The Biology of Mental Disorders

September 1992

OTA-BA-538

NTIS order #PB92-228477

GPO stock #052-003-01299-5
Recommended Citation:

U.S. Congress, Office of Technology Assessment, The Biology of Mental Disorders,

OTA-BA-538 (Washington, DC: U.S. Government Printing Office, September 1992).

For sale by the U.S. Government Printing Office

Superintendent of Documents, MaiI Stop, SSOP, Washington, DC 20402-932X”

ISBN 0-16 -038047-2

ii
In Appreciation

SILVIO O. CONTE

The Office of Technology Assessment dedicates this report to the memory of the late Congressman

Silvio O. Conte, in recognition of his enthusiastic support for research into the brain and mental

disorders. Congressman Conte demonstrated that support in many ways, including his request for

this study. His leadership in this area significantly contributed to the gains, already made and yet

to come, in understanding and treating mental disorders.

. . .

Ill
Foreword

The 1990s bear witness to two opposing realities of mental illness. One is the pressing

and even tragic nature of mental disorders: serious mental disorders, including schizophrenia

and major mood and anxiety disorders, afflict millions of Americans, producing long-lasting

and disabling symptoms. The other reality is improved technologies and advances in brain

research that provide hope for alleviating the substantial burden of mental disorders—to

individuals with these conditions, their families, and society at large-and the continuing

research and development that promises future gains.

Recognizing both the public health problem posed by mental disorders and the recent

gains and future promise of brain research, several congressional committees requested or

endorsed this report, which is the fourth in a series of OTA studies on ‘‘New Developments

in Neuroscience. ’ The House Committees on Appropriations; Energy and Commerce;

Science, Space, and Technology; Veteran Affairs; and the Senate Subcommittee on Science,

Technology, and Space of the Committee on Commerce, Science, and Transportation

requested this study. The study was endorsed by Senator Edward M. Kennedy, Chairman of

the Senate Committee on Labor and Human Resources.

The Biology of Mental Disorders presents a summary of research into the biological

factors associated with schizophrenia, bipolar disorder, major depression, obsessivecompulsive disorder, and panic disorder. The report also discusses support for this research

and the social context in which it moves forward. OTA concludes that, indeed, there have been

important advances in understanding the biology of these disorders, and that rich opportunities

for further research exist. While we know that these mental disorders cannot be understood

in biological terms alone-psychological and social factors are important for a complete

picture of mental disorders and their treatment-we conclude that further biological research

will significantly improve our understanding and treatment of these conditions. Mindful of the

advances and continued opportunities in research, the report provides policy options for action

by the U.S. Congress in three areas: support for research, implications of research findings,

and the dissemination of new information.

OTA prepared this report with the assistance of a panel of advisers and reviewers selected

for their expertise and diverse points of view. Additionally, dozens of individuals from

academia, professional and advocacy groups, and Federal agencies cooperated with OTA staff

through interviews or by providing written material. OTA gratefully acknowledges the

contribution of each of these individuals. As with all OTA reports, however, the responsibility

for the contents of this report is OTA’s alone.

8(?&# L’&A--

JOHN H. GIBBONS

~ Director

1 US. Congress, Office of Technology Assessment, Neurotoxicity: Identifying and Controlling Poisons of the Nervous

System, OTA-BA-436 (Washington DC: U.S. Government Printing OffIce, April 1990); U.S. Congress, Office of ‘Ikchnology

Assessment, Neural Grafling: Repairing the Brain and Spinal Cord, OTA-BA462 (Washingto~ DC: U.S. Government Printing

Office, September 1990); U.S. Congress, Office of Technology Assessment, Biological Rhythms.’ Implications for the Worker,

OTA-BA-463 (Washington DC: U.S. Government Printing Office, September 1991).
New Developments in Neuroscience Advisory Panel

Peter S. Spencer, Chair

Center for Research on Occupational and Environmental Toxicology

Oregon Health Sciences University

Robert H. Blank

University of Canterbury

Christchurch, New Zealand

James F. Childress

Department of Religious Studies

University of Virginia

Charlottesville, VA

Fred H. Gage

Department of Neuroscience

University of California, San Diego

La Jolla, CA

Bernice Grafstein

Department of Physiology

Cornell University, School of

Medicine

New York, NY

Portland, OR

Ronald Kartzinel

Elan Pharmaceutical Research Corp.

Gainesville, GA

Alan Kraut

American Psychological Society

Washington, DC

Franklin E. Mirer

Health and Safety Department

United Auto Workers

Detroit, MI

Albert S. Moraczewski

Pope John XXIII Medical, Moral

Research, and Education Center

Houston, TX

Herbert Paroles

College of Physicians and

Surgeons

Columbia University

New York, NY

Richard M. Restak

Neurological Associates

Washington, DC

The Biology of Mental Disorders Study Panel

Michael S. Gazzaniga

Dartmouth Medical School

Hanover, NH

James T. Havel

Mental Health Policy Resource

Center, Inc.

Washington, DC

David J. Kupfer

Western Psychiatric Institute

and Clinic

Pittsburgh, PA

Ellen McGrath

The Psychology Center

Laguna Beach, CA

Neil J. Risch

Yale University

School of Medicine

New Haven, CT

Sara-Ann Steber

University of Pennsylvania

Philadelphia, PA

Alan A. Stone

Harvard Law School

Cambridge, MA

David B. Wexler

University of Arizona

Tuscon, AZ

David Taiwai Wong

Eli Lilly and Co.

Indianapolis, IN

NOTE: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the advisory panel members.

The panel does not, however, necessarily approve, disapprove, or endorse this report. OTA assumes fi.dl responsibility for the

report and the accuracy of its contents.

vi
OTA Project Staff—The Biology of Mental Disorders

Roger C. Herdman, Assistant Director, OTA

Health and L&e Sciences Division

Michael Gough, Biological Applications Program Manager

David R. Liskowsky, Project Director, New Developments in Neuroscience

Laura Lee Hall, Study Director

Sema K. Aydede, Contractor

Jacqueline T. Keller, Research Assistant

Alan P. Lozier, Intern

Michelle C. Munson, Intern

Claire L. Pouncey, Research Analyst

M. Catherine Sargent, Research Assistant

Support Staff

Cecile Parker, Office Administrator

Linda Journette-Rayford, Administrative Secretary

Jene Lewis, Secretary

Contractors

Blair Burns Potter (editor), Bethesda, MD

John P. Ambrose and J. David Gallagher, National Mental

Health Association, Alexandria, VA

William T. Carpenter, Maryland Psychiatric Research Center, Baltimore, MD

Roland D, Ciaranello, Stanford University School of Medicine, Stanford, CA

John M. Kane, Long Island Jewish Medical Center, Glen Oaks, NY

Jaques M. Quen, New York Hospital-Cornell Medical Center, New York, NY

Greg Scandlen, Health Benefits Letter, Alexandria, VA
Contents

Page

Chapter 1. Summary, Policy Issues, and Options for Congressional Action . . . . . . . . . . . . . . . .

Chapter 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 3. What Are Mental Disorders? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 4. Mental Disorders and the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 5. The Genetics of Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 6. Research Effort and Issues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 7. Public Attitudes and Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Appendix A. Decade of the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Appendix B. Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Appendix C. List of Contractor Documents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Appendix D. Acronyms and Glossary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

35

45

71

101

123

151

169

171

174

175

183
Chapter 1

Summary, Policy Issues, and

Options for Congressional Action
CONTENTS

Page

DECADE OF THE BRAIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

SCHIZOPHRENIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .. .. .. ... ... ......+ . . . . . 6

MOOD DISORDERS: MAJOR DEPRESSION AND BIPOLAR DISORDER . . . . . . . . . 8

ANXIETY DISORDERS: OBSESSIVE-COMPULSIVE DISORDER AND

PANIC DISORDER . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

A SYNTHESIS: UNDERSTANDING THE ROLE OF BIOLOGY . . . . . . . . . . . . . . . . . . . . 13

THE RESEARCH ENTERPRISE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

What Level of Public Concern Motivates Research Into Mental Disorders? . . . . . . . . . 14

What Is the Level of Research Support? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

What Factors Create Barriers to Research? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

IMPLICATIONS OF BIOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

POLICY ISSUES AND OPTIONS FOR CONGRESSIONAL ACTION . . . . . . . . . . . . . . . 21

ISSUE 1: Federal Support for Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

ISSUE 2: Implications of Scientific Advances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

ISSUE 3: Dissemination of New Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Boxes

Box Page

l-A. The Cost of Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

l-B. The Final Symptom: Mental Disorder and Suicide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

l-C. Darkness Visible-A Personal Account of Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

l-D. Media Portrayals of Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

l-E. Eugenics and Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

l-F. Educating the Public About Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Figures

Figure Page

l-l. The Cost of Mental Disorders, 1985 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

l-2. Membership in the Society for Neuroscience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

l-3. Distribution of Federal Support of Neuroscience Research, Fiscal Year 1990 . . . . . . 5

l-4. PET Scan of an Individual With Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

l-5. Mood Disorders Among Twins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

l-6. PET Scan of an Individual With Obsessive-Compulsive Disorder . . . . . . . . . . . . . . . . 13

l-7. NIMH Budget, Fiscal Years 1980-92 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

l-8. Funding of the Division of Basic Brain and Behavioral Sciences,

Fiscal Years 1988-92 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

l-9. Funding of the Division of Clinical Research, Fiscal Years 1980-92 . . . . . . . . . . . . . . 17

Tables

Table Page

l-1. Prevalence of Severe Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

l-2. Obsessions and Compulsions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

l-3. Comparison of Costs and Research Funding, Fiscal Year 1985 . . . . . . . . . . . . . . . . . . . 16

l-4. Drugs in Development for Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

l-5. DEPRESSION Awareness, Recognition, and Treatment Program,

Fiscal Years 1986-91 . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Chapter 1

Summary, Policy Issues, and Options for Congressional Action

Mental disorders can strike with savage cruelty,

producing nightmarish hallucinations, crippling paranoia, unrelenting depression, a choking sense of

panic, or inescapable obsessions. The sheer number

of Americans with mental disorders transforms this

personal tragedy into a widespread public health

problem. Nearly one in three American adults will

experience a mental disorder during his or her

lifetime, whether one of the disorders considered in

this report [schizophrenia, bipolar disorder (commonly known as manic depression), major depression, obsessive-compulsive disorder, and panic disorder; table 1-1], or one of a variety of other

conditions, including cognitive impairment (as in

Alzheimer’s disease), substance abuse or dependence, phobias, and antisocial personality disorder.

Moreover, approximately 1.7 to 2.4 million Americans currently suffer from a persistent and severely

disabling mental disorder, such as schizophrenia or

bipolar disorder.

What are the costs of this public health problem?

The most recent and comprehensive estimate of the

total costs of mental disorders—for fiscal year

1985—added up to $103.7 billion (figure l-l) (box

l-A). When adjusted for inflation, this figure reaches

$136.1 billion in 1991. However, dollar figures

alone, no matter how large, do not convey the toll

mental disorders take. These disorders can be

extremely disabling, significantly compromising

productivity and the ability to work. It has been

estimated that individuals with mental disorders fill

25 percent of all hospital beds and, further, that

one-third of these persons suffer from schizophrenia.

Mental disorders account for an even larger percentTable l-l—Prevalence of Severe Mental Disorders

Adults diagnosed with

disorder during their

lifetimes

Disorder (%)

Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.0

Bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0.8

Major depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9

Obsessive-compulsive disorder . . . . . . . . . . . . . . . . 2.6

Panic disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6

SOURCE: Robins and D.A. Psychiatric Disorders America,

The Epidemiologic Area Study (New York, NY: Free

Press, 1991).

age of hospital beds in Department of Veterans

Affairs (VA) hospitals: Fully 40 percent of all VA

inpatient care is for persons with mental disorders.

Perhaps most tragically, approximately one-third of

homeless single adults and 10 to 15 percent of

individuals who are incarcerated in jails and prisons

have a severe mental disorder such as schizophrenia

or bipolar disorder.

One of the most powerful factors affecting people

with mental disorders and their families is the stigma

often attached to these conditions. While the public’s attitudes and knowledge about mental disorders

have improved during the last 30 years, negative

attitudes toward and ignorance of these disorders

still abound. A sizable number of people continue to

be frightened by the notion of mental illness. The

public fears that people with mental disorders are

violent and dangerous and perceives them to be dirty

and unattractive, therefore often treating them with

disrespect, if not rejecting them outright. Furthermore, despite gains in knowledge about specific

Figure l-l—The Cost of Mental Disorders, 1985

(in billions of dollars)

Other costs

$4.5

Mor

Direct health-related costs

$42.5

In 1985, mental disorders cost the United States more than$103

billion. Approximately 41 percent of that cost-$42.5 billion—

stemmed from hospital care, medication costs, and other treatment costs. Nearly half of the costs of mental disorders-$47.4

billion-derives from lost productivity.

SOURCE: Rice, S. Miller, et al., The Economic Costs 

Alcohol and Drug Abuse and Mental Illness, report submitted to

the Office of Financing and Coverage Policy, Alcohol, Drug

Abuse, and Mental Health Administration, U.S. Department of

Health and Human Services (San Francisco, CA: Institute for

Health and Aging, University of California, 1990).

–3–
4 ● The Biology of Mental Disorders

Box l-A—The Cost of Mental Disorders

How big a problem do mental disorders present to our Nation? What priority should these disorders receive

in the outlay of government funds for research and services? The answers to these questions are often sought in terms

of a dollar figure. However, estimating the toll of mental disorders, or any illness, in economic terms is no easy or

straightforward task. Everything from the cost of hospitalization, which is relatively easy to estimate, to the cost

of reduced productivity, which is more difficult to assess, maybe evaluated. And while rarely included in studies,

the psychological and social tolls on an individual’s life are substantial, though not easily quantified.

During the last 40 years, studies have reported that mental disorders cost the Nation from $3.6 billion to more

than $100 billion each year. The variation in estimates reflects changes over time as well as the use of different

methods of calculation and sources of data. Dorothy Rice and colleagues have derived the most comprehensive

estimate, based on the most recently available survey data. They estimate the total costs of mental

disorders—including schizophrenia, major depression, bipolar disorder (manic-depressive illness), anxiety

disorders, somatization disorder, antisocial personality disorder, and cognitive impairment-to be $103.7 billion

for the year 1985. When adjusted for inflation, this figure reaches $136.1 billion in 1991.

These costs include health-related, or core, costs-that is, the expenditures made and resources lost as a

consequence of having a mental disorder. Such costs makeup 96 percent of the total estimated costs for 1985, or

$99.2 billion. Health-related costs can be broken down further into direct and indirect costs.

Direct health-relatedcosts-$42.5 billion in 1985 and more than $58 billion in 1991—include all expenditures

related to the treatment and support of persons with mental disorders. The vast majority of these direct costs-92

percent-are related to treatment and involve expenditures on hospital and nursing home cam, physician and other

professional services, and drugs (figure l-l). More than 50 percent of the treatment costs—-almost $22 billion in

1985—were spent on care in institutional or hospital settings, such as Department of Veterans Affairs (VA)

hospitals, State and county psychiatric hospitals, private psychiatric hospitals, residential treatment centers for

emotionally disturbed children, and short-stay (general) hospitals. The costs of care provided by office-based

physicians, psychologists, and social workers amounted to approximately $5.7 billion in 1985. Approximately $1.5

billion was spent on prescription drugs, including minor tranquilizers, antidepressants, and antipsychotics. The

estimate reached more than $2.2 billion in 1991, when adjusted for inflation. Support costs, which equaled

approximately $3.2 billion in 1985, include expenditures for research, physician and nurse training, and program

administration (as for health insurance).

Indirect health-related costs estimate the burden of increased morbidity and mortality that accompanies mental

disorders. These estimates, which are based on the National Institute of Mental Health’s Epidemiologic Catchment

Area prevalence data, include the value of lost output caused by decreased productivity, lost workdays, or premature

death. Rice and colleagues do not include measures of the psychological and social effects of mental disorders on

the individual’s life. Morbidity and mortality costs were estimated at $47.4 billion and $9.3 billion, respectively,

in 1985. For 1991, estimates were $60.0 billion for morbidity costs and $11.7 billion for mortality costs. Thus,

according to these data, lost or diminished productivity is the most costly outcome of mental disorders, with

morbidity accounting for nearly 50 percent of the total costs of mental disorders. Furthermore, the cost of morbidity

is not primarily due to institutionalization. Additional analysis, which considers such factors as the prevalence of

mental disorders in various demographic groups, the type of disorder, and income levels, shows that a very large

share of the morbidity costs-$44.l billion in 1985 and $55.8 billion in 1991-derives from noninstitutionalized

individuals.

Mental disorders have other, nonhealth-related effects that impose a cost on society. Nonhealth effects lead

to public and private expenditures on crime control and social welfare administration, the sum of which was

estimated at $1.7 billion by Rice and colleagues. Furthermore, the value of reductions or losses in productivity due

to either incarceration for a criminal offense or time spent to care for a family member with a mental disorder exacts

a price, estimated at approximately $2.8 billion.

SOURCES: D.P. Rice, S. KetiL.S. Miller, et al., The Economic Costs ofAlcohotandDugA buseandMentalIllness: 1985, report submitted

to the Office of Financing and Coverage Policy, Alcohol, Drug Abuse, and Mental Health Administration U.S. Department of

Health and Human Services (San Francisco, CA: Institute for Health and Aging, University of California, 1990); The National

Foundation for Brain Research The Costs ofl)isorders of thellrain (Washington, DC: 1992).
Chapter l---Summary, Policy Issues, and Options for Congressional Action . 5

disorders and their treatment, considerable public

ignorance about mental disorders persists. Although

the stigma attached to mental disorders is complex

in its makeup and effects, negative attitudes and

ignorance have contributed to discrimination in

research support, treatment availability, funding of

mental health care, housing, and employment.

The reality of mental disorders—their symptoms,

prevalence, costs, and associated stigma-commands

the Federal Government’s attention. Despite the fact

that Federal, State, and local governments spend

more than $20 billion each year on mental health

services, with approximately 40 percent of these

public funds derived from Federal sources, the

consensus is that mental health policy is fragmented

and mental health services often deficient. Fundamental to improving the Nation’s efforts on behalf of

people with mental disorders is increasing public

understanding of these conditions. More than a

decade ago the President’s Commission on Mental

Health wrote, “Expanding our understanding of the

functioning of the mind, the causes of mental and

emotional illness, and the efficacy of various treatments is crucial to future progress in mental health.

This report from the Office of Technology Assessment (OTA) offers an appraisal of current knowledge about biological factors in severe mental

disorders—schizophrenia, bipolar disorder, major

depression, obsessive-compulsive disorder, and panic

disorder.l It also reviews support for that research

and considers some of the social implications of data

from biological research into mental disorders.

DECADE OF THE BRAIN

An atmosphere of enthusiasm surrounds neuroscience—an area of interdisciplinary research focused

on how the nervous system works and how it is

affected by disease. Neuroscience is a rapidly

growing field, as reflected in the membership of the

Society for Neuroscience: This professional organization grew from 1,100 members at its inception in

1970 to more than 17,000 in 1990 (figure 1-2). The

1980s saw a nearly 70 percent increase in the number

of papers published in neuroscience and behavioral

research. At least 20 Federal organizations support

research devoted to brain and behavioral research

(figure 1-3), with total Federal expenditures just

exceeding $1 billion in 1990.

20,000

16,000

12,000

8,000

4,000

Figure 1-2—Membership in the Society

for Neuroscience

1,100

17,524

1970 1980 1990

Membership in the Society for Neuroscience has grown dramatically since its inception in 1970.

SOURCE: Society for Neuroscience, 1991.

Figure 1-3—Distribution of Federal Support of

Neuroscience Research, Fiscal Year 1990

Dollars (millions)

I F

NINDS 490

NIA 92

NEI 80

NIH NIDOCD 59

NICHD 58

NIEHS 20

[

NIDR 12

NIMH 402

ADAMHA NIDA 54

NIAAA 29 r VA 34

Other

!

NSF 29

agencies DOD 33

DOE 20

Other

o 100 200 300 400 500

Funding of neuroscience research by various Federal agencies.

KEY: National Institutes of Health; Abuse,

and Health Administration; National of

Neurological Disorders and Stroke; National institute on Aging;

 National Eye Institute; National Institute on

Deafness and Other Communication Disorders; National

Institute on Child Health and Human Development; 

Institute on Environmental Health Sciences; National Institute

of Dental Research; National Institute of Mental Health; 

 National Institute on Drug Abuse; National Institute on

Alcohol Abuse and Alcoholism; VA U.S. Department of Veterans

Affairs; NSF= National Science Foundation; U.S. Department

of Defense; DOE U.S. Department of Energy; Other National

Institute on Disability and Rehabilitation Research, National Aeronautics and Space Administration, Environmental Protection Agency,

U.S. Department of Agriculture, Centers for Disease Control, and

U.S. Food and Drug Administration.

 year 1991.

SOURCE: Office of Technology Assessment, adapted from E. Pennisi and

D. Morgan, “Brain Decade Scientists Court Support,” 

 1990.

 Addictive disorders, disease, and developmental disorders such as autism have been or are being discussed in other OTA reports, and

therefore are not considered in this report.
6 ● The Biology of Mental Disorders

Advances in scientific methods and techniques

have fueled the dramatic increase in neuroscience

research during the last 15 years. Improved methods

for staining nerve cells have made it possible to

pinpoint their precise location in the brain. The

electrical activity of a single channel in a nerve cell’s

membrane-less than one-trillionth of an inch in

diameter-can be measured. Advances in computing, microscopy, and especially imaging technology

underlie the spectacular ability to observe living

brain tissue—from single nerve cells to the intact

human brain. The development of psychological

tests has enabled researchers to correlate observed

brain activity with specific behaviors and thought

processes. And molecular biology has revolutionized the study of the brain, producing monoclinal

antibodies that allow labeling of specific nerve cells,

the cloning of proteins involved in brain function,

and the search for specific genes.

The rapid growth and productivity of neuroscience spearheads, in large measure, the general

interest in the biology of mental disorders and

Congress’ request for this study. Modern neuroscience research is an important part of the contemporary effort to expose the causes of mental disorders.

The National Institute of Mental Health (NIMH), the

primary source of Federal funding for research into

mental disorders, has focused a major portion of its

research plan on the basis of developments in

neuroscience. By strongly supporting neuroscience

research, NIMH aims to ‘‘understand the workings

of the human brain in sufficient detail to effectively

treat or prevent the broad variety of behavioral

disorders and mental illnesses. ’ The spectacular

growth of neuroscience also distinguishes the current focus on the biology of mental disorders from

that of previous eras. While biological models of

mental disorders have been emphasized time and

again in the past, today’s research into the brain’s

functions in mental disorders is supported in a

qualitatively and quantitatively new way by an

expanding base of knowledge about the brain and

behavior.

SCHIZOPHRENIA

Schizophrenia ‘‘is arguably the worst disease

affecting mankind.’ It is not, as commonly misconstrued, split personality. Although important questions remain about its classification, its characterisCredit: Copyright 1992 Bill Lee. Reprinted with permission.

This cartoon, provided by O. Wahl, illustrates the commonly

held misperception that schizophrenia is multiple personalities.

tic symptoms are well defined. Positive symptoms,

which typify psychosis, include hallucinations and

delusions, as well as bizarre behaviors and dissociated or fragmented thoughts. Negative symptoms

include impaired emotional responsiveness, loss of

motivation, general loss of interest, and social

withdrawal.

Schizophrenia is a common disorder, with approximately one in every 100 persons developing it

during the course of his or her lifetime; approximately 1.2 million people have schizophrenia in the

United States at the present time. While schizophrenia does not invariably follow a deteriorating course,

there are substantial and enduring consequences for

many people with this condition. Its onset typically

occurs during the late teens and early 20s, with a

generally younger age of onset and worse prognosis

in men. The expressed symptoms of schizophrenia

may combine in various ways, their severity and

duration fluctuating over time. Schizophrenia is

associated with an increased risk of suicide; approx-
Chapter 1-Summary, Policy Issues, and Options for Congressional Action . 7

Box I-B—The Final Symptom: Mental Disorder and Suicide

In 1987, 11,7 people in every 100,000-more than 30,000 people-killed themselves in the United States,

making it the eighth leading cause of death in the nation. While many factors are associated with suicide, including

medical illness, availability of firearms, or stressful events such as a divorce or loss of a job, data indicate that mental

disorders are a significant antecedent to many suicides in the United States. About 50 percent of all suicide victims

may have suffered a mood disorder, and an estimated 5 to 10 percent of suicide victims suffered from schizophrenia.

Among people with schizophrenia, suicide is the number one cause of premature death, with the estimated

age-adjusted suicide rate averaging 90 per 100,000 women with schizophrenia and 210 per 100,000 men with the

disorder 10 to 15 percent of individuals with schizophrenia commit suicide. The higher rate of suicide among men

versus women with schizophrenia not only mirrors the suicide statistics in the general population, but also reflects

the more severe symptoms that men usually suffer. Some people with schizophrenia may commit suicide as a result

of a psychotic episode-in response to a hallucinatory command. More commonly, however, people with this

condition take their lives early in the course of the illness during a relatively stable period following a recent

hospitalization.

Approximately 15 percent of people with mood disorders will commit suicide, with the suicide rates for men

and women with major mood disorders averaging 400 and 180 per 100,000, respectively, 30 times higher than the

rate in the general population. The link between mood disorders and suicide is well recognized, with recurrent

thoughts of suicide or a suicide attempt being one diagnostic criterion for these conditions. Other mental disorders,

such as panic disorder, also appear to be correlated with suicide. Although there is little information available

concerning the number of people with panic disorder who actually commit suicide, survey data show that

approximately 20 percent of people with this condition will attempt suicide during their lifetime.

High rates of suicide among individuals with major mental disorders like schizophrenia or major depression

provide chilling evidence of the distressing nature of mental disorders. Furthermore, the strong correlation between

mental disorders and suicide indicates that general suicide prevention efforts must include strategies to improve the

treatment of mental disorders.

SOUR~S: C.B. Caldwell and 1.1. Gottesman, “Schizophrenics Kill Themselves Too: A Review of Risk Factors for Suicide,” Schizophrenia

Bulletin 16(4):571-589, 1990; F.K. Goodwin and K.R. JamisorL Munic-Depressive lZ2ness (New York NY: The Oxford University

Press, 1990); J. Johnson, M.M. Weiss- and G.L. Kle~ “Panic Disorder, Comorbidity, and Suicide Attempts,” Archives of

Genera2Psychiatry 47:805-808, 1990; E.K. Moscicki, cbief, Prevention Research Branc4 National Institute of Mental Healt& U.S.

Department of Health and Human Services, personal communicatio~ Apr. 30, 1991; U.S. Department of Health and Human

Services, Public Health Services, National Center for Health Statistics, Monthly Vital Statistks Report 40(8 suppl. 2), 1992,

imately 10 to 15 percent of individuals with this Investigators have examined the possible role of

disorder take their own lives (box l-B).

Currently, there is no way to prevent or cure

schizophrenia; however, treatments that control

some of its symptoms are available. The optimal

treatment generally integrates antipsychotic drugs

and supportive psychosocial treatment. Individuals

acutely ill with schizophrenia may require hospitalization. Furthermore, rehabilitation is generally necessary to enhance social and occupational outcomes.

The complexity of expressed symptoms and the

likelihood that the disorder encompasses various

subtypes, which are not yet reliably distinguishable,

have slowed progress in understanding schizophrenia. Nonetheless, converging research data point to

the alteration of specific brain chemicals and regions

as the biological substrate of the schizophrenias.

several b&in chemicals in schizophrenia, including

serotonin, norepinephrine, various neuropeptides,

and, most recently, glutamate. The most venerable

theory concerning the chemistry of schizophrenia

implicates the brain chemical dopamine. Dopaminereleasing drugs, such as amphetamines, can induce

a psychotic state, and drugs reducing dopamine

function have antipsychotic effects. However, studies looking for simple changes in dopamine levels in

the brain have provided inconsistent results. Thus,

even though there is a consensus that dopamine

plays a role in schizophrenia, the specifics of this

brain chemical’s action remain unknown.

Various studies of the function and structure of

the brain in schizophrenia point to the involvement

of two specific areas, namely, the frontal cortex and
8 ● The Biology of Mental Disorders

the limbic system (figure 1-4). The limbic system

seems to be involved in the positive symptoms and

the frontal cortex in the negative symptoms of

schizophrenia. The precise interaction between these

specific brain regions, as well as the possible

involvement of other areas of the brain, still need to

be clarified.

In addition to pinpointing the regions and chemicals in the brain that underlie the symptoms of

schizophrenia, researchers have put forward several

hypotheses concerning the cause or causes of this

disorder. Information about the course of schizophrenia, its epidemiology, and specific biological

measures suggests that a virus or immune system

problem is a possible culprit. Another hypothesis

asserts that injury to the brain early in life is the

critical factor. Support for this viewpoint stems from

various observations, including the higher rate of

birth complications among individuals with schizophrenia and subtle deviations in neurological and

psychological functions that sometimes precede the

full expression of schizophrenia. Evaluation of the

prevalence and pattern of schizophrenia among

related individuals shows that genetic factors contribute to this disorder; however, the inheritance of

schizophrenia is quite complicated, and nongenetic

factors also play a role. The location of specific

genes involved in schizophrenia remains unknown.

MOOD DISORDERS: MAJOR

DEPRESSION AND

BIPOLAR DISORDER

Mood disorders, which are also referred to as

affective disorders, are characterized by extreme or

prolonged disturbances of mood, such as sadness,

apathy, or elation. These disorders can be divided

into two major groups: bipolar and depressive

disorders. The occurrence of manic symptoms distinguishes bipolar disorders from depressive, or

unipolar, disorders.

The most severe depressive disorder is major

depression. While it has proven difficult to discern

whether depression is a single disorder or a collection of disorders, its expression is well characterized. Box 1-C is a personal account of the symptoms

of depression. Various psychological and somatic

symptoms accompany episodes of depression, including profoundly depressed mood, the complete

loss of interest or pleasure in activities, weight gain

or loss, insomnia or excessive sleepiness, slowed or

Figure 1-4—PET Scan of an Individual

With Schizophrenia

Brain activity in an individual who does not have schizophrenia

(right) and a person who does (left) .The frontal cortex shows more

activity in schizophrenia (white areas).

SOURCE: W. Carpenter, Maryland Psychiatric Research Center and H.

 Associates, Inc.

agitated movement, diminished energy, intense feelings of guilt or worthlessness, a diminished ability

to concentrate, and recurrent thoughts of death or

suicide (see box l-B).

Major depression is a prevalent disorder: Nearly

5 percent of the population will develop it and the

risk is twice as great for women as for men.

Furthermore, its occurrence seems to be increasing

among young people. Major depression typically

has its onset in the late 20s, although it can emerge

at any age. More than 50 percent of patients will

have more than one bout of depression, the average

being five or six episodes during a lifetime. Approximately 15 percent of persons suffering from the

symptoms of depression will die by suicide.

Major advances have taken place in the pharmacological treatment of depression during the last

decade. Various forms of psychotherapy-either

alone or as an adjunct to medication—are also

important to treatment. Severe cases may require

hospitalization; electroconvulsive therapy may be

used in severe cases. In depression that recurs each

fall and winter, known as seasonal affective disorder, or SAD, light therapy can be useful.

Bipolar disorder is a severe mood disorder characterized by manic and depressive episodes. Although

its symptoms are quite well known, questions

remain about how it relates to other disorders, such
Chapter l--Summary, Policy Issues, and Options for Congressional Action ● 9

Box I-C—Darkness Visible—A Personal Account of Depression

Depression is a disorder of mood, so mysteriously painful and elusive in the way it becomes known to the

self—to the mediating intellect—as to verge close to being beyond description. It thus remains nearly

incomprehensible to those who have not experienced it in its extreme mode, although the gloom, ‘the blues’ which

people go through occasionally and associate with the general hassle of everyday existence are of such prevalence

that they do give many individuals a hint of the illness in its catastrophic form. But at the time of which I write I

had descended far past those familiar, manageable doldrums. . . .

It was not really alarming at first, since the change was subtle, but I did notice that my surroundings took on

a different tone at certain times: the shadows of nightfall seemed more somber, my mornings were less buoyant,

walks in the woods became less zestful, and there was a moment during my working hours in the late afternoon when

a kind of panic and anxiety overtook me, just for a few minutes, accompanied by a visceral queasiness-such a

seizure was at least slightly alarming, after all. . . .

I felt a kind of numbness, an enervation, but more particularly an odd fragility-as if my body had actually

become frail, hypersensitive and somehow disjointed and clumsy, lacking normal coordination. And soon I was in

the throes of a pervasive hypochondria. Nothing felt quite right with my corporeal self; there were twitches and

pains, sometimes intermittent, often seemingly constant, that seemed to presage all sorts of dire infirmities. . . .

It was October, and one of the unforgettable features of this stage of my disorder was the way in which my

own farmhouse, my beloved home for 30 years, took on for meat that point when my spirits regularly sank to their

nadir an almost palpable quality of ominousness. The fading evening light-akin to that famous ‘slant of light’ of

Emily Dickinson’s, which spoke to her of death, of chill extinction—had none of its familiar autumnal loveliness,

but ensnared me in a suffocating gloom. . . . That fall, as the disorder gradually took full possession of my system,

I began to conceive that my mind itself was like one of those outmoded small-town telephone exchanges, being

gradually inundated by floodwaters: one by one, the normal circuits began to drown, causing some of the functions

of the body and nearly all of those of instinct and intellect to slowly disconnect. . . .

What I had begun to discover is that, mysteriously and in ways that are totally remote from normal experience,

the gray drizzle of horror induced by depression takes on the quality of physical pain. But it is not an immediately

identifiable pain, like that of a broken limb. It maybe more accurate to say that despair, owing to some evil trick

played upon the sick brain by the inhabiting psyche, comes to resemble the diabolical discomfort of being

imprisoned in a fiercely overheated room. And because no breeze stirs this cauldron, because there is no escape from

this smothering confinement, it is entirely natural that the victim begins to think ceaselessly of oblivion.

SOURCE: Quotedfiom W. Styro~ Darkness Visible (New York, NY: Random House, 1990). Copyright @ 1990 by William Styron. Reprinted

by permission of Random House, Inc.

as major depression and schizophrenia. The depres- or more, with periods of recovery typically separative episodes in bipolar disorder are similar to those

seen in major depression. During a manic episode,

an individual’s mood is extremely elevated, expansive, or even irritable, and his or her self-esteem is

elevated. There is diminished need for sleep, energy

abounds, and thoughts race. Individuals are extremely talkative and distractible and stereotypically

indulge in unrestrained buying sprees or sexual

activity. Psychotic features (i.e., delusions and

hallucinations) are not uncommon during a manic

episode.

Bipolar disorder afflicts approximately 0.8 percent of the population, with men and women being

affected equally. It emerges relatively early in life,

usually during the mid-20s. Episodes of mania or

depression occur every several months to every year

ing the mood swings. This disorder continues

throughout an individual’s lifetime.

Treatment for bipolar disorder is aimed at ending

a manic or depressive episode and preventing its

recurrence. Medication is typically required, and

hospitalization may be required for acute episodes.

The specific symptoms are treated: depressive episodes with antidepressant drugs; psychosis with

antipsychotic medication; and manic symptoms and

relapses with lithium, or, less frequently, carbamazepine. Supportive psychotherapy is generally

required to help patients understand and deal with

the symptoms of bipolar disorder.

The typical symptoms and course of major mood

disorders have led to their being conceptualized as
10 ● The Biology of Mental Disorders

biologically based conditions. Since the discovery

of clinically useful mood-altering medications 30 to

40 years ago, research has focused intensely on the

biology of these conditions. Although the causes of

these disorders remain obscure, studies of brain

chemistry and function, other physical correlates,

and genetic research provide clues about the biology

of major mood disorders. The most consistent of

these observations are discussed below.

A number of different brain chemicals appear to

be involved in mood disorders. The most prominent

hypotheses have focused on a group of brain

chemicals called monoamines, especially norepinephrine and serotonin, because clinically effective

antidepressant medications influence the levels of

these chemicals. While neither depression nor mania

seems to result from a simple decrease or increase of

these chemicals, there is sufficient evidence to

implicate monoamines in mood disorders.

Hormonal abnormalities are common in depression. Many of the symptoms associated with mood

disorders-changes in appetite, sleep patterns, and

sex drive-may be related to these hormonal changes.

One of the most consistent findings in this regard is

an elevation of cortisol in severely depressed individuals. Also, altered mood sometimes accompanies

reproductive events in women—menstruation, pregnancy, childbirth, menopause—suggesting an association between reproductive hormonal alterations

and mood disorders.

Individuals with mood disorders typically have

sleep disturbances. Insomnia or excessive sleeping

often occurs in depression, with REM sleep, during

which dreaming occurs, frequently disrupted. The

sleep of individuals with bipolar disorder is often

affected; during depressive episodes, people may

sleep excessively, and when manic, little or not at all.

Other functions that cycle over time may be

disrupted in mood disorders. For example, many

people with depression exhibit daily and seasonal

fluctuations in mood. Some data suggest that circadian rhythms-biological and behavioral functions that repeat roughly every 24 hours-are

disrupted in mood disorders. Furthermore, animal

studies indicate that some antidepressant medications have an effect on the organization of circadian

rhythms.

Episodes of mania and depression increase in

frequency over time. And while environmental

factors appear to be important in triggering periods

of altered mood in the early stages of bipolar

disorder, mood swings become automatic later on.

The increasingly frequent and spontaneous nature of

mood cycling has led to the development of a

hypothesis about the recurrent nature of bipolar

disorder: the kindling and sensitization hypothesis.

Kindling refers to an experimental model for epilepsy, in which spontaneous seizures occur after

repeated stimulation of a particular region of the

brain. Behavioral sensitization refers to an increasing behavioral response to the same dosage of a drug

following repeated administration. It is possible that

similar brain mechanisms underlie mood swings.

While additional information is needed to confirm

this hypothesis, it is interesting to note that the

medications used to treat bipolar disorder-carbamazepine and lithium-can block kindling and

behavioral sensitization.

The most clearly established biological observation about mood disorders, and especially bipolar

disorder, is that genetic factors play a role. Identical

twins more frequently share mood disorders than do

fraternal twins (figure 1-5). Also, parents, siblings,

and children of individuals with bipolar disorder or

major depression more commonly develop these

conditions. Family and twin studies support a

genetic link between depression and bipolar disorder, although the genetic overlap is not complete.

Clearly, genetic factors are important in both

bipolar disorder and major depression. However,

studies do not reveal a simple pattern of inheritance,

nor do they necessarily implicate the action of a

single gene. Data also indicate that nongenetic

factors must play a role. While many studies have

attempted to locate specific genes that lead to mood

disorders, some with positive results, no strong

evidence fixes a gene for mood disorders to a

specific location.

ANXIETY DISORDERS:

OBSESSIVE-COMPULSIVE

DISORDER AND PANIC DISORDER

Anxiety is a normal human emotion, familiar to us

all. However, anxiety can become extreme, leading

to a disabling feeling of panic, a constant sense of

apprehensiveness, or unrelenting worry about a

possible mishap or accident. The current diagnostic

system for mental disorders distinguishes several

specific anxiety disorders, including panic disorder,
Chapter l--Summary, Policy Issues, and Options for Congressional Action ● 11

Figure 1-5-

0.65

–Mood Disorders Among Twins

0.80 —

Any mood Bipolar Severe Depressionb

disorder disorder depression a

 Identical twins Fraternal twins

Graphically depicted data were derived from evaluation of 110

pairs of twins. Identical twins shared mood disorders, and

especially bipolar disorder, more frequently than fraternal twins.

 episodes of depression.

 than three episodes of depression.

SOURCE: Adapted from A. B. and M. “A

Danish Twin Study of Manic-Depressive Disorders,” British

Journal of Psychiatry 130:330-351, 1977.

phobias, obsessive-compulsive disorder, posttraumatic stress disorder, and generalized anxiety disorder. This report considers two of these conditions—

obsessive-compulsive disorder and panic disorder—

in which the role of biological factors has been more

fully explored.

Obsessive-compulsive disorder (OCD) is characterized by the presence of recurrent and persistent

thoughts, images, or ideas that are experienced by

the afflicted individual as intrusive and senseless

(obsessions) and stereotypical, repetitive, and purposeful actions perceived as unnecessary (compulsions) (table 1-2). A common manifestation of this

disorder is the obsessional feeling of being dirty or

contaminated, which leads to the compulsion of

repeated hand washing. Many individuals with OCD

have another diagnosis, most often depression.

Other problems that may be associated with OCD

include other anxiety disorders, eating disorders,

alcohol abuse, and Tourette’s syndrome.

Once thought to be quite rare, OCD has been

found by more recent epidemiological studies to

affect approximately 2 to 3 percent of the U.S.

population. Males and females appear to be afflicted

equally. The symptoms of OCD begin in childhood

or adolescence in one-third to one-half of all

individuals who develop the disorder; the average

age of onset is 20. Although the symptoms of OCD

sometimes recede completely with time, most patients suffer chronically from OCD, with a waxing

and waning course.

Currently there are two primary treatment approaches for OCD: behavioral therapy and medication. Behavioral therapy entails repeated exposure of

the patient to the stimulus that sets off ritualistic acts.

For example, if an individual has a compulsion that

causes him to wash his hands 20 or 30 times a day,

his hands may be deliberately dirtied, after which he

is prevented from washing them. Medications affecting the brain chemical serotonin have proven

effective, with clomipramine (Anafranil) being commonly used to treat OCD.

As with the other mental disorders considered in

this report, biological factors appear to have a role in

OCD. The fact that drugs which act on the brain

chemical serotonin are sometimes effective in treating OCD implicates biological factors. Studies have

not, however, uncovered a specific abnormality in

serotonin metabolism or activity. Other studies

implicate a genetic component in OCD.

Several lines of evidence indicate that a specific

region of the brain-the basal ganglia-mediates

the symptoms of OCD. Damage to the basal ganglia

can lead to compulsive behavior. And OCD is

sometimes associated with Tourette’s syndrome,

which also involves this region of the brain. These

observations, coupled with data from studies that

show increased activity in the basal ganglia and in

another region of the brain, the orbital system in the

frontal cortex, have led to the hypothesis that OCD

results from the abnormal interaction of these two

regions of the brain (figure 1-6). According to this

hypothesis, the basal ganglia and frontal cortex,

which normally modulate actions based on thoughts

or impulses, do not work properly in OCD.

While controversy remains as to whether panic

disorder is a distinct entity, clinicians have long

recognized panic attacks and the extensive morbidity associated with them. The hallmark symptoms of

a panic attack include a sudden and inexplicable

bout of intense fear associated with strong bodily

symptoms. A panic attack typically unfolds quite
12 ● The Biology of Mental Disorders

Table 1-2—Obsessions and Compulsions

Reported symptom at initial interview

Obsessions (no.) (%)

Concern with dirt, germs, or environmental toxins . . . . . . . . . . . 28 (40)

Something terrible happening (fire, death, or illness of self

or loved one) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 (24)

Symmetry, order, or exactness . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 (17)

Scrupulosity (religious obsessions) . . . . . . . . . . . . . . . . . . . . . . . . 9 (13)

Concern or disgust with bodily wastes or secretions

(urine, stool, saliva) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 (8)

Lucky or unlucky numbers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 (8)

Forbidden, aggressive or perverse sexual thoughts, images,

or impulses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 (4)

Fear might harm others or oneself . . . . . . . . . . . . . . . . . . . . . . . . . 3 (4)

Concern with household items . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 (3)

Intrusive nonsense sounds, words, or music . . . . . . . . . . . . . . . . 1 (1)

Reported symptom at initial interview

Compulsions (no.) (%)

Excessive or ritualized hand washing, showering bathing,

tooth brushing, or grooming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 (85)

Repeating rituals (going in or out of a door, up or down

from a chair) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 (51)

Checking (doors, locks, stove, appliances, emergency brake

on car, paper route, homework) . . . . . . . . . . . . . . . . . . . . . . . . 32 (46)

Rituals to remove contact with contaminants . . . . . . . . . . . . . . . 16 (23)

Touching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 (20)

Measures to prevent harm to self or others . . . . . . . . . . . . . . . . . 11 (16)

Ordering or arranging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 (17)

Counting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 (18)

Hoarding or collecting rituals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 (11)

Rituals of cleaning household or inanimate objects . . . . . . . . . 4 (6)

Miscellaneous rituals (such as writing, moving, speaking) . . . 18 (26)

aThe most frequent obsessions and compulsions among 70 children and adolescents who were diagnosed as having

OCD by the author and her colleagues at the National Institute of Mental Health. The proportions total more than 100

percent because many sufferers have more than one symptom.

SOURCE: J.L. Rapoport, ‘The~iology of Obsessions and Compulsions)” Scientific American 260(3):63-89, 1990.

rapidly; in just a few minutes an extreme sense of

fear overtakes an individual, his or her heart begins

racing, the individual begins to perspire, sometimes

profusely, and he or she has trouble breathing. A

single attack is short-lived, lasting 20 minutes to an

hour, on average. These symptoms often leave a

person believing that he or she is suffering from a

heart attack or is losing his or her mind. In fact, many

individuals with panic disorder seek general medical

care at an increased rate. Panic attacks occur, on

average, about two times a week, although the

frequency varies considerably among individuals.

People with panic disorder often exhibit other

disorders as well. They may fear being in a public

place from which escape is difficult-agoraphobia.

Depression and substance abuse are also common

among individuals with panic disorder.

Data show that approximately one to two persons

in every hundred will develop panic disorder during

their lifetimes, with women being twice as likely as

men to develop the disorder. The disorder usually

first appears during young adulthood, with an

average age of onset of 24 years. Data suggest that

many patients suffer chronically from this condition.

Panic disorder is treated with medication and/or

psychotherapy. Antidepressant drugs and antianxiety agents, such as the benzodiazepine alprazolam,

are used with some effectiveness in panic disorder;

behavioral or cognitive therapy may prove useful in

diminishing the severity or frequency, or both, of

panic attacks.

There are several psychological and biological

theories about the origin of panic disorder. For

example, one cognitive theory posits that individuals may misinterpret normal physiological changes,

such as an increase in heart rate, as dangerous, thus

inducing anxiety and precipitating a panic attack.

Several observations are consistent with a role for

biological factors in panic disorder. Data from
Chapter 1-Summary, Policy Issues, and Options for Congressional Action ● 13

Figure 1-6—PET Scan of an Individual

With Obsessive-Compulsive Disorder

Brain activity in the brain of a person with OCD (right) and the brain

of a person without OCD (left). In OCD, there is increased activit y

in a region of the brain called the frontal cortex.

SOURCE: L. Baxter, UCLA Center for Health Sciences, Los Angeles, CA.

genetic studies indicate that panic disorder may, in

part, be inherited. The action of antianxiety medications has led to hypotheses that naturally occurring

anxiety-provoking chemicals underlie panic disorder or, conversely, that a deficit of natural anxietyblockers is at the root of the disorder. To date,

however, no such substances have been identified.

Research data have also implicated a particular

region of the brain, the limbic system, in anxiety and

possibly panic disorder.

Whatever the cause, several lines of evidence

point to the role of a particular brain region (the

locus ceruleus) and a specific chemical (norepinephrine) in mediating panic attacks. Antidepressant

drugs, which act on norepinephrine, are an effective

treatment for panic disorder. Various drugs and other

substances that stimulate the locus ceruleus and

increase norepinephrine production can also trigger

panic attacks. Continuing research is aimed at

clarifying what role the locus ceruleus plays in panic

disorder, how it might relate to the limbic system

(which is involved in anxiety), and what other

chemicals and regions of the brain may be involved.

A SYNTHESIS: UNDERSTANDING

THE ROLE OF BIOLOGY

What can we conclude about the role of biology

in mental disorders? In its review of research, OTA

found the following evidence that biological factors

are involved in schizophrenia, bipolar disorder,

major depression, OCD, and panic disorder:

●

●

●

●

●

●

Medications can suppress symptoms associated

with these disorders.

Specific mental disorders can often be typified

by distinguishable clinical features, such as age

of onset, symptoms, and course.

These disorders may have associated “physical” symptoms, such as altered sleep patterns

in depression.

Known physical agents and drugs can produce

some symptoms of mental disorders, demonstrating that biological factors can in fact be

causative.

Genetic studies show that the disorders are

influenced by inheritance.

Other areas of research provide evidence about

correlated biological factors and suggest testable hypotheses as to causation.

Some researchers and advocates conclude from

this evidence that biological factors are the predominant cause of severe mental disorders and that the

medical model is the best way to conceive of them.

In contrast, others deplore the talk of “brain

disease,’ citing the incomplete state of our knowledge about what causes these conditions and even

how best to categorize them. The majority of experts

and interested parties-and OTA—recognize that

research data increasingly show that biological

factors play an important role in these disorders.

Furthermore, OTA concludes that advances in

biological research will serve as the linchpin in

improving our understanding of these conditions.

Biological research has not ruled out a role for

psychosocial factors in the mental disorders considered in this report. In fact, it is clear that mental

disorders cannot be understood or treated in biological terms only. Nor does biological research necessarily implicate biological treatments. Environment,

education, and culture exert powerful influences,

and psychological interventions are important for

treatment. Experts increasingly recognize the essential error of discussions that pit biology against

psychosocial factors: The two are obviously and

inextricably interrelated. Sorting out their relative

roles and how they interact in different conditions

will be critical for the development of research and

treatment strategies.

Many questions remain about the biology of

mental disorders. In fact, research has yet to identify
14 ● The Biology of Mental Disorders

specific biological causes for any of these disorders.

Why do we not know more about the biological

causes and correlates of these conditions? One

reason stems from the complexity of these disorders

and the difficulty of categorizing them. Individuals

often exhibit symptoms that reach across categories

of disorders. And a single diagnostic category may

encompass multiple conditions. Furthermore, we do

not completely understand the relationship among

different disorders.

Another reason is our incomplete understanding

of the brain. The brain and behavior are immensely

complicated, and our knowledge of them is still

scant in comparison to what we have yet to learn.

With advancing knowledge about the brain, more

sophisticated hypotheses about mental disorders—

involving how the many chemicals in the brain

work, and how nerve cells and discrete regions of the

brain interact-will be propounded. Given our

nascent understanding of the brain, it will be

necessary to stay the course in what is likely to be a

slow unveiling of the biology of mental disorders.

The search for specific genes involved in mental

disorders has also proven a difficult task. Attempts

to locate specific genes have alternately produced

acclaimed reports of success and contradictory data

followed by the withdrawal of results. While these

events impugn the theory of a simple relationship

between one gene and a particular mental disorder,

they do not rule out the need for further genetic

studies: Evidence from many sources clearly indicates that mental disorders have a genetic component. Nor do past problems necessarily rule out the

action of a major gene in the development of a

mental disorder, at least in some cases. Like the

investigations of other common diseases with complex genetics (e.g., Alzheimer’s disease, diabetes

mellitus), future studies must take into account the

complicated pattern of inheritance, the likely role of

more than one gene operating within different

families and individuals, questions as to what is

inherited, and the undeniable role of nongenetic

factors.

THE RESEARCH ENTERPRISE

The pursuit of knowledge about the biological

aspects of mental disorders rests upon an adequate

research capacity, which in turn is subserved by a

complex enterprise that makes funds available, sets

research priorities, attends to relevant ethical and

policy issues, outfits researchers with equipment and

other resource needs, and provides for education and

training. The answers to three questions shed light

on factors that influence this research enterprise:

What level of public concern motivates research into

mental disorders? What is the level of research

support? What factors form barriers to research?

What Level of Public Concern

Motivates Research Into Mental Disorders?

Several studies and mental health advocates have

claimed that research into mental disorders is

underfunded, attributing the deficiency to the low

priority assigned to these conditions by the public

and policymakers. This assertion stems from three

observations: 1) the Federal investment, as reflected

in the NIMH budgets, declined significantly between the late 1960s and early 1980s; 2) Federal

support for research on mental disorders is comparatively less than its support of other areas of health

research; and 3) there are limited nonFederal sources

of funding, especially from private foundations.

A seminal report from the Institute of Medicine

concluded in 1984 that the:

. . . real buying power of research funding for

mental disorders has dropped sharply during the past

15 years, even as available personnel and basic

knowledge about brain function have expanded dramatically. 3

OTA evaluated the NIMH research budget since

1980, to gauge recent Federal support (figure 1-7).

Between 1980 and 1992,4 NIMH funding of research, including funding of extramural basic and

clinical research, intramural research, and research

training, increased by 6.7 percent annually.5 The rate

of growth from 1986 to 1992 was substantially

higher, at 11.5 percent.6

3 ~StiWte of Medi~~e, Research on Mental Il&~~ and~dictive Di~~rders: Progress ad Prospects (washgto~ DC: National Academy MeSS,

1984).

4 Fisc~ ye~ are indicated.

5 ~sis the average ~Wl ~e~ rate of ~c-ea~e, dete~ed by convefi~g the MMH budget iII current doll~s into Comtmt 1987 dolks, usbg the

gross domestic product deflator as the price index.

6 Based on estimtes, tie ~creme ~ ~~’srese~ch budget Slowd to 7’.7 percent t)etw~n 1991 ~d 1992.
Chapter l-Summary, Policy Issues, and Options for Congressional Action ● 15

600

500

400

300

200

100

0

Figure 1-7—NIMH Budget, Fiscal Years 1980-92

Dollars (millions)

. . . . . ---------------------------------------------------------------------------------------------------------- . . . . . . . . . . . . . . . . 

.. ---- . . . . . . . . n --------------------------- ------------------------------------------------------------------------------- fl-

 a

 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990

Research funding

 Basic and clinical extramural research Intramural research Research 

services funding

 Clinical training Services research Service programs

Funding of the components of the research and services budgets of NIMH.

NOTE: Figures converted to constant 1987 dollars using the 1992 gross domestic product deflator.

 reflects initiation of State grants.

 figures are estimates.

 assumption of constant price index.

SOURCE: Office of Technology Assessment from figures supplied by National Institute of Mental Health, 1992.

Despite the increases, various measures indicate

that during the 1980s the relative investment in

research on mental disorders was considerably less

than that for other diseases. OTA compared the

relative support for research to the total costs of

mental disorders, cancer, and heart disease (table

1-3).7 For every $100 of costs imposed by mental

disorders, $0.30 was spent on research. In comparison, for every $100 of costs of heart disease and

cancer, $0.73 and $1.63, respectively, were spent on

research. It is of interest to note, however, that the

Federal Government’s purchasing power for mental

disorders research increased faster in the 1980s than

did its purchasing power for cancer research.

Previous studies have also called attention to the

historic neglect of research into mental disorders by

private foundations and voluntary health agencies,

which currently form a relatively small, but important source of support for biomedical research. The

1980s did witness new sources of private support for

research into the biology of severe mental disorders,

with the formation of the National Alliance for

Research on Schizophrenia and Depression

(NARSAD) in 1986 and the establishment of the

National Alliance for the Mentally Ill’s (NAMI’s)

Stanley Awards Program. Still, support from such

organizations for mental disorder-related research

stands at a much lower level than private foundation

support for other diseases. For example, in fiscal

year 1991, the American Cancer Society spent

nearly $91 million dollars on research, compared to

NARSAD’s $3.3 million.

What can we conclude about the level of public

concern that surrounds mental disorders, as meas7 and recent stemmed from 
16 ● The Biology of Mental Disorders

Table 1-3—Comparison of Costs and Research Funding, Fiscal Year 1985

Total budget of principal Dollars spent on

costs’ Federal institution research per $l00 of

Illness ($ millions) ($ millions) cost to society

Mental disorders . . . . . . . . . . . . . . . . . . . . 103,691C

310d 0.30

Cancer (malignant neoplasms only) . . 72,494 1,184 1.63

Heart disease . . . . . . . . . . . . . . . . . . . . . . . 69,000 501 0.73

aD.p. Rice, S. Kelman, L.S. Miller, et al., The Economic Costs of Alcohol and Drug Abuse and Mental IIhss: 1985,

report submitted to the Office of Financing and Coverage Policy, Alcohol, Drug Abuse, and Mental Health

Administration, U.S. Department of Health and Human Services (San Francisco, CA: Institute for Health and Aging,

University of California, 1990); D.P. Rice, T.A. Hodgson, and F. Capell, “The Economic Burden of Cancer, 1985:

United States and California,” Cancer Care and Cost: DRGs and Beyond, R.M. Scheffler and N.C. Andrews (eds.)

(Ann Arbor, Ml: Health Administration Press Perspectives, 1989); T. Thorn, Health Statistician, Division of

Epidemiology and Clinical Application, National Heart, Lung, and Blood Institute, National Institutes of Health,

personal communication, 1991.

bNational Institute of Mental Health, National Cancer Institute, and National Heart, Lung, and Blood Institute budgets.

Ccosts of mental disorders include costs of dementia.

dFigure includes $29 million for funding of dementia research by the National Institute on Aging.

SOURCE: Office of Technology Assessment, 1992.

ured by research support? As others have noted, the

historical lack of support for this research was

reversed somewhat in the 1980s: Federal funding for

research into mental disorders increased significantly, and new private sources of funding developed. Even with the increased funding of the 1980s,

however, support for research into mental disorders

falls short of that for other conditions in relation to

their cost to society.

What Is the Level of Research Support?

How much of NIMH’s increasing funding goes to

support the areas of research considered in this

report? OTA examined extramural research funding

in two major divisions of NIMH: the Division of

Basic Brain and Behavioral Sciences (DBBBS) and

the Division of Clinical Research (DCR). In 1991,

these divisions accounted for 74 percent of the

extramural research budget—some $287.2 million.

As indicated by its name, DBBBS supports basic

research aimed at furthering the understanding of

basic brain mechanisms and behavior related to

mental disorders. Over the last few years, DBBBS

has received increasing support, with its research

budget reaching $117.6 million in 1991 (figure 1-8).

Specific areas of neuroscience, including molecular

and cellular biology, cognitive neuroscience, neuroimaging, and psychopharmacology research, have

been particularly favored. The annual rate of increase in its budget was 14.5 percent between 1988

and 1992.

DCR consists of six research-oriented branches;

its total research budget in 1991 was $169.6 million.

Two branches-the Schizophrenia Research Branch

and the Mood, Anxiety, and Personality Disorders

Research Branch-target the disorders considered in

this report and receive 50.3 percent of DCR’s

research budget. Between 1986 and 1992, both of

these branches experienced above average funding

increases (figure 1-9). The DCR’s emphasis on

schizophrenia and mood disorders is further reflected in the fact that 16 of its 23 research centers

focus on these disorders.

What Factors Create Barriers to Research?

Funding is not the sole determinant of research

capacity. Various other factors, ranging from the

availability of animals to the number of trained

researchers, influence the success of the research

enterprise. OTA has identified several areas that, if

neglected, can create barriers to research.

Several issues common to all biomedical research

come to bear on research into mental disorders. For

instance, support for facilities and equipment affects

mental disorders research. Efforts to contain healthcare costs also affect clinical research, since thirdparty payers typically cover the costs of clinical care

in research. Another general issue for mental disorders research centers around the representation of all

members of society in research, regardless of age,

sex, race, or ethnic group; concerns about fairness

and the ultimate implications for health and the

advancement of knowledge have driven congressional and executive branch action. Finally, because

the use of animals, especially nonhuman primates, is

critical for neuroscience and research into mental
Chapter 1-Summary, Policy Issues, and Options for Congressional Action ● 17

Figure 1-8—Funding of the Division of Basic Brain and

Behavioral Sciences, Fiscal Years 1988-92

Dollars (millions)

60- “

A

40--------------------------------------------------------- --- -1 I

. It -

20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

I I

1988 1989 1990 1992

 Biological Behavioral

The funding of the Division of Basic Brain and Behavioral

Sciences broken down into biological and behavioral research

(see text).

NOTE: Figures converted to constant 1987 dollars using the 1992 gross

domestic product deflator.

SOURCE: Office of Technology Assessment from figures supplied by

National Institute of Mental Health, 1992.

disorders, developments concerning the use of

animals in research, including tightening regulations

and increased cost, raise concern.

The fact that mental disorders disrupt human

cognitive, emotional, and social capabilities presents special challenges for researchers. For example, how can these complicated effects be studied or

modeled in animals? Also, the unique nature of

mental disorders raises ethical concerns in clinical

research, requiring a careful balancing of individuals’ needs and interests and the need for continued

research. While these issues cannot be eliminated,

investigators can devise ways of dealing with them

effectively. Finally, the stigma attached to and the

ignorance surrounding mental disorders influence

research in a variety of ways, from hindering

recruitment of subjects to amplying privacy concerns.

OTA considered, in some detail, three issues

identified as significant obstacles to research on

mental disorders: the difficulty of obtaining postmortem brain tissue, the cost of hospitalization, and

the number of clinician-researchers.

