PRACTICE GUIDELINE FOR THE

Treatment of Patients With
Major Depressive Disorder
Third Edition
WORK GROUP ON MAJOR DEPRESSIVE DISORDER
Alan J. Gelenberg, M.D., Chair
Marlene P. Freeman, M.D.
John C. Markowitz, M.D.
Jerrold F. Rosenbaum, M.D.
Michael E. Thase, M.D.
Madhukar H. Trivedi, M.D.
Richard S. Van Rhoads, M.D., Consultant

INDEPENDENT REVIEW PANEL
Victor I. Reus, M.D., Chair
J. Raymond DePaulo, Jr., M.D.
Jan A. Fawcett, M.D.
Christopher D. Schneck, M.D.
David A. Silbersweig, M.D.

This practice guideline was approved in May 2010 and published in October 2010. A guideline watch, summarizing
significant developments in the scientific literature since publication of this guideline, may be available at
http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx.
Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST
The Work Group on Major Depressive Disorder reports
the following potentially competing interests for the period from May 2005 to May 2010:
Dr. Gelenberg reports consulting for Eli Lilly and Company, Pfizer, Best Practice, AstraZeneca, Wyeth, Cyberonics, Novartis, Forest Pharmaceuticals, Inc., GlaxoSmithKline, ZARS Pharma, Jazz Pharmaceuticals, Lundbeck,
Takeda Pharmaceuticals North America, Inc., eResearchTechnology, Dey Pharma, PGxHealth, and Myriad Genetics. He reports serving on speakers bureaus for Pfizer,
GlaxoSmithKline, and Wyeth. He reports receiving research grant funding from Eli Lilly and Company, Pfizer,
and GlaxoSmithKline. He reports stock ownership in
Healthcare Technology Systems.
Dr. Freeman reports that she received research support
from the Meadows Foundation, the National Institute for
Mental Health, the U.S. Food and Drug Administration,
the Institute for Mental Health Research, Forest, GlaxoSmithKline and Eli Lilly and Company (investigatorinitiated trials), and Pronova Biocare (research materials).
She received an honorarium for case-based peer-reviewed
material for AstraZeneca’s website. She reports consulting
for Ther-Rx, Reliant, and Pamlab. She reports receiving
an honorarium for speaking at an APA continuing medical
education program that was sponsored by Forest and anhonorarium for speaking at a continuing medication education program sponsored by KV Pharmaceuticals. She
reports receiving an honorarium from Leerink Swann forparticipating in a focus group.
Dr. Markowitz reports consulting for Ono Pharmaceutical Co., Ltd. (2005). He reports receiving researchsupport from Forest Pharmaceuticals, Inc. (2005). He reports receiving grant support from the National Instituteof Mental Health (2005–2013), the National Alliance for
Research in Schizophrenia and Depression (2005), andMINT: Mental Health Initiative (2005). He reports receiving royalties from American Psychiatric Publishing, Inc.
(2005–2010), Basic Books (2005–2010), Elsevier (2005–2010), and Oxford University Press (2007–2010).
Dr. Rosenbaum reports attending advisory boards for
Bristol-Myers Squibb, Cephalon, Cyberonics, Forest Pharmaceuticals, Inc., Eli Lilly and Company, MedAvante,
Neuronetics, Inc., Novartis, Orexigen Therapeutics, Inc.,
Organon BioSciences, Pfizer, Roche Diagnostics, Sanofiaventis, Shire, and Wyeth. He reports consulting for Auspex Pharmaceuticals, Compellis Pharmaceuticals, EPIX
Pharmaceuticals, Neuronetics, Inc., Organon BioSciences, Somaxon, and Supernus Pharmaceuticals, Inc. He

reports receiving honoraria from lectureships for Boehringer Ingleheim, Bristol-Myers Squibb, Cyberonics,
Forest Pharmaceuticals, Inc., Eli Lilly and Company, andSchwartz Pharma. He was involved in the creation of
the Massachusetts General Hospital Psychiatry Academy(MGH-PA) and has served as a panelist in four satellite
broadcast programs. MGH-PA programs that have industry support are always multi-sponsored, and curriculum
development by the Academy is independent of sponsorship; the curricula from January 2005 to March 2009 included sponsorship support from AstraZeneca, BristolMyers Squibb, Cephalon, Eli Lilly and Company, Forest
Pharmaceuticals, Inc., GlaxoSmithKline, Janssen Medical
Affairs LLC, Ortho-McNeil Pharmaceutical, sanofiaventis, Shire, and Wyeth. He reports equity holdings inCompellis Pharmaceuticals, MedAvante, and Somaxon.
Dr. Thase reports that he provided scientific consultation to AstraZeneca, Bristol-Myers Squibb, Eli Lilly &Company, Forest Pharmaceuticals, Inc., Gerson Lehman
Group, GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante, Inc., Neuronetics, Inc., Novartis,
Otsuka, Ortho-McNeil Pharmaceuticals, PamLab, L.L.C.,
Pfizer (formerly Wyeth-Ayerst Laboratories), ScheringPlough (formerly Organon), Shire U.S., Inc., Supernus
Pharmaceuticals, Takeda (Lundbeck), and Transcept Pharmaceuticals. He was a member of the speakers bureaus for
AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Pfizer (formerly Wyeth-Ayerst
Laboratories), and Schering-Plough (formerly Organon).
He received grant funding from Eli Lilly and Company,
GlaxoSmithKline, the National Institute of Mental Health,the Agency for Healthcare Research and Quality, andSepracor, Inc. He had equity holdings in MedAvante, Inc.,and received royalty income from American PsychiatricPublishing, Inc., Guilford Publications, Herald House,
Oxford University Press, and W.W. Norton and Company.
His wife was employed as the group scientific director for
Embryon (formerly Advogent), which does business with
Bristol-Myers Squibb and Pfizer/Wyeth.
Dr. Trivedi reports that he was a consultant to or on
speaker bureaus for Abbott Laboratories, Inc., Abdi Ibrahim, Akzo (Organon Pharmaceuticals, Inc.), AstraZeneca,
Bristol-Myers Squibb Company, Cephalon, Inc., Cyberonics, Inc., Eli Lilly and Company, Evotec, Fabre Kramer
Pharmaceuticals, Inc., Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica Products, L.P., Johnson& Johnson P.R.D., Meade-Johnson, Medtronic, Neuronetics, Otsuka Pharmaceuticals, Parke-Davis Pharmaceuti-

Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

cals, Inc., Pfizer, Inc., Sepracor, Shire Development, Solvay
Pharmaceuticals, VantagePoint, and Wyeth-Ayerst Laboratories. He received research support from the Agency for
Healthcare Research and Quality, Corcept Therapeutics,
Inc., Cyberonics, Inc., Merck, National Alliance for Research in Schizophrenia and Depression, National Institute of Mental Health, National Institute on Drug Abuse,
Novartis, Pharmacia & Upjohn, Predix Pharmaceuticals(Epix), Solvay Pharmaceuticals, Inc., and Targacept.
Dr. Van Rhoads reports no competing interests.
The Independent Review Panel, including Drs. Reus,
DePaulo, Fawcett, Schneck, and Silbersweig, report nocompeting interests. The Independent Review Panel reviewed this guideline to assess potential biases and foundno evidence of influence from the industry and other relationships of the Work Group disclosed above. The
Steering Committee on Practice Guidelines also reviewed
this guideline and found no evidence of influence fromthese relationships. The development process for thisguideline, including the roles of the Work Group, Independent Review Panel, Steering Committee, APA Assembly, and APA Board of Trustees is described in “Overview
of Guideline Development Process” on p. 11.

Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

AMERICAN PSYCHIATRIC ASSOCIATIONSTEERING COMMITTEE ON PRACTICE GUIDELINESJohn S. McIntyre, M.D., Chair (1999–2009), Consultant (2009–2010)
Joel Yager, M.D., Vice-Chair (2008–2009), Chair (2009–2010)
Daniel J. Anzia, M.D.
Thomas J. Craig, M.D., M.P.H.
Molly T. Finnerty, M.D.
Bradley R. Johnson, M.D.
Francis G. Lu, M.D.
James E. Nininger, M.D., Vice-Chair (2009–2010)
Barbara Schneidman, M.D.
Paul Summergrad, M.D.
Sherwyn M. Woods, M.D., Ph.D.
Michael J. Vergare, M.D.
M. Justin Coffey, M.D. (fellow)
Kristen Ochoa, M.D. (fellow)
Jeremy Wilkinson, M.D. (fellow)
Sheila Hafter Gray, M.D. (liaison)

STAFF
Robert Kunkle, M.A., Director, Practice Guidelines Project
Robert M. Plovnick, M.D., M.S., Director, Dept. of Quality Improvement and Psychiatric Services
Darrel A. Regier, M.D., M.P.H., Director, Division of Research

MEDICAL EDITOR
Laura J. Fochtmann, M.D.

Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

CONTENTS
STATEMENT OF INTENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
OVERVIEW OF GUIDELINE DEVELOPMENT PROCESS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
GUIDE TO USING THIS PRACTICE GUIDELINE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
OFF-LABEL USE OF MEDICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
PART A: TREATMENT RECOMMENDATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
I. EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
A. Coding System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
B. Summary of Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
1. Psychiatric management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
a. Establish and maintain a therapeutic alliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
b. Complete the psychiatric assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
c. Evaluate the safety of the patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
d. Establish the appropriate setting for treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
e. Evaluate functional impairment and quality of life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
f. Coordinate the patient’s care with other clinicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
g. Monitor the patient’s psychiatric status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
h. Integrate measurements into psychiatric management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
i. Enhance treatment adherence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
j. Provide education to the patient and the family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2. Acute phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
a. Choice of an initial treatment modality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
1. Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2. Other somatic therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3. Psychotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4. Psychotherapy plus antidepressant medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
b. Assessing the adequacy of treatment response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
c. Strategies to address nonresponse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3. Continuation phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4. Maintenance phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
5. Discontinuation of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
6. Clinical factors influencing treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
a. Psychiatric factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
b. Demographic and psychosocial factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
c. Co-occurring general medical conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
II. FORMULATION AND IMPLEMENTATION OF A TREATMENT PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
A. Psychiatric Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
1. Establish and maintain a therapeutic alliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2. Complete the psychiatric assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
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3. Evaluate the safety of the patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
4. Establish the appropriate setting for treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
5. Evaluate functional impairment and quality of life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
6. Coordinate the patient’s care with other clinicians . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
7. Monitor the patient’s psychiatric status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
8. Integrate measurements into psychiatric management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
9. Enhance treatment adherence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
10. Provide education to the patient and the family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
B. Acute Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30
1. Choice of initial treatment modality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2. Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
a. Efficacy of antidepressant medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
1. Selective serotonin reuptake inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
2. Serotonin norepinephrine reuptake inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3. Other antidepressant medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
4. Tricyclic antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5. Monoamine oxidase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
b. Side effects of antidepressant medications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
1. Selective serotonin reuptake inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
a. Gastrointestinal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
b. Activation/insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
c. Sexual side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
d. Neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
e. Falls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
f. Effects on weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
g. Serotonin syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
h. Drug interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
i. Discontinuation syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
2. Serotonin norepinephrine reuptake inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3. Other antidepressant medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
a. Bupropion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
b. Mirtazapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
c. Trazodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
d. Nefazodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4. Tricyclic antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
a. Cardiovascular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
b. Anticholinergic side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
c. Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
d. Weight gain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
e. Neurological effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
f. Falls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
g. Medication interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
5. Monoamine oxidase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
a. Hypertensive crises . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
b. Serotonin syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
c. Cardiovascular effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

d. Weight gain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
e. Sexual side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
f. Neurological effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
c. Implementation of pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3. Other somatic therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
a. Electroconvulsive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
1. Side effects of electroconvulsive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2. Implementation of electroconvulsive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
b. Transcranial magnetic stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
c. Vagus nerve stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
4. Psychotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
a. Specific psychotherapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
1. Cognitive and behavioral therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
2. Interpersonal psychotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3. Psychodynamic psychotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4. Problem-solving therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
5. Marital therapy and family therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
6. Group therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
b. Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
c. Combining psychotherapy and medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
5. Complementary and alternative treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
a. St. John’s wort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
b. S-adenosyl methionine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
c. Omega-3 fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
d. Folate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
e. Light therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
f. Acupuncture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
6. Assessing response and adequacy of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
7. Strategies to address incomplete response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
a. Maximizing initial treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
b. Changing to other treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
c. Augmenting and combining treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
C. Continuation Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
D. Maintenance Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
E. Discontinuation of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
III. SPECIFIC CLINICAL FEATURES INFLUENCING THE TREATMENT PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
A. Psychiatric Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
1. Depressive symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
a. Suicidal ideation and behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
b Major depressive disorder–related cognitive dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
2. DSM depressive subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
a. Psychotic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
b. Catatonic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
c. Melancholic features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
d. Atypical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
e. Seasonal pattern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

3. Co-occurring psychiatric disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
a. Dysthymic disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
b. Anxiety disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
c. Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
d. Substance use disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
e. Personality disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
f. Eating disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
B. Demographic and Psychosocial Variables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .65
1. Major psychosocial stressors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
2. Bereavement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
3. Culture and ethnicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
4. Older age. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
5. Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
6. Pregnancy and postpartum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
a. Depression during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
1. Risks of antidepressants during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2. Implementation of pharmacotherapy during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
b. Postpartum depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
7. Family history. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
C. Treatment Implications of Co-occurring General Medical Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .72
1. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
2. Cardiac disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
3. Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4. Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
5. Epilepsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
6. Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
7. Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
8. Sleep apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
9. Human immunodeficiency virus and hepatitis C infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
10. Pain syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
11. Obstructive uropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
12. Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
PART B: BACKGROUND INFORMATION AND REVIEW OF AVAILABLE EVIDENCE . . . . . . . . . . . . . . . 77
IV. DISEASE DEFINITION, EPIDEMIOLOGY, NATURAL HISTORY, AND COURSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77
A. Disease Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77
B. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .78
C. Natural History and Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .81
1. Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
2. Interepisode status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
3. Complications and prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
V. REVIEW AND SYNTHESIS OF AVAILABLE EVIDENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .81
A. Acute Phase Somatic Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .83
1. Antidepressant medications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
a. Selective serotonin reuptake inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
b. Serotonin norepinephrine reuptake inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

c. Other antidepressant medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
1. Bupropion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
2. Mirtazapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
3. Nefazodone and trazodone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
d. Tricyclic antidepressants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
e. Monoamine oxidase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
2. Electroconvulsive therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
3. Transcranial magnetic stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
4. Vagus nerve stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
5. Complementary and alternative treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
a. St. John’s wort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
b. S-adenosyl methionine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
c. Omega-3 fatty acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
d. Folate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
e. Light therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
f. Acupuncture. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
B. Specific Psychotherapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
1. Cognitive and behavioral therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
a. Cognitive-behavioral therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
b. Behavior therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
2. Interpersonal therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
3. Psychodynamic psychotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
4. Marital therapy and family therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
5. Problem-solving therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
6. Group therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
C. Psychotherapy Combined With Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
D. Lack of Response to Pharmacotherapy in the Acute Phase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
1. Maximizing initial treatments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
2. Changing to other treatments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
3. Augmenting and combining treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
E. Continuation Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
F. Maintenance Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
PART C: FUTURE RESEARCH NEEDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
APPENDIX: EDUCATIONAL RESOURCES FOR PATIENTS AND FAMILIES . . . . . . . . . . . . . . . . . . . . . 101
INDIVIDUALS AND ORGANIZATIONS THAT SUBMITTED COMMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
ACKNOWLEDGMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

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Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition

STATEMENT OF INTENT
The APA Practice Guidelines are not intended to be construed or to serve as a standard of medical care. Standards of
medical care are determined on the basis of all clinical data
available for an individual patient and are subject to change
as scientific knowledge and technology advance and practicepatterns evolve. These parameters of practice should be considered guidelines only. Adherence to them will not ensure
a successful outcome for every individual, nor should they
be interpreted as including all proper methods of care or
excluding other acceptable methods of care aimed at thesame results. The ultimate recommendation regarding aparticular clinical procedure or treatment plan must be
made by the psychiatrist in light of the clinical data, the psychiatric evaluation, and the diagnostic and treatment options available. Such recommendations should incorporate
the patient’s personal and sociocultural preferences and values in order to enhance the therapeutic alliance, adherence
to treatment, and treatment outcomes.
This practice guideline was approved in May 2010 andpublished in October 2010.

OVERVIEW OF GUIDELINEDEVELOPMENT PROCESSThis practice guideline was developed under the directionof the Steering Committee on Practice Guidelines. The
development process is detailed in a document entitled“APA Guideline Development Process,” which is available from the APA Department of Quality Improvement
and Psychiatric Services. Key features of this process include the following:• A comprehensive literature review to identify all relevant randomized clinical trials as well as less rigorously
designed clinical trials and case series when evidence
from randomized trials was unavailable• Development of evidence tables that reviewed the key
features of each identified study, including funding
source, study design, sample sizes, subject characteristics, treatment characteristics, and treatment outcomes• Initial drafting of the guideline by a work group (“WorkGroup”) that included psychiatrists with clinical and research expertise in major depressive disorder• Production of multiple revised drafts with widespread
review; 15 organizations and 71 individuals submittedcomments.
• Review of the final draft by an Independent Review
Panel of experts with no relationships with industry,

11

who were charged to evaluate the guideline recommendations for bias from potential conflicts of interest.
• Approval by the APA Assembly and Board of Trustees.
• Planned revisions at regular intervals.
Development of this APA practice guideline was not financially supported by any commercial organization. In
addition, the integrity of the guideline has been ensured
by the following mechanisms:
1. Work Group members were selected on the basis of
their expertise and integrity, and they agreed to disclose all potential conflicts of interest before and during
their work on this guideline to the Steering Committee on Practice Guidelines and to each other. Employees of industry were not included on the group, andthe group was balanced to include some persons withminimal industry relationships. As disclosed on pages
2–3, from initiation of work in 2005 to approval of theguideline in 2010, some members of the Work Groupon Major Depressive Disorder had relationships withindustry for which they received research grants or income from consulting or speaking related to treatments discussed in the guideline.
2. Iterative guideline drafts were broadly circulated to andreviewed by the Steering Committee, other experts, allied organizations, and the APA membership; reviewers were asked to disclose their own potential conflictsof interest relevant to evaluating their comments. Over1,000 comments were received and were addressed bysubstantive revisions by the Work Group. Oversight ofthe draft review and revision process was provided by
the chair and vice-chair of the Steering Committee andby the Medical Editor, none of whom had relationships
with industry.
3. In response to a 2009 report by the Institute of Medicine (1), which advocated that professional organizations that develop and disseminate practice guidelines
should adopt a new policy that members of guideline
work groups have no significant relationships with industry, the following process was implemented: An
independent review panel of experts (“Independent
Review Panel”) having no current relationships withindustry also reviewed the guideline and was charged
with identifying any possible bias. The Independent
Review Panel found no evidence of bias.
The Work Group and the Steering Committee differed on how to rate the strength of recommendation for
psychodynamic psychotherapy. Based on their review of
the available empirical evidence on the use of psycho-

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12
dynamic psychotherapy in individuals with major depressive disorder, the Work Group gave this treatment a level
III rating, i.e., “may be recommended on the basis of individual circumstances.” The Steering Committee gave alevel II rating, “recommended with moderate clinical confidence,” based on the long history of clinical experience
with psychodynamic psychotherapy as well as findings
from several studies of patients who had depressive symptoms but not major depressive disorder per se.
Relevant updates to the literature were identified througha MEDLINE literature search for articles published since
the second edition of the guideline, published in 2000. For
this edition of the guideline, literature was identified
through a computerized search of MEDLINE, using PubMed, for the period from January 1999 to December 2006.
Using the MeSH headings depression or depressive disorder, as well as the key words major depression, major depressive disorder, neurotic depression, neurotic depressive,
dysthymia, dysthymic, dysthymic disorder, endogenous depression, endogenous depressive, melancholia, melancholic, psychotic depression, atypical depression, seasonal
depression, postpartum depression, postpartum depressive
symptoms, unipolar depression, unipolar depressive, or
pseudodementia yielded 39,157 citations. An additional
8,272 citations were identified by using the key words depression or depressive in combination with the MeSH
headings affective disorders or psychotic or the key words
psychosis, psychotic, catatonic, catatonia, mood disorder,mood disorders, affective disorder, or affective disorders.
These citations were limited to English language articles
on human treatments using the MeSH headings central
nervous system stimulants, hypnotics and sedatives, anticonvulsants, tranquilizing agents, electric stimulation therapy, electroconvulsive therapy, psychotherapy, antidepressive agents, and monoamine oxidase inhibitors or the key
words antidepressant, antidepressants, antidepressive, antidepressive agents, antidepressive agents, second generation, antidepressive agents tricyclic, antidepressive agents,
tricyclic, fluoxetine, citalopram, escitalopram, paroxetine,
sertraline, venlafaxine, duloxetine, mirtazapine, nefazodone, trazodone, imipramine, desipramine, nortriptyline,
protriptyline, doxepin, trimipramine, amitriptyline, phenelzine, tranylcypromine, isocarboxazid, moclobemide,
antipsychotic agents, testosterone, thyroid, tri iodothyronine, thyroxine, omega 3, s adenosyl methionine, s adenosylmethionine, St. John’s wort, hypericum, selegiline, anticonvulsant, anticonvulsants, antipsychotic, antipsychotic
agent, antianxiety, anti anxiety, benzodiazepine, benzodiazepines, zolpidem, sedative, sedatives, hypnotic, hypnotics,
zaleplon, eszopiclone, valproate, valproic acid, divalproex,
carbamazepine, oxcarbazepine, gabapentin, topiramate,lamotrigine, lithium, modafinil, methylphenidate, Adder-

APA PRACTICE GUIDELINES
all, amphetamine, amphetamines, dextroamphetamine,atomoxetine, electroconvulsive, vagal nerve stimulation,
vagus nerve stimulation, VNS, rTMS, rapid transcranial
magnetic, repetitive transcranial magnetic stimulation,
magnetic stimulation, deep brain stimulation, psychotherapy, psychotherapeutic, psychotherapies, behavior therapy,
behaviour therapy, cognitive therapy, cognitive behavior
therapy, cognitive behavioral analysis system, cognitive behavioral therapy, cognitive behaviour therapy, cognitive
behavioural therapy, psychoanalytic, interpersonal therapy,
interpersonal psychotherapy, group therapy, family therapy, marital therapy, couples therapy, psychoanalysis, psychodynamic, aversive therapy, desensitization, exposure
therapy, relaxation techniques, or progressive muscle relaxation. This yielded 13,506 abstracts, which were screened
for relevance with a very modest threshold for inclusion,then reviewed by the Work Group.
The Psychoanalytic Electronic Publishing database(http://www.p-e-p.org) was also searched using the terms
major depression or major depressive. This search yielded
112 references. The Cochrane databases were also searched
for the key word depression, and 168 meta-analyses wereidentified. Additional, less formal, literature searches wereconducted by APA staff and individual Work Group members and included references through May 2009. Sourcesof funding were considered when the Work Group reviewed the literature.
The broad scope of this guideline and the substantial
evidence base resulted in some practical tradeoffs. One
such tradeoff worth highlighting is the decision to build
upon literature reviews of the first and second editions of
the guideline, rather than re-do them. This decision is acknowledged to have resulted in an emphasis of study inthis guideline on newer treatments, because the majorityof studies about older treatments, including tricyclic antidepressants and monoamine oxidase inhibitors, were published in decades prior to 1999. Readers are advised thatthe reviews of this older literature are described in theprevious editions of the guideline. The Work Group forthis edition considered the previous editions during theirevidence review, but for practical reasons, that effort is lesswell documented than the group’s analysis of the newer
literature. The treatment recommendations of this guideline, however, were developed to reflect the complete evidence base.
This document represents a synthesis of current scientific knowledge and rational clinical practice regarding
the treatment of patients with major depressive disorder.
It strives to be as free as possible of bias toward any theoretical approach to treatment. In order for the reader toappreciate the evidence base behind the guideline recommendations and the weight that should be given to each

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
recommendation, the summary of treatment recommendations is keyed according to the level of confidence withwhich each recommendation is made. Each rating of clinical confidence considers the strength of the available evidence. When evidence from randomized controlled trials
and meta-analyses is limited, the level of confidence may
also incorporate other clinical trials and case reports as well
as clinical consensus with regard to a particular clinicaldecision. In the listing of cited references, each reference
is followed by a letter code in brackets that indicates thenature of the supporting evidence.

GUIDE TO USING THIS
PRACTICE GUIDELINEThe Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition, consists of three parts(Parts A, B, and C) and many sections, not all of which will
be equally useful for all readers. The following guide isdesigned to help readers find the sections that will be mostuseful to them.
Part A, “Treatment Recommendations,” is published
as a supplement to the American Journal of Psychiatry andcontains general and specific treatment recommendations. Section I summarizes the key recommendations of
the guideline and codes each recommendation according
to the degree of clinical confidence with which the recommendation is made. Section II is a guide to the formulation and implementation of a treatment plan for theindividual patient. Section III, “Specific Clinical Features
Influencing the Treatment Plan,” discusses a range of clinical considerations that could alter the general recommendations discussed in Section I.
Part B, “Background Information and Review of Available Evidence,” and Part C, “Future Research Needs,” arenot included in the American Journal of Psychiatry supplement but are provided with Part A in the complete guideline, which is available in print format from American
Psychiatric Publishing, Inc., and online through the American Psychiatric Association (http://www.psychiatryonline.com). Part B provides an overview of major depressive
disorder, including general information on natural history,
course, and epidemiology. It also provides a structured
review and synthesis of the evidence that underlies therecommendations made in Part A. Part C draws from theprevious sections and summarizes areas for which more
research data are needed to guide clinical decisions.

13

To share feedback on this or other published APA
practice guidelines, a form is available at
http://mx.psych.org/survey/reviewform.cfm.

OFF-LABEL USE OF
MEDICATIONS
Medications discussed in this practice guideline may nothave an indication from the U.S. Food and Drug Administration for the disorder or condition for which they arerecommended. Off-label use of medications by individual
physicians is permitted and common. Decisions about offlabel use can be guided by the evidence provided in the
APA practice guideline, other scientific literature, and clinical experience.

INTRODUCTION
This guideline summarizes the specific approaches totreatment of individuals with major depressive disorder. It
presupposes that the psychiatrist has diagnosed major depressive disorder, according to the criteria defined in
DSM-IV-TR, in an adult patient and has evaluated thepatient to identify general medical conditions that may
contribute to the disease process (e.g., hypothyroidism,
pancreatic carcinoma) or complicate its treatment (e.g.,
cardiac disorders). The treatment recommendations that
follow may also have some relevance for patients who
have depressive symptoms on the basis of other syndromes, such as dysthymic disorder. Because many patients have co-occurring psychiatric disorders, including
substance use disorders, the psychiatrist should also consider applicable treatment guidelines for these diagnoses.
When patients experience depressive symptoms in thecontext of another disorder and do not meet the diagnostic criteria for major depressive disorder, the APA practiceguideline pertaining to the primary diagnosis should be
consulted. For patients found to have depressive symptoms within the context of bipolar disorder, the psychiatrist
should refer to APA’s Practice Guideline for the Treatment ofPatients With Bipolar Disorder (2). Recommendations on
the treatment of depressive disorders in children and adolescents can be found in the American Academy of Childand Adolescent Psychiatry’s Practice Parameter for the Assessment and Treatment of Children and Adolescents With
Depressive Disorders (3).

Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

Part A
TREATMENT RECOMMENDATIONSI.

EXECUTIVE SUMMARY

A. CODING SYSTEM

chiatric history, including identification of past symptoms
of mania, hypomania, or mixed episodes and responses toprevious treatments; a general medical history; a personal
history including information about psychological development and responses to life transitions and major life events;
a social, occupational, and family history (including mooddisorders and suicide); review of the patient’s prescribedand over-the-counter medications; a review of systems; amental status examination; a physical examination; and appropriate diagnostic tests as indicated to rule out possible
general medical causes of depressive symptoms [I]. Assessment of substance use should evaluate past and current useof illicit drugs and other substances that may trigger or exacerbate depressive symptoms [I].

Each recommendation is identified as falling into one ofthree categories of endorsement, indicated by a bracketed
Roman numeral following the statement. The three categories represent varying levels of clinical confidence:[I] Recommended with substantial clinical confidence[II] Recommended with moderate clinical confidence[III] May be recommended on the basis of individual circumstances

B. SUMMARY OF RECOMMENDATIONS
1. Psychiatric management
Psychiatric management consists of a broad array of interventions and activities that psychiatrists should initiate
and continue to provide to patients with major depressive
disorder through all phases of treatment [I].

c.

Evaluate the safety of the patient

A careful and ongoing evaluation of suicide risk is necessary for all patients with major depressive disorder [I].
Such an assessment includes specific inquiry about suicidal thoughts, intent, plans, means, and behaviors; identification of specific psychiatric symptoms (e.g., psychosis,
severe anxiety, substance use) or general medical conditions that may increase the likelihood of acting on suicidal
ideas; assessment of past and, particularly, recent suicidal
behavior; delineation of current stressors and potential
protective factors (e.g., positive reasons for living, strongsocial support); and identification of any family history ofsuicide or mental illness [I]. In addition to assessing suicide risk per se, it is important to assess the patient’s levelof self-care, hydration, and nutrition, each of which can becompromised by severe depressive symptoms [I]. As partof the assessment process, impulsivity and potential forrisk to others should also be evaluated, including any history of violence or violent or homicidal ideas, plans, or intentions [I]. An evaluation of the impact of the depression
on the patient’s ability to care for dependents is an important component of the safety evaluation [I]. The patient’s
risk of harm to him- or herself and to others should also bemonitored as treatment proceeds [I].

a. Establish and maintain a therapeutic alliance
In establishing and maintaining a therapeutic alliance, it isimportant to collaborate with the patient in decision making and attend to the patient’s preferences and concerns
about treatment [I]. Management of the therapeutic alliance should include awareness of transference and countertransference issues, even if these are not directly addressedin treatment [II]. Severe or persistent problems of poor alliance or nonadherence to treatment may be caused by thedepressive symptoms themselves or may represent psychological conflicts or psychopathology for which psychotherapy should be considered [II].
b. Complete the psychiatric assessment
Patients should receive a thorough diagnostic assessment inorder to establish the diagnosis of major depressive disorder, identify other psychiatric or general medical conditions
that may require attention, and develop a comprehensive
plan for treatment [I]. This evaluation generally includes ahistory of the present illness and current symptoms; a psy-

15

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16
d. Establish the appropriate setting for treatment
The psychiatrist should determine the least restrictive
setting for treatment that will be most likely not only toaddress the patient’s safety, but also to promote improvement in the patient’s condition [I]. The determination ofan appropriate setting for treatment should include consideration of the patient’s symptom severity, co-occurring
psychiatric or general medical conditions, available support
system, and level of functioning [I]. The determination of atreatment setting should also include consideration of thepatient’s ability to adequately care for him- or herself, toprovide reliable feedback to the psychiatrist, and to cooperate with treatment of the major depressive disorder [I].
Measures such as hospitalization should be considered forpatients who pose a serious threat of harm to themselves
or others [I]. Patients who refuse inpatient treatment canbe hospitalized involuntarily if their condition meets thecriteria of the local jurisdiction for involuntary admission[I]. Admission to a hospital or, if available, an intensive day
program, may also be indicated for severely ill patients wholack adequate social support outside of a hospital setting,
who have complicating psychiatric or general medical
conditions, or who have not responded adequately to outpatient treatment [I]. The optimal treatment setting andthe patient’s likelihood of benefit from a different level ofcare should be reevaluated on an ongoing basis throughout the course of treatment [I].
e. Evaluate functional impairment and quality of life
Major depressive disorder can alter functioning in numerous spheres of life including work, school, family, social
relationships, leisure activities, or maintenance of healthand hygiene. The psychiatrist should evaluate the patient’s
activity in each of these domains and determine the presence, type, severity, and chronicity of any dysfunction [I].
In developing a treatment plan, interventions should beaimed at maximizing the patient’s level of functioning aswell as helping the patient to set specific goals appropriate
to his or her functional impairments and symptom severity [I].
f. Coordinate the patient’s care with other clinicians
Many patients with major depressive disorder will be evaluated by or receive treatment from other health care professionals in addition to the psychiatrist. If more than one
clinician is involved in providing the care, all treating clinicians should have sufficient ongoing contact with thepatient and with each other to ensure that care is coordinated, relevant information is available to guide treatment
decisions, and treatments are synchronized [I].
In ruling out general medical causes of depressive symptoms, it is important to ensure that a general medical eval-

APA PRACTICE GUIDELINES
uation has been done [I], either by the psychiatrist or byanother health care professional. Extensive or specialized
testing for general medical causes of depressive symptoms
may be conducted based on individual characteristics ofthe patient [III].
g. Monitor the patient’s psychiatric status
The patient’s response to treatment should be carefully
monitored [I]. Continued monitoring of co-occurring
psychiatric and/or medical conditions is also essential todeveloping and refining a treatment plan for an individual
patient [I].
h. Integrate measurements into psychiatric management
Tailoring the treatment plan to match the needs of theparticular patient requires a careful and systematic assessment of the type, frequency, and magnitude of psychiatric
symptoms as well as ongoing determination of the therapeutic benefits and side effects of treatment [I]. Such assessments can be facilitated by integrating clinician- and/or
patient-administered rating scale measurements into initial and ongoing evaluation [II].
i. Enhance treatment adherence
The psychiatrist should assess and acknowledge potential
barriers to treatment adherence (e.g., lack of motivation
or excessive pessimism due to depression; side effects oftreatment; problems in the therapeutic relationship; logistical, economic, or cultural barriers to treatment) andcollaborate with the patient (and if possible, the family) tominimize the impact of these potential barriers [I]. In addition, the psychiatrist should encourage patients to articulate any fears or concerns about treatment or its side effects[I]. Patients should be given a realistic notion of what canbe expected during the different phases of treatment, including the likely time course of symptom response andthe importance of adherence for successful treatment andprophylaxis [I].
j. Provide education to the patient and the family
Education about the symptoms and treatment of major
depressive disorder should be provided in language that isreadily understandable to the patient [I]. With the patient’s permission, family members and others involved in
the patient’s day-to-day life may also benefit from education about the illness, its effects on functioning (including
family and other interpersonal relationships), and its treatment [I]. Common misperceptions about antidepressants(e.g., they are addictive) should be clarified [I]. In addition,
education about major depressive disorder should address
the need for a full acute course of treatment, the risk of relapse, the early recognition of recurrent symptoms, and theneed to seek treatment as early as possible to reduce the risk

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Editionof complications or a full-blown episode of major depression [I]. Patients should also be told about the need totaper antidepressants, rather than discontinuing themprecipitously, to minimize the risk of withdrawal symptoms or symptom recurrence [I]. Patient education also
includes general promotion of healthy behaviors such as
exercise, good sleep hygiene, good nutrition, and decreased
use of tobacco, alcohol, and other potentially deleterious
substances [I]. Educational tools such as books, pamphlets,
and trusted web sites can augment the face-to-face education provided by the clinician [I].

2. Acute phasea. Choice of an initial treatment modality
Treatment in the acute phase should be aimed at inducing
remission of the major depressive episode and achieving afull return to the patient’s baseline level of functioning [I].
Acute phase treatment may include pharmacotherapy, depression-focused psychotherapy, the combination of medications and psychotherapy, or other somatic therapies
such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or light therapy, as described in thesections that follow. Selection of an initial treatment modality should be influenced by clinical features (e.g., severity of symptoms, presence of co-occurring disorders
or psychosocial stressors) as well as other factors (e.g., patient preference, prior treatment experiences) [I]. Anytreatment should be integrated with psychiatric management and any other treatments being provided for otherdiagnoses [I].
1. Pharmacotherapy
An antidepressant medication is recommended as an initial treatment choice for patients with mild to moderate
major depressive disorder [I] and definitely should be provided for those with severe major depressive disorder unless ECT is planned [I]. Because the effectiveness of antidepressant medications is generally comparable between
classes and within classes of medications, the initial selection of an antidepressant medication will largely be basedon the anticipated side effects, the safety or tolerability ofthese side effects for the individual patient, pharmacological properties of the medication (e.g., half-life, actions on
cytochrome P450 enzymes, other drug interactions), and additional factors such as medication response in prior episodes, cost, and patient preference [I]. For most patients, aselective serotonin reuptake inhibitor (SSRI), serotoninnorepinephrine reuptake inhibitor (SNRI), mirtazapine,or bupropion is optimal [I]. In general, the use of nonselective monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, tranylcypromine, isocarboxazid) should be restricted17

to patients who do not respond to other treatments [I],given the necessity for dietary restrictions with these medications and the potential for deleterious drug-drug interactions. In patients who prefer complementary and alternative therapies, S-adenosyl methionine (SAMe) [III] or
St. John’s wort [III] might be considered, although evidence
for their efficacy is modest at best, and careful attention to
drug-drug interactions is needed with St. John’s wort [I].
Once an antidepressant medication has been initiated,
the rate at which it is titrated to a full therapeutic doseshould depend upon the patient’s age, the treatment setting, and the presence of co-occurring illnesses, concomitant pharmacotherapy, or medication side effects [I].
During the acute phase of treatment, patients should be
carefully and systematically monitored on a regular basis
to assess their response to pharmacotherapy, identify the
emergence of side effects (e.g., gastrointestinal symptoms,
sedation, insomnia, activation, changes in weight, and cardiovascular, neurological, anticholinergic, or sexual side effects), and assess patient safety [I]. The frequency of patientmonitoring should be determined based upon the patient’s
symptom severity (including suicidal ideas), co-occurring
disorders (including general medical conditions), cooperation with treatment, availability of social supports, and thefrequency and severity of side effects with the chosen treatment [II]. If antidepressant side effects do occur, an initialstrategy is to lower the dose of the antidepressant or tochange to an antidepressant that is not associated withthat side effect [I].
2. Other somatic therapies
ECT is recommended as a treatment of choice for patients with severe major depressive disorder that is not responsive to psychotherapeutic and/or pharmacologicalinterventions, particularly in those who have significant
functional impairment or have not responded to numerous medication trials [I]. ECT is also recommended forindividuals with major depressive disorder who have associated psychotic or catatonic features [I], for those with anurgent need for response (e.g., patients who are suicidal
or nutritionally compromised due to refusal of food or fluids) [I], and for those who prefer ECT or have had a previous positive response to ECT [II].
Bright light therapy might be used to treat seasonal affective disorder as well as nonseasonal depression [III].
3. Psychotherapy
Use of a depression-focused psychotherapy alone is recommended as an initial treatment choice for patients withmild to moderate major depressive disorder [I], with clinical evidence supporting the use of cognitive-behavioral
therapy (CBT) [I], interpersonal psychotherapy [I], psy-

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18
chodynamic therapy [II], and problem-solving therapy[III] in individual [I] and in group [III] formats. Factorsthat may suggest the use of psychotherapeutic interventions include the presence of significant psychosocial
stressors, intrapsychic conflict, interpersonal difficulties,
a co-occurring axis II disorder, treatment availability, or—most important—patient preference [II]. In women who
are pregnant, wish to become pregnant, or are breastfeeding, a depression-focused psychotherapy alone is recommended [II] and depending on the severity of symptoms,
should be considered as an initial option [I]. Considerations in the choice of a specific type of psychotherapy include the goals of treatment (in addition to resolving major
depressive symptoms), prior positive response to a specific
type of psychotherapy, patient preference, and the availability of clinicians skilled in the specific psychotherapeutic approach [II]. As with patients who are receiving pharmacotherapy, patients receiving psychotherapy should be
carefully and systematically monitored on a regular basis toassess their response to treatment and assess patient safety[I]. When determining the frequency of psychotherapy
sessions for an individual patient, the psychiatrist should
consider multiple factors, including the specific type andgoals of psychotherapy, symptom severity (including suicidal ideas), co-occurring disorders, cooperation with treatment, availability of social supports, and the frequency ofvisits necessary to create and maintain a therapeutic relationship, ensure treatment adherence, and monitor and address depressive symptoms and suicide risk [II]. Marital andfamily problems are common in the course of major depressive disorder, and such problems should be identified
and addressed, using marital or family therapy when indicated [II].
4. Psychotherapy plus antidepressant medication
The combination of psychotherapy and antidepressant
medication may be used as an initial treatment for patientswith moderate to severe major depressive disorder [I]. In
addition, combining psychotherapy and medication may
be a useful initial treatment even in milder cases for patients with psychosocial or interpersonal problems, intrapsychic conflict, or co-occurring Axis II disorder [II]. In
general, when choosing an antidepressant or psychotherapeutic approach for combination treatment, the same issues should be considered as when selecting a medication
or psychotherapy for use alone [I].
b. Assessing the adequacy of treatment response
In assessing the adequacy of a therapeutic intervention, it
is important to establish that treatment has been administered for a sufficient duration and at a sufficient frequency or,in the case of medication, dose [I]. Onset of benefit from

APA PRACTICE GUIDELINES
psychotherapy tends to be a bit more gradual than thatfrom medication, but no treatment should continue unmodified if there has been no symptomatic improvement
after 1 month [I]. Generally, 4–8 weeks of treatment areneeded before concluding that a patient is partially responsive or unresponsive to a specific intervention [II].
c. Strategies to address nonresponse
For individuals who have not responded fully to treatment, the acute phase of treatment should not be concluded prematurely [I], as an incomplete response totreatment is often associated with poor functional outcomes. If at least a moderate improvement in symptoms
is not observed within 4–8 weeks of treatment initiation,
the diagnosis should be reappraised, side effects assessed,
complicating co-occurring conditions and psychosocial
factors reviewed, and the treatment plan adjusted [I]. It isalso important to assess the quality of the therapeutic alliance and treatment adherence [I]. For patients in psychotherapy, additional factors to be assessed include thefrequency of sessions and whether the specific approachto psychotherapy is adequately addressing the patient’s
needs [I]. If medications are prescribed, the psychiatrist
should determine whether pharmacokinetic [I] or pharmacodynamic [III] factors suggest a need to adjust medication doses. With some TCAs, a drug blood level canhelp determine if additional dose adjustments are required [I].
After an additional 4–8 weeks of treatment, if the patient continues to show minimal or no improvement insymptoms, the psychiatrist should conduct another thorough review of possible contributory factors and make additional changes in the treatment plan [I]. Consultation
should also be considered [II].
A number of strategies are available when a change inthe treatment plan seems necessary. For patients treatedwith an antidepressant, optimizing the medication dose isa reasonable first step if the side effect burden is tolerable
and the upper limit of a medication dose has not beenreached [II]. Particularly for those who have shown minimal improvement or experienced significant medicationside effects, other options include augmenting the antidepressant with a depression-focused psychotherapy [I] orwith other agents [II] or changing to another non-MAOI
antidepressant [I]. Patients may be changed to an antidepressant from the same pharmacological class (e.g., fromone SSRI to another SSRI) or to one from a different class(e.g., from an SSRI to a tricyclic antidepressant [TCA]) [II].
For patients who have not responded to trials of SSRIs, a
trial of an SNRI may be helpful [II]. Augmentation of antidepressant medications can utilize another non-MAOI
antidepressant [II], generally from a different pharmaco-

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
logical class, or a non-antidepressant medication such aslithium [II], thyroid hormone [II], or a second-generation
antipsychotic [II]. Additional strategies with less evidence
for efficacy include augmentation using an anticonvulsant[III], omega-3 fatty acids [III], folate [III], or a psychostimulant medication [III], including modafinil [III]. If anxiety
or insomnia are prominent features, consideration can begiven to anxiolytic and sedative-hypnotic medications[III], including buspirone, benzodiazepines, and selective
γ-aminobutyric acid (GABA) agonist hypnotics (e.g., zolpidem, eszopiclone). For patients whose symptoms have
not responded adequately to medication, ECT remains themost effective form of therapy and should be considered[I]. In patients capable of adhering to dietary and medication restrictions, an additional option is changing to a nonselective MAOI [II] after allowing sufficient time between
medications to avoid deleterious interactions [I]. Transdermal selegiline, a relatively selective MAO B inhibitor withfewer dietary and medication restrictions, or transcranial
magnetic stimulation could also be considered [II]. Vagus
nerve stimulation (VNS) may be an additional option for
individuals who have not responded to at least four adequate trials of antidepressant treatment, including ECT[III].
For patients treated with psychotherapy, consideration
should be given to increasing the intensity of treatment
or changing the type of therapy [II]. If psychotherapy isused alone, the possible need for medications in addition
to or in lieu of psychotherapy should be assessed [I]. Patients who have a history of poor treatment adherence orincomplete response to adequate trials of single treatment modalities may benefit from combined treatment
with medication and a depression-focused psychotherapy[II].

3. Continuation phase
During the continuation phase of treatment, the patient
should be carefully monitored for signs of possible relapse[I]. Systematic assessment of symptoms, side effects, adherence, and functional status is essential [I] and may befacilitated through the use of clinician- and/or patientadministered rating scales [II]. To reduce the risk of relapse, patients who have been treated successfully withantidepressant medications in the acute phase should continue treatment with these agents for 4–9 months [I]. In
general, the dose used in the acute phase should be usedin the continuation phase [II]. To prevent a relapse ofdepression in the continuation phase, depression-focused
psychotherapy is recommended [I], with the best evidence
available for CBT.

19

Patients who respond to an acute course of ECT should
receive continuation pharmacotherapy [I], with the best
evidence available for the combination of lithium andnortriptyline. Alternatively, patients who have responded
to an acute course of ECT may be given continuation ECT,
particularly if medication or psychotherapy has been ineffective in maintaining remission [II].

4. Maintenance phase
In order to reduce the risk of a recurrent depressive episode, patients who have had three or more prior major depressive episodes or who have chronic major depressive
disorder should proceed to the maintenance phase of treatment after completing the continuation phase [I]. Maintenance therapy should also be considered for patients withadditional risk factors for recurrence, such as the presenceof residual symptoms, ongoing psychosocial stressors, early
age at onset, and family history of mood disorders [II]. Additional considerations that may play a role in the decision
to use maintenance therapy include patient preference, thetype of treatment received, the presence of side effects during continuation therapy, the probability of recurrence, thefrequency and severity of prior depressive episodes (including factors such as psychosis or suicide risk), the persistenceof depressive symptoms after recovery, and the presence of
co-occurring disorders [II]. Such factors also contribute todecisions about the duration of the maintenance phase [II].
For many patients, particularly for those with chronic andrecurrent major depressive disorder or co-occurring medical and/or psychiatric disorders, some form of maintenancetreatment will be required indefinitely [I].
During the maintenance phase, an antidepressant medication that produced symptom remission during the acutephase and maintained remission during the continuation
phase should be continued at a full therapeutic dose [II]. If
a depression-focused psychotherapy has been used during
the acute and continuation phases of treatment, maintenance treatment should be considered, with a reduced
frequency of sessions [II]. For patients whose depressive
episodes have not previously responded to acute or continuation treatment with medications or a depressionfocused psychotherapy but who have shown a response to
ECT, maintenance ECT may be considered [III]. Maintenance treatment with VNS is also appropriate for individuals whose symptoms have responded to this treatment
modality [III].
Due to the risk of recurrence, patients should be monitored systematically and at regular intervals during themaintenance phase [I]. Use of standardized measurement
aids in the early detection of recurrent symptoms [II].

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20
5. Discontinuation of treatment
When pharmacotherapy is being discontinued, it is best
to taper the medication over the course of at least several
weeks [I]. To minimize the likelihood of discontinuation
symptoms, patients should be advised not to stop medications abruptly and to take medications with them when
they travel or are away from home [I]. A slow taper or
temporary change to a longer half-life antidepressant may
reduce the risk of discontinuation syndrome [II] when discontinuing antidepressants or reducing antidepressantdoses. Before the discontinuation of active treatment, patients should be informed of the potential for a depressive
relapse and a plan should be established for seeking treatment in the event of recurrent symptoms [I]. After discontinuation of medications, patients should continue to bemonitored over the next several months and should receive
another course of adequate acute phase treatment if symptoms recur [I].
For patients receiving psychotherapy, it is important toraise the issue of treatment discontinuation well in advance of the final session [I], although the exact process bywhich this occurs will vary with the type of therapy.

