s three forms, 5–6, 13
genius characteristic, 10–11
iatrochemistry, 11, 13
iatromechanics, 12, 13
ideational insanity, 14
mania, 6–7
neurocentric approach, 13
non-naturalia regulation, 9–10
partial insanity concept, 14
passions’ dichotomy, 11–12
polypharmacy, 9
psychogenic causes, 7
psychology and psychoanalysis, 19–20
reaction type vs. endogeny, 18–19
simple, 15
solidism, 13
with stupor, 15
temperaments and elements doctrine, 11
treatment, 6
unitary psychosis concept, 16
vasocentric approach, 13
Melatonin, action on GABAA receptors, 431
Menopausal depression, 372
Metabotropic G-protein glutamate receptors(mGluR), new anxiety therapies,
783–784
Metachlorophenylpiperazine (mCPP), anxiety
provocation, 718
3-methoxy-4-hydroxyphenylglycol (MHPG),
460–462
Methyl-para-tyrosine, 395–396
depression, 546, 548–549
Metropolol, 401
MGluR, new anxiety therapies, 783–784
MHPG, 460–462
Mianserin, mixed anxiety/depression disorders, 768
Microglia, immune function, 270
Mifeprex, 481
Mifepristone (Mifeprex), 481
Milnacipran, depression, 618

823
MinD, 593
symptoms, 637
Mineralocorticoid receptors, 211
Mini-International Neuropsychiatric Interview (MINI), 51, 131
Minnesota Multiphasic Personality Inventory(MMPI), 96
Minor depression (MinD), 593
symptoms, 637
Mirtazapine,
depression, 400–401, 618
generalized anxiety disorder, 746–747
mixed anxiety/depression disorders, 764,
768
Mississippi Scale (MSS), 140
Mitochondrial transmission, 178
Mitogen-activated extracellular kinase/mitogen-activated protein kinase(MEK1/ERKs), 358–359
Mixed anxiety/depression disorders, 73
adult population treatment, 760–765
clinical perspective, 758–759
commonly used antidepressants, 759
elderly population treatment, 765–769
clinical and pharmacological problems,
766
pharmacotherapy, 757–771
symptoms spectrum, 758
Mixed episodes, acute treatment, 600–602
MK869,
depression, 620
new anxiety therapies, 784–785
MMPI, 96
Mobility Inventory for Agoraphobia (MI), 138
MOCI, 140
Moclobemide,depression, 618
depression with comorbid anxiety disorders, 79–80
dysthymia with depression, 81
Monoamine, depletion, 351, 545–546, 550–
552
Monoamine hypothesis, 569
depression, 349–351
problems, 350–351
Monoamine oxidase inhibitors (MAOIs), 397
depression, 444, 448, 469
general anxiety disorder, 79
genetic factor study, 644
mixed anxiety/depression disorders, 761
panic-agoraphobic, 79
random controlled trials (RCT), 616
social anxiety disorder, 741–742

824
Monoamine oxidase (MAO), 432
Monoamine receptor adaptation hypothesis,
570
Monomania, 15Montgomery-Asberg Depression Ratings
Scale (MADRS), 143, 632, 800–
801
Mood disorders,
adoption studies, 459
alcoholism, 172
CRF, 232–238
family studies, 458–459
genetics, 165–173, 458–459
neurobiology,
adoption studies, 459
family studies, 458–459
twin studies, 459
neurodegeneration, 482
pharmacogenetics, 641–654
study design for, 650–653
twin studies, 459
Mood disorder syndrome, 114–115
Mood stabilizers,
emerging opportunities, 622–623
future, 622
medical complications, 607
patients over 65, 607
pharmacogenetics, 649–650
side effects, 605–606
suicide risk, bipolar disorder, 609–610
MPQ, 93
MRI (see Magnetic resonance imaging)
MRS (see Magnetic resonance spectroscopy)
MSS, 140
Multidimensional Personality Questionnaire(MPQ), 93
Munich Follow-up Study, 75
Munich Vulnerability Study, 214
Muscarinic hypersensitivity breeding, 522–
523
Myers-Briggs Type Indicator (MBTI), 96
NA (see Noradrenaline)
National Comorbidity Survey (NCS), 52, 76,
131, 332, 629
National Institute of Mental Health (NIMH),
Center for Epidemiological Studies, 131
Collaborative Study on the Psychology ofDepression, 75, 128, 462
Natriuretic peptides, 208–210, 220
N-butyl-β-carboline-carboxylic acid ester, endogenous ligands, 429