Figure 1-9—Funding of the Division of Clinical

Research, Fiscal Years 1980-92

Dollars (millions)

40 ,

30

20

10

<

1980 81 82 83 84 85 86 87 88a 89a 90a 91a 92a

Schizophrenia

Mental disorders of the aging

Child and adolescent disorders

Mood, anxiety, and personality disorders

Epidemiology and psychopathology

Prevention

Funding of the six research branches of the Division of Clinical

Research.

NOTE: Figures converted to constant 1987 dollars using the 1992 gross

domestic product deflator.

aFigures include research training.

SOURCE: Office of Technology Assessment from figures supplied by

National Institute of Mental Health, 1992.

The expansion of biological research into mental

disorders makes the availability of postmortem brain

tissue increasingly important. While there are two

federally sponsored brain bank centers in the United

States, as well as an informal supply, the amount of

tissue available for research is simply inadequate.

Improving the banking of brains requires consideration of several factors: funding, standardization of

tissue retrieval and handling methods, attracting

tissue donors, the need for complete medical histories, and safeguarding confidentiality. In an effort to

improve the acquisition process and to better disseminate information about the availability of sources

of brain tissue from various centers, NIMH has

created a task force to make recommendations on

how to coordinate these efforts. A number of

suggestions are under consideration, including the

use of a private institution under contract to NIMH
18 ● The Biology of Mental Disorders

as a clearinghouse for the collection and distribution

of brain tissue. The NIMH task force is also

identifying other needs related to the collection of

brains for research. These include designing systems

to address the problem of the limited samples of

tissue available from persons with specific disorders, and the pressing need for tissue from normal

individuals that can be used as experimental controls.

Studies of subjects who have mental disorders and

who are not taking medications are critical in

investigating the underlying biology of a disorder

and in establishing the effectiveness of new treatments. While several issues influence this research,

the cost of care for medication-free research subjects—

who generally require hospitalization-is a major

obstacle to clinical research. The cost of each

hospital day can range from $300 to over $1,000;

thus, the cost of supporting a single research bed for

a year can range from $109,500 to $365,000. NIMH

funding can be used to support bed costs, but

generally this is not a realistic option, since it would

divert an enormous proportion of funds from other

research activities.

Many experts and organizations have drawn

attention to the apparent shortage of clinician-researchers-namely, psychiatrists and psychologists—

in the United States. Recently, NIMH convened a

task force to make specific recommendations about

the recruitment of investigators into clinical research

careers. While the need for clinician-researchers is

not peculiar to mental health research, some factors

make the situation particularly acute in this field.

Few students in mental health professional training

programs receive formal exposure to research. And

financial issues, including expected salary levels

and the need to pay off medical and/or graduate

school debts, tend to forestall the choice of a

research career.

IMPLICATIONS OF BIOLOGY

Support for neuroscience research, in general and

as it is applied to the study of mental disorders, stems

from a palpable enthusiasm for advances in understanding the human brain. Support for research into

the biology of severe mental disorders is also

intimately linked to the hope for improved treatments for these disorders. While treatments exist,

they are not effective in all cases, and side effects,

some of which are serious, are common. Although a

detailed analysis of the development of new treatments lies outside the purview of this report, OTA

finds that the development of new drugs to treat

mental disorders is one of the greatest promises that

biological research holds. History bears out this

potential, as does the number of drugs being

developed and tested (table 1-4). The increasing and

more precise understanding of the action of chemicals in the brain has facilitated and will continue to

facilitate the development of new medications for

mental disorders. At the same time, important issues

that cannot be overlooked-cost, side effects, forced

treatment-accompany the development and use of

psychoactive medication.

The zeal associated with the current focus on the

biology of mental disorders may benefit from some

tempering. Scientific advances can lead to better

treatment, diagnostic tests, cures, and preventive

measures. However, most new treatments will reflect incremental advances: Significant improvements in the understanding and treatment of mental

disorders are likely to require years, even decades, to

unfold. Some observers have noted that fostering

expectations of rapid progress in discerning the

biological underpinnings of mental disorders or

developing new treatments may provoke impatience, disappointment, or even a backlash against

this research. Perhaps most important, exclusive

emphasis on biological factors could divert resources from other important areas of research and

the provision of care for people currently suffering

from these conditions.

Biological research into mental disorders has

influenced the mental health care finance debate, as

exemplified by recent court cases and State laws.

Coverage for mental health care in both the public

and private sectors is generally lower than coverage

for “physical” illnesses. In order to gain parity in

insurance coverage and to help defray the costs of

these chronic and often severe disorders, some

advocates have emphasized the biological basis of

certain mental disorders, thus invoking the traditional medical model of illness as the most appropriate one for treatment. Also, emphasizing the biological basis of a disorder underlines the fact that the

disorder is outside the control of the individual and

invokes society’s perceived responsibility for providing care. Biological research may also help

insurers in objectively determining an insurable

event, by identifying biological markers for certain

mental disorders, along with effective treatments.
Chapter 1-Summary, Policy Issues, and Options for Congressional Action ● 19

Table 1-4—Drugs in Development for

Mental Disorders

Disorder United States Other countries

Schizophrenia . . . . . . . . . . . . . . . . . . 76 42

Mood disorders . . . . . . . . . . . . . . . . 83 61

Anxiety disorders . . . . . . . . . . . . . . . 91 46

SOURCE: Publications, Surrey, England: Publications, 1992).

Data from research point increasingly to the importance of biological factors in certain mental disorders. This has given rise to other concerns, however,

including coverage of ‘nonbiological’ disorders or

interventions. Furthermore, there is heightened concern about the cost of health care. Given the public

health problem that severe mental disorders present

and the complex issues involved in health care

finance, the way in which care for persons with these

disorders is financed warrants full evaluation.

OTA has identified ways in which information

from research into the biology of mental disorders is

used to counter the ignorance and negative attitudes

that have long been attached to these conditions.

Mental disorders have often been and continue to be

perceived as a sign of moral or personal weakness.

Biological explanations for mental disorders are

used to counter the view that these conditions are

based in moral turpitude, thus exculpating individuals whose disorders may lead to unusual, erratic, or

frightening behavior. Also, the assertion that biological factors contribute to the development of mental

disorders refutes the once-reigning and stigmatizing

notion that bad parenting is the essential, causative

factor. Despite the fact that little or no scientific

evidence supports theories of bad parenting as a

sufficient or necessary cause of severe mental

disorders considered in this report, these theories

continue to shape the attitudes of the public and even

some experts.

The increased emphasis on biological aspects of

mental disorders, while helpful in dismantling some

negative attitudes, is not without limitations. Perceptions of what causes mental disorders are not the

sole source of stigma; other factors, such as personal

experiences and media portrayals (box l-D), influence public attitudes as well. Also, with the increased publicity given biological research data,

questions and worries may arise among individuals

with mental disorders and their families. For example, many family members who have heard about

genetic studies of mental disorders may overestiBlaming the

Credit: Illustration by Robin reprinted by permission of

R. and The Washington Times,

Findings that biological factors underpin certain mental

disorders help relieve individuals and their families

from feelings of guilt.

mate their risk for these conditions. Furthermore, the

perception that mental disorders are inherited could

instill guilt among parents, who fear they might

transmit ‘flaws’ to their progeny. While our current

understanding of the genetics of mental disorders

makes unlikely the development of a single, highly
20 ● The Biology of Mental Disorders

Box 1-D—Media Portrayals of Mental Disorders

Since the late 1950s and early 1960s, studies have consistently revealed a high incidence of media attention

to mental disorders. While media attention contributed significantly to the end of mass warehousing of patients,

often in cruel conditions, much of the information it provided about mental disorders was negative and inaccurate.

Recent studies have shown that although there has been an increase in the frequency of portrayals of individuals

with mental disorders, there has not necessarily been an increase in the accuracy of such portrayals. Surveys of

images of mental disorders on prime-time television conducted in the 1980s found that between 17 and 29 percent

of the shows had some portrayal of mental disorders. Unfortunately, much of that information concerning mental

disorders is inaccurate and stigmatizing.

One of the most persistent and damaging inaccuracies conveyed by the media is the characterization of

individuals with severe mental disorders as violent despite the fact that individuals with severe mental disorders are

more likely to be withdrawn and frightened than violent and are more frequently victims than perpetrators of violent

acts. Violence occurs on television at the rate of approximately six incidents per hour in prime time and 25 incidents

per hour in children’s daytime programming a disprportinate number of these occurrences are either perpetuated

by or against individuals identified as mentally disordered. In fact, characters labeled mentally disordered in

television dramas are almost twice as likely as other characters to kill or be killed, to be violent or fall victim to

violence. Efforts to combat this image are confounded by the fact that some individuals with mental

disorders—particularly when untreated-are at risk of committing violent acts against themselves or others, or both.

Perhaps more troubling is the fact that the stigmatizing equation of severe mental disorder with violence is not

limited to fictional entertainment media. News stories and headlines identifying violent criminals on the basis of

their mental health history, such as the recent Associated Press headline “Woman Who Shot at Restaurant

Previously Committed to Mental Hospital,” saturate the news media, while stories of successful recovery are rare.

Such news stories are damaging to individuals with mental disorders because they suggest both an inescapable

connection between mental disorders and violence and the incurability of mental disorder (that is, even former,

treated mental patients remain prone to violence).

Do these inaccurate and negative depictions of individuals with mental disorders adversely affect public

attitudes? Research has shown that television is able to influence viewers’ attitudes in subtle ways, through the

repetition of images not necessarily labeled as factual. Knowledge specifically concerning the impact of media

depictions of mental disorders on public opinions is limited. Some studies have revealed that programming intended

to increase knowledge of and improve attitudes toward individuals with mental disorders has a positive impact.

However, data indicate that the damaging effects of negative portrayals overwhelm the benefits of the media’s

positive efforts. Negative mass media portrayals of persons with mental disorders generate negative attitudes among

viewers, and corrective information, or disclaimers, has been shown to be largely ineffectual.

Advocacy groups are working to reduce inaccurate and stigmatizing depictions of individuals with mental

disorders in the mass media, For example, the Alliance for the Mentally Ill of New York State operates a Stigma

Clearinghouse that records and responds to inaccurate or stigmatizing media depictions of individuals with mental

disorders, and the National Alliance for the Mentally Ill may soon launch a similar program nationwide. In addition,

the Carter Center in Atlanta, Georgia, has held two conferences addressing the problems of stigma and mental

disorders and the role of the mass media and has subsequently launched a media initiative to address these issues.

SOURCES: Stigma and the Mentally Ill: Proceedings of the First International Rosalynn Carter Symposium on Mental Health Poficy, Nov. 1S,

1985 (Atlan@ GA: Carter Center, 1985); L.R. Marcos, “Media Power and Public Mental Health Policy,*’ American Journal of

Psychiatry 146:1185-1189, 1989; A. Mayer and D. Barry, “Working With the Medkt To Dw@matize Mental Iliness,” Hospitul

and Community Psychiat~ 43:77-78, 1992; Robert Wood Johnson Foundation Program on @ronic Mental Illness, “’Public

Attitudes Toward People With Chronic Mental Illness,” April 1990; O. Wahl, “Mental Illness in the Media: An Unhealthy

CoMitioQ” The Community Imperative, R.C. Barom I.D. RutrnarL and B, Klaczynska (eds.) (Philadelphia, PA: Horizon House

Institute, 1980); O. WaM, Professor, George Mason University, personal communication, Febroary 1992; O. Wahl and J+Y.

Lefkowitz, “Impact of a Television Film on Attitudes Toward Mental Illness,” American Journal of Comnwn ity Psychology

17(4):521-528, 1989; O. Wahl and R. Ro@ “lblevision Images of Mental Illness: Results of a Metropolitan Washington Media

WateL” Journal of Broadcasting 28:599-605, 1982.
Chapter 1--Summary, Policy Issues, and Options for Congressional Action ● 21

predictive genetic test that would be useful across

the general population, the future possibility of

genetic testing-even the perception that mental

disorders are inherited-raises additional concerns

about possible discrimination.

Biological data also may be simplified or misinterpreted. Attributing behavior to biological, especially genetic, factors may lead to the perception that

human actions are predetermineed. Thus, biological

explanations of behavior encroach uncomfortably

on our sense of free will and moral agency.

Furthermore, some observers fear that biological

theories of mental functions reduce human behavior

to the output of the gray mass in our craniums, thus

robbing human thought and emotion of meaning and

import. Individuals with mental disorders may be

especially vulnerable in a society seduced by notions

of biological determinism and reductionism; in this

case, not only are mental functions just the reflection

of brain function, but the brain function is diseased.

The meaning attached to a person’s thoughts and

actions, and the extent to which he or she is

responsible for them, are complex issues requiring

the consideration of biological as well as social,

philosophical, legal, and moral issues, which are

beyond the scope of this report. Nevertheless, it is

important to debunk some of the myths that surround

these issues. Biological theories of causation are not

necessarily more damaging to the person afflicted

with a mental disorder than other theories; one need

only be reminded of the cruel and stigmatizing

concepts of family causation. Nor is it true that a

biological underpinningg is immutable and an environmental one malleable. Recent advances in neuroscience do not suggest that our brains are biologically fried; rather, results increasingly show the

dynamic nature of nervous tissue and its responsiveness to environmental cues throughout life.

POLICY ISSUES AND OPTIONS

FOR CONGRESSIONAL ACTION

The findings of this study attest to the recent

growth of the neuroscience and to a corresponding

surge of interest in the biology of mental disorders.

Researchers have partially uncovered the biological

substrates of some mental disorders and have

propounded testable hypotheses about causes. The

upshot of the scientific advances is expanded

research opportunities, potential treatments, and

new questions regarding how this knowledge is

used. The potential consequences of biological

research into mental disorders raise several policy

issues of congressional interest:

. Federal support for research,

. implications of scientific advances, and

. dissemination of new information.

The following section covers each of these policy

issues and sets forth several options for congressional action. Some options require direct congressional action, while others involve indirect efforts,

such as oversight or direction of the executive

branch. OTA has fashioned a list of reasonable

responses to the policy issues that emerged during

the course of this study. No priority is set nor course

recommended; rather, an analysis of each option and

its likely result is presented.

ISSUE 1: Federal Support for Research

Congress is faced with the question, How should

we support research on mental disorders? The most

important congressional response to this question is

given annually, in the allocation to NIMH; several

observations and results from this study may assist

Congress with its funding decision.

Option 1: Support research at NIMH.

It is no exaggeration to state that advances in

neuroscience have revolutionized the study of mental disorders. While the causes of mental disorders

remain unknown, data from various and diverse

studies illuminate the role of biological factors in

schizophrenia, bipolar disorder, major depression,

OCD, and panic disorder. Furthermore, the intense

efforts and rapid progress in neuroscience portend

increased knowledge about these disorders in the

years to come. New technologies enable scientists to

probe more thoroughly everything from the tiniest

molecules to the interaction of large collections of

nerve cells, giving us insights into the more than 100

billion nerve cells that together make up the brain.

This confluence of technological advances, rapidly

accruing knowledge in the neuroscience, and considerable excitement among researchers calls for, at

the very least, a sustained level of funding for

biological research into mental disorders; undoubtedly, this research enterprise could effectively use

even higher levels of funding. To reduce funding

would be to ignore the opportunities that exist at this

time, thus failing to capitalize on the investment and

gains to date.
22 ● The Biology of Mental Disorders

While this report does not detail the research and

development of specific treatments for mental disorders, OTA finds that one of the greatest promises of

research into the biology of mental disorders is the

development of more effective medications. The

need for and promise of better medications also

argue for continued or enhanced funding. New drugs

resulting from the investment in research could more

than pay for their development costs by offsetting

some of the tremendous burden now borne by

society. For example, it is estimated that the 1969

introduction of lithium to treat bipolar disorder

resulted in average yearly savings in treatment costs

of $290 million in the United States. It was also

estimated that $92 million in lost wages was

regained in the first year following the introduction

of lithium. It is important to note, however, that the

translation of new scientific findings into new

treatments will probably take place over a period of

years, if not decades. Therefore, this must be viewed

as a long-term investment.

Although the social burden of mental disorders is

difficult to compare with that of other types of

illness, it is generally of the same magnitude as

cancer and heart disease. Mental disorders lead to

considerable suffering, disability, and death. These

conditions take a large toll on society, afflicting

millions of Americans and costing the nation more

than $100 billion each year. Yet based on the costs

of the disorders, research spending for mental

disorders is lower than that for cancer or heart

disease. Increased allocation of funds for mental

disorders research would redress this inequity in

funding and demonstrate the priority given to mental

disorders by the Federal Government. The relative

cost of a health problem cannot be the sole determinant of research funding; however, together with the

fact that significant research opportunities exist in

this field, it serves as a strong argument for increased

funds.

It is apparent that several factors argue for

continued, if not increased, funding of mental

disorders research, but Congress must weigh the

relative importance and need for this investment of

Federal dollars against a host of competing programs. It is also important to note that additional

funding would certainly enable researchers to pursue

more scientific opportunities and would yield fruitful gains, but it would also enlarge the system and

increase the number of deserving competitors for

Federal support. Scientific research budgets, including that of the NIMH, have fared well during the past

years of fiscal constraints; however, the growing

Federal debt and mechanisms enacted to address it

have sharpened the competition among federally

financed programs. While a main conclusion of this

report is that continued support for research into the

biology of mental disorders is necessary in order to

reap the potential benefits, this study did not assess

the state of knowledge, relative promise, or warranted priority of other programs or fields of inquiry.

Whatever the level of support for mental disorders

research, it is critical that funding go to the highest

quality research. Given the state of knowledge and

existing research opportunities, how are Federal

monies best invested, with the highest likelihood of

return? OTA finds that maintaining abroad portfolio

of research is the key. Continued investment in basic

research is central to this effort, given the rudimentary, if rapidly growing, state of our knowledge

concerning the brain and its functioning. Basic

neuroscience research will produce more sophisticated hypotheses and methods of analysis, which are

essential to understanding the complex manifestations of mental disorders.

Disorder-targeted funding is also necessary. This

report notes many areas that are prime for research

and that are likely to improve public health. Various

viable hypotheses have been put forth concerning

the causes of mental disorders, but further information is needed concerning the specific manifestations of these conditions and their pattern of

inheritance. Advances in molecular biology and

imaging technologies make possible more detailed

examination of brain function and structure in these

disorders.

Support for disorder-targeted research encompasses clinical studies. Congressional support for

clinical research can be shown in various ways,

among them additional funding for NIMH. The

options that follow are also means of supporting

clinical research.

Option 2: Support clinical research by the VA.

Since the costs of medical care in clinical

investigations at VA hospitals are charged to health

care delivery funds rather than research dollars, a

modest increase in research appropriations could

significantly increase clinical research. Thus, Congress could enhance clinical research by increasing

the VA’s research budget. Furthermore, to foster
Chapter I-Summary, Policy Issues, and Options for Congressional Action . 23

mental disorders research, Congress could direct the

VA to move forward on a recommendation from the

VA Advisory Committee for Health Research Policy, which recommended the creation of a Health

Research Advisory Council to identify and prioritize

those areas with the greatest promise of enhancing

VA health care. The council could be a useful

mechanism for redressing the disparity between VA

medical research expenditures for mental disorders

and their clinical costs.

Option 3: Convene a task force to delineate mechanisms for underwriting bed costs.

Rapidly rising bed costs threaten clinical studies,

which often require hospitalization of subjects

during trials, as well as other persons who are free of

medication. Bed costs can be included in the NIMH

funding made available to the Clinical Research

Centers. Yet few center directors choose to use funds

in this fashion, since it would divert an enormous

proportion of their total funding away from other

priorities. The pharmaceutical industry has recently

recognized the obstacle created by increasing bed

costs; and while some companies have begun

providing support, it is difficult to document the

extent of such support. NIMH has not taken any

direct action in regard to bed costs. In the absence of

congressional action, it is unclear whether NIMH

will address this issue. Thus, this acute need may go

unmet.

Some virtually untapped resources exist to help

defray the expense of bed costs in clinical research.

In an effort to deal with the issue of bed costs,

Congress could direct that a task force be established. The task force could include representatives

of all parties who have a stake in this research and

who can contribute to the solution: clinical investigators, NIMH, health insurance companies, private

foundations, advocacy groups, pharmaceutical companies, State mental hospitals, the VA hospital

system, and general and private hospitals. While it

might be difficult for the many different parties

involved to form a consensus, together they could

devise a workable plan that would take advantage of

existing and unutilized resources (e.g., VA hospitals, State hospitals). In addition to considering cost

issues, the task force could explore research approaches that might be less expensive (e.g., day

hospitals and partial-care centers). NIMH can be

directed to follow the findings and recommendations of the task force.

Option 4: Fund the training of clinician-researchers.

The limited availability of researchers trained as

clinicians has a continuing impact on the quality and

quantity of clinical research. Professionals and

policymakers acknowledge this problem, and NIMH

is poised to address it by enhancing exposure to

research for psychiatrists and psychologists during

training. Support for research centers, which bring

together clinicians and researchers with various

skills to work together on research projects, also

addresses the need for the clinician’s expertise in

studies.

Congress could, however, further respond to the

need for clinician-researchers. Congress established

the National Research Service Awards (NRSA) to

provide for the training of clinician-researchers, but

its appropriations for NRSA have not increased in

the last 12 years. When adjusted for inflation, the

1991 training budget of $26.9 million is $2 million

less than the 1980 budget. Increasing total funding

and increases in the maximum salary for individual

investigators could make this program more effective. Earmarked funds could also be directed to

Research Career Awards and Scientist Development

Award for Clinicians programs, which are generally

considered successful, although underfunded. Simply providing additional training funds is not the

whole solution, or even the most efficient mechanism for dealing with the problem. For example,

forgiveness of medical school debt would be a

powerful incentive. Congress may, therefore, want

to link increased finds to such programmatic issues.

ISSUE 2: Implications of Scientific Advances

Advances in biomedical research during the latter

part of the 20th century have raised new and difficult

ethical, legal, and social questions; research into the

biology of mental disorders is no different. In this

study, OTA considered issues raised both by the

conduct of research and by new findings.

Issues of informed consent and confidentiality

inevitably emerge during the conduct of mental

disorders research. While these issues are neither

new nor entirely unique to the study of mental

disorders, there are special concerns deriving from

the nature of mental illness, its impact on the mind,

and the associated stigma. Furthermore, scientific

advances may add a new twist to these issues. For

example, the process of gathering clinical informa-
24 ● The Biology of Mental Disorders

tion for genetic studies poses questions about what

to tell relatives of individuals with mental disorders

who are contacted for this research. Existing guidelines specify that an Institutional Review Board

(IRB) review the medical, legal, and ethical aspects

of proposed research projects that will involve

human subjects.

The results of research into the biology of mental

disorders also have ethical, legal, and social implications. For example, findings concerning the biology

of mental disorders have become an issue in the

mental health care financing debate. The development of new medication interfaces with ongoing

concerns about the right to refuse treatment. Increased understanding of the genetics of mental

disorders raises the specter of a new age of discrimination against individuals with mental disorders

(box l-E). Advances in brain research challenge our

very conceptualization of the human mind, affecting

such issues as personal responsibility and free will.

Researchers, clinicians, advocates, policymakers,

ethicists, and lawyers have addressed some of the

implications of research findings. However, NIMH

pays little formal attention to the ethical, legal, and

social implications of the results of the research they

sponsor.

Option 1: Direct NIMH to formalize consideration

of ethical, legal, and social issues.

Congress could stipulate that NIMH devise a

systematic plan to deal with the ethical, legal, and

social implications of both the conduct and the

results of mental disorders research. By mandating

such a program and providing funds for it, Congress

would draw attention to these issues and create a

process of anticipating the social impact of research

results. The structure of a program devoted to such

issues could take various forms. It could be modeled

after the National Institutes of Health-Department of

Energy program that considers such implications of

the Human Genome Project: the Ethical, Legal, and

Social Implications, or ELSI, program. Like the

ELSI program, it might fund research into the likely

implications and conduct of biological research into

mental disorders. The NIMH program would foster

the development of knowledge upon which consideration of these issues can be based and would

increase the number of professionals with expertise

in this area.

Such a program is not without potential problems.

Forecasting the impact of scientific advances is

difficult. Also, without a specific focus and a

specific charge, the program might be ineffectual.

The ethical, legal, and social issues raised by

research are complex and sometimes emotionally

charged; they lie at the interface of scientific

knowledge and social values and beliefs. Forming a

consensus about these complex and sensitive issues

is often hard, if not impossible. The resolution of

these issues may be more properly dealt with, in a

democratic society, by a political process such as in

the U.S. Congress rather than an academic or

bureaucratic one.

Option 2: Request topic-specific studies as issues

arise.

Rather than erecting a bureaucratic structure to

handle the ethical, legal, and social implications of

research, Congress could request individual studies

from various governmental or nongovernmental

organizations. This strategy would permit timely

identification of topics for consideration, and the

issues and charges of the study could be clearly

elucidated and circumscribed. While this mechanism would give Congress more direct control over

individual studies and would serve to focus the

studies, it could lead to a piecemeal approach that

does not provide the continuity and comprehensiveness of a permanent program.

Option 3: Establish an advisory commission on the

ethical, legal, and social implications of mental

disorders research.

Individuals with various backgrounds and expertise who are not normally a formal part of the

policymaking process have important insights into

the ethical, legal, and social issues raised by mental

disorders research. Furthermore, such persons have

a stake in how the issues are addressed. In order to

tap into the expertise and interests of these groups,

Congress could establish an advisory commission to

study and make recommendations on aspects of

policy related to the implications of mental disorders

research sponsored by the Federal Government.

Such bodies, including the ongoing Advisory Panel

on Alzheimer’s Disease, have proven useful.

A successful panel would be composed of distinguished and expert representatives from biomedical

research, the social sciences, the legal profession,

care-providing professions, law enforcement, consumers, families, and relevant organizations and

businesses. It is important that membership on the
Chapter 1-Summary, Policy Issues, and Options for Congressional Action . 25

Box l-E—Eugenics and Mental Disorders

In Nazi Germany and the United States during the earlier part of this century, people with mental disorders were

among the initial targets of eugenic policies. People with mental disorders were subjected to immigration

restrictions, involuntary sterilization, and extermination. While modems deny that such practices could be repeated,

the record of eugenics and its historical link to mental disorders raise uncomfortable questions: Is the new age of

genetics a harbinger of a new age of eugenics? Are people with mental disorders especially vulnerable?

Eugenics enjoys a long, well-bred intellectual pedigree, with the cousin of Charles Darwin, Sir Francis Galton,

as its modem forefather. Galton coined the term “eugenics” in 1883, christening the scientific pursuit of improved

inborn human qualities through judicious matings: positive eugenics. Prior to Galton, eugenic notions can be traced

back as far as Plato’s Republic, wherein the philosopher also proposes positive eugenic practices. Of course, the

human genetic pool can be distilled by other means. Negative eugenics refers to the systematic attempt to minimize

the passing of deleterious genes by reducing or preventing the reproduction of individuals carrying such genes.

A number of scientific discoveries planted the seeds of eugenic policies in the 19th and 20th centuries. Galton

himself observed that many accomplished men of his day were linked by blood lines, which led to his belief that

proper matings could produce a race with enhanced intellectual, behavioral, and physical characteristics. In addition,

Galton, as well as others, developed statistical techniques that permitted the quantitative analysis of inherited traits.

While these and other scientific advances were the seeds of eugenics, they were not solely responsible for such

policies in the United States. Social, political, and economic factors of the late l9th and early 20th centuries fertilized

the growth of the eugenics movement. National attention was increasingly focused on social issues of

unemployment, criminality, prostitution, and chronic alcoholism. Also, concerns arose that increased immigration

from southern and eastern Europe was drawing the United States away from its “Anglo-Saxon superiority. ”

At the Federal level, eugenic policies took the form of increasingly restrictive immigration laws, Eugenicists,

asserting the simple inheritance of such traits as lunacy, epilepsy, alcoholism, pauperism, criminality, and

feeblemindedness, proffered scientific rationales for excluding individuals from entry to the United States. It is

important to note that while authentic advances in genetics seeded the eugenics movement, they provided no

evidence for the simple inheritance of the traits mentioned above.

Eugenic considerations also prompted States to enact laws regarding compulsory sterilization. In 1907, Indiana

passed the first law legalizing the compulsory sterilization of inmates at the State reformatory; by 1931,30 States

had passed compulsory sterilization laws applying to individuals categorized as feebleminded, alcoholic, epileptic,

sexually deviant, or mentally ill. Individuals with mental disorders made up half of the 64,000 persons in this

country sterilized for eugenic reason s between 1907 and 1964. When eugenic sterilization laws were challenged in

1927, the Supreme Court ruled the practice was constitutional.

What is the current status of eugenic policies in the United States? While immigration laws still restrict the

entry of people with mental disorders, denial of entry is not based on eugenic principles, but rather on concerns about

whether behavior associated with a disorder poses a threat. State sterilization laws still stand, as does the 1927

Supreme Court ruling upholding them. As of 1987, compulsory sterilization laws remained on the books in 22

States; however, these laws are rarely invoked.

The current application of immigration and compulsory sterilization laws suggests that eugenics is not a major

concern at this time. Furthermore, the understanding that mental disorders do not have a simple genetic basis and

that nongenetic factors play an important role would seem to limit the potential of eugenic policies. Perhaps most

important, Americans repulsion by the Nazi legacy and the emphasis in this country on individual reproductive

rights also make State-deterrnined eugenic policies unlikely. But indirect pressure not to have children may well

come to bear on individuals seen to have a greater genetic risk of mental disorders; society may brand them

irresponsible or immoral for transmitting disorders to their children. Given the financial strain posed by mental

disorders today and the stigma attached to them, in conjunction with scientific advances, it is possible that these

factors could unlock what some call a backdoor to eugenics.

SOURCES: T. Duster, Backdoor to Eugenics (New York, NY: Routledge, 1990); ILL. Carver and B. Garvcx, “Eugenics: Past, Present, and

Future," American Journal of Human Genetics 49:1109-1118, 1991; 1.1. Gottesman, Schizophrenia Genesis: The Origins of

Madness (New York, NY: W.H. Freeman, 1991); D.J. Kevles, In the Name of Eugenics (New York, NY: Knopf, 1985); D. Suzuki

and P. Knudtson, Genethics: The Clash Between the New Genetics and Human Values (Cambridge, MA: Harvard University Press,

1989); N.A. Holtzman, Proceed with Caution: Predicting Genetic Risks in the Recombinant DNA Era (Baltimore, MD: The Johns

Hopkins University Press, 1989).

329-309 0 - 92 - 2 : QL 3
26 ● The Biology of Mental Disorders

commission be balanced in terms of the points of

view represented, something rarely achieved in

mental health policy. This advisory commission

could be established by the Secretary of Health and

Human Services, or Congress itself, and could be

assigned specific issues to address every year or two.

The commission could then study the issue, identify

the problems of concern, develop a consensus on

how such problems can best be met, and present

recommendations for legislation to the Congress and

the States; the commission could also recommend

executive branch regulations, activities, and other

programs.

ISSUE 3: Dissemination of New Information

The Federal Government does not support research into the biology of mental disorders merely to

gain new knowledge. Rather, Federal funds for this

research reflect in large measure a desire for

improved medications as well as for improved

public perceptions of mental disorders and of

individuals with these disorders.

The enthusiasm for and considerable gains in

information about the brain and mental disorders

that have accrued during the last several years speak

to the potential gains in treatment and social

handling of persons with mental disorders. However, to effect better treatment, care, and consideration of such individuals, the knowledge gained from

biological research must be transferred to the public

at large, including individuals with mental disorders

and their families, as well as mental health professionals and policymakers.

There are many indications that the transfer of

new knowledge to those who need and can act upon

it is inadequate. Studies show that providers of

mental health care are sometimes inadequately

informed about the diagnosis and treatment of

mental disorders or that they harbor some negative

feelings about their patients. As noted earlier, the

public at large commonly holds negative attitudes

toward people with mental disorders or are ignorant

about the prevalence, manifestation, or cause of

these disorders. Such ignorance and attitudes have

adverse consequences beyond stigmatizing people

with mental disorders and their families. They also

interfere with successful treatment: Individuals with

Photo credit: Courtesyf the American Psychiatric Association, 1992.

A recent public education campaign, sponsored by the

American Psychiatric Association, highlighted the negative

impact of stigma on treatment-seeking.

a mental disorder may avoid seeking treatment in

order to avoid the associated stigma. Perhaps of most

importance to Congress is the fact that uninformed

and negative attitudes contribute to discriminatory

public policies. A recent report by the Interagency

Task Force on Hopelessness and Severe Mental

Illness highlights the malignant consequences of

negative attitudes on public policy:

Stigmatization, fear, and mistrust regarding people with severe mental illnesses. . are commonplace

in our Nation. Such reactions influence both the

direct responses of community members to these

individuals as well as the development of local,

State, and Federal policies affecting them.

One conclusion that OTA draws from this analysis is that advances in knowledge about mental

disorders do not in themselves ensure better diagnosis, care, or prevention; nor do they guarantee that

public policy keeps abreast of research and development. Those improvements and informed policy also

depend on the dissemination of accurate information

about mental disorders.

The current excitement about brain research,

already recognized by Congress’ declaration of the

1990s as the Decade of the Brain, can provide both

an impetus to and a focus for information dissemination efforts, which began in 1983. That year and

every year since, Congress has passed legislation

that designates one week as Mental Illness Awareness Week.* More recently, several members of the

 a Mental Health Week. subsequent resolution fell under the designation 

Awareness Week.
Chapter 1-Summary, Policy Issues, and Options for Congressional Action ● 27

House of Representatives, who formed a working

group on mental illness, see as one of their first tasks

the education of the “Congress and the American

people about the causes of mental illness and about

new breakthroughs in research and treatment modalities, and to eliminate the ignorance and stigma

surrounding mental illness” (emphasis added).

OTA identifies several options for congressional

action to improve the publics’, providers’, and

policymakers’ understanding of mental disorders.

These options are not mutually exclusive; in fact, a

combination of them may best serve the ultimate

goal of facilitating the transfer of accurate information to the various parties who affect mental health

care and policy.

These options focus on Federal programs, but

they can also influence other dissemination activities. OTA knows full well that there are many other

sources of information about mental disorders. The

media, which often provide a skewed or inaccurate

view of mental disorders, are far and away the

public’s primary source of information about mental

disorders (see box l-D). Furthermore, virtually

every major national mental health organization and

organizations promoting research (e.g., the National

Institute for Brain Research, the Society for Neuroscience) direct educational materials toward the

public. All of these activities may benefit from

improvements in Federal programs that pay attention to recent advances in research and the promise

of more to come.

Option 1: Build upon existing and planned educational efforts on mental disorders supported by

the Federal Government.

The primary Federal source of information on

mental disorders is NIMH. While NIMH has supported an assortment of educational activities, the

centerpiece of its educational effort is the DEPRESSION Awareness, Recognition and Treatment (D/

ART) campaign, which was launched in 1986 (box

l-F). Only last year, NIMH announced a new and

similar program on panic disorder.

Congress can build upon existing and planned

Federal activities, namely the D/ART program, the

panic disorder campaign, and the recommendations

of the Interagency Task Force on Hopelessness and

Severe Mental Illness, to capitalize upon the

strengths of programs already in place. For example,

the use of multimedia presentations, the collaboration with various private organizations, and the

targeting of specific audiences (e.g., care providers)

are all strong points of the D/ART program that

could form a solid foundation for future educational

efforts.

Expanding congressional support for ongoing

Federal educational activities could take several

forms. At the most basic level, Congress could

augment the modest funding for these programs

($8.5 million for D/ART since 1986, or less than $2

million annually). Additional funds could ensure the

expansion of existing programs and the full implementation of planned ones. Of particular importance

to a successful public education campaign are

evaluations of ‘‘outcomes. ’ There has been less

than adequate evaluation of the D/ART program’s

effectiveness, due at least in part to the expense of

such research.

Money is not the only issue. To date, the entire

D/ART program has been managed by only one and

one-half full-time professional staff persons. Thus,

Congress could urge NIMH to give a higher priority

to educational activities in order to maximize the

effectiveness of such programs.

Without establishing any new functions, Congress could direct NIMH to centralize all educational campaigns within a single office, thus improving the efficiency of the programs. At present, the

panic disorder campaign, for example, will be

administered separately from the D/ART program,

even though both have similar goals and objectives:

increased recognition and treatment of a disorder.

Option 2: Target educational activities at secondary

schools.

Currently, students in junior high school and high

school learn little, if anything, about mental disorders, despite the fact that adolescents are especially

interested in the topics of health and human behavior. The Department of Education recognizes the

importance of such instructional opportunities and

includes some mental health information as part of

the health curriculum. That information targets

mental health in the context of family violence, rape,

other emotional crises, the prevention of drug abuse,

stress management, and assertiveness training rather

than specific mental illnesses. Congress could direct

the Department of Education, alone or in conjunction with NIMH, to initiate a grants program to

develop model supplemental curricula on advances
28 The Biology of Mental Disorders

Box l-F—Educating the Public About Depression

Of the 15 million people who experience a major depressive disorder each year, four-fifths can be treated

successfully; yet, only one-third of them seek treatment. Even when people seek treatment, symptoms of a

depressive disorder are often unrecognized or inappropriately treated by health professionals. Given this level of

ignorance, as well as the negative attitudes that surround mental disorders, the Federal Government sponsored its

first major health education program about a specific mental disorder in 1986, with the initiation of the National

Institute of Mental Health’s (NIMH’s) DEPRESSION Awareness, Recognition and Treatment (D/ART) program.

The D/ART seeks to: 1) increase public knowledge of the symptoms of depressive disorders and the availability

of effective treatment, 2) change public attitudes about depression so that there is greater acceptance of depression

as a disorder rather than a weakness, 3) encourage changes in help-seeking behavior to reduce the number of

untreated and inappropriately treated individuals, and 4) provide information to primary care physicians, mental

health specialists, and medical students about advances in diagnosing and treating depressive disorders. The D/ART

program will extend over a decade and consists of three components: a professional training program, a public

education campaign, and a national worksite program.

For fiscal years 1986 to 1991, the D/ART program expended $4.5 million to train health professionals about

recent advances in diagnosis and treatment of depressive disorders (table 1-5). Short-term training courses,

developed for this purpose, have been used to train more than 11,000 primary care physicians, mental health

professionals, and medical students about depressive disorders. In addition, the D/ART program sponsors

continuing education programs in collaboration with professional associations.

In 1988, the D/ART program launched a two-part public education campaign consisting of a multimedia

component to publicize messages about depressive disorders and a community partnership program to extend and

reinforce the media messages at the local level. First, D/ART staff conducted 20 focus groups in nine geographically

dispersed cities and contracted for a survey of 500 people in two cities (Indianapolis, IN and Sacramento, CA) to

find out what people knew about depressive disorders. Furthermore, in the early stages of campaign development,

the D/ART program organized a group of 45 campaign consultant organizations to advise about public education

strategies. The group----comprised of representatives from the major mental health and medical professional

associations as well as health and mental health organizations, businesses, labor, religious, and educational groups,

mental health advocacy groups, foundations, and other Federal agencies----continues to provide advice on campaign

policy matters and to disseminate information on depression.

The D/ART Public Education Campaign has expended $3.6 million in the past 5 years (table 1-5) to develop

educational materials. For example, a total of 16 flyers, brochures, and booklets have been produced and distributed

to more than 13 million people, with some of the publications geared toward the general audience and some to

specific groups, such teenagers, college students, young African-Americans, and older people; some have been

published in Spanish and five Asian languages. Also, close to 1,000 television and 9,000 radio stations have

broadcast public service announcements (PSAs) about depression to as many as two-thirds of households

nationwide. A number of the initial PSAs featured celebrity spokespersons to introduce the campaign.

A critical component of the D/ART program is its community partnership strategy. The Community

Partnership Program consists of 32 mental health groups, mostly “Mental Health Association” and “Alliance for

the Mentally Ill’ organizations, located in 24 States and the District of Columbia. Community partners reproduce

and distribute copies of print materials on depression; conduct public forums, worksite programs, and professional

Table 1-5-DEPRESSION Awareness, Recognition, and Treatment Program, Fiscal Years 1986-91

($ thousands) Total

Area FY 86 FY 87 FY 88 FY 89 FY90 FY 91 FY 86-91

Training . . . . . . . . . . . . . . . . . . . . . . . . 142 520 646 824 1,146 1,250 4,528

(53%)

Public education . . . . . . . . . . . . . . . 292 924 447 745 616 631 3,655

(43%)

Worksite . . . . . . . . . . . . . . . . . . . . . . . N/A N/A 50 5 0 100 100 300

(4%)

Total . . . . . . . . . . . . . . . . . . . . . . . . 434 1,444 1,143 1,619 1,862 1,981 8,483

SOURCE: 1. Davidotf, Director, D/ART Campalgn, National Institute of Mental Healthr Rockville, MD, personal communication, Feb. 28, 1992.
Chapter 1-Summary, Policy Issues, and Options for Congressional Action . 29

seminars; develop videos; appear on television and radio talk shows; sponsor support groups and telephone hotlines,

and carry out other varied educational activities, including brochure translations in five Asian languages. In 1990,

the total dollar value of the programs that were offered and the partners’ direct and in-kind contributions was

estimated at nearly $1.3 million, about ten times the Federal investment in the community Partnership Program.

D/ART also recently initiated a Professional Partnership Program, through which depression-related community

education activities similar to those offered by Community Partners will be developed by universities, foundations,

and professional organizations.

In 1988, the D/ART program established a National Worksite Program as a collaborative effort between NIMH

and the Washington Business Group on Health, a nonprofit health policy group composed of Fortune 500

employers. To date, $300,000 has been expended on this program component. The purpose of the worksite initiative

is to assist employers in reducing the impact of depression on productivity, on health and disability costs, and on

employees and their families. The program disseminates information about depressive disorders to employers and

encourages corporate policies and programs that promote early recognition, quality cost-effective care, and

on-the-job support for individuals experiencing depressive illnesses, The program has developed a‘ ‘Management

of Depression’ model program and published a report based on the experience of seven large U.S. companies that

contributed to development of the model. In 1992, the program will produce a training program for management

personnel and occupational health professionals to improve early recognition and referral to appropriate care for

depression.

Preliminary data suggest that the D/ART program has had some positive effects. For example, prior to the

dissemination of any information, NIMH funded a 1987 telephone survey by the University of Michigan Institute

of Social Research of 500 people (250 in Indianapolis, IN, and 250 in Sacramento, CA) to determine the extent of

their knowledge about depression. The survey found that most people believed that depressed persons could get

better on their own rather than by seeking treatment. In 1990, the American Medical Association conducted a

followup survey of the same group of 500 people. A total of 210 of the original group responded 40 percent of the

responders in Indianapolis and 25 percent of the responders in Sacramento said they knew more about depression

because of the D/ART campaign. AMA also surveyed a new group of 500 people (250 people from each of the two

cities). Of this group, 34 percent of those in Indianapolis and 30 percent of those in Sacramento said they were aware

of the D/ART campaign and its messages. Another survey in North Dakota found that the number of adults treated

for depressive disorders increased 1.5 times and the number of children treated increased 3 times in Human Service

Centers (akin to Community Mental Health Centers) for fiscal years 1986 to 1991. The increase was attributed in

part to the D/ART public and professional education programs and to a State program to develop treatment teams

specifically for children within the Human Service Centers.

Has the D/ART program been a success? While the limited data on the effectiveness of the D/ART program

preclude a quantitatively based answer to this question, several aspects of the program clearly deserve

commendation. With limited resources and personnel (the entire D/ART program is managed by one-and one-half

full-time Federal professional staff persons), the D/ART program established an educational campaign that is

solidly rooted in research advances; the D/ART program carefully devises the messages to be relayed, uses diverse

media to disseminate the messages, and coordinates its efforts with people in the community. D/ART has also

trained substantial numbers of health and mental health care providers through its own efforts and through

collaborations with public and private org anizations. Advancement of this pioneering educational effort on a mental

disorder by the Federal Government-via further study of its effect on the level of awareness, prevalence and

treatment changes, expansion of the program into other communities, and adapting its techniques for educating the

public about other conditions-will require some combination of increased funds and personnel, as well as

highlighting this activity as a priority at the NIMH.

SOURCES: J.E. Barham, Mental Health Ccnsultant, personal communication, May 4, 1992; R. Brown Senior Scientist, Department of Mental

Health, American Medical Association personal communication. June 23, 1992; I. Davidoff, Director, D/ART Campaign, National

Institute of Mental Health, Rockville, MD, personal communication, June 1992; R. Kessler, Institute for Social Research, University

of Michigan, personal communication, June 23, 1992; A. Koss, coordinator of State D/ART Program, Division of Mental Health,

Department of Human Services, B ismarck ND, personal communication, June 22, 1992; D.A. Regier, M.A. Hirschfeld, F.K.

Goodwin, et al., ‘‘The NIMH Depression Awareness, Recognition, and Treatment Program Structure, Aims, and Scientific Basis, ’

American Journal of Psychiatry 145:1351-1357, 1988; D. Regier, Director, Division of Clinical Research National Institute of

Mental Health, personal communication, May 1992; U.S. Department of Health and Human Services, Public Health Service,

Alcohol Drug Abuse and Mental Health Admin istration National Institute of Mental Health, Depression, Awareness, Recognition,

and Treatment (D/ART) Fact Sheet, DHHS Pub. No. (ADM) 90-1680 (Rockville, MD: U.S. DHHS, 1990).
30 ● The Biology of Mental Disorders

in neuroscience and mental disorders. Outstanding

materials, capturing the excitement and complexity

of a scientific area, have been developed on other

topics, including a recent supplement on the genome

project and the ethical issues it poses.

It is important to note that model supplemental

curricula do have some limitations. While they can

be distributed to school districts nationwide, the law

prohibits mandating the use of such materials. Also,

supplemental materials may not be the most fruitful

approach, given the need for comprehensive curriculum development in science education and the large

number of competing supplements now available in

the sciences and in health education.

Option 3: Direct the Federal Government to play a

role in coordinating the training and level of

knowledge of persons caring for individuals with

mental disorders.

Optimal care for individuals with mental disorders relies on providers having accurate, up-to-date

information. Yet, providers face a widening pool of

knowledge from basic, clinical, and rehabilitative

research. Furthermore, the extent to which this

information is included in academic and training

programs remains a matter of institutional choice.

This report did not evaluate in detail the extent of

provider knowledge about mental disorders; however, it did note research evidence that some

providers have less than adequate knowledge about

diagnosing and treating these conditions. As a first

step toward ensuring that providers receive current

and accurate information about mental disorders,

Congress could commission a study on the level of

knowledge of providers and the way in which these

professionals are trained and licensed. Furthermore,

Congress could request that such a study devise

mechanisms for improving the transfer of knowledge to providers.

Option 4: Formalize a mechanism for improving

information transfer and communication among

Federal agencies concerned with mental disorders.

One goal of giving the public information about

mental disorders is to make it easier to develop

public policies that will help people with these

conditions. While such efforts can be important in

shaping the political will needed to bring about

successful policy initiatives, public education is

unlikely to solve many of the problems people with

mental disorders face, at least in the near term.

Indeed, the mechanisms by which Federal policies

on mental disorders are formed and implemented

erect barriers to a rational problem-solving process.

No single agency is primarily responsible for the

issues that affect people with mental disorders;

rather, it is scattered among various agencies,

including several offices and institutes within the

Departments of Health and Human Services (NIMH,

Health Care Financing Administration, and others),

Veterans Affairs, Justice, Labor, Education, Housing and Urban Development, and others. While

NIMH has sometimes offered Federal leadership on

policy issues related to mental disorders, there is

clearly a need for better dissemination of new

research findings, better communication about areas

needing research, and better coordination of policy

planning. This need is likely to become more acute

with the reorganization of the Alcohol, Drug Abuse,

and Mental Health Administration and separation of

NIMH and the newly formed services agency,

SAMHSA, Substance Abuse and Mental Health

Services Administration.

NIMH, recognizing the need for information

transfer, has set out to develop methods and a system

by which knowledge exchange can proceed. Congress could build upon these plans and ensure the

involvement of high-level officials in other Federal

agencies and institutions, so as to create a mechanism for the exchange of information and development of policies and programs, by creating an

Interagency Task Force or Council on Mental

Disorders that would include representatives from

all relevant agencies in the Federal Government. It

could be directed to coordinate research and policy

issues concerning mental disorders and to establish

a mechanism for sharing information among all

officers and employees of the departments carrying

out programs that concern people with mental

disorders.

Some mechanism for facilitating talk among

Federal agencies is needed, given that no single

agency has the jurisdiction or expertise to address

thoroughly the issues associated with mental disorders. The composition of the task force is the single

most important key to its success. Representatives

from every relevant agency should be included. In

addition, task force members should have adequate

experience, expertise, and authority to devise and

help implement policies and programs. The chair of

the task force is also important; ideally, this person
Chapter 1-Summary, Policy Issues, and Options for Congressional Action . 31

would bring personal dedication and sufficient

authority to help drive the group’s efforts. A clear

charge is necessary to focus the work of the group.

Congress could specify topics for study every year

or two and request that a report be made at the end

of that time. The report would elucidate the topic and

provide for policy initiatives.

One topic could be consideration of the financing

of mental health care. Research advances, whether

the development of new treatments or changing

conceptualizations of the causes of mental disorders,

clearly have influenced and will continue to influence the issue of mental health care financing. A

study involving NIMH and other agencies in the

Federal Government with expertise in and jurisdiction over the financing of health care and the

provision of services could review the relevant

factors and issues and develop a cohesive Federal

policy. A final point should be made: Even in the

event of a successful effort on the part of the task

force, certain policy and program suggestions may

be forestalled until adequate funds are provided.
Chapter 2

Introduction
CONTENTS

THE MODERN HISTORY OF NEUROSCIENCE

A CAUTIONARY NOTE . . . . . . . . . . . . . . . . . . . . . . . .

Page

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

THE OTA STUDY ... ... ... ... ... ... ... ... ... .o. ... ..o o. ..*o* 8. + o* o. *.o c. .o ****. * 39

CHAPTER 2 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . 40

Box

Box Page

2-A. The Cost of Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36

Figures

Figure Page

2-1, The Cost of Mental Disorders, 1985 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

2-2. Membership in the Society for Neuroscience ● . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Table

2-1. Prevalence of Severe

Table

Page

Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Chapter 2

Introduction

Mental disorders can strike with savage cruelty,

producing nightmarish hallucinations, crippling paranoia, unrelenting depression, a choking sense of

panic, or inescapable obsessions. The sheer number

of Americans with mental disorders transforms this

personal tragedy into a widespread public health

problem. Nearly one in three American adults will

experience a mental disorder during his or her

lifetime, including schizophrenia, mood disorders,

anxiety disorders, antisocial personality disorder,

substance abuse, or cognitive impairment (23,25)

(table 2-1) (see ch. 3).1 Altogether, approximately

1.7 to 2.4 million Americans currently suffer from a

persistent and severely disabling mental disorder (15).

What are the costs of this public health problem?

The most comprehensive estimate of the total costs

of mental disorders—for the year 1985—is $103.7

billion (24) (figure 2-1) (box 2-A). A recent update

of this figure estimated that the costs of mental

disorders in 1991 reached $136.1 billion (20). Dollar

figures alone, however, no matter how large, do not

convey the toll that mental disorders take. It has been

estimated that individuals with mental disorders fill

25 percent of all hospital beds and, further, that

one-third of these persons suffer from schizophrenia

(10,15). In 1986, more than 2 million episodes of

inpatient care in the United States were provided for

persons with mental disorders (16). Many such

Table 2-l—Prevalence of Severe Mental Disorders

Adults diagnosed with

disorder during their

lifetime

Disorder (o/’\

Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.o

Bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0.8

Major depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.9

Obsessive-compulsive disorder . . . . . . . . . . . . . . . . 2.6

Panic disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6

SOURCE: L. F/. Robins and D.A. Psychiatric Disorders in America,

The Epidemiologic Area Study (New York, NY: Free

Press, 1991).

Figure 2-l—The Cost of Mental Disorders, 1985

(in billions of dollars)

Other costs

$4.5

Direct health-related costs

$42.5

In 1985, mental disorders cost the United States more than $103

billion. Approximately 41 percent of that cost-$42.5 billion—

stemmed from hospital care, medication costs, and other treatment costs. Nearly half of the cost of mental disorders—$47.4

billion-derives from lost productivity.

SOURCE: Rice, S. Miller, et al., The Economic of

Alcohol and Drug Abuse Mental Illness, report submitted to

the Office of Financing and Coverage Policy, Alcohol, Drug

Abuse, and Mental Health Administration, U.S. Department of

Health and Human Services (San Francisco, CA: Institute for

Health and Aging, University of California, 1990).

disorders, including depression, obsessive-compulsive disorder, and panic disorder, are associated with

increased use of general health care services (25).

Productivity and the ability to work are also

significantly compromised by mental disorders (2,

19,44). For example, the results from one study

indicate that major depression leads to a more than

fourfold increase in disability days, defined as days

‘‘in which a person spent all or part of the day in bed

due to illness or was kept from usual activities due

to feeling ill” (4). Data show that approximately

one-third of the homeless population and 10 to 15

percent of individuals incarcerated in jails and

prisons have a severe mental disorder such as

schizophrenia or bipolar disorder (i.e., manicdepressive illness).2

1 from of resulted from Of

more than 20,000 persons in five sites during the early 1980s. Some variation in prevalence estimates was reported between sites. See references 7 and

25 for discussion of the methods used in the ECA program.

 of disorders among the homeless population and among individuals in jails prisons resulted 

estimates, due to definitional problems (see 3), data collection and political views (5,12,14,30,34,35). The percentages cited in the text

represent generally accepted estimates.
36 ● The Biology of Mental Disorders

Box 2-A—The Cost of Mental Disorders

How big a problem do mental disorders present to our Nation? What priority should these disorders receive

in the outlay of government funds for research and services? The answers to these questions are often sought in terns

of a dollar figure. However, estimating the toll of mental disorders, or any illness, in economic terms is no easy or

straightforward task. Everything from the cost of hospitalization, which is relatively easy to estimate, to the cost

of reduced productivity, which is more difficult to assess, may be evaluated. And while rarely included in studies,

the psychological and social tolls on an individual’s life are substantial, though not easily quantified.

During the last 40 years, studies have reported that mental disorders cost the Nation from $3.6 billion to more

than $100 billion each year. The variation in estimates reflects changes over time as well as the use of different

methods of calculation and sources of data. Dorothy Rice and colleagues have derived the most comprehensive

estimate, based on the most recently available survey data. They estimate the total costs of mental

disorders-including schizophrenia major depression, bipolar disorder (manic-depressive illness), anxiety

disorders, somatization disorder, antisocial personality disorder, and cognitive impairment-to be $103.7 billion

for the year 1985. When adjusted for inflation, this figure reaches $136.1 billion in 1991.

These costs include health-related, or core, costs-that is, the expenditures made and resources lost as a

consequence of having a mental disorder. Such costs make up 96 percent of the total estimated costs for 1985, or

$99.2 billion. Health-related costs can be broken down further into direct and indirect costs.

Direct health-related costs--$42.5 billion in 1985 and more than $58 billion in 1991-include all expenditures

related to the treatment and support of persons with mental disorders. The vast majority of these direct costs-92

percent-are related to treatment and involve expenditures on hospital and nursing home care, physician and other

professional services, and drugs (figure 2-l), More than 50 percent of the treatment costs-almost $22 billion in

1985-were spent on care in institutional or hospital settings, such as Department of Veterans Affairs (VA)

hospitals, State and county psychiatric hospitals, private psychiatric hospitals, residential treatment centers for

emotionally disturbed children, and short-stay (general) hospitals. The costs of care provided by office-based

physicians, psychologists, and social workers amounted to approximately $5.7 billion in 1985. Approximately $1.5

billion was spent on prescription drugs, including minor tranquilizers, antidepressants, and antipsychotics. The

estimate reached more than $2.2 billion in 1991, when adjusted for inflation. Support costs, which equaled

approximately $3.2 billion in 1985, include expenditures for research, physician and nurse training, and program

administration (such as health insurance).

Indirect health-related costs estimate the burden of increased morbidity and mortality that accompanies mental

disorders. These estimates, which are based on the National Institute of Mental Health’s Epidemiologic Catchment

Area prevalence data, include the value of lost output caused by decreased productivity, lost workdays, or premature

death. Rice and colleagues do not include measures of the psychological and social effects of mental disorders on

the individual’s life. Morbidity and mortality costs were estimated at $47.4 billion and $9.3 billion, respectively,

in 1985. For 1991, estimates were $60.0 billion for morbidity costs and $11.7 billion for mortality costs. Thus,

according to these data, lost or diminished productivity is the most costly outcome of mental disorders, with

morbidity accounting for nearly 50 percent of the total costs of mental disorders. Furthermore, the cost of morbidity

is not primarily due to institutionalization. Additional analysis, which considers such factors as the prevalence of

mental disorders in various demographic groups, the type of disorder, and income levels, shows that a very large

share of the morbidity costs-$44.l billion in 1985 and $55.8 billion in 1991 ---delves from noninstitutionalized

individuals.

Mental disorders have other, nonhealth-related effects that impose a cost on society. Nonhealth effects lead

to public and private expenditures on crime control and social welfare administration, the sum of which was

estimated at $1,7 billion by Rice and colleagues. Furthermore, the value of reductions or losses in productivity due

to either incarceration for a c riminal offense or time spent to care for a family member with a mental disorder exacts

a price, estimated at approximately $2.8 billion.

SOURCES: D.P. Rice, S. Kelman, L.S. Miller, et al., The Economic Costs of Alcohol and Drug Abuse and Mental Illness: 1985, report submitted

to the Office of Financing and Coverage Policy, Alcohol, Drug Abuse, and Mental Health Administr ation, U.s. Department of

Health and Human Services (San Francisco, CA: Institute for Health and Aging, University of California, 1990); The National

Foundation for Brain Research, The Costs of Disorders of the Brain (Washington, DC: 1992).
Chapter 2-Introduction ● 37

The reality of mental disorders—their symptoms,

their prevalence, and their costs-commands society’s attention, but society’s response is incoherent.

Despite the fact that Federal, State, and local

governments spend more than $20 billion each year

on mental health services, the consensus is that

mental health policy is fragmented and mental

health services often deficient (9,18,26,33,40,43).

While a tangle of clinical, economic, social, professional, and legal issues impinges on mental health

policy, the answer to the question “What causes

mental disorders?” is also important in formulating

rational mental health policy. As stated more than a

decade ago in the President’s Commission on

Mental Health report:

Expanding our understanding of the functioning

of the mind, the causes of mental and emotional

illness, and the efficacy of various treatments is

crucial to future progress in mental health (22).

The fundamental causes of most mental disorders

are unknown. However, the 1980s witnessed an

explosion of biomedical research into the nature of

these disorders (3). While a number of factors,

including the agenda of some professional groups

and the concerns of some consumer advocacy

groups, 3 contribute to the emphasis on the biological

aspects of mental disorders, the rapid growth and

productivity of neuroscience research spearhead this

trend. One indicator of the growth in neuroscience is

the increased membership of the Society for Neuroscience: Membership in this professional organization

grew from 1,100 at its inception in 1970 to more than

17,000 in 1990 (figure 2-2) (28). In 1992, the Society

for Neuroscience has more than 19,000 members

(29). The 1980s saw a nearly 70 percent increase in

the number of papers published in neuroscience and

behavioral research (27). Congress captured this

enthusiasm for neuroscience in its Decade of the

Brain resolution, approved in 1989, to make “the

Nation . . . aware of the exciting research advances

on the brain. . . .’ (Public Law 101-58; see also app.

A to this report).

20,000

16,000

12,000

8,000

4,000

Figure 2-2—Membership in the Society

for Neuroscience

1.100

17,524 / .

7.097

1970 1980 1990

Membership in the Society for Neuroscience has grown dramatically since its inception in 1970.

SOURCE: for 1991.

THE MODERN HISTORY

OF NEUROSCIENCE

Neuroscience research focuses on how the nervous system works and how it is affected by disease.

It is an interdisciplinary field, drawing on expertise

from many diverse fields, including anatomy, physiology, physics, electronics, genetics, biochemistry,

optics, pharmacology, psychology, neurology, psychiatry, neurosurgery, and computer science. The

seeds of modern neuroscience were sown in the late

19th and early 20th centuries, when astute clinical

observations and basic technical advances led to

such fundamental discoveries as the location of

specific functions within the brain and nerve cells.

There was palpable enthusiasm about being on the

brink of understanding the human mind. As is often

observed by today’s neuroscientist, even Sigmund

Freud, the father of psychoanalysis, entertained the

hope of unveiling the brain’s relationship to human

thought and behavior.

The slow march of progress in neuroscience

research proceeded through the subsequent years.