6. Clinical factors influencing treatment
a. Psychiatric factors
For suicidal patients, psychiatrists should consider an increased intensity of treatment, including hospitalization
when warranted [I] and/or combined treatment withpharmacotherapy and psychotherapy [II]. Factors to consider in determining the nature and intensity of treatment
include (but are not limited to) the nature of the doctorpatient alliance, the availability and adequacy of social supports, access to and lethality of suicide means, the presenceof a co-occurring substance use disorder, and past and family history of suicidal behavior [I].
For patients who exhibit psychotic symptoms during
an episode of major depressive disorder, treatment should
include a combination of antipsychotic and antidepressant
medications or ECT [I]. When patients exhibit cognitive
dysfunction during a major depressive episode, they may
have an increased likelihood of future dementia, making it
important to assess cognition in a systematic fashion overthe course of treatment [I].
Catatonic features that occur as part of a major depressive episode should be treated with a benzodiazepine [I] or
barbiturate [II], typically in conjunction with an antidepressant [II]. If catatonic symptoms persist, ECT is recommended [I]. To reduce the likelihood of general medical
complications, patients with catatonia may also require
supportive medical interventions, such as hydration, nutritional support, prophylaxis against deep vein thrombo-

APA PRACTICE GUIDELINES
sis, turning to reduce risks of decubitus ulcers, and passive
range of motion to reduce risk of contractures [I]. If antipsychotic medication is needed, it is important to monitor
for signs of neuroleptic malignant syndrome, to which patients with catatonia may have a heightened sensitivity[II].
When patients with a major depressive disorder also
have a co-occurring psychiatric illness, the clinician should
address each disorder as part of the treatment plan [I]. Benzodiazepines may be used adjunctively in individuals withmajor depressive disorder and co-occurring anxiety [II], although these agents do not treat depressive symptoms, andcareful selection and monitoring is needed in individuals
with co-occurring substance use disorders [I].
In patients who smoke, bupropion [I] or nortriptyline[II] may be options to simultaneously treat depression andassist with smoking cessation. When possible, a period of
substance abstinence can help determine whether the depressive episode is related to substance intoxication orwithdrawal [II]. Factors that suggest a need for antidepressant treatment soon after cessation of substance use
include a family history of major depressive disorder anda history of major depressive disorder preceding the onset of the substance use disorder or during periods of sobriety [II].
For patients who have a personality disorder as well as
major depressive disorder, psychiatrists should institutetreatment for the major depressive disorder [I] and consider psychotherapeutic and adjunctive pharmacotherapeutic treatment for personality disorder symptoms [II].
b. Demographic and psychosocial factors
Several aspects of assessment and treatment differ between women and men. Because the symptoms of some
women may fluctuate with gonadal hormone levels, theevaluation should include a detailed assessment of moodchanges across the reproductive life history (e.g., menstruation, pregnancy, birth control including oral contraception use, abortions, menopause) [I]. When prescribing
medications to women who are taking oral contraceptives,
the potential effects of drug-drug interactions must be
considered [I]. For women in the perimenopausal period,
SSRI and SNRI antidepressants are useful in ameliorating
depression as well as in reducing somatic symptoms suchas hot flashes [II]. Both men and women who are taking antidepressants should be asked whether sexual side effects
are occurring with these medications [I]. Men for whom
trazodone is prescribed should be warned of the risk ofpriapism [I].
The treatment of major depressive disorder in women
who are pregnant or planning to become pregnant requires a careful consideration of the benefits and risks of

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
available treatment options for the patient and the fetus [I].
For women who are currently receiving treatment for depression, a pregnancy should be planned, whenever possible, in consultation with the treating psychiatrist, who
may wish to consult with a specialist in perinatal psychiatry [I]. In women who are pregnant, planning to become
pregnant, or breast-feeding, depression-focused psychotherapy alone is recommended [II] and should always be
considered as an initial option, particularly for mild tomoderate depression, for patients who prefer psychotherapy, or for those with a prior positive response topsychotherapy [I]. Antidepressant medication should beconsidered for pregnant women who have moderate tosevere major depressive disorder as well as for those whoare in remission from major depressive disorder, are receiving maintenance medication, and are deemed to be athigh risk for a recurrence if the medication is discontinued [II]. When antidepressants are prescribed to a pregnant
woman, changes in pharmacokinetics during pregnancy
may require adjustments in medication doses [I]. Electroconvulsive therapy may be considered for the treatment ofdepression during pregnancy in patients who have psychotic or catatonic features, whose symptoms are severeor have not responded to medications, or who prefer treatment with ECT [II]. When a woman decides to nurse, thepotential benefits of antidepressant medications for themother should be balanced against the potential risks to
the newborn from receiving antidepressant in the mother’s
milk [I]. For women who are depressed during the postpartum period, it is important to evaluate for the presenceof suicidal ideas, homicidal ideas, and psychotic symptoms [I]. The evaluation should also assess parenting skills
for the newborn and for other children in the patient’s
care [I].
In individuals with late-life depression, identificationof co-occurring general medical conditions is essential, as
these disorders may mimic depression or affect choice ordosing of medications [I]. Older individuals may also be
particularly sensitive to medication side effects (e.g.,
hypotension, anticholinergic effects) and require adjustment of medication doses for hepatic or renal dysfunction[I]. In other respects, treatment for depression should parallel that used in younger age groups [I].
The assessment and treatment of major depressive disorder should consider the impact of language barriers, aswell as cultural variables that may influence symptom presentation, treatment preferences, and the degree to which
psychiatric illness is stigmatized [I]. When antidepressants are prescribed, the psychiatrist should recognizethat ethnic groups may differ in their metabolism and response to medications [II].

21

Issues relating to the family situation and family history, including mood disorders and suicide, can also affecttreatment planning and are an important element of theinitial evaluation [I]. A family history of bipolar disorder
or acute psychosis suggests a need for increased attention
to possible signs of bipolar illness in the patient (e.g., withantidepressant treatment) [I]. A family history of recurrent major depressive disorder increases the likelihood ofrecurrent episodes in the patient and supports a need formaintenance treatment [II]. Family history of a response
to a particular antidepressant may sometimes help inchoosing a specific antidepressant for the patient [III]. Because problems within the family may become an ongoingstressor that hampers the patient’s response to treatment,
and because depression in a family is a major stress in itself, such factors should be identified and strong consideration given to educating the family about the nature of
the illness, enlisting the family’s support, and providing
family therapy, when indicated [II].
For patients who have experienced a recent bereavement, psychotherapy or antidepressant treatment should
be used when the reaction to a loss is particularly prolonged or accompanied by significant psychopathology
and functional impairment [I]. Support groups may be
helpful for some bereaved individuals [III].
c.

Co-occurring general medical conditions

In patients with major depressive disorder, it is importantto recognize and address the potential interplay between
major depressive disorder and any co-occurring general
medical conditions [I]. Communication with other clinicians who are providing treatment for general medical
conditions is recommended [I]. The clinical assessment
should include identifying any potential interactions between medications used to treat depression and those used
to treat general medical conditions [I]. Assessment of painis also important as it can contribute to and co-occur withdepression [I]. In addition, the psychiatrist should consider the effects of prescribed psychotropic medications
on the patient’s general medical conditions, as well as theeffects of interventions for such disorders on the patient’s
psychiatric condition [I].
In patients with preexisting hypertension or cardiac
conditions, treatment with specific antidepressant agents
may suggest a need for monitoring of vital signs or cardiac rhythm (e.g., electrocardiogram [ECG] with TCA
treatment; heart rate and blood pressure assessment with
SNRIs and TCAs) [I]. When using antidepressant medications with anticholinergic side effects, it is important toconsider the potential for increases in heart rate in individuals with cardiac disease, worsening cognition in individ-

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22

APA PRACTICE GUIDELINES

uals with dementia, development of bladder outlet
obstruction in men with prostatic hypertrophy, and precipitation or worsening of narrow angle glaucoma [I]. Some
antidepressant drugs (e.g., bupropion, clomipramine,
maprotiline) reduce the seizure threshold and should be
used with caution in individuals with preexisting seizure disorders [II]. In individuals with Parkinson’s disease, thechoice of an antidepressant should consider that serotonergic agents may worsen symptoms of the disease [II],that bupropion has potential dopamine agonist effects(benefitting symptoms of Parkinson’s disease but potentially worsening psychosis) [II], and that selegiline has antiparkinsonian and antidepressant effects but may interact
with L-dopa and with other antidepressant agents [I]. In
treating the depressive syndrome that commonly occurs
following a stroke, consideration should be given to thepotential for interactions between antidepressants andanticoagulating (including antiplatelet) medications [I].
Given the health risks associated with obesity and the tendency of some antidepressant medications to contribute toweight gain, longitudinal monitoring of weight (either bydirect measurement or patient report) is recommended[I], as well as calculation of body mass index (BMI) [II]. If
significant increases are noted in the patient’s weight or
BMI, the clinician and patient should discuss potential approaches to weight control such as diet, exercise, change inmedication, nutrition consultation, or collaboration withthe patient’s primary care physician [I]. In patients who
have undergone bariatric surgery to treat obesity, adjustment of medication formulations or doses may be required because of altered medication absorption [I]. For
diabetic patients, it is useful to collaborate with the patient’s primary care physician in monitoring diabetic control when initiating antidepressant therapy or making
significant dosing adjustments [II]. Clinicians should be
alert to the possibility of sleep apnea in patients with depres-II.

sion, particularly those who present with daytime sleepiness, fatigue, or treatment-resistant symptoms [II]. In
patients with known sleep apnea, treatment choice should
consider the sedative side effects of medication, with minimally sedating options chosen whenever possible [I]. Given
the significant numbers of individuals with unrecognizedhuman immunodeficiency virus (HIV) infection and theavailability of effective treatment, consideration should begiven to HIV risk assessment and screening [I]. For patients with HIV infection who are receiving antiretroviraltherapy, the potential for drug-drug interactions needs to beassessed before initiating any psychotropic medications [I].
Patients who are being treated with antiretroviral medications should be cautioned about drug-drug interactions
with St. John’s wort that can reduce the effectiveness of
HIV treatments [I]. In patients with hepatitis C infection,interferon can exacerbate depressive symptoms, making
it important to monitor patients carefully for worsening
depressive symptoms during the course of interferon
treatment [I]. Because tamoxifen requires active 2D6 enzyme function to be clinically efficacious, patients who
receive tamoxifen for breast cancer or other indications
should generally be treated with an antidepressant (e.g.,citalopram, escitalopram, venlafaxine, desvenlafaxine)that has minimal effect on metabolism through the cytochrome P450 2D6 isoenzyme [I]. When depression occurs in the context of chronic pain, SNRIs and TCAs may
be preferable to other antidepressive agents [II]. When
ECT is used to treat major depressive disorder in an individual with a co-occurring general medical condition,
the evaluation should identify conditions that could require modifications in ECT technique (e.g., cardiac conditions, hypertension, central nervous system lesions) [I];these should be addressed insofar as possible and discussed with the patient as part of the informed consent
process [I].

FORMULATION AND IMPLEMENTATION
OF A TREATMENT PLAN

A. PSYCHIATRIC MANAGEMENT
For all patients with major depressive disorder, psychiatric management includes a broad array of possible interventions and activities. Essential components include
educating the patient and when appropriate the family
about depression, discussing treatment options and interventions, and enhancing adherence to treatment. Devel-

oping a successful plan of treatment for individuals withmajor depressive disorder is also promoted by an initial,
thorough assessment of the patient. In addition, the psychiatrist must determine the treatment setting that will bemost likely to enhance the patient’s safety as well as promote improvement in the patient’s condition. These elements of psychiatric management are described in moredetail below.

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
1. Establish and maintain a therapeutic allianceA psychiatric assessment begins with establishing therapeutic rapport and developing an alliance with the patient,regardless of the treatment modalities ultimately selected.
The alliance itself may be the primary active therapeutic
agent even for patients who receive monotherapy withmedication (4). To establish and maintain a therapeutic alliance, it is important for the psychiatrist to be sensitive tothe patient’s concerns. By virtue of their depressed state,patients often view themselves in a negative light. They
may feel unworthy of help, embarrassed or ashamed ofhaving an illness, guilty about placing burdens on family
members or the clinician, and distant or alienated fromothers. Individuals may also have a negative view of priortreatment experiences or have misconceptions about psychiatric treatment, which can color the therapeutic relationship. Such issues require open discussion to educate
the patient about the goals and framework of treatment
and to provide an empathic and trusting environment inwhich the patient feels comfortable expressing his or her
self-doubts, fears, and other concerns. Cultural and religious factors may influence the patient’s view of the depressive illness, his or her receptiveness to psychiatric treatment,
and his or her preference of treatment modalities (5–7).
Establishing a therapeutic alliance with a clinician of a different background may present additional challenges forsome patients. Management of the therapeutic allianceshould also include awareness of transference and countertransference issues, even if these are not directly addressedin treatment.
Because patients frequently have strong preferences
about treatment options, the psychiatrist should identify
the patient’s wishes for treatment and collaborate with thepatient in choosing among effective treatments. In addition, treatment adherence can be enhanced by the deliveryof patient-centered care and by a strong treatment alliance with the psychiatrist. Severe or persistent problemsof poor alliance or nonadherence to treatment may becaused by the depressive symptoms themselves. They may
also represent psychological conflicts or a psychopathological condition for which psychotherapy should be considered.
If possible and appropriate, the family should be included in discussions about the patient’s illness and plans
for treatment. When family members are involved, they
can also be encouraged to play a helpful role in improving
the patient’s adherence to treatment and supporting thetherapeutic alliance.

2. Complete the psychiatric assessment
Patients with symptoms of depression should receive athorough biopsychosocial assessment, both to determine

23

whether a diagnosis of major depressive disorder is warranted and to identify the presence of other psychiatric or
general medical conditions. The general principles andcomponents of a complete psychiatric evaluation have beenoutlined in APA’s Practice Guideline for Psychiatric Evaluation of Adults, Second Edition (8). The evaluation includes ahistory of the present illness and current symptoms, including vegetative symptoms and symptoms of mania or
psychosis, as well as a psychiatric history that particularly
notes current treatments, responses to previous treatments, past hospitalizations or suicide attempts, and thepresence of co-occurring psychiatric disorders. Assessing
the severity of the specific symptoms of depression may
be aided by the use of standardized clinician- or patientadministered rating scales such as those described in Section II.A.8.
Many individuals with depression attempt to alleviate
symptoms through the use of alternative or complementary treatments, over-the-counter or prescription medications or dietary regimens, or through use of caffeine,
tobacco, alcohol, or other substances, which may precipitate or exacerbate depressive symptoms. Consequently,
each of these factors should be carefully assessed. The personal history will include an assessment of psychologicaldevelopment; a sexual history, including history of sexual
abuse or assault; identification of early life trauma, including physical, sexual, or emotional abuse or neglect; determination of responses to life transitions, major life events,
or significant traumas; a social history; and an occupational
history, including history of military service. Co-occurring general medical conditions are common and can influence the diagnosis of major depressive disorder as well
as choices of treatment. Thus, a general medical history isessential, along with a review of the patient’s current medications; a review of systems, including assessment for
pain; and any indicated diagnostic tests or physical examinations. The latter may be done by the psychiatrist or byanother physician or medically trained clinician. A mental
status examination is crucial in identifying signs of depression, associated psychosis, cognitive deficits, and factors
influencing suicide risk (e.g., suicidal ideas, anxiety), as
well as in identifying co-occurring psychiatric disorders.
Because major depressive disorder is associated with functional impairment, the presence, type, and severity of thedysfunction should be evaluated. Impairments can include
deficits in interpersonal relationships and family functioning, work performance, maintenance of health andhygiene, and deficits in quality of life. Whenever feasible,
assessment should also include input from family members
in order to determine the impact of the patient’s condition
on his or her family. Family members and significant others can also report key elements of the patient’s history or

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24
recent status that the patient may minimize or be unable
to recall or report accurately. In addition, family functioning may affect the outcome of the patient’s depressive illness (9, 10).
A family history is also important to obtain and involves the collection of the family pedigree including parents, grandparents, and number and sex of siblings andchildren. For patients with children at home, informationon their symptom state may be useful because of the highpossibility of psychiatric problems in the offspring of a depressed parent (11, 12). Such problems may require intervention or may be an added stressor for the patient. The
family history includes history of depression or other mooddisorders, substance use disorders, psychosis, suicide, andunusual behaviors in the patient’s relatives along with any
associated impairments. Because family history is a potent
and consistent risk factor for mental disorders, formulating diagnosis and treatment decisions for the patient canbe aided by knowing the age of onset and severity of psychiatric symptoms in the patient’s family, as well as relatives’
psychiatric treatment history, especially the tolerability
and effectiveness of those treatments.
In establishing a diagnosis of major depressive disorderas part of the initial assessment, other differential diagnostic possibilities are important to consider. An initialconsideration in the differential diagnosis is mood disorderdue to a general medical condition. Specific medical conditions that are important to consider and that may be associated with a major depressive episode include neurologicalconditions (e.g., stroke, Parkinson’s disease, dementia,
multiple sclerosis), thyroid disorders, metabolic conditions(e.g., hypercalcemia), malignancy, and infectious diseases(13–15). Depressive symptoms that would otherwise bediagnosable as major depressive disorder are diagnosed
instead as a mood disorder due to a general medical condition if the mood disturbance is judged to be the direct
physiological consequence of a specific general medical condition. Similarly, medications used to treat general medical
conditions may induce depressive syndromes. Such medications include transplant anti-rejection agents, chemotherapy agents, interferon, steroids, some antibiotics, andothers. Depression caused by medications is classified in
the DSM-IV-TR as other (or unknown) substanceinduced mood disorder (DSM-IV-TR code 292.84) (16).
Psychosocial stressors and other antecedent events,
and their possible contribution to the generation of depressive symptoms, should be explored in the course of a
psychiatric assessment. Depressive symptoms are a common response to psychosocial stressors, particularly bereavement. Symptoms characteristic of a major depressive
episode may arise after a significant loss; however, the diagnosis of major depressive disorder is generally not given

APA PRACTICE GUIDELINES
unless depressive symptoms are still present 2 months
after the loss, are particularly severe, or are uncharacteristic of or unrelated to bereavement, such as persistentsuicidal ideation or morbid preoccupation with worthlessness or guilt (16). Following a stressor, depressive symptoms that do not reach sufficient number or severity to beclassified as a major depressive episode may be better described as an adjustment disorder. Despite the possible
presence of antecedent stressors, psychiatrists should notdismiss potentially disabling depressive symptoms as “normal,” thereby depriving patients of needed therapeutic attention.
A thorough assessment of depression also includes theevaluation of psychotic symptoms. Major depressive disorder may be associated with mood-congruent and moodincongruent hallucinations and delusions. Depressed patients may not initially present with psychotic symptoms,
and patients may wish to hide shaming or distressing
thoughts. Therefore, psychiatrists should carefully query
patients about such symptoms in order to provide appropriate treatments for them (see Section III.A.2.a). Identifying the presence of atypical, melancholic, or catatonic
features of depression is also important, as such features
may influence the choice of treatments (see Sections
III.A.2.b, III.A.2.c, and III.A.2.d). Considering that major
depressive episodes are common in the course of bipolar I
disorder and that recurrent major depressive episodes arecharacteristic of bipolar II disorder (17), it is important toconsider bipolar disorders as part of the differential diagnosis of major depressive disorder. This distinction is especially
important because the treatments for bipolar disorders often differ from those for major depressive disorder.
All patients who present for treatment for a major depressive episode should be screened for a past history ofmanic or hypomanic episodes and for past adverse reactions to antidepressants that might be consistent with a“switch” into hypomania or mania. Screening instruments
for manic and hypomanic episodes include the Mood Disorders Questionnaire (18) and the Screening Assessmentof Depression–Polarity, which includes three easily administered dichotomous questions (19). However, sincepatients are often unaware of prior hypomanic or manic
episodes, even when questioned carefully, collateralsources of information, such as family members livingwith the patient, may be crucial in uncovering such episodes. Clinical assessment should also include whether or
not the patient is experiencing a mixed episode, which ischaracterized by symptoms of both a major depressive episode and a manic episode that occur nearly every day forat least 1 week.
It is also important to consider the frequency and chronicity of prior episodes of major depressive disorder.

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
Chronic forms of depression—such as dysthymic disorder,“double depression” (dysthymic disorder and major depressive disorder), and major depressive disorder with the“chronic” specifier—are all depressions with a duration ofat least 2 years. In clinical studies, chronic depression has alower response rate than nonchronic depression, but because the placebo-response rate is also lower, the relative
clinical benefit is comparable. The onset of benefit inchronic depression appears more gradual than in nonchronic depression. However, despite a smaller response rateand slower response, it is important to recognize thatchronic depression is not treatment refractory (20). Unfortunately, however, in many patients, chronic depression
remains undiagnosed or, if diagnosed, undertreated (21).
The presence of a family history of a mood disordershould also be determined. Family histories of major depressive disorder and bipolar disorder are common in
those with major depressive disorder, but a family historyof bipolar disorder may indicate increased risk of bipolar
disorder in the patient. A family history of suicide is relevant in determining a patient’s suicide risk (22) and may
also signal the presence of an unrecognized mood disorder in a relative.

3. Evaluate the safety of the patient
Addressing safety concerns may take precedence over establishing a full differential diagnosis or completing thepsychiatric assessment. Because of the increased rates ofsuicide in depressed patients (22–24), a thorough and ongoing evaluation of the patient’s suicide risk is essential.
Some components of an evaluation for suicidal risk aresummarized in Table 1. The psychiatrist should evaluate
the presence of suicidal ideation and behaviors, the extent
to which the patient has made plans for or begun to prepare
for suicide, the availability and lethality of the means for
suicide, and the degree to which the patient intends to act
on suicidal plans. A complete assessment also includes clinical factors that may increase the likelihood of a patient’s
acting on suicidal ideation, including a history of prior suicide attempts and the presence of psychotic symptoms, severe anxiety, panic attacks, impulsivity, and substance use.
Patients should also be asked about a family history of suicide and recent exposure to suicide or suicide attempts byothers. A suicide risk assessment should be individualized
to the particular circumstances of the patient by including
an evaluation of the patient’s strengths, motivation to seek
help, social support systems, and physical health.
Despite the best efforts of the psychiatrist, some patients may engage in self-harm (22). Even with careful assessments of suicide risk, the ability to predict suicidal
behavior is poor, with many false positives (i.e., patients
who appear more likely to make attempts or die by suicide

TABLE 1.

25

Factors to Consider in Assessing Suicide Risk

Lifetime history, nature, seriousness, and number ofprevious attempts and aborted attempts
Presence, history, and lethality of suicidal ideation,
intent, or plans
Access to means for suicide and the lethality of thosemeans, such as access to a firearm
Presence of hopelessness, psychic pain, decreased
self-esteem, narcissistic vulnerability
Presence of severe anxiety, panic attacks, agitation,
impulsivity
Presence and history of aggression and violence
Nature of cognition, such as loss of executive function,
thought constriction (tunnel vision), polarized
thinking, closed-mindedness, poor coping andproblem-solving skills
Presence of psychotic symptoms, such as commandhallucinations or poor reality testing
Presence of alcohol or other substance use
Presence of major psychiatric disorders, such as major
depressive disorder, bipolar disorder, schizophrenia,
anorexia nervosa, alcohol use disorder, other substanceuse disorders, cluster B personality disorders
Recent psychiatric hospitalization
Presence of disabling medical illness, especially withpoor prognosis, such as chronic pain, brain and spinal
cord injury, malignant neoplasm, HIV or acquired
immunodeficiency syndrome (AIDS), Huntington’sdisease, chronic hemodialysis-treated renal failure,chronic obstructive pulmonary disease
Demographic features, such as age, race, marital status,
sexual orientation
Presence of acute or chronic psychosocial stressors, which
may include actual or perceived interpersonal losses,
financial difficulties or changes in socioeconomic status,
family discord, domestic partner violence, and past or
current sexual or physical abuse or neglect
Absence of psychosocial support, such as poor
relationships with family, unemployment, living alone,
unstable or poor therapeutic relationship, recent lossof a relationship
History of childhood traumas, particularly sexual andphysical abuse
Family history of or recent exposure to suicide
Absence of protective factors, such as children in thehome, sense of responsibility to family, pregnancy,
life satisfaction, cultural beliefs, or religiosity
Source: Adapted from APA’s Practice Guideline for the Assessment
and Treatment of Patients With Suicidal Behaviors (22).

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26
but who do not) as well as false negatives (i.e., patients
who appear less likely to make attempts or die by suicide
but who do). The assessment of suicide risk is complicatedby the fact that suicidal individuals often conceal theirthoughts and plans or act impulsively on short-lived suicidal thoughts, making their response to direct questions
an unreliable predictor of dangerousness to self. For thisreason, in addition to using direct questioning, the psychiatrist should also obtain information through observationand collateral history whenever possible (22, 25).
The risk of suicide should also be monitored as treatment proceeds, since variations in depressive symptoms
may be associated with fluctuations in suicide risk. In
youth and young adults, increases in suicidal thoughts andattempts have been reported early in the course of treatment with antidepressants, although no increases in mortality rates were seen in clinical trials (26). Family members
can provide information that increases the likelihood ofearly detection of harmful behaviors. It is also useful toconvey the expectation that family members will call thepsychiatrist if concerns for safety emerge (27). For information about how suicidal ideation or behaviors affect the treatment plan, see Section III.A.1.a.
Although the greatest risk surrounding depression involves the patient’s health, a rare but also potentially disastrous outcome of depression is violence toward others,
including homicide (28, 29). Psychosis, substance abuse,
impulsivity, and a history of aggression increase this risk
(30–32). Psychiatrists accordingly should assess not only
suicidal risk but also history of violence, homicidal ideation, and plans of violence toward others. Additional assessment may be necessary under specific circumstances.
For example, it is important to assess the impact of parental depression (including peripartum depression) on
children in the home, with specific attention given to theparent’s vulnerability to neglect or harm the children (33).
Whenever suicidal or violent ideas are expressed or suspected, careful documentation of the decision-making process is essential. In addition, patients who exhibit suicidal
or violent ideas or intent require close monitoring.

4. Establish the appropriate setting for treatment
Treatment settings for patients with major depressive disorder include a continuum of possible levels of care, frominvoluntary hospitalizations to partial hospital programs,
skilled nursing homes, and in-home care. In general, patients should be treated in the least restrictive setting thatis most likely to prove safe and effective. The psychiatrist
should choose an appropriate site of treatment after evaluating the patient’s clinical condition, including symptom
severity, co-occurring conditions, level of functioning, andavailable support system. The estimated degree of risk to

APA PRACTICE GUIDELINES
self and to others is another significant determinant oftreatment setting. Decisions about treatment setting
should also include consideration of the patient’s ability toadequately care for him- or herself, provide reliable feedback to the psychiatrist, and cooperate with treatment of
the major depressive disorder.
Patients with suicidal or homicidal ideation, intention,or plans require close monitoring. For those at significant
risk, measures such as hospitalization should be considered; hospitalization is usually indicated for patients whoare considered to pose a serious threat of harm to themselves or others. Patients who refuse can be hospitalized
involuntarily if their condition meets the criteria of the local jurisdiction for involuntary admission. Severely ill patients who lack or reject adequate social support outside ofa hospital setting should be considered for admission to a
hospital or intensive day program, if available. In addition,
patients who also have complicating psychiatric or general
medical conditions or who have not responded adequately
to outpatient treatment may need to be hospitalized.
The optimal treatment setting and the patient’s likelihood of benefit from a different level of care should be
reevaluated on an ongoing basis throughout the course oftreatment. Unfortunately, the spectrum of treatment settings available to patients is often limited by lack of availability of options in the geographic setting, lack of ability
to pay for care, and/or limitations imposed by third party
payers.

5. Evaluate functional impairment and quality of life
The assessment of a patient with major depressive disorder
includes a determination of the severity and chronicity ofsymptoms. Even mild depression can impair function andthreaten life and the quality of life. In the extreme, depressed people may be totally unable to function sociallyor occupationally or even to feed and clothe themselves
and maintain minimal personal hygiene. Severely depressed
patients may be immobilized to the point of being bedridden, with associated medical complications.
The psychiatrist should address impairments in functioning and help the patient to set specific goals appropriate
to his or her functional impairments and symptom severity.
This will likely involve helping the patient to establish intermediate, pragmatic steps in the course of recovery. For
example, the psychiatrist may help patients who are having
difficulty meeting commitments to develop a reasonable
plan to fulfill their obligations (e.g., work, family obligations), potentially by making alternative arrangements.
The psychiatrist may advise other patients not to make major life changes while in the midst of a major depressive
episode. Impairments in the patient’s overall quality of life
should also be assessed, which can be done by asking pa-

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
tients what bothers them the most about their depression
and determining how their current activities and enjoyment of life have been altered by their depressive symptoms. The overall goals of treatment of major depressive
disorder should focus on alleviating functional impairments and improving quality of life in addition to achieving
symptom resolution and episode remission.

6. Coordinate the patient’s care with other clinicians
The psychiatrist should assure that a comprehensive assessment of general medical conditions is performed in order
to identify factors that may precipitate or exacerbate depressive symptoms. He or she may initiate the medical
evaluations or coordinate care with other appropriate clinicians. In some situations, review of medical records provided
by the patient will suffice. In other situations, particularly
when medical treatment is indicated, the psychiatrist should,
with the patient’s permission, arrange for collaborative carewith other clinicians. Such collaboration may incorporate
discussion of prescribed medication, including dose changes
and possible drug interactions as well as necessary diagnostic procedures and medical monitoring, which may include
laboratory measures and ECG (34).
In treating the patient’s depressive illness, a multifaceted
approach is typically required that may include provisionof depression-focused psychotherapy, pharmacotherapy,
ECT, or other therapeutic approaches. Under some circumstances, all aspects of treatment will be administeredby one psychiatrist, and this model of care may improve
integration of treatment components (35) or reduce overall treatment cost (36). In other situations, treatment may
require the coordinated effort of several clinicians. Thisdecision is frequently influenced by the clinicians’ expertise in providing the indicated therapeutic modality,
economic factors, availability of treatment, and by the patient’s preferences. When this treatment model is used,
one team member must assume the primary overall responsibility for the patient’s care. This individual serves as
the coordinator of the treatment plan, advocates for theappropriate level of care, oversees the family involvement,
makes decisions regarding which potential treatment modalities are useful and which should be discontinued, helps
assess the effects of medications, and monitors the patient’s safety. Because of the diversity and depth of medical
knowledge and expertise required for this oversight function, a psychiatrist is generally optimal for this role, although this staffing pattern may not be possible in somehealth care settings. If the treatment is split, the psychiatrist who is providing the psychiatric management and the
medication treatment should meet with the patient frequently enough to monitor his or her care. Ongoing co-27

ordination of the overall treatment plan is essential and isenhanced by clear role definitions, plans for the management of crises or relapses, and regular communication
among the clinicians who are involved in the treatment.
Psychiatrists may at times serve as consultants to ongoing treatment of depression by other prescribers. Healthcare professionals other than psychiatrists may prescribe
antidepressant medication for their patients for a variety ofreasons, including convenience, financial reasons, stigma,
and access to care issues (37). Primary care doctors, obstetricians, and physicians of other disciplines may screen for
depression and initiate treatment for patients. In fact, atleast one-fourth of patients presenting to primary care settings may have major depressive disorder, and 70%–80%
of antidepressants are prescribed by a primary care physician
or medical subspecialist (38, 39). Regardless of whether thepsychiatrist is acting as a consultant or transferring ongoing care to another clinician (e.g., with transition from an
inpatient to outpatient setting), communication and coordination of treatment are essential. Optimal communication with other health care professionals can improveoverall treatment by assuring that medical conditions andpsychosocial issues are appropriately addressed. Good communication also decreases the risk that patients will receive
inconsistent information about treatment options and risks
and benefits. Furthermore, communication among clinicians improves vigilance against relapse, side effects, and risk
to self or others.

7. Monitor the patient’s psychiatric status
As treatment progresses, different features and symptomsof the patient’s illness may emerge or subside. The psychiatrist should carefully and systematically monitor changes
in the patient’s psychiatric status, including major depressive disorder symptoms, as well as symptoms of other potential co-occurring conditions (Table 2). Monitoring thepatient’s status for the emergence of or changes in destructive impulses toward self or others is especially crucial; additional measures such as hospitalization or more intensive
treatment should be considered for patients found to be at
higher risk. In addition, the patient should be monitored
for treatment-emergent side effects, some of which may bedifficult to distinguish from symptoms of the underlying
depressive disorder or co-occurring medical conditions.
Significant changes in a patient’s psychiatric status or the
emergence of new symptoms may warrant a diagnostic reevaluation of the patient. For example, patients who noteworsening irritability, increased difficulty sleeping, racing
thoughts, growing impulsivity, euphoria, or rapid shifts inmood should be monitored more closely and may warrant
re-evaluation and consideration of a possible bipolar dis-

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28
order diagnosis. Often family members or caregivers noticechanges in the status of the patient first and are therefore
able to provide valuable input to the psychiatrist.

8. Integrate measurements into psychiatric management
The integration of measurement tools into psychiatric management, which has been referred to as measurement-basedcare, may enhance the quality of care and improve clinicaloutcomes (40). Clinician-rated and/or self-rated scales canhelp determine the trajectory of disease course and effectsof treatment. Many such scales are available in several versions that vary by number of items. Self-rated scales are convenient to use but require review, interpretation, and discussion with the patient. In research studies, commonly used
tools include the Inventory of Depressive Symptoms (IDS),
which is available in clinician-rated and self-rated versions(http://www.ids-qids.org/), the clinician-rated Hamilton
Rating Scale for Depression (HAM-D) (http://healthnet.
umassmed.edu/mhealth/HAMD.pdf) (41, 42), the clinicianrated Montgomery Asberg Depression Rating Scale(MADRS) (http://www.cnsforum.com/streamfile.aspx?filename=MADRS.pdfandpath=pdf) (43), and the self-rated 9item Patient Health Questionnaire (PHQ-9) (http://www.
depression-primarycare.org/clinicians/toolkits/materials/
forms/phq9/) (44, 45). The Beck Depression Inventory(BDI, BDI-II) is another commonly used, copyrighted, 21question multiple-choice self-rated instrument (46).
Systematic measurement of side effects can also assist in
the provision of treatment. Several self-report rating scales
have been developed for assessing side effects of antidepressant treatment and are available in English and Spanish versions (http://www.edc.pitt.edu/stard/public/ assessment_
forms.html). The Frequency, Intensity, and Burden of Side
Effects Rating Scale (FIBSER), which has also been referred to as the Frequency and Intensity of Side Effects
Rating/Global Rating of Side Effect Burden, uses threeglobal Likert scale ratings to assess side effects experienced
over the preceding week (47, 48). The Patient Rated Inventory of Side Effects (PRISE) is a 9-item scale that asks patients about the presence of side effects in eight organ systemdomains, as well as about other side effects (47, 48). A clinician-administered scale, the Toronto Side Effects Scale,that focuses on antidepressant medication side effects is
also available (http://ww1.cpa-apc.org:8080/publications/archives/cjp/2002/march/orAntidepressantsAppendix.asp)(49). The Udvalg for Kliniske Undersøgelser (UKU) side
effect rating scale (50) (available at http:/ /www.cnsforum.
com/streamfile.aspx?filename=UKU. pdfandpath=pdf) isoften used in research studies and may offer clinicians additional questions that could be asked about side effects,
but it is likely to be too detailed for routine clinical use.

APA PRACTICE GUIDELINESTABLE 2.

Items to Monitor Throughout Treatment

Symptomatic status, including functional status, andquality of life
Degree of danger to self and others
Signs of “switch” to mania
Other mental disorders, including alcohol and othersubstance use disorders
General medical conditions
Response to treatment
Side effects of treatment
Adherence to treatment plan
Although the use of rating scales is not yet common
practice in clinical settings, in part due to pragmatic concerns (51), the use of such scales can be valuable in monitoring symptoms and treatment progress. In addition,
electronic monitoring is becoming more feasible, as electronic health records are more commonly utilized andpatients and psychiatrists have increased access to technological tools that can help monitor and record symptoms.
Baseline data and information about treatment-emergent
changes can be collected systematically from the patientand electronically transmitted via telephone or the Internet. In addition to providing secure electronic capture ofpatient data, computerized decision support systems canbe useful in implementing evidence-based treatment for
major depressive disorder (52).

9. Enhance treatment adherence
For treatment to be successful, it is essential to support thepatient’s adherence to all details of the regimen by providing education about the illness and its treatment, maintaining a strong therapeutic alliance, mobilizing family andother supports (including eliciting questions and clarifying
common misconceptions), evaluating factors affecting adherence, and addressing barriers to adherence as they arise.
Major depressive disorder is often a chronic or recurrent
condition that requires patients to participate actively inand adhere to treatment plans for long periods, despite thefact that side effects or requirements of treatments may beburdensome. Patients may have strong preferences for modality of treatment or medication choice, particularly ifthey or a family member have had past experience with thetreatment or medication. When feasible, factoring in these
preferences may improve adherence to treatment. During
the acute phase, patients with major depressive disorder
may be poorly motivated, unduly pessimistic about theirchances of recovery with treatment, suffering from deficits
in memory, or poorly caring for themselves. During the

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
maintenance phase, euthymic patients may undervalue thebenefits of and focus on the burdens of treatment. The psychiatrist should recognize these possibilities, emphasize theimportance of adherence for successful treatment and prophylaxis, and encourage the patient to articulate any concerns regarding adherence (e.g., side effects, costs of treatment, scheduling conflicts, lack of transportation or childcare). Patient and family attitudes about depression and its
treatment can also influence adherence. Family members
can play an important role in promoting optimism about
treatment, assisting patients with adherence and providing
the psychiatrist with input on side effects or other treatment-related concerns that may influence adherence.
Some aspects of adherence will vary with the type oftreatment being used. For example, patients in psychotherapy may experience increased anxiety as they confront fearful or difficult topics. This anxiety, in turn, may decreaseadherence to psychotherapy, and patients may begin to arrive late to or miss therapy sessions. In patients who are
beginning treatment with a medication, common side effects of medication options should be discussed. Patientsshould be involved in treatment decisions and encouraged
to convey input on side effects that they consider reasonable or unbearable. Side effects such as weight gain, cognitive dulling, sexual side effects, sedation or fatigue, andagitation may represent different burdens to different individuals. Emphasizing the following specific topics improves adherence: 1) explaining when and how often to
take the medicine; 2) suggesting reminder systems, suchas pill boxes, alarms, etc.; 3) discussing the need to takemedication for at least 2–4 weeks before beneficial effects
may be noticed; 4) emphasizing the need to take medication even after feeling better; 5) reviewing the need toconsult with the psychiatrist before discontinuing medication; 6) giving the patient an opportunity to express hisor her understanding of the medication, hearing his or her
concerns, and correcting any misconceptions, and 7) explaining what to do if problems or questions arise (53).
Behavioral tailoring, which involves developing an individualized approach to incorporating medication into thedaily routine and can also include simplifying the medication regimen, has demonstrated efficacy for individuals
with schizophrenia and may also be applicable to individuals
with other psychiatric illnesses (54). Adherence may also
be improved by minimizing the cost and complexity of
medication regimens. Most antidepressant medications
are available in generic forms, which are generally lesscostly. For individuals who cannot afford needed medications, some pharmaceutical companies offer patient assistance programs. Information on such programs isavailable from pharmaceutical company Web sites, fromthe Web site of the Partnership for Prescription Assistance

29(http://www.helpingpatients.org), and from Rx Assist(http://www.rxassist.org).

10. Provide education to the patient and the family
Education concerning major depressive disorder and its
treatments should be provided to all patients. Education isan essential element of obtaining informed consent totreatment. Whenever possible, education should also be
provided to involved family members and significant others, although generally the patient’s consent is required
before such information can be shared. Specific topics todiscuss may include that major depressive disorder is a
medical illness and that effective treatments are both necessary and available. This information may be especially
important for patients who attribute their illness to a
moral defect, or for family members who are convincedthat there is nothing wrong with the patient. Education
regarding available treatment options will help patientsmake informed decisions, anticipate side effects, and adhere to treatments. Patients with depression can become
easily discouraged in treatment, especially if there is lessthan a full initial response. The psychiatrist should encourage and educate patients to distinguish between thehopelessness that is a symptom of depression and the relatively hopeful actual prognosis. In addition, for patientstreated with antidepressant medication or ECT, psychiatrists may choose to discuss a predictable progression oftreatment effects: first, side effects may emerge, then neurovegetative symptoms remit, and finally mood improves.
Often significant others notice symptomatic improvement before the patient does.
Given the chronic, episodic nature of major depressive
disorder, exacerbations are common. Patients, as well as
their families, if appropriate, should be instructed about
the significant risk of relapse. They should be educatedto identify early signs and symptoms of new episodes andthe stressors that may precede them. Patients should also
be instructed to seek adequate treatment as early in thecourse of the new episode as possible to decrease the likelihood of a full-blown exacerbation or complications.
Patient and family education also includes general promotion of healthy behaviors such as good sleep hygieneand decreased use of caffeine, tobacco, alcohol, and otherpotentially deleterious substances. For most individuals,
exercise carries benefits for overall health. Data generally
support at least a modest improvement in mood symptoms for patients with major depressive disorder who engage in aerobic exercise (55–61) or resistance training(62, 63). Regular exercise may also reduce the prevalenceof depressive symptoms in the general population, withspecific benefit found in older adults (64, 65) and individuals with co-occurring medical problems (57, 66).

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30

B. ACUTE PHASE
1. Choice of initial treatment modality
The acute phase of treatment lasts a minimum of 6–12
weeks. During this phase, the aims of treatment are to induce remission of symptoms and achieve a full return tothe patient’s baseline level of functioning. In addition to
general psychiatric management (described in Section
II.A), treatment may consist of pharmacotherapy or othersomatic therapies (e.g., ECT, light therapy), depressionfocused psychotherapy, or the combination of somatic andpsychosocial therapies. Selection of an initial treatment modality is influenced by several factors, including the symptom profile, the presence of co-occurring disorders or
psychosocial stressors, the patient’s prior treatment experience, and the patient’s preference.
Psychiatrists should present patients with information
concerning the evidence for a broad range of treatment
options, including somatic therapies and psychosocial interventions. Antidepressant medications can be used as an
initial treatment modality by patients with mild, moderate, or severe major depressive disorder. Clinical featuresthat may suggest that medications are the preferred treatment modality include a history of prior positive responseto antidepressant medications, the presence of moderate
to severe symptoms, significant sleep or appetite disturbances, agitation, patient preference, and anticipation of
the need for maintenance therapy. Patients with major depressive disorder with psychotic features require either
the combined use of antidepressant and antipsychotic
medications or ECT.
Psychotherapy may also be considered as monotherapy
for patients with mild to moderate major depressive disorder. The availability of clinicians with appropriate training and expertise in specific psychotherapeutic approaches
can be a factor in choosing a psychotherapy (67). Other
factors that can influence this choice may be the psychosocial context, patient preference, prior positive responseto psychotherapy, the presence of significant psychosocial
stressors or interpersonal difficulties, co-occurring Axis II
disorders, or the stage, chronicity, and severity of the major
depressive episode. Specifically, many severely depressed
patients will require both a depression-focused psychotherapy and a somatic treatment such as pharmacotherapy.
Pregnancy, lactation, or the wish to become pregnant may
tilt a decision toward psychotherapy as an initial treatment(see Section III.B.6). Given the lower occurrence of side effects and suggestion of enduring benefits associated withdepression-focused psychotherapies (68), such treatments
might be preferable alternatives to pharmacotherapy forsome patients with mild to moderate depression.

APA PRACTICE GUIDELINES
Combining a depression-focused psychotherapy andpharmacotherapy may be a useful initial treatment choicefor patients with moderate to severe major depressive disorder. Other indications for combined treatment include
chronic forms of depression, psychosocial issues, intrapsychic conflict, interpersonal problems, or a co-occurring Axis II disorder. In addition, patients who have had ahistory of only partial response to adequate trials of single
treatment modalities may benefit from combined treatment. Poor adherence with pharmacotherapy may also
warrant combined treatment with medications and psychotherapy focused on treatment adherence.
Electroconvulsive therapy should be considered as a potential treatment option for all patients with major depressive disorder who have psychotic features or catatonia andfor those with an urgent need for response, such as patients
who are suicidal or who are nutritionally compromised as aresult of refusing food. Electroconvulsive therapy may also
be the treatment modality of choice for patients with major
depressive disorder who have a high degree of symptom
severity. Other considerations include the presence of cooccurring general medical conditions that preclude the useof antidepressant medications, a prior history of positive response to ECT, and patient preference. Evidence for TMS
is currently insufficient to support its use in the initial treatment of major depressive disorder.
If a patient with mild depression wishes to try exercise
alone for several weeks as a first intervention, there is little toargue against it (Section II.A.10), provided the patient is sufficiently monitored for an abrupt worsening of mood or adverse physical effects (e.g., ischemia or musculoskeletal
symptoms). The dose of exercise and adherence to an exercise regimen may be particularly important to monitor in theassessment of whether an exercise intervention is useful for
major depressive disorder (69, 70). If mood fails to improveafter a few weeks with exercise alone, the psychiatrist should
recommend medication or psychotherapy. For patients withdepression of any severity and no medical contraindication
to exercise, physical activity is a reasonable addition to atreatment plan for major depressive disorder. The optimal
regimen is one the patient prefers and will adhere to.
Figure 1 summarizes treatment modalities that may beappropriate during the acute phase of treatment depending on the severity of the patient’s symptoms and other associated features of the depressive episode. It is important
to note that other factors may be relevant to treatment decisions for individual patients and that determinations of
episode severity are imprecise, although rating scales may
be helpful in assessing the magnitude of depressive symptoms and their effects on functional status and quality oflife (see Sections II.A.7 and II.A.8).

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31

Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition

Modality
Pharmacotherapy in
Combination With
Depression-Focused
Psychotherapy

Electroconvulsive
Therapy

Severity of Illness

Pharmacotherapy

Depression-Focused
Psychotherapy

Mild to Moderate

Yes

Yes

May be useful forpatients with psychosocial or interpersonal
problems, intrapsychic conflict, or
co-occurring Axis II
disorderYes, for certain
patients

Severe Without
Psychotic Features

Yes

No

Yes

Yes

Severe With
Psychotic Features

Yes, provide both
antidepressant andantipsychotic
medication

No

FIGURE 1.

Yes, provide both
antidepressant andantipsychotic
medication

Yes

Recommended Modalities for Acute Phase Treatment of Major Depressive Disorder

2. Pharmacotherapy
Antidepressant medications have been grouped as follows:
1) TCAs, which for the purposes of this guideline also
include the tetracyclic antidepressant medication maprotiline; 2) SSRIs, which include fluoxetine, sertraline,
paroxetine, fluvoxamine, citalopram, and escitalopram;3) SNRIs, which include venlafaxine, desvenlafaxine, andduloxetine; 4) other antidepressant medications, including bupropion, nefazodone, trazodone, and mirtazapine;and 5) MAOIs, which include phenelzine, tranylcypromine, isocarboxazid, and the transdermal formulation ofselegiline. Although some studies have suggested superiority of one mechanism of action over another, there are
no replicable or robust findings to establish a clinicallymeaningful difference. For most patients, the effectiveness of antidepressant medications is generally comparable
between classes and within classes of medications. Response
rates in clinical trials typically range from 50% to 75% of
patients, with some evidence suggesting greater efficacy
relative to placebo in individuals with severe depressive
symptoms as compared with those with mild to moderate
symptoms (71–73). Although remission rates are less robust
and selective publication of positive studies could affect theapparent effectiveness of treatment (74, 75), these factors
do not appear specific to particular medications or medication classes.
Nevertheless, antidepressant medications do differ intheir potential to cause particular side effects such as adverse

sexual effects, sedation, or weight gain. Therefore, theinitial selection of an antidepressant medication will
largely be based on the tolerability, safety, and cost of the
medication, as well as patient preference and history ofprior medication treatment (Table 3). Other factors include the medication half-life and potential for drug interactions related to properties such as plasma protein
binding or metabolism through the cytochrome P450
system (Tables 4 and 5). On the basis of these considerations, the following medications are optimal for mostpatients: SSRIs, SNRIs, mirtazapine, and bupropion.
Table 6 provides the starting and usual doses of medications that have been shown to be effective for treating
major depressive disorder.

TABLE 3.

Factors to Consider in Choosing an AntidepressantMedication

Patient preference
Nature of prior response to medication
Relative efficacy and effectiveness
Safety, tolerability, and anticipated side effects
Co-occurring psychiatric or general medical
conditions
Potential drug interactions
Half-life
Cost

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32
TABLE 4.

APA PRACTICE GUIDELINES
Cytochrome P450 Enzyme Metabolism of Antidepressive Agents

a

1A2

2B6

2C9

2C19

2D6

3A4

Amitriptyline

+

+

++

++

++

+

Bupropionb
Hydroxybupropion

+

++

+

Citalopram
Desipramine

+
++
++

+

+
++

Desvenlafaxine
Duloxetine

+
++

++

Escitalopram
Fluoxetineb
Norfluoxetine++

Imipramine+++

Maprotiline+

Mirtazapineb8-HydroxymirtazapinebMirtazapine-N-oxide++

Nortriptyline

+

++

++

+

+

+

++
+++

+

++

++

++

++
+

+

++
++

+
++
++

++

+

Paroxetine++

Protriptyline++

Selegiline
Sertraline

++

+

++
++

VenlafaxinebO-Norvenlafaxine

+

+

+

++

+

+

+

+

++
++

+

Sources: (82, 83). The extent to which each medication is a substrate for a specific enzyme is indicated as follows: +++ = exclusive substrate, ++ = major substrate, + = minor substrate.
a
Information about drug metabolism and drug-drug interactions is constantly evolving. The information in this table can serve as a
guide; however, the reader is encouraged to access regularly updated online sources of drug-drug interactions.
b
Active metabolite of parent compound.