Index
Nefazodone,
depression, 154, 618
generalized anxiety disorder, 746
mixed anxiety/depression disorders, 765
posttraumatic stress disorder, 749
PTSD, 447
Neonates,
antidepressants, 521–522
isolation, 524–525
NEO-PI-R, 96
Neopterin, 274
Netamiftide, treatment-resistance depression,
620
Neurasthenia, 27–29, 31
degeneration theory, 28
electriﬁcation process, 28energy conservation law, 28
irradiation, 28
natural force concept, 28
nervous force deﬁciency, 27
reﬂective nerve impulse transport hypothesis, 28
Neuroactive steroids, 211–212
action on GABAA receptors, 428
Neurocirculatory asthenia, 24
Neuroendocrine axis,
Changes,brain structure, 566–567
CRF, 562–564
serotonergic neurotransmission, 565–
566
sleep architecture, 566
somatostatin, 564–565
depression, 562–568
enzyme polymorphisms, 567
Neuroendocrine challenge study, noradrenaline system, 393–394
Neuroendocrine window strategy, 230
Neuroimaging studies, depression, 475–479
Neurokinins, 244
Neuroleptics,
Atypical, bipolar disorder, 600–602
personality disorders, 100
Neurons, immune function, 269–270
Neuropeptides,
alterations, 229–250
panic disorder, 334role, 231–232
Neuropeptide Y (NPY), 243
Neuroplasticity,
estrogen, 372–373
NA system, 390

Index
Neurosteroids, 783
Neurotic anxiety, 32
Neuroticism, SAD, 105
Neurotic syndrome, comorbidity, 72
Neurotransmitter depletion challenge study,
noradrenaline system, 394–397
Neurotransmitter hypothesis, 460–473
adrenergic receptors, 460–464
norepinephrine, 460–464
Neurotransmitters,
antidepressants, 561–577
catecholamine depletion, 546
depression, 548–549
effects, 549
healthy subjects, 548
state-related changes, 549
studies, 548–549
depletion paradigm data, 545–555
monoamine depletion studies, 550–552
monoamines role, 545–546
tryptophan depletion, 546–548
Neurotransmitter systems challenge studies,
SAD, 335
Neurotrophic factors, depression, 475
Neurotrophic hypothesis, 571
depression, 571
Neurotrophin,signaling pathway members, survival andantidepressants, 359–363
synaptic plasticity hypothesis, 359
transduction pathways, 357–359
Neurotrophin-3, 431
Newcastle Diagnostic Scales, 131
NIMH,
Center for Epidemiological Studies, 131
Collaborative Study on the Psychology ofDepression, 75, 128, 462
Nimodipine, bipolar disorder, 600
N-methyl-D-aspartate (NMDA), 472–473
receptor clinical studies, 572
Nonagitated depression, 117
Nonaminergic neurotransmitters, antidepressants, 571–573
Non-major depression, 592–593
Nonmelancholic depression, 523
Nonpainful stressors, animal models, 682–687
Nonpsychotic affective disorders, 171
Noradrenaline (NA) system, 387–404
anatomy, 388
biochemistry, 389
challenge studies, 393–397
humans, 391–401