The serendipitous discovery of several agents that

profoundly affect the symptoms of severe mood

 For Alliance for the Mentally Ill a family-based advocacy aPPro 130,000 members, strongly

supports biomedical research into mental disorders, in part to promote the development of better treatments and, ultimately, cures for mental disorders

(8). staunch support for the biological basis of mental disorders reflects an anti-stigma stance and a rebuttal to theories g the family

for causing mental disorders (see 7).
38 . The Biology of Mental Disorders

o

o

The congressional “Decade of the Brain” resolution, the activities

of executive branch agencies, as well as the private efforts of

scientists and other advocates all demonstrate enthusiasm for

neuroscience research. Pictured is the logo for the National

Foundation for Brain Research, a nonprofit organization that

promotes brain research.

SOURCE: The National Foundation for Brain Research, 1992.

disorders and schizophrenia ushered in a new age of

neuroscience research in the 1950s. The finding that

chemical substances can modulate, even control,

mental dysfunction was not completely alien to

contemporary understanding of the brain, for the

chemical nature of nerve cell communication was

known. It did, however, precipitate an explosion of

research in neurochemistry and psychopharmacology. In the ensuing years, many chemical substances

occurring naturally in the brain-neurotransmitters

and neuropeptides-were identified.

There was also a quantum leap in understanding

how neurotransmitters and neuropeptides influence

targeted nerve cells. Receptor molecules-proteins

embedded in the surface of nerve cells that bind

chemical substances-were identified and isolated.

Like a key inserted into a lock, a neurotransmitter

fits into a specific receptor, producing a cascade of

responses in the receptive neuron (see ch. 4). A

single neurotransmitter may activate several different receptors, located in distinct regions of the brain.

To date, five different receptors have been found to

respond to the brain chemical dopamine alone (31).

The exponential increase in neuroscience research

during the last 15 years reflects, in large measure,

technological advances (for review, see 36,41).

Dramatically improved methods for staining nerve

cells permit researchers to observe the precise

location of these cells in the brain. The electrical

activity of a single channel in a nerve cell’s

membrane-which is less than one-trillionth of an

inch in diameter-an be measured. Progress in

computing and advances in microscopy, especially

imaging technology, underlie the spectacular view

of living brain tissue-from single nerve cells to the

intact human brain. Psychological tests, which

analyze and measure the components of complex

behaviors and thought processes, make possible

analysis of the brain’s functions. And molecular

biology has revolutionized the study of the brain,

resulting in the labeling of specific nerve cells with

monoclinal antibodies, the cloning of receptors, and

the search for specific genes.

The sophisticated methods and technologies of

modern neuroscience research make up the arsenal

being used to expose the secrets of mental disorders.

The National Institute of Mental Health (NIMH), the

primary Federal agency that funds research into

mental disorders, has drawn up its battle plan on the

basis of developments in neuroscience (41,42). By

strongly supporting neuroscience research, NIMH

aims to:

. . . understand the workings of the human brain in

sufficient detail to effectively treat or prevent the

broad variety of behavioral disorders and mental

illnesses (41).

A CAUTIONARY NOTE

It is easy to appreciate how excitement about

neuroscience might affect the study of mental

disorders and foster hope for new treatments.

However, the complexity of the brain and behavior,

the nature of mental disorders, and the potential

repercussions of this research require a note of

caution.

Neuroscience research has produced many exciting results, but it has only scratched the surface of

understanding how the brain functions. The neuroscientist Wilder Penfield realized earlier in this

century that “there was a thrilling undiscovered

country to be explored in the mechanisms of the

mammalian nervous system” (21). The brain is an

immensely complicated organ: It contains 1011 nerve

cells, and estimates suggest that the number of

synapses in the brain, 1014, exceeds the number of
Chapter 2-Introduction ● 39

stars in our galaxy (13). Mapping the terrain of this

still largely “undiscovered country” will require

continued research, cross-disciplinary cooperation,

and sophisticated management of rapidly accruing

information (11).

The complexity of the brain is reflected in its

fictional output: thought, emotion, and behavior.

Thus, mental disorders, which are identified essentially on the basis of psychological and behavioral

traits (1) rather than laboratory findings, are perplexing phenomena, difficult to define and classify (see

ch. 3 for detailed discussion of the definition of

mental disorders). Difficulties in classifying mental

disorders can present a serious challenge to biological and behavioral research.

Neuroscience is based on the concept that behavior, thoughts, and emotions are the results of nerve

cell interaction (36). Mental disorders, like any other

illnesses, however, cannot be understood in biological terms only. As the National Advisory Mental

Health Council Report to Congress (41) acknowledged, each mental disorder ‘‘. . . represents a complex interaction of biological, psychological, and

social variables. ’ While there is overwhelming

enthusiasm for biological research into mental

disorders, there is also concern that emphasizing

biological factors exclusively will shortchange other

important areas of research as well as care of the

mentally ill.

With impressive developments in molecular biology, the neuroscience, and imaging technology,

psychiatry has moved toward a more biological and

medical emphasis. Although these fields hold great

promise, efforts must proceed in a balanced way to

provide high quality management for those currently

ill while seeking more powerful technologies for the

future. The history of mental health care attests to

how endorsement of organic viewpoints and the

professionalization of psychiatry, when it had little

specific to offer in any immediate terms, undermined

constructive and humane efforts for patient management and rehabilitation (17).

Great hope surrounds neuroscience research in

general and biomedical research into mental disorders in particular. Some of the predicted fruits of

neuroscience include new and improved treatments

for mental, neurological, and substance abuse disorders; reduction, prevention, or reversal of agerelated changes in cognition; and development of

measures to enhance cognitive performance and

productivity (6,36,41).

There can be no doubt that neuroscience research

will lead to improved understanding of how the

brain works and even to the development of new

treatments. There also can be no doubt that improved

understanding of the biology of mental disorders

will raise new and difficult questions concerning the

privacy of genetic information, genetic discrimination, the forcible administration of mind-altering

agents, concepts of free will and personal responsibility, the way third-party payers cover mental

disorders, and other issues (6,36). Eugenic policies

(see ch. 5) and treatment approaches used earlier in

this century, which sprang from enthusiasm for (and

sometimes misunderstanding of) biological theories

of mental disorders, serve as a reminder of the

potential misuses of biological advances. Few supporters of neuroscience research mention the potential ethical and legal dilemmas it poses; while the

Federal Government has developed a detailed neuroscience research strategy, no official mechanism for

considering the possible implications of this research, such as the one organized by the Human

Genome Project, has been formalized or even widely

discussed.

THE OTA STUDY

Approximately 40 percent of all public funds

spent on mental health services-$8 billion each

year-derive from Federal sources (33). The Federal

Government is also the primary source of support for

research into mental disorders and mental health,

with NIMH’s research budget totaling $497.4 million in 1991 (see ch. 6). The large Federal investment

in mental health research- combined with congressional interest in neuroscience research-led the

House Committees on Energy and Commerce;

Science, Space and Technology; Appropriations;

and Veterans Affairs and the Senate Subcommittee

on Science, Technology, and Space of the Committee on Commerce, Science, and Transportation to

request and Senator Edward M. Kennedy to endorse

an Office of Technology Assessment (OTA) report

on the status and implications of biological research

into mental disorders.

This report reviews the data from research on the

biology of several mental disorders, including schizophrenia bipolar disorder, major depression, obsessivecompulsive disorder, and panic disorder. These

disorders-some of the most severe and long-lasting

ones that afflict adults-have been subjected to

extensive experimental scrutiny aimed at identifying
40 ● The Biology of Mental Disorders

causal factors in the brain.4 The focus of this report

reflects that of recent research-namely, the widely

held opinion that biological factors contribute significantly to mental disorders and that medication

and other somatic interventions generally form a

critical component of the clinical management of

these disorders.5 The causative roles of psychological and social factors (which are important for a

comprehensive understanding and treatment of mental disorders) and broad mental health issues are

beyond the scope of this report.

In the five chapters that follow, OTA examines: 1)

the nature of mental disorders in general and the

clinical features of the mental disorders considered

in this report; 2) results of research into biological

factors that contribute to these disorders; 3) the

heritability of these disorders and the clinical

implications of genetic research; 4) the support for

research into mental disorders and barriers to

research; and 5) the impact on public attitudes and

policy issues of new knowledge about the biology of

mental disorders.

1.

2.

3.

4.

5.

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American Psychiatric Association, Diagnostic and

Statistical Manual of Mental Disorders, 3rd cd., rev.

(Washington, DC: American Psychiatric Association, 1987).

Anthony, W.A., and Blanch, A., “Supported Employment for Persons Who Are Psychiatrically Disabled: An Historical and Conceptual Perspective, ”

Psychosocial and Rehabilitation Journal 11(2):5-23,

1987.

Barondes, S. H., “The Biological Approach to Psychiatry: History and Prospects,” Journal of iVeuroscience 10:1701-1710, 1990.

Broadhead, W. E., Blazer, D. G., George, L.K., et al.,

“Depression, Disability Days, and Days Imst From

Work in a Prospective Epidemiologic Survey,”

Journal of the American Medical Association 264:

2524-2528, 1990.

Cohen, C. I., “Crime Among Mental Patients—A

Critical Analysis,” Psychia~ic Quarterly 52:100-

107, 1980.

6.

7.

8.

9.

10.

11$

12.

13.

14

15.

16.

17.

18.

Downey, M., “hgal Issues in Brain Science Advances, ’ Courts, Health Science and the Law

1:471-483, 1991.

Eaton, W.W., and Kessler, L.G. (eds.), Epidemiologic Field Methods in Psychiatry: The NIMH Epidemiologic Catchment Area Program (Orlando, FL:

Academic Press, 1985).

Flynn, L., Executive Director, National Alliance for

the Mentally Ill, personal communication, Feb. 27,

1992.

Fr~ R., and Kamlet, M. S., “Direct Costs and

Expenditures for Mental Health in the United States,

1980,” Mental Health, United States, 1985, DHHS

Pub. No. (AIM) 87-1518, C.A. Taube and S.A.

Barrett (eds.) (Washington, DC: U.S. Government

Printing Office, 1985).

Institute of Medicine, Research on A4entalIllness and

Addictive Disorders: Progress and Prospects (Washington, DC: National Academy Press, 1984).

Institute of Medicine, Mapping the Brain and Its

Functions (Washington, DC: National Academy

Press, 1991).

Interagency Council on the Homeless, Outcasts on

Main Street: Report of the Federal Task Force on

Hopelessness and Severe- Mental Illness, (ADS)

92-1904 (Washington, DC: 1992).

Kandel, E.R., Schwartz, J.H., and Jessell, ‘KM.,

Principles of Neural Science, 3rd ed. (New Yorlq

NY: Elsevier Science Publishing, 1991).

bvine, 1. S., and Haggard, L.K., “Homelessness as a

Public Mental Health Problem,” Handbook on

Mental Health Policy in the United States, D.A.

Rochefort (cd.) (New York, NY: Greenwood Press,

1989).

Manderscheid, R.W., and Barrett, S.A. (eds.), Mental

HeaZth, United States, 1987, DHHS Pub. No. (ADM)

87-15518 (Washington, DC: U.S. Government Printing Office, 1987).

Manderscheid, R.W., and Sonnenschein, M.A. (eds.),

Mental Health, United States, 1990, DHHS Pub. No.

(ADM) 90-1708 (Washington, DC: U.S. Government Printing Office, 1990).

Mechanic, D., “Recent Developments in Mental

Health: Perspectives and Services,” Annual Review

of Public Health 12:1-15, 1991.

Mechanic, D., “Strategies for Integrating Public

Mental Health’ Services,” Hospital and Co-mmunity

Psychiatry 42:797-801, 1991.

4 A sm~ but vociferous group of ex-patients, advocates, and others contends that labeling individuals as severely and persistently men@Y W is

pejorative (32). Their antipathy stems, in large measure, from an antipsychiatry stance and rejection of involuntary hospitalization and treatment. While

many in this group generally accept that individuals diagnosed with what are called mental disorders have undeniable deficits and face terrible problems,

they look askance at biological theories of mental disorders because of their association with disparaging labels, forced treatment and other civil liberty

issues. The implications of biological explanations of mental disorders are considered in chapters 3 and 7. A discussion of the important legal, social,

and ethical issues that surround involuntmy commitment and forced treatment are beyond the scope of this report.

5 Addictive &order5, A~eimer~s di5=5e, ~d developmen~ disorders such as autism ~ve been Or me being discussed h Omer OTA reports ~d

therefore are not considered in any detail in this report (37,38,39).
Chapter 2Antroduction ● 41

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32,

33.

Mental Health Policy Research Center, Database,

Policy in Perspective (Washington, DC: July 1990).

National Foundation for Brain Research, The Costs of

Disorders of the Brain (Washington, DC: 1992).

Penfield, W., The Mystery of the Mind (Princeton, NJ:

Princeton University Press, 1975).

President’s Commission on Mental Health, vol. 1,

stock No. 040-000-00390-8 (Washington, DC: U.S.

Government Printing Office, 1978).

Regier, D. A., Farmer, M.E., Rae, D. S., et al.,

“Comorbidity of Mental Disorders With Alcohol

and Other Drug Abuse: Results From the Epidemiologic Catchment Area (ECA) Study,” Journal of the

AmericanMedicalAssociation 264:251 1-2518,1990.

Rice, D. P., Kelrnan, S., Miller, L. S., et al., The

Economic Costs of Alcohol and Drug Abuse and

MentaZ ZZZness: 1985, report submitted to the Office

of Financing and Coverage Policy, Alcohol, Drug

Abuse, and Mental Health Administration, U.S.

Department of Health and Human Services (San

Francisco, CA: Institute for Health and Aging,

University of California, 1990).

Robins, L. N., and Regier, D. A., Psychiatric Disorders in America: The Epidemiologic CatchmentArea

Study (New York NY: Free Press, 1991).

Rochefort, D.A., “Mental Illness and Mental Health

as Public Policy Concerns, ’ Handbook on MentaZ

Health Policy in the United States, D.A. Rochefort

(cd.) (New York, NY: Greenwood Press, 1989), pp.

3-20.

Science Watch, ‘‘Biotechnology, Critical Care, Computing Top List of Lost-Growth Fields in Science,”

Institute for Scientific Information 9:1-2, 1991.

Society for Neuroscience (Washington, DC: 1991).

Society for Neuroscience, Neuroscience Newsletter

23:1, May 1992.

Steadman, H.J., Monahan, J., Duffy, B., et al., “The

Impact of State Mental Hospital Reinstitutionalization on United States Prison Populations, 1968-

1978,” Journal of Criminal Law and Criminology

75:474-490, 1984.

Sunahara, R.K., Hong-Chang, G., O’Dowd, B. F., et

al., “Cloning of the Gene for a Human Dopamine D~

Receptor With Higher Affinity for Doparnine than

Dl,” Nature 350: 614-619, 1991.

Thompson, R., National Association of Psychiatric

Survivors, Bethesda, MD, personal communication,

1992.

Torrey, E. F., Erdman, K., Wolfe, S. M., et al., “Care

of the Seriously Ill: A Rating of State Programs, ’

Public Citizen Health Research Group and National

Alliance for the Mentally Ill, 3rd ed. (Washington,

DC: Public Citizen Health Research Group and

National Alliance for the Mentally Ill, 1990).

34.

35.

36.

37.

38.

39.

40.

41

42.

43.

44.

U.S. Congress, General Accounting Office, Homeless Mentally Ill: Problems and Options in Estimating Numbers and Tren&, GAO/PEMD-88-24 (Washington, DC: August 1988).

U.S. Congress, General Accounting Office, MentaZZy

Ill Inmates, GAO GGD-91-35 B-242958 (Washington, DC: 1991).

U.S. Congress, Office of Technology Assessment,

Impacts ofNeuroscience, background paper, OTA-BPBA-24 (Washington, DC: U.S. Government Printing

Office, March 1984).

U.S. Congress, Office of Technology Assessment,

Children’s Mental Health: Problems and Services,

background paper, OTA-BP-H33 (Washington, DC:

U.S. Government Printing Office, December 1986).

U.S. Congress, Office of Technology Assessment,

Losing a Million Minds: Con$-onting the Tragedy of

Alzheimer’sDisease and OtherDementias, OTA-BA323 (Washington, DC: U.S. Government Printing

Office, April 1987).

U.S. Congress, Office of Technology Assessment,

Technologies for Understanding the Root Causes of

Substance Abuse and AaUiction, in progress.

U.S. Department of Health and Human Services,

Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Caring

for People With Severe Mental Disorders: A National Plan of Research To Improve Services, DHHS

Pub. No. (ADM) 91-1762 (Washington, DC: 1991).

U.S. Department of Health and Human Services,

Alcohol, Drug Abuse, and Mental Health Administration, Approaching the 21st Century: Opportunities for NIMH Neuroscience Research: The National

Advisory Mental Health Council Report to Congress

on the Decade of the Brain, DHHS Pub. No. (ADM)

89-1580 (Washington, DC: 1988).

U.S. Department of Health and Human Services,

Alcohol, Drug Abuse, and Mental Health Administration, A National Plan for Schizophrenia Research:

Panel Recommendiztions, DHHS Pub. No. (ADM)

88-1570 (Washington, DC: 1989).

U.S. Department of Health and Human Services,

Alcohol, Drug Abuse, and Mental Health Administration, Healthy People 2000: National Health Promotion and Disease Prevention Objectives (Washington, DC: 1990).

Wells, K. B., Stewart, A., and Hays, R.D., “The

Functioning and Well-Being of Depressed Patients:

Results of the Medical Outcomes Study,” JournuZ of

the American Medical Association 262:914-919,

1989.
Chapter 3

What Are Mental Disorders?
A

CONTENTS

Page

DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

THE MENTAL DISORDER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S 47

AR

DESCRIPTION OF

Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47—- Mood Disorders . . . . . . . . . . . . . . .

Anxiety Disorders . . . . . . . . . . . . .

CHAPTER 3 REFERENCES . . . . .

Box

3-A. One Day in the Life of Sylvia

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .53

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64

Boxes

Page

Frumkin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .48

3-B. The Final Symptom: Mental Disorders and Suicide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

3-C. Darkness Visible: A Personal Account of Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

3-D. Alcohol, Drugs, and Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

3-E. The Auto

Figure

Accident That Never Was . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

3-1. The Course of Schizophrenia

3-2. Substance Abuse and

Table

Figures

Page

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51

Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57

Tables

Page

3-l. The Diagnosis of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...*...*

3-2. Traditional Antipsychotic Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-3. The Diagnosis of Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,

3-4. The Diagnosis of Mania . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-5. Medications for the Treatment of Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-6. Psychotherapy and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,

3-7. The Diagnosis of Obsessive-Compulsive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-8. obsessions and Compulsions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

47

53

55

55

58

59

62

63

3-9. The Diagnosis of Panic Disorder . . . .. . ... ...;.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Chapter 3

What Are Mental Disorders?

What are mental disorders? For centuries, philosophers, physicians, psychologists, and others have

debated this question, variably defining and classifying mental disorders on the basis of presumed

causes, observed symptoms, preferred treatment

approaches, or social and political values. This lack

of agreement has led many to the pessimistic

conclusion that:

[H]istory or experience has not produced a

generally accepted definition of mental disorder. . .

nor is such a definition likely to be forthcoming in

the foreseeable future (17).

The vagaries of definition do not negate the

concrete problems mental disorders pose for individuals and society. Rather, society is confronted with

the proposition of responding to disorders with

important public health, economic, and social implications in the absence of any neat scheme for

addressing them. This chapter explores the problems

inherent in defining and classifying mental disorders

in general and the symptoms, effects, and treatment

of the specific disorders considered in this report.

DEFINING MENTAL DISORDERS

Defining a general concept such as mental disorders may seem at first blush to be an abstract,

academic pursuit. After all, general concepts of

health, disease, and illness evade easy definition,

spawning debate over the most useful or appropriate

framework for analyzing them (53). Is health simply

the absence of disease? How do social values

influence decisions about what constitutes disease?

The way these general terms are defined influences

the boundaries of medicine, professional interest,

and perceived social responsibility. A series of

recent court decisions on insurance coverage highlights the importance of specifying what mental

disorders are. Decisions both to extend and to limit

insurance benefits stemmed from the definition of

mental disorders accepted by the courts ( 18,63). This

section considers the difficulty of defining mental

disorders, the conceptual frameworks that have been

erected, and the way mental disorders are classified.

Part of the confusion in defining mental disorders

arises from their broad reach and nebulous boundaries. A wide array of behaviors has been classified as

symptomatic of mental disorders, ranging from

premenstrual syndrome, hostility toward others, or

other maladaptive personality traits to full-blown

psychosis (3,67). In addition, it is sometimes difficult to delineate where mental health ends and

mental illness begins. As observed by Emil Kraepelin, the 19th century patriarch of mental disorder

classification:

Wherever we try to mark out the frontier between

mental health and disease, we find a neutral territory,

in which the imperceptible change from the realm of

normal mental life to that of obvious derangement

takes place (36).

While the boundary between physical health and

disease can also be indistinct, the lack of clarity

between mental health and illness contributes to the

impression that mental disorders encompass normal

or willful differences in human thought, behavior,

and emotion.

The way mental disorders are defined influences

issues of research, treatment, social welfare, and

public health and safety. Decisions regarding the

appropriateness of treatment, research funding priorities, the financing of care by third-party payers,

accommodation at the workplace, and criminal

responsibility hinge, in part, on expert and popular

concepts of mental disorders (85). Furthermore,

mental health personnel include many different

professionals and paraprofessionals: psychiatrists,

psychologists, psychiatric social workers, psychiatric nurses, and other therapists and counselors. Each

of these groups has its own area of expertise and

professional agenda, and sometimes they conflict

(72), creating another obstacle to a unified definition

of mental disorders.

The fact that mental disorders affect primarily

thought, emotion, and behavior further hinders

efforts to arrive at a definition. There is a certain

uneasiness about defining as diseased those aspects

of the human mind by which we relate to, empathize

with, and judge each other. The centuries-old

conceptual divide between the mind, as the seat of

thought, and the brain, as a biological entity, impairs

our ability to classify mental disorders as diseases of

the brain. Although an unambiguous link between a

biological process and a higher mental function,

4 5 –
46 ● The Biology of Mental Disorders

such as consciousness, has yet to be completely

delineated, advances in the neurosciences, psychology, and computer science challenge rigid mindbrain dualism. Clinical medicine is also starting to

bridge the mental-physical gap; the influence of

mental factors on physical health and disease, as

well as that of physical factors on mental disorders,

is becoming increasingly apparent (14,26,27,86).

Many persons in the mental health field, including

professional groups (36,46), the National Institute of

Mental Health (97), and other advocates (32), as well

as physicians in general (39), assert the importance

of biological, psychological, and social factors in

understanding and treating health and disease (34).

Unfortunately, the impasse in defining mental

disorders and prioritizing mental health needs has a

negative impact on public perception and stalls the

formulation of public policy. The cause and effect of

this deadlock are described by David Rochefort (85),

a political scientist and expert in mental health

policy:

Since policy design arises from problem definition, lack of consensus about the nature of the

problem being dealt with works counter to a

collective sense of purpose and direction in mental

health policy making. Although advocates for improved mental health care number many, their

influence is often diffused in advancing different

priorities for the investment of limited public resources. The situation is exacerbated by specialists’

inability to reach agreement upon the boundaries of

normal behavior or even the proportion of cases of

recognized abnormality severe enough to warrant

public intervention.

While it might thwart public policy, the definitional dilemma has not impeded research into and

treatment of specific mental disorders. As psychiatristresearcher Nancy Andreasen (8) observes:

Mental illness is an abstract concept, with disputable defining characteristics and debatable boundaries. On the other hand, specific illnesses are more

easily delineated. There are many different kinds of

mental illness that differ in their severity, symptoms,

outcome, and effect on the patient’s life.

The classification of disorders is the cornerstone

of data collection and analysis; it also predicts the

outcome for a particular patient and determines the

mode of treatment. The last decade saw advances in

the classification of specific mental disorders, with

the revision of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental

Disorders (DSM) (3).1 It is difficult to overestimate

the influence of the most recent editions of this

manual: DSM-III (2) and DSM-III-R (3). They are

the most widely used mental health diagnostic

manuals in the world. They provide the framework

for studies of mental disorders, and in most cases a

DSM-diagnosable disorder is required for thirdparty reimbursement of treatment costs. Given its

widespread use and acceptance, the lexicon of

DSM-III-R is used in this report.

DSM-III and DSM-III-R offer several improvements over previous editions of this manual. First,

classifications are not founded on unproven notions

of what may cause specific disorders.2 Both editions

identify most mental disorders on the basis of

expressed mood or thought processes or on observed

behaviors. Second, they improve the reliability of

diagnosis. The criteria for reaching a diagnosis are

explicit, diagnosis is less subjective, and there is

greater agreement on diagnosis among clinicians

(57).

The revised DSMs are not without critics. Some

controversy stemmed from the way specific disorders were selected for inclusion-essentially by

consensus of experts who did not represent the full

spectrum of mental health professionals. In addition,

the detailed criteria for specific disorders make

diagnosis formulaic, diminishing the role of clinical

judgment. However, the increased reliability of

diagnosis is generally considered to outweigh these

criticisms. As stated by one researcher, “We are

better off having it than not” (42).

While the diagnostic categories listed in DSM-III

and DSM-III-R may lead to more reliable diagnoses,

the validity of the categories remains uncertain (83).

Validity refers to how well the description of a

particular disorder reflects the true attributes of a

causative factor or disease process—that is, how

well it reflects what patients really have and what

physicians really see. Mental disorders are classified

on the basis of symptoms because there are as yet no

1 me Rese~ch Dia~ostic criteria(RDC) was a forerunner of DSM-111 (91). It is also used for Rsearch pwoses.

2 while DSM.~ ~d ~-R we ~eu~~ regm~g the cause of di~fict disorders, ~ey ~e not ,s~cdy ath~retical. They apply a categorical model (36)

to diagnosis; that is, their vantage point is one of delimiting categories of disorders in line witb the traditional medical approach. Other models for mental

disorders are also possible.
Chapter 3—What Are Mental Disorders? ● 47

biological markers or laboratory tests for them. Such

groupings, therefore, may not be completely valid—

similar symptoms may result from a variety of

causes. The validity of very few diagnostic categories in the DSM has been demonstrated; in fact,

methods for evaluating diagnostic validity have

been proposed, among them studying the course of

symptoms over time and the eventual outcome of the

disorder, patients’ responsiveness to treatment, the

concentration of the disorder within families, and

biological and psychological measures (81). Alternative approaches to research, such as evaluating the

biology of particular symptoms, are also important

in understanding psychopathology. Obviously, pinpointing the causes of mental disorders would go a

long way toward specifying their boundaries and

validating the way in which they are categorized. As

one researcher states:

Few psychiatric disorders have yet been adequately validated and it is still an open issue whether

there are genuine boundaries between the clinical

syndromes and normality. In the long run validation

depends on the elucidation of etiological process

(58).

A DESCRIPTION OF THE

MENTAL DISORDERS

Despite the fact that defining mental disorders in

general and determiningg their boundaries specifically are difficult tasks, there is no doubt that the

disorders considered in this report-schizophrenia,

bipolar disorder, major depression, obsessivecompulsive disorder, and panic disorder—are genuine and often severe. They generally emerge in late

adolescence or early adulthood (19). They are

chronic and disabling, sometimes ravaging patients

over the entire course of their adult lives. The

following sections provide an overview of each

disorder, summarizing their symptoms, classification, prevalence, course, and most common treatment. Boxes throughout the chapter describe individual experiences with some of the disorders.

Schizophrenia

Schizophrenia ‘‘is arguably the worst disease

affecting mankind” (74) (box 3-A). It assails

thought, perception, emotion, behavior, and movement, distorting an individual’s personal experience

of life and crippling his or her ability to participate

in society.

Table 3-l—The Diagnosis of Schizophrenia

A. Presence of characteristic psychotic symptoms in the active

phase: either (l), (2), or (3) for at least 1 week (unless the

symptoms are successfully treated):

B.

c.

D.

E.

F.

1: Two of the following: - “

a) delusions;

b) prominent hallucinations throughout the day for several

days or several times a week for several weeks, each

hallucinatory experience not being limited to a few brief

moments;

c) incoherence or marked loosening of associations;

d) catatonic behavior;

e) flat or grossly inappropriate affect (emotional tone).

2. Bizarre delusions, i.e., involving a phenomenon that the

person’s culture would regard as totally implausible (e.g.,

thought broadcasting, being controlled by a dead person).

3. Prominent hallucinations [as defined in (l)(b) above] of a

voice with content having no apparent relation to depression or elation, or a voice keeping up a running commentary

on the person’s behavior or thoughts, or two or more voices

conversing with each other.

During the course of the disturbance, functioning in such areas

as work, social relations, and self-care is markedly below the

highest level achieved before onset of the disturbance.

Schizoaffective disorder (a combination of schizophrenia and

mood disorder symptoms) and mood disorder (mania or

depression) with psychotic features have been ruled out.

Continuous signs of the disturbance are seen for at least 6

months.

It cannot be established that an organic factor (brain tumor or

trauma, drug intoxication, etc.) initiated and maintained the

disturbance.

If there is a history of autistic disorder, the additional diagnosis

of schizophrenia-is made only if prominent delusions or

hallucinations are also present.

SOURCE: American Psychiatric Association, Diagnostk and Statistical

Manual of Mental Disorders, 3rd cd., rev. (Washington, DC:

American Psychiatric Association, 1987), as edited by 1.1.

Gottesman, Schizophrenia Genesis: 7he Origins of Madness

(New York, NY: W.H. Freeman and Co., 1991).

Schizophrenia is not split personality, a commonly held misperception (100). Its hallmark is a

disturbance of cognition, the processing of information (table 3-1) (9,42,95,97). Components of thought

may become dissociated or fragmented, the flow of

thought interrupted. Schizophrenia typically impairs

the ability to integrate information, to reason, to

concentrate, or to focus attention or purpose. The

consequence is often an observed vagueness, illogicality, and bizarreness of thinking that, when severe,

restricts interpersonal communication.

Individuals with schizophrenia experience delusions and hallucinations. Delusions are beliefs that

are clearly implausible but that are compelling and

central to an individual’s life experience. Persons

with this disorder may be suspicious or paranoid in

nature. For example, a patient may believe that he or
48 ● The Biology of Mental Disorders

Box 3-A--One Day in the Life of Sylvia Frumkin

Shortly after midnight on Friday, June 16,1978, Sylvia Frumkin decided to take a bath. Miss Frumkin, a heavy,

ungainly young woman who lived in a two-story yellow brick building in Queens Village, New York, walked from

her bedroom on the second floor to the bathroom next door and filled the tub with warm water. A few days earlier,

she had had her hair cut and shaped in a bowl style, which she found especially becoming, and her spirits were high.

She washed her brown hair with shampoo and also with red mouthwash. Some years earlier, she had tinted her hair

red and had liked the way it looked. She had given up wearing her hair red only because she had found coloring

it every six weeks too much of a bother. She imagined that the red mouthwash would somehow be absorbed into

her scalp and make her hair red permanently. Miss Frumkin felt so cheerful about her new haircut that she suddenly

thought she was Lori Lemaris, the mermaid whom Clark Kent had met in college and had fallen in love within the

old “Superman’ ‘ comics. She blew bubbles into the water.

After a few minutes of contented frolicking, Miss Frumkin stepped out of the tub. She slipped on the bathroom

floor-it was wet from her bubble-blowing and splashing-and cut the back of her head as she fell. The cut began

to bleed. She attempted to stop the bleeding by applying pressure to the cut, then wrapped her head in a large towel

and walked back to her bedroom. On the dresser was a bottle of expensive perfume that an aunt and uncle had given

her in May as a thirtieth-birthday present. She poured the contents of the bottle on her cut, partly because she knew

that perfume contained alcohol and that alcohol was an antiseptic . . . and partly because she suddenly thought that

she was Jesus Christ and that her bleeding cut was the beginning of a crown of thorns, She also thought that she

was Mary Magdalene, who had poured ointment on Christ. . . .

Miss Frumkin’s head burned when the perfume came in contact with the open cut, and the bleeding subsided

but didn’t altogether stop. By then, it was after one o’clock. She put on an old nightgown and went downstairs to

the office of the building to tell the night supervisor, Dwight Miller, who was on duty from midnight until

eight-thirty, what had happened. Miller looked at the cut, told Miss Frumkin to get dressed, and said he would drive

her to the emergency room. . . .

As Miller started the car, turned on the car radio, and began to drive toward the hospital, Miss Frumkin seemed

to get excited. The radio was playing Paul McCartney’s song “The Lovely Linda,” and he was singing the words

“La, la, la, la, la, the lovely Linda. ” Unknown to Miller, Miss Frumkin thought that McCartney was singing the

lyrics sarcastically, because he had fallen in love with her and was no longer in love with Linda, his wife. Miss

Frumkin began to talk fervently to the radio. Miss Frumkin and Miller arrived at the emergency room of

L. I.J.-Hillside at two o’clock Miss Frumkin was first interviewed and examined by a nurse. For a few minutes, she

was in sufficient control of herself to let the nurse take her vital signs, test her neurological responses, and look at

her cut, and to answer the questions the nurse asked. . . . She became upset while she was waiting to see a doctor

and an X-ray technician (she began to speak rapidly, and what she said concerned suffering from hypoglycemia and

Wilson’s disease and being Cinderella, and didn’t make much sense); more upset when the X-ray technician took

X rays of her skull and the doctor sewed up the cut (Miss Frumkin was so agitated that the doctor succeeded in

putting in only three of five silk sutures he had intended to put in); and still more upset when it turned out that there

would be a fairly long wait for the skull X rays to be read, Miss Frumkin got so obstreperous while she and Miller

were waiting in the main area of the emergency room that they were shown into one of the small treatment rooms

off to one side that the hospital uses to give people privacy, where they were joined by a hospital security guard.

In the small treatment room, Miss Frumkin’s conduct became increasingly bizarre. She took off all her clothes,

accused Miller of kidnapping her and making sexual advances, and then asked Miller and the security guard to have

sexual relations with her, saying she hadn’t had sex with a man in 5 years. The minute the two men would cover

Miss Frumkin with a hospital gown, she would disrobe again.

Around three o’clock, Dr. Conrad Aaronson, a psychiatric resident, came to observe and question Miss

Frumkin. . . . His impression of Miss Frumkin's condition was that it was an acute exacerbation of chronic

schizophrenia-one of the most common forms of serious mental illness in the world. Dr. Aaronson found that Miss

Frumkin was in no shape to return to her room in Queens Village. He wrote in his report, at 4:15 a.m., ‘‘Patient

removed all her clothing and began chanting and praying on the floor at the conclusion of the interview. . . . Patient

is in need of emergency hospitalization as she represents a danger to herself and to others in her present condition.

Miss Frumkin was asked if she would like to be admitted to the psychiatric division of L. I. J.-Hillside. . . . [S]he

refused to be admitted there. Instead, she asked to be taken to the Creedmoor Psychiatric Center, in Queens

Village--a State mental institution that serves the two million people who live in Queens. . . . She had been a patient

there until about two weeks earlier-from May 9, 1978 to May 31, 1978. . . . Miss Frumkin returned to Creedmoor

. . . at five-thirty, just as the sun was rising. . . .
Chapter 3--What Are Mental Disorders? ● 49

It was after eleven o’clock in the rooming on Friday, June 16, by the time Miss Frumkin had been screened

for admission by Dr. Sun, had changed into State clothes, and had taken a chair in the women’s day hall. Soon she

was on her feet, hurrying over to the nurse on duty. She demanded to use the telephone. When the nurse told her

she would have to wait until another patient had finished making a call, Miss Frumkin screamed at her. The nurse

escorted her to the telephone a few minutes later. Miss Frumkin dialed the extension of Dr. Werner, Creedmoor’s

director. She tried to tell Dr. Werner’s secretary her troubles, but became incoherent. The nurse and a therapy aide

had to struggle with her to get her to put the telephone down. The nurse, who had been at the admission screening,

then led Miss Frumkin to the treatment room and tried to give her the injection of Thorazine that Dr. Sun had ordered

that she be given immediately for agitation. Miss Frumkin refused the injection. She said she would take Thorazine

orally instead. . . . Between sips of the bad-tasting Thorazine, Miss Frumkin called the nurse a jerk, a slut, and a

dodo. After Miss Frumkin’s insults became threats and she started to hit the nurse, the nurse went to Dr. Sun, caught

him just as he was leaving, and got him to write out a seclusion order, which went into effect at twelve-fifteen. Once

Miss Frumkin had been put in the seclusion room, she flopped down on the mattress as if she were relieved to be

there. A few minutes later, a therapy aide brought her lunch on a tray. Miss Frumkin, who had been mumbling

unintelligibly, took the tray, wolfed down the food, and handed the tray back. She soon lay down and dozed off.

When the seclusion order expired, at two-fifteen, the door to the room was opened Miss Frumkin was asleep. She

was left in the room to sleep, with the door open.

Miss Frumkin awakened shortly before four, but she appeared content to stay in the quiet room. Around five

o’clock, she felt hungry, got up, and walked into the day hall. When the door to the dining room corridor was opened,

she went into the corridor and stood in line with the other patients, whispering to herself. . . .

After shoveling into her mouth three helpings of everything served at dinner on June 16, Miss Frumkin

returned to the day hall, settled into an easy chair, and watched television quietly. At nine o’clock she took the 50

milligrams of Moban that Dr. Khanna had prescribed for her. A therapy aide on the evening shift let her watch TV

until ten-thirty before taking her into the dormitory, where the other women were already asleep. She assigned Miss

F’rumkin an empty bed next to a window. . . . Although Miss Frumkin had had little sleep in the last thirty-sixhours,

she wasn’t tired. She got into bed without taking her clothes off and lay quietly under the sheets and under the

bedspread, which the therapy aide had forgotten to remove.

A few minutes after the night shift came on duty, Miss Frumkin got out of bed. She walked hurriedly down

the long corridor from the dormitory to the day hall. She then headed back toward the dormitory, but stopped at the

employees’ lunchroom when she saw a short, stocky black woman named Bernice Parrott sitting there. Miss

Frumkin told her that there was some water on the floor of the day hall and asked her if she had a mop. When Mrs.

Parrott replied that she didn’t, Miss Frumkin. warned her that if she didn’t mop up the water she would report her

to the night supervisor. Mrs. Parrott asked Miss Frumkin to go back to bed, and said she would take care of the water.

Mrs. Parrott went into the day hall, found a puddle of urine on the floor, and went to the utility room to get a mop.

When she returned to the day hall carrying the mop, she found Miss Frumkin standing a few feet from the puddle.

Miss Frumkin ordered Mrs. Parrott, at the top of her voice, to clean up the day hall. Before Mrs. Parrott could clean

anything, Miss Frumkin ran over to her and demanded the mop. Mrs. Parrott held onto the mop with all her strength,

fearful of what Miss Frumkin would do with it if she got her hands on it. Miss Frumkin grabbed Mrs. Parrott’s dress,

struck her several times on the head with her fist, kicked her, and tried to bite her, screaming "Nigger, I’ll nix you!”

as she fought to gain possession of the mop. Mrs. Parrott was in pain, but she whirled around, pinned Miss Frumkin

against a wall, pried herself loose, and ran to the nearest telephone, which was in the ward office. She hurled the

mop through an open door to the employees’ toilet, in the far corner of the office, picked up the telephone, and called

the night supervisor, who was in the secretaries’ office in the central corridor watching some members of the night

shift sign in. Meanwhile, with her free hand Mrs. Parrott continued to fend off Miss Frumkin , who had followed

her into the office and was still after the mop. Mrs. Parrott and Miss Frumkin wrestled; Mrs. Parrott succeeded in

bringing Miss Frumkin to the floor and was able to hold her until the night supervisor came to her assistance. . . .

Mrs. Parrott and the night supervisor put Miss Frumkin into an empty seclusion room. Miss Frumkin was

banging furiously on the door of the seclusion room. The nurse telephoned the doctor on night duty.. . and he gave

her a verbal order to put Miss Frumkin. in seclusion for two hours. Mrs. Parrott and the night supervisor helped the

nurse hold Miss Frumkin down so that the nurse could give her the Thorazine injection for agitation ., . Miss

Frumkin remained agitated all night. . . .

Sheehan. Reprinted b y permission of Houghtonn Mifflin Co.
50 ● The Biology of Mental Disorders

she is a historical figure or that someone has placed

a transmitter in his or her brain. Hallucinations are

perceptions without an objective basis. They most

commonly take the form of voices or, less frequently, visions, bodily sensations, tastes, or smells.

The voices appear to originate from an external

source. They tend to be highly personal and may

direct the patient to do some act, sometimes commanding self-mutilation or other violent behavior.

Another prominent feature of schizophrenia is

impairment of emotional responsiveness. There is a

dulling of emotions or an inappropriateness of

emotional response. Many individuals with schizophrenia exhibit a “wooden” personality, displaying

traits of diminished drive, curiosity, or spontaneity.

Schizophrenia may also lead to a disturbance of

movement. Patients may grimace involuntarily,

walk awkwardly, or suffer impairment of a broad

range of subtle movements.

Delusions, hallucinations, and impairments in

thought that are marked by incoherence, illogicality,

or bizarre behavior together constitute the “positive” symptoms of schizophrenia. These symptoms

are typical of psychosis (7); however, schizophrenia

and psychosis are not synonymous. Psychosis can

accompany other disorders, such as mood disorders,

drug-induced reactions, temporal lobe epilepsy,

Huntington’s disease, encephalitis, and syphilis.

There are many pathological features of schizophrenia that are not psychotic, such as the blunting of

emotions, apathy, and social withdrawal, all “negative” symptoms of schizophrenia (6,7).

While schizophrenia has been well-characterized

as a disorder, symptoms vary widely among patients. Symptoms combine in various ways, and they

change over time. This variability has raised questions about how best to conceptualize schizophrenia.

Is it a single disorder? A group of disorders? A

conglomerate of several disease processes? What is

its relationship to other mental disorders?

German psychiatrist Emil Kraepelin was the first

to consolidate the diverse manifestations of schizophrenia under a single rubric-dementia praecox, or

dementia of the young (62). Eugen Bleuler introduced the term schizophrenia, referring to a split in

mental activities, in 1911 (16). This name emphasizes what Bleuler thought was the primary pathology: the dissociation of thoughts, emotion, and

behavior. This conception of a single underlying

disease process has endured. Those who support this

concept assert that a unified cause or mechanism

produces the various symptoms of the disorder. The

fact that the varying manifestations of schizophrenia

appear to be genetically related (see ch. 5) and that

they often respond to similar treatment approaches

supports the single-disorder model.

Another model considers schizophrenia to be a

clinical syndrome rather than a single disease entity

(97). This view holds that although schizophrenia

can legitimately be distinguished from other mental

disorders (e.g., mood disorders), it has more than one

cause. This has led some persons to refer to it as the

schizophrenias. Because schizophrenia is such a

complex disorder and its underlying pathology

remains elusive, many expect that more than one

cause will eventually be discovered.

Some researchers have proposed that distinct

disease processes independently produce some of

the symptoms of schizophrenia; that is, no single

culprit causes all of the symptoms of schizophrenia.

While, certain symptoms do appear to occur semiindependently (20,93,94)-for example, the extent

of psychosis is only modestly associated with the

extent of social impairment-further study is necessary to test this hypothesis.

Schizophrenia may be related to other mental

disorders. Certain personality disorders, typified by

eccentric behavior, excessive suspiciousness or

paranoia, or extreme indifference to others, are

considered part of the schizophrenia spectrum by

many researchers, since they resemble schizophrenia and tend to run in families with the disorder (see

ch. 5). Some have suggested that mood disorders

with psychotic symptoms may also be related to

schizophrenia (24,35). Similarly, schizoaffective

disorder, which is typified by symptoms of schizophrenia and major mood disorders, has been thought

to stem from some of the same causes as schizophrenia. A relationship between mood disorders and

schizophrenia is suspected because many persons

exhibit symptoms common to both categories of

disorders.

Schizophrenia is a common disorder. Approximately 1 of every 100 persons will develop schizophrenia during the course of his or her lifetime

(30,55,84). That translates into 1.2 million people

with schizophrenia in the United States today. Men

and women appear to be at equal risk, although

schizophrenia generally strikes men at a younger age
Chapter 3—What Are Mental Disorders? ● 51

Figure 3-l—The Course of Schizophrenia

25%0 25%

Improved, recovered

relatively

independent 

Improved, but 

35%

Improved,

relatively

independent

Deceased

 suicide)

 recovered

159’0

10 years later

Hospitalized,

unimproved

Improved, but

extensive support Hospitalized,

unimproved

30 years later

While schizophrenia does not lead inevitably to lifelong disability, the majority of individuals with this rendition suffer long-term

consequences.

SOURCE: Adapted with permission from Torrey, Surviving Schizophrenia: A rev. (New York, NY: Harper & Row, 1988).

and women generally have a better long-term

prognosis.

Demographic data on schizophrenia paint a picture of considerable social and economic distress

(55,95). Individuals who have never been married or

who are divorced or separated suffer schizophrenia

two to three times as often as their married or

widowed counterparts. Compared to the general

population, individuals with schizophrenia are less

likely to hold a college degree or to be employed. If

employed, they are likely to earn less than persons

without schizophrenia. Studies have consistently

shown that schizophrenia occurs more often among

persons in lower socioeconomic groups: It is five

times more prevalent among those at the bottom of

the socioeconomic ladder than those at the top.3

There is a long-standing tendency among both

professionals and laypersons to presume that schizophrenia invariably follows a deteriorating course,

resulting in an exceptionally poor outcome in most

cases. This assumption has always been incorrect.

Patients suffering from the disorder have followed a

variety of courses over the long term, including

some that are relatively benign (figure 3-1). It is true,

however, that there are substantial and enduring

consequences for most patients.

One of the hallmarks of schizophrenia is its early

onset, usually during the late teens and early 20s

(22). Onset of schizophrenia may be sudden, with an

unexpected development of psychosis, or it may be

insidious, with the earliest signs occurring years

before the blatant symptoms of psychosis. Early

signs include emotional withdrawal, diminishing

social engagement, low energy, and idiosyncratic

responses to ordinary events or circumstances.

School performance, social interaction, and emotional responsivity may erode gradually, well in

advance of the onslaught of hallucinations, delusions, and disorganized thought processes. A more

sudden onset usually results in a more favorable

outcome.

Psychotic symptoms may persist over an extended period of time, with the patient never

achieving full recovery, or they may be episodic,

with periods of psychosis followed by relatively

complete recovery (96). A substantial number of

patients continue to manifest symptoms of schizophrenia throughout their lives. The expressed symps hypotheses t. rates of schizophrenia among persons 

hypothesis and the downward drift hypothesis. Simply stated, the breeder hypothesis holds that social stress, such as poverty, causes schizophrenia. The

downward hypothesis states that the disorder itself leads to downward social mobility (29,42).
52 ● The Biology of Mental Disorders

Box 3-B—The Final Symptom: Mental Disorders and Suicide

In 1987, 11.7 people in every 100,000-more than 30,000 people--killed themselves in the United States,

making it the eighth leading cause of death in the nation. While many factors are associated with suicide, including

medical illness, availability of&arms, or stressful events such as a divorce or loss of a job, data indicate that mental

disorders are a significant antecedent to many suicides in the United States. About 50 percent of all suicide victims

may have suffered a mood disorder, and an estimated 5 to 10 percent of suicide victims suffered from schizophrenia.

Among people with schizophrenia suicide is the number one cause of premature death, with the estimated

age-adjusted suicide rate averaging 90 per 100,000 women with schimphrenia and 210 per 100,000 men with the

disorder, 10 to 15 percent of individuals with schizophrenia commit suicide. The higher rate of suicide among men

versus women with schizophrenia not only mirrors the suicide statistics in the general population, but also reflects

the more severe symptoms that men usually suffer. Some people with schizophrenia may commit suicide as a result

of a psychotic episode-in response to a hallucinatory command. More commonly, however, people with this

condition take their lives early in the course of the illness during a relatively stable period following a recent

hospitalization.

Approximately 15 percent of people with mood disorders will commit suicide, with the suicide rates for men

and women with major mood disorders averaging 400 and 180 per 100,000, respectively, 30 times higher than the

rate in the general population. The link between mood disorders and suicide is well recognized, with recurrent

thoughts of suicide or a suicide attempt being diagnostic criterion for these conditions. Other mental disorders, such

as panic disorder, also appear to be correlated with suicide. Although there is little information available concerning

the number of people with panic disorder who actually commit suicide, survey data show that approximately 20

percent of people with this condition will attempt suicide during their lifetime.

High rates of suicide among individuals with major mental disorders like schizophrenia or major depression

provide chilling evidence of the distressing nature of mental disorders. Furthermore, the strong correlation between

mental disorder and suicide indicates that general suicide prevention efforts must include strategies to improve the

treatment of mental disorders.

SOURCES: C.B. Caldwell and I.I. Gottesman, “Schizophrenics Kill Themselves Too: A Review of Risk Factors for Suicide," Schizophrenia

Bulletin 16(4):571-589, 1990; F.K. Goodwin and K.R. Jamison, Manic-Depressive Illness (New York, NY: The Oxford University

Press, 1990); J. Johnson, M.M. Weissman, and G.L. Klerman, ‘‘Panic Disorder, Comorbidity, and Suicide Attempts,’ Archives of

General Psychiatry 47:805-808, 1990; E.K. Moscicki, chief, Prevention Research Branch, National Institute of Mental Health U.S.

Department of Health and Human Services, personal communication Apr. 30, 1991; U.S. Department of Health and Human

Services, Public Health Service, National Center for Health Statistics, Monthly Vital Statistics Report 40(8 suppl. 2), 1992.

toms may combine in various ways, their severity therapy. Acutely ill individuals usually require

and duration fluctuating over time. Schizophrenia

increases the risk of suicide considerably—some 10

to 15 percent of individuals with schizophrenia end

their lives, usually within the first 10 years of

developing the disorder (box 3-B). With age, the

intensity of the psychotic symptoms may diminish,

and many patients with long-term impairments

regain some degree of social and occupational

competence. Although schizophrenia may become

easier to manage, the effects of years of dysfunction

are rarely overcome.

Currently, there is no way to prevent or cure

schizophrenia; however, the symptoms of the disorder can usually be treated. Treatment usually integrates antipsychotic drugs and supportive psychohospitalization; antipsychotic medication; of which

there are several chemical classes, is commonly used

to manage psychosis (table 3-2) (10,50,65).4 While

not as effective in modulating the negative symptoms of schizophrenia, antipsychotic drugs do dininish the positive symptoms. Furthermore, antipsychotic medications seem to affect the course of the

disorder. Data indicate that continued use of these

medications prevents the recurrence of psychotic

episodes (50), and clinical experience suggests that

the earlier antipsychotic medication is administered,

the more benign the course of the disorder (108).

Antipsychotic drugs do have some limitations. As

mentioned above, they are less effective in controlling the negative symptoms of schizophrenia. Also,

4In fact, schizophrenia is the most frequentlyy reported diagnosis among individuals hospitalized for mental disorders, especially in State and county

mental hospitals and Veterans Admini . .stration medical centers (68).
Chapter 3—What Are Mental Disorders? ● 53

Table 3-2—Traditional Antipsychotic Medications

Chemical family Generic name Brand name

Phenothiazines chlorpromazine

thioridazine

mesoridazine

trifluoperazine

perphenazine

fluphenazine

triflupromazine

prochlorperazine

acetophenazine

Butyrophenones haloperidol

pimozide

droperidol

Thioxanthenes thiothixene

chlorprothixene

Dibenzoxazepine Ioxapine

Dihydroindolone molindone

Thorazine and others

Mellaril, Millazine

Serentil

Stelazine, Suprazine

Trilafon

Prolixin, Permitil

Vesprin

Compazine

Tindal

HaIdol

Orap

Inapsine

Navane

Taractan

Loxitane

Moban

SOURCE: R.J. Baldessarini, “Drugs and the Treatment of Psychiatric

Disorders,” The Pharmawlogical Basis of Therapeutics (New

York, NY: Pergamon Press, 1990).

some patients do not respond to traditional antipsychotic agents. Finally, antipsychotic agents have

some side effects, including dry mouth, constipation, blurring of vision, weight gain, restlessness,

and tremor. The most serious side effect is tardive

dyskinesia, which usually appears after taking the

drug for some time. Tardive dyskinesia involves

abnormal involuntary movements of the face,

tongue, mouth, fingers, upper and lower limbs, and

occasionally the entire body. It occurs in at least a

mild form in 25 to 40 percent of patients on

antipsychotic agents and may be severe or irreversible in 5 to 10 percent of cases (10,50).

A newer drug to treat schizophrenia-clozapine—

has claimed the limelight in recent years. It was

shown during the 1970s to help patients who were

resistant to the therapeutic effects of standard

antipsychotic drugs. However, clozapine can cause

a potentially lethal blood disorder: 1 to 2 percent of

the individuals who take it will develop agranulocytosis, which decreases the number of infectionfighting white blood cells (51,52). A recent largescale study in the United States demonstrated

clozapine’s effectiveness in approximately one-third

of those patients who were unresponsive to traditional antipsychotic medication (51,73,89). The

study also showed that clozapine can be used with

relative safety, as long as it is accompanied by

careful monitoring for agranulocytosis. A number of

new antipsychotic drugs are also being developed

(43) (see ch. 4).

Psychosocial treatment is another important aspect of the treatment of schizophrenia (21,66). While

individual psychotherapy based on psychodynamic

principles has been shown to be ineffective, and

perhaps even detrimental (45,59), supportive psychotherapy aimed at helping patients understand

their illness, reducing stress, and enhancing coping

abilities can reduce the amount of medication

necessary and enhance patients’ participation in

treatment (90). Educating the family about the

symptoms and nature of schizophrenia, as well as

providing them with tools to deal with stress, is

increasingly seen as important in the optimal management of schizophrenia (92).

Rehabilitation attempts to minimize the long-term

consequences of schizophrenia rather than to treat

the disorder itself. A wide range of rehabilitation

programs has been shown to enhance social and

occupational outcomes. These programs are adjuncts, but not alternatives, to antipsychotic medication and supportive psychotherapy.

Mood Disorders

Mood disorders, also referred to as affective

disorders, are characterized by extreme or prolonged

disturbances of mood, such as sadness, apathy, or

elation (41,56). DSM-III-R divides mood disorders

into two major groups: bipolar disorders and depressive disorders (3). The occurrence of manic symptoms distinguishes bipolar disorders from depressive, or unipolar, disorders.

The most severe depressive disorder is major

depression (box 3-C). An episode of major depression is characterized by complete loss of interest or

pleasure in activities (table 3-3). Other physical and

psychological symptoms often accompany an episode of major depression, including weight gain or

loss, insomnia or excessive sleepiness, slowed or

agitated movement, diminished energy, intense feelings of guilt or worthlessness, diminished ability to

concentrate, and recurrent thoughts of death or

suicide. Major depression may entail a single

episode or, more commonly, recurrent episodes; it

may be chronic or extremely severe. Psychosis

sometimes occurs as well. A review of 17 studies

concluded that 15 percent of persons suffering from

symptoms of depression will commit suicide (44)

(see box 3-B).

Bipolar disorder, commonly known as manic

depression, is a severe mood disorder characterized
54 ● ‘The Biology of Mental Disorders

Box 3-C-Darkness Visible: A Personal Account of Depression

Depression is a disorder of mood, so mysteriously painful and elusive in the way it becomes known to the

self-to the mediating intellect-as to verge close to being beyond description. It thus remains nearly

incomprehensible to those who have not experienced it in its extreme mode, although the gloom, ‘the blues’ which

people go through occasionally and associate with the general hassle of everyday existence are of such prevalence

that they do give many individuals a hint of the illness in its catastrophic form. But at the time of which I write I

had descended far past those familiar, manageable doldrums. . . .

It was not really alarming at first, since the change was subtle, but I did notice that my surroundings took on

a different tone at certain times: the shadows of nightfall seemed more somber, my mornings were less buoyant,

walks in the woods became less zestful, and there was a moment during my working hours in the late afternoon when

a kind of panic and anxiety overtook me, just for a few minutes, accompanied by a visceral queasiness-such a

seizure was at least slightly alarming, after all. . . .

I felt a kind of numbness, an enervation, but more particularly an odd fragility-as if my body had actually

become frail, hypersensitive and somehow disjointed and clumsy, lacking normal coordination. And soon I was in

the throes of a pervasive hypochondria. Nothing felt quite right with my corporeal self; there were twitches and

pains, sometimes intermittent, often seemingly constant, that seemed to presage all sorts of dire “infirmities. . . .

It was October, and one of the unforgettable features of this stage of my disorder was the way in which my

own farmhouse, my beloved home for 30 years, took on for me at that point when my spirits regularly sank to their

nadir an almost palpable quality of ominousness. The fading evening light-akin to that famous ‘slant of light’ of

Emily Dickinson’s, which spoke to her of death, of chill extinction-had none of its familiar autumnal loveliness,

but ensnared me in a suffocating gloom. . . . That fall, as the disorder gradually took full possession of my system,

I began to conceive that my mind itself was like one of those outmoded small-town telephone exchanges, being

gradually inundated by flood waters: one by one, the normal circuits began to drown, causing some of the functions

of the body and nearly all of those of instinct and intellect to slowly disconnect. . . .

What I had begun to discover is that, mysteriously and in ways that are totally remote from normal experience,

the gray drizzle of horror induced by depression takes on the quality of physical pain. But it is not an immediately

identifiable pain, like that of a broken limb. It may be more accurate to say that despair, owing to some evil trick

played upon the sick brain by the inhabiting psyche, comes to resemble the diabolical discomfort of being

imprisoned in a fiercely overheated room. And because no breeze stirs this cauldron, because there is no escape from

this smothering confinement, it is entirely natural that the victim begins to think ceaselessly of oblivion,

SOURCE: Quoted from W. Styron, Darkness Visible (New York, NY: Random House, 1990). Copyright 1990 by William Styron. Reprinted

by permission of Random House, Inc.

by one or more full manic episodes and one or more concerning the classification of mood disorders

major depressive episodes. During a manic episode,

mood is extremely elevated, expansive, or even

irritable (table 3-4). Self-esteem is elevated, sometimes to delusional proportions; there is diminished

need for sleep; energy abounds and thoughts race;

individuals are often extremely talkative and distractible; and individuals indulge in unrestrained

buying sprees or sexual and other activity. Psychotic

features (i.e., delusions and hallucinations) are not

uncommon during a manic episode.

There are several unresolved issues concerning

the classification of mood disorders. As mentioned,

some observers think that mood disorders, especially in the presence of psychosis, are related to

schizophrenia. Individuals often exhibit symptoms

of both categories of disorders. Other questions

include: “

. Is depression a single disorder? A class of

disorders?

. How are less severe episodes of depression and

other mental disorders related to major depression?

. How is bipolar disorder related to major depression?

A recent report analyzing research on depression

in women stated:

The common belief that depression varies along

a single continuum from ordinary blues to major

depression may be incorrect, because depressions

may differ in kind as well as degree. Depression is

heterogeneous (5).
Chapter 3—What Are Mental Disorders? . 55

Table 3-3—The Diagnosis of Depression

Note: A “Major Depressive Syndrome” is defined as criterion A

below.

A. At least five of the following symptoms have been present

during the same two-week period and represent a change from

previous functioning; at least one of the symptoms is either: 1)

depressed mood, or 2) loss of interest or pleasure. (Do not

include symptoms that are clearly due to a physical condition,

mood-incongruent delusions or hallucinations, incoherence,

or marked loosening of associations.)

1. depressed mood (or can be irritable mood in children and

adolescents) most of the day, neatly everyday, as indicated

either by subjective account or observation by others;

2. markedly diminished interest or pleasure in all, or almost all,

activities most of the day, nearly every day (as indicated

either by subjective account or observation by others of

apathy most of the time);

3. significant weight loss or weight gain when not dieting, or

decrease or increase in appetite nearly every day;

4. insomnia or hypersomnia nearly every day;

5. psychomotor agitation or retardation nearly every day

(observable by others, not merely subjective feelings of

restlessness or being slowed down);

6. fatigue or loss of energy nearly every day;

7. feelings of worthlessness or excessive or inappropriate guilt

(which may be delusional) nearly every day (not merely

self-reproach or guilt about being sick);

8. diminished ability to think or concentrate, or indecisiveness,

nearly every day (either by subjective account or as

observed by others);

9. recurrent thoughts of death (not just fear of dying), recurrent

suicidal ideation without a specific plan, or a suicide attempt

or a specific plan for committing suicide.

B. 1. It cannot be established that an organic factor initiated and

maintained the disturbance.

2. The disturbance is not a normal reaction to the death of a

loved one (uncomplicated bereavement).

C. At no time during the disturbance have there been delusions

or hallucinations for as long as two weeks in the absence of

prominent mood symptoms (i.e., before the mood symptoms

developed or after they have remitted).

D. Not superimposed on schizophrenia, schizophreniform disorder, and others.

SOURCE: American Psychiatric Association, Diagnostk and Statistic/

Manuai of Mental Disorders, 3rd cd., rev. (Washington, DC:

American Psychiatric Association, 1987).