In choosing an antidepressant medication, many psychiatrists also consider the family history of response toparticular medications; however, the impact of this factor
on the likelihood of the patient’s response to these medications is unclear. Nevertheless, the medication experiencesof others close to the patient do influence the patient’s belief about particular medications and pharmacotherapy ingeneral.
The presence of co-occurring psychiatric or general
medical conditions can be a significant factor influencing
the choice of an antidepressant medication. For example,
TCAs are generally not optimal in patients with cardiovascular conditions, cardiac conduction defects, closed angle
glaucoma, urinary retention, significant prostatic hypertrophy, or eating disorders with significant malnutritionor purging. In older adults and others with malnutrition,
autonomic disorders (e.g., diabetic neuropathy, Parkinson’s disease), or low blood pressure, TCAs may exacerbate hypotension and orthostasis, resulting in syncope orfalls. Selective serotonin reuptake inhibitors and SNRIs
may be inappropriate for patients who are experiencing
sexual dysfunction. Patients who are receiving tamoxifen
for breast cancer or other indications should generally betreated with an antidepressant (e.g., citalopram, escitalopram, venlafaxine, desvenlafaxine) that has minimal effecton metabolism through the cytochrome P450 2D6 isoenzyme, because reduced metabolism of tamoxifen throughCYP 2D6 is likely to be associated with lower levels oftamoxifen’s active metabolite (76–79) with the possibility ofpoorer patient outcomes (80, 81).

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33

Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
Cytochrome P450 Enzyme Inhibition by Antidepressive Agents

TABLE 5.

1A2
Amitriptyline

2A6

2B6

a

2C8

+

2C9

2C19

2D6

+

2E1

3A4

+

Bupropion+++

Citalopram

+
b

+
++

Desipramine

+

++

+
++

+

Desvenlafaxine+

Duloxetine++

Escitalopram++

Fluoxetinec
Norfluoxetine
Imipramine++++

Mirtazapine+

Nortriptyline

++

++
++

++

+
+

++
+

++
+

Selegiline+

Sertraline
Desmethylsertralinec
Venlafaxine

+

+
+
+
+

d

Paroxetine

+++
++
+

+++
+
++
+
+

+

+
+

+

+++

+

+

+

+
+

++

++
+
+

+

++
+

+

+
++
+
+

Sources: (82, 83). The extent to which each medication is a substrate for a specific enzyme is indicated as follows: +++ = strong inhibitor, ++ = moderate inhibitor, + = weak inhibitor.
a
Information about drug metabolism and drug-drug interactions is constantly evolving. The information in this table can serve as a
guide; however, the reader is encouraged to access regularly updated online sources of drug-drug interactions.
bcdAlso a metabolite of imipramine. Active metabolite of parent compound. Also a metabolite of amitriptyline.

Because of the need for dietary restrictions and the potential for serious side effects and drug interactions, use of
MAOIs is generally limited to patients who do not respond to other treatments. MAOIs may be particularly
effective for patients with major depressive disorder withatypical features, although many psychiatrists prefer toprescribe SSRIs for such patients because of SSRIs’ greater
safety and tolerability and more favorable adverse effectprofile.
a.

Efficacy of antidepressant medications

1. Selective serotonin reuptake inhibitors
Selective serotonin reuptake inhibitors currently available
include fluoxetine, sertraline, paroxetine, fluvoxamine,
citalopram, and escitalopram. A large body of literature
supports the superiority of SSRIs compared with placeboin the treatment of major depressive disorder. In morethan 10 systematic reviews and meta-analyses, the effectiveness of SSRIs has been compared with that of other antidepressant medications, mainly TCAs. The SSRIs havedemonstrated comparable efficacy to the TCAs (84–88),

even when anxiety symptoms are considered (85, 87–90).
Although a few analyses suggest small advantages of
SNRIs over SSRIs in rates of remission (91), a preponderance of the data finds no significant evidence of the superiority of any other class or agents over SSRIs (84, 89, 90,
92–95). One meta-analysis suggests a slight superiority of
escitalopram compared with other SSRIs and venlafaxine(93), and another found significantly greater efficacy for
escitalopram, sertraline, venlafaxine, and mirtazapine ascompared with duloxetine, fluoxetine, fluvoxamine, andparoxetine (96), but other studies show no differences in
efficacy among individual SSRIs (84, 93–95, 97, 98).
2. Serotonin norepinephrine reuptake inhibitors
The serotonin norepinephrine reuptake inhibitors currently
available are venlafaxine, desvenlafaxine (the principal
metabolite of venlafaxine), and duloxetine. An immediaterelease form of venlafaxine is available, but most clinicians
prefer the extended-release formulation because it is approved for once-daily dosing and may be less often associated with reported withdrawal symptoms.

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34
TABLE 6.

APA PRACTICE GUIDELINES
Dosing of Medications Shown To Be Effective in Treating Major Depressive DisorderaStarting Doseb
(mg/day)

Usual Dosec
(mg/day)

Citalopram
Escitalopram
Fluoxetine

20
10
20

20–60e
10–20
e
20–60

Paroxetine
Paroxetine, extended release
Sertraline

20
12.5
50

20–60
25–75
e
50–200

150
150
150

300–450
300–400
300–450

37.5
37.5
50
60

75–37575–375f50
60–12050150

150–300
150–600

15

15–45

25–50
25–50
25–50
25–50
25
25–50
10–20
75

100–300
100–300
100–300
100–300
50–20075–300
20–60
100–225

15
10
10–20

45–90
30–60
30–60

6

6–12

150

300–600

Generic Name
Selective serotonin reuptake inhibitorsdedDopamine norepinephrine reuptake inhibitor
Bupropion, immediate release
Bupropion, sustained release
Bupropion, extended release
Serotonin norepinephrine reuptake inhibitorsd
Venlafaxine, immediate release
Venlafaxine, extended release
Desvenlafaxine
Duloxetine
Serotonin modulators
Nefazodone
Trazodoneg
Norepinephrine-serotonin modulatordMirtazapine
Tricyclics and tetracyclics
Amitriptyline
Doxepin
Imipramine
Desipramine
Nortriptyline
Trimipramine
Protriptyline
Maprotiline
Monoamine oxidase inhibitors (MAOIs)
Irreversible, nonselective inhibitors
Phenelzine
Tranylcypromine
Isocarboxazid
Irreversible, MAO B selective inhibitorh
Selegiline transdermal
Reversible MAO A selective inhibitor
Moclobemidea

For convenience, medications other than TCAs have been classified by their presumptive mechanism of action. However, the exactbmechanism of action of several medications has yet to be determined or varies by dose. Lower starting doses are recommended forelderly patients and for patients with panic disorder, significant anxiety or hepatic disease, and co-occurring general medical conditions.
c
For some of these medications (e.g., TCAs) the upper dosing limit reflects risk of toxicity or need for plasma level assessment, whereasdfor other medications (e.g., SSRIs), higher doses can be used safely but without evidence for overall superior efficacy. These medications are likely to be optimal medications in terms of safety, the patient’s acceptance of side effects, and the quantity and quality of clinicaleftrial data. Dose varies with diagnosis; see text for specific guidelines. Has been used at doses up to 400 mg/day, although doses abovegh
50 mg/day may not provide additional benefit. This medication is not typically used for this indication. Selegiline selectively inhibits
MAO B at low doses but inhibits both MAO A and MAO B at the higher doses that are typically required for antidepressant activity.
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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
Each of these medications is efficacious (i.e., superior
to placebo in controlled studies and meta-analyses) (95,99), and venlafaxine (75–150 mg/day) and duloxetine(60 mg/day) showed comparable efficacy in a pair of trials(100). For venlafaxine and perhaps desvenlafaxine, clinically significant norepinephrine reuptake inhibition may
not be achieved for the average patient at lower therapeutic doses, although desvenlafaxine has a much greater
bioavailability, resulting in a lower effective dose. In individual studies, venlafaxine and duloxetine are generally aseffective as SSRIs (see the meta-analyses of Nemeroff etal. [101] and Thase et al. [102] for tabulated summaries ofindividual study results from the more than 40 relevant
randomized controlled trials). Results of comparative
studies of desvenlafaxine are not known at this time. Relative to SSRIs, some analyses of pooled data sets have suggested a small advantage for SNRIs (91), which mightafford clinically modest benefits for patients with more severe depression (102) or for patients who have not responded to prior trials of SSRIs (103). However, othermeta-analyses have shown equivalent efficacy for SSRIs
and SNRIs (95), whereas some have shown superiority of
individual medications but no clearcut medication classeffects (96). Relative to TCAs, venlafaxine’s efficacy iscomparable (91, 104, 105), whereas the more recently introduced duloxetine and desvenlafaxine have not beensystematically compared with TCAs.
3. Other antidepressant medications
A number of other antidepressant medications differ structurally or in their pharmacological action from medicationsin the categories just described and are included here.
Although bupropion is classified as a norepinephrine
and dopamine reuptake inhibitor, the latter effect is relatively weak, and its mechanism of action remains unclear(106). There are three formulations of bupropion: immediate release, sustained release, and extended release.
Bupropion is distinct from most antidepressants in nothaving an indication for the treatment of any primaryanxiety disorder, and it may be less well tolerated thanother antidepressants among patients with significant
anxiety. In addition, a meta-analysis showed that SSRIs
were modestly superior to bupropion for a subset of patients with major depressive disorder and anxiety (107).
For individuals with low to moderate levels of anxiety, thesame meta-analysis showed that the efficacy of bupropion
in treating major depressive disorder was roughly comparable to that of the SSRIs (107). Results of anothermeta-analysis suggested that bupropion may be more likely
to improve symptoms of fatigue and sleepiness than atleast some of the SSRIs (108). Bupropion may be a good
choice for patients who have a goal of quitting smoking as
it has U.S. Food and Drug Administration (FDA) approval

35

for this indication, reduces desire for nicotine, and doubles rates of smoking cessation (109, 110). Patients typically experience minimal weight gain or even weight loss
on bupropion (111), and for this reason it may be an appropriate antidepressant for patients who are overweightor obese.
Mirtazapine is thought to work through noradrenergicand serotonergic mechanisms, although this tetracyclic
compound is not a reuptake inhibitor (112). Mirtazapine
has comparable efficacy to SSRIs (113).
Trazodone is the oldest medication from this groupthat is still in wide use. Although trazodone is an effective
antidepressant, relative to placebo (105, 114, 115), in contemporary practice it is much more likely to be used inlower doses as a sedative-hypnotic than as an antidepressant. Despite widespread use of trazodone as a hypnotic,
few data support its use for this indication.
Nefazodone has an analogous structure to trazodone but
somewhat different pharmacological properties. In comparative trials versus SSRIs, nefazodone showed comparable efficacy and overall tolerability (116).
4. Tricyclic antidepressants
Tricyclic antidepressants (amitriptyline, nortriptyline,
protriptyline, imipramine, desipramine, doxepin, and trimipramine) are effective treatments for major depressive
disorder and have comparable efficacy to other classes ofantidepressants, including SSRIs, SNRIs, and MAOIs(85, 105). The efficacy of subclasses of tricyclics (e.g., secondary amines or tertiary amines) appears to be comparable. TCAs may be particularly effective in certain
populations, such as in hospitalized patients (117, 118).
Conventional wisdom is that this advantage is explainedby the superiority of TCAs (versus SSRIs) among the subsetof patients with melancholia or more severe depression,
because such a specific advantage has not been consistently documented in studies of less severely ill outpatients (85, 105, 118).
5. Monoamine oxidase inhibitors
MAOIs currently used as antidepressants include phenelzine, tranylcypromine, isocarboxazid, moclobemide, andthe transdermally delivered formulation of selegiline.
MAOIs have comparable efficacy to other antidepressants for outpatients with major depressive disorder andmay be appropriate for patients with major depressive disorder who have not responded to safer and more easily
used treatments (119, 120). In fact, the role of MAOIs in
major depressive disorder is now almost exclusively reserved for patients who have not responded to at least several other pharmacotherapies. Studies have demonstrated
the effectiveness of MAOIs in patients who have not responded to other antidepressant medications, particularly

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36
TCAs (119). However, the effectiveness of MAOIs relative to other strategies for treatment-resistant patients incontemporary practice remains unclear, particularly forpatients who have not responded to multiple sequential
trials with SSRIs and SNRIs (121).
MAOIs have been shown to be particularly effective intreating depressed patients with atypical features, so psychiatrists should consider using these medications for patients with symptoms such as reactive moods, reverse neurovegetative symptoms, and sensitivity to rejection (119,120, 122). There do not appear to be any significant differences in efficacy among the older MAOIs (119), although
there are important individual differences in responsiveness, and these medications are not interchangeable.
There are no comparative studies of the newer transdermal (skin patch) formulation of selegiline; its efficacy has
only been established relative to placebo (123–125), andclinical experience is limited.
b. Side effects of antidepressant medications
The severity of side effects from antidepressant medications in clinical trials has been assessed both through thefrequency of reported side effects and through the frequency of treatment dropout. The likelihood of different
side effects varies among classes of antidepressant medications, among subclasses, and among individual agents.
In addition, most newer antidepressants are better tolerated than TCAs (84–88, 97, 117, 126) and safer in overdose (127, 128).
When side effects occur during treatment with an antidepressant, an initial strategy is to lower the dose of theantidepressant or to change to an antidepressant that is
not associated with that side effect. As an example, bupropion can be used if patients encounter sexual side effects
with an SSRI medication. When lowering the dose or discontinuing the medication is not effective, additional strategies may be considered. These additional strategies aredescribed in Table 7, which also lists prominent and clinically relevant side effects associated with particular medication classes.
Serotonin syndrome, as the name implies, is presumed
to result from high levels of serotonin in the brain. Although
it can occur with administration of one or more serotonergic medications, it is most severe when an MAOI is
coadministered with another serotonergic medication.
Consequently, great care must be taken when changing
patients from another antidepressant medication to an
MAOI and from an MAOI to other antidepressant medications because of the persistent effects of discontinued
medications. A washout period is essential before and afterusing an MAOI. If the psychiatrist chooses to discontinue
a monoamine-uptake-blocking antidepressant medication

APA PRACTICE GUIDELINES(e.g., SSRI, SNRI, TCA) and substitute an MAOI, toxic
interactions can best be avoided by allowing at least a 2-weekwashout period between medication trials (Table 8). Thelong half-life of the SSRI fluoxetine and its metabolites
necessitates a 5- to 6-week washout period or longer before the use of an MAOI. Additional information about
serotonin syndrome with specific medication classes canbe found in Sections II.B.2.b.1.g. and II.B.2.b.5.b.
Because knowledge of potential drug-drug interactions
is frequently changing, it is useful to consult a frequently
updated drug information database before selecting anantidepressant in a patient taking other medications.
1. Selective serotonin reuptake inhibitors
SSRIs have comparable tolerability overall, but the specific medications differ somewhat in their side effect profiles, which may guide selection of an agent for anindividual patient. Pharmacokinetic issues, including halflife and effect on the CYP-450 enzyme system, are additional considerations in the choice of an SSRI.
a. Gastrointestinal
SSRIs commonly cause nausea, vomiting, and diarrhea(98). These adverse events are generally dose dependentand tend to dissipate over the first few weeks of treatment.
In some patients, however, diarrhea persists.
b. Activation/insomnia
SSRIs sometimes precipitate or exacerbate restlessness, agitation, and sleep disturbances—side effects that often
attenuate with time. Anxiety may be minimized by introducing the agent at a low dose. Akathisia has also been reported in patients taking SSRIs (129) and may contributeto reported restlessness or activation. If akathisia does occur, a beta-blocker or benzodiazepine can be tried to reduce symptoms. Insomnia can be treated by using sleep
hygiene techniques or CBT as a first approach or by adding a sedative-hypnotic medication or trazodone. Somehave found melatonin to be helpful in treating SSRIinduced insomnia.
c. Sexual side effects
Although loss of erectile or ejaculatory function in men
and loss of libido and anorgasmia in both sexes may becomplications of virtually any antidepressant medication,these side effects appear to be more common with SSRIs.
The psychiatrist should ascertain whether the reported sexual dysfunction is a result of the antidepressant medication,
the underlying major depressive disorder, a co-occurring
medical disorder, a disturbance in a relationship, or a needfor education about sexual functioning. If sexual dysfunction is determined to be a side effect of the antidepressant
medication, a number of strategies are available, including

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
TABLE 7.

37

Potential Treatments for Side Effects of Antidepressant Medications

Side EffectAntidepressant AssociatedWith EffectTreatmenta

Cardiovascular
Arrhythmias

TCAs

Avoid in patients with cardiac instability or ischemia.
Attend to interactions with anti-arrhythmics.

Hypertension

SNRIs, bupropion

Monitor blood pressure. Keep dose as low as possible.
Add antihypertensive.

Hypertensive crisis

MAOIs

Seek emergency treatment. If hypertension is severe,
intravenous antihypertensive agents (e.g., labetalol,
sodium nitroprusside) may be required.

Increase in cholesterol

Mirtazapine

Add a statin.

Orthostatic hypotension

TCAs, trazodone, nefazodone, Add fludrocortisone. Add salt to diet.
MAOIs

Anticholinergic
Constipation

TCAs

Encourage adequate hydration. Add bulk laxative.

Delirium

TCAs

Evaluate for other possible contributors to delirium.

Dry mouth

TCAs, SNRIs, bupropion

Suggest use of sugarless gum or candy.

Urinary hesitancy

TCAs

Add bethanechol.

Visual changes

TCAs

Add pilocarpine eye drops.

Headaches

SSRIs, SNRIs, bupropion

Assess for other etiologies (e.g., caffeinism, bruxism,
migraine, tension headache).

Myoclonus

TCAs, MAOIs

Add clonazepam.

Seizures

Bupropion, TCAs, amoxapine Assess for other etiologies, and add anticonvulsant
medication, if clinically indicated.

Neurologic

SexualArousal, erectile
dysfunction

TCAs, SSRIs, SNRIs

Add sildenafil, tadalafil, buspirone, or bupropion.

Orgasm dysfunction

TCAs, SSRIs, venlafaxine,
desvenlafaxine, MAOIs

Add sildenafil, tadalafil, buspirone, or bupropion.

PriapismTrazodone

Obtain emergency urological evaluation.

Activation

SSRIs, SNRIs, bupropion

Administer in the morning.

Akathisia

SSRIs, SNRIs

Add a beta-blocker or benzodiazepine.

Bruxism

SSRIs

Obtain dental consultation, if clinically indicatedDiaphoresis

TCAs, some SSRIs, SNRIs

Add an α1-adrenergic antagonist (e.g., terazosin), central

Other

α2-adrenergic agonist (e.g., clonidine), or
anticholinergic agent (e.g., benztropine).
Fall risk

TCAs, SSRIs

Monitor blood pressure for evidence of hypotension or
orthostasis; assess for sedation, blurred vision, or
confusion; modify environment to reduce risk.

Gastrointestinal (GI)
bleeding

SSRIs

Identify whether concomitant medications may affectclotting.
(continued)

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38

APA PRACTICE GUIDELINESTABLE 7.

Potential Treatments for Side Effects of Antidepressant Medications (continued)

Side EffectAntidepressant AssociatedWith EffectTreatmenta

Other (continued)
Hepatotoxicity

Nefazodone

Provide education about and monitor for clinicalevidence of hepatic dysfunction. Obtain hepaticfunction tests, if clinically indicated.

Insomnia

SSRIs, SNRIs, bupropion

Use morning dosing. Add a sedative-hypnotic at
bedtime. Add melatonin. Provide CBT or education insleep hygiene.

Nausea, vomiting

SSRIs, SNRIs, bupropion

Administer after food or in divided doses.

Osteopenia

SSRIs

If clinically indicated, obtain bone density monitoring
and add specific treatment to reduce bone loss (e.g.,
calcium and vitamin D supplements, bisphosphonates,
selective estrogen receptor agents).

Sedation

TCAs, trazodone, nefazodone, Use bedtime dosing. Add modafinil or methylphenidate.
mirtazapine

Severe serotonin syndrome MAOIs

Obtain emergency evaluation. Consider admission to a
critical care unit.

Weight gain

Encourage exercise. Obtain input from dietician. Ifchanging antidepressants, consider a secondary amine(if a TCA is required) or other antidepressant withfewer weight issues (e.g., bupropion).

SSRIs, mirtazapine, TCAs,
MAOIs

a

Initial approaches to treatment-emergent side effects include decreasing or discontinuing the medication and changing to anotherantidepressant with a different side effect profile. Treatments included here are additional measures.

continuing treatment to assess whether the dysfunction
will disappear with time, lowering the dose, discontinuing
the antidepressant, or substituting another antidepressantsuch as bupropion (130). Specific pharmacological treatments that can be added for arousal difficulties, erectile
dysfunction, or orgasm dysfunction include buspirone (131),bupropion (132), sildenafil (133), and tadalafil (134). Other
phosphodiesterase inhibitors may be also useful in treating
sexual side effects, and a variety of other medications havebeen used with anecdotal success (135, 136).
d. Neurological effects
Selective serotonin reuptake inhibitors can initially exacerbate both migraine headaches and tension headaches.
These effects tend to be transient and improve within thefirst few weeks of treatment. With continued treatment,
SSRIs may actually help prevent and treat migraine headaches (137, 138). Selective serotonin reuptake inhibitors
have also been associated with extrapyramidal side effects,
including akathisia, dystonia, parkinsonism, and tardive
dyskinesia (139, 140). The incidence of such side effects isvery low with SSRIs but may be higher in older patients,
especially those with Parkinson’s disease.

e.

Falls

Selective serotonin reuptake inhibitors, like other antidepressive agents, have been associated with an increased
risk of falls. In studies of nursing home residents, SSRI
use has been associated with an approximately twofold increase in the risk of a fall (141, 142). An even greater riskof falls in patients who were taking SSRIs was noted in acommunity-based cohort study (143). Meta-analyses havealso documented an increased risk of falls in patientstreated with antidepressive agents, in general (144, 145).
The implications of this increase in fall risk are complicated by the decrease in bone density that has been noted
in depressed patients (146) and in patients treated with
SSRIs (147, 148). An increase in the risk of hip fractures
has also been noted (149). Rarely, SSRI use has been associated with bradycardia, which could also contribute tosyncope and falls (150). In all patients, including thosetreated with SSRIs, fall risk may be increased in individuals receiving benzodiazepines or other hypnotic agents(144, 145, 151) and in those receiving multiple medications (144, 145). Systematically reviewing patients’ medication regimens may help to eliminate medications that

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39

Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
TABLE 8.

Required Washout Times Between Antidepressant Trials

To
MAOI

Non-MAOI

Drug with long-half-life metabolites (e.g., fluoxetine)

5–6

Drug without long-half-life metabolites (e.g., TCAs, paroxetine,
fluvoxamine, venlafaxine)

2

MAOI

2

MAOI

2

may no longer be needed, although such interventions
have not been found to alter fall risk, per se (152). Inquiring about a history of falls in the past year and assessing forabnormalities in gait and balance can also help in identifying patients at particular risk for falling (153).
f. Effects on weight
Weight gain, at times substantial, occurs in some patientstaking SSRIs (154). Patients who take paroxetine have ahigher incidence of weight gain than those who take other
SSRIs (98, 155). Fluoxetine causes an initial reduction inweight, which tends to normalize with continued treatment(156).
g. Serotonin syndrome
Use of SSRIs has been associated with the rare development of a syndrome caused by an excess of central nervous
system serotonergic activity. Features of serotonin syndrome include abdominal pain, diarrhea, flushing, sweating, hyperthermia, lethargy, mental status changes, tremor
and myoclonus, rhabdomyolysis, renal failure, cardiovascular shock, and possibly death (157). Although serotonin
syndrome can occur rarely with the use of SSRIs alone, it isusually associated with the simultaneous use of multiple
serotonergic agents and is most severe when SSRIs are given
together with MAOIs. Consequently, when an SSRI is being changed to an MAOI or vice versa, particular attention
must be give to the duration of time between treatments(Section II.B.2.b) to avoid precipitating a potentially lethal
serotonin syndrome. Serotonin syndrome has also been reported when SSRIs are used in combination with tramadol,
high-dose triptans, or the antibiotic linezolid, which also
has some ability to inhibit MAO (158, 159).
h.

Minimum Washout Period(weeks)From

Drug interactions

The potential for drug-drug interactions differs significantly across the SSRIs. Selective serotonin reuptake inhibitors have variable effects on hepatic microsomal
enzymes and therefore cause both increases and decreases
in the blood levels of other medications. For example,
when SSRIs that strongly inhibit the CYP 2D6 isoenzyme(e.g., paroxetine, fluoxetine) are administered concomitantly with tamoxifen, the metabolism of tamoxifen to its
active metabolite is reduced (76–79), resulting in a potential decrease in its efficacy in preventing breast cancer relapse (80, 81). Interaction with other drugs was higher for
fluoxetine, fluvoxamine, and paroxetine than for sertraline, citalopram, and escitalopram (98, 160, 161).
As described above, there can be a potentially lethal interaction between SSRIs and MAOIs: the serotonin syndrome. At least five half-lives should elapse between thetime an SSRI is stopped and an MAOI is started; for fluoxetine discontinuation, this means waiting approximately
5–6 weeks before starting an MAOI; for discontinuation ofother SSRIs, approximately 2 weeks should pass before
starting an MAOI (162). A 2-week waiting period has beensuggested after discontinuing an MAOI before starting an
SSRI or another MAOI (Table 8).
i.

Discontinuation syndrome

Selective serotonin reuptake inhibitors generally should
not be abruptly discontinued after extended therapy and,
whenever possible, should be tapered over several weeks
to minimize discontinuation-emergent symptoms. Clinical experience and a few controlled studies suggest thatamong the SSRIs, discontinuation-emergent symptoms
are more likely with paroxetine than sertraline, citalopram, or escitalopram and least likely to occur with fluoxetine (due to the long elimination half-life of its primarymetabolite, norfluoxetine) (163, 164). Discontinuationemergent symptoms include both flu-like experiencessuch as nausea, headache, light-headedness, chills, and bodyaches, and neurological symptoms such as paresthesias,
insomnia, and “electric shock-like” phenomena. These
symptoms typically resolve without specific treatment
over 1–2 weeks. However, some patients do experience
more protracted discontinuation syndromes, particularly
those treated with paroxetine, and may require a slower
downward titration regimen. Another strategy is to change
to a brief course of fluoxetine, e.g., 10 mg for 1–2 weeks,
and then taper and discontinue the fluoxetine (165).

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40
2. Serotonin norepinephrine reuptake inhibitors
The most common side effects of the SNRIs (venlafaxine,
desvenlafaxine, and duloxetine) are similar to those seen
with SSRIs, including nausea and vomiting, sexual dysfunction, and activation; like the side effects seen with
SSRIs, those with SNRIs can attenuate with continued
use. The SNRIs also are more likely to be associated withside effects that reflect noradrenergic activity, including
increased pulse rate, dilated pupils, dry mouth, excessive
sweating, and constipation. Although all three SNRIs carry
the warning of increased blood pressure, this risk is greater
during therapy with venlafaxine at doses above 150 mg/day(166) than with duloxetine at doses of 60–120 mg/day(167) or desvenlafaxine at doses of 50–100 mg/day (168).
Because this blood pressure increase is dose-related, SNRIinduced hypertension may respond to dose reduction. In
the absence of a reduction in hypertension, a different antidepressant medication may be considered. Alternatively,
in a patient with well-controlled depressive symptoms, it
may be preferable to add an antihypertensive agent rather
than risk a depressive relapse or recurrence with medication tapering. As with the SSRIs, abrupt discontinuationof SNRIs should be avoided whenever possible. Discontinuation symptoms, which are sometimes protracted, aremore likely to occur with venlafaxine (and, by implication,
desvenlafaxine) than duloxetine (100) and may necessitate aslower downward titration regimen or change to fluoxetine. As described above (Section II.B.2.b), there can be apotentially lethal interaction between SNRIs and MAOIs:
the serotonin syndrome.
3. Other antidepressant medications
a. Bupropion
Bupropion differs from other modern antidepressants by
its lack of direct effects on serotonergic neurotransmission
and, as a consequence, a virtual lack of sexual side effects(169). Neurologic side effects with bupropion include headaches, tremors, and seizures (106). The risk of seizures isminimized by avoiding high doses (e.g., using no morethan 450 mg/day), avoiding rapid titration, using divided
dosing schedules for the immediate-release and sustainedrelease formulations, and avoiding use of bupropion in patients with risk factors for seizures. Bupropion should also
not be used in patients who have had anorexia nervosa orbulimia nervosa because of elevated risk of seizures (170).
The risk of seizures may also be increased by the concomitant use of inhibitors of CYP 2B6 (e.g., desipramine,
sertraline, paroxetine, fluoxetine) due to the resulting increase in bupropion blood levels. Bupropion has been associated with a low risk of psychotic symptoms, including
delusions and hallucinations. It should therefore be used

APA PRACTICE GUIDELINES
cautiously in patients with psychotic disorders. Otherside effects with bupropion include agitation, jitteriness,
mild cognitive dysfunction, insomnia, and gastrointestinal upset.
b. Mirtazapine
The most common side effects of mirtazapine include drymouth, sedation, and weight gain. For this reason, mirtazapine is often given at night and may be chosen for depressed patients with initial insomnia and weight loss.
Although these side effects tend to occur early in thetreatment course and may attenuate with continued use,
the weight gain associated with mirtazapine is greater thanthat with other non-TCA, non-MAOI antidepressants (95)and may make it a less attractive choice for some patients. Mirtazapine increases serum cholesterol levels insome patients (171). Although several patients treatedwith mirtazapine were observed to have agranulocytosis
in early studies, subsequent clinical experience has not confirmed an elevated risk (172).
c. Trazodone
The most common side effect with trazodone is sedation.
Because the sedation associated with trazodone is greaterthan that with other non-TCA, non-MAOI antidepressants (95), this can be an advantage in patients with initial
insomnia (173). Trazodone can also cause cardiovascularside effects, including orthostasis, particularly among elderly patients or those with preexisting heart disease. Useof trazodone has also been associated with life-threatening ventricular arrhythmias in several case reports(173). Trazodone also can cause sexual side effects, including erectile dysfunction in men; in rare instances, priapism occurs, which might require surgical correction(174, 175).
d. Nefazodone
Side effects with nefazodone include dry mouth, nausea,
constipation, orthostasis, and visual alterations (176). Sedation is also common and may necessitate a gradualtitration of nefazodone. However, in patients with insomnia, the sedating properties of nefazodone can be helpful
in improving sleep (177). There appears to be a low incidence of treatment-emergent sexual dysfunction (178,179) with nefazodone and, unlike trazodone, it has notbeen associated with priapism. Nefazodone has also been
associated with rare but potentially fatal liver failure (180,181), which has limited its use in recent years. Drug-druginteractions can also be problematic as nefazodone inhibits hepatic microsomal enzymes and can raise levels ofconcurrently administered medications such as certain
antihistamines, benzodiazepines, and digoxin.

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
4. Tricyclic antidepressantsa.

Cardiovascular effects

Cardiovascular effects, including arrhythmias, can beproblematic with TCA treatment. Consequently, a pretreatment ECG is indicated for patients with significant
cardiac risk factors and patients older than age 50 years.
Follow-up ECGs may also be indicated to identify the development of conduction changes, typically during theearly phase of TCA use (182). Tricyclic antidepressantsact similarly to class Ia antiarrhythmic agents such as quinidine, disopyramide, and procainamide, which increase
the threshold for excitation by depressing fast sodium
channels, prolong cardiac cell action potentials throughactions on potassium channels, and prolong cardiac refractoriness through actions on both types of channels(183). As a result, combinations of TCAs with other class
I antiarrhythmic agents can exert additive toxic effects on
cardiac conduction; patients with ventricular arrhythmias
taking another class I antiarrhythmic agent who require
TCA therapy should be under careful medical supervision. Individuals with prolonged QT intervals, whether
preexistent or medication induced, are predisposed to develop ventricular tachycardia (184). Even patients withnormal pretreatment ECG results may develop atrioventricular block with TCAs that reverts to normal after
discontinuation of antidepressant medication treatment(185). Because of these effects on cardiac conduction,
TCAs (like other class Ia antiarrhythmic agents) may
carry an increased risk of serious cardiac adverse effects,
including mortality (186–189). In addition, fatal arrhythmias can occur in the context of TCA overdose (190, 191).
In addition to causing arrhythmias, TCAs can cause anumber of other cardiovascular side effects, including
tachycardia (through muscarinic cholinergic blockade andα-adrenergic blockade) or orthostatic hypotension (throughα-adrenergic blockade). Side effects such as orthostatic
hypotension may in turn lead to events such as dizziness,falls, or fractures, which are of particular concern in elderly
patients (192). Of the TCAs, nortriptyline may be less likely
to contribute to orthostatic blood pressure changes (185).
Preexisting orthostasis, antihypertensive treatment, dehydration, and salt depletion, whether voluntary or a result of diuretic treatment, may contribute to symptomatic
orthostatic hypotension with TCAs. If there is no medical
contraindication, patients with symptomatic orthostatic
hypotension should maintain adequate fluid intake and be
cautioned against extreme dietary salt restriction.
b.

Anticholinergic side effects

All TCAs have antimuscarinic effects; tertiary amine tricyclic antidepressants produce the most anticholinergic side

41

effects, whereas the secondary amines desipramine andnortriptyline have less antimuscarinic activity (193). The
most common consequences of muscarinic blockade are
dry mouth, impaired ability to focus vision at close range,
constipation, urinary hesitation, tachycardia, and sexual
dysfunction. Although patients can develop some degreeof tolerance to anticholinergic side effects, these symptoms may require treatment if they cause substantial dysfunction or interfere with adherence. Impaired visual
accommodation may be counteracted through the use of
pilocarpine eye drops. Dry mouth may be counteracted byadvising the patient to use sugarless gum or candy and ensuring adequate hydration. Constipation can be managed
by adequate hydration and the use of bulk laxatives. Antidepressant medications with anticholinergic side effects
should be avoided in patients with cognitive impairment,
narrow-angle glaucoma, or prostatic hypertrophy. Tricyclic antidepressants can impair memory and concentrationand even precipitate anticholinergic delirium, particularly
in patients who are elderly, medically compromised, or
taking other anticholinergic medicines. Such toxic confusional states may signal the presence of high TCA bloodlevels and can improve with lowering of the dose (194).
c.

Sedation

Tricyclic antidepressants also have affinity for histaminergic receptors and produce varying degrees of sedation. In
general, tertiary amines cause greater sedation, while secondary amines cause less (193). Sedation often attenuatesin the first weeks of treatment, and patients experiencing
only minor difficulty from this side effect should be encouraged to allow some time to pass before changing antidepressant medications. Patients with major depressive
disorder with insomnia may benefit from sedation when
their medication is given as a single dose before bedtime.
d. Weight gain
Tricyclic antidepressants can cause weight gain, possibly
through their histaminergic properties and/or blockade of
5-HT2 receptors (195). The degree of weight gain appears
to vary by agent (e.g., greater weight gain with amitriptyline and less with desipramine), is often dose dependent,
and is potentially reversible with cessation of TCA therapy.
Regular monitoring of weight permits early detection ofweight gain and can allow the treating clinician and patient
to determine whether a management plan to minimize orforestall further weight gain is clinically indicated.
e. Neurological effects
Tricyclic antidepressants can cause myoclonus (196). Since
this may be a sign of toxicity, the clinician may wish tocheck the blood level (if available) to ensure that it is notexcessive. If the level is nontoxic and myoclonus is not

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42bothersome to the patient, the agent may be continued
without a change in dose. If the myoclonus is problematic and the blood level is within the recommended range,
the patient may be treated with clonazepam at a dose of
0.25 mg t.i.d. Alternatively, the antidepressant medication
may be changed. In overdoses, TCAs can cause seizures.
Some vulnerable patients may experience seizures evenon therapeutic doses of a TCA—especially clomipramineand maprotiline (197). Amoxapine, a dibenzoxazepinederivative tricyclic antidepressant, also produces seizures
in overdose and has active metabolites that block dopamine receptors, conferring a risk of extrapyramidal side effects and tardive dyskinesia (198).
f. Falls
Use of TCAs has been associated with an increased risk offalls in a number of studies and meta-analyses, and the relative risk of falling appears comparable to that with SSRI
treatment (141, 144, 145). Although systematic reviews
show a relatively minor effect of orthostatic hypotension on
fall risk, TCAs may contribute to orthostasis and falls in individual patients (153). If orthostatic hypotension is prominent or associated with gait or balance problems, it may
require further evaluation and treatment to minimize thelikelihood of falls (199). Other aspects of fall risk with
TCAs are similar to those that have already been describedfor patients treated with SSRIs (Section II.B.2.b.1.e). Other
causes of falls include bradycardia, cardiac arrhythmia, aseizure, or ataxia.
g. Medication interactions
A number of medications that inhibit, induce, or are metabolized by hepatic microsomal enzymes can interact
with TCAs (200). For example, medications that induce
CYP 3A4 such as carbamazepine or barbiturates will cause
a decrease in serum levels of TCAs. Drugs such as the antipsychotic medication perphenazine or SSRIs such as fluoxetine or paroxetine can inhibit metabolism via CYP
2D6, resulting in a reduced clearance and increased levelsof TCAs. Tricyclic antidepressants can also alter the pharmacokinetics or pharmacodynamics of other medications;for example, TCAs can cause a lowering of valproate levels and reduce the activity of clonidine. Therefore, adjustments in medication doses may be necessary when TCAs
are administered concomitantly with other drugs for which
there is an interaction. The ability to obtain meaningful antidepressant blood levels to guide dosing is an advantage
with several of the TCAs (e.g., nortriptyline, amitriptyline, desipramine, imipramine) (201). Potentially dangerous interactions, including hypertensive crises and serotonin syndrome, can develop when TCAs are administeredwith MAOIs (see Sections II.B.2.b and II.B.2.b.5.b), norepinephrine, or epinephrine.

APA PRACTICE GUIDELINES
5. Monoamine oxidase inhibitorsa.

Hypertensive crises

A hypertensive crisis can occur when a patient taking an
MAOI ingests large amounts of tyramine or other vasoactive amines in foods or medications (202). This reaction ischaracterized by the acute onset of severe headache, nausea, neck stiffness, palpitations, profuse perspiration, andconfusion and can possibly lead to stroke and death (119).
Dietary restrictions include avoiding foods such as aged
cheeses or meats, fermented products, yeast extracts, fava
or broad beans, red wine, draft beers, and overripe or
spoiled foods (202, 203). A number of medications including norepinephrine reuptake blocking drugs (e.g., SNRIs,
TCAs), sympathomimetic vasoconstrictive agents, and overthe-counter decongestants can also produce a hypertensive crisis when used in combination with MAOIs (202,204). Individuals with asthma who receive MAOIs should
be cautioned regarding interactions with sympathomimetic
bronchodilators, although other antiasthma agents appear to be safe. Stimulants may be added to MAOIs, but
only with caution and in selected individuals with treatmentresistant symptoms (205, 206).
At low doses (6 mg/24 hours), selegiline differs fromthe older MAOIs in selectively blocking MAO B. In addition, the transdermal delivery of selegiline bypasses enzyme inhibition in the gut and first-pass metabolism in theliver. As a result, a low-tyramine diet is not needed when
selegiline is prescribed at the minimum therapeutic dose.
However, few safety data are available at higher doses atwhich selegiline becomes nonselective and inhibits both
MAO A and MAO B. Consequently, a low-tyramine diet isneeded when doses of 9 mg/24 hours and higher are prescribed as with other MAOIs (207, 208). Moclobemide,
which is available in Canada but not the United States, differs from the above MAOIs in binding reversibly to MAO
and makes dietary restrictions unnecessary with moclobemide. The potential for drug-drug interactions with selegiline and moclobemide has not been fully studied, but
caution suggests that the same drug interactions should beconsidered as when prescribing the older, nonselective, irreversible MAOIs.
Although some clinicians continue to recommend thatpatients carry nifedipine as a self-administered antidote(e.g., 10 mg by mouth at the first sign of a hypertensivecrisis [209]), this practice has not been approved by the
FDA, and there are concerns about both the safety andefficacy of this strategy, which can produce dangerous
hypotension (210). Definitive treatment of hypertensive
crises usually involves intravenous administration of an
antihypertensive agent (e.g., labetalol, sodium nitroprusside) in an emergency department setting.

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Editionb. Serotonin syndrome
As discussed previously in Section II.B.2.b.1.g, serotonin
syndrome is caused by excess CNS serotonergic activity
and is characterized by abdominal pain, diarrhea, flushing,sweating, hyperthermia, lethargy, mental status changes,
tremor and myoclonus, rhabdomyolysis, renal failure, cardiovascular shock, and possibly death. Serotonin syndrome
most commonly occurs when MAOIs (including reversible
inhibitors of monoamine oxidase and selegiline) are taken
in close proximity to other serotonergic agents, such as buspirone or antidepressants (157, 204, 211). Consequently,
when patients are being changed from an SSRI other thanfluoxetine or an SNRI to an MAOI, a waiting period of atleast 2 weeks is needed between the discontinuation of one
medication and the initiation of the other. When changing
from fluoxetine to an MAOI, a waiting period of at least
5 weeks is needed before the MAOI is started (Table 8).
Other medications that have been reported to produce serotonin syndrome when used in conjunction with MAOIs
include synthetic opioids (e.g., dextromethorphan, meperidine, tramadol, propoxyphene, methadone), nonantidepressant tricyclic compounds (e.g., carbamazepine,
cyclobenzaprine), sibutramine, and over-the-counter cold
products such as chlorpheniramine (204).
c. Cardiovascular effects
Orthostatic hypotension is commonly seen during MAOI
treatment. Possible treatments for this side effect include adding dietary salt to increase intravascular volume,or use of the mineralocorticoid fludrocortisone. Use of
MAOIs can also be associated with the development of
peripheral edema, which may be helped by the use of support stockings.
d. Weight gain
Weight gain is also commonly seen in patients treatedwith nonselective MAOIs. Although clinical experience islimited, results of one 52-week study suggested that treatment with transdermal selegiline may not be associatedwith an increased risk of weight gain (212).
e. Sexual side effects
Sexual side effects seen with MAOI therapy include anorgasmia, decreased libido, and erectile or ejaculatory dysfunction. Sexual side effects may diminish over time orwith reductions in MAOI doses. The transdermal formulation of selegiline appears to have a relatively low risk ofsexual side effects (213).
f. Neurological effects
Treatment with MAOIs can also be accompanied by headaches and insomnia; these side effects may diminish overtime with continued use. Other neurological effects seen
with MAOIs include sedation, myoclonic jerks, paresthe-43sias, intense daytime drowsiness, and, rarely, peripheral
neuropathy.
c.

Implementation of pharmacotherapy

Improvement with pharmacotherapy can be observed as
early as the first 1–2 weeks of treatment, and improvement continues up to 12 weeks. Many patients may show
partial improvement as early as the end of the first week
(214–216). Others achieve improvement within the first
2–4 weeks (217–220). In short-term efficacy trials, all antidepressant medications appear to require at least 4–6 weeks
to achieve maximum therapeutic effects (221, 222). Thereis also evidence for continued accrual of benefit for an additional 4–6 weeks (223). Furthermore, longer time totherapeutic effect has been seen with studies conducted in“real world” settings (224), as well as in studies of patientswith more chronic illness (225, 226) or patients with major depressive disorder complicated with co-occurring medical and/or Axis I disorders (224, 227).
Once an antidepressant medication has been selected,
it can be started at doses suggested in Table 6. Initial doses
should be incrementally raised as tolerated until a therapeutic dose is reached or the patient achieves remission,
provided there has been at least some improvement insymptoms in the initial weeks of treatment (217–220). For
patients who exhibit a partial response to treatment, dosesof antidepressant medications should be maximized, side
effects permitting, before changing to a different antidepressant medication. In some instances, due to factors
such as rapid metabolism of medication (228, 229), patients
may require doses above those noted in FDA labeling. Patients who have achieved some improvement during theinitial weeks of treatment should be encouraged to continue taking antidepressant medication for a total of atleast 4–8 weeks. If at least moderate improvement is notobserved with maximally tolerated doses after 4–8 weeks
of treatment, reappraisal and adjustment of the pharmacotherapy should be considered. Patients with no improvement in the initial weeks of treatment generally need anearlier adjustment of treatment. For these patients, thepsychiatrist should consider changing to another antidepressant rather than increasing the dose of the medication.
For some antidepressant medications, the exact relationships between doses and major depressive disorder symptom response have not been rigorously investigated with
fixed-dose studies, and minimum effective doses have notbeen clearly established; moreover, for other antidepressant medications, some studies have failed to show doseresponse relationships (230, 231). Therefore, the initial
doses and usual adult doses in Table 6 are intended toserve as general guidelines, and actual doses may varyfrom individual to individual.

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44
Titration of the dose to full therapeutic doses generally
can be accomplished over the initial week(s) of treatment
but may vary depending on the development of side effects,
the patient’s age, and the presence of co-occurring medical
and psychiatric conditions. In general, patients who are
older, are medically compromised, or have decreased ability to metabolize and clear antidepressant medications will
require lower doses. In such patients, reduction of initial
and therapeutic doses to 50% of usual adult doses is often
recommended, and dose escalations should be made at a
slower rate than for younger and healthier adults. Doses
will also be affected by the side effect profile of medications
and the patient’s ability to tolerate these side effects. Medication doses should also be tailored to individual patientsdepending on the potential for pharmacokinetic alterations
and drug-drug interactions.
Patients who have started taking an antidepressant
medication should be carefully and systematically monitored to assess their response to treatment, the emergenceof side effects, their clinical condition, safety, and adherence to treatment. Use of clinician- and patient-rated
scales can facilitate such assessments (see Section II.A.8).
Factors to consider when determining the frequency oftreatment visits include the severity of illness, the patient’s
cooperation with treatment, the availability of social supports, the presence of co-occurring general medical illnesses, and the progression of symptom change. Visits
should also be frequent enough to monitor and address
suicide risk and to actively promote treatment adherence,since attrition from treatment continues to be a major
hurdle in maximizing outcomes. Patients in clinical trials
appear to benefit from monitoring once a week or more.
This frequency of monitoring enhances adherence rates
and likely helps patients avoid the demoralization that
may occur before the onset of beneficial effects (216). In
the recently completed STAR*D (“Sequenced Treatment
Alternatives to Relieve Depression”) trial, up to six visitswere recommended during the first 12 weeks (acute phase)of measurement-based treatment at each of the four treatment steps (40). In clinical practice, the frequency ofmonitoring during the acute phase of pharmacotherapy
may vary and can be as often as multiple times per week inmore complex circumstances. The method of monitoring(e.g., face-to-face visits, telephone contact, or contact withanother clinician knowledgeable about the patient) may
vary depending on the clinical context and the treatment
modality.
Although for most patients, monitoring of antidepressant blood levels is not necessary, it may be useful for thosetaking TCAs. For some medications, particularly nortriptyline, amitriptyline, desipramine, and imipramine, blood
drug levels correlate with both efficacy and side effects

APA PRACTICE GUIDELINES(201, 232, 233). When such medications are given, obtaining blood drug levels can be particularly informative when
patients have not responded to treatment with an adequate
dose of antidepressant medication for an adequate duration; when patients are particularly vulnerable to the toxic
effects of a medication and require the lowest possible
effective dose; when there are concerns about patient adherence; and when there is concern that drug-drug interactions are adversely affecting antidepressant medicationlevels. In time, genetic testing may help guide selection or
dosing of antidepressants, but data are currently insufficient
to justify the cost of such tests (229).
Some antidepressant medications, especially TCAs,
can cause significant morbidity and mortality in overdose(190, 191). Ingestion of a 10-day supply of a tricyclic agent
administered at a dose of 200 mg/day is often lethal. Earlyon in treatment, it is prudent to dispense only small quantities of such antidepressant medications and keep in mind
the possibility that patients can hoard medications overtime. Alternatively, in patients who are suicidal, it may be
preferable to employ agents that are safer in overdose
such as the SSRIs, bupropion, or mirtazapine.

3. Other somatic therapiesa.

Electroconvulsive therapy

Electroconvulsive therapy has the highest rates of response
and remission of any form of antidepressant treatment, with
70%–90% of those treated showing improvement (234–236). Although the remission rate with ECT appears to belower when it is used in community settings than when it isused in clinical trials (237), the proportion of patients withmajor depressive disorder who respond to ECT is still
greater than the proportion who respond to antidepressant
medication. In addition, ECT has been associated with significant improvements in health-related quality of life (238).
Consequently, ECT should be considered for patients withsevere major depressive disorder that is not responsive to
psychotherapeutic and/or pharmacological interventions,particularly those with significant functional impairment
who have not responded to numerous medication trials(239). Electroconvulsive therapy may be particularly beneficial and can be considered as a first-line treatment option
for severe major depressive disorder when it is coupled withpsychotic features (240, 241), catatonia (239, 242), suicide
risk (243), or food refusal leading to nutritional compromise, as well as in other situations when a particularly rapid
antidepressant response is required (240), such as with severely ill inpatients (239). Electroconvulsive therapy is also
indicated as a first-line treatment for patients who have previously shown a positive response to this treatment modality
or who prefer it (239).