825[Noradrenaline (NA) system]
locus coeruleus function, 390–391
metabolites, 392
neuroplasticity, 390
physiology and pharmacology, 389–390
post-mortem studies, 393
receptors, 392–393
receptors agonists and antagonists, 400–
401
treatment studies, 397
urine, plasma, and CSF levels, 392
Noradrenergic function,
GAD, 333
OCD, 335
Noradrenergic system,
anxiety, 668–669
anxiety provocation, 706–708
Norepinephrine, 119, 387–404, 460–464
noradrenaline system, 387–404
Norepinephrine and adrenergic receptors,
460–464
noradrenergic dysfunction, 463
receptor subtypes, 464
urinary research, 462–463
Norepinephrine reuptake inhibitors (NRIs),
350
clinical differences between SSRIs, 399–
400
neurotrophin signaling pathway, 361–362
vs. SSRIs, 399–400
Nortriptyline, 153, 154
depression, 83
mixed anxiety/depression disorders, 767
OCD, 445
NPY, 243
NRIs (see Norepinephrine reuptake inhibitors)
Observer rating scales, 792–802
Obsessive compulsive disorder (OCD), 116,
152, 394, 398, 399, 400
antidepressants, 445–446
mechanisms of action, 449
assessment instruments, 139–140
bipolar depression, 76–77
brain imaging, 306–308
combined therapy, 155
epidemiology, 60
etiopathogenic studies, 340
mCPP provocation, 718
MRI, 339
neurochemistry, 335
tryptophan depletion, 780

826
OCD (see Obsessive compulsive disorder)
Oedipus complex, 659, 660
Olanzapine, bipolar disorder, 600
Olfactory bulbectomy, 525
Operational criteria, 631
Outcome, deﬁnitions vs. time course, 637
Overload threshold hypothesis, 365
Oxcarbamazepine, bipolar disorder, 622
Oxytocin, 230, 241
P53, function, 360
Painful stressors, animal models, 686–689
PANDAS, 340
Panic-agoraphobic spectrum, 73
Panic and Agoraphobia Scale (PAS), 137,
802
Panic-Associated Symptom Scale (PASS),
136–137
Panic attacks, 397
imipramine, 83
paroxetine, 83
Panic disorders, 36, 114, 115, 152, 197, 199,
338, 394, 398, 399, 400
antidepressants, 216–218, 446–447
mechanisms of action, 449–450
anxiolytic activity of ANP, 220
brain imaging, 304
carbon dioxide provocation, 712–713
cholecystokinin, 248, 717
cognitive model, 663–664
combined therapy, 155
course, 57
cross-cultural differences, 57–58
depression, 61–62
epidemiology, 56–58
functional anatomy, PET, 338
immune function, 280
instruments, 136–138
life events, 661
and major depression, 77
mCPP provocation, 718
negative feedback loops, 215
neuropeptides, 334
personality disturbances, 662
pharmacotherapy, 733–739
stress-responsive neurohormones, 214–215
yohimbine anxiety response, 669
Panic Disorder Severity Scale (PDSS), 137
Panic provocation studies, 116–117
Panic vulnerability, 117
Paranoid Depression Scale, 802
Paraventricular hypothalamus, 208