There are various ways to conceptualize depression,

based on its course, symptoms, association with

other disorders, and severity (5). For example, it is

known that symptoms of anxiety and depression

often occur together (70). The fact that depression

may be triggered by, or correlated with, different

factors also suggests that depression is heterogeneous. For example, reproductive-related events (e.g.,

menstruation, pregnancy, childbirth, infertility, abortion, and menopause) are related to some cases of

depression among women, who are at greater risk of

depressive disorders than men (5). Seasonality has

also been observed in depressive episodes—namely,

Table 3-4-The Diagnosis of Mania

Note: A “Manic Syndrome” is defined as including criteria A, B,

and C below.

A.

B.

c.

D.

E.

F.

A distinct period of abnormally and persistently elevated,

expansive, or irritable mood.

During the period of mood disturbance, at least three of the

following symptoms have persisted (four if the mood is only

irritable) and have been present to a significant degree:

1. inflated self-esteem or grandiosity;

2. decreased need for sleep, e.g., feels rested after only three

hours of sleep;

3. more talkative than usual or pressure to keep talking;

4. flight of ideas or subjective experience that thoughts are

racing;

5. distractibility, i.e., attention too easily drawn to unimportant

or irrelevant external stimuli;

6. increase in goal-directed activity (either socially, at work or

school, or sexually) or psychomotor agitation;

7. excessive involvement in pleasurable activities which have

a high potential for painful consequences, e.g., the person

engages in unrestrained buying sprees, sexual indiscretions, or foolish business investments.

Mood disturbance sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or

relationships with others, or to necessitate hospitalization to

prevent harm to self or others.

At no time during the disturbance have there been delusions

or hallucinations for as long as two weeks in the absence of

prominent mood symptoms (i.e., before the mood symptoms

developed or after they have remitted).

Not superimposed on schizophrenia, schizophreniform disorder, and others.

It cannot be established that an organic factor initiated and

maintained the disturbance.

Note: Somatic antidepressant treatment (e.g., drugs, ECT) that

apparently precipitates a mood disturbance should not be mnsidered an etioiogic organic factor.

SOURCE: American Psychiatric Association, Diagnostic and Statistical

Manual of Mental Disorders, 3rd cd., rev. (Washington, DC:

American Psychiatric Association, 1987).

in seasonal affective disorder, or SAD. In this

disorder, individuals have a characteristic onset of

depression during the winter months, with remissions or changes from depression to mania during

the spring (87). Depression can also appear in a very

severe form. Melancholia is a severe form of

depression wherein persons take virtually no interest

or pleasure in activities and experience such somatic

symptoms as early morning waking and weight loss.

While a categorical approach to depression may

be convenient for selecting homogeneous groups for

research or designing a treatment strategy, it does

not preclude the possibility that depression is a

single disorder. As stated in a recent psychiatric

diagnostic text:
56 ● The Biology of Mental Disorders

Affective disorders have been divided and subdivided endlessly as investigators endeavor to distinguish ‘normal’ from ‘abnormal’ mood . . . after a

century there is still no agreement about the most

satisfactory classification (40).

Family histories and longitudinal studies provide

evidence that depression may constitute a continuum from the blues to medically recognized depression. For example, the immediate family of individuals with a mild mood disorder are more likely than

other persons to have major depression (82). Also,

many individuals with mild depression go on to

suffer full-blown depression (1,105).

The basis for separating bipolar (manic-depressive) and unipolar (depressive) disorders into different categories of illness has been questioned. After

a comprehensive review of the literature, however,

Goodwin and Jamison conclude that studies evaluating family history, clinical symptoms and course,

the response to pharmacological treatment, and

other factors strongly support recognition of the

distinction between these disorders (41). They also

suggest that bipolar disorder and severe cases of

recurrent depression may share important features

(e.g., response to treatment with lithium) and encourage more research on the cycles in severe mood

disorders.

Nearly 8 percent of the U.S. population will

develop a mood disorder at some time during their

lives (103,104). Bipolar disorder afflicts slightly less

than percent of the population (0.8 percent), with

men and women being affected equally. Nearly 5

percent (4.9 percent) of the population will develop

major depression, which is twice as common in

women as men. Substance abuse often coincides

with major mood disorders (box 3-D).

Mood disorders appear to be increasing among

younger people. Studies show that in this century

each succeeding generation has reported an increased lifetime risk and earlier age of onset of major

depression (60,101,103,106). Why the rates are

increasing is not known. They may reflect an artifact

of the data-collecting process, forgetfulness on the

part of older individuals when surveyed, or a true

increase in depression. Whatever the source of this

‘‘cohort effect,” it is a significant consideration in

certain types of research into depression (e.g.,

genetic research).

Mood disorders have various social correlates,

including marital and employment status (103).

Individuals with a mood disorder, especially bipolar

disorder, are more likely never to have married or to

have been divorced. Major mood disorders and

socioeconomic status are not directly related (103).

While schizophrenia is highly concentrated in the

lower socioeconomic classes, bipolar disorder and

major depression afflict individuals in every class

and occupation. In fact, many highly successful and

creative individuals have suffered a major mood

disorder, suggesting a link between the disorder and

creativity (49).

The onset of major depression typically occurs in

the late 20s, although it can emerge at any time

(56,103). Over 50 percent of patients will have more

than one bout of major depression, the mean number

being five or six episodes in a lifetime (64). The

highest rate of relapse occurs during the months

immediately following recovery from a previous

episode (78).

Bipolar disorder typically begins in the mid-20s

(41). Episodes of mania or depression emerge every

several months to a year or more, with periods of

recovery separating the mood swings. Some individuals exhibit rapid cycling, with multiple episodes in

a single year. Manic episodes tend to begin rather

abruptly, with mild symptoms quickly developing

into a full-blown state of mania, sometimes with

accompanying psychosis. Depressive episodes tend

to begin more slowly. If untreated, episodes last 4 to

13 months, with depressive episodes generally

outlasting manic ones. External events may trigger

an episode, especially in the early phase of the

disorder; with time, episodes of depression and

mania emerge independent of outside events. Bipolar disorder is chronic, with the cycles of mania and

depression, separated by periods of recovery, continuing throughout an individual’s lifetime.

It is useful to conceptualize the treatment of mood

disorders in three phases: treatment of acute episodes, continued treatment, and long-term maintenance, or prophylactic treatment (41,64). Acute

treatment lasts from the beginning of a depressive or

manic episode until its remission. This phase of

treatment usually involves medication or electroconvulsive therapy (see later discussion) and psy-
Chapter 3—What Are Mental Disorders? ● 57

Box 3-D—Alcohol, Drugs, and Mental Disorders

While alcohol and drug problems in society may

not be attributable primarily to mental disorders, they

are apparently exacerbated among people with mental

disorders. Regier and colleagues (1990), in the most

comprehensive study to date, found a high prevalence

of comorbid (that is, occurring at the same time)

mental disorders and alcohol or other drug disorders—

including both abuse and dependence syndromes, as

defined in the DSM-III-R (figure 3-2). They used data

from NIMH’s Epidemiologic Catchment Area (ECA)

survey of 20~91 adults in the community and in

various institutional settings (prisons, mental hospitals, nursing homes, and specialized treatment centers).

The study assessed the prevalence of comorbid

alcohol, other drug, and mental disorders from the

perspective of three categories of primary disorder:

mental disorders, alcohol disorders, and other drug

disorders. Schizophrenia, mood disorders, and anxiety

disorders were among those studied. Specific drugs

studied, in addition to alcohol, include marijuana,

cocaine, opiates, barbiturates, amphetamines, and

hallucinogens.

An estimated 13.5 percent of all adults in the

United States will have a diagnosis of alcohol abuse or

dependence: Of this number, 36.6 percent will have at

least one mental disorder and 21.5 percent another

Figure 3-2-Substance Abuse and Mental Disorders

Comorbidity

13.50% 1.1 % 6.1 %

Epidemiological data suggest that there is a high degree of

comorbidity for mental and addictive disorders in the United

States. For example, 29 percent of individuals with a mental

disorder will also have an addictive disorder.

SOURCE: D.A. Regier, M.E. Farmer, D.S. Rae, et al., "Comorbidity of

Mental Disorders With Alcohol and Other Drug Abuse: Results

From the Epidemiologic Catchment Area (ECA) Study,” Journal

of the American Medical Association 284: 2511-2518, 1990.

drug disorder in their lifetime. Specific comorbid mental disorders found in people with alcohol abuse-dependence

disorder include anxiety disorders (19.4 percent), mood disorders (13.4 percent), and schizophrenia (3.8 percent).

Some 6.1 percent of the total adult population will have abused or been dependent on drugs other than alcohol at

some time in their lives: Of this number, 53.1 percent will have a mental disorder and 47.3 percent will have an

alcohol abuse-dependence disorder. Of people with comorbid mental disorders, 28.3 percent will have an anxiety

disorder, 26.4 percent will have a mood disorder, and 6.8 percent will have schizophrenia.

At some time in their lives, 22.5 percent of all adults in the United States will have a diagnosis of mental

disorder: Of this number, 22.3 percent will also have an alcohol abuse or dependence disorder, 14.7 percent will

have a drug abuse-dependence disorder, and 28.9 percent will have either alcohol or drug disorders. Compared to

individuals with no history of mental disorder, people with a diagnosis of mental disorder face twice the odds of

having alcohol abuse-dependence and over four times the odds of drug abuse-dependence.

Comorbid alcohol and other drug abuse or dependence disorders occur frequently in people with the specific

subtypes of mental disorders included in this study. Of those who develop schizophrenia and related disorders

during their lifetime (approximately 1.0 percent of the U.S. population), 47 percent will abuse or be dependent on

alcohol or other drugs, or both. Thirty-two percent of people with mood disorders (8.3 percent of the total adult

population) will abuse or become dependent on alcohol, other drugs, or both. Within this group, over 60 percent

of people with bipolar disorder will abuse or become dependent on alcohol, other drugs, or both. About 27 percent

of people with major depression will have an alcohol or other drug disorder, or both, odds almost two times greater

than those for people without major depression. The anxiety disorders, as a group, occur at some time in the lives

of 14.6 percent of the population and are highly likely to be associated with an alcohol or other drug abuse or

dependence disorder. For example, 35.8 percent of people with panic disorder and 32.8 percent of people with

obsessive-compulsive disorder will have some form of alcohol or other drug abuse or dependence disorder.

SOURCES: R.E. Drake, F.C. Osher, and M.A. Wallach, “Alcohol Use and Abuse in Schizophrenia A Prospective Community Study, ” Journal

of Nervous and Mental Disease 177:408-414, 1989; F.K. Goodwin and K.R. Jamison, Manic-Depressive Illness (New York, NY:

The Oxford University Press, 1990); D.A. Regier, M.E. Farmer, D.S. Rae, et al., ‘‘Comorbidity of Mental Disorders With Alcohol

and Other Drug Abuse: Results From the Epidemiologic Catchment Area (ECA) Study, ” Journal of the American Medical

Association 264:2511-2518, 1990.

329–309 O - 92 - 3 : Q K3
58 ● The Biology of Mental Disorders

chotherapy; it may involve hospitalizations Continued treatment consists of those interventions maintained from the time of a remission until a second

episode would be expected to occur. Long-term

maintenance is intended to prevent or attenuate

future episodes.

The depressive and manic symptoms of mood

disorders are generally well managed with a wide

array of medications. Significant advances have

occurred in the pharmacological treatment of major

depression during the last decade (10). Traditional

antidepressant medications include tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs),

and newer antidepressant drugs (table 3-5). Various

other agents are under development (see ch. 4). A

therapeutic response usually requires days to weeks;

a good response is predicted on the basis of

symptoms such as insomnia or weight loss, more

severe symptoms, past episodes of depression, or a

family history of mood disorders.

Antidepressant agents have varying side effects.

Tricyclic antidepressants may lead to such side

effects as a dry mouth, constipation, sedation,

nervousness, weight gain, increased appetite, or

diminished sexual drive. MAOIs, which are generally used for patients who fail to respond to tricyclic

antidepressants, can interact with certain foods and

medications, producing potentially fatal bouts of

hypertension. Fluoxetine, or Prozac, is a newer

antidepressant that produces fewer of these side

effects, making it the most widely prescribed antidepressant agent in the United States in 1989. Prozac

often facilitates weight loss. Its side effects include

nausea, tremor, insomnia, and nervousness. A minority of patients may suffer from agitation or

anxiety when using Prozac.6

Psychotherapy, either alone or as an adjunct to

medication, is important in treating depression

(37,38). Various psychotherapeutic approaches are

used, including supportive psychotherapy, behavioral therapy, psychodynamic psychotherapy, cognitive therapy, interpersonal psychotherapy, and others (table 3-6). While studies have generally found

psychotherapy to be an effective intervention in

Table 3-5—Medications for the Treatment

of Depression

Class of medication Generic name Brand name

Tricyclic amitriptyline

antidepressants nortriptyline

protriptyline

desipramine

doxepin

imipramine

Inhibitors tranylcypromine

phenelzine

Newer antidepressants fluoxetine

sertraline

Elavil, Endep

Aventyl, Pamelor

Vivactil

Norpramin, Pertrfran

Adapin, Sinequan

Tofranil, Imavate

Parnate

Nardil

Prozac

Zoloft

SOURCE: Adapted from American Psychological Association, Wbmenand

Depression: Risk Factors and Treatment Issues (Washington,

DC: American Psychological Association, 1990).

depression, positive outcomes have not been linked

to any particular approach (5,33,80,109). This suggests that some element or elements common to all

forms of psychotherapy produce the positive effects.

In cases of severe depression, or when an individual is suicidal, hospitalization may be required.

Electroconvulsive therapy (ECT) may also be used

in these instances (4,15,88). ECT generally relieves

symptoms of depression rapidly, but it results in

memory loss for an indeterminate period of time

following the procedure. In the case of SAD,

phototherapy can be applied (87). This treatment

involves exposure to bright artificial light in the

early morning, in the evening, or at both times. It is

generally effective in relieving the symptoms of

depression in SAD, with few, if any, side effects.

The symptoms of bipolar disorder are treated with

medication (41). Depressive episodes are treated

with antidepressant drugs, as described above.

Severe cases of mania require hospitalization. When

psychosis accompanies bouts of mania, antipsychotic medication is indicated. Lithium carbonate is

crucial in the treatment of bipolar disorder. It is used

to diminish manic symptoms and to prevent new

episodes from occurring. However, lithium does

produce side effects, such as increased thirst and

urination, memory problems, tremor, and weight

gain, that may cause patients not to comply with

treatment. Long-term treatment with lithium, which

S Mood disorders awowt for the second most fr~uent dia~osis in inpatient facilities and for the kgeSt percentage of PatienK ~ Private Psychiatric

hospitals and nonfederal general hospitals (68).

G ~ozac has ken under siege as a factor in suicide and other violent acts. The U.S. Food and Drug~“ “stration has ruled that there is insu.t%cient

evidence indicting the drug.
Chapter 3—What Are Mental Disorders? ● 59

Table 3-6—Psychotherapy and Depression

Modality Definition

Cognitive therapy

Behavioral therapy A form of psychotherapy that focuses on modifying faulty behavior

rather than basic changes in the personality. Instead of probing the

unconscious or exploring the patient’s thoughts and feelings, behavior therapists seek to eliminate symptoms and to modify ineffective or

maladaptive patterns by applying basic learning techniques and other

methods. (Examples: relaxation therapy, self-control therapy, social

skills training.)

A psychotherapeutic approach based on the concept that emotional

problems are the result of faulty ways of thinking and distorted

attitudes toward oneself and others. The therapist takes the role of an

active guide who helps the patient correct and revise his or her

perceptions and attitudes by citing evidence to the contrary or eliciting

it from the patient. The therapist uses cognitive and behavioral

techniques to correct distortions of thinking associated with depression, that is, pessimism about oneself, the world, and the future. Brief

treatment.

Interpersonal psychotherapy A form of psychotherapy in which the therapist seeks to help the

patient to identify and better understand his or her interpersonal

problems and conflicts and to develop more adaptive ways of relating

to others. The therapist focuses on client’s current interpersonal

relationships. Helps clients learn more effective ways of relating to

others and coping with conflicts in relationships. Brief, focused

treatment.

Psychodynamic psychotherapy Any form or technique of psychotherapy that focuses on the

underlying, often unconscious factors (drives and experiences)

that determine behavior and adjustment.

SOURCE: Adapted from American Psychological Association, Women and Depression: Risk Factors and Treatment

Issues (Washington, DC: American Psychological Association, 1990).

is generally necessary, can have toxic effects on the

thyroid gland, the kidney, and the nervous system.

Lithium can also cause abnormalities in the fetuses

of women taking the drug. The anticonvulsive drug

carbamazepine is an alternative for persons who do

not respond to lithium or are intolerant of its side

effects. In addition to drug therapy, supportive

psychotherapy is generally required to help patients

understand and deal with symptoms of bipolar

disorder.

Anxiety Disorders

In this age of crowding, traffic jams, time

pressures, and media bombardment of our minds

with horrific tragedies, it is no wonder that some

people consider this the Age of Anxiety, as Leonard

Bernstein entitled his symphony. Everyone experiences anxiety at some time-that diffuse feeling of

unease or apprehension, usually of a vague or

unknown threat. The manifestations of anxiety vary

from individual to individual and may include a

racing heartbeat, butterflies in the stomach, or a

headache. It is different from fear, which is an

immediate, strong response to sudden and imminent

danger, such as a car approaching rapidly as one

crosses the street. Anxiety may produce a paradoxical effect—bringing about that which the person

fears most. For example, a person who is anxious

about public speaking may find himself or herself

muted by anxiety. However, anxiety can serve a

positive function-it can prompt actions that ward

off potential threats to well-being. For example,

anxiety about an upcoming exam may lead to

increased study.

Anxiety can be pathological. According to the

DSM-III-R, pathological anxiety can be separated

into what are called anxiety disorders, including

panic disorder, phobias, obsessive-compulsive disorder, posttraumatic stress disorder, and generalized

anxiety disorder (3). Pathological symptoms of

anxiety are often present in other disorders, notably

depression (13,40,56,70). Although anxiety disorders are grouped together by their symptoms, they

are quite different in how they are best treated, and

they appear to have quite different causes. We

concentrate on panic disorder and obsessivecompulsive disorder because the role of biological

factors in causing them has been more fully explored

and is considered by many to be paramount.
60 ● The Biology of Mental Disorders

Box 3-E—The Auto Accident That Never Was

I’m driving down the highway doing 55 MPH. I’m on my way to take a final exam. My seat belt is buckled

and I’m vigilantly following all the rules of the road. No one is on the highway---not a living soul.

Out of nowhere an Obsessive-Compulsive Disorder (OCD) attack strikes. It’s almost magical the way it

distorts my perception of reality, While in reality no one is on the road, I’m intruded with the heinous thought that

I might have hit someone . . . a human being! God knows where such a fantasy comes tire.

I think about this for a second and then say to myself, ‘ ‘That’s ridiculous. I didn’t hit anybody. ” Nonetheless,

a gnawing anxiety is born. An anxiety I will ultimately not be able to put away until an enormous emotional price

has been paid.

I try to make reality chase away this fantasy. I reason, ‘‘Well, if I hit someone while driving, I would have felt

it. ” This brief trip into reality helps the pain dissipate. . . but only for a second. Why? Because the gnawing anxiety

that I really did commit the illusionary accident is growing larger-so is the pain.

The pain is a terrible guilt that I have committed an unthinkable, negligent act. At one level, I know this is

ridiculous, but there’s a terrible pain in my stomach telling me something quite different.

Again, I try putting to rest this insane thought and that ugly feeling of guilt. “Come on,” I think to myself,

‘‘this is really insane!”

But the awful feeling persists. The anxious pain says to me, “You Really Did Hit Someone. ’ The attack is now

in full control. Reality no longer has meaning. My sensory system is distorted. I have to get rid of the pain. Checking

out this fantasy is the only way I know how.

I start ruminating, “Maybe I did hit someone and didn’t realize it. . . . Oh my God! I might have killed

somebody! I have to go back and check. Checking is the only way to calm the anxiety, It brings me closer to truth

somehow. I can’t live with the thought that I actually may have killed someone--I have to check it out. . . .

I think to myself, ‘‘Rush to check it out. Get rid of the hurt by checking it out. Hurry back to check it out. God,

I’ll be late for my final exam if I check it out. But I have no choice. Someone could be lying on the road, bloody,

close to death. Fantasy is now my only reality. So is my pain.

I’ve driven five miles farther down the road since the attack’s onset. I turn the car around and head back to the

scene of the mythical mishap. I return to the spot on the road where I “think” it “might” have occurred. Naturally,

nothing is there. No police car and no bloodied body. Relieved, I turn around again to get to my exam on time.

Feeling better, I drive for about twenty seconds and then the lingering thoughts and pain start gnawing away

again. Only this time they’re even more intense, I think, ‘‘Maybe I should have pulled off the road and checked the

side brush where the injured body was thrown and now lies? Maybe I didn’t go@ enough back on the road and

the accident occurred a mile farther back.

The pain of my possibly having hurt somebody is now so intense that I have no choice--I really see it this way.

I turn the car around a second time and head an extra mile farther down the road to find the corpse. I drive by

quickly. Assured that this time I’ve gone far enough I head back to school to take my exam. But I’m not through yet.

“My God,” my attack relentlessly continues, “I didn’t get out of the car to actually look on the side of the

road!

Obsessive-Compulsive Disorder der is the obsessive feeling of being dirty or

Obsessive-compulsive disorder (OCD) is characterized by recurrent and persistent thoughts, images,

or ideas that are experienced as intrusive and

senseless (obsessions) and stereotypic, repetitive,

and purposeful actions perceived as unnecessary

(compulsions) (box 3-E) (79) (table 3-7). Individuals

with OCD cannot resist these persistent ideas or

impulses, although they view them as irrational and

unwanted. One common manifestation of this disorcontaminated, which leads to the compulsion of

repeated hand-washing (table 3-8). Hand-washing

may be so frequent that the skin is rubbed raw.

Another common obsession is excessive doubt,

which leads to compulsive checking. For example,

an individual fears that he or she has left the stove on

or the door unlocked, resulting in his or her checking

and rechecking the stove or door. The doubts often

reflect concern for a dangerous outcome or a
Chapter .3-What Are Mental Disorders? . 61

So I turn back a third time. I drive to the part of the highway where I think the accident happened. I park the

car on the highway’s shoulder. I get out and begin rummaging around in the brush. A police car comes up. I feel

like I’m going out of my mind.

The policeman, seeing me thrash through the brush, asks, “What are you doing? Maybe I can help you?”

Well, I’m in a dilemma. I can’t say, “Officer, please don’t worry. You see, I’ve got obsessive-compulsive

disorder, along with 4 million Americans. I’m simply acting out a compulsion with obsessive qualities.” I can’t

even say, ‘ ‘I’m really sick. Please help me. The disease is so insidious and embarrassing that it cannot be admitted

to anyone. Anyway, so few really understand it, including myself.

So I tell the officer I was nervous about my exam and pulled off to the roadside to throw up. The policeman

gives me a sincere and knowing smile and wishes me well.

But I start thinking again. “Maybe an accident did happen and the body has been cleared off the road. The

policeman’s here to see if I came back to the scene of the crime. God, maybe I really did hit someone . . . why else

would a police car be in the area?’ Then I realize he would have asked me about it. But would he, if he was trying

to catch me?

I’m so caught up in the anxiety and these awful thoughts that I momentarily forget why I am standing on the

side of the road I’m back on the mad again. The anxiety is peaking. Maybe the policeman didn’t know about the

accident? I should go back and conduct my search more thoroughly.

I want to go back and check more. . . but I can’t. You see, the police car is tailing me on the highway. I’m now

close to hysteria because I honestly believe someone is lying in the brush bleeding to death. Yes . . . the pain makes

me believe this. “After all,” I reason, ‘‘why would the pain be there in the first place?’

I arrive at school late for the exam. I have trouble taking the exam because I can’t stop obsessing on the fantasy,

The thoughts of the mystical accident keep intruding. Somehow I get through it.

The moment I get out of the exam I’m back on the road checking again. But now I’m checking two things.

First that I didn’t kill or maim someone and second, that the policeman doesn’t catch me checking. After all, if I

should be spotted on the roadside rummaging around the brush a second time, how in the world can I possibly

explain such an incrimin ating and aimless action? I’m totally exhausted, but that awful anxiety keeps me checking,

though a part of my psyche keeps telling me that this checking behavior is ridiculous, that it serves absolutely no

purpose. But, with OCD, there is no other way.

Finally, after repeated checks, I’m able to break the ritual. I head home, dead tired I know that if I can sleep

it off, I’ll feel better. Sometimes the pain dissipates through an escape into sleep.

I manage to lie down on my bed-hoping for sleep. But the incident has not totally left me--nor has the anxiety.

I think, “If I really did hit someone, there would be a dent in the car’s fender. ”

What I now do is no mystery to anyone. I haul myself up from bed and run out to the garage to check the fenders

on the car. First I check the front two fenders, see no damage, and head back to bed. But. . . did I check it well enough?

1 getup from bed again and now find myself checking the whole body of the car. I know this is absurd, but

I can’t help myself. Finally . . . finally, I disengage and head off to my room to sleep, Before I nod off, my last

thought is, ‘‘I wonder what I’ll check next?”

SOURCE: Description of OCD by a 36-year-old male professional who has the disorder, in J.L. Rapoport, The Boy Who Couldn’t Stop Washing

(New York NY: American Library, 1989). Reprinted by permission of Dr. Rapport.

gnawing sense of guilt. Another common obsession an individual takes hours to eat a single meal or to

is with symmetry or order, leading to the compulsion

of repeatedly going in and out of a door or ordering

and arranging various items.

Less frequently, an individual may be plagued

only by obsessional thoughts, without any compulsions, such as a preoccupation with sexual or

aggressive acts that are abhorrent to the individual.

And finally, individuals may express what is called

‘‘an obsessional slowness. ’ In this manifestation,

brush his or her teeth in a ritualistic fashion.

Many individuals with OCD also have another

diagnosis, the most common being depression (54,79).

In fact, OCD was once posited to be a type of mood

disorder because of the intimate link between its

symptoms and those of depression. Other problems

that may be associated with OCD include other

anxiety disorders, eating disorders, alcohol abuse,

Tourette’s syndrome, and psychosis. The comorbid-
62 ● The Biology of Mental Disorders

Table 3-7—The Diagnosis of Obsessive-Compulsive

Disorder

A. Either obsessions or compulsions:

Obsessions: (l), (2), (3), and (4):

1. recurrent and persistent ideas, thoughts, impulses, or

images that are experienced, at least initially, as intrusive

and senseless, e.g., a parent’s having repeated impulses to

kill a loved child, a religious person’s having recurrent

blasphemous thoughts;

2. the person attempts to ignore or suppress such thoughts or

impulses or to neutralize them with some other thought or

action;

3. the person recognizes that the obsessions are the product

of his or her own mind, not imposed from without (as in

thought insertion);

4. if another Axis I disorder is present, the content of the

obsession is unrelated to it, e.g., the ideas, thoughts,

impulses, or images are not about food in the presence of

an eating disorder, about drugs in the presence of a

psychoactive substance use disorder, or guilty thoughts in

the presence of a major depression.

Compulsions; (l), (2), and (3):

1. repetitive, purposeful, and intentional behaviors that are

performed in response to an obsession, or according to

certain rules or in a stereotyped fashion;

2. the behavior is designed to neutralize or to prevent

discomfort or some dreaded event or situation; however,

either the activity is not connected in a realistic way with

what it is designed to neutralize or prevent, or it is clearly

excessive;

3. the person recognizes that his or her behavior is excessive

or unreasonable (this may not be true for young children; it

may no longer be true for people whose obsessions have

evolved into overvalued ideas).

B. The obsessions or compulsions cause marked distress, are

time-consuming (take more than an hour a day), or significantly interfere with the person’s normal routine, occupational

functioning, or usual social activities or relationships with

others.

however, suffer a continuous or deteriorating course;

their symptoms may become so extreme that hospitalization is necessary. Followup studies of individuals who have been treated clinically show that the

disorder is chronic and recurrent; at least 50 percent

of those treated with psychotherapy or older drug

therapies suffered from the disease for 7 to 20 years.

OCD was long thought to be resistant to treatment, with antidepressant drugs being prescribed to

relieve the accompanying symptoms of depression

(28). Currently there are two primary treatments for

OCD that may be effective: behavioral therapy

and/or medication (28,47,48,76). Behavioral therapy entails repeated exposure of the patient to the

stimulus that sets off a ritualistic act. For example,

if a patient has a compulsion to wash his or her hands

20 to 30 times a day, the patient’s hands may be

deliberately dirtied and the patient prevented from

washing them. This approach seems to be more

effective in treating compulsions than in treating

obsessions. Medications acting on the brain chemical serotonin (see ch. 4) have proven quite effective,

with the drug clomipramine (Anafranil) commonly

used to treat OCD. The therapeutic effects of this

drug may take days or weeks to manifest themselves,

and this drug too may be more effective in treating

compulsions than obsessions. The side effects of

clomipramine are those typical of tricyclic antidepressants (see earlier discussion).

SOURCE: American Psychiatric Association, Diagnostic and Statistical

Manua/ of Menfa/ Disorders, 3rd cd., rev. (Washington, DC:

American Psychiatric Association, 1987).

ity of OCD and neurological disorders such as

Tourette’s syndrome suggests that they have the

same anatomical basis (see ch. 4).

Recent epidemiological data indicate that OCD,

once thought to be quite rare, afflicts approximately

2.6 percent of the U.S. population at some time

during their lives (54). Men and women appear to be

afflicted equally, although OCD may be slightly

more common among women. The symptoms begin

in childhood or adolescence in one-third to one-half

of the individuals who develop the disorder; the

average age of onset is 20. While the symptoms of

OCD usually seem to be unprovoked, stressful life

events may precipitate or exacerbate them. Sometimes symptoms recede completely with time, but

most often patients suffer chronic OCD, with

symptoms waxing and waning. Some patients,

Panic Disorder

The hallmark symptom of panic disorder is a

sudden, inexplicable attack of intense fear that is

associated with powerful physical symptoms. A

panic attack typically unfolds quite rapidly: In just

a few minutes, an extreme sense of fear overtakes an

individual, his or her heart begins racing, he or she

starts to perspire-sometimes profusely-and he or

she has trouble breathing (table 3-9). A single attack

is short-lived, lasting 20 minutes to an hour on

average. These symptoms often leave a patient

believing that he or she is suffering from a heart

attack or is losing his or her mind. Some patients go

to the emergency room in the belief that they are

about to die from a heart attack. In fact, many

individuals with panic disorder seek general medical

professional care at an increased rate (69). Individuals with panic disorder may receive repeated and

extensive diagnostic testing for cardiac or neurological problems (61).
Chapter 3-What Are Mental Disorders? . 63

Table 3-8-Obsessions and Compulsions

Reported symptom at initial interview

Obsessions (no.) (%)

Concern with dirt, germs, or environmental toxins . . . . . . . . . . .

Something terrible happening (fire, death, or illness of self

or loved one) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Symmetry, order, or exactness . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Scrupulosity (religious obsessions) . . . . . . . . . . . . . . . . . . . . . . . .

Concern or disgust with bodily wastes or secretions

(urine, stool, saliva) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Lucky or unlucky numbers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Forbidden, aggressive, or perverse sexual thoughts, images,

or impulses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Fear might harm others or oneself . . . . . . . . . . . . . . . . . . . . . . . . .

Concern with household items . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Intrusive nonsense sounds, words, or music . . . . . . . . . . . . . . . .

28

17

12

9

6

6

3

3

2

1

(40)

(24)

(17)

(13)

(8)

(8)

(4)

(4)

(3)

(1)

Reported symptom at initial interview

Compulsions (no.) (%)

Excessive or ritualized hand-washing, showering, bathing,

tooth-brushing, or grooming . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 (85)

Repeating rituals (going in or out of a door, up or down

from a chair) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 (51)

Checking (doors, locks, stove, appliances, emergency brake

on car, paper route, homework) . . . . . . . . . . . . . . . . . . . . . . . . 32 (46)

Rituals to remove contact with contaminants . . . . . . . . . . . . . . . 16 (23)

Touching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 (20)

Measures to prevent harm to self or others . . . . . . . . . . . . . . . . . 11 (16)

Ordering or arranging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 (17)

Counting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 (18)

Hoarding or collecting rituals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 (11)

Rituals of cleaning household or inanimate objects . . . . . . . . . 4 (6)

Miscellaneous rituals (such as writing, moving, speaking) . . . 18 (26)

aThe most @Uent obsessions and compulsions among 70 children and adolescents who were diagnosed == having

OCD by the author and her colleagues at the National Institute of Mental Health (NIMH). The proportions total more

than 100 percent because many sufferers have more than one symptom.

SOURCE: J.L. Rapoport, “The Biology of Obsessions and Compulsions,” ~“enWicArnerican 260(3):83-89, 1990.

Panic attacks occur about two times a week,

although the frequency varies considerably among

patients. One person’s panic attack may be rare,

having little effect on his or her functioning, while

another’s panic attacks and accompanying anxiety

may be so intense that he or she remains completely

sequestered at home (99). Individuals with panic

disorder often exhibit other disorders. They may

develop a fear of being in public places (agoraphobia), especially because they may be embarrassed or

unable to leave a situation quickly. In fact, the

majority of individuals diagnosed with agoraphobia

are thought to have panic attacks, and approximately

one-third of individuals with panic disorders also

have agoraphobia (107). Depression and substance

abuse are common among individuals with panic

disorder (box 3-D), and these persons may experience other disorders more frequently also, including

mitral valve prolapse, imitable bowel syndrome,

asthma, and migraine headaches.

Data show that approximately one to two persons

in 100 will develop panic disorder during their

lifetime, with women being twice as likely to

develop it as men (31,102). While panic attacks have

been described in children and adolescents, the

average age of onset is 24. Forty percent of patients

experience the onset of panic disorder before the age

of 30 (71).

A panic attack usually emerges unprovoked,

although a stressful life event may precipitate it. As

attacks continue to occur, they preoccupy the

patient, and the patient may become generally

anxious or depressed. Further research is needed to

determine the long-term course of panic disorder;

however, data suggest that many patients suffer

chronic panic attacks, with the severity of symptoms

waxing and waning over time (77).

Panic disorder is treated with medication or

psychotherapy or both (12,25,75). Antidepressant
64 ● The Biology of Mental Disorders

Table 3-9-The Diagnosis of Panic Disorder

A.

B.

c.

D.

E.

At some time during the disturbance, one or more panic

attacks (discrete periods of intense fear or discomfort) have

occurred that were: 1 ) unexpected, i.e., did not occur immediately before or on exposure to a situation that almost always

caused anxiety, and 2) not triggered by situations in which the

person was the focus of others’ attention.

Either four attacks, as defined in criterion A, have occurred

within a 4-week period, or one or more attacks have been

followed by a period of at least a month of persistent fear of

having another attack.

At least four of the following symptoms developed during at

least one of the attacks:

1. shortness of breath (dyspnea) or smothering sensations;

2. dizziness, unsteady feelings, or faintness;

3. palpitations or accelerated heart rate (tachycardia);

4. trembling or shaking;

5. sweating;

6. choking;

7. nausea or abdominal distress;

8. depersonalization or derealization;

9. numbness or tingling sensations (paresthesias);

10. flushes (hot flashes) or chills;

11. chest pain or discomfort;

12. fear of dying;

13. fear of going crazy or of doing something uncontrolled.

Note: Attacks involving four or more symptoms are panic

attacks; attacks involving fewer than four symptoms are limited

symptom attacks.

During at least some of the attacks, at least four of the C

symptoms developed suddenly and increased in intensity

within ten minutes of the beginning of the first C symptom

noticed in the attack.

It cannot be established that an organic factor initiated and

maintained the disturbance, e.g., amphetamine or caffeine

intoxication, hyperthyroidism.

Note: Mitral valve prolapse may be an associated condition,

but does not preclude a diagnosis of panic disorder.

SOURCE: American Psychiatric Association, Diagnostic and Statistical

Manual of Mental Disorders, 3rd cd., rev. (Washington, DC:

American Psychiatric Association, 1987).

drugs (see earlier discussion), including tricyclics

(such as imipramine) and MAOIs (such as phenelzine),

and antianxiety agents (such as the benzodiazepine

alprazolam) are somewhat effective (11,71,107).

The antidepressants generally require several weeks

of administration before they become effective.

Their side effects were discussed previously. Antianxiety agents act quickly and are therefore useful

in acute situations. These medications may pose a

risk of dependence, however, and thus may not be

appropriate for long-term use (23). Behavioral

therapy aimed at reducing phobic avoidance and

anticipatory anxiety may help diminish panic attacks

and the anxiety associated with them. Relaxation

techniques may also be useful. Cognitive therapy,

aimed at helping individuals restructure their thinking and develop a different way of looking at that

which they fear, is also used. Cognitive and behavioral therapy usually diminish the severity and

frequency of panic attacks. There is not enough

information available to compare the effectiveness

of psychotherapeutic and pharmacological approaches.

Further information concerning the optimal duration

of treatment is also necessary.

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Chapter 4

Mental Disorders and the Brain
CONTENTS

Page

METHODS USED TO STUDY MENTAL DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Anatomy and Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

SCHIZOPHRENIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Anatomy and Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Other Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

MOOD DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Biochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Anatomy and Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Other Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ANXIETY DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Obsessive-Compulsive Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Panic Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

IMPLICATIONS FOR TREATMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER 4 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

71

72

74

77

77

79

81

82

82

82

85

86

88

88

88

90

92

92

93

94

Boxes

Box Page

4-A. Cloning Dopamine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

4-B. Serotonin and Suicide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Figures

Figure Page

4-1. Neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

4-2. The Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

4-3. Brain Structures Involved in Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

4-4. MRI Scan of an Individual With Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

4-5. PET Scan of an Individual With Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80

4-6. PET Scans of an Individual With Bipolar Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

4-7. PET Scan of an Individual With Obsessive-Compulsive Disorder . . . . . . . . . . . . . . . . 89

4-8. PET Scan of an Individual With Panic Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Tables

Table Page

4-1. Techniques for Imaging the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

4-2. Drugs in Development for Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Chapter 4

Mental Disorders and the Brain

Studying the factors that play a role in mental

disorders is like putting together a jigsaw puzzle.

The pieces of the puzzle are bits of information about

the workings of the human brain. This chapter

considers the chemistry, structure, and function of

the human brain in mental disorders. Another key

piece in the puzzle is the heritability of these

disorders, which is discussed in chapter 5.

The nature and amount of information available

about the biology of mental disorders reflects the

course of neuroscience research over the years.

During the 1960s and 1970s there were advances in

the methods used to study the chemistry of the brain

and a resulting increase in knowledge about brain

pharmacology and biochemistry. Many scientists

therefore focused their work on the roles of natural

chemicals and pharmaceuticals in mental disorders.

The following decade, the 1980s, saw advances in

molecular biology and imaging technologies, which

in turn led to study of brain anatomy and activity and

the molecules involved. The pace and extent of

research into the biological components of mental

disorders mirror these developments, with the body

of knowledge concerning the chemistry of the brain

being much larger than the growing database about

other factors. Currently, some of the most active

research involves techniques that enable investigators to study the activity of the brain in living

subjects. These advances and the expectation of

future discoveries have infused researchers in the

area of mental disorders with optimism that further

studies will pay off in a greater knowledge of the

brain, a better understanding of disorders, and the

development of new treatments for them.

Scientists examine the activity of the brain to

determine its normal functioning and to see whether

biological factors are associated with a given mental

disorder. When a factor is identified, an important

distinction must be made as to whether it is

correlated with the disorder or in fact causes it. A

correlated factor is one that is linked to the disorder

and may result in some of its symptoms. For

example, a perturbation of the chemical functioning

of an area of the brain may be correlated with

symptoms characteristic of a disorder. Understanding the perturbation can explain how the symptoms

occur-that is, what the biological underpinnings

are-but it does not explain what caused the

chemical disturbance. Thus, a correlated factor—in

this case the chemical perturbation-is secondary to

the underlying cause of the disorder. The consistent

association of either a causative or correlative factor

with a disorder can provide a biological marker to

aid in the diagnosis of the disorder, which in turn can

be critical to research and treatment. The identification of factors that are associated with a disorder can

also provide an understanding of the mechanisms

underlying symptoms; this is crucial to the development of rational therapeutic interventions. Most

basic of all is the identification of specific causes of

mental disorders. To date, research into the biology

of the mental disorders considered here has identified several factors that are associated with their

symptoms; there is much less evidence regarding the

causes of these disorders.

To solve the puzzle of what causes and contributes to mental disorders, all of the pieces have to be

studied and fit together. It is important to note that

not all of them will necessarily be biological.

Although beyond the scope of this report, psychological and social factors also contribute. Thus,

when a biological factor is identified, research must

point out how it interacts with psychological and

social factors that may produce, modify, or determine how mental disorders are expressed. For

example, it may be that biological factors create a

predisposition to certain disorders. The psychological and social experiences of an individual, such as

exposure to stress or a negative life event, may then

shape the likelihood that that factor will manifest

itself as the clinical condition.

METHODS USED TO STUDY

MENTAL DISORDERS

To understand the involvement of biological

factors in mental disorders, researchers conduct

experiments in animals, analyze biological samples

from patients, and study patients’ biochemistry,

brain anatomy, behavior, and mental activities. In

general, basic mechanisms of the brain’s physiology, chemistry, and anatomy are studied in either

animal models that approximate aspects of a disorder or in tissue samples from living persons and

brain samples from deceased ones. Patient popula-

–71-
72 ● The Biology of Mental Disorders

tions are examined to learn more about symptoms

and characteristics associated with disorders. Understanding mental disorders depends on connecting

information from these diverse observations. Ultimately, the most comprehensive information is

derived from studies and techniques that permit

direct measurements in humans, both those with and

those without mental disorders. Although it is very

difficult to study the working brain in humans, new

techniques enable investigators to observe some

physiological processes in living subjects. Refinement of these techniques, and the development of

additional ones, will most likely enhance the understanding of mental disorders.

It is often difficult to put disparate biological

pieces together into a unified hypothesis about the

biological underpinnings of a mental disorder. Many

times, results from studies contradict each other or

are inconsistent, which further complicates this

process. A number of factors contribute to these

contradictions and inconsistencies. A better understanding of the workings of the healthy brain is

essential to understanding what might go wrong in

mental disorders. As a result, there is still much to be

learned. Also, some older research techniques provide only crude measures of brain activity, producing less precise findings. Finally, the difficulty of

distinguishing specific mental disorders may result

in a heterogeneous research population, which can

then produce difficult-to-interpret results. To some

extent, the explosion in neuroscience research in

recent years and the development of new, sophisticated techniques and methodologies for more precise, complex analysis have reduced, and will

continue to alleviate, many of these problems.

Biochemistry

Study of the biochemistry of the brain involves

examining the many chemicals involved in communication and processing of information in the brain.

Neurotransmitters are chemicals released by nerve

cells, or neurons, to communicate with each other.

Neurons are the cells that process information in the

brain. A neuron consists of a cell body with long

extensions, much like the branches of a tree, called

dendrites (figure 4-l). Also projecting out of the cell

body is a single fiber called the axon, which can

extend a great distance (figure 4-l). When a neuron

is activated, it releases a neurotransmitter into the

synapse, the gap between two neurons (figure 4-2).

The molecules of the neurotransmitter move across

the synapse and attach themselves, or bind, to

proteins, called receptors, in the outer wall of an

adjacent cell (figure 4-2). Usually, the axon terminal

is the part of the cell that releases neurotransmitters

into the synapse, and the dendrites and cell body are

the areas of the neuron which contain receptors that

form synapses with the axons of other neurons.

Once the neurotransmitter has activated a receptor, it unbinds from the receptor. It then has to be

Figure 4-l—Neurons

Synapse

Two neurons in synaptic contact.

SOURCE: R. Brain (New York, NY: Bantam Books, 1984).
Chapter Mental Disorders and the Brain ● 7 3

Figure 4-2—The Synapse

Nerve impulse

Autobreakdown

receptor

Neurotransmitters Receptors Receiving cell

The synapse and associated structures.

SOURCE: Office of Technology Assessment, 1992.

removed from the synapse so the synapse will be

available for a new message. This is done either by

the neurotransmitter’s being taken backup into the

neuron that released it (a process called reuptake) or

by it being broken down chemically into compounds

called-metabolizes (figure 4-2).

For each neurotransmitter in the brain, there are

specific receptors to which it can attach. Binding by

the neurotransmitter activates the receptor, which

can have different effects, depending on the receptor. Receptors can be linked to a variety of biochemical and cellular mechanisms that are turned on or off

by the activation of the receptor. A neuron can have

thousands of receptors for many different neurotransmitters. Some neurotransmitters activate neurons (excitatory neurotransmitters), while others

decrease the activity of neurons (inhibitory neurotransmitters).

When a neuron is activated, changes occur in its

membrane, resulting in a shift in the balance of ions

(electrically charged molecules) between the inside

and outside of the neuron. This change in ionic

balance triggers an electrical impulse inside the

neuron. The electrical impulse travels from the cell

body, down the axon, to the axon terminal. At the

axon terminal, the impulse causes the release of

neurotransmitter from the neuron into the synapse.

Sometimes a receptor for one neurotransmitter

can affect a receptor for another neurotransmitter. In

such cases, the receptors are biochemically coupled:

The activation of one modulates the functioning of

the other, either increasing or decreasing its activity.

A neuron can also have receptors for the neurotransmitter it releases; these are usually located near the

site where the neurotransmitter is released into the

synapse (figure 4-2). Such receptors are acted on by

the neuron’s own neurotransmitter to regulate the

release of the neurotransmitter. Thus, these autoreceptors, as they are called, act as a feedback mechanism

to regulate a neuron’s activity. The activity of a

neuron will be determined by the cumulative activity

of all its various receptors.

While receptors are specific for a neurotransmitter, there may be a variety of receptor subtypes,

linked to different cellular mechanisms, that all

respond to the same neurotransmitter. In this way,

one neurotransmitter can have diverse effects in

various areas of the brain. Also, the number of

receptors in the brain is not static. In response to

increased production of a neurotransmitter, the

number of receptors for that neurotransmitter will

decrease; conversely, depletion of a neurotransmitter will result in an increase in the number of

receptors for that neurotransmitter. This mechanism

allows the brain to compensate for changes in

neurotransmitter levels. Such receptor changes are

important in therapeutics; some drugs mimic neurotransmitters by stimulating increases or decreases in

receptor numbers. In some cases, these changes may

be directly related to the drug’s therapeutic effect.

Many chemicals have been identified as neurotransmitters, among them acetylcholine, the catecholamines (norepinephrine, epinephrine, dopamine), serotonin, various amino acids, and peptides,

including certain hormones. Various chemicals in

the brain other than neurotransmitters and their

receptors are necessary for brain function. They may

be associated with the biochemical mechanisms

activated by neurotransmitter-receptor interactions,

involved with the production and breakdown of

neurotransmitters, or responsible for carrying out

metabolic activity.

Abnormalities in any of these chemicals, their

receptors, or the cellular mechanisms that are turned

on or off by the receptors could contribute to mental
74 . The Biology of Mental Disorders

disorders. For example, there may be too much or

too little of a neurotransmitter, or the receptors for a

neurotransmitter may not function properly. Mechanisms activated by receptors maybe defective, or the

systems responsible for deactivating neurotransmitters maybe faulty. Also, breakdowns in the chemical

systems responsible for the normal functioning of

cells in the nervous system may play a role in mental

disorders. Such alterations in neurotransmitter systems have been implicated in the symptoms of

certain mental disorders (see later discussions).

Scientists use a variety of tools and methods to

study these factors. Biochemical assays are available

to measure receptor number and activity, concentrations of neurotransmitters, and many other biochemical parameters of brain function. The majority of

these assays are used with tissue from animals or

from patients (i.e., postmortem brain samples or

tissue samples from living patients). For example,

information about concentrations of neurotransmitters

is derived from measuring these compounds or their

metabolizes in samples of blood or cerebrospinal

fluid (i.e., fluid inside and surrounding the brain and

spinal cord). Nevertheless, such samples provide

only an indirect measure of what is occurring in the

brain. The inability to observe and measure the

chemical activity of the brain directly has hampered

investigators’ understanding of how these processes

may go awry in mental disorders. One new technique that enables scientists to study biochemistry in

the living brain is positron emission tomography

(PET) (see later discussion). In particular, it can be

used to assay some biochemical measures, such as

distribution and number of receptors, in living

human subjects.

The last decade has also seen the application of

molecular biological techniques to study the brain.

Genetic information about the brain and its components is studied and manipulated to understand the

cellular and molecular workings of the brain. While

these new techniques are just beginning to have an

impact on the study of mental disorders, they have

already provided valuable information about receptor subtypes (box 4-A) and other aspects of the

biochemistry of the brain.

Information about underlying biochemical abnormalities is also often derived from studying the

actions of therapeutically effective drugs (i.e., psychopharmacology). In fact, many initial advances in

understanding the biochemistry of mental disorders

came from studies of drug actions in the brain. If a

drug is found to be effective in treating a disorder,

examination of that drug’s chemical action in the

brain may lead to the discovery of an intrinsic

pathology. For example, the finding that effective

antidepressant drugs act on catecholamines led to

the study of these neurotransmitters in depression

(see later discussion). Conversely, drug development may be guided by previously acquired knowledge about a disorder, which directs research efforts

to create compounds that will act on an already

identified pathology. If a specific neurotransmitter

system is identified as being aberrant in a disorder,

drugs can be designed to interact with some aspect

of that system, such as the receptors, to try to reverse

the abnormality.

Anatomy and Activity

Abnormalities in the structure of the brain or in its

activity in specific locations can contribute to mental

disorders. In the brain, neurons that share the same

anatomical region, and to varying degrees the same

function, are assembled into groups called nuclei.

The brain is made up of hundreds of nuclei. Some

consist of neurons that produce many different

neurotransmitters, while others are predominantly of

one type. Axons extending from nuclei convey

information between and among them. Thus, the

brain comprises many nuclei, which are connected

by pathways of axons that contain various neurotransmitters. Information is conveyed and processed

via networks made up of interconnected nuclei.

Some networks of nuclei are particularly relevant

to mental disorders (figure 4-3). In general, these are

networks that control cognitive (i.e., perception,

recognition, reasoning, judgment, imagination), behavioral, and emotional functions. Disruptions of

these areas are likely to be involved in the thinking

and mood disturbances characteristic of severe

mental disorders. The cerebral cortex (the portion of

the brain that is critical in decisionmaking) is

important in this regard, especially the frontal lobes,

which are considered to be the seat of higher-order

. . thinkmg and which enables humans to reason

abstractly. The limbic system, a network of structures (e.g., hippocampus, amygdala, parts of the

temporal lobe of the cortex) located in the upper part

of the brain (figure 4-3) and involved in control of

emotional behavior, is also important in mental

disorders. Additional areas of the brain implicated in

mental disorders are the basal ganglia, a group of
Chapter 4--Mental Disorders and the Brain ● 75

Box 4-A-Cloning Dopamine Receptors

Advances in the ability to manipulate and express genetic information provide an important new means of

studying the brain. One area in which the tools of the molecular biologist have contributed significantly is the

identification of receptor subtypes for neurotransmitters, These techniques have permitted the cloning of genes for

specific receptors and have provided a detailed characterization of the receptor’s three-dimensional structure. Not

only is this information important for understanding better how the brain works, but it also aids the development

of drugs specifically designed to act only on certain receptors. This specificity can increase the efficacy of a drug

while decreasing the side effects it causes. The recent identification of several receptor subtypes for the neurotransmitter dopamine is an example of the contribution molecular biology is making to understanding the brain.

Previous to the use of molecular biological techniques, two dopamine receptors had been characterized, based

on the ability of various drugs to bind to them. For example, drugs that are effective in treating schizophrenia (called

typical antipsychotic drugs) ail bind to the same dopamine receptor--the D2 receptor. In addition, another receptor

that binds dopamine, but not typical antipsychotic drugs, was identified and called the D1 receptor. Other evidence,

derived using pharmacological techniques, suggested that there might be additional dopamine receptors, but it was

not until the gene for each of the dopamine receptor subtypes was identified that their existence was confirmed.

Currently, six dopamine receptor subtypes have been identified and cloned using molecular biological

techniques. Although all of these receptors are acted on by dopamine, they all have slightly different molecular

structures. In addition, there are some differences in their location in the brain, the cellular mechanisms that they

turn on when they are activated, and their ability to bind typical antipsychotic drugs. Both the Dl and D5 receptors

are linked to the same cellular mechanism, are located in the hippocampus and cortex, and do not readily bind typical

antipsychotic drugs. They differ in their ability to bind dopamine and dopamine-like drugs. There are two types of

D2 receptors: Both bind typical antipsychotic drugs, and both are found in parts of the limbic system, basal ganglia,

and cortex. They differ in that each is linked to a different cellular mechanism, and one is a dopamine

autoreceptor— a receptor that lies on the dopamine neuron itself, regulating the cell’s activity (see text). The D3 and

D4 receptors are found predominantly in the limbic system. While it is unclear what cellular mechanisms are

activated by these receptors, the D3 receptor is thought to be an autoreceptor. Neither binds typical antipsychotic

drugs as effectively as D2 receptors, and the D4 receptor readily binds a new atypical antipsychotic drug, clozapine

(see text).

The identification of these dopamine receptor subtypes has provided new insights into how more efficacious

antipsychotic medications can be designed. Since clozapine is a highly effective antipsychotic drug but produces

fewer side effects than typical antipsychotics, it is thought that its mixture of strong binding to D4 receptors and weak

binding to D2 receptors accounts for its action. Currently there is great interest in understanding the various

dopamine receptor subtypes to determine their role in schizophrenia and how drugs can be designed to target them.

The complexity of the dopamine receptor system indicates the many ways that a single neurotransmitter can

have myriad effects in the brain. Molecular biological techniques provide an important tool for clarifying these basic

brain mechanisms, providing new information about how they maybe disturbed in mental disorders and leading

the way for the development of more efficacious medications.

SOURCES: E. Kandel, J. Schwartz and T. Jessell (eds.), Principles of Neuroscience (New York NY: Elsevier Science publishing, 1991); P.

Sokoloff, B. Giros, M. Martres, et al., ‘‘Molecular Cloning and Characterization of a Novel Dopamin e Receptor (D3) as a Target

for Neuroleptics,” Nature 347: 146-151, 1990; R Sunahara, H. Guarn, B. O’Dowd, et al., ‘‘Cloning of the Gene for a Human

Dopamine D5 Receptor With Higher Affinity for Dop amine Than Dl,’ Nature 350:614-619, 1991; H. van Tol, J. Bunzow, H. Guan,

et al., “Cloning of the Gene for a Human Dopamine D4 Receptor With High Affinity for the Antipsychotic Clozapine, ’ Nature

350:610-614, 1991.

nuclei just below the cerebral cortex, some of which flight response); and the raphe nuclei, also found in

coordinate movement and others of which are part of the brainstem (figure 4-3), made up of serotonin

the limbic system; the hypothalamus, a collection of neurons that regulate sleep, are involved with

nuclei at the base of the brain (figure 4-3) that behavior and mood, and are connected to the limbic

regulate hormones and behaviors such as eating, system. It must be kept in mind, however, that if any

. .

drinking, and sex; the locus ceruleus, a nucleus in the of these, or other brain structures, are impaired in a

brainstem (figure 4-3) made up of norepinephrine mental disorder, it is unlikely that only the function

neurons that are intimately involved in the body’s of that structure will be affected. Since the brain is

response to stressful situations (i.e., the fight-or- organized as networks of nuclei, any structural or
Chapter Mental Disorders and the Brain ● 7 3

Figure 4-2—The Synapse

Nerve impulse

Autobreakdown

receptor

Neurotransmitters Receptors Receiving cell

The synapse and associated structures.

SOURCE: Office of Technology Assessment, 1992.

removed from the synapse so the synapse will be

available for a new message. This is done either by

the neurotransmitter’s being taken backup into the

neuron that released it (a process called reuptake) or

by it being broken down chemically into compounds

called-metabolizes (figure 4-2).

For each neurotransmitter in the brain, there are

specific receptors to which it can attach. Binding by

the neurotransmitter activates the receptor, which

can have different effects, depending on the receptor. Receptors can be linked to a variety of biochemical and cellular mechanisms that are turned on or off

by the activation of the receptor. A neuron can have

thousands of receptors for many different neurotransmitters. Some neurotransmitters activate neurons (excitatory neurotransmitters), while others

decrease the activity of neurons (inhibitory neurotransmitters).

When a neuron is activated, changes occur in its

membrane, resulting in a shift in the balance of ions

(electrically charged molecules) between the inside

and outside of the neuron. This change in ionic

balance triggers an electrical impulse inside the

neuron. The electrical impulse travels from the cell

body, down the axon, to the axon terminal. At the

axon terminal, the impulse causes the release of

neurotransmitter from the neuron into the synapse.

Sometimes a receptor for one neurotransmitter

can affect a receptor for another neurotransmitter. In

such cases, the receptors are biochemically coupled:

The activation of one modulates the functioning of

the other, either increasing or decreasing its activity.

A neuron can also have receptors for the neurotransmitter it releases; these are usually located near the

site where the neurotransmitter is released into the

synapse (figure 4-2). Such receptors are acted on by

the neuron’s own neurotransmitter to regulate the

release of the neurotransmitter. Thus, these autoreceptors, as they are called, act as a feedback mechanism

to regulate a neuron’s activity. The activity of a

neuron will be determined by the cumulative activity

of all its various receptors.

While receptors are specific for a neurotransmitter, there may be a variety of receptor subtypes,

linked to different cellular mechanisms, that all

respond to the same neurotransmitter. In this way,

one neurotransmitter can have diverse effects in

various areas of the brain. Also, the number of

receptors in the brain is not static. In response to

increased production of a neurotransmitter, the

number of receptors for that neurotransmitter will

decrease; conversely, depletion of a neurotransmitter will result in an increase in the number of

receptors for that neurotransmitter. This mechanism

allows the brain to compensate for changes in

neurotransmitter levels. Such receptor changes are

important in therapeutics; some drugs mimic neurotransmitters by stimulating increases or decreases in

receptor numbers. In some cases, these changes may

be directly related to the drug’s therapeutic effect.

Many chemicals have been identified as neurotransmitters, among them acetylcholine, the catecholamines (norepinephrine, epinephrine, dopamine), serotonin, various amino acids, and peptides,

including certain hormones. Various chemicals in

the brain other than neurotransmitters and their

receptors are necessary for brain function. They may

be associated with the biochemical mechanisms

activated by neurotransmitter-receptor interactions,

involved with the production and breakdown of

neurotransmitters, or responsible for carrying out

metabolic activity.

Abnormalities in any of these chemicals, their

receptors, or the cellular mechanisms that are turned

on or off by the receptors could contribute to mental
76 ● The Biology of Mental Disorders

Figure 4-3—Brain Structures Involved in

Mental Disorders

Frontal cortex Hypothalamus

\ I

 a,

Hippocampus Raphe nuolei

Temporal cortex

Three-dimensional drawing of the human brain.

SOURCE: Adapted from Lewis E. Calver, University of Texas, Southwestern Medical Center, Dallas, TX, 1992.

functional impairment in part of a network can create

a disturbance throughout the network.

Structural changes associated with mental disorders can include anatomical abnormalities in the

structure of the brain or irregularities in the individual cells within a region of the brain. The classical

techniques for gathering information about brain

structure-the macroscopic and microscopic postmortem examination of normal brains and brains

from individuals who have had mental disorders—

have been augmented with a number of newer

techniques and machines that make possible the

study of the structure of the brain in living persons

(table 4-l). Computerized axial tomography (CAT),

which uses computers to combine a series of x-rays,

provides clearer pictures of the brain than x-rays

alone. Remarkably clear and detailed images of

brain structure are obtained using magnetic resonance imaging (MRI) scans, which detect molecular

changes in the brain that occur when an individual is

exposed to a strong magnetic field. Abnormalities

that can be detected by either CAT or MRI scans

include structural brain abnormalities, changes in

the volume of brain tissue, and enlargement of the

cerebral ventricles.1 Decreases in the volume of

brain tissue and enlargement of the cerebral ventricles indicate either atrophy or underdevelopment of

a brain region.

The activity of the brain can also be studied to

determine damage or malfunctioning in a region of

the brain. Neuropsychologica1 testing seeks to determine brain damage by measuring deficits in a

person’s performance on various tasks. For example,

deficits on tests that measure language performance

imply damage to the regions of the brain that

subserve language skills, while poor performance on

certain types of puzzles indicates abnormalities in

regions devoted to various kinds of cognitive and

sensory information processing. While neuropsychologica1 testing is helpful in identifying areas of

brain pathology, the measures used are indirect, and

exact locations of involved regions can only be

inferred. However, when combined with more direct

methods of looking at the brain, they provide a

powerful tool for studying brain function and

anatomy.