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
1. Side effects of electroconvulsive therapy
Electroconvulsive therapy is a very safe treatment, andthere are no absolute contraindications to its use (239).
Risks of morbidity and mortality, in general, do not exceed
those associated with anesthesia alone (239, 244, 245).
However, the presence of some medical conditions may
necessitate modifications in anesthesia or ECT administration.
Electroconvulsive therapy may have cardiovascular side
effects, mediated by changes in the autonomic nervous
system with the initial stimulus and subsequent seizure
activity (239). More specifically, ECT typically causes atransient rise in heart rate and blood pressure, with associated increases in cardiac workload and intracranial pressure. These effects can be managed by optimizing bloodpressure control prior to ECT and administering antihypertensive agents (e.g., short-acting beta-blockers or
calcium channel blockers) at the time of ECT (239). Arrhythmias, which are usually transient, can also occur inconjunction with ECT and can be managed with usual
antiarrhythmic therapies if they do not resolve spontaneously (239).
Electroconvulsive therapy can also be associated withcognitive effects, the most common of which is a period ofconfusion following the ECT and associated anesthesia
that generally lasts between 30 and 60 minutes (246).
Electroconvulsive therapy also is associated with anterograde amnesia, which typically resolves soon after the last
ECT treatment (247). Some degree of retrograde amnesia, particularly for recent memories, may continue for alonger period of time after the end of the ECT course(247) but is less pronounced for autobiographical memories than for impersonal memories (248). These cognitiveeffects of ECT are related to electrode placement, stimulus
dosage, age, and premorbid cognitive status (249–253).
Retrograde amnesia also improves over time, typically resolving within 6 months (248, 252), although some patients
report incomplete recovery of memories, particularly forevents around the time of the treatment (247, 254). Rarely,
patients report more pervasive and persistent cognitive
disruption, the basis of which is uncertain (252, 255). For
many individuals, however, subjective memory (256) andquality of life (238) is improved following ECT with theresolution of the major depressive episode and its associated deficits in memory or executive functioning (257,258).
2. Implementation of electroconvulsive therapy
The evaluation preceding ECT consists of a psychiatrichistory and examination to verify that ECT is indicated, ageneral medical evaluation (including medical history andphysical examination with cognitive assessment, vital signs,

45

and any specifically indicated laboratory, radiologic, or
imaging studies) to define factors that may influence therisk of ECT, and an anesthesia evaluation to identify andaddress the nature and extent of anesthetic risk and theneed for modification of medications or anesthetic technique (239). This evaluation should include a summary oftreatment indications, treatment risks, and a suggestion of
any indicated additional evaluative procedures, alterations
in treatment, or modifications in ECT technique (239). In
assessing indications for caution (e.g., recent myocardial
infarction, cardiac arrhythmias, intracranial space-occupying lesions), the relative risks and benefits should be
carefully weighed in collaboration with an anesthesiologist, a general medical physician, and other specialists, asnecessary. Once completed, the pre-ECT evaluation willserve as the basis for a specific, individualized discussionof the risks and benefits of ECT relative to other therapeutic options as part of the informed consent process.
With the patient’s permission, it is helpful to educate thepatient’s family about ECT and involve them in discussions relating to consent.
An additional aspect of decision-making prior to ECT
relates to the use of psychotropic medications during the
ECT course. There is growing use of ECT combined withantidepressant medication. Although data supporting thispractice are still few, it does not appear to increase side effects and may augment response (259, 260). An additional
goal of combination treatment is to minimize the risk of
relapse between the end of the ECT course and the attainment of full antidepressant effectiveness. Antipsychotic
medications are typically continued during the ECT
course (239, 261), although most data on this practice comefrom studies of patients with schizophrenia who are receiving ECT. The safety of combining lithium and ECT
has been questioned, although there are conflicting data
(239, 262). Medications that have anticonvulsant properties are often discontinued or given at decreased doses
during the ECT course to minimize effects on seizure induction (239, 261). With benzodiazepines, there is someevidence that concurrent use may diminish ECT effectiveness, particularly when right unilateral electrode placement is used (263).
Electroconvulsive therapy may be administered either
unilaterally or bilaterally (using a bitemporal or bifrontal
electrode placement). Compared with patients who receive bilateral treatment, most patients who receive right
unilateral electrode placement with low stimulus intensities experience fewer cognitive effects but less therapeutic
benefit (253). Stimuli of higher intensity (i.e., 500% above
seizure threshold) are associated with antidepressant effects more comparable to those seen with bilateral electrode placements, although such stimulus intensities are

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46

APA PRACTICE GUIDELINES

not always achievable with existing ECT devices (264). Regardless of what electrode placement is chosen, stimulus
dosing should be individualized and stimulus parameters
adjusted to induce an adequate generalized seizure, which
is typically at least 20 seconds or greater in motor durationand 30 seconds in EEG duration (239). Failure to inducean adequate seizure should be followed immediately byrestimulation at higher energies until an adequate seizure
is elicited.
Electroconvulsive therapy is typically administered
2–3 times/week; less frequent administration has been associated with less cognitive impairment but also a longer
lag in the onset of action (265). In clinical practice, theneed for ECT to be administered at this frequency could
produce logistical barriers for some patients who would
either require hospitalization or transportation after ECT
sessions. The acute course of ECT treatment typicallyconsists of six to 12 treatments and generally does not exceed 20 treatments (239, 266). It is important that treatment continue until symptoms have remitted or clearlyreached a plateau, since relapse rates appear to be greaterand overall prognosis worse if ECT is discontinued prematurely (237). Use of a formal rating scale may be helpful in assessing symptom response as well as the cognitiveside effects of treatment, permitting adjustments in thetreatment parameters or frequency (239, 267).
For more detail on the administration of ECT, see APA’s
The Practice of Electroconvulsive Therapy: Recommendations
for Treatment, Training, and Privileging (A Task Force Reportof the American Psychiatric Association) (239).
b.

Transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) uses a specificallydesigned magnetic coil that is placed in contact with thehead to generate rapidly alternating magnetic-resonanceimaging-strength magnetic fields and produce electricalstimulation of superficial cortical neurons. Based on the
results of a multisite randomized sham-controlled clinical
trial of high-frequency TMS over the left dorsolateralprefrontal cortex (268), TMS was cleared by the FDA in2008 for use in individuals with major depressive disorder
who have not had a satisfactory response to at least one
antidepressant trial in the current episode of illness. However, another large randomized sham-controlled trial of
TMS added to antidepressant pharmacotherapy showedno significant benefit of left dorsolateral prefrontal cortex
TMS (269). In comparisons of actual TMS versus sham
TMS, most (270–272) but not all (273) recent meta-analyses have found relatively small to moderate benefits of
TMS in terms of clinical response. Although the primarystudies used in these meta-analyses are highly overlapping
and the variability in TMS stimulus parameters and treat-ment paradigms complicates the interpretation of research findings, these meta-analyses also support the useof high-frequency TMS over the left dorsolateral prefrontal cortex. Lesser degrees of treatment resistance may
be associated with a better acute response to TMS (274).
In comparison with ECT, TMS has been found in randomized studies to be either less effective than ECT (275)or comparable in efficacy to ECT (276–278), but in thelatter studies TMS was more effective and ECT was lesseffective than is typically seen in clinical trials. A fewer
number of studies have compared cognitive effects of
TMS and ECT. One randomized trial found no significant difference between TMS and non-dominant unilateral ECT on performance on neuropsychological tests
at 2 and at 4 weeks of treatment (276), although a small
open-label trial reported a greater degree of memory difficulties with ECT than with TMS shortly after the treatment course (279).
Across all studies, TMS was well tolerated and was associated with low rates of treatment dropout (270, 280).
Transient scalp discomfort and headaches were the mostcommonly reported side effects (280).
In clinical practice, the need for daily TMS could produce logistical barriers for some patients.
c. Vagus nerve stimulation
Vagus nerve stimulation is approved for use in patientswith treatment-resistant depression on the basis of its potential benefit with long-term treatment. There is no indication for the use of VNS in acute phase treatment ofdepression, as data showed no evidence for acute efficacy(281, 282). Further information on the use of VNS as an
adjunct to other antidepressive treatments is provided in
Section II.B.7.c.

4. Psychotherapy
There has been considerable research on time-limited
psychotherapies for major depressive disorder, although
the number of studies is smaller than for pharmacotherapies. Most research has focused on individual, in-person,
outpatient treatment, in part based on the needs and constraints of research methods. However, research has also
begun to explore psychotherapies in differing formats,including groups, over the telephone, and with computerassistance.
When psychotherapy is part of the treatment plan, it
must be integrated with psychiatric management (Section
II.A) and any other treatments (e.g., pharmacotherapy) thatare being provided. Clinical considerations and other
patient factors should be considered in determining thenature and intensity of psychotherapy. Typically psychotherapy is given in an ambulatory setting, although some

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
psychotherapies might benefit depressed inpatients, given
adequate lengths of stay and courses of treatment (283–285). Like pharmacotherapy, the effectiveness of psychotherapy will vary with the skill and training of the therapist.
Patient factors, such as the nature and duration of depressive symptoms, beliefs and attitudes toward psychotherapy,
and early life experiences (e.g., history of trauma) also affecttreatment response to psychotherapy. Psychotherapy isparticularly useful in addressing the psychosocial stressors
and psychological factors that have an impact on the development or maintenance of depressive symptoms.
Cognitive-behavioral therapy, interpersonal psychotherapy (IPT), and behavioral psychotherapies (e.g., behavioral activation) have demonstrated acute efficacy intreating major depressive disorder. There is less evidence
for other psychotherapies. However, one meta-analysis
found no large differences in long-term efficacy between
any of the major psychotherapies, including dynamic psychotherapy, for mild and moderate depression (286). In
terms of longer term outcomes, psychotherapy is generally
found to have more prolonged effects than pharmacotherapy after cessation of active treatment. In particular, IPT
and CBT have shown lasting benefits in maintaining remission (287–289). These time-limited treatments are essentially equipotent with antidepressant medications foroutpatients with mild to moderate acute depression but
probably should be used in conjunction with medication
for severe or melancholic major depressive disorder. Some
research has suggested patient and illness characteristics
that might predict differential benefits of CBT over IPT,and vice versa, for patients with major depressive disorder(e.g., see reference 290), but such preliminary findings require replication.
Cognitive-behavioral therapy and IPT appear less effective than pharmacotherapy for chronic depression, atleast as acute monotherapy (291–296). Nonetheless, inpatients who respond to medication, psychotherapy may
foster the development of social skills and confidence after years of depression-related impairments (297).
Psychotherapy carries its own “side effects.” A psychotherapy that requires considerable time or patience may
be poorly tolerated. The work of psychotherapy itself may
generate anxiety or other strong feelings, which may bedifficult for patients to manage. An indirect measure of
the relative side effects and tolerability of psychotherapy
can be obtained from the dropout rates in clinical trials;
however, many other factors can also affect these rates(e.g., other burdens of the research trial, specific featuresof the clinical management provided, logistical barriers inattending appointments). Depending on what can reasonably be expected with the given type of psychotherapy, thepsychiatrist should consider a change in the intensity or

47

type of psychotherapy and/or addition or change to medication if psychotherapy for major depressive disorder has
not resulted in significant improvement in 4–8 weeks.
a.

Specific psychotherapies

1. Cognitive and behavioral therapies
In the treatment of depressed patients, psychotherapies
that focus primarily on aspects of cognitive patterns andthose that emphasize behavioral techniques can be usedalone, but are generally used in combination. Cognitivebehavioral therapy combines cognitive psychotherapy
with behavioral therapy and maintains that irrational
beliefs and distorted attitudes toward the self, the environment, and the future perpetuate depressive affects andcompromise functioning. The goal of CBT is to reduce
depressive symptoms by challenging and reversing these
beliefs and attitudes and encouraging patients to change
their maladaptive preconceptions and behaviors in reallife (298).
Cognitive-behavioral therapy is an effective treatment
for major depressive disorder. In meta-analyses, CBT has
generally surpassed control conditions in efficacy and has
had equal efficacy compared with other empirically supported psychotherapies (i.e., IPT and behavior therapy)(299). Studies comparing the effectiveness of CBT withpharmacotherapy, however, are methodologically challenging to conduct, and results are inconsistent (296, 300).
Also unclear is whether CBT is less effective for patientswith more severe depressive symptoms.
Behavior therapy for major depressive disorder is basedon theoretical models drawn from behavior theory (301)
and social learning theory (302). Behavioral activation is a
newly articulated behavioral intervention with some positive preliminary results that merit further study (288,303). Specific behavior therapy techniques include activity scheduling (304, 305), self-control therapy (306),
social skills training (307), and problem solving (308). Behavior therapy involves graded homework, scheduling ofenjoyable activities, and minimizing unpleasant activities(309). Behavior therapy has demonstrated efficacy, at times
superior to cognitive therapy, in treating major depressive
disorder (310).
2. Interpersonal psychotherapy
The focus of IPT is on current life changes, including
losses, role disputes and role transitions, social isolation,
deficits in social skills, and other interpersonal factors that
may interact with the development of the depressive
episode (311, 312). In IPT the goal is to intervene by identifying the current trigger of the depressive episode, facilitating mourning in the case of bereavement, promoting
recognition of related affects, resolving role disputes and

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48role transitions, and building social skills to improve relationships and to acquire needed social supports. In IPT,
major depressive disorder is defined as a medical illness,and the illness, rather than the patient, is blamed for thesymptoms. Interpersonal psychotherapy’s medical model
makes it highly compatible with pharmacotherapy in
combined treatment.
Interpersonal psychotherapy is an efficacious treatment for major depressive disorder (296, 313). Studies
have shown efficacy of this treatment in depressed primary care patients and patients with more severe depression (311). The efficacy of IPT has been demonstrated foradolescents, pregnant and postpartum women, and geriatric patients (311). Interpersonal psychotherapy can also
be used as a monthly maintenance therapy to prevent
relapse (289, 314, 315). Some studies have also suggested
possible subgroups in whom IPT may show differential
efficacy, specifically among HIV-positive patients (316)and patients who have co-occurring obsessive personality
traits and who are single and not living with others (317).
Furthermore, for patients with severe life events, IPT may
have advantages over therapies that do not focus on such
events directly.
3. Psychodynamic psychotherapy
The term “psychodynamic psychotherapy” encompasses a
range of brief to long-term psychotherapeutic interventions (318–320). These interventions derive from psychodynamic theories about the etiology of psychologicalvulnerability, personality development, and symptom formation as shaped by development and conflict occurring
during the life cycle from earliest childhood forward (321–325). Some of these theories focus on conflicts related toguilt, shame, interpersonal relationships, the managementof anxiety, and repressed or unacceptable impulses. Others
address developmental psychological deficits produced byinadequacies or problems in the relationship between thechild and emotional caretakers, resulting in problems ofself-esteem, sense of psychological cohesiveness, and emotional self-regulation (323, 326–330).
Psychodynamic psychotherapy may be brief but usually has a longer duration than other psychotherapies, andits aims extend beyond immediate symptom relief. These
goals are to modify underlying psychological conflicts anddeficits, which increase the patient’s vulnerability to depressive affect and the development of major depressive disorder. Psychodynamic psychotherapy is therefore broader
than most other psychotherapies, encompassing both current and past problems in interpersonal relationships,
self-esteem, and developmental conflicts associated with
anxiety, guilt, or shame. Time-limited, structured psychodynamic psychotherapy may focus more on understand-

APA PRACTICE GUIDELINES
ing the psychological basis of the presenting symptoms oron a selected underlying conflict. Sometimes a goal of psychodynamic psychotherapy, brief or extended, may be tohelp the patient accept or adhere to necessary pharmacotherapy (331).
Although psychodynamic psychotherapy is often usedin clinical practice, its efficacy in the acute phase of major
depressive disorder remains less well studied in controlled
trials than the efficacy in this phase of some other forms of
psychotherapy. This research is reviewed in Part B, Section V.B.3.
4. Problem-solving therapy
Problem-solving therapy is a manual-guided, brief treatment lasting six to 12 sessions. This therapy, often administered by nurses or social workers, has been used toprevent depression in elderly and/or medically ill patients,
and it has also been used to treat patients with relatively
mild depressive symptoms. The approach combines elements of cognitive therapy (addressing negative assessments of situations) and IPT (focal problem solving). Somestudies have reported modest improvement in patientswith mild depressive symptoms. Although problem solving therapy has had limited testing for patients with major
depressive disorder, it may have a role in targeted patient
populations with mild depression (332–335).
5. Marital therapy and family therapy
Marital and family problems are common in the course ofmood disorders, and comprehensive treatment often demands assessing and addressing these problems. Maritaland family problems may be the consequence of major depressive disorder but may also increase vulnerability todeveloping major depressive disorder or retard recovery
from it (336–339). A number of marital and family therapies have been shown to be effective in the treatment
of depression. Techniques include behavioral approaches(338), problem-focused approaches (340), and strategic
marital therapy (341, 342). Family therapy has also beenfound to be helpful in the treatment of more severe forms
of depression in conjunction with medications and hospitalization (343).
6. Group therapyGroup psychotherapy is widely practiced, but research on
its application to major depressive disorder is limited.
Specific types having some data to support their efficacy
include CBT (344–347) and IPT (348–351). Meta-analysesof the relative effectiveness of psychotherapeutic approaches
conducted in group format versus individual format havenot involved patients with rigorously defined major depressive disorder (352–355).

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
On the basis of a very limited controlled study, supportive group therapy has been suggested to have utility in thetreatment of major depressive disorder. In a study of depressed outpatients, a mutual support group and group
CBT were found to be equally effective in reducing depressive symptoms (346). In a study of HIV-positive patients with mild to moderate major depressive disorder,
structured supportive group therapy plus placebo yielded
similar decreases in depressive symptoms to structured
group therapy plus fluoxetine (356). Individuals experiencing stressors such as bereavement or chronic illness may
benefit from contact with others facing similar challenges.
Medication maintenance support groups may also offer benefits, although data from controlled trials for patients with major depressive disorder are lacking. Suchgroups inform the patient and family members aboutprognosis and medication issues, providing a psychoeducational forum that contextualizes a chronic mental illness
in a medical model.
The efficacy of self-help groups led by lay members(357) in the treatment of major depressive disorder has
not been well studied. However, one investigation ofgroup therapies found that a higher proportion of depressed outpatients had remission following treatment ingroups led by professionals than had remission following
participation in groups led by nonprofessionals (346).
Further study is needed on the possibility that self-helpgroups may serve a useful role in enhancing the support
network and self-esteem of participating patients withmajor depressive disorder and their families.
Overall, group therapy has some evidence to support
its use as well as the potential advantage of lowered cost,inasmuch as one or two therapists can treat a larger number of patients simultaneously. This advantage needs to beweighed against the difficulties in assembling the group,
the lesser intensity of focus patients receive relative to individual psychotherapy, and potentially adverse effects
from interactions with other group members.
b. Implementation
It can be useful to establish an expected duration of psychotherapy at the start of treatment. Communicating thisexpectation may help mobilize the patient and focus treatment goals, yet there are few data available on the optimal
duration of specific depression-focused psychotherapies.
In many trials, CBT and IPT have been delivered in approximately 12–16 weekly sessions. In a subanalysis of one
clinical trial, CBT delivered in 16 weeks was more effective than CBT delivered in 8 weeks for those with severe
major depressive disorder (358). Moreover, evidence suggests benefit from monthly continuation phase treatment
with IPT in reducing the probability of relapse (314). In

49

addition, patients with chronic, treatment-resistant depression may require long-term treatment.
The optimal frequency of psychotherapy has not been
rigorously studied in controlled trials. The psychiatrist
should consider multiple factors when determining thefrequency for individual patients, including the specific
type and goals of the psychotherapy, the frequency necessary to create and maintain a therapeutic relationship, thefrequency of visits required to ensure treatment adherence, and the frequency necessary to monitor and address
suicide risk and other safety concerns. Time-limited brief
psychotherapies may mobilize many depressed patients tomore rapid improvement. The severity of illness, the patient’s cooperation with treatment, availability of social
supports, cost, geographic accessibility, and presence of
co-occurring general medical problems may also influence visit frequency. The frequency of outpatient visits
during the acute phase is generally weekly but may vary
based on these factors. Some experienced clinicians findthat sessions are needed at least twice weekly, at least initially, for patients with moderate to severe depression.
Regardless of the type of depression-focused psychotherapy that is selected, the clinician should carefully andsystematically monitor the patient’s response to treatment,
which can be facilitated by the use of clinician- and patientrated scales at regular intervals (see Section II.A.8). If 4–8
weeks of treatment do not yield at least moderate improvement (≥20% diminution in symptoms), the clinician
should thoroughly review and reappraise the treatment
plan.
c.

Combining psychotherapy and medication

Several meta-analyses of studies of the combination of
psychotherapy and pharmacotherapy for patients withmajor depressive disorder have documented a modest advantage for the combination as compared with one or theother modality alone (359–361). Particularly large additive effects have been observed in individual studies of patients with chronic depression (362), patients with severerecurrent depression (359), and hospitalized patients(285). Combined treatment might therefore be considered a treatment of first choice for patients with major depressive disorder with more severe, chronic, or complex
presentations. Combining family therapy with pharmacotherapy has also been found to improve posthospital carefor depressed patients (343).
Dual treatment combines the unique advantages of eachtherapeutic modality: while pharmacotherapy may provide
earlier symptomatic relief, psychotherapy yields broader
and longer lasting improvement (363). Psychotherapy canalso be used to address issues that arise during pharmacotherapy, such as decreased adherence. However, the advan-

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50
tage of routinely combining interventions may be modest
for patients with less severe depressive symptoms (359).
There are no empirical data from clinical trials to help
guide the selection of particular antidepressant medications
and particular models of psychotherapeutic approaches
for individuals who will receive the combination of bothmodalities. In general, the same issues that influence thesedecisions when choosing a monotherapy will apply, andthe same doses of antidepressant medication and the same
frequency and course of psychotherapy should be used forpatients receiving combination modality treatments as areused for patients receiving them as a monotherapy.
Results from a series of recent studies provide indirect
evidence that for patients who have had only a partial response to pharmacotherapy, adding a course of CBT may
be an effective strategy for preventing relapse (363–368).
During 12 weeks of treatment in the STAR*D study, cognitive therapy was as effective as either augmenting withbupropion or buspirone or changing antidepressants tobupropion, sertraline, or venlafaxine. However, patients
who did not respond to an initial course of citalopram wereless likely to accept cognitive therapy as a change or augmentation option than they were to accept a different medication option (369), perhaps due to the nature of the study
design.

5. Complementary and alternative treatments
As defined by the National Center for Complementaryand Alternative Medicine, complementary and alternative
medicine is “a group of diverse medical and health caresystems, practices, and products that are not presently considered to be part of conventional medicine.” As the definitions are usually applied, “complementary” therapies areused conjunctively with conventional medicine, “alternative” therapies are used in place of conventional medicine,and “integrative” medicine makes use of all therapies appropriate to an individual patient’s needs.
The use of integrative therapies is increasingly common, although training and comfort with complementary
and alternative modalities vary greatly by practitioner.
Many patients do not spontaneously disclose use of complementary or alternative treatments to health care professionals, so it is particularly important that direct inquiry aboutsuch treatments be part of routine health care questions.
At this time, there are several modalities that have modest evidence for antidepressant efficacy and deserve
further study. Some of these modalities can be recommended with enthusiasm for their general health benefits;
however, patients should be informed that evidence for
their antidepressant efficacy as monotherapy is limited orabsent.

APA PRACTICE GUIDELINES
a. St. John’s wort
St. John’s wort is a plant widely used to treat depressive
symptoms. Overall, studies of St. John’s wort show greater
consensus and support for benefits in mild to moderate major depressive disorder, as compared with less consistentfindings in patients with more severe symptoms. One review of 14 short-term, double-blind trials conducted in
outpatients with mild to moderate symptoms of major depressive disorder concluded that St. John’s wort in doses of
300 mg/day and 1,800 mg/day had efficacy that was superior to placebo (105). St. John’s wort had generally comparable efficacy and fewer side effects than low-dose TCA
treatment (e.g., 30–150 mg/day of amitriptyline) (105), butdoses at the low end of this range would not be expected to
produce therapeutic benefits. However, in the two largest
controlled studies conducted in the United States (370,371), effects of St. John’s wort did not differ from placebo,
which somewhat limits confidence in the magnitude of theantidepressant actions of St. John’s wort. In addition, preparations of St. John’s wort are not regulated by the FDA asa drug and lack standardization of their ingredients, composition, and potency. Based on the evidence cited, St.
John’s wort would not meet the FDA’s minimum requirements to be declared an effective antidepressant and is notrecommended for general use in treating depression.
Another important consideration with St. John’s wort
is the potential for drug-drug interactions (372–374). St.
John’s wort appears to induce the metabolism of drugs via
CYP 3A4, reducing the efficacy of medications, including
antiretroviral medications, immunosuppressants (including cyclosporine), antineoplastic agents, anticoagulants(including warfarin), oral contraceptives, and hormone
replacement therapy (373, 374). Unwanted pregnancies
have been reported with concomitant St. John’s wort andoral contraceptive use (373, 375, 376), and rejection of transplanted organs has been observed when St. John’s wort istaken concurrently with cyclosporin (374). The significant
decreases in antiretroviral medication levels with concomitant St. John’s wort use suggest that these medications will be less effective in treating HIV infection (374).
Effects of St. John’s wort on P-glycoprotein have also been
observed, altering the pharmacokinetics and pharmacodynamics of medications such as digoxin that are transported by this route (374). Apart from affecting bloodlevels of nonpsychiatric medications, the safety and efficacy of the combined use of St. John’s wort with other antidepressant medications is not known. The combined useof St. John’s wort with MAOIs is contraindicated.
b. S-adenosyl methionine
S-adenosyl methionine is a naturally occurring molecule.
In humans, it is concentrated in the liver and the brain and

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
serves as a methyl donor in the synthesis of biologically
active compounds such as phospholipids, catecholamines,
and the neurotransmitters dopamine and serotonin (377).
Cerebrospinal fluid levels of SAMe are lower in individuals with severe major depressive disorder, compared with
control subjects (378), and treatment with SAMe increases
CSF SAMe and 5-hydroxyindoleacetic acid levels (379).
S-adenosyl methionine is available for both parenteral andoral administration (380).
Some data support the efficacy and tolerability of SAMein patients with major depressive disorder. Oral, intravenous, and intramuscular formulations have been assessed
and appear efficacious in at least pilot studies (381–383).
Like St. John’s wort, SAMe is not regulated by the FDA
and lacks standardization of its composition and potency.
S-adenosyl methionine has been compared with TCAs
and has been reported to have greater efficacy while being more tolerable (381). It is unclear at present how
SAMe compares to SSRIs in efficacy and cost-efficiency.
While some data support the use of SAMe as monotherapy and as augmentation therapy, the data at this time, aswith St. John’s wort, are insufficient to make a recommendation for its use in the treatment of major depressive disorder.
c. Omega-3 fatty acids
Most studies of omega-3 fatty acids for major depressive
disorder have been adjunctive studies, in which patientswere already receiving antidepressant medications but still
met the criteria for major depressive disorder. Studies varyin the omega-3 fatty acids used (eicosapentaenoic acid
[EPA], docosahexaenoic acid [DHA], or the combination),and doses and durations of study trials have also varied. It isdifficult to interpret the literature on this treatment given
the heterogeneity in study design and outcomes.
Omega-3 fatty acids are generally recommended as an
adjunctive therapy for mood disorders, as health benefits,
including those for cardiovascular health, are well established, and individuals with psychiatric disorders may
be at greater risk for obesity, metabolic problems, andother health problems than the general population (384,385). More evidence is required to establish a definitiverole in the acute treatment of major depressive disorder.
Doses of 1–9 grams have been studied in mood disorders,with a majority of evidence supporting use of lower
doses. Adjunctive EPA or the combination of EPA and
DHA (the combination found in most commerciallyavailable brands) appears most useful, with less evidence
for DHA alone for the treatment of major depressive
disorder. Further data are needed to ascertain the role ofomega-3 fatty acids as monotherapy for major depressive
disorder.

d.

51

FolateFolate has been primarily assessed as a predictor of antidepressant medication response and as an adjunctive
treatment. Low folate blood levels have been associatedwith lack of response and slower response to fluoxetine formajor depressive disorder (386, 387), and higher folate
levels at treatment baseline appear associated with better
response to antidepressants (388). Folate has been studied
as an adjunctive treatment compared with placebo in addition to fluoxetine, with significantly greater improvement in those receiving folate, especially among female
patients (389).
Folate is a low-risk intervention with general healthbenefits. Folate protects against neural tube defects inearly pregnancy. In general, 0.4–1 mg of folate is recommended for women of reproductive age. Considering themodest evidence that supports folate as an augmentation
strategy and its attractive risk-benefit profile, folate canbe recommended as a reasonable adjunctive strategy for
major depressive disorder that carries little risk and may
decrease birth defects in the case of pregnancy. Data areinadequate to suggest efficacy as a monotherapy.
e. Light therapy
Bright light therapy appears effective for seasonal affective disorder and nonseasonal major depressive disorder, as demonstrated in generally short-term, placebocontrolled trials (390–394), although some studies havemethodological limitations (395). The mechanism of action for light therapy is not clear but appears to involvethe serotonergic neurotransmitter system (396, 397).
There is some evidence that light therapy may hasten the
response to treatment with antidepressant medication(398). Open-label data also support light therapy for patientswith major depressive disorder that has not responded to
antidepressant medication (399). Greater intensity of lightis associated with efficacy (400). Light therapy also may
augment the antidepressant benefits of partial sleep deprivation (401, 402). Monitoring for mania and hypomania
may be appropriate with initiation of light therapy, as hypomania has been reported (392). However, in generalbright light therapy is a low-risk and low-cost option fortreatment.
f. Acupuncture
Acupuncture is a treatment modality that is part of traditional Chinese medicine. Its efficacy is somewhat difficult
to assess, as much of the research is published in Asian languages and overlooked in typical literature searches. In
addition, there is significant variation in the acupuncturetechniques used as well as limited descriptions of methodology and diagnosis (403). One randomized trial showed

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52
comparable benefits of electroacupuncture and amitriptyline (404), and another small randomized trial in depressed
women showed benefits of acupuncture relative to a shamcontrol (405). However, a subsequent larger study did not
replicate these results (406), and a recent meta-analysis
concluded that acupuncture was not associated with any
benefits in treating major depression in terms of responseor remission rates (407). Assuming needles are properly
sterilized, there do not appear to be substantial risks ofacupuncture treatment. However, based on current evidence, acupuncture is not recommended in the treatmentof major depressive disorder.

APA PRACTICE GUIDELINESTABLE 9.

Potential Reasons for Treatment Nonresponse

Inaccurate diagnosis
Unaddressed co-occurring medical or psychiatricdisorders, including substance use disorders
Inappropriate selection of therapeutic modalities
Inadequate dose of medication or frequency ofpsychotherapy
Pharmacokinetic/pharmacodynamic factors affecting
medication action
Inadequate duration of treatment
Nonadherence to treatment
Persistent or poorly tolerated side effects

6. Assessing response and adequacy of treatment

Complicating psychosocial and psychological factors

The goal of acute phase treatment for major depressive disorder, insofar as possible, is to achieve remission and a return to full functioning and quality of life. Remission isdefined as at least 3 weeks of the absence of both sad moodand reduced interest and no more than three remaining
symptoms of the major depressive episode (408). However,
it is not uncommon for patients to have substantial but incomplete symptom reduction or improvement in functioning during acute phase treatment. A number of studies haveprovided compelling evidence that even mild residual
symptoms at the end of a depressive episode are associatedwith significant psychosocial disability, compared with asymptomatic remission (409); a more than three times faster
relapse to a subsequent major depressive episode (410); andin first-episode patients, a more chronic future course (410–412). The presence of mild residual symptoms has beenshown to be an even stronger predictor of a subsequent return to a major depressive episode than a prior history ofmultiple episodes of major depressive disorder (410). For
this reason, it is important not to conclude the acute phaseof treatment prematurely for partially responsive patients.
Throughout treatment, both the patient’s response and theadequacy of treatment must be vigilantly and systematicallymonitored. Use of structured measures of depression
symptom severity, side effects, treatment adherence, andfunctional status can facilitate identification of patients who
have not had a complete response to treatment (40, 44).
If a patient is found to have an incomplete treatment
response, the treatment itself should be evaluated. Medications must be thoughtfully selected and given at an adequate dose and for an adequate duration. Similarly,
psychotherapy must be well chosen for the patient, skillfully executed, and conducted over an appropriate periodof time with an adequate frequency of visits. In addition to
being caused by inadequate treatment, poor response may
result from multiple other factors (413) that are enumerated in Table 9.

Inadequately trained therapist or poor “fit” between
patient and therapist
For pharmacotherapy, determination of the adequacy oftreatment requires ensuring that antidepressant medications have been used for an adequate dose and duration.
This can be assessed using standardized measurement instruments (414). Generally, adequate treatment with anantidepressant medication for at least 4–6 weeks is necessary before concluding that a patient is not responsive or
only partially responsive to a particular medication (218,221). For patients with no improvement in symptoms
during the initial weeks of treatment, treatment should be
reevaluated and possibly changed. Furthermore, there islittle evidence to support extending antidepressant medication trials beyond 6 weeks in patients who have shown
no response. Patients with chronic forms of depression orwith co-occurring Axis I disorders or general medical
conditions may require a longer duration of acute phasetreatment before concluding that a different treatment
strategy is indicated (224).
For psychotherapy, treatment should be reassessed if
there has not been meaningful improvement after a few
months, depending on what can reasonably be expected forthe given type of psychotherapy. Patients should be reassessed every 3–4 months to ensure adequate improvement.
Regardless of treatment modality, lack of improvement
over time warrants reconsideration of interventions, given
the large number of available treatment options.

7. Strategies to address incomplete response
The psychiatrist should consider a change in treatment
for patients who have not fully responded to an adequate
acute phase treatment over a sufficient time, generally
4–8 weeks. The treatment plan can be revised by implementing one of several therapeutic options, including op-

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition

53

Response
None or Partial

Full

Initial weeks

If treatment is well-tolerated, maintain
Assess adherence. If clinical severity
current treatment approach.
warrants and treatment is well tolerated,consider increasing medication dosage or
intensity of psychotherapy, especially ifthere is no response. If symptoms aresevere or life-threatening, consider ECT.

At 4–8 weeks

In patients treated with an antidepressant, Go to continuation phase.
consider increasing the dose (if welltolerated), changing to a different
antidepressant, and changing to oraugmenting with psychotherapy.
Augmentation therapy or ECT may
also be considered.
For insufficient response to psychotherapy,
consider changing the intensity or typeof psychotherapy and/or adding orchanging to medication.
For ECT, see guideline text.

Throughout treatment

In patients who have significant side effects with antidepressant treatment, consider
changing to a different antidepressant, reducing the dose, or treating the side effect.
Also consider changing to psychotherapy or ECT.
If trials of two medications from the same antidepressant class have been ineffective,
consider changing antidepressants to a different class.
For patients with difficulty tolerating psychotherapy, consider changing the intensity ortype of therapy and/or adding or changing to medication.

FIGURE 2.

Assessment of Treatment Tolerability and Adequacy of Response

timizing the initial treatment, changing to a different
treatment, and combining treatments. These options are
outlined in Figure 2 and described in more detail below.
Following any change in treatment, the patient should
continue to be closely monitored. If there is not at least amoderate improvement in major depressive disorder
symptoms after an additional 4–8 weeks of treatment, thepsychiatrist should conduct another thorough review. This
reappraisal should include the following: verifying the patient’s diagnosis and adherence; uncovering and addressing clinical factors that may be preventing improvement,such as the presence of co-occurring general medical conditions or psychiatric conditions (e.g., alcohol or substanceabuse); evaluating for potential drug-drug interactions;obtaining collateral information from those involved withthe patient; and uncovering and addressing psychosocial,
psychological, and personality factors that may be impeding recovery (Table 9). If no new information is uncovered
to explain the patient’s lack of adequate response, othertreatment options should be considered, including ECT
and a consultation from an expert in mood disorders. Despite optimal treatment, some patients may continue tohave chronic depressive symptoms. For these patients, thepsychiatrist should add a disease management component
to the overall treatment plan. This component involves
setting realistic expectations, improving functioning, anddeveloping self-management skills (415, 416).
a. Maximizing initial treatments
For patients who have not fully responded to treatment
for depression, an initial strategy is to optimize the intensity of psychotherapy or maximize the dose of medication,
especially if the upper limit of the antidepressant dose has
not been reached. Decisions about pharmacotherapy will
involve a balancing of efficacy, side effects, and medication adherence. Dose escalation and management of side
effects at critical decision points are essential in order toavoid premature discontinuation of the chosen antide-

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54

APA PRACTICE GUIDELINES

pressant medication and to maximize the dose and duration of the antidepressant therapy (40, 218).
Because of pharmacokinetic and pharmacodynamic
differences among individuals, some patients may require
doses higher than those approved by the FDA to achieveadequate blood levels of a medication and receive therapeutic benefits. Patients who have had their dose increased should be monitored for increased severity of side
effects; dose increases should be considered only for patients who do not have significant or intolerable side effects while taking the medication. Frequent follow-up
contact (either in person or via the phone) may be necessary to address symptoms, side effects, and patient adherence in order to personalize treatment to the specificclinical needs of the patient. When available and clinicallymeaningful, therapeutic ranges for blood levels of antidepressant medications are useful in optimizing medication
dosing (201, 232, 233).
Individual differences are common in the time to response and the tolerability of treatments. For patients who
have shown a partial response to treatment, particularly
those with features of personality disorders and prominent
psychosocial stressors, extending the antidepressant medication trial (e.g., by 4–8 weeks) may allow up to one-thirdof patients to respond more fully (417–419).
In patients who are receiving psychotherapy, similar
principles apply in terms of monitoring and adjustingtreatment in the context of nonresponse or difficulty tolerating psychotherapy (331). Factors to be considered include the frequency of sessions, the type of psychotherapy
being used, the quality of the therapeutic alliance, and thepossible need for medications in lieu of or in addition topsychotherapy. Whereas increasing the frequency of therapy sessions is a reasonable approach to nonresponse, thisapproach is based on clinical wisdom and has not beensystematically studied.
b.

Changing to other treatments

Changing to a different non-MAOI antidepressant medication is a common strategy for patients with treatmentresistant major depressive disorder, especially those whohave not shown at least partial response to the initial medication regimen. Although there are no specific patientcharacteristics that predict which medication to choose(420), results from STAR*D suggest that changing to asecond-step treatment results in additional remission rates
of about 25%, and further changes are associated with continued remission, albeit at lower rates (about 13%–14%).
Treatment can be changed to a non-MAOI antidepressant
medication from the same pharmacological class (e.g.,
from one SSRI to another SSRI) or to one from a different
class (e.g., from an SSRI to a TCA) (369, 421–422). Adding

or changing to a depression-focused psychotherapy should
also be considered for patients with major depressive disorder who do not respond fully to medication treatment.
Other strategies for patients who do not respond adequately to pharmacotherapy include changing to an
MAOI after allowing sufficient time between medications
to avoid hazardous interactions (see Table 8). Transcranial
magnetic stimulation could also be an option, as it appears
to be safe and well tolerated (270, 280). In addition, it has
shown small to moderate benefits in most (268, 270–272)
but not all (269, 273) clinical trials and recent meta-analyses. Recent randomized trials suggest that quetiapine
monotherapy also produces a greater reduction in depressive symptoms than placebo (423, 424), with comparable
efficacy to duloxetine (424), although the potential side effects of second-generation antipsychotic treatment need
to be taken into consideration. ECT remains the most effective therapy for patients with treatment-resistant symptoms (239, 425), although results of clinical trials differ
on whether patients with medication-resistant symptoms
have responses to ECT that are comparable to those ofpatients without documented medication resistance (426–428).
c. Augmenting and combining treatments
Pharmacotherapy can be combined with a depressionfocused psychotherapy, both as an initial treatment plan,
and as a strategy to address nonresponse to treatment in
one modality or the other. See Section II.B.4.c above forfurther information about combining pharmacotherapy
and psychotherapy.
Antidepressant medications can be augmented with another non-MAOI antidepressant or with other, nonantidepressant agents. The addition of a second non-MAOI
antidepressant may be helpful, particularly for patients
who have had a partial response to antidepressant monotherapy (429). One option is to add a second non-MAOI
antidepressant medication from a different pharmacological class, taking care to avoid drug-drug interactions. Another option is to add an adjunctive, nonantidepressant
medication—such as lithium, thyroid hormone, an anticonvulsant, a psychostimulant, or a second-generation(atypical) antipsychotic. More information about thesestrategies is given later in this section.
Some limited evidence and clinical experience support
the addition of bupropion to an SSRI. This combinationis generally well tolerated, although bupropion, a moderately potent inhibitor of CYP 2D6, increases blood levelsof some SSRIs (430). In one study, combined treatment
with bupropion and an SSRI resulted in better outcomesthan either therapy alone (431). Another commonly usedstrategy is the combination of mirtazapine and an SSRI or

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
venlafaxine. Generally, mirtazapine 15–30 mg at bedtime
is added to the incompletely effective antidepressant andtitrated up to 45 mg/day on the basis of response and tolerability (432).
For patients with pronounced anxiety or persistentinsomnia not adequately relieved by an SSRI or SNRI, adjunctive use of anxiolytic and sedative-hypnotic medications is common (433, 434). These include benzodiazepines
such as clonazepam (435) and selective GABA agonists suchas zolpidem (436) and eszopiclone (437). Buspirone has also
been used adjunctively in anxious individuals (429). Although adjunctive therapy of anxiety or insomnia can hasten symptomatic relief, there is no evidence of sustained
benefit, and some patients have difficulty stopping the anxiolytic or hypnotic medication (438, 439).
Lithium, thyroid hormone, and stimulants are sometimes combined with antidepressants to augment response. Lithium is the most extensively studied of theseadjuncts (440–443) and may also reduce the long-termrisk of suicide (444). The interval before full response to
adjunctive lithium is said to be in the range of several days
to 6 weeks. The blood level required to enhance the effects of antidepressants still has not been confirmed. If effective and well tolerated, lithium should be continued atleast for the duration of acute treatment and perhaps beyond the acute phase for purposes of relapse prevention.
Thyroid hormone supplementation, even in euthyroid
patients, may increase the effectiveness of antidepressant
medication treatment, whether used as an augmentation
agent (445, 446) or in combination with an antidepressantfrom the outset of therapy (447). The dose typically used
for this purpose is 25 mcg/day of triiodothyronine, increased to 50 mcg/day if the response is inadequate after
about a week. The duration of treatment required has notbeen well studied.
Second-generation antipsychotic medications may increase the rates of response or remission of depressive
symptoms in patients who typically have not responded tomore than two medication trials (448), even when psychotic symptoms are not present. Generally, in clinicalpractice, lower doses are used for antidepressant augmentation than for treatment of psychosis. For example, thecombination of olanzapine and fluoxetine has been extensively studied (449–452) and is typically initiated with 6 mgof olanzapine and 25 mg of fluoxetine daily and titrated upward as tolerated to a maximum of 18 mg of olanzapine and75 mg of fluoxetine daily. Aripiprazole has received FDA
approval for augmentation of antidepressive agents and istypically initiated at 2.5–5 mg/day and titrated upward as
tolerated to a maximum of 15 mg/day (453). With quetiapine, doses of 25 to 400 mg/day have been used, with benefits for depressive symptoms found in some (454, 455) but

55

not all (456) clinical trials. Risperidone augmentation, indoses of up to 3 mg daily (457, 458) also appears to improve
the response to antidepressant agents. In most of these trials,
the onset of the effect of second-generation antipsychotic
augmentation has been rapid, although the magnitude of
the advantage relative to placebo has been relatively modest. In the only two trials to utilize active comparisongroups, the combination of olanzapine and fluoxetine was
not significantly more effective at study endpoint than continued therapy with nortriptyline (450) or venlafaxine (451).
Naturalistic follow-up data also suggest that long-term
weight gain can be problematic for many patients receiving
second-generation antipsychotic augmentation therapy,
particularly with the olanzapine-fluoxetine combination(459). In addition, a recent meta-analysis suggests that therate at which SGA augmentation is discontinued is nearlyfour-fold greater than study discontinuation among subjects randomly assigned to placebo (448). When comparedwith other strategies for antidepressant nonresponders, augmentation with a second-generation antipsychotic carries
disadvantages: the high cost of many agents, the significant
risk of weight gain and other metabolic complications (e.g.,dyslipidemia, hypertriglyceridemia, glucose dysregulation,
diabetes mellitus), and potential risk of hyperprolactinemia, tardive dyskinesia, neuroleptic malignant syndrome,
and QTc prolongation. Thus, the advantages and disadvantages of antipsychotic medications should be consideredwhen choosing this augmentation strategy. In addition,
when augmentation with a second-generation antipsychotic
is effective, it is uncertain how long augmentation therapy
should be maintained.
Many clinicians find that augmentation of antidepressants with low doses of stimulants such as methylphenidate
or dextroamphetamine may help ameliorate otherwise
suboptimally responsive depression (460–462), although
not all clinical trials have shown benefits from this strategy (463). More recently, the novel compound modafinilhas shown modest benefit when combined with SSRIs, related to specific effects on residual symptoms such as fatigue and hypersomnolence (464–467). Although there
are no clear guidelines regarding the length of time stimulants or modafinil should be coadministered, in one extension study the effects of modafinil were maintained across
12 weeks of additional therapy (468). Physicians prescribing modafinil for this off-label use should become familiar
with rare but dangerous cutaneous reactions to it, including reported instances of Stevens-Johnson syndrome,
toxic epidermal necrolysis, drug rash with eosinophilia
and systemic symptoms (469), and cytochrome P450 interactions. Modafinil can also induce CYP 3A4 and render
contraceptive medications and other medications metabolized through this route ineffective.

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56
Although their use in this context has not been extensively evaluated, anticonvulsants such as carbamazepine,
valproic acid, and lamotrigine may offer some benefit in
the treatment of medication-resistant major depressive
disorder (121, 429, 470–473).
A rarely used strategy is the combined use of a TCA or
trazodone and an MAOI (474, 475). The combination of a
TCA and an MAOI has been used for more than three
decades for treatment of some of the most treatmentresistant depressive disorders; however, the risk of drugdrug interactions necessitates careful monitoring (119).
Of particular concern with these combinations is the serotonin syndrome, characterized by delirium, hyperthermia,
hyperreflexia, myoclonus, and, rarely, death (see Section
II.B.2.b.5.b). Use of an MAOI in combination with a
TCA and related antidepressants should probably not be
considered until other pharmacological strategies for patients with treatment-resistant illness have been exhausted;
psychiatrists and patients choosing to use the combination of an MAOI and a TCA should be well acquainted
with the potential hazards and carefully weigh the relative
risks and benefits of such a strategy.
Vagus nerve stimulation was approved for use in patients whose symptoms have not responded to at least
four adequate trials of antidepressant medications and/or
ECT. Acute benefits were not observed in the shamcontrolled portion of the VNS trial (282). When compared with a parallel treatment-as-usual arm, the longterm (1–2 year) open-label extension showed small (476,477) but persistent (478) improvements in symptoms with
VNS that could be clinically significant for some patients.
Other open-label studies have also shown some benefit
when VNS is used simultaneously with pharmacotherapy(479–481).
As with any surgical device implantation, there is asmall risk of postsurgical infection (482). A majority of individuals experience hoarseness or voice alteration during
stimulation, and coughing, dyspnea, and neck discomfort
are common (281, 481) but generally are tolerable to patients (282, 479). Patients also need to be informed of theimplications of having an implanted VNS device for future medical care (482). For example, with a VNS devicein place, brain MRI requires the use of a special sendreceive coil. The VNS device may affect the operation ofother implanted devices such as cardiac pacemakers or
defibrillators and other procedures such as diathermy, andwhole body or radiofrequency receive-only MRI are contraindicated. VNS is also contraindicated in the presenceof bilateral or left cervical vagotomy.
Relative to other antidepressive treatments, the role of
VNS remains a subject of debate. However, it could beconsidered as an option for patients with substantial symp-

APA PRACTICE GUIDELINES
toms that have not responded to repeated trials of antidepressant treatment.