IndexParaventricular nucleus, 233
Parental Bonding Instrument (PBI), 660
Parent-of-origin effects, 178
Parkinson’s disease, 387
Paroxetine,anxiety disorders, 155
depression, 83, 617, 620
with comorbid anxiety disorders, 79–80
generalized anxiety disorder, 744–745
major depression, 648
MDE, OCD, and panic disorder, 399
mixed anxiety/depression disorders, 763,
767
panic attacks, 83
panic disorder, 736–737
posttraumatic stress disorder, 748
serotonin transporter gene study, 647
social anxiety disorder, 740–741
unipolar major depression, 643
PAS, 137, 802
PASS, 136–137
Paykel’s Clinical Interview for Depression,
635
PBI, 660
PDQ-R, 102
PDS, 141
PDSS, 137
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal
infections (PANDAS), 340
Penn State Worry Questionnaire (PSWQ),
132, 135
Peptides, anxiety, 784–785
Periaqueductal gray matter, 449
Perinatal stress, 522
Personality, 91–106, 661–662
anxiety, 106
anxiety disorder, 661–663
anxiety related traits, 104–105
anxious vs. depressed, 662
assessment instruments, 96–97
basic dimensions, 92
big ﬁve factors, 92
biological aspects, 93–96
depression, 104–106
DRD3, 95
DRD4, 94
environmental effects, 93–94
genetics, 93–96
5-HTTLPR, 94
models, 92
molecular genetics, 94Index[Personality]
multiple gene interactions, 94–95
psychosocial aspects, 96
serotonergic function, 95
speciﬁc ligands, 95
Personality Disorder Questionnaire (PDQ-R),
102
Personality disorders, 97–102
antidepressants, 101
anxiety, 103–104
depression, 102–103
DSM-IV, 98
neuroleptics, 100
prevalence, 97–99
psychopharmacological drugs, 98–102
PET (see Positron emission topography)
PFC, 355
Pharmacodynamic factors, 644
antidepressant response, 647–649
Pharmacogenomics, 642
Pharmacokinetic factors, 644
Phlebotomy, melancholia, 6Phobias, 22, 193–196
brain imaging, 305–306
personality disturbances, 662
simple, 194
Phobic anxiety, 22
Phobic anxiety-depersonalization syndrome,
35
Phosphatidylinositol-3-kinase/protein kinase
B (PI-3-K/Akt), 358–359
Phosphorylation, action on GABAA receptors, 432
Photophobia, carbon dioxide, 711
Phrenitis, 7
PI-3-K/Akt, 358–359, 371
neuronal plasticity and survival, 371–372
PI-3 kinase, 358
function, 360
Pineal function circadian rhythm, 483
Pittsburgh Study of Maintenance Treatment
for Recurrent Depression, 588–589
Plasma, NA, 392
Platelet-derived growth factor, 431
Platelets,
aggregability, 483
NA, 392
Polyamines, 432
Polygenic trait, 645
Polyglutamine disease, 177
Polymorphism, 196
POMC, 233

827
Positron emission topography (PET), 290,
476–478
functional anatomy,
panic disorder, 338
SAD, 338
functional neuroimaging studies, 477
GAD, 304
panic disorders, 304
PTSD, 309
unipolar depression, 476–478
Postmenopause,depression, 373
dysphoria, 431
Postmortem studies,
neuropeptide, 232
Postpartum dysphoria, 431
Posttraumatic Stress Diagnostic (PDS), 141
Posttraumatic stress disorder (PTSD), 36,
116, 117, 152, 339, 398, 399, 401
antidepressants, 447
mechanisms of action, 450–451
assessment instrument, 140–141
brain imaging, 308–310
catecholamine function, 335
combined therapy, 156
epidemiology, 60
MRI, 339, 340
neurochemistry, 335
new therapies, 781
pharmacotherapy, 747–749
sodium lactate provocation, 705–706
stress-responsive neurohormones, 215
yohimbine provocation, 715
Prebagalin, social anxiety disorder, 743
Predictive validity, animal models, 506–507
Prefrontal cortex (PFC), 355
Pregnancy, bipolar disorder, 607–609
Pregnanolone, 431
Premenstrual syndrome, 431
Present State Examination, 129, 661
PRIME-MD, 130
Progesterone, anxiety, 211
Proinﬂammatory cytokines,
antidepressants, 574–576
depression, 575
etiological role in depression, 575
Projection, 27
Prolactin response, 118
Proopiomelanocortin (POMC), 233
Propranolol, 401
anxiety, 669
Protein, stress, 353

828
Protein kinase B (Akt-1), function, 360
Proteomics, 642
PSWQ, 132, 135
Psychasthenia, 29–31
chronic fatigue syndrome, 29
depersonalization, 29
distinctive features, 29
hypochondria, 29
panic attacks, 30
psychological functioning,hierarchical levels, 30
theory, 29
somato-form disorder, 29
stereotyped movement disorder, 29
types, 29
Psychomotor stimulants, 518–519
Psychopharmacological bridge technique,
230
Psychopharmacological drugs, personality disorders, 98–102
PTSD (see Posttraumatic stress disorder)
Public speaking, fear, 22
Putative drug targets, 642
Putrescine, 432
Quantitative encephalographic asymmetry,
116
Quantitative psychopathology, 127
R121919, 219
Radioligand studies,bipolar disorder, 302–303
social anxiety disorder, 306
Radionuclide imaging, 291–292
Rapid cycling, 601, 622
bipolar disorder, 603–604
Rapid eye movement (REM), 511, 522
RAS, 357–358
function, 360
Rasch’s Probability Test Theory, 800
RBD, 593
RDC, 128–129, 143, 479
Reboxetine,
depression, 617
major depression, 398–399
Rebreathing technique, carbon dioxide, 711
Receptor-speciﬁc drugs, 119
Recovery, 585
Recurrence, 584
Recurrent brief depression (RBD), 593
Recurrent depression, 586
RED method, 177