Measurement of electrical activity in the brain

using the electroencephalograph (EEG) provides a

more direct indication of brain function, and combining the EEG with computer analysis provides an

even more detailed measure. Electrical activity can

be measured while subjects are resting or engaging

in some sort of sensory or cognitive task. By

examining the electrical patterns of the brain,

investigators can observe changes in normal brain

responses and where they occur. A shortcoming of

these measures is that they reflect the cumulative

activity of broad areas of the brain, usually near the

surface. This makes it more difficult to locate areas

of possible pathology.

PET scanning and single-photon-emission computed tomography (SPECT) are imaging techniques

that reveal brain activity. They do so by creating

computerized images of the distribution of radioactively labeled materials in the brain. Researchers

administer labeled materials to a subject either by

injection or inhalation. Subsequent distribution of

 The cerebral ventricles are spaces in the brain that are filled with fluid.
Chapter 4-Mental Disorders and the Brain ● 77

Table 4-l—Techniques for Imaging the Brain

Technique How it works What it images

Computerized axial Computer construction of x-ray

tomography (CAT) images

Magnetic resonance Images molecular changes in

imaging (MRI) brain cells when exposed to a

strong magnetic field

Computer analysis of Creates maps of brain electrical

electroencephalogram activity by computer analysis of

(EEG) EEG

Single-photon-emission Creates images of the distribucomputed tomography tion of radioactively labeled sub-

(SPECT) stances in the brain following

either injection into the blood or

inhalation

Positron emission Creates images of the distributomography (PET) tion of radioactively labeled substances following injection into

the blood

Structure

Structure and activity (when used in

conjunction with a magnetically active

substance)

Activity

Activity (regional cerebral blood flow)

Activity (regional cerebral blood flow,

glucose utilization) and neurochemical

activity (receptor number and distribution)

SOURCE: Office of Technology Assessment, 1992.

these materials reflects the activity of the brain.

Recently, MRI scanning has also been adapted for

this function. PET, SPECT, and MRI enable researchers to measure the utilization of glucose or the

amount of blood flowing in a region of the brain (i.e.,

regional cerebral blood flow). Both glucose utilization and regional cerebral blood flow are indicators

of brain activity: The more active a region is, the

more blood will flow through it and the more

glucose it will use. Abnormal activity levels in

specific brain regions, in the whole brain, or in the

normal asymmetry of activity between the two sides

of the brain can be discerned with these techniques.

Also, as previously mentioned, PET scanning can be

done following the injection of labeled drugs that

attach to specific receptors, making it possible to

visualize the number and distribution of receptor

populations. As with EEG measures, these scanning

techniques can be done either while the subject is at

rest or doing a task. While the imaging techniques

now being used to study mental disorders will

undoubtedly be refined, they provide for the first

time a window through which to view the human

brain at work.

SCHIZOPHRENIA

The symptoms of schizophrenia reflect a broad

range of cognitive and emotional dysfunctions that

are commonly categorized as either positive or

negative symptoms (see ch. 3). Positive symptoms

include hallucinations and delusions, paranoid psychosis, as well as bizarre behaviors and thought

disorder. Negative symptoms include emotional

flattening (i.e., flat affect), loss of motivation,

general loss of interest, and social withdrawal. In

some cases, specific alterations in the biochemistry

or anatomy of the brain have been associated with

either positive or negative symptoms. As with other

severe mental disorders, there are many clues

available regarding schizophrenia, and a number of

hypotheses have been put forward in an attempt to

unify this information into an explanation of the

underlying pathology.

Biochemistry

Dopamine

The most prominent and enduring theory regarding the biochemistry of schizophrenia concerns the

role of the neurotransmitter dopamine. This theory

is based on two sets of observations about drug

action. First, drugs that increase dopamine activity,

such as amphetamine, L-dopa, cocaine, and methylphenidate, sometimes induce a paranoid psychosis

in normal individuals that is similar to some aspects

of schizophrenia. The same drugs, when administered to patients with schizophrenia, sometimes

induce a transitory worsening of symptoms, particularly increasing psychosis and disturbance of

thought. Second, and in contrast, drugs that block

certain dopamine receptors often ease the symptoms, in particular the positive symptoms, of schizophrenia. In general, there is a close correlation

between how well these drugs block dopamine

receptors and their antipsychotic effect. The thera-
78 ● The Biology of Mental Disorders

peutic effectiveness of dopamine-blocking drugs

and the ability of dopamine-enhancing drugs to

worsen the symptoms of schizophrenia provide

evidence for the role of excessive concentrations or

transmission of dopamine in at least some aspects of

the disorder. Nevertheless, studies that have tried to

measure dopamine activity in schizophrenia are less

conclusive (81).

The concentrations of certain chemicals (e.g.,

homovanillic acid, a metabolize of dopamine) can be

measured by scientists to provide information about

dopamine activity. A number of investigators have

measured these chemicals in the tissue and fluids of

persons with and without schizophrenia. If higher

concentrations of dopamine are associated with

schizophrenia, then higher concentrations of these

chemicals would be expected in persons with

schizophrenia. The results are inconclusive. A review of this research (12) shows that in some studies

higher dopamine concentrations were found in

persons with schizophrenia; in others no such

association was found. Conflicting results have also

been found in studies of dopamine receptors, although one subtype of dopamine receptor (the D2

receptor) may be increased in schizophrenia (12).

Thus, regardless of the index of dopamine activity

examined in studies, results are variable. Data

supporting the dopamine-excess hypothesis are usually contradicted by data that fail to find differences

between persons with schizophrenia and controls.

Part of this variability is undoubtedly due to the

imprecision of some of the measures used. The use

of newer, more sophisticated techniques may resolve some of these contradictions. For example, as

previously described, there are a number of dopamine receptor subtypes (see box 4-A). As the ability

to study these receptor subtypes improves, alterations in a specific receptor population may become

evident. Part of the variability in results may also be

due to differences in the characteristics of the

patients with schizophrenia studied. Factors such as

how long an individual has had the disorder and his

or her age when it first appeared can affect findings.

There also is some evidence that dopamine

activity may be associated with specific symptoms

of schizophrenia. For example, when changes reflecting increased dopamine function are observed, they

often occur in patients with prominent positive

symptoms, particularly psychosis (12). Other studies support the proposition that dopamine deficiency

is associated with the negative symptoms of schizophrenia. For example, a correlation between low

levels of dopamine chemicals in cerebrospinal fluid

and negative symptoms has been reported (59). In

addition, dopamine-blocking drugs used to treat the

positive symptoms of schizophrenia produce behaviors suggestive of the negative symptoms in animals

and humans free of mental disorders (81,88). Thus,

the contradictions between dopamine excess and

dopamine deficiency as explanations for schizophrenia can be reconciled by proposing that each is

associated with different symptoms of the disease—

that is, positive and negative symptoms, respectively

(12,60,88)-and that each involves different neural

networks (see later discussion). However, these

hypotheses are controversial and it is possible that

one or both are incorrect. Nonetheless, most scientists agree that dopamine plays some role in schizophrenia.

Other Neurotransmitters

Alterations in the amount or function of other

neurotransmitters in persons with schizophrenia

have also been examined by researchers. Both

increased and decreased levels of serotonin have

been postulated as being associated with schizophrenia. The decreased-level hypothesis was based on

the effects of LSD (lysergic acid diethylamide),

which blocks serotonin activity in the brain and

causes effects that are similar to some of the positive

symptoms (e.g., hallucinations) seen inpatients with

schizophrenia (21). These observations were not

supported by other data; in particular, they were

contradicted by evidence that some drugs effective

against schizophrenia reduce serotonin activity.

Also, as with the dopamine hypothesis, measures of

serotonin in the blood, cerebrospinal fluid, and

postmortem brain tissue do not provide clear answers. Both increased and decreased measures of

serotonin and its metabolizes in blood and cerebrospinal fluid have been observed, and results from

measures in postmortem brain tissue have been

inconclusive (53). Thus, while there is some indication that serotonin activity may be altered in

schizophrenia, the exact nature of its involvement is

unclear.

Both an excess and a deficiency in the activity of

the neurotransmitter norepinephrine have been associated with schizophrenia, although data indicate

that an excess of norepinephrine is more likely to

produce symptoms (80,90). Increased norepineph-
Chapter Mental Disorders and the Brain . 79

rine has been observed in the cerebrospinal fluid and

blood of patients with schizophrenia (21,82). Since

dopamine and norepinephrine have complex interactions, namely, that disturbances in one affect the

other, it is unclear whether any observed increase in

norepinephrine is primary to schizophrenia or secondary to changes in the dopamine system (53).

These neurotransmitters interact with and modulate the activity of many other neurotransmitter and

neuropeptide systems; awareness of this fact has led

to the study of these chemicals in schizophrenia. The

opiate peptides are thought to affect dopamine

neurons, and naloxone, a drug that blocks opiate

receptors, may have antipsychotic properties (53). In

addition, there have been findings relating other

peptides to schizophrenia (53). Since alterations in

such neuropeptides could facilitate, inhibit, or otherwise alter the pattern of activity of other nerve cells,

further study of the status of peptides in schizophrenia is warranted.

Finally, a more specific neurotransmitter hypothesis involves the action of the drug phencyclidine

(PCP) (31). PCP can produce symptoms that resemble both the positive and the negative symptoms of

schizophrenia and can exacerbate these symptoms in

people with the disorder. It is thought that PCP

produces these dual effects by acting at different

sites in the brain (21). PCP inhibits the activity of the

excitatory neurotransmitter glutamate by interfering

with the receptor for glutamate. From that observation, it has been speculated that inhibition of the

glutamate receptor in the hippocampus results in the

negative symptoms associated with schizophrenia

(21). PCP also weakly blocks the reuptake of

dopamine, and in other areas of the limbic system

there is some evidence that PCP inhibition of

glutamate secondarily causes an increase in dopamine activity. These effects on dopamine could

result in the positive symptoms of schizophrenia. In

both instances, there is implicit involvement of

glutamate in the onset of symptoms of schizophrenia. While there is currently little experimental

evidence to support this hypothesis, it represents a

new avenue of investigation in schizophrenia research.

Thus, while it is likely that dopamine plays some

role in schizophrenia, the involvement of other

neurotransmitters is unclear. Since brain neurotransmitter systems interact with each other, it is often

difficult to isolate a cause-effect relationship. The

modulatory action that neurotransmitters exert suggests that there may be complex interactions in

schizophrenia between dopamine systems and these

other brain chemicals.

Anatomy and Activity

Alterations in a number of brain structures,

notably the frontal cortex and limbic system, have

been implicated in schizophrenia. In particular,

ventricular enlargement and evidence of changes in

the size of various brain regions have been observed

in imaging studies and postmortem examinations

(figure 4-4). Limbic structures, such as the hippocampus and parts of the temporal lobes, are most

affected. However, the specificity of these findings

for schizophrenia has been questioned because

they also occur in normal aging and in a variety of

other neurological and psychiatric conditions (10,

21).

Attempts to replicate these findings have yielded

contradictory results. In some cases, evidence of

changes in the volume of the frontal cortex and

temporal lobes has been observed, but the data are

not conclusive and additional studies are needed to

confirm the results (10). Some PET studies have

examined brain metabolism in schizophrenia and

have observed decreased activity in the frontal

cortex and limbic structures, as well as increased

Figure 4-4—MRI Scan of an Individual

With Schizophrenia

Brain structure shown of individual who does not have schizophrenia (top) and a person who does (bottom). The ventricles are

enlarged in schizophrenia (black areas).

SOURCE: W. Carpenter, Maryland Psychiatric Research Center, and H.

 I_Oats Associates, Inc.
80 ● The Biology of Mental Disorders

Figure 4-5-PET Scan of an Individual

With Schizophrenia

Brain activity in an individual who does not have schizophrenia (right) and a person who does (left). The frontal shows

more activity in schizophrenia (white areas).

SOURGE: W. Carpenter, Maryland Psychiatric Research Center, and H.

 Associates, Inc.

activity in the basal ganglia (10,21) (figure 4-5). In

general, these studies indicate that decreased frontal

cortex activity is associated with the negative

symptoms of schizophrenia. This coincides with

data from animal studies, which indicate that damage to the frontal lobes produces behaviors similar to

the negative symptoms.

EEG studies that show a higher incidence of

abnormal electrical activity in the brain of patients

with schizophrenia than in normal subjects provide

further evidence of the involvement of the frontal

cortex. These abnormalities often appear in the

temporal lobe as well. Impairments on neuropsychological tests, such as problem-solving and attention deficits, also indicate that these structures are

affected in schizophrenia (34,39). For example, 65

percent of patients with schizophrenia often have

difficulty visually following a moving object, compared to 8 percent of subjects who do not have

schizophrenia (21) (see ch. 5). It is thought that

defects in maintaining attention, as a result of a

dysfunction in the frontal lobes and limbic system,

contribute to these visual task defects.

These data have led to a number of hypotheses

that attempt to unify the information regarding brain

structures implicated in schizophrenia. In particular,

these theories assign important functions to the

limbic system and frontal cortex. The limbic system

is integral to motivation, gratification, memory, and

many other emotions and thought-processes whose

disturbance is associated with psychosis and the

other positive symptoms of schizophrenia. The

frontal cortex has been implicated in the negative

symptoms of schizophrenia. The proposed theories

differ as to whether the two sets of dysfunctions

should be viewed as dependent or independent and

in the specific structures presumed to be involved.

One theory postulates that they are dependent and

that an insult during the development of the brain

that affected the functioning of the frontal cortex

(see later discussion) can lead to negative symptoms

(84). Since the frontal cortex and limbic system are

interconnected, with the frontal cortex inhibiting

activity in the limbic system, this theory posits that

the dysfunction of the frontal cortex reduces the

inhibition on the Iimbic system, leading to the

positive symptoms.

Another theory suggests that positive and negative symptoms are mediated by two different networks within the frontal cortex and limbic system

and that dysfunction in one of these networks is

separate from dysfunction in the other (9). This

coincides with data from PET studies which show

that negative symptoms are only correlated with

decreased activity in the frontal cortex.

A third theory implicates a disruption in the

activity of the basal ganglia and its interaction with

other brain structures (16,17). This theory is based

on three experimental findings: First, there is

increased metabolic activity in the basal ganglia of

patients with schizophrenia; second, patients with

schizophrenia have difficulty performing visual

attention tasks, which are mediated by areas of the

cortex; and third, animals with lesions in dopaminecontaining areas of the brain that project to the basal

ganglia display some of the behavioral impairments

seen in schizophrenia. This evidence has led to the

hypothesis that schizophrenia is related to impaired

activity in a network composed of the basal ganglia,

certain cortical areas, and other brain structures and

that the impairment is secondary to decreased

dopamine activity.

These hypotheses attempt to find a basis for the

disturbed behaviors observed in schizophrenia; they

are overlapping and not always mutually exclusive.

The available data point to networks involving

certain limbic structures in psychosis and networks

involving the frontal cortex in negative symptoms.
Chapter 4-Mental Disorders and the Brain ● 81

The precise interaction between these networks and

the possible involvement of other brain structures

and areas still need to be clarified. Based on these

theories, predictions (which can themselves be

tested with additional studies) can be made about the

involvement of various areas of the brain in schizophrenia.

Other Factors

Immune and Viral Factors

Viral theories for the cause of schizophrenia are

derived from reports that a number of viral and

immune indices, such as the number and function of

immune system cells, are deviant inpatients with the

disorder (13,32,83). Also, there is some epidemiological evidence to support a viral hypothesis.

Schizophrenia may have a north-to-south prevalence

gradient, may be endemic in a few areas (e.g.,

northern Sweden), and occurs somewhat more often

in persons born in the winter. It has also been

observed that fetuses in the second trimester of

gestation during an influenza epidemic have an

increased risk of developing schizophrenia as adults.

However, it has been difficult to conduct definitive

studies, since any potential marker of an immune or

viral process associated with schizophrenia is applicable in only some cases and is subject to interpretation as secondary to conditions associated with the

disease (e.g., crowding of hospitalized patients,

exposure of individuals living in low socioeconomic

circumstances, and poor health habits).

Developmental Factors

The observed changes in brain volume of persons

with schizophrenia, and the cellular alterations that

accompany these changes, are thought to be irreversible but not progressive (54). Current information

suggests that the magnitude and nature of anatomical and morphological changes in schizophrenia are

present at the onset of the disorder and do not vary

over the lifetime of an individual. A possibility is

that these abnormalities reflect changes that occurred very early in life or in utero, either as the

result of some specific damage or a pathological

alteration in the normal development of the brain.

Evidence that developmental factors may play a

role derives from the observation that infants born

after a complicated pregnancy or labor are at

increased risk for developing schizophrenia as

adults (41,42). One mechanism by which gestational

or birth complications may alter brain development

is diminished oxygen supply (i.e., hypoxia). This

theory is attractive for two reasons. First, many

pregnancy and birth complications are associated

with temporary hypoxia. Second, limbic structures,

especially the hippocampus, are among the most

sensitive areas in the developing brain to the adverse

consequences of hypoxia. Also, subtle deviations in

neurological and psychological functioning have

been observed from infancy in children who are at

high risk of developing schizophrenia (11). Although far from established, it is possible that early,

adverse gestational influences on the developing

brain create a risk of both birth complications and,

later, schizophrenia. A corollary to this proposition

is that a pathological influence operating early in

gestation alters the development of the brain to

create subsequent vulnerability to schizophrenia. An

intriguing possible instance of this proposition is the

relationship, discussed earlier, between pregnancy

during influenza epidemics and the development of

schizophrenia.

What specific alterations in the brain may result

from such insults is unknown; however, it is clear

that subtle deviations in the development of the brain

could create dysfunctions associated with specific

behaviors. Furthermore, it is possible that such

subtle brain abnormalities are not manifest until

much later in life, when new demands are placed on

the brain systems during adolescence and adulthood.

Postmortem findings of abnormalities in the number

and organization of some nerve cells (1,37) suggest

that the developmental process of cell migration, by

which the cells in the brain become organized into

the normal pattern of neuronal networks, may have

gone awry in schizophrenia. Altered cell migration

could be a genetic result, might be caused by

gestational insults, or might involve an interaction of

both. Another process that might be involved is the

pruning of nerve cells that occurs as the brain

develops (18). During early development, the brain

has more neurons than it needs; the fine-tuning

necessary for efficient functioning involves eliminating certain nerve cells and many of the synapses

connecting cells. Failure to prune nerve cells and

synapses adequately, or an error in selecting which

ones to prune, could underlie dysfunctions that lead

to the manifestation of the symptoms of schizophrenia. Whatever developmental processes play a role

in schizophrenia is still an open question.
82 ● The Biology of Mental Disorders

Synthesis

Although various alterations in the biochemistry,

anatomy, and activity of the brain have been

observed in schizophrenia, there are several important points regarding these data (21). The high

variability among patients on any one of the

biological factors and the lack of agreement among

studies about many of them suggest that schizophrenia is a heterogeneous disorder, with patients

exhibiting different clusters of symptoms. This

variability could also reflect the effects of other

factors, such as psychosocial variables, on the

biological components. The fact that some of the

biological abnormalities observed in schizophrenia

are also seen in other conditions calls into question

their specificity to, and their role in, schizophrenia.

Despite the equivocal nature of the research

findings, conclusions can still be drawn from them.

Dopamine plays a role in at least some of the

symptoms of schizophrenia; however, the characteristics of that involvement are unclear, and dopamine’s precise relationship to the positive and

negative symptoms of schizophrenia remains to be

elucidated. The role of other neurotransmitters in

schizophrenia, and if and how they interact with

dopamine systems, needs to be clarified. Given the

cognitive and emotional functions governed by the

frontal cortex and limbic system, it is not surprising

that alterations in these regions have been implicated

in schizophrenia. Abnormal functioning of the

frontal lobes has been one of the most consistent

findings in schizophrenia, and, while less well

documented, there does seem to be a relationship

between decreased frontal cortex activity and negative symptoms. Positive symptoms appear to be

associated with increased metabolic activity in the

limbic system.

While completed studies furnish valuable information regarding what might be wrong in the brain

of a person with schizophrenia, the question of why

schizophrenia occurs remains unanswered. The role

of abnormal brain development or an injury to the

brain, either during development or early in life, is

an important avenue of investigation. As with other

factors associated with schizophrenia, the precise

mechanisms that may be involved are subject to

speculation. The interaction of such a precipitating

event with genetic factors (see ch. 5) is another

plausible cause.

MOOD DISORDERS

Mood disorders include major depression and

bipolar disorder. As the name indicates, major

depression is marked by a deep depression that can

be unremitting. Bipolar disorders are characterized

by periods of depression alternating with manic

episodes. Sadness is a normal human emotion in

response to various life events, but depression that

has no known cause or unremitting depression that

interferes with normal activity is pathological.

Available data regarding the role of biological

factors in major depression and bipolar disorder

often overlap. This reflects the fact that these

disorders may be closely linked. The depressed state

may be mediated by the same brain regions in both

conditions. However, different brain mechanisms

may be involved in the manic state and the swing

from depression to mania that is characteristic of

bipolar disorder.

Biochemistry

Neurotransmitter Systems

Prominent hypotheses concerning depression have

focused on altered function of the group of neurotransmitters called monoamine (i.e., norepinephrine, epinephrine, serotonin, dopamine), particularly

norepinephrine (NE) and serotonin (25,51,70). Evidence that monoamines are involved comes from the

knowledge of the mechanism of action of the two

classes of clinically effective antidepressant medications—tricyclic antidepressants and monoamine oxidase inhibitors (MAOIS). Tricyclic antidepressants

block the reuptake of neurotransmitters, and MAOIs

block the action of monoamine oxidase, the enzyme

involved in the chemical breakdown of the monoamine transmitters once they are released into the

synapse. The net effect of both of these types of

drugs is to prolong the activity of these neurotransmitters in the synapse.

In the 1960s, the clinical observation that patients

who were taking a norepinephrine-blocking drug for

high blood pressure developed depression led to the

hypothesis that depression was the result of low

concentrations of monoamine, in particular NE

(25). Some experiments have shown that patients

with bipolar disorder have decreased NE metabolizes

during depression and increased amounts during

mania, which supports the NE imbalance hypothesis; other studies, however, have shown that patients
Chapter 4--Mental Disorders and the Brain ● 83

Box 4-B—Serotonin and Suicide

More than 30,000 Americans commit suicide each year, making it the eighth leading cause of death in the

Nation. It is the second leading cause of death among adolescents. Changes in a number of indices of serotonin

activity are correlated with suicide attempts and suicide completions. Suicidal behavior is associated with decreased

concentrations of serotonin and its metabolizes in cerebrospinal fluid and the brain. Among successful suicides,

decreased concentrations are usually found in the brainstem, where the raphe nuclei, the major serotonin-containing

nuclei in the brain, are located. Also, increased numbers of serotonin receptors have been observed in the brains of

suicide victims, usually in the frontal cortex. Since certain frontal cortex neurons receive connections from those

of the raphe nuclei, it is possible that the receptor increase is a compensatory response to decreased serotonin activity

in the raphe neurons. A decrease in the number of serotonin autoreceptors in suicide victims has been reported in

some studies. Finally, suicide attempters, as compared to nonattempters, show decreased release of the hormone

prolactin following administration of a serotonin-stimulating drug. This blunted prolactin response is indicative of

a low level of serotonin activity. These data indicate that a net decrease in serotonin activity in the brain is associated

with suicidal behavior.

These data do not mean that decreased serotonin causes a person to commit suicide. First of all, not every

suicide victim exhibits decreased serotonin. For example, serotonin metabolize concentrations are not reduced in

individuals with bipolar disorder who attempt suicide, compared to individuals with bipolar disorder who do not

attempt suicide. Also, there is some evidence that among suicide attempters, measures of decreased serotonin

activity correlate with the lethality of the method us@ that is, the more violent the attempted suicide method (e.g.,

cutting arteries v. drug overdose), the more depressed the serotonin activity. In addition, some of these same

measures of serotonin activity, such as low levels of serotonin metabolizes in the cerebrospinal fluid and blunted

response to prolactin, can be observed in individuals who exhibit impulsive and aggressive behavior. This suggests

that, rather than causing suicide, decreased serotonin activity is correlated with a behavioral predisposition that can

lead to suicide. If individuals who are burdened with feelings of despondency also have depressed serotonin activity,

the propensity for aggression may be directed internally, tragically resulting in a successful suicide attempt.

SOURCES: E.F. Coccaro and J.L. AstiIl, ‘‘Central Serotonergic Function in Parasuicide,’ Progress in Neuro-Psychop harmacology &

Biological Psychiatry 14:663-674, 1990; K.Y. Little and D.L. Sparks, “Brain Markers and Suicide: Can a Relationship Be Found?”

Journal of Forensic Sciences 35:1393-1403, 1990; J.J. Mann, V. Arango, M.D. Underwood, et al., “Neurochemical correlates of

suicidal Behavior Involv ement of Serotonergic and Non-Serotonergic Systems,” Pharmacology and Toxicology 3:37-60, 1990;

J.J. Mann, V. Arango, and M.D. Underwood, ‘ ‘Serotonin and Behavior, ‘‘Annals of the New York Academy of Sciences 60&476-484,

1990; L.C. Ricci and M.M. Wellman, ‘‘Monoamines: Biochemical Markers of Suicide?” Journal of Clinical Psychology

46:106-116, 1990.

with major depression exhibit increased concentra- addition, decreased dopamine metabolizes have been

tions of NE metabolizes (51,70).

As more information has been gathered, it has

become clear that the chemistry of depression is

more complex and that other neurotransmitters,

especially serotonin, maybe involved. For example,

fluoxetine, a highly effective antidepressant drug

that is widely prescribed, acts exclusively on serotonin.

Although the results from studies of serotonin

metabolizes are not conclusive, there is some indication that concentrations of serotonin are decreased in

mood disorders (25). Also, low concentrations of

serotonin metabolizes have been observed in people

who commit suicide (box 4-B). As a result of these

findings, it has been hypothesized that decreased

serotonin plays a role in mood disorders (25,46). In

observed in some, but not all, studies of depression.

One fact that argues against the monoamine

imbalance hypothesis is the time lag between

administration of antidepressant medications and

their clinical effect. These medications increase

neurotransmitter levels almost immediately upon

administration, but their therapeutic effects often do

not appear until 2 or 3 weeks after initiation of drug

therapy. This time lag has led to the suggestion that

the receptors for monoamines may be involved—

specifically, that the clinical effects of these drugs

are due to reductions in the number of receptors to

compensate for the drug-induced increased levels of

monoamine neurotransmitters. It would take weeks

for such compensatory changes to come about.

One hypothesis related to drug-induced changes

in receptors involves a receptor for NE (25). There
84 ● The Biology of Mental Disorders

are a number of NE receptor subtypes. One is an

autoreceptor that decreases the release of NE into the

synapse when it is activated. It has been hypothesized that these NE autoreceptors are overly active

in depression. The therapeutic effects of antidepressant drugs are the result of exposing the autoreceptors to higher concentrations of neurotransmitter,

which decreases their number, ultimately increasing

the activity of the NE-containing neurons. While this

hypothesis would explain the delayed appearance of

clinical effects of antidepressant dregs, studies of the

NE autoreceptor in depression have found no

specific evidence of an abnormality to date.

Currently, no clear evidence links abnormal

serotonin receptor activity in the brain to depression

(51). Increased receptors for serotonin have been

observed in the brains of suicide victims (box 4-B),

but there are conflicting results from studies that

have examined serotonin receptors in depressed

persons (25). Changes in serotonin receptor activity

have been measured indirectly in mood disorders,

notably bipolar disorder, using blood platelets (a

type of cell found in the blood) which also contain

serotonin and are used to investigate mechanisms

related to serotonin and its receptors (46). Both

increased numbers of a subtype of serotonin receptor

and decreased sites for the reuptake of serotonin into

the platelets have been seen in the platelets of

persons with depression (46). However, it is unclear

how these changes relate to serotonin activity in the

brain of persons with major depression and bipolar

disorder.

While there is sufficient evidence to support the

notion that abnormalities in monoamine systems are

an important component of depression, the data

currently available do not provide consistent evidence either for altered neurotransmitter levels or for

disruption of normal receptor activity. This has led

to a dysregulation hypothesis, which states that there

is a more general perturbation in the mechanisms

that regulate the activity of the monoamine neurotransmitters and that clinically effective drugs restore efficient regulation (70). Linked to this hypothesis is the fact that the monoamine systems interact

with each other-the activity of one affects and

modulates the activity of another. Based on available

data, it has been proposed that decreased activity

within the NE-serotonin component of the system is

associated with depression, while increased activity

of the NE-dopamine component tends to promote

mania (25).

Complicating the picture is the fact that other

neurotransmitters have been implicated in bipolar

disorder. Based on evidence that agents which

activate acetylcholine systems can induce depression and that agents which block such activity have

some ability to alleviate depression (51), it has been

postulated that increased acetylcholine activity induces depression and decreased activity induces

mania (15,25,30,70). Furthermore, a number of

investigators have proposed that the salient mechanism may be the balance between NE and acetylcholine systems, with a predominance of acetylcholine activity associated with depression and a

predominance of NE activity associated with mania

(25,28,51,70). A role for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has also

been put forth, based on the paradoxical finding that

increased GABA activity has both an antidepressant

and an antimanic effect (25,40,51). Given that

GABA is a ubiquitous inhibitory neurotransmitter, it

is possible that increasing its activity can result in

the modulation of a number of other neurotransmitter systems, which could explain its broad range of

effects. Finally, there is evidence that some neuropeptides may also be involved in mood disorders

(6,23,25). In particular, decreased levels of somatostatin and increased levels of corticotropin-releasing

factor are associated with depression.

Thus, a number of neurotransmitters have been

implicated in mood disorders, with NE and serotonin

being the most prominent. Lithium is the most

effective drug for the treatment of mania and for

controlling the mood swings between depression

and mania that characterize bipolar disorder. It is not

known how lithium affects the activity of neurons,

but like many other chemicals that are important to

normal brain functioning, lithium is an ion—that is,

a molecule that has an electrical charge. It is thought

that, whatever its action on neurons, lithium has

many different effects in the brain (8). It increases

serotonin activity, decreases acetylcholine activity,

affects the activity of both norepinephrine and

dopamine, and inhibits some of the intracellular

mechanisms that are initiated by activation of

receptors. Since lithium has such a broad range of

actions that can affect the neurotransmitter systems

implicated in mood disorders, its therapeutic effect

may be due to its capacity to correct the neurotransmitter abnormalities associated with mania and

depression, and to prevent the changes in neuro-
Chapter 4-Mental Disorders and the Brain ● 85

chemical balance that are thought to be responsible

for the mood swings of bipolar disorder.

Neuroendocrine Systems

Abnormalities in hormone regulation are common

in depression (7,25,70,71), perhaps because regulation of hormones and the glands that secrete them is

under the control of the same neurotransmitters in

the brain that are thought to be dysfunctional in

depression. In particular, the activities of the pituitary, adrenal, and pineal glands are affected. Many

of the symptoms associated with depression (e.g.,

changes in appetite, sleep, and sex drive) may be

related to these hormonal changes, which means that

the hormonal abnormalities may be secondary to the

neurotransmitter alterations of the disorder (7).

Nonetheless, there is great interest in studying these

changes in hopes of discovering a biological marker

and developing diagnostic tests for depression.

A number of hormones have been studied to

determine if depressed persons consistently exhibit

abnormal concentrations of them or show an abnormal release of them in response to some sort of

pharmacological challenge. Current information indicates that while some of these hormones are

altered in depression, variability in baselines and

pharmacological response, as well as the possibility

of changes due to other causes, makes them unreliable markers for depression (7,70,71).

Depressed persons often have elevated concentrations of the hormone cortisol (7,25,70,71), which

results from increased concentrations of corticotropinreleasing factor. In healthy individuals, administration of the drug dexamethasone suppresses the

concentration of cortisol in the blood. The dexamethasone-suppression test (DST), developed as a test of

hormone functioning, has been studied as a possible

diagnostic tool in depression. Approximately 40 to

50 percent of persons diagnosed with major depression have an abnormal DST in that they do not

suppress cortisol in response to dexamethasone (70).

In very severe cases, particularly psychotically

depressed patients, the percentage ranges from 60 to

80. It is not known why only some patients show an

abnormal DST. Whether this reflects variability in

response to DST or a subpopulation of depressed

patients has yet to be resolved. Therefore, there are

several problems with using the DST as a diagnostic

tool (7,25,70,71). Aside from the fact that not all

depressed patients show an abnormal DST, a number of other clinical (e.g., Alzheimer’s disease,

anorexia nervosa) and nonclinical conditions (e.g.,

fasting, ingestion of caffeine) can result in abnormal

DSTs. Although its effectiveness as a diagnostic tool

is limited, the test maybe useful in predicting which

patients are likely to relapse following cessation of

drug therapy: If DST results remain abnormal during

therapy, the patient is more likely to relapse once the

antidepressant is withdrawn (7).

Another aspect of endocrine function related to

depression is the association between depression

and reproduction-related events in women (2).

Hormonal alterations related to menstruation, pregnancy, childbirth, and menopause can affect neurotransmitters that regulate mood and behavior. The

evidence regarding the relationship between these

hormonal fluctuations and the occurrence of depression is mixed. Nevertheless, the clear association of

mood alterations with these reproductive events in

some women suggests an area for additional investigation. Understanding these biochemical interactions could provide new insights into the pathology

of depression.

Anatomy and Activity

It is unclear which areas of the brain may be

involved in mood disorders. The data regarding

anatomical defects and activity in the brain of

persons with mood disorders are equivocal. Given

that few studies have been conducted and that their

results have varied, it is impossible to come to any

conclusions regarding relationships between the

data and the cause and symptoms of mood disorders.

Overall, the data suggest an association between

mood disorders and abnormalities of large regions of

the brain, especially the frontal and temporal lobes;

they also imply an abnormal difference between the

left and right sides of the brain. Normally, the left

and right sides of the brain are involved in different,

although overlapping, functions. For example, the

left is usually more specialized for language and

logical “thinking, while the right is more involved

with spatial processing. As a result of these different

functions, the two halves of the brain often exhibit

different levels of activity. In mood disorders, some

of the normal differences in activity level between

the right and left sides of the brain appear to be

altered.

Few postmortem studies have investigated anatomical alterations in the brains of persons with

mood disorders, although a number of studies have
&5 ● The Biology of Mental Disorders

examined depression and mania that are secondary

to other insults to the brain (e.g., tumors, stroke,

wounds) (25). Often, the trauma-induced alteration

in mood occurs as a single episode of either

depression or mania; there are only a few reports of

bipolar disorder occurring as a result of brain

damage. Although the secondary nature of the

disorders severely limits the usefulness of these

studies, some anatomical patterns can be discerned.

In general, depression and mania are associated with

damage to the frontal and temporal lobes of the

brain, while bipolar disorders are associated with

diverse areas of the brain. Depression tends to be

associated with damage to the left side of the brain

and mania with damage to the right (25).

Additional information has been derived from

studies using CAT and MRI scans (25). While not

conclusive, data from CAT scans indicate that

patients with mood disorders, especially bipolar

disorder, have decreased cortical volume. The clinical features most frequently correlated with decreased cortical volume are psychotic symptoms and

poor response to treatment. The few MRI studies of

persons with bipolar disorder indicate that there may

be some structural abnormalities present, especially

in the frontal and temporal lobes (25).

Studies measuring cerebral blood flow and glucose utilization have also produced some evidence

of abnormal activity in mood disorders (25,85)

(figure 4-6). The available data suggest that persons

with bipolar disorder, as well as persons with major

depression, show decreased activity in a specific

portion of the frontal lobes called the prefrontal

cortex; persons with bipolar disorder also show a

more general decrease in activity involving the

whole cortex and the left frontal lobes (25). Thus,

these studies implicate the left side of the brain.

However, results of studies using neuropsychological testing and observations of electrical activity in

the brain caused by performing a task implicate a

deficit in the right side (25,74,86). Neuropsychological testing consistently finds deficits in tasks related

to right-hemisphere functioning, such as spatial

learning and memory, among persons with mood

disorders (25). The imaging data, which are consistent with the postmortem studies, are from studies of

the brain in its resting state, whereas the neuropsychological testing and electrophysiological studies

measured the active functioning of the brain in

response to a task. It is unclear whether the

divergence in observations represents discrete abFigure 4-&PET Scans of an Individual

With Bipolar Disorder

Brain activity in a person when depressed (top and bottom rows)

and when in the manic state (middle row).

SOURCE: L. Baxter, M. J. et al., “Cerebral Metabolic

Rates for Glucose in Mood Disorders: Studies With Positron

Emission Tomography and F1 8,” Archives

of Genera/ Psychiatry 1985 (copyright 1985 

American Medical Association).

normalities that are detected selectively by the

different methods. Additional data need to be

collected, using imaging techniques in conjunction

with performance tasks, to clarify this issue and to

determine the significance of these differences in

activity on the two sides of the brain.

Other Factors

Sleep and Biological Rhythms

Sleep disturbances are common in persons with

major depression (25,38,68,70) and, like the alterations in endocrine function discussed earlier, are

likely to be secondary to a primary pathology. Sleep

consists of rapid eye movement (REM) sleep (the

time during which dreaming takes place) and

non-REM sleep. Both REM and non-REM sleep can

be monitored with the EEG. In the course of a night,

REM and non-REM sleep cycle approximately

every 90 minutes. In depression, the first REM

period occurs earlier than normal after sleep begins,

the time spent in REM sleep is increased, and the

length of non-REM sleep decreases. In 80 to 85

percent of depressed persons, sleep is broken by

frequent awakenings, while the remaining percentage show features of hypersomnia. It has been

suggested that depressed persons can be differentiated from other individuals on the basis of the
Chapter Mental Disorders and the Brain ● 8 7

abnormalities in REM sleep (70). The early occurrence of REM sleep has been repeatedly demonstrated in depression. Based on these observations,

it has been suggested that shortened REM latency,

and possibly other REM sleep measures, can be used

to diagnose depression (70); others question the

specificity of these changes to depression (25).

The sleep of persons with bipolar disorder is often

disturbed and varies with clinical state, severity, and

stage of the disorder (25). When depressed, bipolar

patients may sleep excessively, and when manic,

may sleep little or not at all. Sleep can also influence

the switch from one phase to another. Sleep loss

often precedes, and may trigger, a manic episode.

Also, one or two nights of sleep deprivation can have

a short-term antidepressant effect (25,79). This

evidence indicates that in some cases mania can be

prevented and depression treated by appropriate

manipulation of the sleep-wake cycle (25).

The sleep cycles previously described are an

example of a biological rhythm. The preceding

report in the Office of Technology Assessment’s

neuroscience series (79) describes and discusses

biological rhythms-the changes in various physiological and behavioral functions that repeat at

regular intervals and provide a framework of temporal organization for those functions-and their

effects. and consequences. While sleep stages are

measured in minutes, many biological rhythms (e.g.,

body temperature, secretion of hormones, sleepwake cycle, alertness, memory) have a 24-hour cycle

and are called circadian rhythms. For example, body

temperature fluctuates over 24 hours, with peak

body temperature occurring during the day and

lowest body temperature occurring at night.

The cyclic pattern of bipolar disorder and the fact

that people with depression exhibit daily and seasonal fluctuations in mood suggest a link between

mood disorders and biological rhythms. Whether

that link is causative or correlative is unknown (79).

Changes in biological rhythms have been observed

in some persons with mood disorders (25,72). The

fact that animal studies have indicated that some

antidepressant medications have an effect on the

organization of circadian rhythms provides a further

link between mood disorders and biological

rhythms. Finally, a seasonal variation in the occurrence of depression has been observed. A specific

syndrome of winter depression, which remits during

the summer, has been identified and named seasonal

affective disorder (SAD). Although it is not clear

whether SAD is associated with altered biological

rhythms, it is related to changes in the length of

daylight across the seasons. Exposure to additional

light during the winter is an effective treatment for

SAD.

Kindling and Sensitization

Recurrences of mania and depression in bipolar

disorder tend to increase in frequency overtime. The

neurobiological phenomena of electrical kindling

and behavioral sensitization observed in animals

may provide clues to the physiological mechanisms

underlying this pattern of cycling (25). Repeated

administration of low-level electrical stimulation to

an area of the brain results in kindling, or increased

responsiveness to electrical stimulus that leads to the

development of seizures. If the stimulation is

repeated frequently enough, the area becomes so

sensitive that seizures will occur spontaneously.

Similarly, behavioral sensitization refers to the

increasing behavioral response that results from

repeated administration of the same dose of a

stimulant drug.

While these phenomena are not directly analogous to the mood disturbances of bipolar disorder,

they do share certain characteristics (62). For

example, in each, early episodes require a precipitating event, while later ones can occur spontaneously.

Also, repeated exposure to precipitating events leads

to more frequent occurrence of episodes. These

characteristics coincide with the concept that early

episodes of mania or depression result from some

sort of psychosocial stress but later episodes can

occur in the absence of such a stimulus, and with the

observation that episodes tend to occur with a

shorter and shorter cycle.

Thus, the same or similar brain mechanisms

controlling kindling and sensitization could play a

role in the cycling of bipolar disorder. Some

evidence for this is seen in the fact that serotonin,

norepinephrine, and GABA, neurotransmitters implicated in mood disorders, all inhibit the kindling

phenomenon (25). Also, lithium, which is efficacious in treating bipolar disorder, blocks behavioral

sensitization, while carbamazepine, an antiseizure

medication that is also effective in bipolar disorder,

blocks kindling.
88 ● The Biology of Mental Disorders

Immune and Viral Factors

Results from some studies have raised the possibility that mood disorders may be associated with

abnormalities in the body’s immune system or with

viral infection (25). For example, some studies

indicate that persons with major depression may

have a compromised immune system, as indicated

by their diminished response to infectious challenges. Also, some studies have found increased

antibodies to certain viruses that infect the nervous

system (i.e., cytomegalovirus, herpes, and Borna

disease virus) in some persons with mood disorders.

Thus, there is limited evidence that immune system

dysfunction or viral infection may be associated

with mood disorders in some persons, although the

available data are far from conclusive. If such

associations exist, it is unclear what relationship

they may have to the onset and symptoms of the

disorder.

Synthesis

There are many disparate pieces to the puzzle of

mood disorders, and fitting the available ones

together is difficult. Early theories that depression

and bipolar disorder are the result of a simple

imbalance in norepinephrine or that a specific

anatomical locus could be identified are now recognized as simplistic. Clinically effective drugs have

shown that adjusting the activity in monoaminecontaining regions of the brain has an antidepressant

effect. Whether this indicates there is a primary

dysfunction in these regions in depression has yet to

be proved. The implications of the other factors

described in this section are also unclear.

An approach that encompasses the diversity of

experimental data and is at the same time harmonious with the clinical profile of the disorders is

needed in order to construct a meaningful hypothesis. As discussed in chapter 3, it is unclear whether

depression is a single disorder or a collection of

disorders. This possible heterogeneity complicates

attempts to delineate biological factors that might be

involved. It is likely that the same regions of the

brain mediate depression in both major depression

and bipolar disorder. If separate subtypes of depression exist, this same network of structures is likely

to be involved; what differentiates the disorders may

be the factors that disrupt the network. This idea

coincides with information suggesting that mood

disorders occur because integrated control systems

in the brain are disrupted, rather than because of

defects in specific regions. The explanations that

there is an overall dysregulation in the balance

between the different monoamine neurotransmitter

systems and that the brain mechanisms which

control biological rhythms may be involved in mood

disorders are examples of hypotheses involving

disruptions of integrated control systems. As more

information is gathered about these and other

systems, researchers will gain a clearer understanding of how they maybe disrupted in mood disorders.

ANXIETY DISORDERS

Anxiety is a normal human emotion that can help

people cope with certain situations. It is only when

anxiety or its manifestations become excessive and

interfere with normal performance or health that

they are considered pathological and termed a

disorder (see ch. 3). Anxiety disorders include

generalized anxiety disorder, panic disorder, obsessivecompulsive disorder (OCD), social and simple

phobias, and posttraumatic stress disorder (PTSD).

This discussion will be limited to the disorders in

which biological factors have been most extensively

studied, namely, OCD and panic disorder.

Obsessive-Compulsive Disorder

Idiosyncratic daily rituals and odd personal habits

are ubiquitous. It is only when obsessions or

compulsions, or both, cause marked distress, occupy

more than 1 hour a day, and cause significant social

or occupational dysfunction that the diagnosis of

OCD is made (63) (see ch. 3). OCD is commonly

accompanied by depression. Symptoms include

recurrent obsessions with fears of contamination,

harming others, and worries that doors are not

locked or lights have not been turned off. Compulsions such as washing, checking, counting, and

rearranging are common. Though most patients

know that these thoughts and behaviors are irrational, they cannot put them out of their mind. The

involuntary, repetitive nature of the cognitive or

motor behaviors associated with OCD, coupled with

recent experimental findings, suggests a role for

biological factors in OCD.

Biochemistry

Drugs that are effective in treating OCD act by

blocking the reuptake of serotonin into the neuron

from which it was released (49,50,87). Not all

persons with OCD respond to these drugs (91),
Chapter Mental Disorders and the Brain ● 8 9

however, and it is unclear whether these persons

represent a subgroup of patients with OCD (91). The

potency of drugs that block serotonin reuptake

suggests that persons who do respond may have

abnormal serotonin functioning, but supporting

evidence is meager. Like other neurotransmitter

systems, the serotonin system is complex. Serotonin

is found in a number of specific areas of the brain,

and several receptor subtypes have been identified.

While a few studies have shown that drugs that block

serotonin receptors can exacerbate OCD symptoms,

no abnormalities in the synthesis, release, reuptake,

metabolism, or receptors of serotonin in patients

with OCD have been identified in other studies (87).

Also, while the reuptake-blocking effects of drugs

occur immediately, the therapeutic response usually

does not develop until after several weeks of

treatment (24,87). This delay suggests that the

clinical effect could be the result of adaptive changes

in the serotonin or other neurotransmitter systems in

response to the changes in serotonin levels induced

by the drugs (87). Thus, it is not certain whether

these drugs act directly on a primary defect of the

disorder or whether they act indirectly, via the

serotonin system, to counteract the effects of a

primary defect.

It has also been proposed that dopamine systems

play a role in OCD (24). Symptoms of OCD

sometimes result from damage to the basal ganglia,

which have high concentrations of dopamine. Tourette’s syndrome, a disorder characterized by motor

and vocal tics, and often symptoms of OCD as well,

is thought to result from a dysfunction of the

dopamine system in the basal ganglia. Based on

observations that serotonin can inhibit the activity of

dopamine systems and that the basal ganglia receive

input from serotonin-containing neurons, a hypothesis has been put forward that an alteration in the

normal interaction of these neurotransmitter systems

in the basal ganglia may be involved in OCD (24).

There are some preliminary findings that drugs that

act on dopamine may have an effect on OCD (24),

and data from anatomical studies also indicate a role

for the basal ganglia in OCD. This hypothesis is

considered in greater detail in the next section,

which describes the basal ganglia and some of their

anatomical connections.

Anatomy and Activity

Persons with OCD exhibit a variety of abnormalities on neuropsychological tests (91). In general,

329=309 O - 92 - 4 : QL3

Figure 4-7—PET Scan of an Individual

With Obsessive-Compulsive Disorder

Brain activity in the brain of a person with OCD (right) and the brain

of a person without OCD (left). In OCD, there is increased activity

in the frontal cortex.

SOURCE: L. Baxter, UCLA Center for Health Sciences, Los Angeles, CA.

these tests point to dysfunctions in the frontal lobes,

basal ganglia, and hippocampus. For example,

persons with OCD often perform poorly on tests that

measure memory and attention. PET studies of

glucose utilization have shown greater than normal

activity in parts of the basal ganglia and an area of

the frontal cortex, the orbital cortex, in OCD (4,5,91)

(figure 4-7). Data from the few CAT studies that

have been ‘done indicate that the only difference

between the brains of OCD patients and controls is

a decrease in the size of various regions in the basal

ganglia (64,91). These data, coupled with those

previously discussed, lead to the hypothesis that

OCD is the result of an abnormal interaction

between the basal ganglia and other areas of the

brain, principally the orbital cortex (4,5,35,64,91).

These areas work together to coordinate movement

in response to thought. If the basal ganglia are

damaged, involuntary movements such as tics occur.

The thoughts and impulses that often make up

obsessions (e.g., those related to aggression, hygiene, sex, and danger) are thought to be generated

in the frontal cortex. In normal individuals, the basal

ganglia-orbital system filters these impulses, putting

them aside so that they are not acted upon. According to this theory of OCD, the filtering effect that

keeps an individual from acting on thoughts or

impulses does not work properly. As a result, a

thought occurs and the person takes action. Again,

the association with Tourette’s syndrome is striking.

Individuals with this disorder exhibit not only motor
90 ● The Biology of Mental Disorders

tics, but involuntary vocalizations, often of an

obscene or socially unacceptable nature (such as

racial epithets). The basal ganglia-orbital cortex

hypothesis posits a dysfunction in the normal control

of thoughts (obsessions), which can lead to reactive

motor activity (compulsions).

Panic Disorder

Panic disorder is marked by recurrent periods of

intense fear that last for several minutes. The attacks

are not triggered by anxiety-provoking situations,

and patients often report that they occur ‘‘out of the

blue. ’ Many persons with panic disorder experience

varying degrees of anxiety between attacks in

anticipation of the next panic attack (57). This ‘‘fear

of fear’ often results in patients with panic disorder

developing agoraphobia, the fear of being in public

places.

Several theories have been postulated to explain

panic disorder (57). One views panic as the result of

hyperactivity of the physiological mechanisms that

are normally activated in stressful situations (i.e., the

sympathetic nervous system). Another posits that

individuals have an increased psychological sensitivity to normal fluctuations in physiological responses. This theory suggests that patients may

misinterpret normal physiological changes as dangerous, inducing more anxiety and precipitating a

panic attack. Another theory suggests that there is a

primary defect in brain mechanisms related to the

neurotransmitter norepinephrine, which is associated with the sympathetic response. A role for

sensitivity to the chemicals lactate and carbon

dioxide, for hyperventilation, and for dysfunction in

the temporal lobe of the brain have also been

proposed. There is experimental evidence to support, or in some cases refute, these various theories.

Thus, while there are a lot of puzzle pieces, there is

currently no unified theory of panic disorder.

Biochemistry

Information about the pharmacology associated

with panic disorder can be derived both from drugs

that are effective in treating the disorder and from

agents that induce a panic attack when given to a

patient. The most effective drugs for treating anxiety

are the benzodiazepines. In high doses, these drugs

are also effective in controlling panic disorder.

Benzodiazepines exert their antianxiety effects indirectly, by increasing the action of the inhibitory

neurotransmitter GABA. The discovery that there

are specific receptors in the brain for benzodiazepines indicates that there must be a chemical

produced by the brain that would normally attach to

these receptors (although such a chemical has yet to

be discovered). Benzodiazepine receptors are coupled to GABA receptors, and activation of the

former accentuates the effects of GABA, which

turns off overly active brain cells (14,76).

Unlike GABA and its receptors, which are found

throughout the brain, benzodiazepine receptors are

located in only a few brain structures. Thus, not all

GABA receptors are coupled with benzodiazepine

receptors. The GABA receptors that are coupled to

benzodiazepine receptors and that respond to the

drug are known as GABAA receptors. The areas of

the brain that contain both benzodiazepine and

GABAA receptors include the hippocampus and the

amygdala, both limbic system structures (76). As

described previously, the Limbic system plays a role

in controlling emotional behavior. Thus, it is thought

that the antianxiety effect of benzodiazepines results

from their action on GABAA receptors in the

hippocampus and amygdala.

Another compound, buspirone, is effective for

treating general anxiety, but instead of affecting

GABA, it acts on other chemical systems in the

brain. Buspirone decreases the activity of the neurotransmitter serotonin in some areas of the brain and

activates receptors for the neurotransmitter dopamine in other areas (76). Buspirone acts on serotonin

systems through a complex interaction with a

number of different subtypes of serotonin receptors.

This action, coupled with other experimental findings, has led to the speculation that increased

activity in serotonin-containin g areas, particularly

the raphe nuclei, maybe involved in anxiety (55). It

is thought that the raphe nuclei, via their connections

with the limbic system, may be involved in mediating anxious behavior and that activation would

cause anxiety.

The most effective drugs for treating panic

disorder are the drugs used to treat depression,

although they exert a therapeutic action in panic that

is different from that in depression (76). The efficacy

of these drugs has led to the theory that panic results

from overactivity of the norepinephrine systems in

the brain that mediate the fight-or-flight response,
Chapter Mental Disorders and the Brain ● 91

principally the locus ceruleus (3,43,55,65). It should

be kept in mind, however, that the neurons in the

locus ceruleus make connections with neurons in the

limbic system and can affect their activity. The

hypothesis is that a panic attack is the result of

inappropriate activation of the norepinephrine system in the locus ceruleus. Studies have shown that

panic attacks can be caused by drugs that increase

either the activity of cells in the locus ceruleus or the

release of norepinephrine from them, whereas the

antidepressants used to treat panic decrease the

activity of the locus ceruleus (29,55,61,76).

Any number of agents can provoke panic attacks

in persons who suffer from panic disorder, including

the chemical lactate (administered intravenously)

and carbon dioxide (inhaled). At a high enough

concentration, carbon dioxide will also induce panic

in controls. The mechanism by which these agents

cause panic attacks is unknown (22,27,73,76). Lactate has complex actions in the brain, including

effects on serotonin, norepinephrine, and other

transmitter systems, as well as areas of the brain that

respond to changes in blood chemistry and regulate

respiration (73). Inhalation of carbon dioxide upsets

the balance of oxygen in the blood and can affect its

acidity (27). The areas of the brain that monitor and

control functions such as respiration and the cardiovascular system are connected with the locus ceruleus as part of the fight-or-flight response. One theory

holds-that the norepinephrine system in the locus

ceruleus is unusually sensitive in persons with panic

disorder. Thus, according to this theory, lactate and

carbon dioxide cause changes in either the body or

the brain that indirectly activate the norepinephrine

system in the locus ceruleus, precipitating a panic

attack (27,55,73,92). Lactate induces a panic attack

in about 80 percent of persons with panic disorder

(55). This high correlation has led to the suggestion

that lactate response can be considered a diagnostic

marker for the disorder (20), although variability in

the characteristics of the response among patients

has called this into question (55).

While it seems likely that the locus ceruleus is

involved in panic disorder, other experimental

evidence raises the question as to whether that role

is primary or secondary to the cause of the disorder

and whether other brain systems are also involved

(76). For example, serotonin has also been implicated in the genesis of panic attacks (55,58,76).

Serotonin connections to the locus ceruleus inhibit

the activity of locus ceruleus cells, and drugs that

potentate the action of serotonin suppress panic

attacks (76). It has been postulated that a primary

decrease in activity in this serotonin-inhibiting

system may play a role in inducing panic attacks (58)

and that the role of the locus ceruleus is secondary

to this effect. In addition, the action of caffeine

indicates that other brain systems besides the locus

ceruleus may be involved. Caffeine can precipitate

a panic attack in persons with panic disorder

(55,76,77). As a result, people who suffer from panic

attacks often learn, on their own, to avoid caffeineladen products such as coffee and chocolate. Caffeine’s principal action in the brain is to block the

receptors for the inhibitory neurotransmitter adenosine. However, caffeine also has some effect on

norepinephrine, dopamine, and benzodiazepine systems. It is not known whether caffeine produces

panic by inhibiting adenosine activity, some other

action, or a combination of these (77). It is also

unclear how or whether caffeine’s panic-inducing

action relates to the occurrence of panic disorder.

Anatomy and Activity

The few CAT and MRI studies that have examined the brain structure of persons with panic

disorder provide evidence of brain atrophy or

underdevelopment, particularly in the frontal and

temporal lobes (33). However, given the limited

number of studies that have been done, the signifcance of these results is unclear and must be

considered preliminary (33).

Abnormal activity has also been observed in the

brains of persons with panic disorder (26,44,45,67).

At rest, panic disorder patients who are sensitive to

lactate exhibited increased cerebral blood flow to the

parahippocampal gyrus (PHG), an area of the

cerebral cortex that is associated with the limbic

system (figure 4-8). Normal controls or lactateinsensitive panic patients did not show these changes.

Based on these results, it was proposed that a PHG

abnormality was involved in a predisposition to

panic, and it was further hypothesized that activation

of a norepinephrine pathway to the PHG initiates an

attack (67). However, this hypothesis is based on

limited data, and conflation will require additional studies. Furthermore, it does not explain what

mechanism might be present in lactate-insensitive

panic disorder patients. Other studies have demon-
92 ● The Biology of Mental Disorders

Figure 4-8-PET Scan of an Individual

With Panic Disorder IMPLICATIONS FOR

TREATMENT

Whole brain activity (left side) and abnormal activity in the

parahippocampal gyrus (right side) in the brain of a person with

panic disorder in the nonpanic state.

SOURCE: E. Good Samaritan Hospital, Phoenix, AZ.

strated that there is an increase in cerebral blood flow

during lactate-induced panic attacks (67).

Synthesis

There is evidence that a number of different

biological factors play a role in OCD and panic

disorder. The possible role of the basal gangliaorbital cortex system in OCD is an intriguing theory,

coupling areas of the brain involved in cognitive and

motor activity. Further examination of these brain

regions, the role of dopamine mechanisms, and their

interactions with serotonin systems are important

areas for future research related to OCD. Both limbic

structures and the locus ceruleus are implicated in

panic disorder. Data suggest that the limbic structures mediate generalized feelings of anxiety, influenced by the activity of GABA, while the locus

ceruleus controls an active response to anxietyprovoking stimuli (i.e., panic attacks). The anatomical connections between these two regions of the

brain suggest that there might be some interaction of

these systems in panic disorder, but additional study

of these systems and their interaction is necessary.

One of the greatest promises of research into the

biology of mental disorders is the development of

more efficacious treatments-particularly drugs. At

the same time, effective treatment of a mental

disorder must take into consideration all aspects of

the disorder—biological, psychological, and social.

Thus, developments related to biological factors

associated with a disorder contribute to the total

therapeutic protocol available to treat patients.

The antipsychotic drug chlorpromazine, used to

treat persons with schizophrenia, provides an example of the development of a biological treatment. The

discovery that chlorpromazine was an antipsychotic

drug was serendipitous (36). The drug was originally

developed in the search for an effective antihistamine; the chance clinical observation that it had an

antipsychotic effect led to its use in schizophrenia.

Once chlorpromazine’s effect was established, research into its mechanism of action led to the finding

that it exerted its effect by blocking the D2 dopamine

receptor subtype (see earlier discussion). This led in

turn to the development of additional antipsychotic

drugs, called typical antipsychotics, that also act by

blocking D2 dopamine receptors.

The chlorpromazine story also illustrates the point

that most therapeutic advances in psychopharmacology have occurred by chance. A drug discovered to be efficacious was then examined further, to

advance researchers’ understanding of the biological

mechanisms underlying a disorder (36).

The impetus for developing new drugs comes

from the fact that current drugs are imperfect (89).

Side effects are common, and not all patients

respond to a given drug. In general, these problems

result from existing drugs’ inability to act selectively

on the symptoms of a disorder. For example, while

typical antipsychotic drugs act by blocking D2

receptors in areas of the brain involved with

schizophrenia symptoms, they also block D2 receptors in other areas of the brain, which produces the

movement side effects characteristic of these drugs.

Another example is the side effects associated with

antidepressant drugs, which result when the antidepressants act on other neurotransmitter systems

besides the monoamine systems thought to be

involved with depression.
Chapter Mental Disorders and the Brain ● 9 3

Beyond the need for more efficacious drugs with

fewer side effects, the financial impact that more

effective treatments can have is another factor

driving the search for new drugs. Improved treatments can decrease total treatment costs by reducing

the need for hospitalization; they can decrease other

financial effects as well, such as lost wages due to

disability. For example, a study conducted in 1980

estimated that the introduction of lithium in 1969,

for the treatment of bipolar disorder, resulted in an

average yearly savings in treatment costs of $290

million in the United States (66). It was also

estimated that in the first year following the introduction of lithium, $92 million in lost wages was

regained (66).

By attaining a better understanding of what

neurochemical systems are affected in a disorder and

how those systems interact with others, more

effective drugs can be developed to treat the

symptoms of a disorder while minimizing side

effects. The recent strides that have been made in

basic neuroscience research, particularly advances

in molecular and cellular neurobiology, will facilitate this process (75,78). The ability to clone

receptor subtypes and identify precisely the molecular structure of receptors and other biochemical

constituents of the brain will enable scientists to

construct drugs that act more precisely. Thus, the

development of drugs for mental disorders is entering a new phase in which both clinical and basic

research findings will be applied to the design of

more efficacious medications.