C. CONTINUATION PHASE
Continuation phase pharmacotherapy is strongly recommended following successful acute phase antidepressanttherapy, with a recommended duration of continuation
therapy of approximately 4–9 months (assuming good andconsistent control of depression symptoms). The goal ofcontinuation treatment is to prevent relapse (i.e., the reemergence of significant depressive symptoms or dysfunction) in the vulnerable period immediately following
remission (i.e., a complete alleviation of symptoms) (408,410, 411). The possibility of relapse should be carefully
monitored during the continuation phase as this is whenrisk of relapse is highest (483). Within the first 6 months
following recovery from a major depressive episode, relapse of depressive symptoms is common, with the proportion of patients with relapse ranging from 20% of patientsin mixed samples (484–487) to as many as 85% of severely
depressed inpatients receiving treatment with ECT (234,488, 489). These studies also show that relapse rates are
greater if antidepressant treatment (including ECT) is
discontinued or reduced in dose or intensity following recovery (234, 489, 490). There is evidence that patients
who do not completely recover during acute treatment
have a significantly higher risk of relapse (and a greaterneed for continuation treatment) than those who have noresidual symptoms (227, 491, 492). Similarly, patients
who have not fully achieved remission with psychotherapy are at greater risk of relapse in the near term (364,365, 367, 493, 494). To reduce the risk of relapse during
the continuation phase, treatment should generally continue at the same dose, intensity, and frequency that wereeffective during the acute phase. Although the number ofrandomized controlled trials of antidepressant medications in the continuation phase is limited, the available
data indicate that patients treated for a first episode of uncomplicated major depressive disorder who exhibit a satisfactory response to an antidepressant medication should
continue to receive a full therapeutic dose of that agent for
at least 4–9 months after achieving full remission (105,225, 495).
Published studies for the continuation phase with older
TCAs as well as newer medications have consistently
shown efficacy of these medications in preventing relapse,
compared with placebo. Lithium has also been shown tohave efficacy in preventing relapse (496).
Cognitive-behavioral therapy may prevent relapse ofdepression when used as augmentation to medication
treatment. It may also bestow an enduring, protective ben-

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
efit that reduces the risk of relapse after the treatment has
ended (363). Cognitive group therapy helps to prevent relapse and recurrence for patients in remission after a major depressive episode (497). Mindfulness-based cognitive
therapy is a variant of cognitive therapy that encourages
patients to pay attention to their thoughts and feelings in
the moment and to accept them rather than judging or
trying to change or disprove them. Among patients withremitted depression, mindfulness-based cognitive therapy groups may reduce risk of relapse for patients who
have already experienced three or more episodes (498).
Such benefits for CBT (and potentially, for other psychotherapies) would offer an advantage over pharmacotherapy, which works only as long as the patient continues theantidepressant medication.
Continuation therapy is also essential in reducing relapse risk after an acute course of ECT (239). Althoughrelapse occurs for many patients regardless of continuation strategy (234, 488, 489), remission of symptoms following successful treatment with ECT may be maintainedwith either pharmacotherapy or continuation ECT (234).
Research shows that continuation ECT is comparable inefficacy to the combination of nortriptyline and lithium(234) and that the latter combination is superior to
nortriptyline alone in preventing relapse (489). Although
there is limited information regarding prognostic factors,
relapse may be less likely among patients with melancholic depression who receive continuation ECT after remission with acute ECT than among those who receive
continuation pharmacotherapy after remission with acute
ECT (499).
Given the significant risk of relapse during the continuation phase of treatment, it is essential to assess depressive symptoms, functional status, and quality of life in asystematic fashion, which can be facilitated by the use of
periodic, standardized measurements. It is often helpful
for patients and families to identify particular signs (e.g.,lack of engagement in specific activities that are usually enjoyed, specific “signal” symptoms or patterns of thought)that are typical of their earlier depressive episodes and may
suggest the beginnings of a depressive relapse. Furthermore, any sign of symptom persistence, exacerbation, or
reemergence or of increased psychosocial dysfunction
during the continuation period should be viewed as a harbinger of possible relapse.
If a relapse does occur during the continuation phase, areturn to the acute phase of treatment is required. An initial
step is often to increase the dose of medication (500) or,with continuation ECT, to increase the frequency oftreatment (501). For patients receiving psychotherapy, an
increased frequency of sessions or a shift in the psychotherapeutic focus may be needed. It is also essential to de-57

termine whether any specific precipitants are contributing
to the relapse of depression. For example, the onset or
worsening of psychosocial stressors, substance use disorders, or general medical conditions can contribute to increased depressive symptoms. In addition, decreased
treatment adherence or reductions in medication bloodlevels (e.g., due to drug-drug interactions or increased cigarette use) can also prompt a depressive relapse.

D. MAINTENANCE PHASE
Patients with chronic and/or recurrent major depressive
disorder who complete the continuation phase without
relapse proceed to the maintenance phase of treatment, inwhich the goal is to protect susceptible patients against recurrence of subsequent depression.
Patients who have had three or more prior major depressive episodes should receive maintenance treatment.
Within the first 6 months following recovery from a major depressive episode, 20% of patients will experience arecurrence (484). Between 50% and 85% of patients will
have at least one lifetime recurrence, usually within 2 or 3
years (502), although there is little consistency in the time
to recurrence for any individual patient (484). Patients
who have had a prior major depressive episode also have ahigh risk of experiencing subsequent affective episodes
other than another major depressive episode, such as a
manic, hypomanic, or dysthymic episode (503). The number of lifetime major depressive episodes is significantly
associated with the probability of recurrence, such that therisk of recurrence increases by 16% with each successive
episode (484).
Maintenance therapy should be considered morestrongly for patients with additional risk factors for recurrence, such as the presence of residual symptoms, ongoing
psychosocial stressors, family history of mood disorders,
and the severity of prior episodes (504) (see Table 10). Additional considerations that may play a role in the decision
to use maintenance therapy include patient preference,the presence of side effects during continuation therapy,
and the severity of prior depressive episodes, including
factors such as psychosis or suicide risk. Due to the risk ofrecurrence and the importance of early detection of recurrent symptoms, patients should be monitored periodicallyand in a systematic fashion during the maintenance phase;such assessments can be facilitated by the use of standardized rating scales, as described in Section II.A.8.
In general, the treatment that was effective in the acuteand continuation phases should be used in the maintenancephase.
Among the therapeutic options available for maintenance treatment, antidepressant medications have received

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58
TABLE 10.

APA PRACTICE GUIDELINES
Risk Factors for Recurrence of Major Depressive
DisorderPersistence of subthreshold depressive symptoms
Prior history of multiple episodes of major depressive
disorderSeverity of initial and any subsequent episodes
Earlier age at onset
Presence of an additional nonaffective psychiatricdiagnosis
Presence of a chronic general medical disorder
Family history of psychiatric illness, particularly mooddisorderOngoing psychosocial stressors or impairment
Negative cognitive style
Persistent sleep disturbances
the most study. There have been more than 30 trials of pharmacotherapy in the maintenance phase, and results havegenerally demonstrated the effectiveness of antidepressant medication for relapse prevention (105, 226, 314, 505–
507). Many of these trials used TCAs (314, 506), although
results of trials involving newer antidepressant medications have been assessed in a recent meta-analysis (507).
Lithium has also been used as maintenance treatment for
major depressive disorder (441). Despite this, there is limited information on many of the clinical decisions involving
medication use in the maintenance phase. Even though
lower doses of medication are less likely to produce side
effects, results from one study suggest that full doses aresuperior to lower doses in the maintenance phase (508).
Particularly if medications are well-tolerated, it is generally advisable to prescribe the same antidepressant medication doses for maintenance therapy that were effective
in prior phases of treatment. Even with adequate maintenance treatment, pharmacotherapy is not invariably successful in preventing relapse and return of symptoms, whichstill occur in as many as 25% of individuals (509, 510). It is
unclear whether some relapses during maintenance therapy are loss of therapeutic efficacy, a phenomenon thathas been referred to as tachyphylaxis, but many such relapses appear related to inadequate prophylactic effectsof medication (511). When relapses occur, clinicians
typically address them using the same approaches described
to treat incomplete responses to treatment, such as increasing the dose of medication, changing to a different
medication, or adding another medication or a depressionfocused psychotherapy to augment therapeutic response(510, 512).
There have been fewer investigations of the effectiveness of psychotherapy in the maintenance phase. Nonethe-less, several studies have shown that acute psychotherapies
for major depressive disorder also have maintenance benefits. For example, even once-monthly maintenance IPT
has been shown to forestall relapse in patients at high risk
for relapse (289, 314, 315, 513). Most of these studies haveused once-monthly maintenance IPT, but research has
not demonstrated that frequency of sessions affects outcome (289). In one study, maintenance cognitive therapy
delivered over 2 years was as effective as maintenancemedication for recurrent major depressive disorder (514).
Combining psychotherapy—such as CBT, cognitive therapy, or IPT—with pharmacotherapy in the maintenancephase has also been considered by investigators. Some
results suggest that the combination of antidepressant
medications plus psychotherapy may be more effective inpreventing relapse than treatment with single modalities(314, 365, 506, 515, 516).
For patients receiving treatment with pharmacotherapy and/or psychotherapy, the frequency of visits during
the maintenance phase should be set according to theclinical condition and the specific treatments being used.
The frequency can range from as low as once every several
months for stable patients who require only psychiatricmanagement and medication monitoring to as high as
once or twice per week for those receiving psychodynamic
psychotherapy. For CBT and IPT, maintenance-phasetreatments usually involve a decreased frequency of visits(e.g., once a month). The duration of the maintenancephase will vary depending on the frequency and severityof prior major depressive episodes, the tolerability oftreatments, and patient preferences. For many patients,
some form of maintenance treatment may be required indefinitely.
Electroconvulsive therapy has also been used in themaintenance phase, although evidence for its benefits
comes largely from case reports (239). Patients who exhibit
repeated episodes of moderate or severe major depressive
disorder despite optimal pharmacological treatment or patients who are medically ineligible for such treatment may
be maintained with periodic ECT. Although the optimal
frequency and duration of maintenance phase ECT treatments has not been well studied, maintenance ECT isoften administered monthly; individuals for whom thisis insufficient may find treatment at more frequent intervals to be beneficial (501).

E. DISCONTINUATION OF TREATMENT
If maintenance-phase treatment is not indicated, stablepatients may be considered for discontinuation of treatment after the continuation phase. The precise timing
and method of discontinuing psychotherapy and pharma-

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
cotherapy for major depressive disorder have not beensystematically studied.
The decision to discontinue treatment should be basedon the same factors considered in the decision to initiate
maintenance treatment (Table 10), including the probability of recurrence, the frequency and severity of past episodes, the persistence of depressive symptoms after
recovery, the presence of co-occurring disorders, and patient preferences. The type of treatment being received
may also play a role in the decision making. In general,
psychotherapy has a longer lasting treatment effect andcarries a lower risk of relapse following discontinuation
than pharmacotherapy. In terms of timing, patients should
be advised not to discontinue medications before holidays,
significant events (e.g., weddings), or stressful events.
Patients should be carefully monitored during and immediately after treatment discontinuation to ensure that
remission is stable. The highest risk for a relapse is seen in
the first 2 months after discontinuation of treatment.
Hence, it is important to schedule a follow-up visit during
this period to ensure stability.
When pharmacotherapy is being discontinued, it isbest to taper the medication over the course of at least
several weeks. Such tapering allows for the detection ofrecurring symptoms at a time when patients are still partially treated and therefore more easily returned to fulltherapeutic treatment if needed. In addition, such tapering can help minimize the incidence of antidepressant
medication discontinuation syndromes, particularly withparoxetine and venlafaxine (98, 163, 164). Discontinuation
syndromes are problematic because their symptoms include disturbances of mood, energy, sleep, and appetiteand can therefore be mistaken for or mask signs of relapse(517). Consequently, patients should be advised not tostop medications abruptly and to take medications withthem when they travel or are away from home. Discontinuation syndromes have been found to be more frequent after discontinuation of medications with shorter half-lives,and patients maintained on short-acting agents should

III.

59

have their medications tapered gradually over a longer period (518, 519). Another strategy is to change to a brief
course of fluoxetine, e.g., 10 mg for 1–2 weeks, and thendiscontinue the fluoxetine (165). The psychiatrist shouldclosely monitor patients withdrawing from antidepressants and provide reassurance that symptoms are timelimited and can be addressed by more gradual tapering(see Section II.B.2.b.1.i).
How to end psychotherapy is typically dependent on
the type of therapy. For time-limited approaches, termination is usually broached from the initiation of treatment
and periodically revisited, as the therapist-patient dyad
notes which session they are in, how many remain, andhow they have progressed toward defined goals. In dynamically oriented psychotherapy, the therapist typicallyraises termination as an issue well in advance of the final
session, using the opportunity to explore remaining andunresolved issues in transference.
Before the discontinuation of active treatment, patients should be informed of the potential for a depressive
relapse. Early signs of major depressive disorder should be
reviewed, often with a family member, and a plan established for seeking treatment in the event of recurrent
symptoms. Patients should continue to be monitored
over the next several months to identify early evidence ofrecurrent symptoms. Again, systematic assessment ofsymptoms, side effects, adherence, and functional statusduring this period of high vulnerability is strongly recommended. If a patient does suffer a recurrence after discontinuing medication, treatment should be promptly
reinitiated. Usually, the previous treatment regimen towhich the patient responded in the acute and continuation
phases should be reinitiated (520). Patients who have a recurrence following discontinuation of antidepressanttherapy should be considered to have experienced anothermajor depressive disorder episode and should receive
adequate acute-phase treatment followed by continuation-phase treatment and possibly maintenance-phasetreatment.

SPECIFIC CLINICAL FEATURES INFLUENCING THE
TREATMENT PLAN

A. PSYCHIATRIC FACTORS
1. Depressive symptoms
a. Suicidal ideation and behaviors
Because suicide is the worst outcome of major depressive
disorder, a patient’s risk for suicide must be assessed re-peatedly over the course of treatment. For patients whoreport suicidal ideation, intention, or planning, close surveillance is necessary (see Sections II.A.3 and II.A.4). Psychiatrists should consider greater intensity of treatment
for suicidal patients, including hospitalization when warranted and/or combined treatment with pharmacother-

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60
apy and psychotherapy. In patients at high risk for suicide
and in whom a particularly rapid antidepressant responseis required, consideration should be given to the use of
ECT (239, 243, 521). Patients with major depressive disorder who present to an emergency department with suicidal ideation, or who have made a suicide attempt, shouldbe triaged to determine their level of safety and establish
the appropriate level and setting of care. Upon entrance
to the emergency department, they should be searched topermit removal of potentially dangerous items, such as
weapons and personal belongings that could cause harm(e.g., sharp objects, belts, shoes, medications). Factors toconsider in determining the nature and intensity of treatment include (but are not limited to) access to and lethality of suicide means, past and family history of suicidal
behavior, co-occurring substance abuse, the availability
and adequacy of social supports, and the nature of thedoctor-patient alliance.
To lower the risk of suicide, the psychiatrist should also
treat modifiable risk factors, such as anxiety (especiallypanic attacks), insomnia, agitation, psychotic symptoms,
and substance abuse (22), in addition to treating the major
depressive episode. Among inpatients who died by suicide,
Busch et al. (522) observed that a great majority wereadmitted for indications other than suicidal ideation, andanxiety and agitation were common, suggesting that such
symptoms should be addressed if they are present. Family
members can also play an important role in detecting andpreventing suicidal behaviors. When permitted by the patient, the psychiatrist should educate those close to thepatient concerning appropriate interventions and encourage communication.
There has been a growing controversy about the risk ofsuicidal ideas and behaviors (sometimes referred to as“suicidality”) after initiation of antidepressant treatment.
Although information on such risk continues to evolve, apredictive relationship to suicide has never been demonstrated. Clinical experience has long suggested that patients may develop the energy and capacity to act on selfdestructive plans made earlier in the course of their illness
if neurovegetative and psychomotor symptoms respondto antidepressant treatment before mood improves. Morerecently, meta-analyses of data from clinical trials haveshown statistically significant increases in suicidal thoughts
or behaviors in individuals age 25 years or younger who
are treated with antidepressant medication, comparedwith placebo, with an approximately 1.5- to 2.5-fold increase in the relative risk (26, 523–530). In percentage
terms, it is estimated that one to three of 100 individuals
age 25 years or younger could potentially have an increasein suicidal thoughts or behaviors with antidepressanttreatment (26), although there has been no evidence of in-

APA PRACTICE GUIDELINES
creased mortality in the study subjects as a result of suicide(531). To alert clinicians to the need for vigilance andcommunication during the initial phase of antidepressanttreatment, the FDA has issued a black-box warning pertaining to children, adolescents, and young adults that advises of this increase in the risk of suicidal thinking andbehavior; information on the warning is available on the
FDA Web site at http://www.fda.gov/cder/drug/antidepressants/default.htm. In making decisions about treatment, this awareness of a potential increase in suicidal
thinking and behavior in children, adolescents, and young
adults must be balanced against the negative effects, including suicide, of untreated depression (532) as well as
the demonstrated benefits of antidepressant treatment(523, 533–535). For adults age 65 years or older, a reviewof the evidence from clinical trials showed a decrease in
the risk of suicidal thinking or behaviors with antidepressant treatment, with no change in risk detected for other
adults (age 25 to 64 years) (536).
For additional details about the treatment of suicidal
individuals, clinicians are encouraged to consult APA’s
Practice Guideline for the Assessment and Treatment of Patients With Suicidal Behaviors (22).
b. Major depressive disorder–related cognitive dysfunction
Cognitive inefficiency and impairment are common features of major depressive disorder. Many depressed patients
report slowed thoughts, poor concentration, distractibility,
and reduced capacity to process information. They also display diminished attention to self-care and to their environment. Transient cognitive impairment, especially involving
attention, concentration, and memory storage and retrieval,
are demonstrable through neuropsychological testing (537).
In extreme cases, especially in elderly patients, these deficits
are so prominent that patients appear to have dementia. For
individuals who exhibit symptoms of a dementia syndrome,
it is crucial that any underlying depressive disorder be identified and treated.
Among depressed patients, the differential diagnosis ofcognitive dysfunction includes degenerative dementias(such as Alzheimer’s disease and Pick’s disease) and reversible causes (such as vitamin B12 deficiency, folate deficiency,
testosterone deficiency, substance use). Several clinical features help distinguish major depressive disorder–related
cognitive dysfunction from other dementia syndromes.
When performing cognitive tasks, depressed patients generally exert less effort and report greater incapacity than dopatients with dementia. The latter, especially in more advanced stages, typically do not recognize their cognitive
failures, since insight is impaired. In contrast, depressed
patients may report being unable to think or remember.
Patients with major depressive disorder–related cognitive

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
dysfunction lack the signs of cortical dysfunction (i.e., aphasia, apraxia, agnosia) encountered in dementias such as
Alzheimer’s disease (538, 539). Nevertheless, distinguishingdementia from depression-related cognitive dysfunction
can be difficult, particularly as the two may coexist. For further discussion of the co-occurrence of dementia and depression, the reader may also wish to consult APA’s Practice
Guideline for the Treatment of Patients With Alzheimer’s Disease and Other Dementias, Second Edition (539).
The detection of major depressive disorder–related
cognitive dysfunction alerts the psychiatrist to the needfor treatment of the underlying major depressive disorder,
which should in turn reduce the signs and symptoms ofthe cognitive dysfunction. Although initially reversible,major depressive disorder–related cognitive dysfunction
increasingly appears to be a harbinger of subsequent dementia (540, 541). In addition, research suggests that certain types of executive cognitive dysfunction predict greater
disability and limited treatment response in geriatric patients with depression (542, 543).

2. DSM depressive subtypesa.

Psychotic features

Major depressive disorder is sometimes accompanied byhallucinations or delusions, which may be congruent orincongruent with the depressed mood. Recognition of
psychosis is essential among patients with major depressive disorder as it is often undetected, resulting in ineffective treatment (544–546). Psychotic features constitute arisk factor for recurrent major depressive disorder and recurrent psychosis and hence indicate the need for maintenance treatment.
Electroconvulsive therapy is highly effective in treating
psychotic depression (241) and can be considered as afirst-line treatment option whenever major depressive
disorder is associated with psychotic features (239, 243,
547). Pharmacotherapy can also be used as a first-line
treatment option for major depressive disorder with psychotic features. Psychotic depression typically responds
better to the combination of an antipsychotic and an antidepressant medication rather than treatment with either
component alone (547–549), although some research has
shown comparable responses for antidepressive treatment
or antipsychotic treatment alone (550, 551). Lithium augmentation is helpful for some patients who have not responded to combined treatment with antidepressant andantipsychotic medication (262, 552).
b. Catatonic features
A catatonic syndrome sometimes occurs in the context ofmajor depressive disorder (553–556) and is characterized

61

by at least two of the following manifestations: immobility, as evidenced by catalepsy or stupor; extreme agitation;
extreme negativism; peculiarities of voluntary movement,
as evidenced by posturing, stereotyped movements, mannerisms, or grimacing; and echolalia or echopraxia (556,557). The presence of catatonia should prompt a thorough differential diagnosis as it can also occur in association with general medical conditions and with several
other psychiatric disorders, including bipolar disorderand schizophrenia (556, 558, 559). Catatonic signs often
dominate the clinical presentation and may be so severe as
to be life-threatening, compelling the consideration of urgent somatic treatment. Patients with catatonic features
may also need supportive medical interventions including
hydration, nutrition, prophylaxis against deep vein thrombosis, turning to prevent bed sores, and passive range of
motion to prevent contractures. Intravenous administration of a benzodiazepine (e.g., lorazepam, diazepam) or abarbiturate (e.g., amobarbital) may induce rapid relief(242, 553) and can be followed by continued oral administration for patients who show an initial response. Whensuch intervention is ineffective, the clinician should consider the urgent use of ECT (239, 242). The efficacy of
ECT in catatonia is well documented in the case series
literature (239) and is usually apparent after a few treatments. After catatonic manifestations recede, antidepressant medication treatments may be needed during acuteand maintenance phases of treatment. In addition to antidepressant medications, ongoing treatment may include
ECT, lithium, antipsychotics, or a combination of theseapproaches, depending upon the patient’s condition. Patients with catatonia may have an increased susceptibility
to neuroleptic malignant syndrome when exposed to antipsychotic medications (560), and this should be considered in planning treatment.
c. Melancholic features
Melancholic features describe characteristic somatic
symptoms, such as the loss of interest or pleasure in all, or
almost all, activities or a lack of reactivity to usually pleasurable stimuli. Other symptoms include worsened depression in the morning, early morning awakening, andsignificant anorexia or weight loss, among others (16).
Major depressive disorder with melancholic features is responsive to both pharmacotherapy and ECT. Serotoninnorepinephrine reuptake inhibitors and TCAs may havean advantage over SSRIs for this patient population (561,562). Psychotherapy may be less appropriate for patientswith melancholia (563), particularly if the symptoms prevent engagement with the therapist (e.g., lack of interestin activities). Major depressive disorder with melancholicfeatures may also be associated with an added risk of sui-Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

62cide (564) and an increased risk of subsequent recurrence
despite the use of maintenance pharmacotherapy (509).
d. Atypical features
Major depressive disorder with atypical features is characterized by a pattern of marked mood reactivity and at least
two additional symptoms, including leaden paralysis, along-standing pattern of interpersonal rejection sensitivity,
significant weight gain or increase in appetite, and hypersomnia (the latter two of which are considered reversed
vegetative symptoms) (16). The phrase “atypical features”
distinguishes this depressive subtype from the more classical “endogenous” presentation of depression, but it does
not connote an uncommon or unusual form of depression.
Atypical features are more common in women, are associated with an earlier age at onset of depression and a greater
degree of associated anxiety disorders, and frequently havea more chronic, less episodic course, with only partial interepisode recovery (565, 566). These atypical features arealso common in the depressed phase of bipolar I disorderand bipolar II disorder (567, 568), indicating a need for
careful screening for manic or hypomanic episodes in patients who present with atypical depressive symptoms.
In the treatment of major depressive disorder withatypical features, MAOIs have greater efficacy than TCAs
(122, 569–572). Some data also support the use of SSRIs,
bupropion, and CBT in this patient population (573–577). Electroconvulsive therapy is also effective in treating patients with atypical features (578). The presence andseverity of specific symptoms as well as safety considerations should help guide the choice of treatment for major
depressive disorder with atypical features. For example, if
a patient does not wish to, cannot, or appears unlikely toadhere to the dietary and medication precautions associated with MAOI treatment, the clinician should consider
alternative antidepressant medication or psychotherapy.
e. Seasonal pattern
A seasonal pattern of major depressive disorder is characterized by a regular temporal relationship between particular periods of the year and the onset and remission ofsymptoms, which is not the result of seasonally related
psychosocial stressors (e.g., seasonal unemployment, significant anniversaries). The most common presentationin the northern hemisphere is the regular appearance ofsymptoms between early October and late November andregular remission from mid-February to mid-April. Episodes of major depressive disorder with seasonal patternfrequently have atypical features such as hypersomnia andovereating. Some of these patients experience manic or
hypomanic episodes as well; hence, it is important to diagnose bipolar disorder when appropriate.

APA PRACTICE GUIDELINES
The entire range of treatments for major depressive
disorder may be used to treat major depressive disorderwith seasonal pattern, either in combination with or as analternative to light therapy. As a primary treatment, lighttherapy may be recommended as a 1- to 2-week time-limited
trial (395), primarily for outpatients with clear seasonalpatterns. For patients with more severe forms of major
depressive disorder with seasonal pattern, the use of lighttherapy is considered adjunctive to pharmacological intervention. In terms of specific antidepressive agents, theextended release formulation of bupropion is FDA approved
for use with patients who have major depressive disorderwith seasonal pattern.

3. Co-occurring psychiatric disorders
Co-occurring psychiatric disorders generally complicate
treatment. Patients with major depressive disorder who
also have other psychiatric disorders have greater symptom severity and are more challenging to treat than patients with major depressive disorder alone. Yet thepresence of co-occurring Axis I or Axis II disorders should
not lead clinicians to conclude that patients are untreatable. Furthermore, other Axis I or Axis II disorders may
masquerade as major depressive disorder or may seem toco-occur with the depression. In these cases, the other apparent disorders evanesce with successful treatment of theunderlying major depressive disorder.
a.

Dysthymic disorder

Dysthymic disorder is a chronic mood disorder withsymptoms that fall below the threshold for major depressive disorder. Because of this, it may escape notice andmay be inadequately treated. Nonetheless, it can causesignificant suffering and disability. In some patients, bothdysthymic disorder and major depressive disorder (socalled “double depression”) may be diagnosed.
In the treatment of dysthymic disorder and chronic
major depressive disorder, there is demonstrated efficacy
for antidepressant medications, including TCAs, SSRIs,
other newer agents, and MAOIs. Unfortunately, clinical
trials provide little evidence of the relative efficacies ofparticular agents (105, 579). In general, pharmacotherapy
of dysthymic disorder resembles that for episodes ofmajor depressive disorder; responses to antidepressant
medications by patients with dysthymic and chronic
major depressive disorders have been comparable to the
responses by patients with major depressive disorderepisodes (580). In “double depression,” antidepressant
medication can reverse not only the acute major depressive episode but also the co-occurring dysthymic disorder(581).

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
Patients with dysthymic disorder, as well as patientswith chronic and severe major depressive disorder, typically have a better response to the combination of pharmacotherapy and psychotherapy than to either alone(294, 295), although results of combined treatment studies have been mixed and complicated by methodologicalproblems (582).
b. Anxiety disorders
As a group, anxiety disorders are the most commonly occurring psychiatric disorders in patients with major depressive disorder (583). A 2005 epidemiological study
found that among individuals with major depressive disorder, 62% also met the criteria for generalized anxiety
disorder, 52% for social phobia, 50% for posttraumaticstress disorder (PTSD), 48% for panic disorder, 43% for
specific phobia, and 42% for obsessive-compulsive disorder (584). In addition, agitation and anxiety, including
panic attacks, are frequent co-occurring symptoms ofmajor depressive disorder. The appearance of anxiety andagitation in patients in a major depressive episode, particularly when accompanied by racing or ruminative thoughts,
should alert the clinician to the possibility of a mixed
mood state of a bipolar spectrum disorder (585).
In studies of major depressive disorder with a cooccurring anxiety disorder, both depressive symptoms andanxiety symptoms respond to antidepressant medication
treatment (586). However, TCAs and SSRIs may initiallyworsen rather than alleviate anxiety symptoms, including
panic attacks; patients should be so advised, and these
medications should be introduced at low doses and slowly
increased when treating such patients. Adjunctive antipanic agents, such as benzodiazepines, may be necessary
as well. Selective serotonin reuptake inhibitors are beneficial for patients with co-occurring depression and social
anxiety disorder (587) and co-occurring depression and
PTSD (588). Bupropion is comparable to SSRIs in thetreatment of patients with major depressive disorder andlow to moderate levels of anxiety (82), but studies vary as
to whether bupropion is (589) or is not (590) effective inthe treatment of panic disorder. Because benzodiazepines
are not antidepressants and carry their own adverse effects
and toxicity, including abuse and dependence, benzodiazepines should not be the primary pharmacological agentsfor patients with major depressive disorder who have cooccurring anxiety symptoms. These agents may be usedadjunctively with other antidepressive treatments, however (591). Psychotherapies such as CBT, behavioral therapy, and IPT may also be used to treat anxiety symptoms
in the context of major depressive disorder (591, 592).
Obsessive-compulsive symptoms are also common inpatients with major depressive episodes. In addition, ob-

63sessive-compulsive disorder may appear as a co-occurring
condition in some patients with major depressive disorder. Clomipramine and SSRIs have demonstrated efficacy
in managing obsessive-compulsive symptoms in addition
to treating depression (593–595).
c. Dementia
Patients with dementia are predisposed to depression, andthe psychiatrist should therefore screen for depression inthis population, although this is sometimes challenging(539). One screening tool is the Cornell Scale for Depression in Dementia, which incorporates self-report withcaregiver and clinician ratings of depressive symptoms(596). Treatment of major depressive disorder in the cognitively impaired patient requires careful supervision andmonitoring of the patient’s pharmacotherapy; this may
entail education of home health aides, nursing home staff,
and others. Antidepressants are likely to be efficacious intreatment of depressive symptoms, but they do not improve cognition, and data on antidepressant use in patients with dementia are limited (597–599). Individuals
with dementia are particularly susceptible to the adverse
effects of muscarinic blockade on memory and attention.
Therefore, individuals with dementia generally do bestwhen given antidepressant medications with the lowest
possible degree of anticholinergic effect, e.g., bupropion,
fluoxetine, sertraline, trazodone, and, of the tricyclic
agents, desipramine or nortriptyline (600). Alternatively,
some patients do well when given stimulants in small
doses. Electroconvulsive therapy is also effective in major
depressive disorder superimposed on dementia. It should
be used if medications are associated with an excessive riskof adverse effects, are not tolerated, or if immediate resolution of the major depressive disorder episode is medically indicated (such as when it interferes with thepatient’s acceptance of food). In individuals with dementia, ECT treatment may be associated with a transient
worsening of the patient’s cognitive status (239, 601, 602).
APA’s Practice Guideline for the Treatment of Patients With
Alzheimer’s Disease and Other Dementias, Second Edition(539) contains more information about the treatment ofdepression and dementia.
d. Substance use disorders
Major depressive disorder frequently occurs with alcohol
or other substance abuse or dependence. Therefore, thepsychiatrist should obtain a detailed history of the patient’s substance use. With the patient’s permission, family
members, friends, or co-workers can be collateral sourcesof information. If the evaluation reveals a substance use
disorder, this should be addressed in treatment. A patientwith major depressive disorder who has a co-occurring

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64

APA PRACTICE GUIDELINES

substance use disorder is more likely to require hospitalization, more likely to attempt suicide, and less likely toadhere to treatment than a patient with major depressive
disorder of similar severity uncomplicated by substanceuse (603–608).
Detoxifying patients before initiating antidepressant
medication therapy is advisable when possible (110). Antidepressants may be used to treat depressive symptoms
following initiation of abstinence if symptoms do not improve over time. It is difficult to identify patients who should
begin a regimen of antidepressant medication therapy
soon after initiation of abstinence, because depressive
symptoms may have been induced by intoxication and/or
withdrawal of the substance. A family history of major depressive disorder, a history of major depressive disorderpreceding alcohol or other substance abuse, or a history ofmajor depressive disorder during periods of sobriety raises
the likelihood that the patient might benefit from antidepressant medication, which may then be started early intreatment. Comparing the temporal pattern of symptoms
with the periods of use and abstinence of the substance
may help to clarify the patient’s diagnosis. Repeated, longitudinal psychiatric assessments may be necessary to distinguish substance-induced depressive disorder from cooccurring major depressive disorder, particularly becausesome individuals with substance use disorders reduce
their substance consumption once they achieve remissionof a co-occurring major depressive disorder.
Co-occurring substance use, especially with stimulant
drugs, raises the risk of deleterious interactions with MAOIs,
although few such events have been reported (609). Benzodiazepines and other sedative-hypnotics carry the potential for abuse or dependence and should rarely beprescribed to patients with co-occurring substance use
disorders, except as part of a brief detoxification regimen.
Hepatic dysfunction and hepatic enzyme induction frequently complicate pharmacotherapy of patients with alcoholism and other substance abuse. These conditions
may require careful monitoring of blood levels (as appropriate for the medication), therapeutic effects, and side effects to avoid the opposing risks of either psychotropic
medication intoxication or underdosing.
For individuals with nicotine dependence who wish tostop smoking, bupropion and nortriptyline treatment increase smoking cessation rates by about twofold (109) andwould be useful to consider when selecting a specific antidepressive agent (110).
e.

Personality disorders

For patients who exhibit symptoms of both major depressive disorder and a personality disorder, psychiatrists
should consider appropriate treatment for each. Major

depressive disorder should generally be the initial target;
if evidence of a personality disorder persists when the depressive symptoms have resolved, psychotherapeutic andadjunctive pharmacotherapeutic approaches may be helpful (610–615). Patients with virtually any personality disorder exhibit a less satisfactory antidepressant medication
treatment response, in terms of both social functioning
and residual major depressive disorder symptoms, than do
individuals without personality disorders (616). Personality disorders tend to interfere with treatment adherence
and development of a psychotherapeutic relationship. Furthermore, many personality disorders increase the risk of
episodes and increase time to remission of major depressive disorder (617, 618). Patients with various personality
disorders also showed high rates of new-onset major depressive episodes in a large prospective study (619) and wereat higher risk of attempting suicide than patients withouta co-occurring personality disorder (620).
Axis II diagnoses should be made with caution during amajor depressive episode, as depressive symptoms may exaggerate or mimic personality traits. Treatment of the depressive disorder for these patients can cause the apparent
personality disorder symptoms to remit or greatly diminish. Depressed patients may believe that their current
symptoms have been present from early life, when in fact
they only began with the current episode. Such misperceptions often hinder accurate diagnosis. Some Cluster C
personality disorders (e.g., avoidant, dependent, obsessive-compulsive) may reflect the residual impact of recurrent
depressive symptoms and may remit with maintenancetherapy (621).
Patients with borderline personality disorder have aparticularly high rate of major depressive disorder: 20%
in a community sample (622) and 50% in clinical samples(623). About 10%–15% of patients with major depressive
disorder have co-occurring borderline personality disorder (624), and the percentage increases significantly in
hospital and partial hospital samples. Patients with borderline personality disorder often exhibit mood lability,
rejection sensitivity, inappropriate intense anger, and depressive “mood crashes.” These symptoms are also common in patients with depression, particularly with atypicalfeatures, complicating the diagnosis of these disorders.
Antidepressants are in general less effective in treating depressive episodes in patients with major depressive disorder and borderline personality disorder (625–629), withan overall response rate to all therapies of 20% (630).
For patients with major depressive disorder and borderline personality disorder, the personality disorder mustalso be addressed in treatment. Symptoms of both disorders can initially be treated with an SSRI or SNRI. Behavioral impulsivity and dyscontrol can also be treatedCopyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
with low-dose antipsychotics, lithium, and some antiepileptic medications. Monoamine oxidase inhibitors, although efficacious, are not recommended due to the risk ofserious side effects and the difficulties with adherence todietary restrictions. Psychotherapeutic approaches such as
dialectical behavioral therapy and psychodynamic psychotherapy have been useful in treatment of borderline
personality disorder as well. In patients with borderline
personality disorder particular attention must be paid tothe maintenance of therapeutic rapport, which is frequently
disrupted, and to the risk of self-harm and suicide, which
occurs in 8%–10% of such individuals. More information
about the treatment of borderline personality disorder canbe found in APA’s Practice Guideline for Treatment of Patients
With Borderline Personality Disorder (610).
f. Eating disorders
Eating disorders are also common in patients with major
depressive disorder (631). Selective serotonin reuptake
inhibitors are the best studied medications for treatmentof eating disorders, with fluoxetine having the most evidence for the effective treatment of bulimia nervosa (170).
Antidepressants may be less effective in patients who areseverely underweight or malnourished, and normalizing
weight should take priority in these patients. Although
SSRIs and psychotherapy are widely used for patientswith anorexia nervosa, the evidence base on which thesepractices rest is modest. Patients with chronic anorexia
nervosa have in general been less responsive to formal
psychotherapy. On the other hand, evidence strongly supports the use of CBT in the treatment of bulimia nervosa.
Other therapies (e.g., IPT, group therapies, family therapy) and medications such as SSRIs have also been studied
and have demonstrated effectiveness for this disorder.
Bupropion should be avoided in individuals with eating
disorders due to the increased risk of seizures in these patients. Electroconvulsive therapy has not generally been
useful in treating eating disorder symptoms. Although
there are few data to guide treatment of co-occurring major depressive disorder and eating disorders, it is reasonable to optimize treatment of both disorders based onthese and other considerations. More information about
the treatment of eating disorders can be found in APA’s
Practice Guideline for the Treatment of Patients With Eating
Disorders, Third Edition (170).

B. DEMOGRAPHIC AND PSYCHOSOCIALVARIABLES
1. Major psychosocial stressors
Major depressive disorder may follow a substantial adverse life event, especially one that involves the loss of an

65

important relationship or life role. This is particularly
true in initial episodes of depression, with psychosocial
stressors being less associated with the onset of recurrent
episodes (632). Lower socioeconomic status, nonmarriedstatus, unemployment, urbanization, and violent trauma
seem to increase the risk of developing major depressive
disorder, whereas religious belief may decrease it (633–635). Among those exposed to trauma, the prevalence ofmajor depressive disorder seems to be higher among persons who develop PTSD than among those who do not(636). A recent meta-analysis underlined that among refugees, PTSD was diagnosed in one of 10 and one in 20 had
major depressive disorder (637).
Marital discord has been identified as a potent risk factor
in women for the development of depression (638, 639).
Problems in the family setting may become an ongoingstressor that hampers the patient’s response to treatment.
Ambivalent, abusive, rejecting, or highly dependent family
relationships may predispose an individual to major depressive disorder. The psychiatrist should screen for such factors and consider family therapy, as indicated, for thesepatients. Family therapy may be conducted in conjunction
with individual and pharmacological therapies. Even for instances in which there is no apparent family dysfunction, it
is important to provide the family with education about thenature of the illness and to enlist the family’s support andcooperation with the treatment.
The psychiatrist may choose to treat a major depressive
episode with an antidepressant, even if a major stressor
preceded the episode. Nonetheless, attention to the relationship of both prior and concurrent life events to theonset, exacerbation, or maintenance of major depressive
disorder symptoms is an important aspect of the overall
treatment approach and may enhance the therapeutic alliance, help to prevent relapse, and guide the current
treatment. A close relationship between a life stressor andmajor depressive disorder suggests the potential utility ofa psychotherapeutic intervention coupled, as indicated,with somatic treatment.

2. Bereavement
Bereavement is a particularly severe stressor that can trigger a major depressive episode. However, grief, the natural
response to bereavement, resembles depression, and thissometimes causes confusion. Psychiatrists treating bereaved individuals should differentiate symptoms of normal
acute grief, complicated grief, and major depressive disorder, as each of these disorders requires a unique management plan. Normal grief should be treated with support
and psychoeducation about symptoms and the course ofmourning; complicated grief requires a targeted psychotherapy, with or without concomitant medication (535,

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66640); and major depressive disorder should be treated withmedication and/or depression-focused psychotherapy.
Acute grief is the universal reaction to loss of a loved
one, and it is a highly dysphoric and disruptive state (641).
Acute grief is characterized by prominent yearning andlonging for the person who died, recurrent pangs of sadness and other painful emotions, preoccupation withthoughts and memories of the person who died, and relative lack of interest in other activities and people. Despite
the similarity with depression, only about 20% of bereaved people meet the criteria for major depressive disorder. Successful mourning leads to resolution of acutegrief over a period of about 6 months. Integrated grief remains as a permanent state in which there is ongoing sadness about the loss often accompanied by ongoing feelingsof yearning for the person who died. However, when thedeath is accepted, and grief integrated, the person is againinterested in his or her own life and other people.
Complicated grief is a recently recognized syndrome inwhich symptoms of acute grief are prolonged, associatedwith intense and persistent yearning and longing for thedeceased person, and complicated by guilty or angry ruminations related to the death and/or avoidance behavior.
Studies of individuals bereaved by the attacks of September, 11, 2001, have demonstrated that complicated grief is
a distinct condition from either major depressive disorder
or PTSD (642, 643). It is important to note that treatment
for depression is not effective in relieving symptoms ofcomplicated grief (640).
Although DSM-IV-TR excludes the diagnosis of major
depressive disorder during the first 2 months following
bereavement, major depressive disorder in the wake of bereavement can impede the course of mourning. Bereavement-related depression responds to antidepressant
medication and should be treated; otherwise it is likely to
become chronic and impairing (644). There is no indication that depression in the context of bereavement differsfrom other major depressive episodes, and data indicatethat chronicity of bereavement-related depression over
13 months is similar to chronicity of depression in othercontexts (644).

3. Culture and ethnicity
An appreciation of cultural and ethnic variables is important to the accurate diagnosis of major depressive disorderand in the selection and conduct of psychotherapy andpharmacotherapy (645–647). Although major depressive
disorder is seen across cultural and ethnic groups, and theage at onset, gender differences, and prevalence of co-occurring conditions are similar across cultures, the actual
incidence and prevalence of depression vary (648–656).
Furthermore, some evidence suggests that patients of dif-

APA PRACTICE GUIDELINES
ferent cultures express depressive symptoms differently,
particularly somatic and psychomotor symptoms (657).
Specific cultural variables may also influence the assessment of major depressive disorder symptoms. For example, in some cultures, depressive symptoms may be more
likely to be attributed to physical diseases (658). In addition, language barriers can impede accurate psychiatricdiagnosis and effective treatment (659), and, even when
speaking the same language, individuals of different cultures may use different psychological terms to describe
their symptoms (6, 7). In addition, the importance of individual experience should not be underestimated in thetherapeutic relationship (660). The assessment and treatment process can also be influenced by religious beliefs(5). Individuals with high levels of religious involvement
may have diminished rates of major depressive disorder(661, 662).
Differences in the utilization of psychiatric services bysome cultural and ethnic groups have been well documented. Relative to Caucasians, African Americans andLatinos appear less likely to receive treatment for mooddisorders (663–665).
Several studies have underscored the lower frequency
of use of antidepressant drugs (and more specifically,
SSRIs) (648, 666–669), ECT (670), and psychotherapy(671, 672) in minority groups, compared with Caucasians. If
treatment for depression is initiated, African Americans are
disproportionately more likely to receive pharmacotherapy (672), to drop out of treatment (673), and to develop
chronic symptoms (674) than are Caucasian patients.
These differences in mental health service use by minority
populations appear to have a number of potential causes.
Cultures and ethnicities may differ in the degree to which
psychiatric illness is stigmatized (675) and in the preferences of individuals for treatment (676–678). For example, studies have found that Hispanic individuals weremore likely to prefer counseling than whites, whereas African Americans varied across studies in their relative
preference for counseling rather than pharmacotherapy(6, 679). Service use by minority populations is more affected by financial constraints (including those related toinsurance) and social barriers (e.g., stigma) than the use ofcomparable services by Caucasians (664, 680, 681). In addition, pharmacological factors may play a role in patient
preferences and adherence, as ethnic groups may differ intheir relative rates of metabolism (682–684) and side effects and response to antidepressant medications (685–688).

4. Older age
The combined prevalence of major depression, dysthymic
disorder, and “minor” depression in individuals over age

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
60 years has been reported to be as high as 25%, and major depressive disorder has been reported to be present in
14%–42% of nursing home residents (689). Elderly patients typically display more vegetative signs and cognitive disturbance but report less subjective dysphoria than
younger patients. Major depressive disorder may consequently be misattributed to physical illness, dementia, or
the aging process itself. For older adults with chronic
illness or physical disability, including those expected toremain in a long-term care facility, depression may be erroneously regarded as expected or inevitable, and therefore
untreatable (690). As a result, it is common for major depressive disorder to be undiagnosed and untreated amongolder adults.
As in all depressed individuals, a suicide risk assessment
is an essential element of the evaluation process in older
individuals. Although older adults constitute only 13% of
the U.S. population, they account for 19% of all suicides,with elderly white men having the highest rates of completed suicides (691). This increase in suicide risk with aging in some demographic groups should be taken into
consideration when estimating suicide risk and developing a plan to reduce such risk.
Several general medical conditions common amongolder adults are risk factors for depression. In addition,
the presence of depression often exacerbates the course of
the co-occurring medical condition and is a risk factor forpoor outcomes. For example, elderly patients who are depressed and recovering from hip fractures have poorer
functional outcomes from rehabilitative care and are lesslikely to return to full ambulation, compared with older
adults with hip fractures who are not depressed (692–694). There is also frequent co-occurrence of major depressive disorder and cardiovascular disease; 25% or moreof those with cardiovascular disease also have major depressive disorder, and co-occurring depression increases
the morbidity and mortality of cardiovascular illness(695–697). The term vascular depression has been used todescribe depression occurring in late life in patients withclinical evidence of cerebrovascular disease (698), although at this time it has not been established as a uniquesubtype of depression. In addition, major depressive disorder is a complication of cerebral infarction (see Section
III.C.3). There is also a high prevalence of major depressive disorder among patients with dementia, and mood
symptoms may precede cognitive symptoms and diagnosis of dementia (see Section III.A.3.C).
Just as patients with medical conditions should bescreened for depression, patients exhibiting symptoms ofdepression should be thoroughly evaluated for the presence of co-occurring medical conditions, as major depressive disorder and general medical illnesses frequently

67

coexist, especially in elderly patients (696, 699). This evaluation should include a systematic review of the patient’s
medications. Some medications have been reported to induce depressive symptoms (e.g., beta-blockers), although
they may simply be producing lethargy and fatigue thatmimic depression (700, 701). Consequently, the psychiatrist must carefully assess whether a given medication iscontributing to depressive symptoms before prematurely
altering what may be a valuable treatment. Patients undergoing their first major depressive episode in old age
should be assessed for an undiagnosed neurological orother general medical disorder that may be responsible
for the depressive symptoms. Similarly, frequently cooccurring symptoms of major depressive disorder, such as
lassitude or pain, may mimic symptoms of a general medical condition. Pain in older adults, especially from orthopedic sources, may contribute significantly to the presenceof depression in this population (702).
Once the patient has been thoroughly assessed, thetreatment considerations for depressed geriatric patientsare essentially the same as for younger patients. A metaanalysis has shown that SSRIs; TCAs; and cognitivebehavioral, behavioral, and psychodynamic therapies are
all superior to placebo in the acute treatment for depression in subjects older than age 55 years (703–708). In addition, treatments for depression have been shown to beeffective in nursing home populations (709, 710), as wellas in inpatient and traditional outpatient settings of care.
However, compared with younger individuals, older patients may be more likely to experience relapses and lesslikely to achieve a full response to treatment with antidepressant medications (711–714). In contrast, ECT is not
only effective as a treatment for depression among older
individuals, but those over age 65 years actually have better response rates than younger patients (715). Consideration should also be given to combined treatment withpharmacotherapy and psychotherapy, as evidence for theefficacy of stand-alone psychotherapy, such as CBT, isweak (716). Although the role of stimulants for antidepressant monotherapy is very limited, these compounds
have some role in apathetic major depressive disorder inelderly patients with complicating general medical conditions. Late-life depression associated with vascular disease
has also been found to respond well to treatment with antidepressants (717) and, in one unreplicated study, to
TMS (718). Furthermore, in a recent randomized controlled trial, administering escitalopram prophylacticallyto patients who had experienced a stroke resulted inlower rates of depression at 12 months (334). Psychosocial factors are also frequent contributors to depression
among older adults and should be addressed as part of thetreatment plan (719, 720).

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68
There are several considerations in prescribing medications for elderly patients. As with any patient, the psychiatrist should attempt to use as few medications as possible,
and this is especially important given the complexity andmultiplicity of issues in elderly patients. It is often usefulto use medications that address several issues at once, suchas choosing mirtazapine for a depressed, elderly patient withweight loss and insomnia. Elderly patients typically require
a lower oral dose than younger patients to yield a particular blood level, and they tolerate a given blood level lesswell. Nevertheless, the blood levels at which antidepressant medications are maximally effective for elderly patients appear to be the same as those for younger patients(721, 722). Dose regimens should be adjusted for agerelated metabolic changes, with close attention paid tohepatic and renal metabolic function. For patients who
are receiving other medications, careful attention shouldbe paid to potential drug interactions (160, 161, 723–725)(Tables 4 and 5).
Elderly patients are particularly prone to orthostatic
hypotension and cholinergic blockade; for this reason,
SSRIs, SNRIs, and other antidepressants should be considered over MAOIs or TCAs. Among the TCAs, desipramine and nortriptyline should be considered overamitriptyline, imipramine, and doxepin, due to increasing sensitivity to side effects and toxicity with advancing
age. Treatment with SSRIs causes the syndrome of inappropriate antidiuretic hormone secretion (SIADH) at ahigher rate in elderly patients than in younger patients (726,727). Patients taking SSRIs have a three times greater riskof developing SIADH than patients taking other antidepressants, with the greatest risk among elderly patients(728).
For maintenance treatment, one study has shown that
antidepressant medication (nortriptyline) and IPT are effective for elderly patients with recurrent major depressive disorder (315), yet a trend toward superior response
was observed for combined pharmacotherapy and IPT,
compared with pharmacotherapy alone. Another study
demonstrated that paroxetine (but not monthly psychotherapy) was effective as maintenance therapy for elderly
patients (729). For older patients with particularly severe or treatment-resistant depressive illness, addition ofmaintenance ECT to nortriptyline appears to improvetreatment outcome (730). Among elderly patients who
have had prior depression, the risk of developing anotherepisode of major depressive disorder is substantially increased in those who develop or report sleep disturbance(731). Sleep disturbances may function as independent
predictors of depression and are not simply prodromal depressive symptoms.

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A body of systematic evidence suggests a particularvalue for various forms of collaborative or team-basedcare for elderly patients. Such care combines, for example,
specialty mental health consultation/intervention withprimary care management or community-based outreachand monitoring of care (732, 733). Older adults with depression can benefit from integration of mental healthservices in the setting where they typically receive theirgeneral medical care. It has been shown that support foralgorithm-driven depression care processes within the
primary care outpatient practice can lead to increased
treatment adherence and improved clinical outcomes, including a reduction in mortality (734).