Index
Reﬂective nerve impulse transport hypothesis, neurasthenia, 28
Regional central nervous system, 355
Regional central nervous system (CNS), 355
Relapse, 584
factors, 587
REM, 511, 522
Remission, 584
full, 584
partial, 584
Repeat expansion detection (RED) method,
177
Research Diagnostic Criteria (RDC), 128–
129, 143, 479
Reserpine, MDD, 336
Resident-intruder test, 521
Response, 584
Response preventive therapy, anxiety disorders, 155
Reversible inhibitors of monoamine oxidase(RIMA), dysthymia, 81
Revised NEO Personality Inventory (NEOPI-R), 96
RIMA, dysthymia, 81
Risperidone, bipolar disorder, 600–601
Robisartan, new anxiety therapies, 781
Rolipram, depression, 277
Rorschach inkblot test, 96
Rosenthal effect, 796
SAD (see Seasonal affective disorder)
SADS, 128–129, 630
SAS, 801, 803–804
SAS-SR, 636
SAT, 240
Scale of Psychomotor Retardation, 143
Scales,aims and methods, 789–790
combining, 796
construction, scoring and criteria, 790–793
characteristics values, 791
visual analog methods, 790–791
correlation, 790
empirical methods, 793
factor and cluster analysis, 795
identical syndrome scores correlation, 795
mean and standard deviation, 792–793
reliability/validity dilemma, 791
research, 789–804
SCAN, 129
Schedule for Affective Disorders and Schizophrenia (SADS), 128–129, 630

IndexSchedules for Clinical Assessment in Neuropsychiatry (SCAN), 129
Scheler’s emotions theory, 20
Schizoaffective disorders, 171, 392, 622
Schizophrenia, 171–172
Schizophreniform disorder, 16
SCID, 51, 103, 129
SCID-P, 635
SCL-90, 796, 804
SCL-90R, 103, 132–133
SCL-90-R anxiety subscale, 804
Seasonal affective disorder (SAD), 105
functional anatomy,
MRS, 338–339
PET, 338
neurochemistry, 335
neuroticism, 105
Selective serotonin/norepinephrine reuptake
inhibitors (sSNRI), 350
Selective serotonin reuptake inhibitors(SSRIs), 98
anxiety disorders, 155
depression, 444–445
dysthymia, 81
general anxiety disorder, 79, 744–745
mixed anxiety/depression disorders, 761–
763, 767
neurotrophin signaling pathway, 361–362
new anxiety therapies, 779
new depression treatment, 617
vs. NRIs, 399–400
OCD, 445
panic-agoraphobic, 79
panic disorder, 733–738
posttraumatic stress disorder, 747–748
PTSD, 447
social anxiety disorder, 739–744
Self-Rating Anxiety Scale (SAS), 801, 803–
804
Self-rating scales, 802–804
clinical procedures, 796
subjective state, 797
Self-Report Symptom Inventory (SCL-90),
796, 804
Separation anxiety, 660
Separation-induced ultrasonic distress vocalization, 685
Septo-hippocampal system, anxiety, 666
Serotonergic system, 118
animal studies, 669
anxiety, 669
OCD, 335