The antipsychotic drug clozapine and the antidepressant fluoxetine are examples of this new generation of drugs. Clozapine, a so-called atypical antipsychotic drug, not only blocks D2 receptors but also

acts on other dopamine receptors (see box 4-A) and

on serotonin receptors to create different effects on

these systems in different areas of the brain (47).

Clozapine is thought to block sufficient dopamine in

appropriate areas of the brain to control psychosis,

while acting on other areas of the brain to avert the

blanket D2 blockade that produces side effects.

Unlike traditional antidepressants, which have a

broad effect on catecholamine and other neurotransmitter systems, fluoxetine (Prozac) was designed

specifically to block serotonin reuptake (69). As a

result, it has an antidepressant action equivalent to

that of older drugs, but without many of their side

effects.

Table 4-2—Drugs in Development for

Mental Disorders

Disorder United States Other countries

Schizophrenia . . . . . . . . . . . . . . . . . . 76 42

Mood disorders . . . . . . . . . . . . . . . . 83 61

Anxiety disorders . . . . . . . . . . . . . . . 91 46

SOURCE: PJB Publications, Pharmaprojecfs (Surrey, England: PJB Publications, 1992).

Both of these drugs are improvements on older

medications, but neither is totally without problems.

Although clozapine does not produce the movement

side effects associated with typical antipsychotic

drugs, it is associated with an even more dangerous

side effect. About 2 percent of persons taking

clozapine develop a potentially deadly blood disease, agranulocytosis. As a result, anyone taking the

drug must be tested regularly; if there is any

indication of the disease, treatment must be stopped.

The need for constant monitoring makes administration of clozapine costly, ranging between $6,000 and

$9,000 a year (19). While fluoxetine has many fewer

side effects than older antidepressants, it is associated with such adverse reactions as nausea, nervousness, insomnia, and headache (56).

Despite these problems, the advantages of these

drugs make them highly popular. For example, in

spite of the costs associated with clozapine, results

from a study demonstrated that over a 2-year period

there was a savings of approximately $16,000 per

patient, per year, as a result of decreased hospitalizetion among 37 patients who had taken the drug (48).

Total U.S. sales of clozapine in 1991 were estimated

to be $60 million (19), while 1990 sales for

fluoxetine were put at $500 million (52). Currently,

a number of other drugs, which may represent

further improvements on the medications that have

been used in the past to treat mental disorders, are

being developed and tested (table 4-2). These new

drugs represent the latest efforts to apply information derived from the study of the biology of mental

disorders to treatment of patients.

SUMMARY AND CONCLUSIONS

Evidence exists for the activity of a variety of

biological factors in each disorder reviewed in this

report. However, it is difficult to put the strands of

evidence together in a unified hypothesis about the

role of biological factors in a given disorder.
94 ● The Biology of Mental Disorders

Most of the biological factors that have been

identified relate to changes in the brain that are

correlated with a disorder. These include alterations

in neurotransmitter systems, such as the association

of increased or decreased levels of dopamine with

the various symptoms of schizophrenia and the role

of monoamines in mood disorders. Disruptions in

brain activity are associated with disorders as well,

such as the decreased activity found in the frontal

lobes of persons with schizophrenia and the increased activity in the basal ganglia of persons with

OCD. These factors, and the others discussed in this

chapter, provide insights into the mechanisms underlying the symptoms displayed by patients. A

better understanding of such mechanisms should

enable scientists to develop more effective treatments.

Less is known about the causes of mental

disorders. The influence of various factors, such as

developmental and viral factors, has been hypothesized, but as yet there is no definitive explanation for

any of these disorders. To understand what leads to

the onset of mental disorders, researchers must

consider the role of psychological and social factors

and how they may interact with a pathological

biological condition. For example, the alterations in

the limbic system and locus ceruleus associated with

panic disorder may represent a biological predisposition that is shaped by an individual’s experiences

to determine whether and how the disorder is

manifested, while the kindling-sensitization model

of bipolar disorder suggests that life events can

modify abnormal brain activity.

It is essential to learn how the healthy brain works.

Research in the basic neuroscience provides the

foundation for research on the biology of mental

disorders. Advances in the neuroscience have

resulted in the development of new techniques and

improvements on old ones that greatly increase our

ability to study the brain. Combining such techniques as neuropsychological testing or biochemical

analysis with brain imaging techniques extends that

ability even further. Current research is increasingly

taking multidimensional approaches to the study of

mental disorders, integrating data concerning different aspects of brain functioning and behavior into

testable hypotheses. That trend is expected to

accelerate.

Essential to this effort will be strategies for

studying the integrated networks of brain structures

that control behaviors. Some mental disorders may

be collections of disorder subtypes, indicating that

the normal functioning of a network that mediates a

behavior can be disrupted at various points. The

ultimate goals of research are to understand how

brain structures work in concert to produce behavior,

how this process is disrupted in mental disorders,

and what factors cause it to go awry.

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Chapter 5

The Genetics of Mental Disorders
CONTENTS

Page

BASIC GENETIC CONCEPTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

STUDYING THE INHERITANCE OF MENTAL DISORDERS .. .. .. ... ... ... s....

GENETICS OF SCHIZOPHRENIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

GENETICS OF MOOD DISORDERS . . . . . . . . . . . . . . . . .. .. .. .. .. .. .. .+. . . . . . . . . . . .

GENETICS OF ANXIETY DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

THE CHALLENGE OF MAPPING GENES FOR MENTAL DISORDERS . . . . . . . . . .

What Accounts for Complex Genetics? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

What Is Inherited? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

IMPACT OF GENETIC RESEARCH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Boxes

Box

101

103

106

107

108

109

109

111

112

113

116

Page

5-A. Eugenics and Mental Disorders.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

5-B. Genetic Counseling for Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Figures

Figure Page

5-l. Substrates of Inheritance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

5-2. A Simple Pattern of Inheritance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

5-3. The Chromosome Swap in Meiosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

5-4. Mood Disorders Among Twins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

Tables

Table Page

5-1. NIMH Genetic Research Investment Fiscal Year 1991 . . . . . . . . . . . . . . . . . . . . . . . . . 101

5-2. Relatives’ Risk of Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

5-3. Risk of Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Chapter 5

The Genetics of Mental Disorders

Few theories in biology provoke as heated a

debate as the notion that human behavior in general,

and mental disorders in particular, have a genetic

basis. While there could be no more potent evidence

of a biological basis than the identification of

causative genes, none has yet been found. On the

other hand, opponents of this theory characterize it

as deterministic, casting behavioral genetics as the

enemy of free will. Furthermore, discriminatory

social policies, linked to genetic theories of behavior

and mental disorders in the past, are an ever present

specter in this field.

On this stage of invective and praise, the search

for genes linked to mental disorders continues,

propelled by one of the all-time largest research

projects in the history of biology—the Human

Genome Project-and supported by the primary

funding agency for research into mental disorders,

the National Institute of Mental Health (NIMH)

(table 5-l). This gene hunt has resulted in claims of

success in finding genes for bipolar disorder and

schizophrenia, only to be followed by contradictory

data and withdrawal of claims.

Despite the polemics and clashing research findings, there remains powerful evidence from multiple

sources that many mental disorders, including the

ones considered in this report, have a genetic

component. The only evidence to date that mental

disorders are caused, at least in part, by biological

factors comes from genetic studies, However, the

inheritance of mental disorders is far from simple,

and nongenetic factors also play a role. This chapter

summarizes what is known about the inheritance of

schizophrenia, major mood disorders, and anxiety

disorders. A technical section explains why specific

genes are so difficult to find. Finally, the chapter

considers some of the implications of what is known

about the inheritance of these conditions. First, the

basis of inheritance is reviewed.

BASIC GENETIC CONCEPTS

In nearly every cell of the body, instructions for

making protein—the chemicals required for the

function and structure of cells-are encoded in

genes, the fundamental units of heredity. Humans

have 50,000 to 100,000 genes, as many as half of

which function primarily in the brain. The existence

of these now famous substrates of inheritance was

predicted long before modern chemistry or microscopy could resolve the minute structure of the cell.

By crossbreeding pea plants and meticulously observing the resulting colors and shapes, the Augustinian monk Gregor Mendel (1822-1884) hypothesized that offspring receive discrete elements

of inheritance from their parents.

Genes are made up of deoxyribonucleic acid

(DNA), a double-stranded molecule that twists into

a helix (figure 5-l). Complementary chemical subunits, called base pairs, tether the two strands of the

helix: guanine with cytosine and adenine with

thymine. The linear sequence of bases in each strand

of DNA forms the genetic code. It is this sequence

of bases in genes that determines the structure of

proteins and regulates cell activity. In all, an

estimated 3.3 billion base pairs constitute the human

genome, of which only a small fraction-l to 3

percent—is believed to code for proteins.

Genes, along with intervening regions of DNA

that do not appear to code for proteins, are folded

into rod-shaped bodies, or chromosomes. Each

human cell except gametes (eggs and sperm) contains 23 pairs of chromosomes: 22 pairs of autosomes and 1 pair of sex chromosomes, either two

Table 5-1—NIMH Genetic Research Investment, Fiscal Year 1991a

Total costs of Number of Genetics as a

genetic research grants percent of budget

Division of Clinical Research . . . . . . . . . . . . . . . . . . . . . $25,629,833 b

88 15%

Division of Basic Brain and Behavioral Sciences . . $13,351,201 55 10.9Y0

NIMH total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . $38,981,043 143 8.7%

a~ese figures represent funding for research where the primary focus is human genetics of mental disorders.

b$2,0go,812, or 8.14 per~nt, of the Division of Clinical Research’s genetics budget, is devoted to Diagnostic centers

Cooperative Agreement.

SOURCE: National Institute of Mental Health, 1992.

–101–
102 . The Biology of Mental Disorders

Figure 5-l—Substrates of Inheritance

Nucleotide base pairs

Series of thousands to millions of base pairs form genes, the

substrates of inheritance. Genes, which are strewn along chromosomes in the cell nucleus, code for specific proteins.

SOURCE: Office of Technology Assessment, 1992.

X chromosomes, in women, or an X and a Y

chromosome, in men. Each gene has a specific

address, or locus, on the chromosomes, with two

versions, or alleles, of each gene inherited from each

parent. If the two alleles at a particular locus are

identical, the individual is said to be homozygous;

when the two alleles differ, heterozygous. Some

alleles are dominant, requiring only one copy to

cause expression of a trait, or phenotype (figure 5-2).

In such cases, an individual expresses the dominant

phenotype regardless of whether the hereditary

information for a trait, or genotype, is homozygous

or heterozygous. Other alleles are recessive and

require two copies of the allele for expression of the

trait. In other words, the individual must be homozygous for the gene, with two recessive alleles, in order

to express the recessive phenotype. Of course, the

inheritance of traits can be much more complex.

Many traits reflect the action of several genes as well

as the environment. Or a gene may not be expressed,

even when present. These complexities have important implications for the study of mental disorders.

Eggs and sperm have only 23 chromosomes (22

autosomes and one sex chromosome), and these

form the genetic contribution from our parents-that

is, we receive one set of chromosomes from each.

During the production of gametes, the 23 pairs of

chromosomes are duplicated in the parent cell,

endowing it with four copies of each chromosome

(figure 5-3). The parent cell divides twice, producing

Figure 5-2—A Simple Pattern of Inheritance

DD Dd Dd dd

The father and mother both have a dominant version, or allele, of

a gene (D) and a recessive version (d). Both express the dominant

trait, indicated by shading. Each offspring has a 75 percent

chance of receiving either one or two copies of the dominant allele

and therefore expressing the dominant trait. One out of four times

an offspring will receive two recessive versions of the gene and

exhibit the recessive trait, shown in white.

SOURCE: Office of Technology Assessment, 1992.
Chapter 5—The Genetics of Mental Disorders . 103

four gametes, each with a single copy of the 23

chromosomes. However, the production of gametes

does not simply involve the separation of chromosome pairs-considerable genetic reshuffling also

occurs. The pairs of chromosomes lineup near each

other before their final departure to separate gametes. As the pairs of chromosomes draw near one

another, they actually exchange segments. This

segment exchanger recombination-has important implications for linkage analysis, a technique

used to map genes.

STUDYING THE INHERITANCE

OF MENTAL DISORDERS

Observers have long noticed that behavioral traits,

such as mental disorders, tend to run in families,

suggesting the involvement of genetic factors. However, the genetics of human behavioral traits is more

difficult to study than other phenotypes. Aside from

the ethical impossibility of human breeding experiments and the relatively long time between generations, the phenotype itself is complex.

Behavior . . . is not just another phenotype.

Because behavior involves the functioning of the

whole organism rather than the action of a single

molecule, a single cell, or a single organ, behavior is

the most complex phenomenon that can be studied

genetically . . . (83).

Despite these difficulties, methods have been

developed to take advantage of “natural” breeding

studies. Observing the prevalence and pattern of

behavioral traits among related individuals helps

illuminate their genetic basis. Charles Darwin’s

cousin, Francis Galton (1822-1911), launched this

approach to the study of the genetics of human

behavior. The prodigious Galton explored the inheritance of intelligence, developed new statistical

methods for analyzing such traits, and introduced the

study of twins (85). Unfortunately, his work also

ushered in the ugly era of eugenics in this century

(box 5-A).

Classic investigations into human inheritance

include adoption, twin, and family studies. These

approaches seek to answer the following questions:

Are these traits inherited? What is the relative

contribution of genetic versus nongenetic factors?l

What is the pattern of inheritance? Is the trait

Figure 5-3-The Chromosome Swap in Meiosis

Chromosomes, with alleles of genes A, B, and C, come together

in pairs before gametes are formed in meiosis.

Each chromosome in the pair duplicates itself.

Chromosomes attach to each other.

Crossing over upon breaking and rejoining of chromosomes.

a

B

c

Chromosomes with new gene combinations after crossing over.

Alleles that are far apart-e. g., A and B-maybe separated during

meiosis. Alleles that are close together-e.g., B and C-are less

likely to be separated.

SOURCE: Office Technology Assessment, 1992.

 Nongenetic, or so-called environmental, factors may include biological, psychological, or social components. Thus, the now nature versus

nurture debate does not necessarily boil down to biological versus psychosocial factors.
104 ● The Biology of Mental Disorders

Box 5-A—Eugenics and Mental Disorders

In Nazi Germany and the United States during the earlier part of this century, people with mental disorders were

among the initial targets of eugenic policies. People with mental disorders were subjected to immigration

restrictions, involuntary sterilization, and extermination. While modems deny that such practices could be repeated,

the record of eugenics and its historical link to mental disorders raise uncomfortable questions: Is the new age of

genetics a harbinger of a new age of eugenics? Are people with mental disorders especially vulnerable?

Eugenics enjoys along, well-bred intellectual pedigree, with the cousin of Charles Darwin, Sir Francis Galton,

as its modem forefather. Galton coined the term “eugenics” in 1883, christening the scientific pursuit of improved

inborn human qualities through judicious matings: positive eugenics. Prior to Galton, eugenic notions can be traced

back as far as Plato’s Republic, wherein the philosopher also proposes positive eugenic practices. Of course, the

human genetic pool can be distilled by other means. Negative eugenics refers to the systematic attempt to minimize

the passing of deleterious genes by reducing or preventing the reproduction of individuals carrying such genes.

A number of scientific discoveries planted the seeds of eugenic policies in the 19th and 20th centuries. Galton

himself observed that many accomplished men of his day were linked by blind lines, which led to his belief that

proper matings could produce a race with enhanced intellectual, behavioral, and physical characteristics. In addition,

Galton, as well as others, developed statistical techniques that permitted the quantitative analysis of inherited traits.

While these and other scientific advances were the seeds of eugenics, they were not solely responsible for such

policies in the United States. Social, political, and economic factors of the late 19th and early 20th centuries fertilized

the growth of the eugenics movement. National attention was increasingly focused on social issues of

unemployment, criminality, prostitution, and chronic alcoholism. Also, concerns arose that increased immigration

from southern and eastern Europe was drawing the United States away from its “Anglo-Saxon superiority. ”

At the Federal level, eugenic policies took the form of increasingly restrictive immigration laws, Eugenicists,

asserting the simple inheritance of such traits as lunacy, epilepsy, alcoholism, pauperism, criminality, and

feeblemindedness, proffered scientific rationales for excluding individuals from entry to the United States. It is

important to note that while authentic advances in genetics seeded the eugenics movement, they provided no

evidence for the simple inheritance of the traits mentioned above.

Eugenic considerations also prompted States to enact laws regarding compulsory sterilization. In 1907, Indiana

passed the first law legalizing the compulsory sterilization of inmates at the State reformatory; by 1931,30 States

had passed compulsory sterilization laws applying to individuals categorized as feebleminded, alcoholic, epileptic,

sexually deviant, or mentally ill. Individuals with mental disorders made up half of the 64,000 persons in this

country sterilized for eugenic reasons between 1907 and 1964, When eugenic sterilization laws were challenged in

1927, the Supreme Court ruled the practice was constitutional.

What is the current status of eugenic policies in the United States? While immigration laws still restrict the

entry of people with mental disorders, denial of entry is not based on eugenic principles, but rather on concerns about

whether behavior associated with a disorder poses a threat. State sterilization laws still stand, as does the 1927

Supreme Court ruling upholding them. As of 1987, compulsory sterilization laws remained on the books in 22

States; however, these laws are rarely invoked.

The current application of immigration and compulsory sterilization laws suggests that eugenics is not a major

concern at this time. Furthermore, the understanding that mental disorders do not have a simple genetic basis and

that nongenetic factors play an important role would seem to limit the potential of eugenic policies. Perhaps most

important, American repulsion by the Nazi legacy and the emphasis in this country on individual reproductive rights

also make State-determined eugenic policies unlikely. But indirect pressure not to have children may well come to

bear on individuals seen to have a greater genetic risk of mental disorders; society may brand them irresponsible

or immoral for transmitting disorders to their children. Given the financial strain posed by mental disorders today

and the stigma attached to them, in conjunction with scientific advances, it is possible that these factors could unlock

what some call a backdoor to eugenics.

SOURCES: T. Duster, Backdoor to Eugenics (New York, NY: Routledge, 1990); K.L. Gamer and B. Gamer, “Eugenics: Past, present, and

Future, ” American Journal of Human Genetics 49:1109-1118, 1991; 1.1. Gottesman, Schizophrenia Genesis: The Origins of

Madness (New York, NY: W.H. Freeman, 1991); D.J. Kevles, In the Name of Eugenics (New York, NY: Knopf, 1985); D. Suzuki

and P. Knudtson, Genethics: The Clash Between the New Genetics and Human Values (Cambridge, MA: Harvard University press,

1989); N.A. Holtzman, Proceed with Caution: Predicting Genetic Risks in the Recombinant DNA Era (Baltimore, MD: The JOhns

Hopkins University Press, 1989).
Chapter 5—The Genetics of Mental Disorders ● 105

dominant? Recessive? Determined by more than one

gene?

Adoption studies, though variable in design,

compare the presence of a trait among biological

versus adoptive family members or other control

groups. They attempt to disentangle the influence of

genes from that of the environment and can provide

powerful evidence of a genetic effect. Generally,

they do not rule out the effect of nongenetic factors

that preceded adoption, such as possible prenatal

influences. While few adoption studies have evaluated the genetics of anxiety disorders, they provide

evidence about the inheritance of mood disorders

and schizophrenia.

Twin studies compare how often identical twins,

who are genetically identical, and fraternal twins,

who have the genetic similarity of nontwin siblings,

are similar, or concordant, for a trait. A high

concordance rate for a trait among identical twins

versus fraternal twins usually demonstrates a genetic

basis for the trait. The absence of 100 percent

concordance among identical twins shows that

nongenetic factors also play a role in producing the

trait.

Twin studies raise several issues, including the

certainty with which identical twins versus fraternal

twins are identified; the way in which twins are

sampled; the assumption that identical and fraternal

twins experience the environment identically; the

definition of concordance; and the statistical methods for measuring concordance (39,85). All of these

factors must be weighed when evaluating data from

twin studies.

Of all the traditional approaches to studying

genetics, family studies have been used most frequently to evaluate mental disorders. Such studies

consider whether a trait runs in families. The familial

nature of a trait is essential for proving it is inherited;

however, such data do not conclusively demonstrate

the genetic basis of a trait, since family members

share not only genes but also their environment.

Showing that a trait is more prevalent within a

family than in a control population suggests the

importance of genetic factors. The observation that

a trait is more common among first-degree relatives—

parents, siblings, and offspring-than more distant

ones strengthens the genetic hypothesis. The way in

which a trait is distributed among family members

may also elucidate the mode of inheritance. For

example, if a trait is never passed from father to son,

an X-linked gene is implicated. More complicated

quantitative techniques may reveal other aspects of

the mode of inheritance. While family studies

provide part of the foundation for the genetic theory

of mental disorders, they have not resolved how

these disorders are inherited.

Classic genetic studies are quite useful. And data

from these studies form the sole existing support for

the genetic basis of mental disorders. This research

produces the bottom line of genetic influence, that is,

distinguishing the relative influence of heredity

from that of the environment (84). But there is a limit

to what classic genetic studies can reveal. They

cannot identify a specific gene defect. Because of

this limitation, researchers have been eager to apply

the new, powerful tools of modem genetics to the

study of mental disorders.

The search for the molecular genetic underpinnings of mental disorders in the last several years has

involved mostly the technique of linkage analysis.

Linkage analysis can determine whether a single

gene makes a major contribution to a trait and where

that gene is located. A positive finding of linkage

shows that a nearby gene plays an important role in

the inheritance of the investigated trait. It maps the

gene to a location on the chromosomes; it does not

isolate the specific gene or reveal its function.

Linkage analysis takes advantage of the fact that

although alleles for genes of most traits are inherited

independently-since they lie on different chromosomes or are so far apart on a single chromosome

that they are separated during the chromosome

segment exchange that occurs during meiosis—

those lying close together on the same chromosome

are usually inherited together. Their loci, or chromosomal positions, are linked (see figure 5-3). The

actual distance between two loci can be estimated by

determining how frequently the alleles at those sites

are inherited together. If the alleles for two traits are

passed on together 90 percent of the time (and 10

percent of the time they are not), they are said to have

a 10 percent recombination fraction, which corresponds to roughly 1 million base pairs. A recombination fraction of 50 percent indicates that the alleles

for two genes are not linked; they are far removed

from each other on a single chromosome or on

separate chromosomes.

Linkage analysis uses genetic markers-traits or

DNA sequences—with known chromosomal ad-
106 . The Biology of Mental Disorders

dresses. In the past, traits such as color blindness or

blood type served as markers; however, they were

quite limited in their usefulness. There were not very

many of them, and they lacked variability, an

important feature in a genetic marker. The surge in

popularity of linkage analysis in the last decade

reflects the discovery of new breeds of genetic

markers, including restriction fragment length polymorphisms, or RFLPs (pronounced rif’ lips), and,

more recently, microsatellite repeat markers (7,1 1).

These markers derive from variation in the very

DNA sequence, revealed by the techniques of

molecular genetics. And because these markers span

the entire genome, they enable investigators to

search for linked genes, regardless of their location.

Linkage analysis is used to distinguish two

questions: Given the way a trait is distributed within

a family under investigation, does the responsible

gene lie within a short and specified distance from

the genetic marker? Or is it so far away from the

marker that the gene was inherited independently?

That is to say, are the two loci (for the gene of

interest and the genetic marker) likely to be linked or

not in this family? The probability that either of the

questions is true is expressed in the form of an odds

ratio. Traditionally, an odds ratio of 1,000 to 1 has

been taken as proof of linkage (75): It is 1,000 times

more likely that the gene loci are linked than not. An

odds ratio of less than 1 to 100 has been regarded as

proof against linkage. Odds ratios are typically

transformed into LOD scores, their base 10 logarithm. Therefore a LOD score of 3 (log10 1,000/1) or

greater is considered evidence of linkage; linkage is

rejected with a LOD score of-2 (log10 1/100) or less.

Upon finding a LOD score of nearly 7—placing

the likelihood of linkage at 10 million to l—a

researcher would seem to have near absolute proof

of linkage. In fact, such a finding has been reported

for schizophrenia (96). But, as with all statistical

tests, certain assumptions must hold true if the

results are to be meaningful. And there is always a

chance that a positive finding is spurious, a random

occurrence. For example, with a LOD score of 3,

there is a 1 in 20 chance that the finding of linkage

is spurious. The confusion and controversy that

surround the gene search in mental disorders stem

from the fact that these conditions violate the rules

and assumptions of linkage analysis. The problems

associated with this method are considered in a

subsequent section, but first, the available evidence

that these conditions have a genetic basis is summarized.

GENETICS OF SCHIZOPHRENIA

Classic genetic studies show that schizophrenia

has a genetic component (for review, see 38,39,49,54,

102). Data from family studies lead to estimates that

first-degree relatives of an individual with schizophrenia have approximately 10 times the general

risk of developing the disorder. Twin and adoption

studies also implicate genetic factors. Although

estimates vary, data consistently show that a person

whose identical twin has schizophrenia is at higher

risk for schizophrenia than a person whose fraternal

twin has the disorder (table 5-2). Adoption studies

indicate that schizophrenia runs in biological but not

adoptive families (53). These data also point to a

genetic relationship between schizophrenia and

other disorders, such as schizotypal personality

disorder (50).

Clearly, schizophrenia has a genetic component.

But genetics is not the whole picture. Twin studies

indicate that genetic factors do not entirely account

for the development of schizophrenia; an identical

twin of someone with schizophrenia exhibits the

disorder approximately 30 to 50 percent of the time.

Thus, nongenetic factors must also be important.

Furthermore, important questions about genetics

persist. Even though having a family member with

schizophrenia increases the likelihood of developing

the disorder, many family members do not develop

schizophrenia, and 80 to 90 percent of individuals

with schizophrenia have no first-degree relative with

the disorder (38). The distribution of schizophrenia

within families is not consistent with any simple

pattern of inheritance. Studies generally rule out the

Table 5-2—Relatives’ Risk of Schizophrenia

Relationship Risk (%)

First degree

Parents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6

Siblings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1

Children “””””” . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.8

Children of two parents with schizophrenia . . . 46.3

Second degree

Half siblings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2

Uncles/aunts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4

Nephews/nieces . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.0

Grandchildren . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.7

SOURCE: Adapted from 1.1. Gottesman, Schizophrenia ancf Genetic Risks

(Arlington, VA: National Alliance for the Mentally Ill, 1984).
Chapter 5—The Genetics of Mental Disorders . 107

action of a single gene without determining whether

a couple of genes, or many genes, are important in

producing schizophrenia.

A report that an uncle and nephew with schizophrenia shared a chromosome defect—an extra copy

of part of chromosome 5—impelled the search for a

schizophrenia gene on this chromosome (8,31,51,

62,95). Linkage to chromosome 5 was asserted soon

thereafter in a study of seven British and Icelandic

families (96). A simultaneously reported study in a

separate kindred in Sweden ruled this linkage out

(52). Subsequent studies have since rejected a link

between chromosome 5 and schizophrenia (2,26,41,

47,63,77,93).

Studies have evaluated the linkage of schizophrenia to the classic genetic marker, the HLA (humanleukocyte-associated) antigen system on chromosome 6. The HLA antigen system is a collection of

genes important for immune function. An early

study provided only weak evidence of linkage to the

HLA system (106), and four subsequent studies

ruled out linkage to the HLA system and a wide

variety of other classical markers (1,14,36,60).

While schizophrenia has not been linked to a region

of the X chromosome thought to play a role in

bipolar disorder (23; see later discussion), preliminary data support linkage to a region that lies at the

ends of the X and Y chromosomes (18).

GENETICS OF MOOD DISORDERS

What do classic genetic studies indicate about the

inheritance of mood disorders? Identical twins share

mood disorders more frequently than do fraternal

twins (for review, see 32,61,74,103,105). For example, data show that the identical twin of an individual

with bipolar disorder would exhibit that disorder

three times more often than would a fraternal twin

(32) (figure 5-4). Parents, siblings, and children of

individuals with bipolar disorder or major depression more commonly develop these disorders, although the estimated incidence among family members varies among studies. Only a few adoption

studies have evaluated the inheritance of mood

disorders. Data from these studies generally support

the role of inheritance in mood disorders (for review,

see 32,74).

The heritability of mood disorders appears to be

correlated with the severity of the condition. Bipolar

disorder has the largest genetic component of all

mood disorders, and recurring bouts of depression

0.8

0.6

0

Figure 5-4—Mood Disorders Among Twins

0.65

0.80

0.36- -

Any mood Bipolar Severe Depressionb

disorder disorder depression

 Identical twins Fraternal twins

Graphically depicted data were derived from evaluation of 110

pairs of twins. Identical twins shared mood disorders, especially

bipolar disorder, more frequently than fraternal twins.

 episodes of depression.

 episodes of depression.

SOURCE: Adapted from A. B. and M. “A

Danish Twin Study of Manic-Depressive Disorders,” British

Journal of Psychiatry 130:330-351, 1977.

appear to be more directly heritable than a single

episode. Also, major depression that has an earlier

age of onset maybe more heritable. Family and twin

studies suggest a genetic link between depression

and bipolar disorder. For example, identical twins,

who often share the same mood disorder, not

infrequently have different forms (10). Similarly,

first-degree relatives of a person with bipolar

disorder are at greater risk of developing any mood

disorder than the general population (32). But the

genetic overlap between major depression and

bipolar disorder is not complete (1 10). For example,

while rates of major depression are greatly increased

among the relatives of an individual with bipolar

disorder, the opposite is not true: The relatives of an

individual with major depression are not at a much

higher risk for developing bipolar disorder.

Family and twin studies demonstrate the importance of genetic factors in both bipolar disorder and

major depression. However, studies do not reveal a

simple pattern of inheritance, nor do they implicate
108 . The Biology of Mental Disorders

the action of a single gene. The genetic relationships

between major depression and bipolar disorders,

between schizoaffective disorder and mood disorders, as well as among various subtypes of depression are not clear (see ch. 3). And since identical

twins are not always concordant for mood disorders,

nongenetic factors must also play a role.

Many studies have attempted to locate specific

genes that lead to mood disorders. So far, they have

focused on the X chromosome and chromosomes 11

and 6.

Since the first reports in 1969 that, in some

families, fathers do not transmit mood disorders to

their sons (87,117), many studies have described

attempts to find a gene for mood disorders on the X

chromosome (6,24,30,34,35,57,66-7 1). Although a

few of the studies report significant evidence of

linkage-a LOD score over 3—the results are not

unanimous. Some provide only equivocal support

for X linkage, and others, according to their LOD

scores, completely rule out linkage to the X chromosome.

What explains these conflicting data? The use of

a specific marker, the Xg blood group, accounts for

some of the inconsistencies. Studies using the Xg

blood group, which is located far from the other

markers used to date, have never shown linkage. The

remaining discrepancies may result from genetic

heterogeneity: Genetic factors leading to mood

disorders may vary among families.

The finding of X linkage in more than one study

supports the hypothesis that a gene on that chromosome leads to mood disorders in some families.

Nonetheless, doubts about the X linkage of mood

disorders persist. The report of linkage to one

marker, the F9 marker, does not easily square with

positive findings for other, somewhat distant markers. Another study of 10 families without male-tomale transmission failed to map mood disorders to

the X chromosome, despite the prediction that many

such families would display this linkage (9,92). And

while there has been disagreement about the pedigrees used in this study refuting X linkage (3,29,42,116),

the results question how frequently a gene on the X

chromosome accounts for inherited cases of mood

disorders, even in families without father-to-son

transmission.

The scientific and popular press heralded a report

linking mood disorders to chromosome 11 among a

group of Amish families in Pennsylvania (27). The

Amish are an ideal population for studying the

genetics of all kinds of disorders, especially mental

disorders. They are the progeny of a small group of

people who emigrated from Europe in the early 18th

century (27). Since they seldom marry outside their

own community, they have preserved a relatively

homogeneous genetic heritage. Also, due to their

religious convictions, they forswear the use of drugs

and alcohol, abuse of which may confound the

diagnosis of mood disorders.

The results of the Amish study conflicted with

two reports on non-Amish families published about

the same time (25,43). These studies ruled out

linkage of mood disorders to chromosome 11 in nine

families. Furthermore, results from a followup study

of the same Amish families 2 years later disputed the

original findings (48). The reanalysis, which included new family members and a change of

diagnosis in two individuals due to the subsequent

onset of mood disorders, also excluded the possibility that mood disorders are linked to a gene on

chromosome 11.

Several studies have evaluated the possible linkage of mood disorders to the HLA system on

chromosome 6(12,36,46,55 ,56,97-101,108,109,114,

115). Four produced evidence of linkage, with one

reporting odds of approximately 108 to 1 (109).

However, there are questions concerning the methods used in some of these studies. Gershon (33), for

example, points out that the remaining studies

produced no evidence of linkage. Therefore, no

strong evidence fixes a gene for mood disorders on

chromosome 6. Other studies, not described here,

provide equivocal evidence, at best, for linkage of

mood disorders to other chromosome markers (105).

GENETICS OF

ANXIETY DISORDERS

Panic disorder and obsessive-compulsive disorder (OCD) appear to have a genetic component,

although inheritance of these disorders has undergone less experimental scrutiny than that of schizophrenia and mood disorders. While several family

studies have been conducted, only a few twin studies

and no adoption studies have analyzed the inheritance of these anxiety disorders. Further studies are

necessary to discern the role of genetics in these

disorders.
Chapter 5—The Genetics of Mental Disorders ● 109

Several family studies have found higher rates of

panic disorder among frost-degree relatives of a

person with panic disorder than among control

populations (79,112). Also, there appears to be a

greater frequency of agoraphobia—the fear of being

in public places—with panic disorder among family

members (21). These family studies have also

distinguished between panic disorder and other

disorders. For example, data indicate that panic

disorder is distinct from generalized anxiety disorder (112) but that families of individuals with both

panic disorder and depression are at increased risk of

depression, panic disorder, and other conditions

(20). Thus, the data indicate that panic disorder does

run in families. Information from the few twin

studies performed to date suggests that panic attacks,

if not panic disorders, have a heritable component

(21,104). No adoption studies of panic disorder have

been conducted (104).

Based on the observed pattern of panic disorder in

families, researchers have begun the search for

genetic linkage. A recent linkage study provides

preliminary evidence that a gene found on chromosome 16 might influence panic disorder (20-22);

other linkage studies are underway (111).

Investigators of the genetics of OCD have used

both family and twin studies; there are no adoptive

studies (107). Data from family studies suggest that

OCD has a genetic component (13,81,86,107), as do

data from twin studies (13,81). They also suggest a

link between OCD and Tourette’s syndrome (80,82).

No data from linkage studies of OCD have been

reported to date.

THE CHALLENGE OF MAPPING

GENES FOR MENTAL DISORDERS

Although evidence from multiples sources indicates that schizophrenia, bipolar disorder, and major

depression, as well as panic disorder and OCD, have

a genetic component, linkage studies have not

succeeded in locating specific genes for these

disorders. Attempts to pin mental disorders to

specific chromosomes have produced acclaimed

reports of linkage and subsequent contradiction of

findings (89). These conflicting results have been

analyzed in a series of papers (5,33,59,72,89,91).

Two basic, unanswered questions confound linkage

analysis of mental disorders: What accounts for the

complex genetics of mental disorders? And what is

inherited?

What Accounts for Complex Genetics?

Linkage analysis has achieved spectacular success in mapping diseases with a simple genetic basis,

such as Huntington’s disease and cystic fibrosis.

Such diseases are rare in the general population, and

a single gene can easily account for their occurrence.

Mental disorders, like many cancers, Alzheimer’s

disease, and diabetes mellitus, present a much more

complicated picture of inheritance. Although they

also tend to run in families, they are common in the

general population and no single gene can account

for all cases.

Several factors may contribute to the complex

pattern of inheritance of mental disorders, thus

confounding linkage analysis:

●

●

●

●

Distinct factors, genetic or nongenetic, may

lead independently to a disorder.

A gene that sometimes produces a particular

disorder may not always do so.

Several genes acting in concert may be necessary to produce a disorder.

Nongenetic factors contribute to the development of a disorder.

The most optimistic explanation for inconsistent

linkage results is genetic heterogeneity-that is, one

gene leads to a disorder in some families, while a

different gene operates in others. With this explanation, reports mapping a mental disorder to a specific

chromosome in some families but refuting linkage in

others can both be correct.

Several types of evidence may implicate genetic

heterogeneity. Reports of linkage to different chromosomes may support this hypothesis. Distinct

clinical profiles, symptoms, patterns of inheritance,

and other biological measures among families may

also indicate the action of separate genes (89). Given

the complex characteristics of schizophrenia and

mood disorders, it would be surprising if they did not

have a heterogeneous basis. Some data suggest

subtypes of these disorders; e.g., major depression

seems to be more concentrated in families when it

has an early age of onset (113). In general, however,

clinical subsets of these disorders are not firmly

established, and linkage studies (as well as diagnostic classification systems) have not incorporated

them. On the contrary, many linkage studies have

included a wide spectrum of mental disorders.
110 . The Biology of Mental Disorders

Experts caution against interpreting conflicting

linkage results alone as proof of genetic heterogeneity. Only replication of a finding of linkage provides

strong evidence that a nearby gene leads to the

disorder (5,32,89). Furthermore, evidence of linkage

to more than one gene is required to prove that a

disorder is genetically heterogeneous.

Separate genes operating among and even within

families make the search for linkage more difficult.

One strategy is to study large families with many

members who are afflicted with mental disorders (5).

A single, large family, especially one that is

relatively isolated, is more likely to be genetically

homogeneous. The presence of a disorder in many

family members also predicts, but does not prove,

that a single gene is the culprit.

This approach has some disadvantages. Large

families with many members showing a mental

disorder are relatively rare. Also, a single gene that

produces schizophrenia or mood disorders in certain

families may only rarely do so in the general

population. In this event, the finding of linkage will

not lead to a genetic test that is generally useful. Of

course, mapping a mental disorder to a specific gene,

even in a few families, may lead to improved

understanding of the disorder.

So far, this discussion has focused on the possible

genetic heterogeneity of mental disorders. Various

nongenetic factors may also be responsible. That is,

a disorder maybe produced by genetic or nongenetic

factors. In fact, nongenetic factors can produce a

phenocopy of a disorder—that is, symptoms that

mirror the genetically derived disorder. For example, depression produced by genetic factors may be

symptomatically indistinguishable from depression

provoked by external factors. While diagnostic

criteria ferret out conditions obviously caused by a

known and distinct factor, such as chemically

induced symptoms, it is currently impossible to

identify some phenocopies.

Sometimes a trait is not expressed even though the

gene coding for it is present. In other words, only a

fraction of persons carrying a particular gene actually display the trait. This is called incomplete

penetrance. The causes of incomplete penetrance are

unknown, although it is believed that modifying

genes or other factors may thwart gene expression.

Akin to incomplete penetrance is variable expressivity, where expression of a disorder varies in individuals with the gene from very severe symptoms to

nearly none at all. The complex pattern of inheritance of mental disorders is commonly attributed, at

least in part, to this phenomenon.

There are other unexplained aspects of the genetics of mental disorders. For example, if a single gene

causes a disorder, is it dominant or recessive? How

many alleles are there? While incomplete penetrance

and these other unknown factors complicate linkage

analysis, they need not preclude it (16,19,37).

Linkage studies commonly consider a range of

estimates for these variables and factor in such

considerations as age of onset, cohort effect, and

nonrandom mating, which often occurs in mental

disorders (see ch. 3) (5). Accounting for all of these

variables and unknowns does, however, require

statistical adjustments, since they violate the assumptions of LOD score analysis (15,90).

Given the unknown parameters of inheritance, the

sib-pair method of analysis offers some advantages

in the search for genes linked to mental disorders

(89). This method is based on the fact that, if a

marker and a trait are linked, pairs of siblings who

share a trait will be more likely to have the same

genetic marker than could be expected by chance.

The sib-pair method does not require prior knowledge of the mode of inheritance, as does the LOD

score method. Furthermore, this approach does not

require extended pedigrees, which may be difficult

to find.

Although the problems discussed thus far complicate linkage analysis, they do not rule it out as a

reasonable research approach. However, successful

linkage analysis relies on a single gene making a

major contribution to a disorder. While research has

not resolved the number of genes involved in

producing mood disorders or schizophrenia, data do

suggest that a single gene is unlikely to make a major

contribution inmost cases of schizophrenia or mood

disorders (89,105).

Why, then, does linkage analysis remain a serious

research endeavor? First, a major-gene effect, at

least in some families, has not been ruled out in

major mood disorders and schizophrenia. A large,

systematic linkage study, though expensive, is the

only available method likely to answer the question,

Is a single gene linked to these mental disorders?

Such an approach could then locate a major gene if

it exists in the families studied or rule out the

presence of such a gene. Also, new techniques and

methods of analysis are being advanced all the time,
Chapter 5—The Genetics of Mental Disorders . 111

possibly resulting in new ways of searching for

genes. Another rationale for continued linkage

analysis is that a gene may contribute in a large way

to these mental disorders in a few families. Single

genes have been linked to a fraction of cases of other

complex disorders, such as Alzheimer’s disease

(94). Unfortunately, studies have not identified

families where prior evidence suggests that a single

gene produces a mental disorder (89).

What if, as suspected by some observers, many

genes, each with a very small effect, underlie these

disorders? There is little likelihood that linkage

analysis could locate one of many minor genes.

Other techniques would be required (e.g., see 58).

The absence of 100 percent concordance for

schizophrenia and mood disorders between identical

twins implicates the importance of nongenetic

factors in the genesis of these disorders (4). Other

types of studies also point out that genetic factors

and the environment, nature and nurture so to speak,

produce mental disorders (95). Nongenetic factors

may range from exposure to a chemical or virus to

social interactions. Research has not identified these

factors precisely (58,88); however, mapping a major

gene that leads to increased susceptibility to a mental

disorder may facilitate research into nongenetic

factors (4,28,78,95).

What Is Inherited?

In order to map a gene, it is crucial to identify

correctly the inherited trait, or phenotype. While the

problems mentioned above are common to all

complex disorders, uncertainty about what is inherited plagues mental disorders especially.

How well does the current classification of mental

disorders define the inherited phenotype? Researchers disagree. Some are confident that rigorous use of

the available diagnostic classifications will serve

genetic research well. Others are uncomfortable that

these diagnostic classes have not been validated and

have no biological marker. It is perhaps ironic that

while psychiatry looks hopefully to genetic research

for help in refining systems of disorder classification

(95), questions in the current classification system

may impede genetic research.

When performing a linkage study, this question

emerges: Are some disorders genetically related?

For example, should a study attempting to map the

gene for schizophrenia include only individuals with

schizophrenia? Or should it include individuals with

other forms of psychosis too? Individuals with any

mental disorder?

Family studies provide some clues about the

genetic relationship among disorders. For example,

data suggest that bipolar disorder is genetically

related to depression (32). Schizophrenia appears to

run in families with schizotypal personality disorder

and possibly other types of psychotic disorders

(17,49). Agoraphobia and panic disorder appear to

be genetically related (76), as do OCD and Tourette’s syndrome (80,82). Further studies are needed

to establish which disorders appear together in

families and thus may be genetically related.

In practice, linkage studies have generally taken

the approach of doing multiple analyses of different

sets of mental disorders, ranging from core diagnoses to a broad spectrum of disorders. Two points

warrant consideration. First, statistical accommodation is necessary for multiple analyses. Second,

decisions concerning which diagnoses to include in

each analysis must precede the study.

Instead of using an entire diagnostic class for

linkage analysis, such as depression, some subset of

the class may more accurately reflect the inherited

trait, for example, recurrent bouts of depression or

depression with an early age of onset. Although the

identification of such ‘‘phenotype markers’ is in its

infancy, there are several potentially useful biological and psychological markers for specific subsets of

disorders. Response to drug treatment is one such

possibility, and it forms the basis of pharmacogenetics (64). Similar responsiveness to the same drugs

may identify individuals with genetically related

disorders. Tsuang and Faraone (105) review data

supporting the conclusion that individuals who

respond well to certain antidepressant agents tend to

have relatives who respond well to these agents. In

general, linkage analysis has not yet incorporated

such markers.

Another possible answer to the question, What is

inherited? is illustrated by research into abnormal

eye movements and schizophrenia (44,45). Individuals with schizophrenia sometimes have a problem

with smooth-pursuit eye movements (SPEM); that

is, they may have difficulty maintaining a focus on

moving objects. Approximately 65 percent of individuals with schizophrenia, versus 8 percent of the

general population, have problems with SPEM.

Furthermore, data suggest a genetic link between
112 . The Biology of Mental Disorders

schizophrenia and these eye-movement abnormalities. Forty-five percent of the parents and siblings of

individuals with schizophrenia exhibit SPEM abnormalities. Both identical twins exhibit schizophrenia

or problems with SPEM, or both, 80 percent of the

time. On this basis, researchers are looking for a

gene that accounts for either schizophrenia or

abnormal eye movement (51,65).

Ultimately, clues about what is inherited may

suggest specific genes that underlie mental disorders. Identifying such candidate genes will enable

researchers to target their search for linkage. One

candidate gene was the gene that codes for the D2

receptor. This receptor binds the brain chemical

dopamine. Antipsychotic agents, which are used to

treat schizophrenia, also bind to the D2 receptor (see

ch. 4). However, studies aimed at mapping schizophrenia to the gene for the D2 receptor failed to

establish linkage (51,73). One of several other

candidate gene approaches sought to link bipolar

disorder to a receptor for another brain chemical,

serotonin (41); it also failed to establish linkage. The

absence of a known etiology for mental disorders has

thwarted the candidate gene approach to linkage

analysis so far. However, continued advances in

molecular biology and neuroscience will undoubtedly provide information on new possible targets for

candidate gene searches.

IMPACT OF GENETIC RESEARCH

optimism generally surrounds today’s genetic

research into mental disorders. The modern-day

sleuth-the molecular genetics researcher-is on

the trail of perhaps the most enigmatic of all human

afflictions. High hopes for an improved understanding of mental disorders and better, more rational

treatments are pinned to this research.

This typically American enthusiasm for scientific

progress may benefit from some temperance. Undoubtedly, genetic research will advance our understanding of at least some mental disorders, but rapid

achievement of this goal is not likely. Researchers

caution that identifying the location of relevant

genes may require several years. And mapping a

gene is only the first step in understanding the

etiology of a mental disorder. The next step involves

identifying the specific gene, which can take years.

For example, the location of the gene for Huntington’s disease was found in 1983 (40), but the gene

has yet to be identified. Understanding how a gene’s

action is translated into something as complex as a

mental disorder will probably demand a great deal of

further research.

But genetic research has already had some important effects. One has been on the general perception

of mental disorders (see ch. 7). Our overwhelming

acceptance of the hereditary basis for mental disorders is astonishing. Only two decades ago, the idea

that psychosocial factors produced schizophrenia

dominated scientific thought, leading, for example,

to the pervasive and brutally stigmatizing stereotype

of the ‘‘schizophrenogenic’ mother (see ch. 7).

Family, adoption, and twin studies in the 1960s

and 1970s established a solid theoretical basis for the

role of genetics in mental disorders. These data,

coupled with the revolution in genetics, fueled the

emphasis on genetic research and focused the public

spotlight on it. The frequent newspaper headlines

and increasing number of books for the layperson

evidence the spreading perception that mental disorders are inherited.

What is the impact of this perception that mental

disorders are inherited? Perhaps more than any other

type of research, genetics identifies mental disorders

as biological. Thus, proponents of the biologicalmedical model of mental disorders generally support

and commend this research. In a review article on

genetics and mental disorders, leaders in the psychiatric community state that “wider recognition of the

biological basis for mental illnesses (derived from

genetic research) may allow these illnesses, finally,

to be seen as similar to other medical problems”

(78).

Spurious interpretation of the fact that genetic

factors contribute to mental disorders can result in

the belief that genes are destiny. This interpretation

is founded on the false assumptions that human

behavior is simply programmed by genes and that no

useful intervention-barring a eugenic approach—

can be developed. In fact, an environmental intervention can be successful in treating a genetic

condition, as exemplified by phenylketonuria, or

PKU. PKU is a single-gene defect that, if untreated,

leads to mental retardation. This result can be

prevented if a diet low in a particular amino acid

(phenylalanine) is provided during the early years of

life.

A few voices caution against the overemphasis on

genetic factors in mental disorders, noting that
Chapter 5—The Genetics of Mental Disorders . 113

genetics does not completely account for these

disorders and that a single-gene cause is unlikely to

be found (58,83). What danger is there in overemphasizing the role of genetics? Although considered

unlikely today, past enthusiasm for genetics led to

atrocious abuses, such as the sterilization of individuals with mental disorders (see box 5-A). In this era

of tight competition for research support, funding for

genetic research may supplant support for other

types of research. Some fear that unfulfilled expectations of quickly finding a particular gene or a new

treatment may lead to impatience, disappointment,

perhaps even a backlash against genetic research.

Since there is an increasing appreciation of the

genetic component of mental disorders, it is not

surprising that patients and family members would

seek advice on the inheritance of these disorders.

What information can genetic counseling provide on

mental disorders (box 5-B)? At this point, one

cannot unequivocally predict whether an individual

will or will not develop a disorder (table 5-3).

Genetic counseling can only provide a general

estimate of risk for a disorder. While relatives are at

increased risk of a mental disorder, estimates of risk

are not easily adapted to individuals. They vary

among studies (105) and are not specific-an

individual’s risk may exceed or fall short of average

estimates. One important message of genetic counseling is that family members do not usually face a

large threat of developing a disorder. For example,

on average only 10 to 15 percent of individuals with

schizophrenia or mood disorders, on average, will

have a child with the disorder. Given that family

members face a relatively low risk of developing a

mental disorder, genetic counseling is often in the

position of putting patients and family members—

who may have overestimated their risk of a severe

disorder-at ease (95).

Individuals could receive much more specific

information during genetic counseling once genetic

tests for mental disorders have been developed.

Genetic tests are typically the frost spin-off from the

successful mapping of a gene for a disorder,

preceding treatment advances by many years. While

no such tests are available now, and it may be

somewhat premature to raise concerns about genetic

testing for mental disorders, data point to the

importance of genetic factors. Therefore, tests for a

genetic predisposition to some mental disorders may

be technically feasible in the future. Our current

understanding of the genetics of mental disorders

makes a single, highly predictive genetic test that is

useful across the general population unlikely. Data

from genetic studies predict that such genetic tests

could possibly take the following forms:

●

●

A major gene found in a subset of families with

a disorder could lead to the development of a

genetic test. It would be highly predictive of

mental disorders within a few families but not

useful in other families.

Discovery of a gene that contributes to the

development of a disorder, but alone cannot

produce the disorder, may lead to a genetic test

for increased susceptibility. This scenario is

commonly envisioned for many disorders that

are produced by genetic and nongenetic factors,

such as diabetes, some cancers, coronary heart

disease, and hypertension. Not everyone testing positive for the gene will develop the

disorder. On a far more positive note, such

individuals may be able to control their destiny

by avoiding known risk factors.

SUMMARY AND CONCLUSIONS

Advances in genetics have bequeathed an increasing understanding of how simple traits are inherited,

what the cellular and molecular substrates of inheritance are, and, more recently, the identity of genes in

human disease. Interest in probing the inheritance of

human behavior has paralleled our increasing knowledge of genetics. However, the study of human

Table 5-3—Risk of Mental Disorders (In percent)

ObsessiveBipolar compulsive Panic

Schizophrenia disorder Major depression disorder disorder

To general population 1.0 0.8 4.9 2.6 1.6

To first-degree relative

(parent, child, or sibling) 9.0-13.0 a

4.0-9.0 5.9-18.4 25.0 15.0-24.7

a% percent when both parents affOCtOd.

SOURCE: K. Berg and D.G. Kirch, National Institute of Mental Health, 1992.
114 ● The Biology of Mental Disorders

Box 5-B-Genetic Counseling for Mental Disorders

According to researchers and other experts, individuals with mental disorders and their families have become

increasingly interested in knowing the risk of inheriting these conditions. Such information is relayed in the context

of genetic counseling, a clinical service that provides an individual and sometimes his or her family with information

about heritable conditions. Unfortunately, empirical data on mental disorders and genetic counseling are sorely

lacking.

Genetic counseling for mental disorders apparently occurs quite rarely. Who does seek it? Some individuals

in the early stages of their disorder seek genetic counseling on the impact the disorder is likely to have on a potential

spouse or children. The majority of genetic counseling requests come from relatives of affected individuals

concerned about incipient or potential mental disorders in another family member or reproductive issues.

Prospective spouses may also request information regarding both their partner and their potential offspring.

The accepted aim of genetic counseling is to provide information. It is generally held that genetic counseling

should be nondirective and show the highest respect for the requester’s autonomy. While it is no simple task to relay

complicated concepts of risk it is perhaps even more difficult to do so in a nondirective manner. Furthermore,

individuals request genetic information for a reason: to make reproductive decisions, to seek comfort or assuage

fears. Genetic counseling in general is concerned with the psychological effects of receiving frightening

information; given the psychopathology in mental disorders, this concern will most likely be amplified. For this

reason, some people believe that psychiatrists should provide genetic counseling. However, many physicians have

less-than-adequate knowledge of genetics. And no professional organization (e.g., American Psychiatric

Association) or government institution (e.g., the National Institute of Mental Health) has put forth guidelines on the

practice of genetic counseling for mental disorders.

A common concern of individuals seeking genetic counseling for mental disorders is reproductive decisions:

Should we have children? Various factors may come to bear on such a decision, including the perceived risks and

burdens of a mental disorder among offspring. Current risk estimates are not specific and generally are not very high.

Thus, as stated by one genetic researcher, “Avoiding childbearing is not necessary, even from the most hardheaded

primary prevention viewpoint.”

One measure of the burden of a disorder arises from its clinical profile: age of onset, associated morbidity,

available treatment, and cost of treatment. From this standpoint, mental disorders pose a considerable burden. They

usually emerge in early adulthood and are often chronic. Although there is no cure, treatments that control the

symptoms of mental disorders are available. Genetic counseling should deliver information regarding possible

treatment, course, and community resources. This becomes crucial for the decisionmaking process insofar as

awareness, early diagnosis, and provision of the correct treatment can limit the burden of the disorder,

There is also a subjective component to estimating the burden of a disorder in offspring. First, the desire for

children can be strong. Furthermore, patients and their families assess the burden quite differently. In one study of

schizophrenia, 92 percent of well family members versus 25 percent of affected individuals viewed schizophrenia

behavior and mental disorders has always proved The inheritance of panic disorder and of OCD has

difficult.

Methods traditionally used to examine the genetics of mental disorders include adoption, twin, and

family studies. Data from these approaches indicate

that mental disorders are at least in part inherited.

Adoption, twin, and family studies reveal that

schizophrenia has a genetic component. Twin and

family studies, in particular, point to the importance

of genetic factors in bipolar disorder and major

depression. The heritability of these mood disorders

seems to correlate with severity; bipolar disorder

appears to have the clearest genetic component,

followed by recurring bouts of major depression.

undergone less scrutiny; however, based on data

largely from family studies, it appears that genetic

factors are involved. Data also indicate that nongenetic factors play a role in all of the mental disorders

examined in this report. Questions concerning the

inheritance of these disorders remain: specifically,

the precise definition of what is inherited and the

number of genes involved.

Spectacular advances in molecular genetics have

enabled researchers to locate specific genes for

diseases caused by a major gene. However, despite

early claims of success and evidence from multiple

sources that schizophrenia, bipolar disorder, and
Chapter 5—The Genetics of Mental Disorders ● 115

as a severe, debilitating disorder entailing extreme burden. With regard to childbearing decisions, 29 percent of

parents versus 66 percent of affected individuals reported that they would have children (either in hindsight or in

the future), given their present understanding of schizophrenia,

Another concern sometimes voiced when considering the burden of a mental disorder, especially bipolar

disorder, relates to its possible link with creativity. Historical analysis and some systematic studies increasingly

support this link. The concern is whether the creative output balances the burden of a severe mental disorder. The

link between mental disorders and creativity raises the question, What is the value of a human being with a mental

disorder? Does it lie in his or her creative output or contribution to society? Or does it emerge from the simple fact

that he or she is a human being? While the creative output of individuals with mental disorders can be a source of

pride, this consideration may pit the interests of society against those of the individual.

Prominent psychiatric geneticists generally reject directive counseling on reproductive decisions, emphasizing

the benefit of genetic information for the individual, the rather low risk of inheriting these disorders, and their

treatability. Exceptions to the prohibition against directive counseling are generally supported when severely

affected individuals are involved or both spouses are afflicted. Risk to offspring greatly increases when both parents

are affected. Also, pregnancy may severely exacerbate the symptoms of a mental disorder. Research concerning

pregnancy, childbirth, and childrearing in persons with mental disorders, while limited reveals possible

complicating factors for both mother and offspring, including birth complications, potential teratogenic and other

negative effects of psychotropic drugs on offspring, and the effect of pregnancy and the postpartum period on the

mother’s mental disorder, such as increased symptoms or heightened severity of symptoms.

Given the reluctance to counsel against childbearing, the question arises, How is information about the genetics

of mental disorders useful to affected individuals and their families? As previously mentioned, it may relieve

excessive fears of passing on the disorder to offspring. It also enhances the likelihood of early intervention. Being

alert to early symptoms of a disorder will permit early treatment, perhaps forestalling the most debilitating

symptoms, Unfortunately, knowledge about genetic risk does not open the door to prevention. No known

interventions can prevent the development of severe mood disorders or schizophrenia. This potential scenario

underscores the need for research into the prevention of mental disorders.

SOURCIN: H.S. Gershon, “Genetics,” Manic-Depressive /iZness, F.K. Goodwin and K.R. Jarnison (eds.) (New York NY: Oxford University

Fress, 1990); E.S. Gersho~ National Institute of Mental Heal@ personal communication, 1391; 1A Gottesru~ Schizophrenia

Genesis: The Origins of Mxtness mew York NY: W.H. Free- 1991); K.K. Kidd, Yale University, penonal cornmunicatio~

1991; M. Lappe and J.A. Brody, “Genetic Counseling: A Psychotherapeutic Approach to Autonomy in Decision Making,” M.A.

Sperber and L.F+ JaNik (eds.), Psychiatry and Genetics: Psychological, Ethical, and Legal Considerations (New York NY: Basic

Books, 1976); J. Marks, Sarah Lawrence College, pcmmal communicatio~ 1991; P.M. Schulz, “Patient and Family Attitudes

About Schizophrenia: hnplications for Genetic Counseling,” Schizophrenia Bulletin 8:504-513, 1982; S,D. Targurn and E.S.

GershorL “pregnancy, Genetic Counseling, rmdthe Major Psychiatric Disorders,” Genetic Diseases in Psychiatry, MaterrmlE~ects

and ~eta2 Outcome J,D. Schulwm and J.L. Simpson (eds.) (New Yorlq NY: Academic Press, 1981); M.’E Tsuang, “Genetic

Counseling for Psychiatric Patients and Their Families,” American Journal of Psychiatry 135:1465-1475, 1978; U.S. Congress,

Office of ‘Rdnology Assessrnen4 Genetic Monitoring and Screening in the WorkpZace, O’E4-BA-455 (Washington DC: U.S.

Government Printing OffIce, 1990).

major depression have a genetic component, linkage to continued advances in molecular genetics and

studies have failed so far to find specific genes for

these disorders. Gene searches are difficult because

these mental disorders probably are caused by more

than one gene, both genetic and nongenetic factors

contribute to them in an unknown way, and identification of the phenotype is difficult.

The complexity of the genetics of mental disorders and past failures to locate specific genes should

not promote a pessimistic view of this research.

Rather, our knowledge to date points out the need for

various types of studies and can serve as a guide for

future research endeavors. Furthermore, we can look

analytical techniques to help discern the specifics

about the genetics of mental disorders. A wise

investment of research dollars would support a broad

effort, including continued family, twin, and adoption studies, the development of analytical methods

for complex genetics, the search for major and minor

genes using various approaches, and the investigation of nongenetic factors.

What is the impact of all this excitement in the

field of genetics? Commentators have noted that the

public increasingly views mental disorders as inherited, in sharp contrast to only a couple of decades
116 . The Biology of Mental Disorders

ago. There is also an air of expectation that genetics

will improve our understanding and treatment of

these disorders. It is important that such hopes be

tempered with realism. A long-term investment in

this research is necessary, given the complexity of

these disorders. At this point, the clinical implications of these data are limited; therefore, only limited

information about the risk of inheritance can be

provided to persons with mental disorders and their

families. Finally, past abuses of genetic knowledge

and the potential for a genetic test for mental

disorders remind us of the necessity for great care in

the use of genetic information and underscore the

need to consider the social, ethical, and legal

implications of this research.

1.