5. Gender
As part of the diagnostic assessment of a woman with major depressive disorder, there should be a detailed inquiry
regarding reproductive life history and mood symptoms
associated with reproductive life events, such as menses,
use of oral contraceptive agents, peripartum, infertility,
menopause, and pregnancy loss due to abortions, miscarriages, and perinatal losses. Although associations between reproductive factors and major depressive disorder
are neither widespread nor consistent, some women may
be particularly vulnerable to fluctuations in gonadal hormone levels (735). The perimenopausal transition has
been identified as a high-risk period for new-onset major
depressive disorder, with high variability of sex hormones
as a risk factor (736, 737). Women in the perimenopausal
transition may benefit from the use of serotonergic antidepressants, for mood and also for somatic symptoms suchas hot flashes (738).
Since women are often caretakers in families, psychosocial stresses such as caring for an ill husband, child, orparent must be carefully assessed. Treating depressed
mothers is associated with improved prognosis for theirchildren as well (739). Maternal remission from depression
was associated after 3 months with significantly decreased
diagnoses and symptoms in their children, compared withchildren of mothers whose depression had not remitted.
Thus, treating depressed mothers may crucially benefit
both the patients and their children.
The patient’s gender also factors into other treatment
considerations for major depressive disorder. For example, the risks of certain adverse effects from treatments
may also differ by gender. When prescribing trazodone tomen, it is important to provide education about the risk ofpriapism (174). Older men typically have prostatic hypertrophy, making them particularly sensitive to anticholinergic effects of some antidepressants on the bladderoutlet. While both men and women may experience de-

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Editioncreased libido or anorgasmia while taking SSRIs, men
may also experience ejaculatory dysfunction (740). Some
women who are taking birth control pills require higher
doses of TCA medications because of the induction of thehepatic enzymes responsible for medication metabolism.
Similarly, medications that induce hepatic enzymes, suchas anticonvulsants used as adjunctive treatment, reduce
the effectiveness of contraceptives.

6. Pregnancy and postpartum
Major depressive disorder during pregnancy and postpartum presents unique treatment considerations. During
these periods, approximately 10% to 15% of perinatal
women will experience major depressive disorder, which
is at least as common as rates reported for women in nonreproductive states (741, 742). Evaluation and communication of risks and benefits of antidepressants during
pregnancy and breast-feeding is challenging and must include the risks of untreated maternal mood disorder, thelimited body of research that informs safety of antidepressants, and the general lack of prospective long-term data
following antidepressant exposure in utero and throughlactation.
Depression-focused psychotherapy or other nonmedication therapies may be considered first for some women,
and psychotherapy should be considered as part of thetreatment plan whenever possible. As childbearing is a life
stressor with psychosocial repercussions that may be amenable to psychotherapy, psychotherapy may serve to minimize medication exposure in some women. Although
there is little controlled research, psychotherapies appear
efficacious in antenatal and postpartum depression, with
IPT being the best studied (743, 744). Therefore, depression-focused psychotherapies such as IPT and CBTshould be considered in the treatment plan as a first-line
treatment or in combination with medication to minimize
medication exposure, especially if the individual has experienced a good response to a particular psychotherapy inthe past or strongly prefers to avoid medication.
a. Depression during pregnancy
Psychiatrists should be familiar with the management ofmajor depressive disorder in the context of pregnancy(745). More than 80% of women in the United States will
have children (746), and about half of pregnancies are
unplanned (747). Therefore, pregnancies—including unplanned pregnancies—are likely to occur during the courseof treatment of major depressive disorder, as it is often achronic and/or recurrent condition that is a major causeof disability during the reproductive years and disproportionately affects women, compared with men. In consid-

69

eration of the high prevalence of both unplanned pregnancy
and major depressive disorder in women, the risks andbenefits of antidepressants and untreated maternal depression during pregnancy should be discussed with all female patients who have reproductive potential. Wheneverpossible, a pregnancy should be planned in consultation
with a treating psychiatrist, who may wish to consult witha specialist in perinatal psychiatry. For women who are
pregnant or planning to become pregnant, decisions
about treatment for depression require weighing multiple
benefits and risks for the woman as well as for the fetus.
Making such decisions may require several discussions
and will generally involve discussions with the patient’s
partner as well as her obstetrician.
Antidepressant medications carry some reported risks
in pregnancy (see below), but so does untreated depression. Suicide risk, marital discord, the inability to engage
in appropriate obstetrical care, and difficulty caring forother children must also be considered. There are also serious and well-characterized risks to the fetus of exposure
to maternal major depressive disorder, including the possibility of low birth weight secondary to poor maternal
weight gain (or frank weight loss) and increased risk of obstetrical complications such as premature delivery (748).
Antidepressant efficacy has not been determined for
pregnant women, and questions remain as to whether
medications have equivalent efficacy during pregnancy,
compared with the nonpregnant state. Some safety data
are available, but the findings often conflict, making datainterpretation challenging and difficult to apply to thecare of individual patients. Nevertheless, antidepressant
medication should be considered and discussed as an option with pregnant women who have moderate to severe
major depressive disorder.
For women who are in remission from major depressive disorder and receiving maintenance medication
and/or for women deemed to be at high risk for a recurrence if the medication is discontinued, the risks of treatment with medications must also be weighed against therisks of alternative treatment options and untreated depression. Relapse rates for women with a history of major
depressive disorder are high during pregnancy, especially
if antidepressants are discontinued (749).
1. Risks of antidepressants during pregnancy
The impact of the duration and timing of antidepressant
exposure during pregnancy requires further study. Wisneret al. (750) reviewed the risks associated with the use ofantidepressants during pregnancy, and a growing body ofcomplicated literature has followed. Overall, risk of teratogenicity with antidepressants following first trimester

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70
exposure appears to be low, although some rare birth defects have been observed to occur at higher rates with useof specific SSRIs (751, 752). First-trimester paroxetine
exposure has been associated with cardiac malformations,a finding that resulted in changes in FDA labeling for paroxetine from C to D (753); labeling changes have been
made to all SSRI antidepressants with regard to this possibility when used during pregnancy. There have been
conflicting results regarding whether first-trimester paroxetine exposure and cardiac teratogenicity are associated(754, 755). For fluoxetine, one study (756) found a higher
incidence of three or more minor physical anomalies in
infants exposed to fluoxetine than in a control group, andfetuses exposed to fluoxetine after 25 weeks’ gestation had
lower birth weights, which were associated with lower
maternal weight gain. Although one case-control study
reported a potential association between late antenatal
SSRI use and the rare but serious condition of persistentpulmonary hypertension in the newborn (PPHN) (757),
two subsequent retrospective chart review studies showedno such association (758, 759). An additional case-control
study (760) showed a marginally significant increase in therelative risk of PPHN with SSRI use, but the estimatedrate of PPHN occurrence was 1.5 per 1,000 births, whichis less than the rate of 2.7 per 1,000 births reported by others (758) in non-SSRI exposed infants. Therefore, while
many physicians are concerned about the reported association between SSRIs and PPHN, the preponderance ofevidence from published studies on this topic does notsupport an association. Use of SSRIs may also be associated with prematurity (761, 762), although untreated depression and stress during pregnancy may also contributeto the risk of prematurity (748, 763). Some naturalistic
studies and health care utilization studies suggest that
antidepressants are associated with shorter length of gestation (761, 762), but there have been no randomized studies of the treatment of antenatal major depressive disorderthat would adequately control for untreated maternal depression, antidepressant use, and confounding variables
related to treatment selection. With late pregnancy antidepressant use, some but not all studies show a risk of
medical complications such as prematurity and a transientneonatal withdrawal/adaptation syndrome (761, 764). The
syndrome in the neonate appears to be associated with antidepressant use in the third trimester, has been reported
in babies exposed in utero to TCAs and SSRIs, and includes transient symptoms such as jitteriness, tremor, difficulty with feedings, and other symptoms (764). Several
studies, involving relatively small samples, have examined
effects of antidepressant exposure during pregnancy on
subsequent childhood behavior and development andfound minimal (765) or no (766–768) effects on language,

APA PRACTICE GUIDELINES
cognition, or motor or behavioral development independent of maternal depressed mood during pregnancy andthe child’s early life (766, 767).
2. Implementation of pharmacotherapy
during pregnancy
No controlled trials inform the use of antidepressantsduring pregnancy. Dose requirements may change during
pregnancy because of changes in volume of distribution,
hepatic metabolism, protein binding, and gastrointestinal
absorption. Pharmacokinetic changes in late pregnancy
may result in lower blood levels, with clinical implications, although more study is needed to develop monitoring and dosing guidelines. The limited data in this area
demonstrate that pregnant women metabolize TCAs and
SSRIs more rapidly in late pregnancy (769–774).
A number of factors influence antidepressant choiceduring pregnancy. If a woman has had a history of a good
response to or is already taking a particular antidepressant, it is logical to consider that antidepressant among
first-line treatments in an effort to minimize the numberof different medication exposures. Using a single agent isalso preferable to using several medications concomitantly. Because paroxetine use is classified as having a higher
level of risk than other SSRIs, it should not be considereda first-line treatment when selecting a new antidepressantfor a pregnant patient. Fluoxetine has the longest half-lifeand is more likely to be demonstrated at high levels innewborns after in utero exposure. Sertraline has been
demonstrated to have lower cord blood levels than other
SSRIs, although the clinical significance of this is unknown (775). Although there are few data for bupropion
and safety in pregnancy, its benefits for smoking cessation
may make it especially useful in women who have major
depressive disorder and who smoke cigarettes, as tobacco
is a known teratogen. Given these data, it is recommended
that consideration be given to using an antidepressantwith some available safety information that has beenstudied in pregnant women. For women who discontinue
medication during pregnancy and are deemed at risk for
postpartum depression, medication can be restarted following delivery.
Electroconvulsive therapy is also recommended as atreatment option for major depressive disorder during
pregnancy (239). The current literature supports thesafety for mother and fetus, as well as the efficacy of ECT
during pregnancy (239). The psychiatrist should consider
ECT for pregnant patients with moderate to severe depression who are unresponsive to or unsuitable for pharmacotherapy, for pregnant patients with major depressive
disorder with psychotic features, and for pregnant patients electing to use this modality as a matter of prefer-

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Editionence after having weighed the relative risks and benefits of
ECT and other treatment options. For details on the useof ECT during pregnancy, refer to The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging (A Task Force Report of the American
Psychiatric Association) (239).
b. Postpartum depression
Major depressive disorder with postpartum onset is defined in DSM-IV-TR as a major depressive episode withonset within 4 weeks of delivery. However, the occurrence
and course of major depressive disorder in childbearing
women is heterogeneous, and definitions of postpartum
depression may evolve with continued research (16, 776).
In major depressive disorder with postpartum onset, anxiety symptoms are more prevalent than in major depressive disorder occurring at other times (777). It is notuncommon for women with postpartum depression toexperience obsessions and/or compulsions, and obsessions may often involve thoughts of harming the baby,
which must be differentiated from postpartum psychosis.
Psychiatrists should provide psychoeducation about major depressive disorder to pregnant and postpartum
women and their families to improve the detection of major depressive disorder during pregnancy and the postpartum period.
Several other psychiatric conditions may follow childbirth (778). The transient 7- to 10-day depressive condition referred to as “postpartum blues” is by definition too
mild to meet the criteria for major depressive disorder anddoes not require medication. In addition to providing reassurance, psychiatrists should encourage mothers who
experience postpartum blues to increase psychosocial support and obtain help with the care of the infant. Puerperal
psychosis is a more severe disorder complicating one totwo of 1,000 births. Although postpartum psychosis israre, women with this disorder may have homicidal impulses toward the newborn; for this reason, careful assessment of homicidal as well as suicidal ideation, intention,and plans is important. Postpartum psychosis must always
be treated as a psychiatric emergency, with hospitalizationconsidered for the safety of the mother and baby (779).
Many patients who have had episodes of this type ultimately prove to have bipolar disorder (780).
The woman’s parenting skills for both the newborn
baby and any other children in her care must be carefully
assessed. Untreated maternal major depressive disorder,and specifically postpartum depression, have negative
consequences for children, with adverse effects on attachment and child development (781, 782). Major depressive
disorder can seriously interfere with the new mother’s abil-71

ity to provide physically and emotionally appropriate carefor her baby and other children. The psychiatrist should
work with the patient to develop a plan to manage this effect, such as enlisting family members to assist with childcare.
Antidepressants are often prescribed for postpartum depression, according to the same principles delineated forother types of major depressive disorder, despite a limited
number of controlled studies. Two placebo-controlled trials of SSRIs (fluoxetine and paroxetine) have been published for the treatment of postpartum depression, withfluoxetine appearing more efficacious than placebo andparoxetine being comparable to placebo on primary outcome measures of depressive symptoms (783, 784). Wisneret al. (785) did not find a difference in response and remission rates in a randomized controlled trial of sertraline versus nortriptyline for postpartum major depressive disorder.
Open studies of other antidepressants in postpartum
women suggest efficacy, although some studies included
only a small number of participants (786). Paroxetine alone
and paroxetine plus CBT both produced a significant change
from baseline in one study, but there was no placebo-onlygroup for comparison (787).
Patients and clinicians are often concerned about therisks of possible exposure to antidepressants during
breast-feeding. These risks, however, must be weighedagainst the well-known, and at times profound, risks to
the woman and her children of untreated postpartum
depression. Mothers should be counseled regarding therelative risks and benefits when making these treatment
decisions. Antidepressant medications are considered
compatible with breast-feeding, but long-term data are
not available regarding risks and benefits. Although there
have been some suspected case reports of adverse effects
in breast-feeding infants exposed to maternal antidepressants, most studies show low levels of exposure via breast
milk, with the exception of fluoxetine, which appears tohave a dose-related risk for detectable levels in infant sera
(788, 789). At this time, there are no studies which havedetermined a “safe” amount and duration of antidepressant exposure in the fetus and newborn. However, exposure to antidepressants via breast milk is considered
substantially lower than in-utero exposure. Women who
elect to breast-feed while taking antidepressants should be
supported in doing so, given the widely known healthbenefits (e.g., immune system effects) to infants who arebreast-fed. Similarly, women who elect to bottle-feedshould also be supported in this decision. Some women
will not accept treatment with antidepressant medication
while they are breast-feeding. Depression-focused psychotherapy can be recommended instead.

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72
7. Family history
Major depressive disorder is one and one-half to threetimes as common among those with a first-degree biological relative affected with the disorder as in the general
population. In addition, the rates of depression, anxiety,and other disorders are increased more than two- to sixfold in the offspring of depressed parents. A family historyof depression is associated with an earlier age at onset of
depression (790), and children of depressed parents are
more likely to have depression with a chronic and recurrent course (791). Furthermore, a family history of recurrent major depressive disorder increases the chances thatthe patient’s own illness will be recurrent and that the patient will not fully recover between episodes (792). A family history of bipolar I disorder, bipolar II disorder, or
acute psychosis probably increases the chances that thepatient’s own major depressive disorder is a manifestationof bipolar rather than unipolar depression, and that antidepressant medication therapy may incite a switch tomania (793). Patients with such a family history should bequestioned particularly closely regarding a prior historyof mania or hypomania and should be carefully observed
for signs of a switch to mania during treatment with antidepressant medication.
There are no real predictors of response to individual
antidepressants, yet in the absence of other information
clinicians sometimes rely on family history of therapeutic
benefit to select a specific medication for a family member. Although it does not have specific support in the literature, this practice appears reasonable.

C. TREATMENT IMPLICATIONS OF COOCCURRING GENERAL MEDICAL CONDITIONS
In patients with co-occurring medical conditions, there isa higher prevalence of major depressive disorder than in
the general population. Furthermore, co-occurring medical conditions in patients with major depressive disorder
are associated with poorer outcome (794, 795). A numberof medical conditions are known to cause mood symptoms, such as stroke, hypothyroidism, carcinoma of thepancreas, and many others. Apart from directly causing
depressive symptoms, debilitating, painful, and chronic
medical conditions often constitute an ongoing stressor
that predisposes patients to depressive episodes. Nevertheless, a depressive episode, in any context, is never a“normal” response to illness and consequently warrants
treatment.
In addition to the increased risk of major depressive
disorder with general medical conditions, depressive episodes increase the risk of certain general medical conditions,

APA PRACTICE GUIDELINES
such as heart disease. (796). Due to the interrelationshipbetween depression and medical illness, it is very important to recognize and treat depressive symptoms in medically ill patients, and vice versa. The psychiatrist should
also attend to the potential for interactions between antidepressants and the co-occurring medical conditions aswell as any nonpsychiatric medications that the patient
may be taking.

1. Hypertension
The presence of treated or untreated hypertension may influence the choice of an antidepressant, as a few antidepressant medications have been associated with increases inblood pressure. With SNRIs such as venlafaxine and duloxetine, dose-dependent elevations in blood pressure areusually mild, although more severe hypertension has also
been observed (166, 797). However, another study foundno increase in hypertension with duloxetine dosed up to
80 mg/day (798). Hypertension induced by SNRIs may respond to a decrease in the medication dose, or an alternative
antidepressant medication may be considered. Alternatively, for a patient with well-controlled depressive symptoms, it may be preferable to add an antihypertensive agent
rather than risk a depressive relapse or recurrence withmedication tapering.
Antihypertensive agents and antidepressant medications may interact to either intensify or counteract the effect of the antihypertensive therapy (799). The action ofantihypertensive agents that block alpha receptors (e.g.,prazosin) may be intensified by antidepressant medications that block these same receptors, notably the TCAs
and trazodone. Tricyclic antidepressants may antagonize
the therapeutic actions of guanethidine, clonidine, or alpha-methyldopa. Concomitant antihypertensive treatment, especially with diuretics, increases the likelihoodthat TCAs, trazodone, or MAOIs will induce symptomatic
orthostatic hypotension.
Side effects of antihypertensive agents, such as fatigue
or sexual dysfunction, may also confound the evaluationand interpretation of depressive symptoms. It has also
been thought that beta-blockers, especially propranolol,
may account for depressive symptoms in some patients,
but this association has been questioned (700, 701).

2. Cardiac disease
Depression increases the risk of cardiovascular disease(800). In addition, patients who are depressed following a
myocardial infarction have an increased rate of mortality,
compared with patients without depression (801–803).
Following an acute myocardial infarction, the decreased
survival rates of depressed patients may in part be due to

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
lower heart rate variability in these patients, comparedwith nondepressed patients (804). Particularly in patientswith a history of major depressive disorder (805), there isevidence that the depressive symptoms associated withcardiac illness respond to antidepressants (717, 806, 807).
However, studies in which the attempt has been made to
influence cardiac-related mortality through treatment ofdepression have shown mixed results (808–811).
A depressed patient with a history of a cardiac problem
should be monitored for the emergence of cardiac symptoms, ECG changes, persistent tachycardia, or orthostatic
blood pressure decrements. Consultation with the patient’s cardiologist before and during antidepressant medication treatment may be advisable, especially for patients
who have recently had a myocardial infarction. Increases
in heart rate and blood pressure may be associated withthe use of agents with noradrenergic properties such as
SNRIs and stimulants; thus, changes in heart rate and bloodpressure should be assessed after treatment with theseagents is instituted in patients with coronary artery disease, hypertension, or congestive heart failure. Although
TCAs have been used effectively to treat major depressive
disorder in patients with some forms of ischemic heartdisease (812), psychiatrists should take particular care inusing TCAs for patients with a history of ventricular arrhythmia, subclinical sinus node dysfunction, conduction
defects (including asymptomatic conduction defects), prolonged QT intervals, or a recent history of myocardial infarction (184, 185, 813–818). Selective serotonin reuptake
inhibitors, SNRIs, and bupropion appear to be safer forpatients with preexisting cardiac disease; several SSRIs
have been used safely in patients with cardiac disease inlarge clinical trials (807, 809, 810, 819). Electroconvulsive
therapy can also be used safely in individuals with cardiac
disease or arrhythmias, although specialist consultationand modifications in ECT technique or anesthesia may be
indicated (239, 245, 820–822). Monamine oxidase inhibitors do not adversely affect cardiac conduction, rhythm,
or contraction but may induce orthostatic hypotension
and have risks relating to drug-food and drug-drug interactions.

3. Stroke
Depression is observed in approximately one-third to
one-half of individuals in the weeks to months following astroke, with a substantial proportion developing major
depressive disorder (334, 823, 824). Although conclusionsof meta-analyses are mixed (825, 826), some researchsuggests that antidepressant treatment immediately following a stroke may reduce rates of depression (334) andpossibly mortality (827). Among psychotherapeutic ap-

73

proaches to preventing depression after stroke, problemsolving therapy has been best studied, but findings are inconsistent (334, 825).
When depression develops after a stroke, it has detrimental effects on quality of life (823). In addition, thepresence of depression 1 month following a stroke has
been associated with an increase in subsequent mortality(828). Use of screening tools such as the PHQ-9 may help
to identify depressive episodes after stroke (829), and caremanagement may improve outcomes once poststroke depression is recognized (830). Psychotherapies have notbeen well studied as treatments for poststroke depression;
however, a meta-analysis of randomized trials that havebeen conducted did not show efficacy (825). Findings on
the therapeutic effects of antidepressants in post-stroke
depression have been mixed, perhaps due to the substantial heterogeneity of study populations and designs (831,832). Although a meta-analysis did not show any difference in the rate of depressive remission with antidepressant treatments compared with placebo (832), patients
receiving an antidepressant did show more improvement
in depressive symptoms (831, 832) and a greater proportion were classified as treatment responders (831). Individual randomized controlled trials have shown therapeutic
benefits for several SSRIs, including fluoxetine, sertraline,
and citalopram (833–836), and for the TCA nortriptyline(837, 838); however, not all studies have shown benefit forsome of these agents (837, 839–841). Nevertheless, for individuals with poststroke depressive symptoms, a trial ofantidepressant therapy may be considered, with SSRIs
being better tolerated and having fewer contraindicationsin this older and more medically ill population (842, 843).
However, in individuals who are receiving concomitanttreatment with anticoagulant (e.g., warfarin) or antiplatelet(e.g., dipyridamole, clopidogrel, aspirin) medications, it isimportant to consider the potential for an increased bleeding risk due to drug-drug interactions with antidepressants (844, 845).

4. Parkinson’s disease
Major depressive disorder occurs to some degree in 40%–
50% of patients with Parkinson’s disease. Patients with
Parkinson’s disease experience alterations of serotonergicand noradrenergic systems that may induce depression.
There is no evidence favoring any particular antidepressant medication from the standpoint of therapeutic efficacy and safety for patients with Parkinson’s disease
complicated by major depressive disorder (846). A metaanalysis of placebo-controlled studies identified a clear
benefit for both active treatment and placebo, but it did
not find differences between them (847). Although SSRIs

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74
can be used, there is some risk of worsening of Parkinson’s
disease symptoms (increases in “off” time and exacerbation of tremor) with agents that are primarily serotonergic(848). Bupropion, in contrast, exerts a beneficial effect on
the symptoms of Parkinson’s disease in some patients but
may also induce psychotic symptoms, perhaps because of
its agonistic action in the dopaminergic system (849).
Noradrenergic agents and SNRIs may also be preferable
to SSRIs. Nonselective MAOIs (e.g., tranylcypromine,
phenelzine, isocarboxazid) may adversely interact with Ldopa products (850). Selegiline, also known as L-deprenyl, is a selective type B MAOI recommended in the treatment of Parkinson’s disease. Selegiline loses its specificity
for MAO B in doses greater than 10 mg/day. As a result, it
may induce serotonin syndrome when given in higher
doses in conjunction with serotonin-enhancing antidepressant medications. The theoretical benefits of the antimuscarinic effects of some of the tricyclic agents in thetreatment of patients with major depressive disorder with
Parkinson’s disease are offset by the memory impairmentthat may result. Amoxapine, an antidepressant medication
with dopamine-receptor-blocking properties, should be
avoided for patients who have Parkinson’s disease. Lithium may, in some instances, induce or exacerbate parkinsonian symptoms. Electroconvulsive therapy exerts atransient beneficial effect on the symptoms of idiopathic
Parkinson’s disease in many patients (851, 852); however,it might occasionally worsen L-dopa-induced dyskinesias
and induce a transient interictal delirium (853), which necessitates reductions in doses of dopamine agonist medications (239).

5. Epilepsy
The prevalence of depression in individuals with epilepsy
appears to be increased in secondary and tertiary care center samples, although in population-based studies this increase is not well established (854). On the other hand,
major depressive disorder significantly increases the riskof unprovoked seizures even after the adjustment of age,sex, length of medical follow-up, and medical therapies
for depression (855). In addition, some antidepressantdrugs, such as TCAs and bupropion, lower the seizure
threshold and have a dose-dependent epileptogenic potential. This seizure risk is intermediate for immediaterelease formulations of bupropion, maprotiline, andTCAs (in particular, clomipramine) and low for sustainedrelease formulations of bupropion (17, 197, 856).
Major depressive disorder in patients with seizure disorders can usually be safely and effectively managed according to the same principles outlined for patients
without seizures. In particular, SSRIs and SNRIs are not

APA PRACTICE GUIDELINES
likely to increase the risk of developing seizures (856–858). However, blood levels of TCAs may be increased byseveral antiepileptic drugs, increasing the side-effect burden of the anticholinergic and other side effects of tricyclics (859).
Some anticonvulsants appear useful for treatment andprophylaxis of mood disorders (e.g., carbamazepine, valproate, lamotrigine). Thus, in patients with depression andepilepsy, consideration can be given to concomitant prescription of an anticonvulsant (or elevating the dose of an
existing anticonvulsant). Nevertheless, anticonvulsant compounds may also have a negative effect on mood for somepatients (859). For example, barbiturates and possibly vigabatrin have been associated with an increased risk for
depression (860). In addition, a recent FDA statement notedthat increased rates of depression and suicide risk may be
associated with anticonvulsants (861).

6. Obesity
Many individuals with major depressive disorder will beoverweight or obese, given the high prevalence of excess
weight in the general population (862). In addition, rates
of depression may be increased in obese individuals, particularly among women and in those with a body mass index (BMI) greater than 40 (863). Individuals with obesity
resulting from binge eating disorder also have higher rates
of depression (170). In the subgroup of patients with atypical depression, increased eating and weight gain are
symptomatic of the depressive disorder (864). For other
patients, the lack of motivation and energy that occur withdepression can make it difficult to maintain an exercise
regimen or nutritional dietary habits. In addition, treatment with many antidepressant medications appears tolead to weight gain (865) and also makes it more difficult
to lose weight in a structured weight management program(866).
In treating individuals with major depressive disorder
who are overweight or obese, the effects of treatment on
weight should be considered in selecting a therapeutic approach. If pharmacotherapy is used, the selection of an antidepressant medication should include consideration of
its relative tendency to contribute to weight gain, whichis generally greatest with mirtazapine, TCAs (tertiary
TCAs more so than secondary TCAs), and MAOIs andless prominent with SSRIs and SNRIs (865). Bupropion is
generally weight neutral and has been associated withmodest weight reduction when used to treat major depressive disorder in obese adults (867, 868). Longitudinalmonitoring of weight, either by direct measurement or
patient report, can permit monitoring of BMI, as well as
early intervention if weight gain becomes a problem with

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
antidepressant treatment. Patients’ concerns about weightgain may also contribute to poor adherence, and monitoring of weight can facilitate such discussions. The impact
of weight on medication dosing should also be considered. In one study, greater relative body weight was associated with a lesser likelihood of response to a fixed dosetrial of an antidepressant (869), perhaps suggesting a needfor increases in medication dose with increasing bodyweight.
Psychotherapeutic approaches to treatment avoid thepotential for medication-induced weight gain and may
also have modest benefits in weight management. Cognitive-behavioral therapy has shown efficacy in the treatment of binge eating disorder (170, 870) and could
potentially be used in addressing obesity (871) and medication-induced weight gain (872).
The increasing use of surgical treatments for obesity
also has implications for the treatment of patients withmajor depressive disorder. Depression is common among
bariatric surgical candidates and, in and of itself, is not acontraindication for surgery (873–877). Long-term follow-up studies show improvements in co-occurring general medical conditions (878), as well as decreases in
depressive symptoms and improved quality of life withweight loss (879–881). However, weight loss after surgery
may be less pronounced in individuals with a lifetime diagnosis of major depressive disorder (882) or in those withsevere psychiatric illness that has required hospitalization(883). Close follow up is important following bariatricsurgery in order to assess for changes in psychiatric symptoms, assist patients in the psychological and psychosocial
adaptation to weight loss, and adjust medication regimens. Particularly following jejunoileal bypass or biliopancreatic diversion, but also following gastric bypass
procedures, altered dissolution (884) and absorption of
medication may require adjusting the dose of medicationor changing from a slow-release to an immediate-releaseformulation (875).

75

significant dosing adjustments, it is useful to collaborate
with the patient’s primary care physician in monitoring
diabetic control because fluctuations in fasting blood glucose may occur. Some evidence suggests that use of TCAs
may be associated with worsened glycemic control, andother antidepressants (such as SSRIs) may be preferable to
TCAs for patients with diabetes (896, 897).

8. Sleep apnea
The possible contribution of obstructive sleep apnea (OSA)
to depressive symptoms is an important consideration, particularly in patients who are obese, report excessive daytime
sleepiness, or have treatment-resistant depressive symptoms. Symptoms such as fatigue and poor sleep quality canoccur in sleep apnea as well as in major depressive disorder,
requiring a careful assessment to distinguish whether either
or both disorders are present. Underrecognition of OSA iscommon, and rates of OSA appear to be increasing with theincreasing prevalence of obesity (898). Although the prototypical sleep apnea patient is likely to be obese with a history of snoring, sleep apnea may still be present even in theabsence of these findings (899). Individuals with OSA orexcessive daytime sleepiness appear to have greater rates ofdepression than comparison groups (900–902), although therates of depressive symptoms and major depressive disorder diagnosis fluctuate across studies (903). In addition, epidemiological findings suggest an increasing likelihood ofdepression with increasing sleep-related breathing disorder
severity (904). With initiation of continuous positive airway
pressure treatment, improvement in OSA symptoms has
been associated with decreased depressive symptoms (905,906), in addition to reductions in OSA-associated healthrisks (898). Consequently, recognition and treatment of
OSA is important among individuals with major depressive
disorder. Identification of OSA is also important to treatment planning, as use of sedating medications can exacerbate OSA and worsen daytime sleepiness, with associatedcomplications (907).

7. Diabetes

9. Human immunodeficiency virus and hepatitis C infections

Diabetes mellitus is common in the general population,
particularly in overweight or obese individuals (885).
However, it is not clear whether an association exists between diabetes and major depressive disorder, as metaanalyses and epidemiologic studies yield mixed results(886–888). Some patients may have reduced adherence todiet and medications when depressed (889), but there areinconsistent findings on whether successful treatment ofdepression (with medication, psychotherapy, and/or collaborative care) improves glycemic control (889–896). However, when initiating antidepressant therapy or making

According to the Centers for Disease Control and Prevention, more than one million individuals in the UnitedStates were living with HIV infection by the end of 2003
(908), with increased rates among individuals with psychiatric disorders, including substance use disorders (909).
Estimates suggest that at least one-fifth of infected individuals have unrecognized infection (910), necessitating
increased efforts to identify HIV infection (911), given
the availability of effective treatment (912). Consequently,
clinicians treating patients with major depressive disordershould consider screening for HIV.

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76
Rates of major depressive disorder are increased amongindividuals with HIV infection, compared with HIV-negative individuals (913). When treating major depressive disorder in patients who also have HIV, antidepressant
medications can be used safely and effectively (914, 915),
although high placebo response rates and high study attrition rates have sometimes confounded interpretation of research findings (916, 917). When antidepressants are used,
SSRIs are better tolerated than TCAs (918, 919). In individuals who are receiving treatment with antiretroviral
agents, it is important to check for potential drug-drug interactions when choosing a medication regimen (920). Significant interactions can also occur if St. John’s wort is taken
by patients receiving antiretroviral medications. Although
few studies have been conducted in patients who meet diagnostic criteria for major depressive disorder, individualand group psychotherapies using interpersonal, cognitivebehavioral, and psychoeducational approaches have also
been associated with reductions in depressive symptoms
among patients with HIV infection (316, 921–926).
Persons with mental illness also have elevated rates ofinfection with hepatitis C (927), and infection with hepatitis C is commonly present in individuals with HIV infection (928). Among individuals with hepatitis C, depressive
symptoms are common, and many patients fully meet thecriteria for major depressive disorder (929). Treatment of
hepatitis C with interferon appears to be associated with afurther increase in the risk for depression, although findings vary depending upon the study population, concomitant medications (e.g., ribavirin), and the type of interferon
used for therapy (930, 931). The increase in depressive
symptoms with interferon treatment may also be more
prominent in patients with greater levels of pretreatment
depression (932). This suggests a need for careful monitoring if patients with current major depressive disorder areadministered interferon, particularly since many patientstreated with interferon have unrecognized or insufficiently
treated depression (933). Studies in which antidepressant
medications were administered concomitantly with interferon have shown inconsistent prophylactic effects (934,935). However, antidepressant therapy does seem to be effective when used to treat depression that develops in thecourse of interferon therapy for hepatitis C infection (936,937). Consequently, major depressive disorder should not
be viewed as a contraindication to the treatment of hepatitis
C infection, particularly given the severe long-term hepatic
complications associated with chronic infection (938).

10. Pain syndromes
Pain syndromes and major depressive disorder frequently
co-occur. Although the reported prevalence of pain
among depressed patients varies with cultural differences

APA PRACTICE GUIDELINES
and study design, one-half to two-thirds of depressed individuals will typically note some type of pain (702, 939–
941). Conversely, in primary care settings, individuals
with pain symptoms are about twice as likely to be depressed as those without pain, and the rates of depression
are further increased if pain is chronic or involves multiple
types of pain (940, 942). It is important to note that individuals with co-occurring pain and depression tend tohave worse treatment outcomes and poorer overall functioning than those with either condition alone (940, 942–
944). Consequently, every patient with depression should
be assessed for the presence, nature, location, and severityof pain complaints.
Overall, antidepressant treatment has been associatedwith reductions in pain symptoms among individuals withpsychogenic or somatoform pain disorders (945). However, among trials of second-generation antidepressants inindividuals with co-occurring pain and depression, duloxetine, venlafaxine, and paroxetine seem to be of comparable but relatively minor benefit (939, 946, 947).
Neuropathic pain is commonly associated with diabetic
peripheral neuropathy but may also have other etiologies
such as postherpetic neuralgia. For neuropathic pain in
general, evidence-based guidelines recommend the use of
TCAs or SNRIs (948, 949). Of the antidepressant medications, TCAs have been found to be most effective in decreasing pain associated with both postherpetic neuralgia(950, 951) and diabetic neuropathy (949, 952) but have noapparent effect on HIV-associated neuropathic pain (949).
Given the greater tolerability of SNRI antidepressants,
these agents may sometimes be chosen before a TCA for apatient with co-occurring depression and neuropathic pain.
In addition, if a TCA is used, therapeutic drug monitoring
may be helpful, given the wide variability of TCA bloodlevels across individuals (953).
Similar effects have been found for the use of antidepressants to prevent migraine and tension-type headaches.
In patients with and without co-occurring depression,
TCAs show greater efficacy than SSRIs (954, 955), but
SNRIs also have some evidence for efficacy (956, 957). In
individuals with tension-type headaches, addition of stressmanagement therapy may augment the effects of TCA
treatment (958).
Antidepressant treatment is also recommended for individuals with fibromyalgia, as it is associated with reductions in pain and often leads to improvements in function,with the best evidence available for amitriptyline (959).
Beneficial effects are observed in those with or without
co-occurring major depressive disorder (960–962). Although evidence from controlled trials is more limited fornonpharmacological approaches than for antidepressanttreatment, education, exercise, and CBT are generally rec-Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
ommended for the treatment of fibromyalgia in combination with antidepressant medication (963, 964).
In the context of rheumatoid arthritis, antidepressant
medications also appear to be effective in reducing pain as
well as treating depressive symptoms (965–967). Evidence
for psychosocial treatment is less consistent, with mindfulness meditation and emotion regulation therapy being
associated with reduced pain and enhanced coping in individuals with rheumatoid arthritis and depression (968),
but CBT having mixed results (966, 968). In individuals
with co-occurring depression and osteoarthritis, collaborative depression care has been associated with reduced
pain severity, improved function, and enhanced quality oflife in those with low pain scores at baseline but had no effect when compared with usual treatment in those withsevere arthritis pain (969, 970).
For individuals with chronic low back pain, there areconflicting opinions about the utility of antidepressant
medications in reducing pain or improving function, evenin the presence of co-occurring depression (971, 972).
Nevertheless, antidepressant medications may still be indicated to treat depression on the basis of individual circumstances.
Since depressed patients with concurrent pain are often treated by primary care physicians and other medical
specialists with a variety of potent analgesic medications,
including narcotics, psychiatrists treating such patientsare advised to be in contact with these other physicians
initially and on a regular ongoing basis as indicated. The
purposes of such contacts are to review the entire treatment plan, to assure that all prescribing physicians areaware of the full extent of pharmacological interventions,
to coordinate specific prescribing areas and responsibili-

77

ties so that patients do not receive prescriptions for thesame medications or have their doses for given medications adjusted by several different prescribing clinicians,
and to set up a mechanism and plan whereby all prescribing clinicians consistently keep one another informed
about changes in their treatment plans and prescriptions.

11. Obstructive uropathy
Enlarged prostate size and other causes of bladder outlet
obstruction are relative contraindications to the use of antidepressant medication compounds with antimuscarinic
effects. For this reason, tertiary amine TCAs are best
avoided in these patients. Benzodiazepines, trazodone,and MAOIs may also retard bladder emptying. The antidepressant medications with the least propensity to do
this are SSRIs, SNRIs, and bupropion. If a TCA is chosen,
the secondary amine desipramine is the least likely tocause urinary hesitancy or retention.

12. Glaucoma
Medications with anticholinergic potency may precipitate
acute narrow-angle glaucoma in susceptible individuals(i.e., those with shallow anterior chambers) (973). Patientswith glaucoma receiving local miotic therapy may betreated with antidepressant medications, including thosepossessing anticholinergic properties, provided that theirintraocular pressure is monitored during antidepressant
medication treatment. Prescription of agents lacking
anticholinergic activity avoids this risk. Other agents
sometimes used in psychiatry, e.g., topiramate and related
sulfa-based medications, may cause acute angle closure
glaucoma by ciliary body edema, a different mechanism(974).

Part BBACKGROUND INFORMATION AND REVIEWOF AVAILABLE EVIDENCEIV.

DISEASE DEFINITION, EPIDEMIOLOGY, NATURAL HISTORY,AND COURSE

A. DISEASE DEFINITION
The DSM-IV-TR criteria for major depressive episode andmajor depressive disorder are listed in Table 11. The cardi-

nal feature of a major depressive episode is either a depressed mood or loss of interest or pleasure in usual activities that persists over a period of at least 2 weeks and is

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78
accompanied by a constellation of depressive symptoms
such as changes in eating or sleeping patterns, fatigue, difficulty concentrating, indecision, thoughts of death or suicide, or feelings of worthlessness, helplessness, or hopelessness (16). It is important to note that these symptoms must
represent a change from the individual’s usual self and causeclinically significant distress or impairment. In addition,
they cannot be attributable to bereavement or another disorder, including a substance-induced condition or a general
medical condition. In some individuals, hallucinations ordelusions may occur in the context of a major depressive episode, in which case the episode would be specified as “Severe With Psychotic Features.” When psychotic features
are present, they may either be mood congruent (typicallyinvolving themes such as guilt, punishment, personal inadequacy, or disease) or mood incongruent. Although not apart of the DSM-IV-TR criteria, anxiety and somatic symptoms (particularly muscular, respiratory, and genitourinary)
can also be seen in the context of major depressive disorder(975). Episodes of major depression may also be distinguishable by their longitudinal course (e.g., chronic if
symptoms are present for at least 2 years, postpartum onset
if symptoms occur within 4 weeks postpartum, seasonal pattern if the timing of episodes is regularly associated with a
specific time of year) (16) and characteristic subsets of episode features (Table 12).

B. EPIDEMIOLOGY
Information on the current prevalence of major depressive disorder comes from two large community surveys,
the National Comorbidity Survey Replication (NCS-R)
study (976) and the National Epidemiologic Survey of Alcoholism and Related Conditions (NESARC) (655). In
the NCS-R, the lifetime prevalence of major depressive
disorder among the 9,090 adult participants was 16.2%,
with a 12-month prevalence of 6.6%. The NESARC, which
included more than 43,000 adults found slightly lower
prevalence rates than the NCS-R (13.25% lifetime and5.28% 12-month), perhaps because the sample included
previously omitted groups of individuals with lower prevalence rates (655). A number of sociodemographic factors
appears to be associated with an increased prevalence ofmajor depressive disorder, including female sex, being
middle-aged, being never or previously married, having a
low income, being unemployed, or being disabled (655,976), In the NESARC, being Native American increased
risk relative to being Caucasian, whereas being Asian,Hispanic, or black decreased risk (655).
The impact of major depressive disorders on individuals and their families is substantial. Virtually all individuals
in the NCS-R who had a major depressive episode in the

APA PRACTICE GUIDELINES
preceding 12-month period experienced significant levelsof symptom severity as assessed by an independent rating
scale (976). For more than 50% of individuals, symptoms
were rated at severe or very severe (976) and were associated with substantial role impairment (977).
Major depressive disorder rarely occurs in isolation;
anxiety disorders, substance use disorders, personality disorders, and impulse control disorders commonly co-occur
with major depressive disorder in community samples (655,976) as well as in individuals in psychiatric treatment (978).
In the NCS-R, major depressive disorder was found to cooccur with at least one other DSM-IV disorder in twothirds of those surveyed (976), but from a temporal standpoint major depressive disorder was the primary diagnosis
in only about 12% of these individuals (976). In contrast, ina study of patients in psychiatric treatment in the UnitedStates, 84% of major depressive disorder patients had atleast one co-occurring condition: 61% had a co-occurring
Axis I condition, 30% a co-occurring Axis II condition, and
58% a co-occurring Axis III condition (978). Anxiety disorders were the most common co-occurring disorder in theprior 12 months in both the NCS-R (57.5% of the sample)(976) and the NESARC (36.1% of the sample) (655). Of
the anxiety disorders, the greatest association was seen withgeneralized anxiety disorder and the weakest association
with specific phobia (655). Substance use disorders in thepreceding 12-month period were less common in the
NCS-R (8.5%) (976) than in the NESARC, in which
14.1% of the individuals with major depressive disorder
had an alcohol use disorder, 26.0% had nicotine dependence, and 4.6% had another substance use disorder (655).
Personality disorders were present in 37.9% of individuals
with major depressive disorder in the NESARC (655). Obsessive-compulsive, paranoid, schizoid, and avoidant personality disorders were most common among subjects withmajor depressive disorder; avoidant, dependent, paranoid,and schizoid personality disorders had greater odds ratios
for association with major depressive disorder than otherpersonality disorders (655).
Treatment of major depressive disorder does not always
occur and may be delayed. The average time to treatmentin the NESARC was approximately 3 years, and only about
60% of the sample with major depressive disorder received
treatment (655). The NCS-R also evaluated history andadequacy of treatment for major depressive disorder (976).
Of respondents who reported having had a major depressive episode in the last year, just more than one-half had received treatment but less than one-half of these individuals(about one-fifth of the total) received adequate treatment(976). These findings highlight the need for changes in thedelivery of mental health services to enhance the timelinessand quality of care for major depressive disorder.

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
TABLE 11.

79

DSM-IV-TR Criteria for Major Depressive Episode and Major Depressive Disorder

Diagnosis

Criterion/Symptom Description

Major depressive episodeA. At least five of the following symptoms have been present during the same
2-week period and represent a change from previous functioning; at least oneof the symptoms is either 1) depressed mood or 2) loss of interest or pleasure(do not include symptoms that are clearly due to general medical condition or
mood-incongruent delusions or hallucinations).
1.

2.

3.

4.
5.
6.
7.

8.
9.

Depressed mood most of the day, nearly every day, as indicated either by
subjective report (e.g., feels sad or empty) or observation made by others(e.g., appears tearful)Markedly diminished interest or pleasure in all, or almost all, activities
most of the day, nearly every day (as indicated either by subjective accountor observation made by others)
Significant weight loss when not dieting or weight gain (e.g., a change ofmore than 5% of body weight in a month), or decrease or increase inappetite nearly every day
Insomnia or hypersomnia nearly every day
Psychomotor agitation or retardation nearly every day (observable byothers, not merely subjective feelings of restlessness or being slowed down)
Fatigue or loss of energy nearly every day
Feelings of worthlessness or excessive or inappropriate guilt (which may bedelusional) nearly every day (not merely self-reproach or guilt about beingsick)
Diminished ability to think or concentrate, or indecisiveness, nearly everyday (either by subjective account or as observed by others)
Recurrent thoughts of death (not just fear of dying), recurrent suicidal
ideation without a specific plan, or a suicide attempt or specific plan forcommitting suicide

B. The symptoms do not meet criteria for a mixed episode.
C. The symptoms cause clinically significant distress or impairment in social,occupational, or other important areas of functioning.
D. The symptoms are not due to the direct physiological effects of a substance(e.g., a drug of abuse, a medication) or a general medical condition (e.g.,
hypothyroidism).
E. The symptoms are not better accounted for by bereavement, i.e., after the lossof a loved one, the symptoms persist for longer than 2 months or arecharacterized by marked functional impairment, morbid preoccupation withworthlessness, suicidal ideation, psychotic symptoms, or psychomotor
retardation.
Major depressive disorder,
single episodeA. Presence of a single major depressive episode.
B. The major depressive episode is not better accounted for by schizoaffective
disorder and is not superimposed on schizophrenia, schizophreniform disorder,
delusional disorder, or psychotic disorder not otherwise specified.
C. There has never been a manic episode, a mixed episode, or a hypomanic
episode.
(continued)

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80

APA PRACTICE GUIDELINESTABLE 11.

DSM-IV-TR Criteria for Major Depressive Episode and Major Depressive Disorder (continued)

Diagnosis

Criterion/Symptom Description

Major depressive disorder,
recurrent

A. Presence of two or more major depressive episodes (each separated by at least
2 months in which criteria are not met for a major depressive episode).
B. The major depressive episodes are not better accounted for by schizoaffective
disorder and are not superimposed on schizophrenia, schizophreniform
disorder, delusional disorder, or psychotic disorder not otherwise specified.
C. There has never been a manic episode, a mixed episode, or a hypomanic
episodeSource. Reprinted from Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American
Psychiatric Association, 2000. Copyright © 2000, American Psychiatric Association.

TABLE 12.

Selected DSM-IV-TR Major Depressive Episode Specifiers

Criteria for Melancholic Features Specifier
A. Either of the following, occurring during the most severe period of the current episode:1.

loss of pleasure in all, or almost all, activities

2.

lack of reactivity to usually pleasurable stimuli (does not feel much better, even temporarily, when something
good happens)

B. Three (or more) of the following:1.

distinct quality of depressed mood (i.e., the depressed mood is experienced as distinctly different from thekind of feeling experienced after the death of a loved one)2.

depression regularly worse in the morning

3.

early morning awakening (at least 2 hours before usual time of awakening)

4.

marked psychomotor retardation or agitation5.

significant anorexia or weight loss

6.

excessive or inappropriate guilt

Criteria for Atypical Features Specifier
A. Mood reactivity (i.e., mood brightens in response to actual or potential positive events)
B. Two (or more) of the following features:1.

significant weight gain or increase in appetite2.

hypersomnia

3.

leaden paralysis (i.e., heavy, leaden feelings in arms or legs)

4.

long-standing pattern of interpersonal rejection sensitivity (not limited to episodes of mood disturbance) that
results in significant social or occupational impairment

C. Criteria are not met for With Melancholic Features or With Catatonic Features during the same episode.
Criteria for Catatonic Features Specifier
The clinical picture is dominated by at least two of the following:1.

motoric immobility as evidenced by catalepsy (including waxy flexibility) or stupor

2.

excessive motor activity (that is apparently purposeless and not influenced by external stimuli)

3.

extreme negativism (an apparently motiveless resistance to all instructions or maintenance of a rigid postureagainst attempts to be moved) or mutism

4.

peculiarities of voluntary movement as evidenced by posturing (voluntary assumption of inappropriate or
bizarre postures), stereotyped movements, prominent mannerisms, or prominent grimacing

5.

echolalia or echopraxia

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition

C. NATURAL HISTORY AND COURSE
The age at onset of major depressive disorder varies widely,although the average age at onset is the late 20s. Although
the onset of the first episode is rarely before puberty, the disorder may begin at any age (655, 976). Symptoms of major
depressive disorder typically develop over days to weeks.
Prodromal symptoms, including generalized anxiety, panic
attacks, phobias, or depressive symptoms that do not meetthe diagnostic threshold may occur over the preceding several months. In some individuals, however, major depressive
disorder may develop suddenly, as in the wake of severe psychosocial stress. The duration of a major depressive episodealso varies. The mean duration of a major depressive episodewas 16 weeks in the NCS-R (976), with a median duration forthe longest depressive episode of 24.3 weeks in the NESARC(655). In treated patients, the median time to recovery from amajor depressive episode is approximately 20 weeks (979).
Untreated, episodes typically last 6 months or longer. Somepatients with major depressive disorder eventually have amanic or hypomanic episode, and they will then receive a
new diagnosis of bipolar I disorder or bipolar II disorder.