829
Serotonin (5HT), 297–299, 464–468
depletion paradigm, 546–548
metabolizing enzymes, 199
neuroendocrine challenge paradigms, 465–
466
new anxiety therapies, 779–782
receptor gene, 198
receptor subtypes, 466–467
transporter, 466–468
transporter gene, 196, 198
tryptophan, 465
Serotonin hypothesis, affective disorders, 465
Serotonin reuptake inhibitors (SSRIs), 119,277, 350, 399, 617
Serotonin reuptake transporter, 527
Serotonin system,
GAD, 333
MDD, 336–337
panic disorder, 334
SAD, 335
Serotonin transmission, major depressive disorder, 297–299
Serotonin transporter, 340–341, 466
major depression, 647–648
Serotonin transporter gene, 115
Serotonin transporter promotor region polymorphism, 94
Sertraline, 153
depression, 80, 277, 617
generalized anxiety disorder, 745
MDE, OCD, and panic disorder, 399
mixed anxiety/depression disorders, 762,
767
personality disorder, 102
posttraumatic stress disorder, 748
social anxiety disorder, 741
Shock-induced ultrasonic vocalization, 688–
689
Shock-probe burying, 686–687
Sickness behavior, 270–271, 272
Sigma antagonists, depression, 621–622
Simple phobias, 36, 333
Single nucleotide polymorphisms (SNPs),
642
Single photon emission computerized tomography (SPECT), 290, 305, 338–
339, 476–478
Sjobring Personality Scale, 662
SL-651.498, 427
Sleep,
deprivation, 554–555
encephalography, 116

830
SLEs (see Stressful life events)
Smoking cessation, 618
bupropion, 618
SNPs, 642
Social Adjustment Scale-Self Report (SASSR), 636
Social anxiety disorder, 152
brain imaging, 305–306
combined therapy, 155
course, 59–60
epidemiology, 59–60
pharmacotherapy, 739–749
under recognition, 59
Social hierarchy, 520–521
Social interaction test, animal studies, 418
Social phobia, 36, 114, 193, 195–196, 333,
392, 400 (see also Social anxiety
disorder)diagnostic speciﬁcity, 712–713
instruments, 138–139
and major depression, 77, 79
Social Phobia and Anxiety Inventory (SPAI),
139
Social Readjustment Rating Scale, 660–661
Social separation, 524–525
Sodium lactate,anxiety states provocation, 704–711
cognitive theories, 709–710
diagnostic speciﬁcity, 705–706
etiology, 706–711
hyperventilation, 709
MHPG, 707
neuroendocrine ﬁndings, 708
respiratory and biochemical ﬁndings, 708–
709
response after various medications, 707–708
study reliability and validity, 705–706
Soldier’s heart, 24
Somatostatin, 244–247, 431
depression, 246–247
SPAI, 139
SPECT, 290, 305, 338–339, 476–478
Spectrum comorbidity, diagnostic and therapeutic implications, 81–84
Spectrum model, 73–74
Sperimine, 432
Spermidine, 432
Spiritus animalis, 12
SSD, 635–636
SSNRI, 350
SSRIs (see Selective serotonin reuptake inhibitors)

Index
St. John’s Wort (hypericum perforatum),
511, 618–619
depression, 618–619
STAI, 803
Standardized assessment instruments, 791
Standardized rating scales, 793–797
standardization level, 794–795
Stanley Foundation Bipolar Treatment Outcome Network, 76State-Trait Anxiety Inventory (STAI), 803
Steroids,
animal studies, 431
neuroactive, 211–212
action on GABAA receptors, 428
Stevens-Johnson syndrome, 602
Stimulation test, corticotropin releasing factor, 235–236
Stress, 511–513
antidepressants, 368–369
brain overload, 363–368
brain structure and function modiﬁcation,
353–355
cardiovascular abnormalities, 369
depression, 473–475
gene expression regulation, 355–357
hippocampus, 475
neuroendocrine abnormalities, 369–370
protein expression modiﬁcation, 353
removal or reduction, 368–370
Stress- brain-derived neurotropic factor(BDNF) hypothesis, 357–363
neurotrophin hypothesis of synaptic plasticity, 359
neurotrophin signaling pathway members,
359–363neurotrophin transduction pathways, 357–
359
Stressful life events (SLEs), 355
depression, 351–352
kindling hypothesis, 352
multiple impact, 352
Stress-induced brain overload, 363–368
Stress response, 208–212
CRH, 208–210
animal studies, 209–210
CRH receptors, 208–210
glucocorticoid receptors, 211–212
glucocorticoids, 211–212
mineralocorticoid receptors, 211
natriuretic peptides, 208–210
neuroactive steroids, 211–212
nongenomic and genomic effects, 212