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St. Clair, D., BlackWood, D., Muir, W., et al., “No

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St. George-Hyslop, P. H., Tanzi, R. E., Polinshy,

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95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

Alzheirner’s Disease Maps on Chromosome 21,”

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Schulz, S. C., “Genetics of Schizophrenia: A Status

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Sherrington, R., Brynjolfsson, J., Petursson, H., et

al., “Localization of a Susceptibility Locus for

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Smeraldi, E., and Bellodi, L., “Possible Linkage

between Primary Affective Disorder Susceptibility

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Smeraldi, E., Negri, F., Melica, A. M., et al., “HLA

System and Affective Disorders: A Sibship Genetic

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Suarez, B.K., and Croughan, J., “Is the Major

Histocompatibility Complex Linked to Genes that

Increase Susceptibility to Affective Disorder? A

Critical Appraisal,” Psychiatry Research 7:19-27,

1982.

Suarez, B.K., and Reich, T, “HLA and Major

Affective Disorder,’ Archives of General Psychiatry 41:22-27, 1984.

Targum, S.D., Gershon, E. S., Vi Eerdewegh, M.,

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Closely Linked to or Associated With Bipolar

Manic-Depressive Illness,” Biological Psychiatry

14:615-636, 1979.

Tienari, P., Sorri, A., Lahti, I., et al., “Interaction of

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1985.

Torgersen, S., “Genetic Factors in Moderately

Severe and Mild Affective Disorders,” Archives of

General Psychiatry 43:222-226, 1986.

Torgersen, S., “Twin Studies in Panic Disorder,”

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120 . The Biology of Mental Disorders

111.

112.

113.

114.

Mental Disorders, McClelland and Kerr (eds.)

(London: England, 1991).

Weissman, M.M., personal communication, 1992.

Weissman, M. M., “Panic Disorder: Epidemiology 115.

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1969).
Chapter 6

Research Effort and Issues
CONTENTS

Page

RESEARCH EFFORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123

National Institute of Mental Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Other Federal Agencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .130

Nonfederal Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 131

RESEARCH ISSUES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .133

Animal Models of Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134

Clinical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

Training of Clinician-Researchers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

CHAPTER 6 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .145

Box

Box Page

6-A. Neuroscience at the National Science Foundation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

Figures

Figure Page

6-1. NIMH Budget, Fiscal Years 1970-92 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

6-2. NIMH Budget, Fiscal Years 1980-92 ● . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

6-3. Structure of the Division of Basic Brain and Behavioral Sciences . . . . . . . . . . . . . . . . 127

6-4. Funding of the Division of Basic Brain and Behavioral Sciences,

Fiscal Years 1988-92 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

6-5. Structure of the Division of Clinical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

6-6. Funding of the Division of Clinical Research, Fiscal Year 1980-92 . . . . . . . . . . . . . . 130

6-7. Distribution of Federal Support of Neuroscience Research, Fiscal Year 1990 . . . . . 132

Tables

Table Page

6-1. Comparison of Costs and Research Funding, Fiscal Year 1985 . . . . . . . . . . . . . . . . . . 125

6-2. Funding of Extramural and Intramural NIMH Research, Fiscal Year 1991 . . . . . . . 126

6-3. Distribution of Research Funds by the Division of Basic Brain and

Behavioral Sciences (DBBBS), Fiscal Year 1991 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

6-4. Distribution of Research Funds by the Division of Clinical Research,

Fiscal Year 1991 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

6-5. Research Centers Funded by the Division of Basic Brain and

Behavioral Sciences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .131

6-6. Clinical Research Centers Funded by the Division of Clinical Research . . . . . . . . . . 131

6-7. Department of Veterans Affairs Funding of Mental Disorders Research,

Fiscal Years 1986-91 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

6-8. States Funding Mental Health Research, Fiscal Year 1985 . . . . . . . . . . . . . . . . . . . . . . 132

6-9. Animal Models of Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Chapter 6

Research Effort and Issues

This chapter describes the funding of research into

the biology of mental disorders and discusses issues

surrounding the conduct of that research. The

conduct of this research is shaped by many forces,

including scientific developments, the availability

of resources, and public support for it. Advances in

the neuroscience have especially increased interest

in the biology of mental disorders and have fostered

the expansion of research in this field. These

developments have influenced the decisions of

policymakers regarding funding levels and priorities

for research.

Beyond funding decisions, a number of issues

affect scientists’ ability to carry out this research.

Some of these issues are unique to the study of the

biology of mental disorders. They involve specific

methodological and technical considerations associated with experiments. Other issues are related to the

willingness of individuals to participate in research

and their awareness of the need for this research and

what is required to carry it out. Impediments

associated with these issues can slow the rate of

progress in this field.

This chapter provides an analysis of the funding

decisions that have been made regarding research

into the biology of mental disorders. It also examines

the issues associated with this research and describes

some actions that have been, and can be, taken to

lessen their retarding influence.

RESEARCH EFFORT

Improving the understanding of mental disordersboth their causes and treatment-requires financia1

support for research, including (but not limited to)

basic neuroscience research and research devoted

specifically to the biology of mental disorders.

Federal sources of funding are the most important

delimiting factor in this research.

Decisions about the amount and distribution of

research dollars reveal the priority society places on

addressing mental disorders and the thinking about

where the greatest advances are likely to occur. In

this section, the Office of Technology Assessment

(OTA) examines both the financial support for

mental health research in general and the investment

in research on the biological factors that contribute

to mental disorders. The major source of this funding

is the National Institute of Mental Health (NIMH),

the oldest and largest institute of the Alcohol,

Drug Abuse, and Mental Health Admin stration

(ADAMHA), within the U.S. Department of Health

and Human Services.

National Institute of Mental Health

Figure 6-1 presents the finding of NIMH from

1970 until the present, adjusted for inflation.1 Total

funding and funding for research and services are

presented. This breakdown represents the dual role

of NIMH: conducting and supporting research and

research training on the biological, behavioral,

public health, and social science aspects of mental

disorders; and conducting research on the development and improvement of mental health services and

supporting such services. Research funding2 includes extramural research, intramural research, and

research training, while service funding includes

service programs,3

services research, and clinical

training? From 1970 until the early 1980s, NIMH

experienced a decrease in its budget. Since the early

1980s, this trend has been reversed (see later

discussion), although the total NIMH budget for

1992 is less than for 1970.

1 To eliminate the effect of inflatio~ the NIMH budget was converted into constant 1987 dollars using the gross domestic product deflator as the

price index (12).

z Rese~ch tibg is defied, in this chapter, as that extramural research supported by the Division of Basic Brain and Behavioral Sciences ~d the

Division of Clinical Research and intramural research it excludes the extramural budget of the Division of Applied and Services Researc& which

supports services research and the portion of the intramural budget devoted to services research. It also excludes funds for AIDS research.

3 Fi~es for 1970-81 do not include ~~g of semices prog~ which were ~ntinued ~der block ~ts to the Shtes s@t@ ill 1982 (See later

text). Service activities that continued to be funded by MMH are service planning and demonstration projects, programs related to the legal protection

and advocacy for individuals with mental disorders, and programs for the homeless.

4 while cmc~ training also includes aspects of research tr aining, the major focus of the clinical training programs is to prepare professionals to

enhance the effectiveness of services to persons with mental disorders.

–123–
124 ● The Biology of Mental Disorders

Figure 6-1—NIMH Budget, Fiscal Years 1970-92

o I I I I I I I I I I I I

70 72 74 76 78 80 82 84 86 88 90 92

Fiscal year

 Total funding ---- services fundingb

 Research funding a

The research, services, and total budgets of NIMH from 1970 until

the present.

NOTE: Figures converted to constant 1987 dollars using the 1992 gross

domestic product deflator.

 funding for research training and extramural and

intramural research, excluding funding for services research (see text).

 services programs, services research, and clinical

training. Figures for 1970-1981 do not include funding of services

programs that were continued under block grants to the states starting in

1982.

 figures are estimates. 1992 figures are on the

assumption that the index is going to stay constant at its 1991 level.

SOURCE: Office of Technology Assessment from figures supplied by

National Institute of Mental Health, 1992.

The history of NIMH funding is an indication of

the priority that has been placed on research into

mental disorders. In the past, others have noted an

underfunding of mental disorders research by examining such factors as the costs of mental disorders to

society and the number of people affected (17).

Another indication of relative support can be derived

by comparing the research finding and social costs

of mental disorders to those of cancer and heart

disease (table 6-l). The latter were chosen for

comparison to mental disorders because they exact

comparable costs from society (1,44). The costs of

all these disorders were derived in a similar manners

If the total cost to society of mental disorders,

including dementia (42), is compared with the total

1985 budget of NIMH and the portion of the budget

of the National Institute on Aging devoted to

dementia research, one finds that for every $100 of

social costs, $.30 was spent on research. In comparison, for every $100 of social costs of cancer (41),

$1.63 was spent on research, and for every $100 of

social costs of heart disease (44), $.73 was spent on

research.

A similar underfunding of research into mental

disorders is apparent when the average annual rates

of increase in the NIMH and National Cancer

Institute (NCI) budgets are compared. When adjusted for inflation using the gross domestic product

(GDP) deflator as the price index, the purchasing

power of the total NIMH budget dropped an average

of 1 percent per year between 1970 and 1991. During

the same period, NCI’s purchasing power increased

an average of 5 percent per year. If the same

comparisons are made for just the 1980s, however,

this trend is reversed: Not only does the purchasing

power of the NIMH budget increase, it increases

faster than the purchasing power of the NCI budget

(an average of 3.0 percent per year compared to 0.7

percent). 6 Thus, while research into mental disorders

receives less support than research into cancer and

heart disease, relative to their respective costs to

society, it has increased somewhat in the last 10

years.

Figure 6-2 shows the research and services

budgets of NIMH between 1980 and 1992 (29). The

average annual real rate of increase in research

funding between 1980 and 1992 was 6.7 percent.

After 1986, the rate of increase accelerated to 11.5

percent. The increase in NIMH’s research budget in

1987 constant dollars between 1991 and 1992 is 7.7

percent, which is less than the 11.5 percent average

annual real rate of increase between 1986 and 1992.

Nonetheless, if the trend between 1986 and 1992

continues through the 1990s, it would compensate

for the years when research on mental disorders did

not keep up with inflation or with the advances in

 disorders, disease include direct health-related costs health-related 

(morbidity costs, the value of goods and services that were not produced, and mortality costs, the value of future output lost due to premature death).

Costs of mental disorders also include costs, such as losses in productivity due to time spent to care for a family member with a mental

disorder (see box 

6 of for 

subtracted total budgets between and 1981. After 1981, categorical Federal support for service programs is no of the 

budget.
Chapter Research Effort and Issues . 125

600

500

400

300

200

100

0

Table 6-l—Comparison of Costs and Research Funding, Fiscal Year 1985

Total budget of principal Dollars spent on

costs’ Federal institution research per $l00 of

Illness ($ millions) ($ millions) cost to society

Mental disorders . . . . . . . . . . . . . . . . . . . . 103,691C

310d0.30

Cancer (malignant neoplasms only) . . 72,494 1,184 1.63

Heart disease . . . . . . . . . . . . . . . . . . . . . . . 69,000 501 0.73

 S. et al., The Economic Costs of Alcohol and Drug and Mental 

report submitted to the Office of Financing and Coverage Alcohol, Drug Abuse, and Mental Health

Administration, U.S. Department of Health and Human Services (San Francisco, CA: Institute for Health and Aging,

University of California, 1990); Rice, Hodgson, and F. “The Economic Burden of Cancer, 1985:

United States and California,” Cancer Care and and Beyond, and Andrews 

(Ann Arbor, Ml: Health Administration Press Perspectives, 1989); T. Thorn, Health Statistician, Division of

Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, National Institutes of Health,

personal communication, 1991.

 Institute of Health, National Cancer Institute, and National Heart, Lung, and Blood Institute 

 of disorders include costs of dementia.

dFigure includes $29 for funding of dementia research by the National Institute on 

SOURCE: Office of Technology Assessment, 1992.

Figure 6-2—NIMH Budget, Fiscal Years 1980-92

Dollars (millions)

. . . . .

-----

. . . . .

-----

. . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..1

1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991b1992 c

Research funding

 Basic and clinical extramural research Intramural research Research training

Services funding

 Clinical training Services research Cl Service programs

Funding of the components of the research and services budgets of NIMH.

NOTE: Figures converted to constant 1987 dollars using the 1992 gross domestic product deflator.

 reflects initiation of State block 

 and 1992 figures are estimates.

 figures on assumption of price index.

SOURCE: Office of Technology Assessment from figures supplied by National Institute of Mental Health, 1992.
126 . The Biology of Mental Disorders

Table 6-2—Funding of Extramural and Intramural NIMH Research, Fiscal Year 1991a

Funding Percent of

NIMH research ($ millions) research budget

Extramural

Division of Basic Brain and Behavioral Sciences . . . . . . . . . . . . . . . 124.2 25.7

Division of Clinical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169.6 35.1

Division of Applied Sciences and Services Research . . . . . . . . . . . 42.0 8.7

AIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62.3 12.8

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398.1 82.3

Intramural . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85.7 17.7

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483.8 100.0

aFunding for research training is included in budgets for extramural and intramural re.seard.

SOURCE: National Institute of Mental Health, 1991.

funding for other diseases. In 1991, research funding

made up 75 percent of the total funding for research

and services.

Before 1982, the single most important aspect of

services funding was the service programs-the

categorical Federal support of community mental

health and social services programs (figure 6-2).7

‘The drastic decline in NIMH funding for services in

1982 reflects the end of an era of categorical Federal

support. Almost all of these service programs were

later continued under five block grants, administered

by ADAMHA, to the States (36). When the categorical support is subtracted from services funding in

1980 and 1981, NIMH’s purchasing power in this

area dropped an average of 1.1 percent per year

between 1980” and 1992. Since 1986, however,

NIMH’s purchasing power in this area has increased

an average of 13.4 percent per year, reflecting the

overall increase in NIMH finding.

Funding of all extramural and intramural NIMH

research in 1991 is given in table 6-2.8 Extramural

research received 82 percent of the total NIMH

research budget. To analyze the recent research

emphasis at NIMH, the two divisions of extramural

research-the Division of Basic Brain and Behavioral Sciences and the Division of Clinical Research—

are examined. These two divisions account for 74

percent of the extramural budget and 61 percent of

NIMH’s total research budget.

The Division of Basic Brain

and Behavioral Sciences

The Division of Basic Brain and Behavioral

Sciences (DBBBS) consists of seven branches that

support brain and behavioral research aimed at

furthering the understanding of mental disorders

(figure 6-3). DBBBS was formed in 1989, when the

Division of Basic Science was reorganized to reflect

the diversity of research areas being supported by the

division and to allow more efficient administration

of the large number of research grants being funded

(58). The three branches of the Division of Basic

Science (i.e., Neuroscience Research, Health and

Behavior Research, and Behavioral Research) were

restructured into the current seven branches. The

restructuring and renaming of the division also

reflected an increased emphasis at NIMH on the role

of behavioral research in understanding mental

disorders (27).

Budget figures provided by NIMH divide the

funding of DBBBS into two components—behavioral research (Basic Behavioral and Cognitive

Sciences Research Branch, Personality and Social

Processes Research Branch, and Basic Prevention

and Behavioral Medicine Research Branch) and

biological research (Molecular and Cellular Neuroscience Research Branch, Cognitive and Behavioral

Neuroscience Research Branch, Neuroimaging and

Applied Neuroscience Research Branch, and Psychopharmacology Research Branch) (29). Since the

latter four branches directly concentrate on brain

mechanisms related to mental disorders, an analysis

of their funding provide a rough estimate of DBBBS

support for research into the biological factors that

contribute to mental disorders. However, because of

the interaction of biology and behavior in mental

disorders, research projects often overlap. Thus, a

project funded by one of the biological branches may

include behavioral aspects in its design; conversely,

7~~g for th~e Semice pro~5 is included in the budget figures for 1980 ad 1981 ~ fi~6-2.

g ~ this table, budget figures for extramural and intramural research include support of research x.
Chapter 6-Research Effort and Issues ● 127

Figure 6-3-Structure of the Division of Basic Brain and Behavioral Sciences

Office of the

Director

The NIMH Division of Basic Brain and Behavioral Sciences is made up of seven research branches.

SOURCE: Office of Technology Assessment, 1992.

Table 6-3—Distribution of Research Funds by the Division of Basic Brain and

Behavioral Sciences (DBBBS), Fiscal Year 1991

Funding Percent of

Research branch ($ millions) research budget

Basic Behavioral and Cognitive Sciences . . . . . . . . . . . . . . . . . . . . . . . . .

Personality and Social Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Basic Prevention and Behavioral Medicine . . . . . . . . . . . . . . . . . . . . . . .

Molecular and Cellular Neuroscience . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Cognitive and Behavioral Neuroscience . . . . . . . . . . . . . . . . . . . . . . . . . .

Neuroimaging and Applied Neuroscience . . . . . . . . . . . . . . . . . . . . . . . . .

Psychopharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13.5

18.4

12.4

22.3

22.0

14.2

14.8

$1 17.6a

11.5

15.6

10.5

19.0

18.7

12,1

12.6

100.0

 does not include $6.6 million of the budget allocated to the Contracts and Interagency 

and-the Small Business Innovation Research Program.

SOURCE: National Institute of Mental Health, 1991.

a study that is funded through one of the behavioral

branches may have a biological component to it.

Table 6-3 shows the distribution of funds among

the research branches of DBBBS for 1991. Of the

$117.6 million research budget of the DBBBS,9 38

percent is allocated to the three behavioral branches

and 62 percent to the four biological branches (29).

Figure 6-4 presents the funding of biological and

behavioral research, adjusted for inflation, for 1988

support. The portion of the total DBBBS budget

devoted to biological research, adjusted for inflation, increased from 60 percent in 1988 to 65 percent

in 1992. Taken as an indicator of funding for the

study of biological factors associated with mental

disorders, these figures reveal vigorous support. The

average 14.5 percent annual rate of increase is above

the 11.5 percent rate for the total NIMH research

budget between 1986 and 1992 (see previous

discussion).

through 1992. Both areas show a steady increase—

biological by 70 percent, with an average annual real Division of Clinical Research

rate of increase of 14.5 percent, and behavioral The Division of Clinical Research (DCR) consists

research by 38 percent, with an average annual rise of six research-oriented branches and one that

of 8.5 percent—indicating consistent and strong supports programs in mental health education (see

9 Innovation Research 

is not included in this analysis.
128 ● The Biology of Mental Disorders

Figure6-4-Funding of the Division of Basic Brain and

Behavioral Sciences, Fiscal Years 1988-92

Dollars (millions)

80 I

60- “

A

40- “ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 

20

0 I I

1988 1989 1990 1991 1992

 Biological Behavioral

The funding of the Division of Basic Brain and Behavioral

Sciences broken down into biological and behavioral research

(see text).

NOTE: Figures converted to constant 1987 dollars using the 1992 gross

domestic product deflator.

SOURCE: Office of Technology Assessment from figures supplied by

National Institute of Mental Health, 1992.

ch. 7) (figure 6-5) (26). Table 6-4 shows the

distribution of funding among the six research

branches in 1991 (29). Two of these branches

support studies of specific mental disorders considered in this report-the Schizophrenia Research

Branch and the Mood, Anxiety, and Personality

Disorders Research Branch. These two branches

account for the largest share-50.4 percent—

of the $169.6 million total research budget of the

DCR for 1991.

Trends in support for specific areas of mental

disorders research can be discerned by examining

the funding of the DCR branches. Figure 6-6

illustrates that funding, adjusted for inflation, for

1980 through 1992 (29). One notable trend is the

increase in funding of research related to schizophrenia. From 1986 until the present, the Schizophrenia

Research Branch experienced a 156 percent increase

in funding, with an annual average real rate of

increase of 17.4 percent. The other branches saw an

annual average increase of 10.7 percent over the

same period. The Mood, Anxiety, and Personality

Disorders Research Branch also experienced consistently higher-than-average finding during this

period. The Prevention Research Branch is the only

branch to have experienced a net decline in funding

(-20.5 percent) between 1980 and 1992.

NIMH Centers

NIMH also supports research on mental disorders

through specialized centers administered by DBBBS

and DCR. These centers foster collaborative research in specific areas, bringing together teams of

researchers who contribute various skills to the

research projects. Funding for these centers is

included in the overall budgets for these divisions.

DBBBS administers three types of centers, all of

whose major research emphasis is the biology of

mental disorders (table 6-5). Of the $9.0 million total

support for DBBBS centers in 1991, $5.4 million (60

percent) funded the five Centers for the Neuroscience of Mental Disorders. All five focus specifically

on schizophrenia. Their purpose is to integrate

research on schizophrenia with neuroscience approaches to brain function and dysfunction. The

second group-the Centers for Neuroscience Research--consists of three centers funded with $3.2

million. The goal of these centers is to pursue novel

and innovative research on specialized areas of

neuroscience related to mental disorders. Currently,

there is only one center in the third groupFunctional Brain Imaging Center for the Study of

Mental Disorders. NIMH plans to add new centers to

this group in the next several years in order to

expand multidisciplinary research on brain imaging

technologies.

DCR provided $22.4 million for 23 research

centers in 1991 (table 6-6) (28). These centers focus

on four areas of mental disorders research—

schizophrenia, mood disorders, child, and aging.

The research of 19 of these centers can be characterized as biological (28), accounting for 82 percent

($18.4 million) of the total DCR research center

budget. The remaining four centers, one in each of

the four areas, conduct research related to psychosocial factors. Sixteen of the centers are involved in

research related to either schizophrenia or mood

disorders. These 16 receive $14.4 million, or 64

percent of the DCR research center budget.

In addition to these research centers, NIMH also

funds 10 gene-bank diagnostic centers that collect

blood samples and diagnostic data from patients and

their families for use in genetic studies of mental

disorders (see ch. 5).
Chapter 6-Research Effort and Issues ● 129

Figure 6-5-Structure of the Division of Clinical Research

F

The NIMH Division of Clinical Research is made up of six research branches

training branch.

SOURCE: Office of Technology Assessment, 1992.

1

Education and

Training Branch

and an education and

Table 6-4-Distribution of Research Funds by the Division of Clinical Research,

Fiscal Year 1991

Funding Percent of

Research branch ($ millions) research budget

Schizophrenia Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.3 24.9

Mood, Anxiety, and Personality Disorders Research . . . . . . . . . . . . . . . 43.0 25.4

Mental Disorders of the Aging Research . . . . . . . . . . . . . . . . . . . . . . . . . 24.6 14.5

Child and Adolescent Disorders Research . . . . . . . . . . . . . . . . . . . . . . . . 27.0 15.9

Prevention Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.7 7.5

Epidemiology and Psychopathology Research . . . . . . . . . . . . . . . . . . . 20.0 11.8

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169.6 100.0

SOURCE: National Institute of Mental Health, 1991.

Summary of NIMH Funding

Since NIMH is the principal Federal institution

that plans and supports research on mental disorders,

its funding and the research emphasis within it

provide a fairly accurate illustration of the overall

research emphasis in the United States. Over the past

decade, total support of NIMH has increased,

reversing a previous trend of undersupport. This is

particularly evident in the increases in funding that

have occurred since 1986. OTA’s analysis indicates

that NIMH is a multifaceted organization, responsible for many things, including research on biological, behavioral, public health, and sociological

aspects of mental disorders, with an emphasis on

biological research.

The extramural research funding of DBBBS and

DCR supports studies on a variety of biological,

behavioral, and social science aspects of mental

disorders. Analysis of the distribution of this funding reveals two areas of emphasis. First is the

emphasis on basic research related to biological

factors associated with mental disorders, an emphasis that overlaps with the recommendations of the

National Advisory Mental Health Council (51).

Over half the total budget of DBBBS is devoted to

funding those branches that emphasize biology; with

four exceptions, all of the research centers funded by

DCR and DBBBS emphasize biological research.

The second emphasis is research on the severe

mental disorders included in this report: schizophrenia and mood and anxiety disorders. In 1991, the two

branches of DCR devoted to research on these

disorders received 50.3 percent of the total DCR

budget, and since 1986 the Schizophrenia Research

Branch has experienced the highest rate of growth of

any DCR branch. Also, the majority of research

centers (16 out of 23) funded by DCR focus
130 ● The Biology of Mental Disorders

Figure 6-6-Funding of the Division of Clinical

Research, Fiscal Years 1980-92

Dollars (millions)

40 ,

0 I I I I

198081

+

+

+

82 83 84 85 86 87 8 8a

8 9a9 0a 91a 92a

Schizophrenia

Mental disorders of the aging

Child and adolescent disorders

Mood, anxiety, and personality disorders

Epidemiology and psychopathology

Prevention

Funding of the six research branches of the Division of Clinical

Research.

NOTE: Figures converted to constant 1987 dollars using the 1992 gross

domestic product deflator. research training.

SOURCE: Office of Technology Assessment from figures supplied by

National Institute of Mental Health, 1992.

specifically on these disorders. The emphasis on

schizophrenia research again coincides with recommendations of the National Advisory Mental Health

Council (52).

Other Federal Agencies

Although NIMH is the principal Federal institution that funds research related to mental disorders,

others contribute. One such Federal agency, the

Department of Veterans Affairs (VA), specifically

funds research on mental disorders. In fiscal year

1991, the VA spent approximately $15 million on

some 230 research projects related to mental disorders (31). Of this $15 million, approximately $700,000

supports various projects at three centers devoted to

the study of the neurobiology of schizophrenia (i.e.,

Denver VA Hospital, Bronx VA Hospital, West

Haven VA Hospital) (7). The remaining funds

support research into various aspects of mental

disorders, including biological factors (31). The

total VA medical research budget for fiscal year

1991 was $216 million (4). It has been noted that

there is a disparity between VA medical research

expenditures and VA clinical costs regarding mental

disorders (4). Mental disorders account for 40

percent of all VA bed days, while 7 percent of

research monies are allocated to mental disorders

research. A report recently completed by the VA

Advisory Committee for Health Research Policy

recommended the creation of a Health Research

Advisory Council to identify and set priorities for

those areas with the greatest promise of enhancing

VA health care (4). This council would be a

mechanism for addressing issues such as the disparity related to mental disorders. Table 6-7 shows VA

funding of research projects related to mental

disorders for fiscal years 1986 through 1991.

The remainder of Federal funding in this area is

devoted to support of neuroscience research. As

previously discussed (see ch. 2), neuroscience is an

interdisciplinary field encompassing many different

areas. Research in the neuroscience fuels the study

of the biological factors that contribute to mental

disorders. While not all neuroscience projects are

directly applicable to mental disorders, research in

many areas (e.g., cellular and molecular neuroscience, neurochemistry, neuropharmacology) all contribute to the foundation that supports the study of

biological mechanisms associated with mental disorders.

Many Federal institutions have programs devoted

to various aspects of neuroscience research (figure

6-7). In fact, Federal funding for this broadly defined

area of research was more than $1 billion in 1990

(48). Federal funding institutions include NIMH

(see earlier discussion) as well as the National

Institute on Drug Abuse and the National Institute on

Alcohol Abuse and Alcoholism and a number of

institutes within the National Institutes of Health

(NIH). The National Institute of Neurological Disorders and Stroke (NINDS) is the major source of such

funding at NIH, with an expenditure of almost $500

million in fiscal year 1990 (figure 6-7). Other

institutes at NIH that fund neuroscience research are

the National Institute on Aging, National Eye

Institute, National Institute on Deafness and Other

Communication Disorders, National Institute on

Child Health and Human Development, National
Chapter Research Effort and Issues ● 131

Table 6-&Research Centers Funded by the Division of Basic Brain and

Behavioral Sciences

Funding

Center Number ($ millions)

Neuroscience of Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5.4

Neuroscience Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.2

Functional Brain imaging for the Study of Mental Disorders . . . . . . . . 1 0.4

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 9.0

SOURCE: National institute of Mental Health, 1991.

Table 6-6-Clinical Research Centers Funded by the Division of Clinical Research

All Centers Centers doing biological research

Funding Funding

Area of research Number ($ millions) Number ($ millions)

Aging . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.9 4 3.1

Schizophrenia . . . . . . . . . . . . . . . . . . 8 7.8 7 6.5

Mood disorders . . . . . . . . . . . . . . . . 8 8.8 7 7.9

Child . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.9 1 0.9

Total . . . . . . . . . . . . . . . . . . . . . . . . 23 22.4 19 18.4

SOURCE: National institute of Mental Health, 1991.

Table-6-7—Department of Veterans Affairs Funding of

Mental Disorders Research, Fiscal Years 1986-91

Funding Projects

Fiscal year ($ millions) (no.)

1986 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.8 119

1987 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.6 198

1988 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.0 204

1989 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.6 221

1990 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.6 214

1991’ . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 15.0 230

aEstimated.

SOURCE: UIS. Departmentof Veterans Affairs, 1992.

Institute of Environmental Health Sciences, and the

National Institute of Dental Resemch. Other Federal

agencies funding neuroscience research include the

Department of Veterans Affairs, the National Science Foundation,10 the Department of Energy, the

Department of Defense, the National Institute on

Disability and Rehabilitation Research, the National

Aeronautics and Space Administration, the Environmental protection Agency, the Department of Agriculture, the Centers for Disease Control, and the

Food and Drug Administration.

The diversity of Federal organizations that fired

this research necessitates interagency communication. An official channel for such communication

has been set up through the Office of Science and

Technology Policy’s Federal Coordinating Council

for Science, Engineering, and Technology (FCCSET

—pronounced ‘fro-it’ ‘). FCCSET provides a forum

for coordinating executive research and development activities; it has received special attention from

the President’s Science Adviser and has proven

itself a workable mechanism in coordinating research in such areas as high-performance computing

(48). Among the leadership for FCCSET’s neuroscience subcommittee (Subcommittee on Brain and

Behavioral Sciences) are senior agency personnel

from the chief Federal agencies funding neuroscience research, namely, NIMH and NINDS.

Nonfederal Support

State and private sources also support research on

mental disorders, but these sources have generally

been very limited (21,43). This funding is not

limited to research on the biology of mental disorders, but rather supports all types of mental health

research. A survey conducted in 1987 found that of

the 45 States that provided figures, 26 funded some

aspect of mental health research (i.e., services

research and research into understanding mental

disorders) (table 6-8) (43). Funding for this research,

approximately $17 million in 1985, represented no

more than 0.3 percent of the total State expenditures

for mental health. Factors that affected a State’s

likelihood of funding research were its population,

10 Recently, tie Natio~ Science Fomdation reorganized its research structure for neuroscience and behavioral research. BOX 6-A descri~s ~s

reorganization.
132 . The Biology of Mental Disorders

Figure 6-7—Distribution of Federal Support of

Neuroscience Research, Fiscal Year 1990

Table 6-8-States Funding Mental Health Research,

Fiscal Year 1985

Dollars (millions)

NINDS 490

NIA

NEI 80

NIH NIDOCD 59

NICHD 58

NIEHS 20

402

Other

agencies

I

100 200 300 400 500

Arizona New York

California North Carolina

Colorado Ohio

Connecticut Oklahoma

Florida Oregon

Georgia Pennsylvania

Hawaii Rhode Island

Illinois South Carolina

Indiana Tennessee

Iowa Texas

Maryland Utah

Massachusetts Virginia

Michigan Washington

SOURCE: B.A. Ridge, Pincus, R. et al., “Factors That

Influence State Funding for Mental Health Research,” 

and Community Psychiatry 1989.

Funding of neuroscience research by various Federal agencies.

NOTE: National Institutes of Health; ADAMHA Alcohol, Drug

Abuse, and Mental Health Administration; National

Institute of Neurological Disorders and Stroke; 

Institute on Aging; National Eye Institute; National

Institute on Deafness and Other Communication Disorders; 

 National Institute on Child Health and Human Development;

 National Institute on Environmental Health Sciences;

 National Institute of Dental Research; NIMH National

Institute of Mental Health; National Institute on Drug Abuse;

 National Institute on Alcohol Abuse and Alcoholism; VA 

U.S. Department of Veterans Affairs; NSF National Science

Foundation; DOD U.S. Department of Defense; DOE U.S.

Department of Energy; Other= National Institute on Disability and

Rehabilitation Research, National Aeronautics and Space Administration, Environmental Protection Agency, U.S. Department of

Agriculture, Centers for Disease Control, and U.S. Food and Drug

Administration.

SOURCE: Office of Technology Assessment, adapted from E. Pennisi and

D. Morgan, “Brain Decade Scientists Court Support,” The

Scientist 1990.

which affects levels of available funds, and the

existence of other research support and research

facilities. The survey also noted that the political

environment and the individual characteristics of

State leaders, both of which are susceptible to the

influence of lobbying and advocacy activity, play a

role in determining whether State funds will be

allocated for mental health research.

Foundations are another nonfederal source of

funding for research. Since foundations possess

uncommitted funds that can be used to support new

projects relatively quickly, they represent a more

flexible source of funds than government entities

(21). An analysis of foundation funding for mental

health research during the period from 1983 to

198511 revealed that of the 4,402 foundations

reviewed, 63 had an interest in mental health and 15

of these 63 had made grants for mental health

research (21). In addition, 29 foundations that did

not list mental health as an interest had given grants

for mental health research. These grants encompassed all aspects of mental health research. Of the

44 foundations that had made grants to mental health

research only 1 percent of the foundations reviewed—

almost half had a national orientation and over half

held assets of $50 million or more.

The National Alliance for Research on Schizophrenia and Depression (NARSAD) is a source of

foundation funding for research into the biology of

mental disorders. NARSAD is the largest private

sector, noncorporate funder of mental disorders

research (30). It was founded in 1986 by the major

citizen’s organizations in mental illness advocacy

and services-National Alliance for the Mentally Ill,

National Mental Health Association, National Depressive and Manic Depressive Association—to be

their research arm. All of NARSAD’s funds for

research are raised through gifts from the public.

Since 1987, the alliance has funded 424 research

grants with $16 million. The Stanley Foundation

also supports research into the biology of mental

disorders, focusing on severe mental disorders,

including schizophrenia and mood disorders, with

approximately $1.5 million a year. Finally, the

Scottish Rite Foundation, which was founded in

1935, has long funded mental disorders research,

focusing explicitly on understanding the nature and

causation of schizophrenia. It funds approximately

25 grants a year with $750,000.

 of for information from all foundations was available.
Chapter 6-Research Effort and Issues . 133

Box 6-A—Neuroscience at the National Science Foundation

In January 1992, two new directorates were established at the National Science Foundation (NSF). The

Directorate for Social, Behavioral, and Economic Sciences (SBE) and the Directorate for Biological Sciences (BIO)

replaced the Directorate for Biological, Behavioral, and Social Sciences. This reorganization was spurred by

congressional pressures to increase the emphasis on the behavioral and social sciences at NSF. The result was the

formation of SBE to fund such research.

This reorganization also had a direct effect on neuroscience research at NSF. Previously, neuroscience projects

were funded primarily through the Division of Behavioral and Neural Sciences within the Directorate for Biological,

Behavioral, and Social Sciences. Under the reorganization, the behavioral component is now included in SBE, while

the neural component is part of BIO. Neuroscience research is now housed in the Division of Integrative Biology

and Neuroscience within BIO. The Neuroscience Program/Cluster is the major program funding neuroscience

research, with a budget of $30.6 million in fiscal year 1992. It is divided by topic into seven program elements. These

include neural mechanisms of behavior, neuroendocrinology, sensory systems, synaptic mechanisms, neuronal and

glial mechanisms, developmental neuroscience, and computational, cognitive, and theoretical neurobiology.

The establishment of a directorate devoted to behavioral and social sciences was greeted with enthusiasm

within those scientific communities. However, the initial announcement of this reorganization resulted in some

trepidation within the neuroscience community. There were fears that neuroscience research was going to be

dispersed among different disciplines: for example, that cellular neuroscience was to be part of a general program

on cell biology and that developmental neuroscience was to be part of a developmental biology program. There were

concerns that this would represent a dismantling of neuroscience research support at NSF, concerns that were

allayed by the establishment of the current organizational structure.

The fact that neuroscience research will no longer share a common directorate with psychology and cognitive

sciences suggests a separation of brain and behavioral research; however, under the new organization there are plans

to maintain linkages of these disciplines through initiatives that cut across directorates. An example is an initiative

in cognitive science that will involve a total of five NSF directorates. More recently, a Decade of the Brain working

group was established that cuts across four directorates. While language, cognitive, and social behavior are now

housed in the SBE directorate, the Division of Integrative Biology and Neuroscience has a program cluster in

physiology and behavior that includes support for animal behavior in both field and laboratory settings.

SOURCES: M. Baring~ “Neuroscience at Risk at NSF,” Science 254:643, 1991; M. Clutter, “Neuroscience at NSF: Opportunities From

Change,” NeuroscienceNewsletter 23(1):8, 1992; “Neuro Nerves Calmed,” Science 255:680-681, 1992; “NSFD.irwtorate: Yes!”

APS Observer 4(6):l,28-31, 1992; K. Olse~ Leader, Neuroscience Program, National Seienee Foundatio~ personal communieationj February/May 1992.

RESEARCH ISSUES

Other factors besides financia1 support influence

the environment in which research into the biology

of mental disorders takes place. OTA has identified

several issues in this research that, if not addressed,

can hamper progress. These issues relate to the

development of animal models of mental disorders,

the study of clinical populations, and the training of

individuals to conduct this research. Some of these

issues are unique to the study of the biology of

mental disorders; others, while not confined to this

area of research, are particularly pertinent to it. The

unique nature of attempting to understand complex

human behavior and how it sometimes goes awry, as

well as public and professional attitudes toward

mental disorders, can present impediments to research. The stigma of mental disorders and the lack

of awareness among the public, patients and their

families, and medical personnel as to the requirements of this research present difficulties. These

factors affect many aspects of research, ranging from

basic scientific concerns to ethical implications.

Addressing these issues will result in a more

supportive environment for research. This section

discusses the problems associated with using animals as models of mental disorders and examines the

impact of the debate over the use of animals in

biomedical research. A number of general issues

associated with the use of patients in research on

mental disorders are described. Two specific issuesthe collection and banking of brain tissue for study

and the conduct of clinical trials with medicationfree subjects—are discussed. Finally, concerns about

the number of clinician-researchers available to
134 . The Biology of Mental Disorders

conduct research are also discussed. Initiatives that

have been undertaken to address these issues are

described, and areas for additional action are

sented.

preAnimal Models of Mental Disorders

As in other areas of biomedical research, animal

models play an important role in advancing the

understanding of mental disorders. In designing

animal models for the study of human diseases,

scientists seek to develop in animals disorders that

resemble aspects of human pathology. Ideally, an

animal model of a disorder is identical to the human

disorder in cause, symptoms, underlying mechanisms, and responsiveness to treatment. In reality,

this ideal is rarely achieved. Disruption of the

processes that control thoughts and emotions is

particularly difficult to replicate in nonhumans. The

delusional thinking of schizophrenia, the despair of

depression, and the fear and dread of anxiety

disorders are all complex cognitive-emotional

states. As a result, a model encompassing all

attributes of a mental disorder is probably impossible to achieve; certainly, no such model exists now

(16).

Even though human mental disorders cannot be

modeled exactly in animals, useful animal models

exist. At the most basic level, fundamental information about the anatomy, molecular biology, chemistry, and other functions of the brain can be gained

from animal studies. Also, animal models have been

designed to study and evaluate specific aspects of a

mental disorder (table 6-9), including the basic

biological mechanisms that may contribute to its

symptoms, the hypothesized causes, and the drugs

used for treatment.

one important issue to consider in animal research is the choice of species. The decision as to

which species is most appropriate is made by

considering the purpose of the model, the design of

the experiment, and what kind of information is

sought. In studying basic neurobiological mechanisms, which are often the same across species, any

species can be used. For example, information about

how a drug interacts with a receptor can be gathered

in any species that has that receptor. For models of

more complex behaviors, mammals are the most

appropriate species (table 6-9). The use of primates

is particularly important in the study of mental

disorders since they most closely resemble humans

in their behavior and brain structure.

As more is learned about a disorder, new areas of

interest are identified for study. For example,

positron emission tomography (PET) imaging studies have shown that decreased activity in the frontal

cortex is a common characteristic of persons with

schizophrenia (ch. 4). Scientists have used this

information to investigate the frontal cortex in

animals, particularly primates, using various experimental techniques on these animals that could not be

used on patients (13) (table 6-9). Thus, recent

progress in the neuroscience has ushered in a new

phase in the use of animals for the study of mental

disorders.

Some aspects of human mental disorders are

particularly difficult to replicate in animals, such as

the social withdrawal and blunted emotional responsiveness seen in schizophrenia (15,51,57). The

development of models encompassing these characteristics would yield valuable information and represents an area for future research.

As in other areas of biomedical research, the

controversy surrounding the use of experimental

animals has had an impact on research into mental

disorders (34). The debate encompasses a range of

positions, from animal welfare to animal rights (50).

Animal welfare generally concerns proper treatment, shelter, and care of animals used in studies;

animal rights is the concept that animals have

intrinsic rights equal to human rights (50). As a

result, some advocates of animal rights argue that

animals should not be used for any human purpose,

including biomedical research (50).

Federal laws, State laws, and guidelines written

by executive branch agencies all regulate the use of

animals (46). The Animal Welfare Act, which was

enacted in 1966, is the primary Federal law setting

requirements for the care and use of animals in

research. As a result of increased concern about the

care and use of animals, the Animal Welfare Act was

amended in 1985 to enhance the requirements for

animal care. To enforce the amended act, the U.S.

Department of Agriculture (USDA) has issued a

series of new regulations and standards for the use of

animals in a variety of settings, including biomedical research (54 F.R. 36112; 54 F.R. 36123; 55 F.R.

28879; 56 F.R. 6426). At the same time, new

regulations were also enacted under the Public

Health Service’s (PHS) Guidelines for Animal Care
Chapter 6-Research Effort and Issues ● 135

Table 6-9—Animal Models of Mental Disorders

Disorder Features Species typically used

Schizophrenia

Amphetamine-induced psychosis

Primate prefrontal cortex

Depression

Learned helplessness

Maternal separation

Mania

Drug- and surgically induced hyperactivity

Bipolar Disorder

Sensitization and kindling

Anxiety

Conflict mode

Social interaction

Drug-induced or brain-stimulated anxiety

Open-field paradigm

Genetic models

Obsessive-compulsive disorder

Spontaneous paw licking

Displacement behaviors

Administration of amphetamine produces schizophrenia-like

symptoms.

Surgical damage to prefrontal cortex produces schizophrenialike deficits in visual tracking

Animals exposed to unpredictable stimuli, with no control over

occurrence, exhibit stress and some of the same behaviors

seen in depression.

infants separated from their mothers exhibit some behaviors

roughly analogous to depression.

Various drugs and destruction of certain areas of the brain

produce a persistent hyperactivity y that shares some

features of mania.

Using either repeated administration of stimulant drugs or

low-level electrical brain stimulation, patterns of behavior

are produced that mimic the progressive, increased frequency of cycling between mania and depression that

occurs in bipolar disorder.

Animals both rewarded and punished for performing a task

exhibit anxious behavior.

Placing two males in an unfamiliar setting and bright light

produces less social interaction, which is overcome with

antianxiety drugs.

Various drugs and electrical stimulation of certain brain

regions produce anxiety -like behavior.

Rodents exposed to large, open, novel, well-lit areas exhibit

high rates of activity that are decreased by antianxiety

drugs.

A strain of rats and a line of pointer dogs exhibit increased

reactivity and “nervousness”.

Some species of dogs lick their paws to the point of causing

physical damage, a behavior thought to share features of

OCD.

Normally fixed patterns of activity (e.g., pecking, grooming,

digging, head turning) that can become excessive under

stress (e.g., captivity) are thought to be related to the

ritualistic behaviors seen in OCD.

Rats, mice, primates

Primates

Rats

Primates, rats,

hamsters

Rats

Rats

Various species

Rats

Rats

Rodents

Rats, dogs

Dogs

Various species

SOURCE: Offioe of Technology Assessment, 1992.

and Use. These guidelines oversee the use of animals

in all settings funded by the PHS and are generally

used in most animal facilities throughout the public

and private sectors. Both the new USDA and PHS

regulations impose more stringent standards for the

care, handling, housing, and use of animals in

biomedical research than had previously been in

place. The PHS regulations coverall animals used in

research, while the USDA regulations exclude

rodents and birds. In January 1992, a Federal judge

ruled that the USDA regulations should be expanded

to include rodents and birds (8).

Implementation of these regulations has increased

the costs of conducting research. The USDA estimated that capital expenditures (e.g., renovation of

animal housing, construction of aseptic surgical

facilities, new equipment) for all establishments and

persons affected by the new USDA regulations

would be $876 million over the first 2 to 3 years (54

F.R. 10831). The USDA also estimated that the

regulations would increase annual operating costs

by $207 million (54 F.R. 10831). These figures do

not take into account the costs of including rodents

and birds under the regulations.
136 . The Biology of Mental Disorders

The actions of animal rights groups have compelled many institutions to initiate more rigorous

security precautions to safeguard their facilities and

personnel, thereby incurring additional costs (34).

Concern about such actions prompted Congress to

pass a bill (S. 544, Animal Research Facilities

Protection Act of 1991) that makes it a Federal crime

to vandalize facilities used for research or to remove

animals from such facilities.

It is feared that the controversy over the use of

animals in research will impede research in other

ways (34). Apprehension regarding possible adverse

actions by animal activists can affect decisions about

types of research protocols to be used and the species

selected for study. As previously mentioned, primates are crucial to research on the biological factors

in mental disorders. It has been noted that the

combined effects of increased financial costs of new

regulations and activities of animal activists have

particularly constrained the use of primates in

biomedical research (23).

Clinical Research

Clinical research involves two broad areas-the

development and testing of potential new treatments

and the conduct of studies aimed at unveiling the

underlying pathology and causes of a disorder. Thus,

it includes studies that use human subjects in various

types of experiments, the collection of tissue samples (e.g., blood, cerebrospinal fluid) for analysis,

and the examination of donated brains from people

who have died. Regardless of the type of clinical

research being conducted, several general issues

emerge. These relate to the recruitment and selection

of subjects, the inclusion of representative populations in clinical studies, and the costs of conducting

this research. This section discusses these general

issues and describes the issues associated with two

specific research situations-the banking and use of

postmortem brain tissue and clinical studies with

medication-free subjects.

Whatever the research, subjects must be recruited

to participate in studies. The willingness of individuals to participate in such studies is often linked to

their awareness of the need for subjects. Also, the

stigma and negative attitudes associated with mental

disorders (see ch. 7) can lessen the willingness of

individuals to participate in studies. A variety of

approaches are used to recruit subjects. Sometimes

volunteers are recruited through an advertisement or

public service announcement describing, for example, the symptoms of a disorder and announcing the

need for subjects in a study. Patient support and

advocacy groups often inform their members of the

need for subjects. Usually, such individuals are

screened over the telephone and then in person to

determine their eligibility for a particular research

project. Most often, however, subjects are recruited

from patients receiving treatment, on an inpatient or

outpatient basis, at a clinic or medical center.

Regardless of the source of subjects, participants

in a research protocol in any area of biomedical

research must provide their informed consent to

participate (6). Informed consent is a large and

complex topic that has been addressed extensively

elsewhere (47). Briefly, U.S. Department of Health

and Human Services (DHHS) regulations guide

informed consent in all research funded by DHHS;

in addition, these regulations are widely used as

guidelines in institutions that do not receive Federal

funding (47). The regulations specify that informed

consent for participation in a study is governed by

each institution’s Institutional Review Board (IRB).12

Obtaining informed consent from patients with

mental disorders raises some unique problems (6). In

order to provide informed consent, the possible

benefits and risks associated with an experimental

procedure must be explained to the individual. He or

she must understand these factors, rationally weigh

them, and then make a decision as to whether or not

to participate. The nature of some mental disorders

may make an individual incompetent to render such

a decision and thus to provide informed consent. In

some cases, if the disability associated with a

disorder is permanent, the individual can be declared

legally incompetent and a guardian appointed to

make decisions for him or her. In that case, the

guardian can provide consent for participation in

research. However, most individuals with mental

disorders are not declared legally incompetent, since

they are capable of making decisions related to their

welfare when their disorder is under control (6).

Thus, the ability of individuals with a mental

disorder to understand what they are being asked to

consent to can vary, depending on their condition.

As a result, the question of whether a person is

providing a valid informed consent must be careIZ IRB,S review tie m~ical, legal, and ethical aspects of all proposed research projects using h~an subjwts.
Chapter 4-Research Effort and Issues ● 137

fully determin ed based on his or her competency at

the time. It is the role of the IRBs and researchers to

ensure that the decision truly represents informed

consent.

Once subjects are recruited, their appropriateness

for inclusion in an experimental protocol must be

determined. The validity of a study’s results is

dependent on the selection of a homogeneous

experimental group made up of individuals who

have all been accurately diagnosed as having the

same disorder. A number of factors can complicate

this selection process. As discussed in chapters 3 and

5, some mental disorders that are classified as a

single disorder, such as schizophrenia, may actually

consist of subtypes. Also, patients frequently have

multiple disorders. Depression is frequent, for example, among patients with obsessive-compulsive disorder. Finally, the familiarity of investigators with

diagnostic issues surrounding a disorder, such as the

existence of subtypes, may vary. These factors can

result in lack of homogeneity among subjects within

a study or across different studies. Heterogeneity

within and across samples can confound the results

of studies or make it difficult to compare results of

different studies. One of the problems that has beset

research into the biological factors associated with

mental disorders is the difficulty of replicating

findings, even though the same methods are used

and the same disorders are being studied. Some of

this difficulty is due to the selection of experimental

subjects (52).

NIMH has suggested that some of these problems

can be partially alleviated by ensuring that research

teams include a clinical investigator who is aware of

the diagnostic and clinical issues related to the

disorder being studied (52). To make it easier to find

individuals with such expertise, NIMH has suggested establishing diagnostic centers that could

provide consultation and intensive short-term training in diagnostic and other clinical issues (52). Such

centers could result in a more integrated and

coherent approach to clinical diagnosis.

It is difficult to estimate how many clinical studies

of mental disorders are conducted each year, but

there are clearly hundreds. Study populations may

vary in size from 15 or 20 patients to several hundred

patients at various facilities. Sample size is determined by the goal of the study. If it involves new

drug development, several hundred patients are

required to discern the safety and effectiveness of the

experimental drug.

In general, adults between the ages of 18 and 55

to 60 are included in these studies. Adolescents and

children pose special problems in clinical research,

both in terms of consent and because in some cases

there is no clear-cut diagnosis during the very early

stages of a disorder. Persons over the age of 55 or 60

are frequently excluded from clinical research because they are likely to have other illnesses that

require medications, which would complicate the

investigation. As a result, adolescents, children, and

the elderly are understudied populations in whom

significant mental disorders can occur and for whom

a variety of important questions related to cause and

treatment frequently go unanswered. Clearly, research does focus on some disorders that are

relatively specific to childhood (e.g., attention deficit disorder with hyperactivity) or later life (e.g.,

senile dementia of the Alzheimer type), but these age

groups are infrequently studied for disorders such as

depression and schizophrenia.

Women of childbearing age are often excluded

from experimental drug trials because of the potentially damaging effects of such drugs on conception

and fetal development. To some extent this concern

is driven by fear of litigation. Sponsors and investigators fear that if a woman conceives while taking an

experimental drug, despite their warnings against

such action, they will be found liable for any damage

to the fetus. This policy results in a situation where

efficacy is more clearly established in men than it is

in women. Some have argued that the policy of

denying women of childbearing age the opportunity

to participate in clinical trials is demeaning to

women.

The prevalence and expression of some mental

disorders vary by sex. For example, depression is

twice as prevalent among women as men (see ch. 3),

and schizophrenia often has an earlier onset and

more difficult course in men than women (see ch. 3).

Thus, understanding mental disorders requires that

women be included in clinical trials and that gender

differences be studied specifically. Concern about

the lack of such studies, and other issues related to

women’s health, resulted in congressional calls for

a greater emphasis in this area (1 1). Accordingly, the

PHS initiated an Action Plan for Women’s Health

(56) that outlines the goals established by PHS

agencies in regard to these issues (33). The Office of
138 ● The Biology of Mental Disorders

Women’s Health, within PHS, will be in charge of

monitoring its progress.

ADAMHA has set a number of goals related to

mental disorders research as part of this plan. These

goals augment the NIH/ADAMHA policy on the

inclusion of women in research first established in

1986 and updated in 1990 (54). These include

increasing research initiatives concerned with sexrelated differences in mental disorders and promoting and enforcing a policy regarding the inclusion of

women in clinical research. Steps to achieve these

goals include identifying specific areas for future

study and requiring that all applications and proposals for clinical research funding include women in

their research protocol, where appropriate. When

women are to be excluded, there must be justification for doing so. In addition, ongoing research

studies will be monitored to ensure that they comply

with the policy.

The finding that ethnic groups may differ in their

sensitivities to drugs indicates the need to consider

ethnic differences when studying the biology of

mental disorders (14). Such ethnic differences and

other public health concerns regarding minorities

led ADAMHA and NIH to establish a policy in 1987

(updated in 1990) regarding the inclusion of minorities in research (55). This policy requires that

applicants for research funding give appropriate

attention to inclusion of minorities in study populations, unless compelling scientific or other justification for not including minorities is provided. While

the purpose of the policy is the inclusion of

minorities in studies, it also encourages attention to

gaps in knowledge about specific U.S. racial and

ethnic minorities and health problems that significantly affect them. As with the policy regarding the

inclusion of women in research, this policy is

intended to ensure that every effort is made to

include minorities in applications for clinical research funds. Failure to comply with the policy is

sufficient grounds for not receiving a research

award.

A final factor that affects clinical research,

including research into mental disorders, is the

changing landscape of health-care financing in the

United States. While a discussion of the effects of

cost-containment efforts on clinical research is

beyond the scope of this report, it is important to

note that costs associated with mental disorders

research have traditionally been enfolded in the

costs of clinical care (39). That is, diagnostic and

treatment procedures that are normally administered

to a patient as part of their care may also be used in

research. Implementation of measures to control

health-care costs may disrupt this traditional piggybacking of clinical research studies onto standard

clinical care (39). As a result, other mechanisms for

covering these costs will need to be developed.

These could include efforts by academic health

centers to manage existing budgets in a way that will

allow them to continue to participate in clinical

research, private funding of research, and additional

research funding from Federal sources (39).

Brain Banks

Federal agencies and researchers have emphasized the importance of postmortem brain tissue

samples for the study of mental disorders (38,51,52).

Brains from deceased patients can be examined for

anatomical and morphological abnormalities, and

samples of brain tissue can be assayed to discern any

changes in pharmacological and chemical activity

(see ch. 4). Without doubt, the most crucial issue in

regard to the study of brains after death is lack of

availability (24,25,52): There is agreement in the

scientific community that the demand for tissuewhich has increased in parallel with the emphasis on

research into the biological factors of mental disorders—far exceeds the available supply. There is also

a great need for control tissue, from unaffected

individuals, for comparison with the pathological

samples. Factors related to the handling and distribution of tissue and issues associated with the donation

of brains by patients and their families hamper the

collection of brains (25).

Currently, two centers in the United States, which

have been in operation for about 25 years, are funded

to serve specifically as brain banks (24,51). One is

located at Harvard University and one at the VA’s

Wadsworth Medical Center in West Los Angeles.

The operations of both banks are cofunded by NIMH

and NINDS. In addition, both receive some support

from private institutions. The Harvard University

brain bank was federally supported at a level of

$350,000 in fiscal year 1990, $374,000 in fiscal

1991, and a projected $400,000 in fiscal 1992 (58).

Federal support for the VA facility in fiscal 1990 was

approximately $330,000 (58).

These centers supply tissue samples to researchers upon request. Their inventories consist of brains

from patients with a variety of neurological and
Chapter 6-Research Effort and Issues . 139

psychiatric disorders, as well as from normal individuals. Samples from neurological patients comprise the bulk of these collections. Figures from the

Harvard brain bank indicate that of their current

inventory of 944 brains, 94 are from individuals who

had some form of mental disorder, 116 are from

controls, and the remainder are from patients with

neurological conditions (45). The VA bank has a

current inventory of 1,149 brains, of which 121 are

from patients with mental disorders and 202 from

controls (45). It must be kept in mind, however, that

when a request for tissue is received, it is usually for

a specific region of the brain, depending on the

disorder being studied. For example, studies of

schizophrenia often examine areas of the frontal

cortex. As a result, although the brain bank may have

a brain from a patient with schizophrenia on hand,

there may be no more tissue remaining from the

frontal cortex. In 1991 the Harvard brain bank

received written requests for samples from 233 cases

of patients with mental disorders (22). This number

is an underestimate of the actual demand, since

many initial inquiries are made by telephone, and if

they cannot be met, a written request is never made.

These banks have established standardized procedures for storing tissue—namely, freezing one half

of a donated brain and placing the other half in

formaldehyde (24). This allows tissue from the same

individual to be studied using either chemical or

anatomical techniques. However, many new methodologies cannot use tissue that has been stored in

either fashion and require different handling procedures. In order for tissue samples to be useful,

therefore, it is necessary to coordinate handling

procedures with experimental needs (25). These

methodological problems, and the fact that the

demand for tissue has grown rapidly over the past

few years, have led to the establishment of 15 to 20

additional brain collections at various institutions in

the United States. In general, these collections have

been established by individual research groups

conducting studies on brain tissue. The expenses of

maintaining g the collections are met by funding

sources that support the ongoing research. Often, the

researchers who maintain the collections enter into

collaborations with other scientists to share samples.

As a result, an informal network has developed

among neuroscientist regarding where brain samples might be obtained.

It is crucial to have complete medical records and

histories of persons whose brains are being studied

in order to correctly diagnose the clinical disorder

and provide information about treatment history and

the presence of other medical conditions. Samples

from medical examiners are frequently from suicide

victims or homeless individuals whose medical

records are inaccessible or nonexistent. Absence of

proper categorization and information about other

factors that might affect the outcome of experiments

severely limits the usefulness of collected tissue.

This is especially important regarding control samples, where it is critical that the individual not suffer

from a mental disorder. From the patient’s and

survivors’ perspective, it is essential that mechanisms be in place to ensure confidentiality. The

comprehensiveness of such safeguards could affect

the decision by patients and their families to donate

tissue. It has been proposed that some of these

impediments can be lessened by the creation of a

national registry of voluntarily preregistered, prediagnosed tissue donors (51). This would ensure that

tissue would be available from patients with a

recorded, comprehensive medical history.

In an effort to improve the acquisition process and

to better disseminate information about the availability of sources of brain tissue from various centers,

NIMH has created a task force to make recommendations on how to coordinate these efforts (24). A

number of suggestions are under consideration,

including using a private institution under contract

to NIMH as a clearinghouse for the collection and

distribution of brain tissue. An example of the type

of organization that could serve such a function is

the National Disease Research Interchange, a private, nonprofit foundation funded by NIH that is

involved with the procurement and distribution of

other organs and tissues for research purposes. The

NIMH task force is also identifying other needs

related to the collection of brains for research. These

include designing systems to address the problem of

the limited samples of tissue available from persons

with specific disorders, especially bipolar disorder,

and the pressing need for tissue from normal

individuals that can be used as experimental controls

(24).

Beyond the concerns raised by the handling and

distribution of tissue, other issues related to brain

donation play a significant role in availability. While

the specifics for donation may vary by locale, in

general, arrangements for donation of brain tissue, as

for all organs and tissues for transplantation and

research purposes, are made according to the guide-
140 . The Biology of Mental Disorders

lines provided by the Uniform Anatomical Gift Act

of 1987.13 That act prohibits compensation for such

donation. If a patient desires to donate tissue, he or

she can sign a document of gift, a legally valid

donation that is carried out upon his or her death.

Also, once an individual has died, the family has

authority to consent to donation. In some cases,

patients with mental disorders are not capable of

providing consent for donation (see earlier discussion of informed consent), and unlike the donation

of other organs, the stigma and negative attitudes

associated with mental disorders (see ch. 7) may

inhibit the willingness of individuals to donate.

Also, the severely mentally ill are often estranged

from their families, making it difficult to find family

members quickly to give permission for a brain

donation. Finally, there is a lack of awareness among

patients, their families, and the general public of the

acute need for brain tissue. The result is that patients

and their families often do not make arrangements

for donation of tissue that could be useful to

researchers. It has been proposed that increased

education of patients, their families, and the public

regarding the research community’s need for brain

tissue to study could enhance efforts to acquire brain

samples (24,25,52).

Even in cases where a donation has been arranged

by patient and family alike, retrieval of the tissue can

be difficult (25). Often it is difficult to make

arrangements to deliver the body to an appropriate

facility with a pathologist to collect the sample. The

increased costs and declining number of autopsies

present another obstacle. Even when an individual

dies in a setting that allows an autopsy, fewer of

these procedures are performed, and brain tissue is

rarely examined and collected for study. Another

factor contributing to this problem is the lack of

awareness among medical examiners of the need for

tissue samples for research into mental disorders.

In summary, a variety of factors contribute to the

shortage of brain tissue available for study. The

NIMH task force has been instituted to recommend

ways of enhancing the system for collecting and

distributing tissue and coordinating tissue handling

with the needs of researchers. The establishment of

a clearinghouse and a national registry for brain

donation are possible means of reaching these goals.