1. Recurrence
Major depressive disorder is unremitting in 15% of patientsand recurrent in 35%. About half of those with a first-onset episode recover and have no further episodes (502).
After three episodes, the risk of recurrence approaches
100% in the absence of prophylactic treatment. Individuals with major depressive disorder superimposed on dysthymic disorder carry a greater risk for having recurrent
episodes of major depressive disorder than those without
dysthymic disorder (410). When major depressive disorder is recurrent, its course varies. Some people have episodes separated by many years of normal functioning,others have clusters of episodes, and still others have increasingly frequent episodes as they age.

2. Interepisode status
Functioning usually returns to the premorbid level between

V.

81

episodes. However, 20%–35% of patients have persistentresidual symptoms and social or occupational impairment.
Patients who continue to have depressive symptoms but fall
below the diagnostic threshold for major depressive disorder are considered to be in partial remission. Residual depressive symptoms increase the risk of relapse. Anxiety andsomatic symptoms are particularly prominent residual
symptoms of major depressive disorder (980).

3. Complications and prognosis
Major depressive disorder adversely affects the patient andothers. The most serious complication of a major depressive episode is suicide (including suicide/homicide). Major
depressive disorder is also associated with significant medical comorbidity and complicates recovery from othermedical illnesses, such as myocardial infarction (see Section
III.C.1). Beyond its impact on the patient alone, major depressive disorder also affects the patient’s marital, parental,social, and vocational functioning (981). The disorder, especially when recurrent or chronic, may distress other individuals in the patient’s social network, e.g., children,
spouse, and significant others. If the patient is a parent, thedisorder may affect his or her ability to fulfill parental role
expectations (982) and increase the likelihood of children
becoming depressed as well (see Section III.B.5). Major depressive episodes are associated with occupational dysfunction, including unemployment, absenteeism, and decreased
work productivity (977, 983). In fact, in terms of the level ofdisability for the population as a whole, major depressive
disorder was second only to chronic back and neck pain indisability days per year (977).
The prognosis for major depressive disorder depends on
many factors, such as treatment status, availability of supports, chronicity of symptoms, and the presence of co-occurring medical and psychiatric conditions. With treatment,
however, the prognosis is generally good (984). Most patients will respond to acute treatment, and continuation andmaintenance treatment with acutely active treatments has
been shown to lower the risk and severity of relapse.

REVIEW AND SYNTHESIS OF AVAILABLE EVIDENCE

Translating the product of science into a decision about asingle human patient raises the concept of epistemology:
how we know what we think we know and how certain we
can be about that knowledge. Like all guidelines, this one
is an attempt to distill clinical research into recommendations that will be clinically applicable to the unique indi-vidual who presents for treatment. Science can neverprovide all of the answers that a doctor or patient wishes
and, at times, the knowledge base may consist primarily of
accumulated wisdom from clinical experience. In addition, every scientific protocol reflects a series of compromises, and each compromise may restrict internal and/or

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82
external validity, as described later in this section. No one
study, with its inevitable limits, can reveal “truth.” Thewise scientist—and physician—demands replication. Whenmultiple trials, with different methods, come to similar
conclusions, the clinician can be reasonably confident in
the results.
Many aspects of the design of research studies can influence the interpretation of the data and their implication forclinical practice. When translating efficacy evidence toclinical practice, it is important to assess the adequacy ofthe sample size (given modest effect sizes of antidepressant treatments), the nature and validity of the control
condition, the length of the treatment trial, the nature of
the participant population, the type and reliability of theoutcome measure, and publication bias (in favor of positive trials) (74, 985, 986).
Some issues also exist that are specific to pharmacotherapy trials. First, it is important to consider whether
and what type of comparison group was used (e.g., placebo or active agent). In trials of antidepressant medication treatments, high placebo response rates could makedetection of true treatment effects difficult in wellcontrolled trials, as well as explain observed treatment effects in trials with less robust controls. It is also important
to consider whether trials were blinded and, if so, whether
medication side effects could reveal the identity of active
agents. Issues related to the outcomes measured in trials
are important as well. A variety of different outcome measures are employed, and a report of “efficacy” could referto symptom reduction (e.g., reduction in the frequency orseverity of major depressive disorder symptoms), response (e.g., reduction in major depressive disorder symptoms below a threshold), or prevention of relapse. Despite
the fact that a 2006 American College of Neuropsychopharmacology task force report (408) emphasized the needto aim for remission as a primary goal, studies may not bedesigned and powered statistically to assess remission as a
primary outcome. Until recently most research studies
have reported response rates, often defined as a reduction
by 50% in the measured severity of depression. In addition, data often come from short-term (6- to 12-week)
efficacy trials that cannot show whether treatments are effective over the medium- and long-term. There has also
been recent concern that the apparent effect size of antidepressants has been exaggerated, due to the lack of reporting or selective publication of negative clinical trial
data (74, 75). A national database of clinical trial data
(http://clinicaltrials.gov/) is being expanded in an effort tomake these data available and transparent (987). However,most meta-analyses were published prior to this initiative,
and previously conducted studies will not be subject to theprovisions of recent regulations (988).

APA PRACTICE GUIDELINES
Evaluating the efficacy of psychotherapeutic approaches for major depressive disorder can also be challenging. Although there have been a number of welldesigned trials of CBT and IPT in large samples, for someother types of psychotherapy, few or no clinical trials havebeen conducted. In studies evaluating psychotherapy
against a variety of control conditions such as waiting lists,
other forms of psychotherapy, medications, placebos, or ano-control group, it is difficult to make comparisons of theobserved treatment effect sizes among trials. Some trials
have not examined the effects of psychotherapy exclusively
among patients with major depressive disorder and may
not have specifically assessed improvement in major depressive disorder as an outcome. In other trials, the natureof the psychotherapeutic intervention has been insufficiently described, making it difficult to apply the study
findings to psychotherapeutic approaches used in practice.
In evaluating the impact of a particular intervention,
several statistical concepts are helpful to understand. If one
starts with the assumption that the treatment group and thecontrol group are equivalent (i.e., no effect of treatment),
the p value indicates the probability that the treatmentgroup will show an outcome that is equal to or more extreme
than the observed treatment outcome (989). Although specific values of p (e.g., 0.05) are commonly considered to bestatistically significant, the p value does not address thepossibility, known as a type II error, that the treatmentgroup and control group will have similar outcomes eventhough the treatment is actually effective. This possibility
can be reduced, to some extent, by using sufficiently sizedresearch samples, which should be calculated as part of thestudy design (i.e., power analysis). Because these concepts
are difficult to grasp and provide limited information about
the clinical importance of an observed impact of treatment,
several other measures are often used. One approach to indicating the benefit of a treatment relative to a control condition is the number needed to treat (NNT), which is thenumber of individuals who would have to be treated to prevent one negative outcome (or benefit one patient) (990).
When applied to adverse effects, such a measure is termed
the number needed to harm (NNH). The effect size is ameasure of the magnitude of the difference between thetreatment group and the control group, which also considers the variability of the measurements. When the statistic
Cohen’s d is used to measure the size of a treatment effect,a general rule-of-thumb is that d=0.2 represents a small effect, d=0.5 represents a medium effect, and d=0.8 (orgreater) represents a large effect of the intervention (991).
In addition to being used in describing the results of individual studies, effect sizes are also used in comparing andsynthesizing the results of multiple clinical trials throughmeta-analyses.

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition

A. ACUTE PHASE SOMATIC TREATMENTS
1. Antidepressant medicationsa.

Selective serotonin reuptake inhibitors

Many studies and meta-analyses have compared SSRIs
among themselves as well as with other classes of antidepressants. Differences in efficacy and tolerability between SSRIs and TCAs, assessed through a meta-analysisof 102 studies (85), found no overall difference in efficacy
between TCAs and SSRIs. However, TCAs appeared
more efficacious in inpatients (p=0.012), and amitriptyline was more effective than SSRI comparators (p=0.012),
although publication bias could not be excluded. By contrast, SSRIs as a class (p<0.01) and, more specifically, paroxetine (p=0.001), fluoxetine (p<0.01), sertraline (p<0.05),
and citalopram (p<0.01) had a significantly lower rate ofdropouts for side effects. Other meta-analyses have compared the SSRIs among themselves and with other newer
antidepressant agents. Cipriani and colleagues (96) performed a multiple-treatments meta-analysis, which encompassed 117 randomized controlled trials and 25,928 subjects.
Incorporating efficacy and treatment discontinuation, theyfound the greatest degree of overall acceptability withescitalopram and sertraline, with greatest efficacy for
mirtazapine, escitalopram, venlafaxine, and sertraline ascompared with duloxetine, fluoxetine, fluvoxamine, paroxetine, and reboxetine. Gartlehner and colleagues (95)also compared the benefits and side effects of secondgeneration antidepressants including SSRIs using 6 goodor fair-quality systematic reviews or meta-analyses and
155 good- or fair-quality double-blind, placebo-controlled, or head-to-head randomized controlled trials of atleast 6 weeks' duration to assess efficacy and 35 observational
studies with at least 100 participants and follow-up of atleast 12 weeks to assess harms. Although the side effectprofiles and onset of action differed among the antidepressants, no differences in efficacy or effectiveness were
found.
A systematic review of 28 randomized studies (89) showed
that, even in anxious depression, SSRIs (fluoxetine, paroxetine, citalopram, sertraline, and escitalopram) are comparable in efficacy to other antidepressant medications(bupropion, amitriptyline, mirtazapine, imipramine, nefazodone, and venlafaxine), both in depression and anxiety
parameters. When compared with venlafaxine, fluoxetine
was less effective both in depression and anxiety scores,
while paroxetine was less effective in anxiety scores only.
No differences were found between venlafaxine and theother SSRIs.
A Cochrane meta-analysis (84) that included 132 randomized studies (almost all double blind) did not find sig-

83

nificant differences in fluoxetine efficacy versus TCAs.
When fluoxetine was compared with newer antidepressants, venlafaxine was superior, and within the class of
SSRIs, sertraline was significantly superior. However, fluoxetine was significantly better tolerated than TCAs as aclass and, more specifically, was better tolerated than amitriptyline, clomipramine, desipramine, and imipramine; nodifferences were noted in comparison with all of the othermedications. Similar meta-analyses compared sertraline(126) and escitalopram (992) to other antidepressive agents.
Although differences were small, there was a trend for sertraline to be more acceptable and efficacious than comparator antidepressants, including TCAs, SSRIs, and several
newer antidepressants (126). Escitalopram was found to be
more efficacious than citalopram and fluoxetine in terms of
response and remission of depressive symptoms and was associated with lower rates of treatment discontinuation thansubjects receiving duloxetine (992).
Another meta-analysis of 21 studies (98) compared efficacy and tolerability of each SSRI (except escitalopram)against the SSRI class overall and showed no difference inefficacy among the drugs. Rates of dropout due to side
effects were significantly lower in patients treated withsertraline (p<0.05) and significantly higher in patientstreated with fluvoxamine (p<0.01), although the dropout
rate in fluvoxamine-treated patients appeared to vary withmedication dose. In this meta-analysis, side effects anddiscontinuation reactions were observed more often withparoxetine than with other SSRIs. Interaction with otherdrugs was higher with fluoxetine, fluvoxamine, and paroxetine than with sertraline and citalopram, although citalopram was overrepresented in deaths due to overdose.
A systematic review based on 18 randomized, doubleblind trials (94), which compared escitalopram with either
citalopram, venlafaxine, paroxetine, sertraline, or bupropion, found no differences in efficacy between escitalopram
and the other medications (except for the comparison
with citalopram, which showed a significant difference in
two of four studies). Rates of study withdrawal due to side
effects were lower with escitalopram than with venlafaxine (p<0.05) or paroxetine (p<0.05).
Another meta-analysis of 32 randomized clinical trials
studied the efficacy and tolerability of antidepressants inpeople older than age 55 years (704). This study foundthat there was no difference in efficacy between TCAs and
SSRIs, but SSRIs were better tolerated. Compared withpatients who were taking TCAs, patients who were taking
SSRIs were less likely to withdraw from the study overall
or because of side effects, in particular. The qualitative
analysis of side effects showed a small increase in gastrointestinal and neuropsychiatric side effects associatedwith TCAs.

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84Overall, the findings of multiple randomized trials andmeta-analyses indicate comparable efficacies for SSRIs
relative to TCAs, although some data suggest greater efficacy for TCAs in inpatient samples. Selective serotonin
reuptake inhibitors also appear to have comparable efficacy to other non-TCA antidepressants, although venlafaxine shows superior efficacy in some studies, andcomparisons of SSRIs and MAOIs have not been done. In
terms of tolerability, SSRIs show consistently fewer dropouts in clinical trials than TCAs, and side effects are also
reported less often with SSRIs. There also do not seem tobe significant differences in efficacy among the SSRIs.
Fluvoxamine appears to have more side effects and more
problems with drug interactions than the other SSRIs;
drug interactions are also more problematic with fluoxetine and paroxetine than with citalopram, escitalopram, or
sertraline.
b. Serotonin norepinephrine reuptake inhibitors
The efficacy of venlafaxine, desvenlafaxine, and duloxetine,
which are classified as SNRIs, and mirtazapine, which(although not an SNRI) also enhances both serotonin andnorepinephrine neurotransmission, has been demonstrated in placebo-controlled studies of depressed patients(101, 102, 105, 113, 993, 994, 995). A number of studies
have contrasted these “dual-action” antidepressants with
the SSRIs. Although most individual studies have notfound statistically significant differences (see, for example, references 226 and 421), meta-analyses of controlled
studies of venlafaxine (101, 104, 996, 997), duloxetine(102), and mirtazapine (113) using SSRIs as comparators
have generally documented small (i.e., 4%–10%) albeit
reliable differences in the likelihood of response or remission favoring the dual-action drugs. Papakostas et al.
(995) similarly found an average difference of 4% in response/remission rates in a meta-analysis of a broader
grouping of antidepressant drugs that affect norepinephrine and serotonin. These average effects are generally
below the magnitude of difference that is widely considered to be clinically significant. It is possible that a small
average difference in an overall pool of patients may obscure larger and more meaningful differences among
selected subgroups of depressed patients (e.g., more severely depressed patients [102], inpatients [561], or postmenopausal women [998]), but this suggestion has yet tobe confirmed by analyses of larger data sets. At present,
the efficacy of desvenlafaxine has only been establishedversus placebo (993, 994); there are not yet any publishedstudies assessing its benefits relative to other antidepressants. Nevertheless, as the principal active metaboliteof venlafaxine, it is likely to have a comparable efficacy
profile.

APA PRACTICE GUIDELINES
Perahia et al. (999) conducted a randomized controlled
trial of duloxetine versus paroxetine and placebo in an
outpatient setting in patients who met the criteria for
major depressive disorder. After 8 weeks, duloxetine at
80 mg/day (N=93) and at 120 mg/day (N=103) was foundto be superior to placebo (N=99). However, paroxetine
was not superior to placebo in this study. Perahia et al. also
conducted a relapse prevention study (1000), in which patients were randomly assigned to receive duloxetine orplacebo for 26 weeks after a 12-week open-label treatment phase. The 136 patients who received duloxetine
had a relapse rate of 23%, compared with the 39% relapse
rate among the 142 patients who received placebo(p≤0.005). A large cohort study by Raskin et al. (1001)
followed 1,279 patients in 52 treatment centers taking
80–120 mg/day of duloxetine over 52 weeks. Patientswere assessed by multiple instruments at 6, 28, and 52
weeks. At 6 weeks, 50.8% achieved a score of <8 on the
HAM-D. The rate of response increased to 75.6% at week
28 and 81.7% at week 52, with no safety concerns identified in the course of the study.
Venlafaxine extended release (XR) has also been extensively studied. Rudolph and Feiger (1002) conducted
an 8-week outpatient trial of venlafaxine XR comparedwith fluoxetine and placebo. In this trial, 100 patients received venlafaxine XR (75–225 mg/day), 193 received fluoxetine (20–60 mg/day), and 98 received placebo.
Remission rates, determined by an HRSD score of <8,were 37% in the venlafaxine XR arm, 22% in the fluoxetinearm, and 18% in the placebo arm. Sauer et al. (1003)
compared 76 patients who received venlafaxine XR (75–150 mg/day) with 75 patients who received amitriptyline(75–150 mg/day). Venlafaxine XR yielded response rates
of 39.5%, compared with 41.7% for amitriptyline. SaizRuiz et al. (1004) followed 59 patients receiving venlafaxine over 6 months. Seventy percent of these patients completed the study, and the response rate, determined by a
50% reduction in the HRSD score, was 81%. In anothercohort study, Mitchell et al. (1005) found response rates at
8 weeks to be 52.6%, measured by the MADRS, among
312 patients with treatment-resistant illness taking venlafaxine in an open-label trial. Response rates at 10 months
as measured by the MADRS increased to 73% in 149 patients who continued treatment in an extension phase of
the study (1006).
Fewer studies have been conducted with desvenlafaxine; however, meta-analysis shows that it also is efficacious
in the acute treatment of major depressive disorder (99).
In the nine randomized, double-blind, placebo-controlled 8-week long trials with desvenlafaxine, there were1,342 subjects in fixed dose study arms (50, 100, 200, or
400 mg/day), 463 subjects in flexible dose study arms

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition(100–400 mg/day), and 1,108 subjects in placebo study
arms. Desvenlafaxine showed greater efficacy than placebo in rates of response as well as remission, with nogreater benefit (and greater discontinuation rates) at doses
greater than 50 mg daily. Overall rates of treatment discontinuation due to adverse effects were 3% for placebo
and 12% for desvenlafaxine (168). Treatment emergent
adverse effects included transient nausea and erectile dysfunction in men. Mean blood pressure was statistically increased in the desvenlafaxine group, but this change wasclinically significant in only 2% of desvenlafaxine subjects, compared with 1% of the placebo group.
c.

Other antidepressant medications

1. Bupropion
Meta-analyses of controlled trials have shown that bupropion is superior to placebo and is generally comparable inefficacy to both TCAs and SSRIs (105, 169, 1007). All
three formulations of bupropion are superior to placebo(106), and early studies with the immediate-release formulation found it to be generally comparable in efficacy
to the TCAs (105, 1008–1011). The newer sustainedrelease and extended-release formulations have been primarily compared with the SSRIs, and meta-analyses haveestablished comparable efficacy (169, 1012).
Several studies have compared bupropion sustained release (SR) to SSRIs and placebo. A randomized controlled
trial by Croft et al. (1013) compared bupropion SR to sertraline and placebo over 8 weeks of treatment and foundboth drugs to have efficacy superior to placebo. Bupropion SR had a lower rate of sexual dysfunction than sertraline. These findings were confirmed in a 16-week study
that again compared bupropion SR with sertraline andplacebo (1014). Another 8-week study found bupropion
SR, but not sertraline, to be superior to placebo and again
documented lower rates of sexual dysfunction with bupropion SR than sertraline (1015). Similar results were foundwhen bupropion SR was compared with other SSRIs. One
study comparing bupropion SR with paroxetine foundequivalent efficacy (1016). In another trial, with approximately 150 patients in each arm, bupropion had similar
efficacy to fluoxetine with a significantly lower burden ofside effects (1017). Lower rates of sexual dysfunction havealso been found with bupropion compared with sertraline(1013–1015) or paroxetine (1016). A survey of 6,297 patients in primary care settings found the incidence of sexual
dysfunction with bupropion to be 22%–25%. This incidence was comparable to the incidence with nefazodone(28%) but lower than that with SSRIs and venlafaxine(36%–43%) (1018). Several small studies have examined
whether bupropion might serve as a potential treatment

85

for SSRI-induced sexual side effects, with varying results(132, 1019, 1020).
Bupropion has also been studied as a treatment for anxiety associated with major depressive disorder. In one
large trial, patients were randomly assigned to receive bupropion SR (N=234), sertraline (N=225), or placebo(N=233). Patients treated with bupropion SR or sertraline
experienced significantly greater relief from anxiety symptoms than those who received placebo. Compared withsertraline, bupropion appeared to be associated with similar relief of anxiety in patients with major depressive disorder (1021).
Bupropion has also been shown to reduce the risk of relapse following successful antidepressant treatment withbupropion. In a 44-week double-blind trial of bupropion
responders (1022), patients were randomly assigned to continue taking bupropion or change to placebo. Continued
treatment with bupropion after acute phase response reduced the risk of relapse, compared with placebo, with few
differences in side effects reported between the two groups.
2. Mirtazapine
The efficacy of mirtazapine has been established in placebo-controlled studies (1023, 1024), two individual studies versus venlafaxine (1025, 1026), and in meta-analysesof studies comparing it to TCAs (1027–1029) and SSRIs(1030). Quitkin et al. (1030) analyzed three studies comparing patients with major depressive disorder treatedwith mirtazapine (N=289) to patients treated with fluoxetine or paroxetine (N=285). Although mirtazapine andSSRIs had similar efficacy over 6–8 weeks, a greater proportion of patients had onset of therapeutic benefit atweek 1 with mirtazapine as compared with an SSRI (13%versus 6%). In a meta-analysis by Watanabe et al. (1031),
mirtazapine was superior to SSRIs in response and remission rates at 2 weeks (12 trials), although it was comparable to SSRIs at the end of treatment (6–12 weeks). In a
subgroup analysis, mirtazapine produced greater responsethan paroxetine (three trials) and venlafaxine (two trials).
At 2 weeks as well as at the end of 6–12 weeks’ treatment(8 trials used to obtain outcomes), mirtazapine had comparable efficacy to TCAs. A meta-analysis of six studies(1027) found mirtazapine to have comparable efficacy toamitriptyline over 6–8 weeks, with both drugs showing
superiority to placebo.
Several randomized controlled trials have comparedmirtazapine to SSRIs. Benkert et al. (1032) randomly assigned patients with major depressive disorder to treatment with mirtazapine (N=127) or paroxetine (N=123)
over 6 weeks, and Wade et al. (1033) randomly assigned
197 primary care patients with HAM-D scores of atleast 18 to mirtazapine (N=99) or paroxetine (N=98) over

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86
24 weeks of treatment. In both studies, the treatments had
equal efficacy at study endpoint, but mirtazapine demonstrated a different profile of side effects. Another trial randomly assigned elderly depressed patients (at least age
65 years) to mirtazapine (N=126) or paroxetine (N=120)
over 8 weeks (1034). Compared with paroxetine, mirtazapine showed a greater benefit at day 14, had less attrition
for side effects, and was significantly more effective in improving sleep. It was also more effective in reducing
HAM-D scores by the study endpoint, although response
and remission rates were not significantly different. Two
randomized trials, one 8 weeks long (N=299) (1035) andthe other a 6-week study (N=132) in Chinese patients,
have compared treatment with mirtazapine to fluoxetineand found no differences in overall efficacy, although theonset of improvement and side effect profiles differed aswith paroxetine. A similar pattern of outcomes was also
observed when mirtazapine was compared with citalopram(N=270) in an 8-week trial (1036) and when an oral disintegrating form of mirtazapine was compared with sertraline (N=345) in another 8-week trial (1037).
Mirtazapine has also been compared with venlafaxine(both immediate release [IR] and extended release [XR]
forms) in randomized controlled trials. In an 8-week trial,
Guelfi et al. (1025) followed patients with major depressive disorder (HAM-D scores of at least 25) receiving mirtazapine (N=78) and venlafaxine IR (N=79). Mirtazapine
and venlafaxine did not differ significantly in depression
outcomes, although sleep was better with mirtazapine,and significantly more patients taking venlafaxine IR (15%)
dropped out due to side effects, compared with patientstaking mirtazapine (5%). A similar 8-week trial (1026)
found no significant differences in final outcome or tolerability between venlafaxine XR and mirtazapine, althoughmirtazapine showed greater benefit during the first 15 daysof therapy.
Patients with major depressive disorder who were notresponsive or who were intolerant of two prior treatmentswith antidepressants were randomly assigned to treatment with mirtazapine (N=114) or nortriptyline (N=121)
for up to 12 weeks as part of the STAR*D trial (471). Remission rates were 12% for mirtazapine and 20% for nortriptyline. There were no significant differences in any
outcome measure, and the medications were comparably
tolerated. Neither mirtazapine nor nortriptyline was particularly effective as monotherapy for patients who had
not benefited from two consecutive treatment trials.
Mirtazapine has been shown to decrease rates of relapse following acute phase treatment. Thase et al. (1038)
compared 78 patients who received mirtazapine to 78 patients who received placebo over 9 months following an
8- to 12-week treatment with an antidepressant. Patients

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taking mirtazapine had about a 50% reduction in relapse
rates. However, patients taking mirtazapine gained 1.4 kg
more weight than those taking placebo across the 9 monthsof continuation phase therapy.
3. Nefazodone and trazodone
The efficacy of nefazodone has been established in placebo-controlled trials, with efficacy comparable to both
TCAs and SSRIs (105, 1039–1042); however, its recent
use has been limited after case reports suggested a risk ofrare but potentially fatal hepatotoxicity (180). While anearly review of trazodone (114) concluded that trazodone
is as effective as TCAs in the treatment of depression,other investigators have found trazodone to be less effective than other antidepressant medications (115, 1043–
1045), a conclusion supported by the results of at least one
meta-analysis (93). In a review of 18 studies from 1980
through 2003, Mendelson (173) found that trazodone, whencompared with various control groups, did improve sleep.
However, it was also associated with significant side effects, and tolerance may develop with prolonged use.
d.

Tricyclic antidepressantsSince the first trial in which a tricyclic compound (imipramine) was shown to improve major depressive disorder
symptoms (1046), hundreds of subsequent randomized
controlled trials have demonstrated the efficacy of this antidepressant class as a treatment for major depressive disorder (105). Several reviews of this early literaturesuggested that approximately 50%–75% of patients withmajor depressive disorder treated with tricyclic and related antidepressant medications respond, compared with
25%–33% of patients who receive placebo (487, 1047–1049). The efficacy of individual agents and subclasses oftricyclics (e.g., secondary amines or tertiary amines) appears to be comparable, although amitriptyline may possess a slightly stronger effect across all studies (1050), andthe tertiary amine tricyclics (amitriptyline, clomipramine,
and imipramine) may have a stronger antidepressant effect than the secondary amine tricyclics and maprotiline
in studies of hospitalized depressed patients (117).
The meta-analysis of Barbui et al. (1050) reviewed 181
randomized controlled trials of amitriptyline, generally of
6–8 weeks’ duration, in inpatient and outpatient settings.
Amitriptyline was found to be superior to SSRIs in studies
of inpatients, but there was no difference in efficacy inoutpatients. Selective serotonin reuptake inhibitors were
better tolerated. Arroll et al. (1051) compared TCAs with
SSRIs in a meta-analysis of 15 randomized controlled trials in primary care settings. Both TCAs and SSRIs wereeffective, but tolerability comparisons across studies favored SSRIs. Wohlfarth et al. (1052) reviewed 30 random-

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
ized controlled trials conducted between 1979 and 1991,
with a combined sample size of 1,555 men and 2,331 women.
Tricyclic antidepressants were more effective than placebo across age and gender groups.
Several trials have compared TCAs against interpersonal therapy and CBT and against the combination of
TCAs and IPT or CBT. Reynolds et al. (1053) followed
80 patients who were at least age 50 years and had a bereavement-related depression in a 16-week factorial design
trial in which patients received IPT or case management
and nortriptyline or placebo. Nortriptyline (with or without IPT) was more effective than placebo (with or without
IPT). Patients receiving combined nortriptyline and IPT
had the highest study completion rate. Interpersonal psychotherapy alone (i.e., IPT plus placebo) was not foundto be an effective treatment for bereavement-related major depressive disorder. However, in a continuation trial(N=107) over 24 months (315), combination therapy was
found to be more effective than monotherapy in patientsage 70 years or older. All patients had been first stabilizedon combination nortriptyline and IPT before entering
the continuation phase. In a 16-week randomized controlled trial among 102 elderly patients with major depressive disorder, Thompson et al. (1054) found thatcombined treatment with CBT and nortriptyline was superior to CBT alone, which was superior to nortriptyline
alone. Combined treatment was particularly effective inpatients with severe depression, as measured by HAM-D
scores.
For patients with major depressive disorder who received ECT following a prior nonresponse to treatment
with an antidepressant, van den Broek (1055) found that
12 patients randomly assigned to receive imipramine(200–300 ng/mL plasma level) had a greater improvement
in all measures in preventing relapse than the 15 patientsrandomly assigned to receive placebo.
Results of some investigations have suggested that TCAs
are particularly effective for patients with more severe
symptoms of major depressive disorder (1056–1060), as well
as for patients with melancholia (562, 1061–1063). Superior
efficacy for TCAs, compared with SSRIs, has been documented in meta-analyses of inpatient studies (117).
e. Monoamine oxidase inhibitors
Monoamine oxidase inhibitors have also been shown in
multiple trials to be effective treatments for major depressive disorder. Although some earlier comparisons employing lower doses of MAOIs found TCAs to be superior,
MAOIs are now considered to have comparable efficacy
to TCAs for most patients with major depressive disorder(119, 120, 1064–1067). Results of several investigations
suggest that MAOIs may be particularly effective in treat-87

ing subgroups of patients with major depressive disorderwith atypical features such as reactive moods, reversed
neurovegetative symptoms, and sensitivity to rejection(572, 1068, 1069). Monoamine oxidase inhibitors havealso been shown to be effective treatments for some patients who have not responded to other antidepressant
medications (1064, 1067, 1070, 1071).
In more recent controlled trials, 6 mg/24 hours oftransdermal selegiline was compared with placebo in 177
adults with major depressive disorder in a 6-week trial(1072). The transdermal patch was found to be more effective than placebo and was well tolerated without theneed for dietary restrictions. These findings were replicated in two subsequent studies by Amsterdam (124)(N=365; dose, 6 mg/24 hours; duration, 6 weeks) andFeiger et al. (125) (N=265; dose, 6–12 mg/24 hours; duration, 8 weeks).
Tranylcypromine in doses of 30–60 mg/day has been
compared with the combination of venlafaxine IR (up to
300 mg/day) and mirtazapine (up to 60 mg/day) in 109 patients with treatment-resistant depression in a 12-weekrandomized trial (121). Neither the MAOI (7% remissionrate) nor the combination strategy (14% remission rate)
were particularly effective in this group of difficult-totreat depressed patients, although efficacy was compromised by the use of low tranylcypromine doses. Monoamine oxidase inhibitor therapy was significantly less welltolerated and had a significantly higher dropout rate.
Limited evidence suggests that the nonselective MAOIs
have comparable efficacy. Tranylcypromine and phenelzine
were found to have similar response rates (44% and 47%,
respectively) in a 5-week trial of 77 patients with severe major depressive disorder who had been nonresponsive to a
TCA or SSRI medication (1073). Clinical experience suggests that some patients who fail to benefit from one ofthese MAOIs may benefit from a different one—after allowing a several-week period of washout.

2. Electroconvulsive therapy
The efficacy of ECT has been demonstrated in multiple
clinical trials, including trials of real versus sham ECT. In
a meta-analysis of the efficacy of ECT in the treatment ofdepressive disorders, the six trials (256 patients) that included sham ECT controls yielded a standard effect sizeof 0.91 favoring real ECT, consistent with a strong effectof active ECT (235). In the one sham ECT study thatused unilateral ECT, no difference was found, but thetreatment was not delivered sufficiently above the seizure
threshold to be effective (236). In comparison with pharmacotherapy, meta-analyses similarly show an advantage
for ECT with a standard effect size of 0.80 across 18 trials

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88(1,144 participants) (235). Comparisons of ECT against
specific antidepressant classes show ECT to be superior
to SSRIs, TCAs, and MAOIs (236, 425). In terms of technical aspects of ECT administration, meta-analyses show
a more substantial effect of bilateral ECT than unilateral
ECT (236), with a standard effect size of 0.32 for 22 trials
and 1,408 participants (235). However, many of the included studies did not adjust the stimulus doses of ECT toaccount for differences in seizure threshold across patients, which may have increased the apparent benefit ofbilateral ECT. When stimulus dosing was assessed, higher
stimulus doses relative to the patient’s seizure thresholdwere associated with greater benefit than stimulus doses
closer to the seizure threshold (standard effect size = 0.73
for seven trials and 342 participants) (235). The efficacy of
ECT given twice weekly did not differ from that of ECT
given 3 times/week (236).
Much information about ECT response and specificfactors that predict response has come from the Consortium for Research in ECT (CORE) study, a large trial
funded by the National Institute of Mental Health (NIMH)
in which continuation pharmacotherapy was comparedwith continuation ECT. In the acute phase of that trial inwhich 253 patients were treated with bitemporal ECT
3 times/week, 79% of the sample had an acute sustained response, with remission occurring in 75% of patients after
ECT (mean number of treatments = 8 ± 3). Response to
ECT occurred rapidly, with over one-half of patients showing response by the end of the first week of treatment (240).
Suicidal ideation also resolved rapidly during the course of
ECT, with substantial resolution in 38% by the end of thefirst week, 61% by the end of the second week, and 80% by
the end of the treatment course (243). Individuals who wereolder (715) or who exhibited psychosis (241) or atypical features (578) had a greater likelihood of achieving remission,
although the presence of melancholic features was not associated with a greater likelihood of response (499). Also,
unlike prior studies that had shown reduced rates of remission with ECT in patients with treatment-resistant depression (1074, 1075), the CORE study found that neither
resistance to antidepressants as a whole nor resistance toany specific class of antidepressants was associated with analtered response to ECT (426).
In contrast to the high rates of ECT response found in
the CORE study and in meta-analyses of clinical efficacy
trials, ECT appears to have a lower rate of response when
delivered in community settings. Prudic et al. (237) examined clinical outcomes following ECT and over 6 monthsof follow-up in 347 patients who received ECT at one ofseven hospitals in the New York metropolitan area. Remission occurred in only about one-third to one-half ofthe sample, and two-thirds of those with remission expe-

APA PRACTICE GUIDELINES
rienced a relapse during the follow-up period. Having residual symptoms, psychotic features, or a co-occurring
personality disorder conferred a heightened risk of relapse.
Other studies have delineated technical factors relating
to the efficacy of ECT, including stimulus intensities andelectrode placements. Sackeim et al. (253) randomly assigned 96 depressed patients to treatment with a bitemporal or right unilateral electrode placement at a low dose or
high dose relative to the patient’s seizure threshold. Patients treated with bilateral ECT had comparable response
rates regardless of stimulus dose (65% for low dose versus
63% for high dose), whereas patients receiving low-doseright unilateral ECT had only a 17% response, and thosereceiving high-dose right unilateral ECT had an intermediate response (43%). In a subsequent randomized doubleblind study of 80 depressed patients, an even higher doseof right unilateral ECT was used (500% above the seizure
threshold). At this stimulus dose, right unilateral ECT
showed comparable efficacy to bilateral ECT (65%) andsuperior efficacy to right unilateral ECT given at 50% or
150% above seizure threshold, for which the response
rates were 35% and 30%, respectively. That high-doseright unilateral ECT has comparable benefits to bilateral
ECT has also been shown in two randomized studies by
McCall et al., one of which included 77 patients and usedright unilateral ECT at eight times the seizure threshold(1076) and one of which included 72 patients and used ahigh fixed dose of 403 millicoulombs for right unilateral
ECT (1077).
Several smaller studies have examined bifrontal electrode placement in comparison with bitemporal or right
unilateral electrode placements. Bailine et al. (1078), who
studied 48 patients with scores of 17 or higher on the 17item version of the Hamilton Rating Scale for Depression(HAM-D-17) who were randomly assigned equally toreceive bifrontal or bitemporal ECT (mean number oftreatments = 6 ± 2.5), reported no difference in remission
rates between the two groups. Ranjkesh et al. (1079)
found no difference in HAM-D scores among patients receiving at least eight sessions of bifrontal (moderate dose,
N=15), bitemporal (low dose, N=15), or right unilateral(high dose, N=15) electrode placement in an Iranian inpatient sample of patients with an initial score of 16 or
higher on the 24-item Hamilton Rating Scale for Depression (HAM-D-24). Similarly, Eschweiler et al. (1080)
compared the effects of six right unilateral ECT treatments (250% stimulus intensity of titrated threshold) andsix bifrontal ECT treatments (150% of threshold) overa 3-week period in a randomized double-blind trial of
92 patients and found no difference in response rates between the two electrode placements.

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
In addition to efficacy and ECT technique, the cognitive effects of ECT have been a focus of considerable
study, typically as a part of studies examining various electrode placements. In terms of the time to recover reorientation after ECT, Sackeim et al. (253) found that patients
receiving bilateral ECT took substantially longer to regain their orientation than patients receiving right unilateral ECT, and the time to regain orientation increased
with the stimulus dose. In addition, the time to regain orientation immediately after ECT, as well as the patient’s
baseline cognitive status, predicted the patient’s cognitive
status after the ECT course and at 2-month follow-up assessment (251). Regardless of the stimulus dose of right
unilateral ECT that was used, bilateral ECT was associatedwith more prominent effects on cognition at follow-up assessments (253, 1081). Relative to bilateral ECT (at one
and one-half times the seizure threshold), high-dose right
unilateral ECT (at eight times the seizure threshold) produced comparable effects on memory, and neither electrodeplacement produced prolonged anterograde amnesia(1076). Lisanby et al. (248) studied 55 patients with major
depression in a randomized double-blind trial of bitemporal and right unilateral ECT at low and high stimulus
doses and compared the patients’ function on a Personal andImpersonal Memory Test with that of a parallel group of
normal control subjects. Bitemporal ECT was found tocause more prominent impairments that were most notable for impersonal events and that were independent ofstimulus dose or clinical outcome. Studies of other electrode placements have shown either no difference (1080)
or beneficial effects (1078, 1079) of bifrontal electrodeplacement relative to bitemporal electrode placement. Another factor that may relate to memory dysfunction is thenumber of ECT treatments administered per week, with
two studies showing less prominent amnesia with twiceweekly ECT rather than ECT given 3 times/week (1082).
The cognitive effects observed in naturalistic community settings also appear to differ from those observed inresearch trials (252). The seven hospitals in the community
study showed considerable variation from one anotherimmediately after ECT and at the 6-month follow-up assessment. These differences seemed primarily related todifferences in ECT technique across sites, with use of sine
wave stimulation and bilateral ECT being associated withgreater and more persistent cognitive effects on several
cognitive measures, compared with brief pulse and right
unilateral ECT. Given the lower efficacy rates for ECTthat were also seen in the community sample, residual orrecurrent depressive symptoms may also have contributed
to the poorer cognitive outcomes. These findings suggest
a need to optimize efficacy as well as minimize cognitiveeffects in clinical practice.

89

3. Transcranial magnetic stimulation
A substantial number of studies of TMS have been conducted, but most have had small sample sizes, and the studies overall have yielded heterogeneous results. Further
complicating the interpretation of the TMS literature isthe variability in stimulation intensities (relative to the motor threshold), stimulus parameters (e.g., pulses/second,
pulses/session), anatomical localization of stimulation, andnumber of TMS sessions in the treatment course. A recent
meta-analysis of 24 studies (with a total of 1,092 subjects)
found that individuals with treatment-resistant depression
were more likely to respond to TMS than to sham treatment (25% with TMS versus 17% with sham; NNT=6)(270). However, for active treatment and for sham treatment, remission occurred in fewer than 10% of subjects(270). Another meta-analysis that included 33 studies also
found active TMS to be more effective than sham treatment in patients with major depression but also noted substantial variability across studies (271). Studies withstimulation intensities below 90% of motor threshold appeared to show less benefit (271). Based on a meta-analysis
that included six independent trials of left dorsolateral prefrontal cortex TMS in a total of 195 patients, older individuals and those with treatment-resistant depressive episodes
may also be less likely to respond (1083). Another metaanalysis of these six clinical trials found TMS to be no different from sham treatment overall in the treatment of major depression; however, the power within these studies todetect a difference was generally low (273). Schutter (272)also examined studies of TMS over the left dorsolateral prefrontal cortex and found an overall weighted mean effect sizeof 0.39 for TMS based on findings from 30 studies and
1,164 patients. This meta-analysis did not find any differences in the response of individuals with medication-resistant major depression as compared with those without
documented medication resistance, nor did it find any evidence of study heterogeneity or publication bias. Multiple
earlier meta-analyses also demonstrated benefits of TMS(1084–1087), but include an overlapping set of studies withthose assessed in more recent meta-analyses. If anything,
however, earlier studies demonstrated less efficacy for
TMS than more recent studies (272, 1088). The durationof TMS effects has not been well studied, but one metaanalysis of 14 studies showed a robust response to TMS
compared with sham TMS after 2 weeks of treatment (standardized mean difference = −0.35; 95% confidence interval= −0.66 to −0.04), but no statistically significant benefit ofactive TMS at 2-week follow-up (1089).
The largest published trial of TMS was a randomized,
double-blind, multisite study of patients who had not responded to one to four prior trials of antidepressant therapy and were free of other medications at the time of the

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90
study (268). Subjects received sham TMS (N=146) or active TMS delivered to the left dorsolateral prefrontal cortex, 5 times/week for 4–6 weeks with 10 pulses/second and3,000 pulses/session at 120% of motor threshold. At
weeks 4 and 6 of the study there was a trend for greater
improvement in MADRS scores in the active TMS group,
but this result did not reach statistical significance. Ratesof remission also did not differ between the two groups,
although secondary outcome measures, including the
HAM-D and response rates, did indicate a beneficial effect of TMS. In an open-label extension study of this trial(1090), 85 subjects who had received sham TMS showedsignificant reductions in MADRS scores after changing toactive TMS; 42.4% of these patients met response criteria, and 20% had remission of their depressive symptoms
by 6 weeks. Of subjects who had received active TMS andcontinued to receive an additional 6 weeks of treatment(N=73), 26% showed a response to TMS, and 11% achieved
symptom remission. Subsequent analysis of the data fromthese trials (274) showed that lesser degrees of treatment
resistance were associated with better response to TMS.
The lack of a co-occurring anxiety disorder also appeared
to be associated with a better response to TMS in the
open-label extension phase of the trial.
In another large multisite trial conducted in Europe, 127
subjects with treatment-resistant depression who were being
treated with antidepressant medication (venlafaxine or mirtazapine) were randomly assigned to receive active (N=62)
or sham (N=65) TMS delivered to the left dorsolateralprefrontal cortex, 5 times/week with 10 pulses/second and2,000 pulses/session at 110% of motor threshold for 3 weeks.
The two groups did not differ in their degree of improvement on the MADRS, HAM-D, or BDI scales, and a similar proportion of individuals in each group (31%) wereclassified as having responded to treatment (269).
Other smaller studies have compared TMS with ECT,with variable results. One of these studies showed ECT tobe substantially more effective than TMS acutely in termsof HRSD scores and the proportion of responders at theend of the study, and, on the majority of outcome measures, ECT retained this benefit over TMS after 6 monthsof follow-up (275). In the other studies that compared
TMS with ECT, rates of remission and response werecomparable for the two treatments, although the response
and remission rates for ECT in these studies were somewhat lower than typically reported in clinical ECT trials,
and rates of response to TMS were higher than those reported in sham controlled trials of TMS (276–278, 1091).
An additional randomized single-blind trial compared the
responses of individuals who received 2 weeks of thriceweekly unilateral ECT with the responses of individuals
who received one unilateral ECT session and four TMS

APA PRACTICE GUIDELINES
sessions each week (1092) and found no statistically significant differences in efficacy or side effects between the
two approaches. The cognitive effects of TMS and ECThave been assessed in one open study (279), in which subjects treated with TMS reported memory to be unchanged
or improved approximately 9 days after the treatment
course as compared with unilateral ECT, which was associated with a greater degree of subjective, retrograde, andanterograde memory difficulties shortly after the end of
the treatment course. A subsequent randomized singleblind trial (276) showed no significant difference between
individuals who received TMS and those who received
unilateral ECT when neuropsychological performance wastested at 2 and at 4 weeks of treatment. However, there
was a trend for worsened performance in those receiving
ECT versus a trend for improved performance in thosereceiving TMS.
Analysis of aggregate safety data from more than 10,000
treatment sessions with 325 patients treated at 23 clinicalsites in the United States, Australia, and Canada showedthat TMS was well tolerated, with less than 5% of subjects
leaving the study due to adverse effects and no seizures ordeaths observed (280). The most common adverse effects
were transient headaches or scalp discomfort. Overall, side
effects of treatment were mild to moderate in intensity anddissipated over the initial week of treatment.

4. Vagus nerve stimulation
The FDA approved VNS for treatment-resistant depression based on efficacy data from two different samples, forwhich acute and longer term data are available. The firstsample consisted of 60 outpatients with chronic or recurrent major depressive disorder, bipolar I disorder, or bipolar II disorder who had not responded to at least two
medication trials from different antidepressant classes. This
cohort was first followed in an open-label fashion with 10
weeks of active stimulation after a 2-week period to permit
recovery from surgery (281). On the primary outcome measure, the 28-item Hamilton Rating Scale for Depression(HAM-D-28), 30.5% of the sample showed a response (defined as at least a 50% reduction from the baseline HAMD-28 score) and 15.3% of the sample had a full remissionof symptoms (defined as HAM-D-28 of less than 11). Response was less likely to occur in patients who had received
a greater number of unsuccessful antidepressant trials or
who had received ECT prior to VNS. This cohort was thenfollowed for up to 2 years naturalistically, with changes to
psychotropic medications and VNS stimulus parameters
permitted (479). In a last-observation-carried-forward analysis, response rates were 44% and 42% after 1 and 2 years,
respectively, with remission rates of 27% and 22% at 1 and2 years, respectively (479).

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
A subsequent VNS trial was a multisite randomized
trial with 235 participants that included an acute shamcontrolled phase (282) and a longer term naturalistic follow-up phase (477) and comparison with a relatively similar
treatment-as-usual sample. In the acute phase, nonpsychotic outpatients with treatment-resistant major depressive disorder (N=210) or patients with depressed phasebipolar disorder (N=25) received 10 weeks of active or
sham treatment after 2 weeks of recovery from implantation surgery. In terms of response (i.e., at least 50% reduction in HAM-D-24 score), there was no significant
difference with VNS treatment (15.2% response vs. 10%
for sham). These findings may be confounded by the frequent occurrence of hoarseness or voice alteration withstimulation (281), which may have affected the blinding of
the study subjects or investigators. During the longer
term naturalistic follow-up phase, in which changes inmedication were permitted, the active VNS group received 9 additional months of VNS, and the sham group
received 12 months of VNS (282). A repeated-measureslinear regression analysis of the primary outcome measure
showed significant reductions in HAM-D-24 scores, withresponse and remission rates of 27.2% and 15.8%, respectively, at the study endpoint (282). A similar but nonrandomized treatment-as-usual group (N=124) showed a
response rate of 13%, suggesting a benefit of VNS (476).
To determine whether the benefits of VNS were durable, data from the studies described earlier in this section
were combined, and the persistence of the antidepressive
response was determined (478). Of individuals who had
shown an early response (by 3 months of VNS), 66.7% and64.6% of the overall group had maintained that response at
1 and 2 years, respectively. Of those who had shown a late
response (by 12 months of VNS), 68.5% had maintainedthat response at 2 years, suggesting persistent benefits of
VNS.
An additional uncontrolled multisite European trial
showed somewhat lower rates of sustained response (44%)
at 1 year of VNS treatment, although overall response andremission rates at 1 year were 53% and 33%, respectively(481). Other smaller, open-label trials have been recently
reviewed and also show reductions in depressive symptoms
when VNS is used in combination with other antidepressive treatments for individuals with treatment-resistant depression (480).
Across all studies, VNS was generally viewed as tolerable (480). Rates of study dropout were low (about 1%)
during the initial 3 months of treatment (282), with about
80% of subjects continuing with VNS at the end of 2 years(479). Voice alteration or hoarseness occurred in about
two-thirds of subjects in conjunction with stimulation(281). Coughing occurred in about one-quarter of individ-

91

uals (281), and dyspnea and neck pain were also commonly
reported (481).