IndexStress-responsive neurohormones, 207–221
depression and anxiety treatment, 215–220
GR blockade, 219
Structured Clinical Interview for DSM-IIIR,
Patient Edition (SCID-P), 635
Structured Clinical Interview for DSM(SCID), 51, 103, 129
Study designs,
case-control, 651
demographic variables, 652
family-based association, 651
multiple loci interaction, 653
phenotype deﬁnition and evaluation, 653
population effects, 652–653
random assignment, placebo-controlled,
double-blind, 651–652
Substance P, 244
depression, 620
new anxiety therapies, 783
Subsyndromal comorbidity, 71–74
Subsyndromal depression, 586
Subthreshold comorbidity, 72
Subthreshold depressive symptoms (SSD),
635–636
Suicidal ideation and behavior, 171
Suicidality,
biological basis, 273–274
helper cells role, 272–274
TH-1 serotonin link, 273–274
Suicide,bipolar risk and mood stabilizers, 609–610
impulsivity, 105–106
serotonin behavior link, 565
Susceptibility genes, DNA level, 173–178
Symptom Check List-90 (SCL-90R), 103,
132–133
Symptomless auto immune thyroiditis (SAT),
240
Synaptic plasticity hypothesis, 359
Syndromal comorbidity, 71–74
Systematic desensitization therapy, 35
Systematic distortion, 796
Tachykinin receptor, 527–528
Tail-suspension test, 515
Taiwan Psychiatric Epidemiological Project,52
Taylor Anxiety Scale, 801
Taylor Manifest Anxiety Scale (TMAS), 803
TCA (see Tricyclic antidepressants)
TCI, 96
TDT, 651

831
Temperament and Character Inventory (TCI),
96
Temporal-epileptic symptoms, 35
Terror psychoses, 25
TH-1 (see also Helper cells)
cytokines, major depression, 273–274
serotonin link, suicidality, 273–274
TH-2 (see Helper cells)
Therapy-refractory depression, 603
Thyroid,
axis, 238–240
dysfunction, psychiatric manifestations,239
Thyroid hormones, 431
bipolar disorder, 600
GABAA receptors, 431
Thyroid stimulating hormone (TSH), depression, 239–240
Thyrotropin-releasing factor (TRH), 238–
240, 243
anxiety disorders, 240
depression, 239–240
Tianeptine,
depression, 618
neurotrophin signaling pathway, 362
TMAS, 803
TNF-alpha, 281
Topiramate, bipolar disorder, 622
TPQ, 96, 105
Transmission disequilibrium tests (TDT), 651
Transmission mode, 460–484
Tranylcypromine, 469
Traumatic neuroses, 25Trazodone,
depression, 277
mixed anxiety/depression disorders, 768
posttraumatic stress disorder, 749
Treatment-resistance depression, 620
Trema, 27
TRH, 238–240
Tricyclic antidepressants (TCA), 350, 616
depression, 444, 460
dysthymia, 81
general anxiety disorder, 79
genetic factor study, 644
mixed anxiety/depression disorders, 760–
761, 767
panic-agoraphobic, 79
panic disorder, 444
posttraumatic stress disorder, 748–749
random controlled trials (RCA), 616
social anxiety disorder, 741

832
Tridimensional Personality Questionnaire(TPQ), 96, 105
Trier Social Stress Test (TSST), 237
Trk signaling pathways, 358
Tryptophan, 118, 395–396
neurobiology, 465
panic disorder, 450
Tryptophan depletion, 546–548
amino acids, 547
behavioral responses, 553
depression, 553–555
effects in remitted patients, 555
healthy subject, 549, 553
healthy subjects, 549, 553
light therapy and sleep deprivation, 554–
555
mechanisms, 547
memory and cognitive effects, 553
preclinical data, 547
studies, 549, 553–555
TSH, depression, 239–240
TSST, 237
Tumor necrosis factor-alpha (TNF-alpha), 281
Twin and family studies, anxiety disorders, 673
Twin pillar model, 20–22, 21
Tyrer’s Brief Scale for Anxiety, 135–136
Ultradian cycling therapy, 600
Ultra-ultra rapid therapy (see Ultradian
cycling therapy)
Unconditioned fear, 338
Unipolar depression, 22, 197, 461–462
familial genetic inﬂuences, 169–170
genes and environment, 173
genetics, 171
PET, 476–478
twin studies, 168
Unipolar major depression,
remission, 633
social function and cognition study, 636
SSRI treatment study, 643
Urine, NA, 392
Valproate, bipolar disorder, 600–602
Valproic acid, bipolar disorder, 622

IndexValues distribution, 792
Vascular disease, 483
platelet aggregability, 483
Venlafaxine,
depression, 618
generalized anxiety disorder, 746
major depression, 400
mixed anxiety/depression disorders, 763–
764, 767–768
PTSD, 447
social anxiety disorder, 741
Venlafaxine XR, mixed anxiety/depression
disorders, 767
Ventral tegmental area (VTA), 337
Verapamil, bipolar disorder, 600
Viloxazine, mixed anxiety/depression disorders, 768
Vitalism, 34
Waiting behavior, 526
Wallach Memory Recognition Test, 481
War, anxiety, 23–25
White matter hyperintensities (WMH), 293
Wolfram syndrome (WFSI), 176
World Health Organization (WHO), 50
Collaborative Study on Psychological
Problems in General Health Care,74
US Alcohol, Drug Abuse, and Mental
Health Administration Task Forceon Psychiatric Assessment Instruments, 131
Yale-Brown Obsessive Compulsive Scale(Y-BOCS), 139, 445
Yohimbine,
anxiety provocation, 714–715
anxiety response, 669
inconsistencies, 715
symptoms produced, 715
Zimelidine, panic disorder, 734
Zung Self-Rating Depressive Scale (Zung
SDS), 142
Zurich Cohort Study of Young Adults, 75About the Editors

Siegfried Kasper is a Professor of Psychiatry and Chair of the Department of General
Psychiatry, University of Vienna, Austria. The author or coauthor of over 800 professional
publications, he is Coeditor-in-Chief of the International Journal of Psychiatry in Clinical
Practice and serves on the editorial boards of the European Archives of Psychiatry and
Neuroscience, European Psychiatry, and Neuropsychopharmacology, among other journals. President of the Austrian Society of Neuropsychopharmacology and Biological Psychiatry, he is a Fellow of the Royal College of Psychiatrists (UK) and an honorary memberof the Czech and Romanian Society of Neuropsychopharmacology. Dr. Kasper received
the M.D. degree (1976) from the University of Innsbruck, Austria.
Johan A. den Boer is Professor in the Department of Psychiatry, University of Groningen,
The Netherlands. The author or coauthor of over 200 professional publications, he is amember of the International Society of Neuroendocrinology and the British Associationof Psychopharmacology, among other organizations. Dr. den Boer serves on the editorial
boards of CNS Drugs and European Psychiatry and received the M.D. degree (1982)
and the Ph.D. degree (1988) in psychiatry from the State University of Utrecht, The
Netherlands.
J. M. Ad Sitsen is Professor of Clinical Pharmacology in the Medical Faculty, Utrecht
University, The Netherlands. The author or coauthor of more than 80 professional publications, he is a member of the European College of Neuropsychopharmacology, the British
Pharmacological Society, and the Dutch Association for Pharmacology. Dr. Sitsen received the Pharm.D. degree (1970), the Ph.D. degree (1972) in medicinal chemistry, andthe M.D. degree (1980) from the State University of Utrecht, The Netherlands.