5. Complementary and alternative treatments
a. St. John’s wort
Despite a large number of trials examining St. John’s wort(usually in the form of Hypericum perforatum extract), there
is no consensus on its efficacy in major depressive disorder.
A 2005 Cochrane meta-analysis (1093) provided a summary of treatment studies utilizing St. John’s wort for thetreatment of major depressive disorder. The published studies demonstrate heterogeneity in methods used and greatinconsistency in study outcomes. A number of doubleblind studies have demonstrated its superiority over placebo, although some have not (370, 371). In addition, St.
John’s wort may have better tolerability than TCAs and
SSRIs, and several randomized studies have shown noninferiority relative to approved antidepressant medications,although the distinctive taste of St. John’s wort extract may
have caused some unblinding during the studies.
Among the larger and most rigorous recently published placebo-controlled trials, the studies by Shelton etal. (371) (N=200) and Davidson et al. (370) (N=340) did notdemonstrate a difference between St. John’s wort and placebo on primary outcome measures, but Lecrubier et al.
(1094) found a significant difference between St. John’s wortand placebo in mild to moderate depression (N=375). In
addition, a recent review of 14 short-term, double-blind
trials conducted in outpatients with mild to moderate
symptoms of major depressive disorder demonstrated that
St. John’s wort in doses of 300 mg/day and 1,800 mg/day
had efficacy superior to placebo and was generally comparable to low-dose TCA treatment (e.g., 30–150 mg/dayof amitriptyline) (105). Side effects were observed in alower proportion of individuals taking St. John’s wort
than among those taking a TCA (25% vs. 40%) (105).
b. S-adenosyl methionine
A number of studies have found SAMe to be efficacious inoral doses that range from 800 mg/day to 1,600 mg/day. In
a double-blind trial, 15 inpatients with major depressive
disorder received oral SAMe or placebo for 21 days (1095).
Six of nine patients receiving SAMe demonstrated response
as defined by a reduction of 50% or more in HAM-D
scores, and depression ratings compared with placebo weresignificantly lower in the SAMe group than in the placebogroup at days 14 and 21. Side effects were mild and transient. In a meta-analysis of studies comparing effects ofSAMe with those of TCAs, SAMe was found to have better
tolerability and greater efficacy in the treatment of depression, although the doses of TCAs were subtherapeutic insome studies (381). Data from two multicenter studies also

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92
demonstrated that parenteral and oral formulations ofSAMe were comparable in efficacy to the TCA imipramine(1096), although side effects were significantly more frequent in the imipramine-treated group. In one of the larger
controlled trials, which included 293 participants, Pancheri
et al. (382) found SAMe (administered intramuscularly at adose of 400 mg/day) and imipramine (administered bymouth at a dose of 150 mg/day) to be similarly efficacious in
a 4-week trial. Other studies have focused on specific subgroups of patients, such as HIV-positive patients and postmenopausal women (1097, 1098).
c. Omega-3 fatty acids
Two large meta-analyses found benefits of omega-3 fatty
acids overall in mood disorder trials (384, 385) but also
highlighted the heterogeneity of study designs and results. The one monotherapy study of DHA for major depressive disorder in adults did not demonstrate benefit of
DHA over placebo (1099), although small trials in major
depressive disorder in children and in pregnant women
did demonstrate a benefit of monotherapy with omega-3
fatty acids (EPA and DHA) (1100, 1101).
d. Folate
In a study by Coppen and Bailey (389) that included
127 subjects, 94% of women who received fluoxetine and
500 mcg/day of folate responded to treatment, comparedwith 61% of those who received fluoxetine and placebo(p<0.005). Patients who received folate were also lesslikely to report side effects (p<0.05).
e. Light therapy
In a meta-analysis, Golden et al. (395) found clinically significant benefit of bright light therapy in seasonal major depressive disorder (eight studies), with a large effect size
(0.84), and in nonseasonal major depressive disorder inthree studies with a medium effect size (0.53). However, theauthors, who were participants of an APA work group on
the topic of light therapy, determined that many of thestudies of light therapy for mood disorders had methodological flaws, including small sample sizes, with only 13% of
the studies they assessed meeting the inclusion criteria for
their meta-analysis. Bright light therapy in nonseasonal
major depressive disorder was not found to be significantly
more efficacious than placebo in trials when used adjunctively in addition to antidepressants. As determined by the
APA work group, an adequate placebo condition requires amaximum dose of 300 lux (versus at least 3,000 lux-hours
for an active treatment condition for bright light treatment). Randomized, placebo-controlled studies haveranged from 7–42 days in treatment duration, with provision of between 2,500–10,000 lux illuminance of whitelight, with delivery time between 0.5–6 hours/day. SomeAPA PRACTICE GUIDELINES
published studies were found to have bright light exposure
at levels too high to constitute a scientifically valid control
condition, and the difficulty in creating a reasonable control condition for bright light therapy may have contributed
to the limited evidence base to date. Control groups have included lower doses of white light, red light, active lightavoidance, negative air ionizer, and no treatment. Despite
heterogeneity of designs and results, evidence supports theefficacy of bright light as a monotherapy for acute major
depressive disorder. Individualization of a regimen may berequired in terms of lux, length of exposure, and time of dayof delivery. In addition, patients should be monitored for
emergence of mania during treatment (1102).
f. Acupuncture
Assessment of the evidence base for acupuncture is complicated by the fact that many reports are in Asian languages
and therefore often overlooked by English language literature searches. Results from studies in acupuncture are difficult to interpret, because the description of the methods isoften limited and there is variability in diagnosis and in interventions (403). Wang et al. (407) published a recent
meta-analysis of eight trials of acupuncture and depression
chosen from more than 200 studies on the basis of having
a randomized design, specific diagnostic criteria for depression, and specific acupuncture interventions (manual,electro-acupuncture, or laser). The depression criteria included DSM, International Classification of Diseases, andChinese Classification of Mental Disorders criteria. The
meta-analysis did not demonstrate a benefit of acupuncture
over control conditions on either response rates or remission but was based on a small number of trials with variable
methodological quality. Consequently, additional systematic study is required to assess the role of acupuncture formajor depressive disorder.
There have been few randomized, double-blind, placebocontrolled studies to inform the use of acupuncture for depression. In one published study, Allen et al. (405) compared
38 women, ages 18–45 years, who were assigned to three different groups: an acupuncture regimen specifically chosen toaddress their depression, sham acupuncture, or a waiting-list
control condition. The active acupuncture group experienced a significantly greater remission rate. However, Allenet al. (406) failed to replicate these results in a larger randomized trial, in which 151 patients with major depressive disorder received acupuncture specific for depression, shamacupuncture, or a waiting-list condition. After 8 weeks, there
was no evidence of benefit for the acupuncture intervention
specific for depression, compared with sham acupuncture or
the waiting-list condition. Response rates were 22% for the
depression-specific acupuncture treatment and 39% for thesham acupuncture treatment.

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
In another randomized study, Luo et al. (404) comparedeffects of electro-acupuncture combined with placebo medication to the effects of amitriptyline in 241 inpatients.
Electro-acupuncture appeared equivalent to amitriptyline
at a dose of 150–175 mg/day in treating depression, withgreater improvement for symptoms of anxiety, cognitive
problems, and somatization; it also resulted in a lower side
effect burden than amitriptyline. However, no group received the placebo medication alone, and no sham treatment was used to elucidate nonspecific benefits of acupuncture treatment.

B. SPECIFIC PSYCHOTHERAPIES
1. Cognitive and behavioral therapies
a. Cognitive-behavioral therapy
In the three decades since its first evaluation as a treatment for major depressive disorder, CBT has been extensively studied in controlled trials. When meta-analyses
have quantified the efficacy of CBT compared with notreatment or minimal treatment, effect sizes have been
fairly robust, generally near or above one standard deviation in the outcome measures (514, 1103–1106). Relative
to other treatments, estimates of CBT efficacy frommeta-analyses have been less consistent, although effectsizes for CBT have generally been comparable to thosefor other short-term forms of psychotherapy (e.g., IPT
and brief dynamic psychotherapy) (1107).
Factors relating to the administration of CBT may influence response. Some data suggest that the efficacy of
CBT may vary depending upon the severity of major depressive disorder, with less efficacy in individuals withmore severe symptoms (1108). Individuals with moderate
to severe depression may need more skilled CBT therapists to achieve therapeutic benefits (67). Other trials havefailed to show a differential response to treatments on thebasis of initial symptom severity, possibly because of lackof statistical power (1109, 1110).
Recent research has raised questions about the relative
strengths of the cognitive and the behavioral componentsof CBT. Dimidjian et al. (310) randomly assigned 241 patients with major depressive disorder to receive CBT,
behavioral activation, paroxetine, or placebo. Among patients with more severe depression, behavioral activation
had similar efficacy to medication, and both were superior
to CBT. This study shows that behavioral interventions
may be preferable to cognitive techniques for patientswith more severe depressive symptoms.
According to a data synthesis of studies conducted between 1980 and October 2004, conducted by Hollon et al.

93(363), CBT and IPT can be as effective as medications in
the acute treatment of depressed outpatients. Comparable
rates of medication and CBT response have also been foundin a number of randomized trials. For example, Jarrett et al.
(576) compared CBT to phenelzine and placebo in a 10week randomized trial that included 108 patients with major depressive disorder with atypical features. Cognitive-behavioral therapy had comparable efficacy at achieving
response (indicated by a HAM-D score of 9 or lower), andboth were superior to placebo in an intent-to-treat analysis.
In another study, DeRubeis et al. (67) reported that among
240 patients randomly assigned to receive paroxetine, CBT,or placebo, CBT was comparable to paroxetine but was notclearly superior to placebo at 8 weeks. In addition, at 16
weeks, CBT and paroxetine showed comparable rates of response and remission in individuals with moderate to severe
major depressive disorder.
In subanalyses of the NIMH Treatment of Depression
Collaborative Research Program study, CBT was less effective than imipramine plus clinical management amongindividuals with moderate depression (defined by scoresof 20 or higher on the HAM-D or scores of 50 or lower on
the Global Assessment of Functioning); there was also atrend for CBT to be less effective than IPT (1108). No
differences were observed between CBT, IPT, imipramine plus clinical management, or placebo plus clinicalmanagement among less severely depressed subjects. At
study endpoint as well as at 18-month follow-up, there
were no significant differences among these treatmentgroups in degree of symptom reduction or ratings of current clinical condition. However, at the 18-month followup assessment, patients receiving IPT or CBT reported asignificantly greater capacity to establish and maintain interpersonal relationships and to recognize and understandsources of their depression than patients in the imipramine plus clinical management group or the placebogroup (1111).
Unlike medications, CBT decreases the risk of relapse
even after this treatment is terminated (363), and continuing CBT in the maintenance phase further decreases thisrisk. In a maintenance treatment study by Paykel et al. (368),
158 patients with partial remission from a major depressive episode while taking medication were randomly assigned to clinical management or clinical management and
CBT. Cognitive-behavioral therapy was given in 16 sessions over 20 weeks, with two booster sessions at 72 weeks.
Relapse reduced from 47% to 29% with CBT, and CBT was
associated with higher remission rates. Bockting et al. (497)also compared treatment as usual (including medication)
to treatment as usual and CBT in a German outpatient
sample of 187 patients. Cognitive-behavioral therapy had“significant protective effect” that increased with number

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94
of prior episodes. For patients with five or more prior depressive episodes, CBT lowered relapse from 72% to46%. This study suggests that psychotherapy may have aprotective effect, especially for more severely ill patients.
b. Behavior therapy
Although numerous trials have examined the efficacy of
behavior therapy, relatively few have employed random
assignment and adequate control conditions. Two metaanalyses found behavior therapy superior to a waitinglist control condition (observed in seven of eight trials)(487, 1107). Results of individual clinical trials have suggested that behavior therapy may be superior in efficacy
to brief dynamic psychotherapy (1112, 1113) and generally comparable in efficacy to cognitive therapy (1114–
1117) or pharmacotherapy (283). One post hoc examination of clinical trial data found that response to behavior
therapy may be more likely in patients with less initial severity of major depressive disorder symptoms (1118),
but other studies have not found this relationship (1119–
1121).
More recently, “dismantling studies” comparing the full
CBT package to some of its elements suggest that behavioral activation, the behavioral component of CBT, may
be as efficacious or more efficacious than CBT as a whole,particularly for patients with greater depressive severity(310, 1122). Behavioral activation not only outperformed
CBT and placebo with respect to more severely depressed
patients, but it was as efficacious as medications regardlessof severity (310) and more enduring following treatment
termination (288). In addition, activity scheduling, a behavioral activation treatment in which patients learn how
to increase the number of pleasant activities and interactions with their environment, was found in a meta-analysis to be an effective treatment for depression (706).

2. Interpersonal therapy
Like CBT, IPT was developed to treat patients with major
depressive disorder and has demonstrated efficacy in aseries of randomized clinical trials (1123, 1124). In the
NIMH Treatment of Depression Collaborative Research
Program study, IPT had greater efficacy than pill placebo
plus clinical management and was comparable to imipramine plus clinical management for patients with more
severe major depressive disorder, whereas cognitive therapy was not superior to placebo. Among patients withmild depressive severity (defined as scores less than 20 on
the HAM-D or greater than 50 on the Global Assessmentof Functioning scale), IPT, CBT, and imipramine plus
clinical management did not differ from placebo plus clinical management (1108). The degree to which patient andtherapist can resolve the interpersonal crisis on which IPT

APA PRACTICE GUIDELINES
focuses (e.g., a role transition) appears to correlate withsymptomatic improvement (1125).
Other studies have found IPT effective in treating
pregnant and postpartum women with major depressive
disorder (743, 1126) and depressed patients in a developing country (351). A controlled trial of IPT has also demonstrated its effectiveness for depressed primary carepatients (1127). After 8 months, the proportions of patients treated with IPT, nortriptyline, or usual care whoachieved remission were 46%, 48%, and 18%, respectively.
In a study of depressed HIV-positive patients, greater improvements were observed after IPT or IPT plus imipramine than after supportive psychotherapy or CBT (316).
However, a large recent study found no benefit for IPT
over clinical management in depressed cardiac patients(807).
Many trials have been conducted comparing IPT, bothas monotherapy and augmentation, to various control
conditions and active comparators, both in acute phasetreatment and continuation and maintenance therapy.
Generally, IPT is superior to treatment as usual and is aneffective augmentation strategy for patients receiving
pharmacotherapy. A meta-analysis of 13 studies of IPT
conducted from 1974 to 2002 reported that, in nine of thestudies, IPT was superior to placebo (1123). In addition,
IPT was more efficacious than CBT. However, the combination of IPT and medications was not significantly
more effective than medication monotherapy for acute orprophylactic treatment.

3. Psychodynamic psychotherapy
Psychodynamic psychotherapy has been used widely inclinical practice for the treatment of patients with depressive symptoms and syndromes and is sometimes preferredby patients (361). However, its efficacy in major depressive disorder has not been adequately studied in controlled trials. Using the available evidence to determine
the efficacy of psychodynamic psychotherapy in the treatment of major depressive disorder is complicated by several
problems. In some early studies, variants of psychodynamic psychotherapy served as a nonspecific comparison
treatment to other psychotherapeutic interventions, but
the details of the psychodynamic psychotherapy employed
were poorly defined (1107). Subsequently, some clinical
trials of psychodynamic psychotherapy have reported
short- and long-term therapeutic benefits (as described inreferences 1128–1130), but few of these trials were randomized or assessed treatment fidelity; some included
concomitant pharmacotherapy, and most studied patientswith a multiplicity of symptoms and diagnoses, such as depressed patients who did not meet the DSM-IV criteria
for major depressive disorder. These limitations make it

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Editiondifficult to draw conclusions from meta-analyses that incorporate a variety of study populations and designs (286,1130, 1131). A recent meta-analysis (1132) acknowledgedthat the quality of available studies on psychodynamic
psychotherapy for treatment of depression was not optimal. In addition, use of low-quality studies in meta-analyses of psychotherapy may lead to overestimations ofeffect sizes (1133). With these caveats, some findings frommeta-analyses of short-term (1132) and long-term (1130)
psychodynamic psychotherapy suggest possible benefits
in individuals with depressive symptoms (1132) and suggest that long-term psychodynamic psychotherapy may
have beneficial effects in individuals with depressive andanxiety symptoms (1130). To confirm these results and extend them to individuals diagnosed with major depressive
disorder, further research with more rigorous study designs will be needed.

4. Marital therapy and family therapy
Reviews have concluded that marital therapy is effective
for treating depressive symptoms and reducing risk for relapse (1134, 1135). In a recent meta-analysis of eight marital therapy trials, marital therapy had comparable efficacy
to individual psychotherapy for the treatment of depression (1136). A lower dropout rate was found for marital
therapy than for medication therapy, although this result
was heavily influenced by a single study. Marital therapy
was superior in treating depressive symptoms, comparedwith minimal or no treatment. These findings were weakened by methodological problems affecting most studies,such as the small number of cases available for analysis inalmost all comparisons, and the significant heterogeneity
among studies.
Results from individual studies suggest that the efficacy
of marital therapy may depend on whether marital distressis present. In one study, a greater proportion of depressedsubjects with marital distress responded to marital therapy
than to cognitive therapy (88% vs. 71%), but among depressed subjects without marital distress, a greater proportion responded to cognitive therapy than to marital therapy(85% vs. 55%) (1137). In another study of depressed subjects with marital discord, marital therapy and CBT wereequally effective and both were more effective than a waiting-list condition (1138). A pilot randomized trial found“conjoint” (marital) IPT for depressed married womenequipotent to individual IPT in alleviating depression andsuperior in improving marital satisfaction (1139).
A randomized controlled trial of antidepressant drug
therapy in comparison to couple therapy for depressed outpatients found a lower dropout rate and greater improvement in subjective symptoms of depression, at no greater
cost, for the couple therapy group (342). Patients recruited95

during a psychiatric hospitalization for major depressive
disorder were randomly assigned to pharmacotherapy
alone; combined pharmacotherapy and cognitive therapy;
combined pharmacotherapy and family therapy; and combined pharmacotherapy, cognitive therapy, and family therapy. Patients who received treatment that included a family
therapy component were more likely to improve and hadsignificant reductions in interviewer-rated depression andsuicidal ideation, compared with those whose treatment did
not include family therapy (343).

5. Problem-solving therapy
Some studies have reported modest improvement in subjects with mild depressive symptoms treated with problem-solving therapy. For example, Dowrick et al. (1140)
treated 452 subjects with depressive or adjustment disorders, comparing groups that received eight sessions ofproblem-solving therapy to control groups given six sessions of group preventive education. At 6 months, the authors found a 2.6-point difference on the BDI favoring
problem-solving therapy (NNT=6). Treatment effects at
1 year did not differ. Problem-solving therapy may haveadvantages over usual care for home-bound geriatric patients with depressive symptoms (1141). Unfortunately,usual care often means little care.
Alexopoulos et al. (335) reported that 12 sessions ofproblem-solving therapy were superior to supportive
psychotherapy for depressed geriatric patients with major
depressive disorder and executive dysfunction. Anotherstudy showed problem-solving therapy to have greater
benefit than usual care in preventing depression (1142).

6. Group therapy
A mostly European body of research suggests that the individual psychotherapies validated in treating depression
also work in group format. Most of these studies havesought to demonstrate efficacy rather than exploring thetechnical aspects of group therapy.
Group cognitive therapy has shown benefits in the acutetreatment of major depressive disorder. For example, Ayenand Hautzinger (347) randomly assigned 51 depressed,
menopausal women for 3 months of weekly, 2-hour sessions of cognitive group therapy, of group supportive psychotherapy, or a waiting list. Both active treatments were
well tolerated and relieved depressive and menopausal
symptoms better than the control condition. At 1-year follow-up, group CBT was more beneficial than group supportive therapy. In contrast, group CBT was ineffective intreating dysthymic disorder. Ravindran et al. (293) found
sertraline superior to placebo but 12 weeks of group CBT
no better than placebo and ineffective in augmenting sertraline in treatment of patients with dysthymia.

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96
McDermut et al. (1143) conducted a meta-analysis of
48 research reports assessing the efficacy of group therapy
for the treatment of depression in individuals with various
types of depressive disorders (depressive spectrum disorders). Analyses suggested that participants in treatment
showed significant clinical improvement.
Forms of group CBT have also shown promise in lowering relapse risk. Bockting et al. (497) reported that for the
41% of 187 patients with remission who had a history of atleast five episodes of recurrent major depressive disorder,
augmenting usual treatment with brief group CBT lowered relapse rates from 72% to 46% over a 2-year period.
Teasdale et al. (498) found that group mindfulnessbased cognitive therapy as an augmentation strategy was
beneficial relative to treatment as usual in reducing relapse rates over 60 weeks for 145 patients with recurrent
depression who reported at least three prior major depressive episodes.
Interpersonal psychotherapy has also been adapted to agroup format (1144). Although IPT is less well studied
than CBT, small trials of group IPT suggest its benefits asboth a preventive intervention (350) and a treatment for
postpartum depression (349). A group combining interpersonal and cognitive elements improved outcome relative to fluoxetine alone among patients with dysthymia
who responded to fluoxetine (1145).

C. PSYCHOTHERAPY COMBINEDWITH PHARMACOTHERAPY
Although many psychiatrists prefer to use a combination of
psychotherapy and pharmacotherapy to treat patients withdepression, controlled studies conducted in the 1970s and1980s did not consistently find a significant advantage forroutinely combining therapies, compared with one or theother treatments provided alone (1146). Part of the problem in establishing the additive value of psychotherapy andpharmacotherapy in these early studies was methodological: the specific effects of each modality (i.e., over and above
the so-called nonspecific effects of therapeutic support andplacebo-expectancy factors) are relatively modest, andnone of the early studies of combined therapy had the statistical power to reliably detect such small effects. Consistent with this appraisal, a meta-analysis of these earlystudies found an average effect size of about 0.3 (1147),
which is both a clinically significant effect and an advantagethat would usually not be found to be statistically significant in a study of 100 or fewer patients. A meta-analysis ofindividual patient data performed by Thase et al. (359),
which compared remission rates of nearly 600 patientstreated in studies of CBT, IPT, and IPT in combination

APA PRACTICE GUIDELINES
with either imipramine or nortriptyline, confirmed a modest overall advantage for combined treatment versus CBTor IPT alone but found a differential impact linked to severity and history of recurrent depressive episodes. Specifically, whereas combined treatment had a small advantage
over psychotherapy alone among patients with less severe
depression, there was a fourfold difference in remission
rates among the subset of patients with more severe, recurrent depressive episodes.
The advantage of combined treatment over pharmacotherapy alone in more severe depression was evident in awell-controlled inpatient study of Schramm et al. (285).
Conducted in Germany, this 5-week trial included 124 hospitalized patients with major depressive disorder; results
showed a 70% response rate to IPT plus pharmacotherapy,
compared with a 51% response rate to pharmacotherapy
alone. In a Swiss study in which 74 outpatients were randomly assigned to receive 10 weeks of clomipramine plus
psychodynamic therapy or clomipramine alone, the combination treatment produced greater improvements in global
functioning, greater cost savings, lower rates of hospitalization, and fewer lost work days (1148).
Keller et al. (362) examined the outcomes of more than
600 patients with chronic depression who were randomly
assigned to treatment with the antidepressant nefazodone
or a form of CBT (cognitive behavioral analysis system of
psychotherapy [CBASP]) singly or in combination. The
authors found a large additive advantage for the two treatments in combination. Specifically, response rates for combined treatment were approximately 20% higher at theend of 12 weeks of treatment, compared with the monotherapies, which were comparably effective. It is noteworthy
that patients receiving combined treatment experienced theearlier benefit that characterized the pharmacotherapy aswell as the later emerging benefit that characterized thepsychotherapy (362). A post hoc analysis of these results
revealed that the advantage of the combined approach was
explained by a broader spectrum of efficacy: pharmacotherapy alone was significantly less effective than CBASP
among the subset of patients with a history of childhood
trauma, whereas the opposite trend was evident among
the patients treated with psychotherapy alone (1149). Patients with chronic depression were thus more likely tobenefit from combined treatment whether or not they had
a history of early adversity.
In the STAR*D study, patients with depression who did
not have remission following an initial 12-week course ofcitalopram therapy were offered the opportunity to add
or change to Beck’s model of cognitive therapy in addition
to the various pharmacotherapy options being studied.
Among those who opted to add a therapeutic adjunct toongoing citalopram, about one-third consented to be ran-

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
domly assigned to strata that included both cognitive therapy and medications (buspirone or bupropion). Results at
the end of 12 weeks of therapy indicated that cognitive therapy was as effective as medication augmentation, althoughpatients opting for combined pharmacotherapy responded
faster (369).
One historic limitation of the literature on combined
treatment of depression has been that a vast majority ofstudies have concerned cognitive therapy and IPT, andthere has been a dearth of studies on the more widely practiced forms of psychodynamic psychotherapy. An informative series of studies by one group of investigators in the
Netherlands has helped to partly address this issue. The
first trial compared outcomes of 167 outpatients with depression across 6 months of treatment with either algorithm-guided antidepressant pharmacotherapy alone or
pharmacotherapy combined with a manual-based form oftime-limited dynamic psychotherapy (1150). Significant
differences favored combined treatment with respect toretention in treatment and the likelihood of remission. A
secondary analysis determined that the advantage of combined treatment was largely explained by the large difference among patients with co-occurring Axis II disorders(1151). In a second study of 191 depressed outpatients,
time-limited dynamic therapy alone was compared against
psychotherapy in combination with algorithm-guided
pharmacotherapy (1152). In this trial, there were significant differences favoring combined therapy on patientrated outcomes, although the numeric difference between
groups on remission rates was not statistically significant.
The investigators next conducted a pooled analysis of thedata from these two trials, also including a third smaller
study that did not include a combined therapy arm (361).
The analysis included data for more than 300 depressed
outpatients and confirmed the advantage of combined
treatment over the monotherapies across studies on mostoutcome variables.
Two meta-analyses of study results have confirmed theadvantage of combining pharmacotherapy and various
forms of time-limited psychotherapies (360, 1153). The latter report confirmed that the advantage was larger amongstudies of patients with more severe symptoms and among
those with more chronic depressive disorders (1153).

D. LACK OF RESPONSE TO PHARMACOTHERAPYIN THE ACUTE PHASE
1. Maximizing initial treatments
Several studies have shown improved efficacy with higher
doses of medication, supporting the strategy of increasing
the medication dose for patients who do not respond to an

97

initial trial of a medication. As an example, Bech et al. (1154)
conducted a randomized controlled trial in which patients
meeting the criteria for major depressive disorder wererandomly assigned to receive placebo or citalopram in dosesof 10 mg/day (N=129), 20 mg/day (N=130), 40 mg/day(N=130), or 60 mg/day (N=129). Treatment continued
for 6 weeks, and depressive symptoms were measured by
21-item Hamilton Rating Scale for Depression, MADRS,Clinical Global Impression, and 56-item Symptom Checklist. The percentages of patients lost to follow-up were
9% for placebo, 7% for citalopram at 10 mg/day, 2% forcitalopram at 20 mg/day, 2% for citalopram at 40 mg/day,and 3% for citalopram at 60 mg/day (nonsignificant p values). The 10- and 20-mg doses were more efficacious thanplacebo, but they were inferior to the 40- and 60-mg doses(p<0.05). The 20-, 40-, and 60-mg doses had significantly
more side effects than placebo, measured by dropout rates
due to side effects (p<0.05).

2. Changing to other treatments
The recently completed STAR*D trial examined various
strategies for patients with treatment-resistant depression.
STAR*D was a multisite, multistep, prospective randomized controlled trial comparing treatments and treatment
strategies in outpatients with major depressive disorder(48). The study provided data on treatment effectiveness,or “real world” outcomes in typical patients, making theresults generalizable to standard practice. The study wasorganized into four levels. In level 1, 2,876 outpatients
received citalopram for up to 14 weeks. In level 2, nonresponders (N=1,493) were offered three alternatives, whichwere selected based on patient choice: change to anothermedication (N=727), augment citalopram with anothermedication (N=565), or start psychotherapy (N=147). If
the patient changed to another medication, he or she was
randomly assigned to receive sertraline, bupropion SR, orvenlafaxine XR. Patients who chose medication augmentation were randomly assigned to augment citalopram
with bupropion SR or buspirone. Patients who agreed tostart psychotherapy were randomly assigned to change tocognitive therapy (discontinuing citalopram) or to augment with cognitive therapy (continuing citalopram). For
patients who did not respond to level 2, level 3 offered twoalternatives: changing or augmenting with another medication. Patients in the change group were randomly assigned to receive mirtazapine (N=114) or nortriptyline(N=121) for up to 14 weeks. Patients in the augmentationgroup were randomly assigned to receive lithium (N=69)
or triiodothyronine (N=73) for up to 14 weeks. Finally,level 4 randomly assigned nonresponders from level 3
to receive tranylcypromine (N=58) or the combination of

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98
venlafaxine XR and mirtazapine (N=51). STAR*D therefore
provides data for several randomized controlled trials ofchange or augmentation of medications at various stages.
Two such studies based on STAR*D data provide evidence
for continued efficacy of medication augmentation (429)
and medication change (471) for treatment-resistant depression. Remission rates were equivalent and approximately 25% upon changing from citalopram to either an
SSRI or SNRI or bupropion at the second step; there wasno difference in remission between changing to either
mirtazapine or nortriptyline at the third step.
A number of previous studies evaluated changing froman SSRI to another SSRI, changing from an SSRI to an
SNRI, and changing from an SSRI to bupropion or mirtazapine. These previous studies were either small in sizeor, in the vast majority of instances, were neither randomized nor blinded. A few trials have been conducted inwhich patients who did not respond to an initial antidepressant medication were changed to a non-MAOI antidepressant medication from the same pharmacological class(e.g., from one TCA to another) or to one from a different
pharmacological class (e.g., from a TCA to an SSRI). Although results from these trials have been variable, up to
50% of patients have been found to respond (i.e., have symptom improvement of at least 50%) to a second non-MAOI
antidepressant medication trial—even when the second antidepressant was from the same class as the first (421). Data
regarding the types of treatment-resistant patients who aremost likely to benefit from particular changes in medication are limited.

3. Augmenting and combining treatments
Traditionally, augmentation agents with the most evidence for efficacy have included lithium and thyroid hormone for partial responders to traditional antidepressant
medications (1155). Recent studies have significantly advanced the literature now with the two augmentation randomized controlled trials in STAR*D (429, 446) and theuse of adjunctive aripiprazole (453, 1156). In the mostrecent large-scale trial—a component of the STAR*D
study—lithium augmentation of citalopram was neither
particularly well tolerated nor more effective than thyroid
augmentation (446).
The second-step augmentation trial in the STAR*D
study evaluated the comparative efficacy of add-on sustained-release bupropion and add-on buspirone in patients who had not achieved adequate remission status
following an initial trial with citalopram. Both agents as
adjuncts were associated with remission rates of around
30% on primary outcome measures. Patients who did nothave remission with up to 12 weeks of citalopram therapy were as likely to benefit from adjunctive buspirone

APA PRACTICE GUIDELINES(15–60 mg/day) as they were to benefit from adjunctive
bupropion (150–400 mg/day) (429). However, adjunctive
treatment with bupropion SR was superior to adjunctive
buspirone on a number of key secondary measures (224).
The findings of 16 placebo-controlled, randomized
clinical trials of second-generation antipsychotic augmentation therapy for patients with major depression disorder(N=3,480) have recently been evaluated in a meta-analysis(448). Augmentation with a second-generation antipsychotic agent was significantly more effective than placebo
in terms of rates of response and remission. Although aripiprazole has received FDA approval as an adjunct to second-step antidepressant medications for patients who had
not achieved satisfactory response to at least two prior antidepressant medication trials, this meta-analysis showed
no differences in response or remission rates among the individual medications (448). Discontinuation rates for adverse effects were also higher in the active augmentationgroups compared with placebo, suggesting that such effects
need to be taken into consideration when choosing to augment antidepressant response with a second-generation antipsychotic agent. To date, few data from controlled studies
address the longer term efficacy or side effects of combining antidepressants and antipsychotics.
Combining an SSRI and a TCA induced a rapid antidepressant response in one preliminary study (1157). In asecond study, patients taking this combination also had agreater likelihood of remission, compared with patients
receiving monotherapy with an SSRI or a TCA (1158).
The efficacy of combining mirtazapine and an SSRI wasdemonstrated in one placebo-controlled study (432). Mirtazapine and venlafaxine led to a 13.7% remission rate inpatients who had not responded to three prior medication
trials as part of the STAR*D study (121). Case reports suggest that stimulant medications may be effective adjuncts
to antidepressant medication therapy (205), although the results of larger scale clinical trials have not demonstrated
efficacy (462, 463).

E. CONTINUATION TREATMENT
Although randomized controlled trials of antidepressant
medications in the continuation phase are limited, theavailable data indicate that patients treated for a first episode of uncomplicated major depressive disorder who
exhibit a satisfactory response to an antidepressant medication should continue to receive a full therapeutic dose ofthat agent for at least 16–20 weeks after achieving and maintaining full remission (105, 225, 495).
Two clinical trials have examined the effects of continuation treatment following an acute course of ECT. In arandomized double-blind trial that included 84 individu-

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
als with major depressive disorder whose symptoms had
remitted with ECT, the combination of nortriptyline (target steady-state level, 75–125 ng/mL) plus lithium (target
steady-state level, 0.5–0.9 mEq/L) was associated withlower relapse rates over the 24-week trial (39%) than either nortriptyline alone (60%) or placebo (84%) (489). A
subsequent trial found that continuation pharmacotherapy with lithium plus nortriptyline (N=94) was comparable
in efficacy to continuation ECT (N=89) in maintaining
remission (46.3% versus 46.1%) after a successful acutecourse of ECT (234). The group receiving medication reported a greater number of treatment-emergent side effects than the ECT group, but there were no differencesin cognitive impairment reported between the treatmentgroups.
A few studies have examined treatment with psychotherapeutic interventions administered in the continuation phase. One study found that among patients who
responded to acute treatment with cognitive therapy, those
who continued this treatment over 2 years had lower relapse rates than those who did not have continuation
treatment (493). Results from a series of studies (365, 367,494) suggest that CBT may be an effective continuation
treatment following antidepressant medication therapy
for preventing relapse (364).
In a randomized controlled trial of cognitive grouptherapy as an adjunct to treatment as usual, Bockting et al.
(497) studied 187 patients with recurrent major depressive
disorder who were currently in remission. Cognitive grouptherapy was found to be effective in preventing relapse/
recurrence, and this protective effect increased in concert
with the number of previous depressive episodes.
Hollon et al. (68) assessed 104 patients with major depressive disorder who had responded to cognitive therapy,
pharmacotherapy, or placebo and had remained improved
during a 12-month continuation phase. Patients were withdrawn from treatment and followed for an additional 12months. Cognitive therapy patients, who were allowed no
more than three booster sessions over that year, had a lower
rate of relapse (31%) than those withdrawn from medication (76%). They also exhibited no greater likelihood ofdepressive relapse than patients who continued pharmacotherapy (47%), suggesting possible lasting benefits ofcognitive therapy.

F. MAINTENANCE TREATMENT
The multicenter Prevention of Recurrent Episodes ofDepression With Venlafaxine for Two Years (PREVENT)
study was designed to evaluate patients with recurrent
unipolar major depressive disorder randomly assigned toreceive venlafaxine XR or fluoxetine. At the end of a 10-99

week acute phase treatment, response rates were 79% forboth venlafaxine XR and fluoxetine, with remission rates
being 49% and 50%, respectively. In the 6-month continuation phase, response rates were 90% (venlafaxine XR)
and 92% (fluoxetine), with rates of sustained remission of
52% and 58%, respectively. The cumulative probability ofrecurrence through the first 12 months of the maintenancephase treatment was 23.1% for venlafaxine and 42% forplacebo. The cumulative probability of recurrence throughthe second 12 months of maintenance treatment was 8%
in the venlafaxine XR group and 44.8% in the placebo group(226, 1159).
There have been fewer investigations of the effectivenessof psychotherapy in the maintenance phase. In one study,
maintenance cognitive therapy delivered over 2 years was aseffective as maintenance medication for recurrent major
depressive disorder (514). Other reports indicate that IPT
may effectively lengthen the interepisode interval forpatients with recurrent depression who do not receive
medication (289, 314, 513, 1056). Maintenance CBT as
augmentation to medication prevented relapse relative to
medication plus treatment as usual (368, 497, 1160).
Monthly maintenance psychotherapy with CBASP was
more effective over a 1-year period than an assessmentonly control condition for patients with chronic depression who had responded to acute treatment and remained
improved in continuation therapy with CBASP (1161). A
6-year follow-up of patients treated with medication andcontinuation CBT found weakening but continuing ongoing benefits lasting as long as 3.5 years after completing
CBT (1162). Research on cognitive therapy has exploredthe concept of an enduring benefit by acquiring persistentskills that reduce the risk of depressive relapse after treatment has ended (68, 1110).
The combined use of psychotherapy, such as CBT,
cognitive therapy, or IPT, and pharmacotherapy in themaintenance phase has also been considered by investigators. Some results suggest that the combination of antidepressant medications plus psychotherapy may be
additionally effective in preventing relapse over treatment
with single modalities (314, 365, 506, 515, 516). However,in individuals older than age 70 years who received maintenance treatment with paroxetine and clinical management, interpersonal therapy and placebo, paroxetine andinterpersonal therapy, or placebo and clinical management, the combination of paroxetine and interpersonal
therapy offered no benefits over paroxetine and clinicalmanagement and each were superior to the other treatment conditions (729).
Electroconvulsive therapy has also been used in themaintenance phase. Evidence for its benefits comeslargely from case reports and case series (1163–1168), al-

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10 0though a retrospective case-control study (1169) and arandomized prospective trial in older adults (730) demonstrated longer times to recurrence with use of maintenance
ECT. The optimal frequency, duration, and method of

APA PRACTICE GUIDELINES
discontinuing maintenance ECT treatment have not beensystematically studied, but typically ECT is tapered gradually with a return to more frequent treatments if depressive symptoms emerge (501).

Part C
FUTURE RESEARCH NEEDS
Notable progress has been made in our understanding ofmajor depressive disorder and its treatment. However,there are still many unanswered questions about optimizing and individualizing treatment. The following areas require additional study.
To “personalize” care, and someday even prevent depression, we must understand factors that cause it. In thenearer term, science can focus on predictors of benefit andadverse effects of specific treatments. Potential causes ofdepression or moderators of treatment response may befound through genomics, proteomics, physiological markers, personality traits, personal experiences, co-occurring
conditions, or clusters of specific depressive symptoms.
Culture, race, and ethnicity merit study in shaping treatment selection and predicting response and side effects.
Even if science were to offer perfect and personalized
treatments for depression, patients must be able to gain
access to care and adhere to recommended interventions.
Thus, research must develop better ways to deliver treatment, optimizing effectiveness as well as efficacy. Research should also consider the cost-effectiveness of careand effects of treatment on functioning and quality of life.
As the U.S. population ages and co-occurring illnesses
become more common, studies are needed on ways to integrate care for depression with treatment for other psychiatric and medical problems. Most studies of major
depressive disorder have examined the acute phase of treatment. More research is required on the continuation andmaintenance phases. Questions abound on the persistenceof biological and psychosocial treatment effects, whentreatment may safely be discontinued, how recurrent depression differs from chronic varieties in the long term, andmore.
The science of psychotherapy research continues to
evolve. We need to understand how specific types of therapy compare to one another in the treatment of major depressive disorder and how to select a treatment for anindividual. Research must disentangle nonspecific factors

from the unique features of a theoretically derived approach. It would be important to determine the components of specific psychotherapies that are responsible for
efficacy, the patient-specific factors that moderate the efficacy of these therapies, the indications for using a particular psychotherapy, and the optimal duration andfrequency of psychotherapy for particular patient subgroups, types of psychotherapy, or phases of depression
treatment. Outcome measures of psychotherapy studies
should not only examine acute symptom response but also
whether psychotherapies have enduring, protective effects in averting relapse and recurrence of depression after
treatment has ended. A manual-based model of psychodynamic therapy for depression (1170) may be helpful inthe development of evidence concerning this approach.
Strategies for sequencing psychotherapy in the overall
treatment of major depressive disorder and for combining
psychotherapy (either with pharmacotherapy or anotherpsychotherapy) merit further study.
Much work remains to be done on medication intervention in depression. We should address the comparative
efficacies, relative short- and long-term side effect profiles,
and specific clinical indications of different antidepressant
medications, augmentation strategies (e.g., second-generation antipsychotic medications, lithium, thyroid hormone) and combination treatment approaches (e.g., SSRIs
and other moieties). This would include determining if
particular treatments or combinations of treatments havedifferential efficacy in specific subgroups of patients withdepression (e.g., patients with psychotic depression) and,for medications other than the TCAs, whether relationships exist between medication blood levels and therapeutic responses or side effects. Initial studies of monotherapy with second-generation antipsychotic agents appear
promising, but additional study of the acute and long-term
benefits and side effects is essential. The definition and implications of treatment-resistance for treatment selection
also requires further clarification.

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Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
Electroconvulsive therapy remains the treatment of best
established efficacy against which other stimulation treatments (e.g., VNS, deep brain stimulation, TMS, otherelectromagnetic stimulation therapies) should be compared. Approaches to reducing cognitive side effects of
ECT, speeding response to ECT, or determining the indications and best methods for maintenance ECT could improve patient care. More research is also needed on the
optimal approaches (e.g., treatment schedule, stimulation
parameters) for delivering newer stimulation therapies. Additional research on light therapy would be helpful, including determining its effectiveness as adjunctive treatment in
nonseasonal major depressive disorder or as a primary
treatment for seasonal major depressive disorder in the101

maintenance phase. Given patients’ frequent use of complementary therapies, additional research on these therapies, including acupuncture, is warranted. Further study of
exercise in acute and maintenance treatment of depression
would also be useful, including assessment of the benefits ofexercise in minimizing side effects of the other therapies
and in optimizing health, functioning, and quality of life.
In time, brain imaging, genomics, proteomics, andother recent advances in neuroscience should help us“carve nature along its joints,” allowing major depressive
disorder to be broken into discrete diseases with definedand personalized treatments. In the meantime, clinical investigation focused on existing and novel treatment strategies remains essential.

Appendix
EDUCATIONAL RESOURCES FOR PATIENTS AND FAMILIESAcademy of Cognitive Therapy
http://www.academyofct.org
California Teratogen Information Service and Clinical Research
Tel: 1–800–532–3749 (CA only)
Tel: (610) 543–2131
http://www.otispregnancy.org
ConsumerLab.com
Tests herbal and vitamin products for purity and posts theresults on the Web
http://www.consumerlab.com
Depression After Delivery, Inc.
91 East Somerset Street
Raritan, NJ 08869
Tel: (800) 944–4773
http://www.depressionafterdelivery.com
Depression and Bipolar Support Alliance
730 Franklin Street
Suite 501
Chicago, IL 60610–7224
Tel: (312) 642–0049
Tel: (800) 826–3632
http://www.ndmda.org

Healthy Minds, Healthy Lives
American Psychiatric Association
http://www.healthyminds.org
International Foundation for Research and Education on Depression
2017-D Renard Court
Annapolis, MD 21401
Tel: (410) 268–0044
http://www.ifred.org
International Society of Interpersonal Psychotherapy
http://www.interpersonalpsychotherapy.org
KidsHealth.org
http://www.kidshealth.org
Massachusetts General Hospital Women’s Mental
Health Program
http://www.womensmentalhealth.com
Mental Health America
2000 N. Beauregard Street
6th Floor
Alexandria, VA 22311
Tel: (703) 684–7722
Tel: (800) 969–6MHA (6642)
TTY Line: (800) 433–5959
http://www.nmha.org

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be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

10 2
MentalHelp.net
http://www.mhnet.org
Motherisk.com
Database maintained by the Toronto Hospital for Sick
Children
http://www.motherisk.com
NARSAD
60 Cutter Mill Road
Suite 404
Great Neck, NY 11021
Tel: (516) 829–0091
http://www.narsad.org
National Alliance on Mental Illness
Colonial Place Three
2107 Wilson Blvd., Suite 300
Arlington, VA 22201
Tel: (703) 524–7600
Help Line: (800) 950-NAMI [6264]
http://www.nami.org
National Center for Complementary andAlternative Medicine
National Institutes of Health9000 Rockville Pike
Bethesda, MD 20892
http://nccam.nih.gov/
National Institute of Mental Health
Depression Information Program
6001 Executive Boulevard

APA PRACTICE GUIDELINES
Room 8184, MSC 9663
Bethesda, MD 20892–9663
Tel: (301) 443–4513
TTY Line: (301) 443–8431
http://www.nimh.nih.gov/health/topics/depression/index.shtml
National Institute of Mental Health
Mental Health Topics
http://www.nimh.nih.gov/health/topics/index.shtml
National Institute of Mental HealthPublic Information and Communications Branch
6001 Executive Boulevard
Room 8184, MSC 9663
Bethesda, MD 20892
Tel: (866) 615–6464
http://www.nimh.nih.gov/publicat/index.cfm
National Library of Medicine
U.S. government online repository of articles publishedin peer-reviewed medical journals
http://www.ncbi.nlm.nih.gov/
entrez/query.fcgi?db=PubMed
Postpartum Support International
http://postpartum.net
Substance Abuse and Mental Health Services
Administration’s National Mental Health
Information Center
http://mentalhealth.samhsa.gov/

INDIVIDUALS AND ORGANIZATIONS THAT SUBMITTEDCOMMENTS
M.T. Abou-Saleh, M.B.Ch.B., M.Phil., Ph.D.,
F.R.C.Psych.
Jonathan E. Alpert, M.D., Ph.D.
Robert J. Barth, Ph.D.
Carl C. Bell, M.D.
Franco Benazzi, M.D., Ph.D.
Joseph Berger, M.D.
Dan G. Blazer, M.D., Ph.D.
David W. Brook, M.D.
Joseph R. Calabrese, M.D.
Anita H. Clayton, M.D.
C. Edward Coffey, M.D.
Mirean Coleman, M.S.W., L.I.C.S.W., C.T.
C. Deborah Cross, M.D.

Mark A. Demitrack, M.D.
Wayne H. Denton, M.D., Ph.D.
P. Murali Doraiswamy, M.D.
Javier I. Escobar, M.D., M.S.
Giovanni Andrea Fava, M.D.
Max Fink, M.D.
Tony Fowke, A.M.
Andrew J. Francis, M.D., Ph.D.
Glen O. Gabbard, M.D.
Gary G. Gintner, Ph.D.
Leslie Hartley Gise, M.D.
Michael J. Gitlin, M.D.
Predrag Gligorovic, M.D.
Jack M. Gorman, M.D.

Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
Ellen Grabowitz, M.D.
Michael F. Grunebaum, M.D.
John G. Gunderson, M.D.
Ana Maria B. Gutierrez, M.D.
Steven D. Hollon, Ph.D.
Joseph J. Horak, Ph.D.
Douglas G. Jacobs, M.D.
Bradley R. Johnson, M.D.
Lewis L. Judd, M.D.
Gabor I. Keitner, M.D.
James H. Kocsis, M.D.
Lorrin M. Koran, M.D.
Milton Kramer, M.D.
Arthur Lazarus, M.D., M.B.A.
Ellen MacKenzie, M.D.
Lauren Marangell, M.D.
Kathleen Ries Merikangas, Ph.D.
Helen Millar, M.D.
Stuart A. Montgomery, M.D.
Anthony T. Ng, M.D.
Mary Olinger, M.D.
Maria Oquendo, M.D.
George I. Papkostas, M.D.
Jagoda Pasic, M.D., Ph.D.
Michael Posternak, M.D.
Lawrence H. Price, M.D.
Mark Hyman Rapaport, M.D.
Steven P. Roose, M.D.
Anthony J. Rothschild, M.D.
Peter Roy-Byrne, M.D.
John P.D. Shemo, M.D., D.F.A.P.A.

103

David A. Solomon, M.D.
Robert Stern, M.D., Ph.D.
Joel E. Streim, M.D.
Shona Sturgeon, M.Soc.Sc.
Richard P. Swinson, M.D., F.R.C.P.C., F.R.C.Psych.
Michael J. Telch, Ph.D.
John Chapman Urbaitis, M.D.
Eduard Vieta, M.D., Ph.D.
Karen Dineen Wagner, M.D., Ph.D.
Risa B. Weisberg, Ph.D.
Myrna M. Weissman, Ph.D.
Kimberly A. Yonkers, M.D.
Mark Zimmerman, M.D.
American Academy of Neurology
American Academy of Psychoanalysis and Dynamic
Psychiatry
American Association for Marriage and Family Therapy
American Association of Emergency Psychiatry
American Geriatrics Society
American Group Psychotherapy Association
American Mental Health Counselors Association
American Neuropsychiatric Association
Association for Behavior and Cognitive Therapy
Association of Family Psychiatrists
Canadian Psychiatric Association
Community Mental Health Council, Inc.
National Association of Social Workers
Society for Adolescent Medicine
World Federation for Mental Health

ACKNOWLEDGMENT
Massimiliano Beghi, M.D., assisted with the evidence review for this guideline.

REFERENCES
The following coding system is used to indicate the nature of the supporting evidence in the references:[A]

Randomized double-blind clinical trial. A study of an intervention in which subjects are prospectively followed over time, there are treatment and control groups, subjects are randomly assigned to the twogroups, both the subjects and the investigators are blind to the assignments.

[A−] Randomized clinical trial. Same as above but not double-blind.
[B]

Clinical trial. A prospective study in which an intervention is made and the results of that intervention are
tracked longitudinally; study does not meet standards for a randomized clinical trial.

Copyright 2010, American Psychiatric Association. APA makes this practice guideline freely available to promote its dissemination and use; however, copyright protections are enforced in full. No part of this guideline may
be reproduced except as permitted under Sections 107 and 108 of U.S. Copyright Act. For permission for reuse, visit APPI Permissions & Licensing Center at http://www.appi.org/CustomerService/Pages/Permissions.aspx.

10 4

APA PRACTICE GUIDELINES[C]

Cohort or longitudinal study. A study in which subjects are prospectively followed over time without any specific intervention.

[D] Case-control study. A study in which a group of patients and a group of control subjects are identified in thepresent and information about them is pursued retrospectively or backward in time.
[E]

Review with secondary data analysis. A structured analytic review of existing data, e.g., a meta-analysis or adecision analysis.

[F]

Review. A qualitative review and discussion of previously published literature without a quantitative synthesis of the data.

[G] Other. Textbooks, expert opinion, case reports, and other reports not included above.
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