Institution of such a system will require that special

attention be paid to concerns about the privacy of

patients and families that participate. Other measures needed to increase tissue donation involve

educating the public and relevant medical personnel

to the acute need for such tissue. These education

efforts could be implemented by the Federal Government, patient advocacy groups, or professional

organizations. Finally, any efforts to decrease the

stigma and negative attitudes associated with mental

disorders could affect the willingness of patients and

their families to donate tissue.

Clinical Studies With Medication-Free Subjects

Studies using subjects who have mental disorders

and who are not taking medications are critical in

investigating the underlying biology of a disorder, in

establishing the effectiveness of new treatments, and

in addressing biological and psychosocial factors

leading to relapse. The medications used to treat

mental disorders have a variety of effects on

biological characteristics, particularly neurotransmitter systems in the brain. In order to study the

biological factors contributing to a disorder, it is

necessary to eliminate the potentially confounding

effects of drug treatment. Drug effects can last for

varying periods, depending upon the specific measure of interest; they may persist for weeks, months,

or years following discontinuation of use (10,20). As

a result, there may be a need to study not only

medication-free patients, but in some situations

patients who have never been treated with drugs.

There are several obstacles to identifying and

recruiting patients who have never received any

prior treatment. Persons experiencing the onset of

the more severe mental disorders, such as schizophrenia or bipolar disorder, are frequently hospitalized during a crisis and may be admitted first

through an emergency room or taken to a municipal

hospital. In most cases, some treatment will be

administered immediately, and it may be 24 to 48

hours before the patient is admitted to a ward where

clinical research might be taking place. If a system

is in place to do so, such individuals can be identified

by the first treatment contact and referred immediately to the research team. There are relatively few

municipal hospitals where such systems are in place.

Often patients, particularly those with private insur13 me U&om ~tofic~ Gift Act (TJAGA) WM first drtited in 1968 by the National Conference of Commissioners on UnifOrm State Lttws. It

addresses the domtion and receipt of human cadavers or parts of cadavers for research, educatio% therapy, or transplantation. The UAGA was updated

in 1987 (47).
Chapter Research Effort and Issues ● 141

ance, are admitted to a private hospital or a

psychiatric unit in a general hospital. Like municipal

hospitals, few of these hospitals have clinical

research programs in place.

In those settings where there is an ongoing

research program, a patient will be referred to a

research team before treatment is administered,

although it can still be difficult to recruit patients

into clinical research during the initial stages of the

illness. Withholding treatment or using an experimental treatment cannot be done without the informed consent of the patient (see earlier discussion). It is especially important that the patient

understand the possible risks associated with these

experimental protocols. A potential personal sacrifice is often involved, even for those patients who

are willing and able to give informed consent. A

drug-free interval may mean the prolongation or

reappearance of a psychotic episode, depression, or

anxiety state. Also, depending on the experiment,

participating in a research protocol may mean taking

an experimental drug or placebo when a known

effective treatment is available. This would require

either altruism or dissatisfaction with prior treatment

on the part of the patient. In most trials involving

new drug development, the investigator makes a

commitment to provide alternative standard treatment if the patient does not improve during the

course of the trial as a result of being on the placebo

or an experimental compound. As with other types

of research, the IRB must review experimental

protocols to ensure that prospective subjects are

informed of all contingencies and that informed

consent is obtained.

If investigators wish to study patients who have

been previously treated, the patients may need a

lengthy drug washout. This can be a considerable

challenge. Managing patients without medication

for many days or weeks can be difficult, often

requiring hospitalization and close monitoring by

hospital personnel. Moreover, it is difficult to justify

inpatient care for insurance reimbursement purposes

if it is not standard treatment. Further complicating

many cases, it is often unclear how long a washout

is necessary to eliminate the undesirable drug effect,

because the research needed to establish this has not

been conducted.

As a result of these factors, the cost of care during

a drug washout or clinical study can be an important

obstacle to the conduct of research. The cost of each

hospital day can range from $300 to over $1,000;

thus a 2-week washout or a 6-week experimental

drug trial can result in a significant number of

unreimbursed bed days. Assuming a daily bed cost

of $400, supporting one such bed for an entire year

would require $146,000. In regard to Federal support

for these expenses, bed costs can be included in the

funding available to the Clinical Research Centers

supported by NIMH. Few center directors choose to

use funds in this fashion, however, since this would

divert an enormous proportion of their total funding

from other priorities (28). This contrasts with NIH’s

General Clinical Research Centers Program, which

includes specific provisions for bed costs (39). In the

recent past, the pharmaceutical industry has recognized the obstacle created by bed costs and some

companies have provided support. It is difficult at

present to document either the extent of such support

or the overall impact that it is having on research.

There are several other reasons why patients may

need to be hospitalized. In many cases it may be

important to monitor or control diet, use of alcohol,

nicotine, activity levels, and use of over-the-counter

medication to eliminate variables that might influence measures of interest. In addition, to study

biological factors in one disorder, it is frequently

necessary to have a control group of either normal

subjects or individuals with a different condition.

Recruiting and assessing such reference groups

under similarly controlled conditions is facilitated in

an inpatient setting.

Thus, a number of obstacles hamper clinical

studies of medication-free patients or patients who

have never been on medication. However, the

importance of such studies for understanding the

biology of mental disorders and developing treatments for them requires that these obstacles be

overcome. High inpatient costs and the costs and

other problems associated with drug washout periods are substantial obstacles to these studies. Reevaluation of the funding mechanisms to support these

studies is an important initiative to address these

obstacles. Developing systems to promote the identification and recruitment of appropriate patients is

another action that could facilitate these studies.

Training of Clinician-Researchers

As previously discussed, research into the biology

of mental disorders relies heavily on clinical research. Carrying out this research requires the skills
142 ● The Biology of Mental Disorders

of many different professionals, including neuroscientist (usually individuals with a Ph.D. in

neuroscience or other disciplines such as physiology, anatomy, psychology, biochemistry), physicians (M.D.s), and clinical psychologists (persons

with a Ph.D. in clinical psychology). Often, in order

to bring these diverse skills to a research project,

studies are conducted as collaborations among

teams of researchers. Given the importance of

experimental protocols that use patients, it is not

surprising that there is a significant role for individuals who are trained as both clinicians and researchers. However, while the number of neuroscientist

has increased in the last 20 years (see ch. 2), many

experts and organizations have expressed concern

about the shortage of clinician-researchers in the

United States engaged in mental disorders research

(2,3,5,9,19,35,52, 53). The training to be a clinician

is different from that needed to be a researcher, and

often the two are separated in the fields of psychology and psychiatry. The result is that clinically

trained professionals (e.g., psychiatrists, clinical

psychologists) may not be trained to do research

(52).

Concerns within the medical community about

the lack of clinical researchers are not confined to the

field of psychiatry. A 1990 report from the Institute

of Medicine noted an apparent decline in the overall

number of clinician-researchers, as indicated by a 15

percent decrease in the number of physicians applying for grants for the first time to NIH between 1965

and 1985 and a slight decrease in the number of

physicians reporting research activity between 1983

and 1986 (18). The added burden of conducting

research, coupled with the reduced financial incentives associated with many research positions compared to private practice, lead some young physicians to opt for a career of clinical practice. In the

field of psychiatry, there are additional factors that

contribute to this situation.

Traditionally, there has not been a strong emphasis on research in psychiatry (9). This can be seen in

the results of recent surveys examining research

activities in departments of psychiatry across the

United States (32,37). For example, in one survey,

only 26 percent of psychiatry faculty members with

an M.D. degree spent at least 20 percent of their time

in research-related activities (37). The authors of

that survey compared their results to those of a

survey of internal medicine departments, which

found that 42 percent of M.D. faculty members had

a similar level of involvement in research. Another

measure of the low level of research activity in

psychiatry departments is the percentage of departments with ongoing research. This same survey of

psychiatry departments indicated that 50 percent of

the faculty conducting research are located at 13

percent of the schools (37). This concentration of

researchers within a few departments of psychiatry

coincides with earlier data showing that in 1983,77

percent of all grants awarded by NIMH went to 10

percent of psychiatry departments (9).

An important factor associated with research

activity is exposure to research and research training

during clinical training (32,35,37). One survey

found that 67 percent of researchers, compared to 36

percent of nonresearchers, had a medical school

background that included research experience (37).

Similar results were obtained in another survey,

which found that among faculty members who were

not exposed to research training in medical school,

26 percent did not go on to conduct research,

whereas only 9 percent of those who had medical

school research training never engaged in research

(32). The association of postdoctoral research training with current research activity is even more

striking, with 63 percent of active researchers having

had such training, compared to 11 percent of

nonresearchers (37). These results indicate the

importance of research experience and training in

determining future research activities. The lack of

research activity in psychiatry departments results in

an environment in which students have little or no

opportunity to observe and experience ongoing

research.

Some suggestions, such as developing and expanding opportunities for medical students to be

involved in an intensive research experience, have

been made to enhance recruitment of clinicianresearchers (2,35). Other suggestions include requiring all resident physicians to receive some experience in planning or conducting empirical research

and establishing a formal research track for psychiatry residents who are interested in research careers.

The willingness of medical specialties to accommodate students doing research during their residencies

varies. The National Advisory Mental Health Council has observed that psychiatry is a specialty in

which more can be done to encourage exposure to

research during residency (52). Also, the importance

of established researchers as mentors to students has

been noted (2,9,19,32,35,52). Reinforcing this is the
Chapter 6-Research Effort and Issues . 143

observation that many of the skills required of a

clinician-researcher are not easily taught through a

standard curriculum (9). The presence of an experienced individual who can serve as a teacher and role

model to a young person early in his or her

professional education has been cited as a significant

factor in the development of many research careers

(2,9,19,32,35,52,).

Within psychology, there is a distinction between

clinical and nonclinical psychologists. Nonclinical

psychologists have research training in fields that

can contribute to the study of the biology of mental

disorders. These individuals have skills that are

distinct from those of clinical psychologists and for

which clinical researchers’ skills cannot substitute.

Thus, the concern about research training for clinical

psychologists includes the need for individuals who

can complement them in nonclinical areas of investigation.

It has been estimated that over half of all clinical

psychology students do not pursue research careers

(40). There are several factors that contribute to this

(27). In general, the accreditation requirements for

programs that award a Ph.D. in clinical psychology,

while including research requirements, emphasize

clinical practice. Also, the trend among students in

recent years has been toward clinical practice instead

of research. As with M.D.s, part of the reason for this

is the disparity between the financial incentives

available to practicing clinicians and research clinicians. Evidence of this trend is seen in the increasing

popularity of programs and specific professional

schools that award a doctor of psychology degree

(Psy.D.) rather than a doctor of philosophy. These

programs are practitioner-oriented and involve little,

if any, research training. Another factor that inhibits

the role of clinical psychologists in research is that

departments of psychology at universities are usually located within a college of liberal arts and do not

have ready access to patients with severe mental

disorders. As a result, many clinical psychologists

who are involved in research do not study biological

factors related to mental disorders (28).

Recently, NIMH convened a task force to make

specific recommendations about the recruitment of

investigators into clinical research careers (53).

According to the task force:

Many of these recommendations will not require

major new investments of funds, but reflect a

focusing and targeting of available resources. Others

require new funding approaches and mechanisms,

but these are achievable within the authorities of the

NIMH.

Several of the task force’s recommendations

relate to expanding research opportunities for students, residents, and junior faculty. These include:

●

●

●

●

Establishing research clerkships for medical

students in laboratories;

using summer workshops at research facilities

to expose residents and fellows to various

topics in the field;

Promoting and funding the development of

research curriculums as part of residency programs in psychiatry; and

Developing supplemental grants, to be awarded

to established principal investigators, to support a variety of student activities related to the

development of a research career.

The task force also recommended that research

career development information be organized and

distributed to predoctoral and postdoctoral students,

psychiatry residents, and junior faculty members. It

was suggested that this information could best be

disseminated through professional societies that

have large student memberships, such as the American Psychological Association, the American Psychological Society, and the American Psychiatric

Association.

The principal source of Federal funding for

clinician-researcher training related to psychology

and psychiatry is NIMH. Funding for clinicianresearcher training comes from two sources within

NIMH that support research training in general.

National Research Service Awards (NRSA) are

training awards funded by the research training

budget of NIMH (see earlier discussion). Since

1986, the research training budget of NIMH has

experienced an average annual real rate of increase

of 5 percent (figure 6-l). However, when adjusted

for inflation, the 1991 budget of $26.9 million is

$23.6 million-$2 million less than the 1980 budget.

Thus, the recent period of growth in funding has not

compensated for an earlier period of decline. In

addition to the NRSA training awards, non-NRSA

awards, which are funded through NIMH research

funds, also support research training.

There are a number of NRSA and non-NRSA

training mechanisms (49). Three programs specifically support the training of clinician-researchers
144 . The Biology of Mental Disorders

(28), two of which are non-NRSA awards. The

Academic Award program is for clinicians (i.e.,

clinical psychologists, physicians, nurses, social

workers) who would like to conduct research as well

as maintain a clinical practice. This support is

awarded to an individual for 5 years. In fiscal year

1991 the program supported 21 persons, half of them

psychiatrists and half clinical psychologists, with

$2.2 million. The Scientist Development Award for

Clinicians is for clinicians who want to become

full-time researchers. Funding for this program was

$2.0 million in fiscal 1991, supporting 20 individuals. Finally, the NRSA M.D.-Ph.D. Predoctora1

Fellowship program provides tuition and a stipend

for persons to complete all the requirements for

obtaining both degrees. NIMH funded 15 such

students in fiscal 1991 with total funding of $349,000.

In addition to these specific awards, there are

other general research training programs. These

include other non-NRSA awards such as the Scientist Development Award, the Level 2 Research

Scientist Development Award, the First Independent

Research Scientist Trainee (FIRST) Awards, and the

other grants that make up the NRSAs. Other NRSA

grants include awards to institutions to support

training (e.g., Institutional Research Training

Grants) and awards to individuals (e.g., individual

fellowships and Minority Access to Research Career

Awards). Any of these programs can fund the

training of clinician-researchers. For example, of the

137 FIRST awards made in 1990 by NIMH, 40 (29

percent) supported physician-investigators (28), while

of the 996 NRSA awards given in 1985, 70 (7

percent) went to physicians (37).

A dearth of psychiatric clinician-researchers is

also evident in the VA system (4). As with NIMH,

the VA maintains a career development program to

provide training for researchers. In the period from

1987 to 1990, 11 out of 297 awards went to

psychiatrists. As in other settings, a major obstacle

to recruiting and retaining clinician-researchers in

the VA system is the inability to compete with

salaries offered in private practice. In an effort to

resolve this problem to some extent, Congress

passed legislation in April 1991 authorizing “special pay’ increases for VA physicians based on

length of service, whether they work in medical

specialties facing extraordinary difficulties or in

geographic areas with special needs (4).

In Sum mary> here is concern about the lack of

emphasis placed on the training of clinicianresearchers in the field of mental disorders research.

As a result, there is a need for strategies to increase

the recruitment of qualified individuals into research

training programs. Integral to this effort will be

enhancing the incentives to pursue a research career,

increasing financial support for training programs,

and modifying attitudes within the psychiatric and

psychological communities regarding clinical and

research training. While there is clearly a role for

Federal institutions in this endeavor, the NIMH task

force highlighted the crucial role that academic

institutions, particularly departments of psychiatry,

must play in fostering a supportive environment for

research training.

SUMMARY AND CONCLUSIONS

The pace of research into understanding the

biological factors that contribute to mental disorders

is determined by the level of financial support it

receives and the environment in which it is conducted. In the past, underfunding and lack of a

supportive environment have impeded progress in

this research. Actions to counter some of these

trends have been taken in recent years, although

impediments do still exist.

Analysis of the funding of NIMH reveals that a

trend toward underfunding has been reversed over

the past decade. In particular, the last 5 years have

seen a steady increase in allocations to NIMH. The

distribution of these funds indicates that research

into understanding biological factors related to

mental disorders is a high priority. Another priority

is research furthering the understanding of the severe

disorders considered in this report. These areas of

research emphasis, coupled with the support of basic

neuroscience research at a number of Federal

institutions, hold out the promise that during the next

decade there will be a significant increase in the

understanding of the role biological factors play in

severe mental disorders.

While some of the financial constraints that have

hampered this research in the past have eased, there

are still issues which need to be addressed to ensure

that the promise of increased funding can be

realized. OTA identified a number of issues that can

impede progress in this field, including the ability to

use animals to study mental disorders, issues related

to the study of clinical populations, and the training
Chapter 6-Research Effort and Issues ● 145

of clinician-researchers. Some of these overlap with

other areas of research, but all are especially relevant

to the study of the biology of mental disorders. The

unique nature of trying to understand the human

mind, coupled with the traditional character of

public attitudes toward mental disorders, makes

these issues particularly pertinent to this area of

research.

Overcoming the impediments posed by these

issues will create a more supportive environment for

research. Doing so will require action by professional and consumer organizations, changes in

policy of Federal agencies, and initiatives spurred by

congressional action. On the one hand, the issue of

using animals to model mental disorders is a

scientific one and is best addressed by continued

support of research. On the other hand, policy

decisions regarding the broader controversy surrounding the use of animals in biomedical research

will also have an impact on this research. The issues

associated with the study of clinical populations,

such as increasing tissue resources and facilitating

the conduct of these studies, are related to individuals’ attitudes and awareness about what is required

to conduct this research. Impediments can be lessened by educating the public, patients and families,

and medical personnel to the needs of the research

community and by decreasing the stigmatizing

attitudes that can hamper the willingness of individuals to participate in research. Impediments associated with the banking of tissues and the conduct of

studies with medication-free patients can be lessened by enhancing the resources for, and support of,

these enterprises. Increasing the number of clinicianresearchers will require an adjustment in the emphasis placed on research training within professional

and academic institutions, as well as the support of

programs to carry out this training.

Actions have been taken to address some of these

issues. As a result of congressional initiatives,

policies have been instituted within PHS regarding

the inclusion of special populations in clinical

research. Also, NIMH has convened task forces on

increasing the collection and banking of brain tissue

and the training of clinician-researchers. While these

initial steps will enhance the research environment,

additional efforts are needed. For example, education programs for increasing public and patient

awareness need to be enhanced, and specific concerns, such as the costs of clinical research and

stimulating interest among clinicians in conducting

research, still need to be addressed. These will

require the implementation of additional programs

and policies by NIMH. The role of Congress in this

effort is to specify issues that could be better

addressed by these agencies and to facilitate their

ability to respond to them.

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Chapter 7

Public Attitudes and Policy
CONTENTS

Page

PUBLIC ATTITUDES TOWARD MENTAL DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . 151

THE IMPACT OF BIOLOGICAL RESEARCH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

Perceptions of Responsibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

The Link Between Mental Disorders and Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

CHAPTER 7 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

Boxes

Box Page

7-A. The Barriers Erected by Stigma: A Patient’s Perspective . . . . . . . . . . . . . . . . . . . . . . . 151

7-B. Educating the Public About Depression . . . . . . . . . . . . . . . ..*...,* . . . . . . . . ....**.* 154

7-C. Americans With Disabilities Act: Employing People With Mental Disorders . . . . . 157

7-D. Media Portrayals of Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

Figure

Figure Page

7-1. Level of Comfort With People With Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . 152

Table

Table Page

7-l. DEPRESSION Awareness, Recognition, and Treatment Program,

Fiscal Years 1986-91 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Chapter 7

Public Attitudes and Policy

Researchers have partially uncovered the biological substrates of the mental disorders considered in

this report and have propounded testable hypotheses

as to causation. These scientific advances portend

increased research opportunities as well as the

development of improved treatments. But as is true

for science in general, this research interacts with

broad social and political factors (56,58). Support—

or lack thereof-reflects social attitudes and the

efforts of advocacy groups. The results of biomedical research also affect society. Improved understanding of the cause of a disorder can influence the

public’s response to individuals with a particular

disorder as well as the direction of public policy.

This chapter attempts to tease out some of the

social effecters of biological research into mental

disorders and some of the implications of data

arising from these studies. What factors have led to

enthusiasm for biological research into mental

disorders? What are the limitations of this approach?

How might information about the biology of mental

disorders influence public attitudes and policy? The

chapter begins with a general description of public

attitudes toward mental disorders.

PUBLIC ATTITUDES

TOWARD MENTAL DISORDERS

Mental disorders incur stigma, “a mark of disgrace or reproach” (72) (box 7-A). Surveys of 30

and more years ago showed that ‘the mentally ill are

regarded with fear, distrust, and dislike by the

general public” (41) and that persons labeled as

mental patients tended to be stigmatized and

shunned (51). And negative attitudes toward and

ignorance of these disorders still abound (33). A

sizable number of people continue to be tightened

by the notion of mental illness and believe that

others are frightened also, although it is becoming

less socially acceptable to say so (50). A recent

survey conducted for the National Organization on

Disability (40) found that only a minority of persons

polled (19 percent) felt very comfortable with a

person with a mental disorder (figure 7-1).1 Despite

gains in knowledge about specific disorders and

Box 7-A—The Barriers Erected by Stigma: A Patient’s Perspective

We had met under the most unusual circumstances, in a place we came to call “The Funny Farm. . . .“ We

were initiated into a stigmatizing sorority. . . .

[Having] experienced the problems and barriers that lie before us in “normal” society. . . the scene has been

repeated in many different settings: a supervisor who viewed my work and abilities as outstanding and my rate of

productivity as very high before my illness, but who recommended disability retirement when I was depressed and

less productive; a university that graduated me with high honors, admitted me into its graduate program with

outstanding recommendations, and then sent me a form letter in response to my request for readmission (following

my illness) saying, “You do not meet our admission requirements;’ and community mental health agencies that

rejected my offers to be of assistance because I ‘‘scared’ mental health professionals. . . .

The literature says little about us individually. Most researchers group us, thereby reinforcing the stigma. Some

lay odds on our recovery and predict high rates of suicide. Some experiment with us, offering convincing evidence

that we can be trained-rehabilitated. Others raise ethical concerns about studying us, but justify their actions by

noting that useful data can be obtained by following us. Some have tried to document that public attitudes toward

the mentally ill have changed.

If my own research and experiences are representative, public attitudes have not changed. From my

perspective, researchers continue to define stigma with statistics. Physicians continue to locate emotional pain

points with questions. Families continue to treat mental illness as a silent, shameful disease. Clergymen continue

to preach that mental illness is the result of satanic influence. The barriers remain. They are real. . . .

SOURCE: Anonymous, Schizophrenia Bulletin 6:544-546, 1980.

1 The survey included a random sample of 1,257 people interviewed by telephone between May 15 and June 18, 1991. The estimated margin of error

was * 3 percent.

–151–
152 . The Biology of Mental Disorders

70%

60%

50%

40%

30%

20%

10%

0%

Figure 7-l—Level of Comfort With People

With Mental Disorders

Very comfortable

47%

39%

Blind Deaf In a Mentally Mentally

wheelchair retarded ill

A survey conducted by Louis Harris & Associates, Inc., for the

National Organization on Disability indicated that of all the

disabilities asked about, people felt least comfortable with people

with mental illness.

SOURCE: Adapted from National Organization on Disability, “Public

Attitudes Toward People With Disabilities,” survey conducted by

Louis Harris and Associates, Inc., 1991.

their treatment, considerable ignorance about mental

disorders persists: For instance, 64 percent of

college freshmen thought schizophrenia referred to

multiple personalities (68). Data from research also

have indicated that some providers of mental health

care are themselves inadequately informed as to the

diagnosis and treatment of mental disorders (for

example, see 44,61,73).

While widespread and incontrovertible, the stigma

attached to mental disorders is a difficult concept to

define. Many stress the deliberate nature of stigma:

Stigma refers to the process by which people who

lack certain traits denigrate people who possess

them, and it leads to individual differences in social

interaction, prejudice, and discrimination (62).

Clearly, ignorance about mental disorders—their

symptoms, treatability, or causes-can serve as a

fertile breeding ground for negative attitudes. However, a lack of knowledge about mental disorders

cannot explain all of the stigma that exists. For

example, a 1990 national survey2 of public attitudes

toward people with chronic mental illness found

Credit: Copyright Bill Lee. Reprinted with permission.

This cartoon, provided by O. Wahl, illustrates the commonly

held misperception that schizophrenia is multiple personalities.

widespread evidence of the “not in my backyard”

phenomenon, expressed as resistance to treatment

and housing facilities in the community, with the

incidence of opposition increasing with income and

educational level (55). Even mental health care

providers sometimes harbor negative attitudes toward individuals with mental disorders, especially

those with severe and persistent conditions (8). In

1987, the American Psychiatric Association Task

Force on the Chronic Mental Patient determined that

among professionals such as ourselves, and among

paraprofessionals, there are prevailing attitudes—

that working with [chronic] patients is unrewarding

and dull, and that . . . prestige is not available for

working in [chronic patient] programs (34).

While stigma is attached to many serious medical

conditions, people with mental disorders are subject

to much more rejection: Public attitudes toward

mental disorders are more akin to those directed at

drug addiction, prostitution, and ex-convict status

 of Americans representative of the total population of adults 21 older. four focus

groups, two in Pennsylvania and two in Ohio, were conducted, as well as in-depth telephone interviews with 17 mental health opinion leaders.
Chapter 7Public Attitudes and Policy . 153

than cancer, diabetes, and heart disease (2,33). The

stigma reflects-in part-the fear or uneasiness

evoked by individuals who display unusual or

threatening behavior. Results from studies suggest

that a sizable portion of the public harbors the belief

that mental disorders are linked to violent behavior

(35). As might be expected, the belief that people

with mental disorders are more prone to violent acts

leads to a strong rejection of people afflicted with

these conditions (32).

The stigma attached to mental disorders, with all

its variable expressions and sources, has important

social implications. Afflicted individuals and their

families suffer acutely from the stigma attached to

mental disorders (28,7 1). Many family members feel

uncomfortable talking about their problem and may

feel responsible and isolated as a result (13, 29, 71).

Ignorance and negative attitudes also interfere with

successful treatment: Individuals with a mental

disorder may avoid seeking treatment to avoid the

associated stigma or simply because they are unaware of its availability. And as mentioned above,

providers themselves may be inadequately informed

about the recognition or treatment of mental disorders, or may harbor negative attitudes toward people

with these conditions (5, 9, 43, 73). Finally, data

show that people with mental disorders react in a

negative fashion, in the belief that other people view

them negatively (10, 31)

The stigma attached to and ignorance of mental

disorders is mirrored in the discrimination in the

financing of treatment, housing, employment, and

the funding of research, a topic considered in this

report. Previous studies (21, 49) and mental health

advocates (for example, see 17) have demonstrated

the underfunding of research into mental disorders

compared to their social cost, attributing the deficiency to the low priority assigned to these conditions by the public and policymakers. The Office of

Technology Assessment’s (OTA) analysis also shows

that, relative to their social costs, cancer and heart

disease research receive substantially more finding

than mental disorders research (see ch. 6). Thus,

while the 1980s did witness a significant increase in

Federal funding for research into mental disorders

and new private sources of funding, support for

research into mental disorders still fell short of that

for other conditions in relation to their cost to

society.

Credit: Courtesy of the American Psychiatric Association, 1992

A recent public education campaign, sponsored by the

American Psychiatric Association, highlighted the negative

impact of stigma on treatment-seeking.

Thus, the impact of stigma on public policy is

compelling and undeniable. This finding echoes the

results of a recent report by the Interagency Task

Force on Hopelessness and Severe Mental Illness

(20):

Stigmatization, fear, and mistrust regarding people with severe mental illnesses . . . are commonplace in our Nation. Such reactions influence both

the direct responses of community members to these

individuals as well as the development of local,

State, and Federal policies affecting them.

A conclusion that OTA draws from this analysis is

that the dissemination of accurate knowledgeabout

mental disorders—to the public at large, families,

consumers, care providers, and policymakers--is

essential to improving the lives of individuals with

mental disorders and fair and informed policymaking

(box 7-B).

The negative influence of stigma and ignorance

on public policy cannot be offered as a simple or

complete explanation for failures in public policy.

Attitudes toward mental disorders reflect the influence of a number of factors, ranging from beliefs

about the origin of mental disorders, fear of individuals who are thought to be violent, and media

portrayals. Furthermore, the way in which stigma

contributes to policy formation is difficult, if not

impossible, to distill precisely. The policy areas

affectedly negative public attitudes-research funding, treatment, housing, mental health care finance,

and employment—are not influenced by stigma

alone, but by other factors, such as the structure of

 n – – : 
154 . The Biology of Mental Disorders

Box 7-13-Educating the Public About Depression

Of the 15 million people who experience a major depressive disorder each year, four-fifths can be treated

successfully; yet, only one-third of them seek treatment. Even when people seek treatment, symptoms of a

depressive disorder are often unrecognized or inappropriately treated by health professionals. Given this level of

ignorance, as well as the negative attitudes that surround mental disorders, the Federal Government sponsored its

first major health education program about a specific mental disorder in 1986, with the initiation of the National

Institute of Mental Health’s (NIMH’s) DEPRESSION Awareness, Recognition and Treatment (D/ART) program.

The D/ART seeks to: 1) increase public knowledge of the symptoms of depressive disorders and the availability

of effective treatment, 2) change public attitudes about depression so that there is greater acceptance of depression

as a disorder rather than a weakness, 3) encourage changes in help-seeking behavior to reduce the number of

untreated and inappropriately treated individuals, and 4) provide information to primary care physicians, mental

health specialists, and medical students about advances in diagnosing and treating depressive disorders. The D/ART

program will extend over a decade and consists of three components: a professional training program, a public

education campaign, and a national worksite program.

For fiscal years 1986 to 1991, the D/ART program expended $4.5 million to train health professionals about

recent advances in diagnosis and treatment of depressive disorders (table 7-l). Short-term training courses,

developed for this purpose, have been used to train more than 11,000 primary care physicians, mental health

professionals, and medical students about depressive disorders. In addition, the D/ART program sponsors

continuing education programs in collaboration with professional associations.

In 1988, the D/ART program launched a two-part public education campaign consisting of a multimedia

component to publicize messages about depressive disorders and a community partnership program to extend and

reinforce the media messages at the local level. First, D/ART staff conducted 20 focus groups in nine geographically

dispersed cities and contracted for a survey of 500 people in two cities (Indianapolis, IN and Sacramento, CA) to

find out what people knew about depressive disorders. Furthermore, in the early stages of campaign development,

the D/ART program organized a group of 45 campaign consultant organizations to advise about public education

strategies. The group-comprised of representatives from the major mental health and medical professional

associations as well as health and mental health organizations, businesses, labor, religious, and educational groups,

mental health advocacy groups, foundations, and other Federal agencies-continues to provide advice on campaign

policy matters and to disseminate information on depression.

The D/ART Public Education Campaign has expended $3.6 million in the past 5 years (table 7-1) to develop

educational materials, For example, a total of 16 flyers, brochures, and booklets have been produced and distributed

to more than 13 million people, with some of the publications geared toward the general audience and some to

specific groups, such teenagers, college students, young African-Americans, and older people; some have been

published in Spanish and five Asian languages. Also, close to 1,000 television and 9,000 radio stations have

broadcast public service announcements (PSAS) about depression to as many as two-thirds of households

nationwide. A number of the initial PSAS featured celebrity spokespersons to introduce the campaign.

A critical component of the D/ART program is its community partnership strategy. The Community

Partnership Program consists of 32 mental health groups, mostly “Mental Health Association” and “Alliance for

the Mentally Ill” organizations, located in 24 States and the District of Columbia. Community partners reproduce

and distribute copies of print materials on depression; conduct public forums, worksite programs, and professional

Table 7-I—-DEPRESSION Awareness, Recognition, and Treatment Program, Fiscal Years 1986-91

($ thousands) Total

Area FY 86 FY 87 FY 88 FY 89 FY 90 FY 91 FY 86-91

Training . . . . . . . . . . . . . . . . . . . . . . . . 142 520 646 824 1,146 1,260 4,528

(53%)

Public education . . . . . . . . . . . . . . . 292 924 447 745 616 631 3,666

(43%)

Worksite . . . . . . . . . . . . . . . . . . . . .,, N/A N/A 50 50 100 100 300

(4%)

Total . . . . . . . . . . . . . . . . . . . . ,,.. 434 1,444 1,143 1,619 1,862 1,$81 8,483

SOURCE: 1. Davidoff, Director, D/ART Campaign, National Institute of Mental Health, Rockville, MD, personal communication, Feb. 28,1992.
Chapter 7-Public Attitudes and Policy . 155

seminars; develop videos; appear on television and radio talk shows; sponsor support groups and telephone hotlines,

and carry out other varied educational activities, including brochure translations in five Asian languages. In 1990,

the total dollar value of the programs that were offered and the partners’ direct and in-kind contributions was

estimated at nearly $1.3 million, about ten times the Federal investment in the Community Partnership Program.

D/ART also recently initiated a Professional Partnership program, through which depression-related community

education activities similar to those offered by Community Partners will be developed by universities, foundations,

and professional organizations.

In 1988, the D/ART program established a National Worksite Program as a collaborative effort between NIMH

and the Washington Business Group on Health, a nonprofit health policy group composed of Fortune 500

employers. To date, $300,000 has been expended on this program component. The purpose of the worksite initiative

is to assist employers in reducing the impact of depression on productivity, on health and disability costs, and on

employees and their families. The program disseminates information about depressive disorders to employers and

encourages corporate policies and programs that promote early recognition, quality cost-effective care, and

on-the-job support for individuals experiencing depressive illnesses. The program has developed a‘ ‘Management

of Depression” model program and published a report based on the experience of seven large U.S. companies that

contributed to development of the model. In 1992, the program will produce a training program for management

personnel and occupational health professionals to improve early recognition and referral to appropriate care for

depression.

preliminary data suggest that the D/ART program has had some positive effects. For example, prior to the

dissemination of any information, NIMH funded a 1987 telephone suvey by the University of Michigan Institute

of Social Research of 500 people (250 in Indianapolis, IN and 250 in Sacramento, CA) to determine the extent of

their knowledge about depression. The survey found that most people believed that depressed persons could get

better on their own rather than by seeking treatment. In 1990, the American Medical Association conducted a

followup survey of the same group of 500 people. A total of 210 of the original group responded; 40 percent of the

responders in Indianapolis and 25 percent of the responders in Sacramento said they knew more about depression

because of the D/ART campaign. AMA also surveyed a new group of 500 people (250 people from each of the two

cities). Of this group, 34 percent of those in Indianapolis and 30 percent of those in Sacramento said they were aware

of the D/ART campaign and its messages. Another survey in North Dakota found that the number of adults treated

for depressive disorders increased 1.5 times and the number of children treated increased 3 times in Human Service

Centers (akin to Community Mental Health Centers) for fiscal years 1986 to 1991. The increase was attributed in

part to the D/ART public and professional education programs and to a State program to develop treatment teams

specifically for children within the Human Service Centers.

Has the D/ART program been a success? While the limited data on the effectiveness of the D/ART program

preclude a quantitatively based answer to this question, several aspects of the program clearly deserve

commendation. With limited resources and personnel (the entire D/ART program is managed by one- and one-half

full-time Federal professional staff persons), the D/ART program established an educational campaign that is

solidly rooted in research advances; the D/ART program carefully devises the messages to be relayed, uses diverse

media to disseminate the messages, and coordinates its efforts with people in the community. D/ART has also

trained substantial numbers of health and mental health care providers through its own efforts and through

collaborations with public and private organizations. Advancement of this pioneering educational effort on a mental

disorder by the Federal Government-via further study of its effect on the level of awareness, prevalence and

treatment changes, expansion of the program into other communities, and adapting its techniques for educating the

public about other conditions—will require some combination of increased funds and personnel, as well as

highlighting this activity as a priority at the NIMH.

SOURCES: J.E. Barham, Mental Health Consultant personal communications May 4, 1992; R. Brown Senior Scientist Department of Mental

Health American Medical Association personal communication June 23, 1992; I. Davidoff, director, D/ART Campaign, National

Institute of Mental Health, Rockville, MD, personal communication, June 1992; R. Kessler,lnstitute for Social ResearchUniversity

of Michigan, personal communicatiorn, June 23, 1992; A. Koss, coordinator of State D/ART Program Division of Mental Health,

Department of Human Services, Bismark ND, personal communication% June 22, 1992; D.A. Regier, M.A. Hirschfeld, F.K.

Goodswin, et al., “The NIMH Depression A wariness, Recognition, and Treatment Program: Structure, Aims, and Scientific Basis,”

American Journal of Psychiatry 145:1351-1357, 1988; D. Regier, Director, Division of Clinical Research, National Institute of

Mental Health, personal communication May 1992; U.S. Department of Health and Human Services, Public Health Service,

Alcohol Drug Abuse and Mental Health Administration National Institute of Mental Health, Depression, Awareness, Recognition,

and Treatment (D/ART) Fact Sheet, DHHS Pub. No. (ADM) 90-1680 (Rockville, MD: U.S. DHHS, 1990).
156 . The Biology of Mental Disorders

service delivery, available treatments, economic

constraints, and existing laws. Thus, influencing

mental health policy requires not only dispelling the

myths and negative attributes surrounding mental

disorders but also paying attention to the other

factors that affect these issues. For example, efforts

to fight employment discrimination were focused on

the inclusion of individuals with mental disorders in

the recently passed Americans With Disabilities Act

(ADA) (box 7-C). It is hoped that the ADA will have

a profound effect on individuals with mental disorders by opening options in employment now unavailable to them.

THE IMPACT OF

BIOLOGICAL RESEARCH

The ongoing revolution in neuroscience has

invigorated research into mental disorders, leading

to new discoveries about and increased emphasis on

the biological underpinningof of these conditions.

This is not the first time that the biological component of mental disorders has been emphasized—

concepts of mental illness historically have been

cyclic in nature (15,16,59). Nor have previous hopes

concerning the curability or biological basis of

mental disorders always correlated with improved

public attitudes or care for those with these disorders. Current biological research into mental disorders is different from that done in previous eras,

however. It is set on the stage of what has been called

a new age of neuroscience (l).

The research that is possible, or is already taking

place, represents not just an extension of earlier

efforts but a qualitative change. From a base of

knowledge about the brain in general, neuroscience

is now making the first exploratory inroads into the

features that characterize us as humans: the ability to

create and to calculate, to empathize, to recall and

plan (Enoch Gordis quoted in 1).

General developments in brain research, complete

with rapid technological advances and the contribution of a host of scientific areas, distinguish current

biological research into mental disorders.

Most experts in the mental health field appreciate

the fact that biological factors play an important role

in the mental disorders considered in this report.

Furthermore, advocates who focus on the biological

Photo credit: M. Catherine Sargent, 1992

Developments in neuroscience have received increasing

attention, as illustrated in this exhibit of the American

Psychological Association at the Smithsonian Institution.

aspects of mental disorders are an increasing force,

joining and shaping the debate of policy issues. This

section considers some of the social impacts of the

biology of mental disorders—that is, how the gains

from neuroscience research and the perception that

mental disorders have a biological basis influence

public attitudes toward mental disorders and mental

health policy. The discussion is organized under two

broad titles: Perceptions of Responsibility and The

Link Between Mental Disorders and Medicine.

Perceptions of Responsibility

Despite the regular reemergence of biological

explanations for mental disorders since the classical

Greek period (48,57,59), these conditions have often

been perceived as a sign of moral weakness or the

manifestation of evil. The view that the antisocial,

irrational, withdrawn, or unpredictable behavior

sometimes produced by mental disorders stems from

moral turpitude persists to this day, even among

some medical researchers and caregivers (23). A key

finding of a 1991 survey of public attitudes by the

National Mental Health Association evidences these

social beliefs or judgments: 43 percent of American

adults see depression as a personal weakness (39).3

Also, a 1988 survey by the Utah Division of Mental

Health and the Alliance for the Mentally Ill found

that 71 percent of respondents thought severe mental

 Association is on a nationwide telephone interview of 1,022 adults age older conducted 

October 18 and 23, 1991.
Chapter 7--Public Attitudes and Policy ● 157

Box 7-C—Americans With Disabilities Act: Employing People With Mental Disorders

The Americans With Disabilities Act of 1990 (ADA), which received the President’s signature on July 26,

1990, is the most expansive civil rights legislation passed since the 1964 Civil Rights Act. Under the ADA, the

estimated 43 million Americans with disabilities, including those with mental disorders, will be afforded protections

from discrimination similar to those prohibiting discrimination based on race, sex, national origin, and religious

affiliation. Equality of opportunity and protection from discrimin ation for individuals with disabilities is guaranteed

in the areas of employment (Title I), public transportation and other State and local government services (Title II),

public accommodations (Title III), and telecommunications (Title IV).

The ADA definition of a person with a disability applies to individuals meeting one of the following criteria:

1) having a physical or mental impairment that substantially limits one or more of the person’s major life activities;

2) having a record of such an impairment; or 3) being regarded as having such an impairment. While the law refrains

from delineating specific disabilities, it does define “major life activities”: caring for oneself, performing manual

tasks, walking, seeing, hearing, speaking, breathing, learning, and working. Thus, the act applies only to mental

disorders that are severe enough to significantly affect a major life activity. Also, the law affords protection from

disc rumination based on health or treatment history to persons who have recovered from a physical or mental illness

or have at some point been inappropriately diagnosed or misclassified as having a mental or physical disorder.

Finally, the ADA directly addresses the negative impacts of the stigma associated with mental disorders, since it

protects individuals from being denied employment on the basis of negative attitudes and misperceptions

concerning mental disorders in the absence of a legitimate, job-related reason.

While the ADA covers almost every aspect of life in which people with disabilities might encounter

discrimination, the employment provisions are likely to have the most profound impact on the lives of individuals

with mental disorders. Title I of the ADA prohibits discrimination

. . . against a qualified individual with advisability. . . in regard to job application procedures, the hiring, advancement,

or discharge of employees, employee compensation, job training, and other terms, conditions, and privileges of

employment.

Title I requires employers to provide reasonable accommodation to qualified employees, including physical

modifications in order to make existing facilities used by employees readily accessible to and usable by individuals

with disabilities. Alternatively, it may require nonphysical adjustments including job restructuring, part-time or

modified work schedules, and other such modifications. Such nonphysical modifications may be especially

important for people with mental disorders. Employers are required to make reasonable accommodations unless it

can be demonstrated that the accommodation would impose an undue hardship on the operation of the business.

This safeguards the viability of businesses and organizations by protecting employers from incurring unreasonable

burden in the provision of needed accommodations. Such a burden may include the disruption of business as well

as excessive financial expense.

Ironically, while the provisions of the ADA may serve to combat the stigma of mental disorders, they may also

raise the specter of stigma--because coverage under ADA is dependent upon disclosure of disability. Persons with

“hidden disabilities’ ’-those not apparent to an observer, such as mental disorders-are covered only if the

disability is revealed Individuals with a severe mental disorder or a history of mental disorder are often reluctant

to disclose their disability, and the provisions of the ADA preclude preemployment inquiry into mental health

history; however, employers are required to make reasonable accommodations only if the disability is known.

While this landmark act has the potential to benefit individuals with mental disorders greatly, hurdles remain

in the ADA’s implementation phase. Certain issues have yet to be resolved, including the determination of who

exactly is covered the precise definition of reasonable accommodation for individuals with mental disorders, the

provision of an adequate definition of the role of medication in reasonable accommodation for individuals with

mental disorders, and the promulgation of such information to both covered individuals and employers.

SOURCES: Americans With Disabilities Act of 1990, Public Law No. 101-336, 1990; House Report No. 101=$85, Pt. 1 (Committee on Public

Works and Transportation), Pt. 2 (Commi ttee on Education and Labor), Pt. 3 (Committee on the Judiciary), and Pt. 4 (Committee

on Energy and Commerce), all accompanying H.R. 2273; LL. Mancuso, ‘‘Reasonable Accommodation for Workers With

Psychiatric Disabilities, ” Psychosocial Rehabilitation Journal 14(2):3-19, 1990; LL. Mancuso, Director, Path project, National

Association of State Mental Health Directors, Alexandria, VA personal communication, Feb. 21, 1992; National Mental Health

Association ADA.: Americans With Disabilities Act of 1990 (Public Law 101-336), 1991; L.J. Scallet and C.F. Rohrer, Analysis:

Americans With Disabilities Act and Mental Health (Washington DC: Policy Resource Center, 1990).

329=309 O - 92 - 7 : QL3
158 ● The Biology of Mental Disorders

illness was due to emotional weakness, 65 percent

thought bad parenting was to blame, 35 percent cited

sinful behavior, and 45 percent believed that the

mentally ill bring on their illness and could will it

away if they wished (67). These beliefs have

contributed to the public condemnation of unusual

or frightening behavior produced by mental disorders, as well as to the shame and guilt experienced

by patients and their families.

A biological explanation of the unusual, erratic, or

tightening behavior sometimes associated with

mental disorders challenges the notion of moral

turpitude directly. When atypical behavior is attributed to biological factors, an individual with a

mental disorder is less likely to be perceived as the

perpetrator of immoral actions than as the victim of

forces beyond his or her control. Thus, a biological

understanding of severe mental disorders may remove the blame for antisocial or atypical behavior

from a person with the disorder.

While biological explanations may absolve individuals of some of the blame for their illness, such

theories are not always associated with more benevolent treatment by society. Biological theories have

led to abuses in the past, such as eugenic practices

(see ch. 5). And other theories as to the origin of

mental disorders—such as early childhood experiences—have been used to exculpate individuals

from responsibility for their behavior. Furthermore,

biological explanations may not be sufficient to

overcome society’s fear of violent or very bizarre

individuals with mental disorders or the stereotype

of the ‘‘berserk madman. ’ The media spotlight on

a hideous crime committed by an ‘‘ex-mental

patient” reinforces the link in the public’s mind

between mental disorders and violence (box 7-D)4

Attributing behavior to biological, and especially

genetic, factors may lead to the perception that

human actions are predetermined. Biological explanations of behavior encroach uncomfortably on our

sense of free will and moral agency (11).

[M]ost of us aren’t comfortable with genetic

explanations for our own or anyone else’s behavior.

We are proud of our freedom, individuality, and

powers of self-determination (53).

American psychologist and philosopher William

James struggled with this dilemma more than 100

years ago. James felt that our sense of self, needed

to lend meaning to our existence, maybe incompatible with the necessary assumption of psychology

and neuroscience that the “prediction of all things

without exception (including human behavior) must

be . . . possible” (quoted in 11). Thus, neuroscience’s exploration of the human brain challenges the

way in which we think about the mind in general.

Individuals with mental disorders may be especially vulnerable when society is seduced by notions

of biological reductionism and determinism. These

notions can cause individuals with mental disorders

to feel dehumanized, with less control over their

minds. Insensitively labeling the way a person feels,

thinks, or behaves as diseased can diminish his or her

sense of “personhood” (36,60), as revealed in the

following passage (37):

I have discussed the diagnostic label ‘schizophrenia’ with a number of patients. Interestingly, they

often say that they do not mind the label itself, but it

is the inaccurate attributions made to them because

of it that they find objectionable. They know quite

well when they are manifestly schizophrenic. They

know it from their personal phenomenology at a

point in time. They object to being seen as schizophrenic when they are not; they object to being

treated as dependent children when it is not necessay; they object to having to lie to obtain work for

which they are qualified; and they object to their not

being listened to and taken seriously because they

are, after all, ‘schizophrenic. ’

The extent to which persons are responsible for

their actions-even if there is a biological underpinning—is far from resolved; it requires the consideration of social, philosophical, legal, and moral

issues that are beyond the scope of this report.

However, it is important to debunk the myth that

modern neuroscience necessarily leads us to conclusions of biological reductionism and determinism.

Recent advances in neuroscience do not suggest that

our brains are biologically fixed or immutable;

rather, results increasingly show the dynamic nature

of nervous tissue and its responsiveness to environmental cues throughout life. And as Owen Flanagan

d-e most individ~s with a severe men~ disorder are not violen~ the questio~ “Are mental disorders linked to violence?” k Zi COmpkX One.

A psychotic episode can lead to a violent act. However, the relationship between mental disorders and violent acts is a complex one, being influenced

by various factors, among other things the nature of the disorder, the availability of adequate treatmen~ and the law (35).
Chapter 7--Public Attitudes and Policy ● 159

BOX 7-D—Media Portrayals of Mental Disorders

Since the late 1950s and early 1960s, studies have consistently revealed a high incidence of media attention

to mental disorders. While media attention contributed significantly to the end of mass warehousing of patients,

often in cruel conditions, much of the information it provided about mental disorders was negative and inaccurate.

Recent studies have shown that although there has been an increase in the frequency of portrayals of individuals

with mental disorders, there has not necessarily been an increase in the accuracy of such portrayals. Surveys of

images of mental disorders on prime-time television conducted in the 1980s found that between 17 and 29 percent

of the shows had some portrayal of mental disorders. Unfortunately, much of that information concerning mental

disorders is inaccurate and stigmatizing.

One of the most persistent and damaging inaccuracies conveyed by the media is the characterization of

individuals with severe mental disorders as violent despite the fact that individuals with severe mental disorders are

more likely to be withdrawn and frightened than violent and are more frequently victims than perpetrators of violent

acts. Violence occurs on television at the rate of approximately six incidents per hour in prime time and 25 incidents

per hour in children’s daytime programming; a disproportionate number of these occurrences are either perpetuated

by or against individuals identified as mentally disordered. In fact, characters labeled mentally disordered in

television dramas are almost twice as likely as other characters to kill or be killed, to be violent or fall victim to

violence. Efforts to combat this image are confounded by the fact that some individuals with mental

disorders-particularly when untreated-are at risk of committing violent acts against themselves or others, or both.

Perhaps more troubling is the fact that the stigmatizing equation of severe mental disorder with violence is not

limited to fictional entertainment media News stories and headlines identifying violent criminals on the basis of

their mental health history, such as the recent Associated Press headline “Woman Who Shot at Restaurant

Previously Committed to Mental Hospital,” saturate the news media, while stories of successful recovery are rare.

Such news stories are damaging to individuals with mental disorders because they suggest both an inescapable

connection between mental disorders and violence and the incurability of mental disorder (that is, even former,

treated mental patients remain prone to violence).

Do these inaccurate and negative depictions of individuals with mental disorders adversely affect public

attitudes? Research has shown that television is able to influence viewers’ attitudes in subtle ways, through the

repetition of images not necessarily labeled as factual. Knowledge specifically concerning the impact of media

depictions of mental disorders on public opinions is limited. Some studies have revealed that programming intended

to increase knowledge of and improve attitudes toward individuals with mental disorders has a positive impact.

However, data indicate that the damaging effects of negative portrayals overwhelm the benefits of the media’s

positive efforts. Negative mass media portrayals of persons with mental disorders generate negative attitudes among

viewers, and corrective information, or disclaimers, has been shown to be largely ineffectual.

Advocacy groups are working to reduce inaccurate and stigmatizing depictions of individuals with mental

disorders in the mass media. For example, the Alliance for the Mentally Ill of New York State operates a Stigma

Clearinghouse that records and responds to inaccurate or stigmatizing media depictions of individuals with mental

disorders, and the National Alliance for the Mentally Ill may soon launch a similar program nationwide. In addition,

the Carter Center in Atlanta, Georgia, has held two conferences addressing the problems of stigma and mental

disorders and the role of the mass media and has subsequently launched a media initiative to address these issues.

SOURCES: Stigma and theMentallyIll: Proceedings of the First International Rosalynn Carter Symposium on Mental Health Policy, Nov. 15,

1985 (Atlanta, GA: Carter Center, 1985); L.R. Marcos, “Media Power and Public Mental Health Policy,” American Journal of

Psychiatry 146:1185-1189, 1989; A. Mayer and D. Barry, “Working With the Media To Destigmatize Mental Illness,” Hospital

and Community Psychiatry 43:77-78, 1992; Robert Wood Johnson Foundation Program on Chronic Mental Illness, “Public

Attitudes Toward People With Chronic Mental Illness,” April 1990; O. Wahl, “Mental Illness in the Media: An Unhealthy

Condition,” The Community Imperative, R.C. Baron, I.D. Rutman, and B. Klaczynska (eds.) (Philadelphia% PA: Horizon House

Institute, 1980); O. Wahl, Professor, George Mason University, personal communication, February 1992; O. Wahl and J.Y.

Lefkowitz, “Impact of a Television Film on Attitudes Toward Mental Illness,” American Journal of CommunityPsychology

17(4):521-528, 1989; O. Wahl and R. Roth, “Television Images of Mental Illness: Results of a Metropolitan Washington Media

Watch,” Journal of Broadcasting 28:599-605, 1982.
160 ● The Biology of Mental Disorders

Blaming the

Credit: Illustration by Robin Applesteinr reprinted by permission of

R. Applestein and the Washington Times

Findings that biological factors underpin certain mental

disorders help relieve individuals and their

families from feelings of guilt.

(11) observes in his recent book, The Science of the

Mind, science permits:

. . . a model for conceiving of the mind that allows

for the beliefs: that actions can be done on purpose;

that action can be rational; that deliberation can

result in free choice; that such choices can go against

very powerful desires and inclinations; that we can

think of humans as responsible-all this without the

paradoxical requirement that some actions, namely

those of our free will, be totally uncaused.

The assertion that biological factors contribute to

the development of mental disorders challenges the

once reigning theory that they are caused by bad

parenting. For example, psychoanalytic thought

posited that psychic damage during early childhood

produced schizophrenia and other mental disorders.

This concept evolved into the focus on the “schizophrenogenic” mother-that is, a mother with overbearing tendencies, warped psychosexual development, and near-psychotic behavior who produces

schizophrenia in her offspring (12). Since little or no

scientific evidence supports these theories as sufficient or necessary causes of the severe mental

disorders considered in this report, most experts

reject them (14,25). However, the message that

mental disorders are a response to cruel social and

family conditions nonetheless continues to shape the

attitudes of the public and even some experts (28).

For example, data from a 1989 study showed that

textbooks in abnormal psychology implicitly support the concept of the schizophrenogenic parent

(69).

Given that family members are often viewed as

the agents of mental illness, it is understandable that

they embrace biological theories of mental disorders. When families belonging to the National

Alliance for the Mentally Ill (NAMI) were asked

what had helped them to cope with stigma, 73.2

percent indicated that “research findings which

establish a biological basis for mental illness helped

much or very much in dealing with stigma” (71).

The concept that a biological defect causes a mental

disorder largely exonerates family members and the

individuals themselves from blame, placing it instead on a disease process (22). The solace found by

families in biological explanations of mental disorders is revealed in this passage, written by the father

of a son with obsessive-compulsive disorder (52):

It May Not Be Your Fault That You or Your Child

Has Obsessive-Compulsive Disorder! Early toilet

training, a rigorously disciplined home environment,

an unresolved Oedipal complex, and endless demands that your child clean up her “disgusting”

room may not be and is probably not the cause of this

illness.

Obsessive-Compulsive Disorder, the flu, and

diabetes may have at least one thing in common—
Chapter 7--Public Attitudes and Policy . 161

the cause. The disease is possibly biological; it may

even be inherited from one generation to another, as

suggested in my family’s case. However, OCD

manifests itself as strange behavior while the other

two show up as physical illnesses. To my wife and

me this understanding that there might be a physical

cause was a great relief. . . .

At the same time, strict adherence to biological

theories may impair psychosocial research into the

development, relapseand treatment of menta , l

disorders. While beyond the scope of this report, it

is important to note that some data suggest that

psychosocial factors play a role in mental disorders.

For example, research findings point out the role of

what is called disruptive emotional expression, or

EE, in schizophrenia. Studies suggest that people

with schizophrenia who spend time in a stressful

environment (that is, an environment with high EE)

are more likely to suffer a relapse (24,27,64). The

message from such studies is not a return to the cruel

and stigmatizing concepts of family causation, but

rather an acknowledgment that the emergence,

symptoms, and course of mental disorders are

multifactorial.

Genetic models of mental disorders may unintentionally recast the stigma and discrimination experienced by individuals with mental disorders and their

families. With increased knowledge about the genetics of mental disorders, new questions emerge. Will

individuals who pass on a gene or several genes

predisposing their offspring to a mental disorder be

viewed as blameworthy for having children? Will

insurance coverage or employment be denied on the

basis of a “positive” genetic test in the future?

Some groups and individuals interested in or

afflicted by genetic diseases voice concerns about

potential genetic discrimination-’ ’the denial of

rights, privileges, or opportunities on the basis of

information gathered via genetic tests” (65). Eugenic policies in the past (see ch. 5) and popular

support of prenatal testing for genetic diseases (and

termination of the pregnancy in the event of a

positive test) foster concern about possible genetic

discrimination (47). It may be premature to raise

concerns about genetic testing for mental disorders,

given their complex and poorly understood genetic

underpinnin gs (see ch. 5). However, that some

mental disorders have a genetic component is

strongly supported by research data. Therefore, tests

for a genetic predisposition to some mental disorders

may well be technically feasible in the future. Given

the stigma attached to individuals with mental

disorders and their families, the chronic nature of

disorders, and the current barriers to insurance and

employment, genetic testing-a even the perception that genetics accounts for these conditions—

could become a tool for dis criminating against

individuals with mental disorders and their families.

The Link Between Mental Disorders

and Medicine

Intimately linked to the emphasis on biological

aspects of severe mental disorders is the hope that

biomedical research will lead to new treatments and,

ultimately, cures for these disorders (19). As stated

in NAMI’s platform (38):

For the purposes of research, the National Alliance has defined serious mental illnesses as those

brain diseases that are at the present time neither

preventable nor curable but are controllable with

proper medication and support services. . . . Biomedical research will yield better treatment and a

cure for these diseases.

Hope for a cure has accompanied many eras of

mental health policy. In addition to the desire to

eliminate the complicated problems associated with

severe mental disorders, the current hopes for a cure

spring from general optimism for biomedical research, the track record of biomedical research in

finding treatment and cures for disease in general,

the past and continuing development of drugs used

to treat many individuals with mental disorders, and

the neuroscience revolution. In light of the considerable advances of neuroscience research in general, it

is hard not to be infected by this hope. A realistic

viewpoint is necessary, however, to stay the course

of what is likely to be a slow unraveling of the

secrets of the brain. Furthermore, policymakers and

advocates must also be wary of the danger, not

always resisted in the past, of emphasizing research

at the expense of providing adequate care for people

with mental disorders.

Biological research on mental disorders has

entered into the issue of mental health care finance.

Currently, financial barriers limit access to treatment. Insurance coverage for mental health care is

generally inferior to coverage for “physical” illnesses (3,42,54,66). Recently, advocates have lobbied for the designation of certain mental disorders

as biological, or brain-based, in order to gain parity

in insurance coverage (6,19,46). In the first case of
162 ● The Biology of Mental Disorders

its type, a father sued Arkansas Blue Cross and Blue

Shield for increased coverage for the care of his

daughter, who was hospitalized for bipolar disorder.

His insurance policy provided for extensive coverage for physical conditions but limited coverage for

‘‘mental, psychiatric, or nervous’ disorders. The

plaintiff argued that bipolar disorder is a biological

disorder and therefore should be considered ‘ ‘physical’ under the terms of the policy. In this case,

Arkansas Blue Cross and Blue Shield v. Doe (4), the

courts ruled that bipolar disorder ‘ ‘is a physical

condition within the meaning of the Blue Cross

contract.

State legislatures also have begun to address the

issue of providing equal treatment for biologically

based mental disorders. For example, a bill that

became law in Maine in 1992 requires group insurers

that offer coverage for disorders of the brain to offer

the same coverage for biologically based severe

mental disorders. The law specifies all of the

conditions included in this report: schizophrenia,

bipolar disorder, major depression, panic disorder,

and obsessive-compulsive disorder.

Advocates who would identify specific mental

disorders as “brain-based” invoke the traditional

medical model of illness as the most appropriate one

for treatment in order to tap into society’s perceived

responsibility for providing health care. Will discovery that certain mental disorders are ‘brain-based’ —

or renaming them as such—achieve insurance parity? Clearly, pinpointing a diagnostic entity with a

biological marker-coupled with treatment--can be

useful for third-party payers, as expressed by William S. Custer, director of research at the Employee

Benefit Research Institute (7):

One underlying problem with mental health

benefits is the difficulty in defining an insurable

event. An insurable event is whatever triggers

benefit payment. Ideally that event should be out of

the control of the insured individual or the individual’s agent (in this case, the provider). The difficulty

in insurance plan design for mental health benefits is

that for at least some conditions, the need for mental

health care is subjectively determined. More importantly, individuals seeking treatment must choose

between several types of providers (psychologists,

psychiatrist, social workers, etc.) and settings (hospitals, halfway houses, clinics, etc.), and more than 150

different modalities (45), with little information

about the efficacy of treatment or quality of care. . . .

These problems could potentially be alleviated for

those with mental disorders that have a biological

cause and for which effective treatments can be

found. For those illnesses, the detection of the

biological cause would define an insurable event, for

which an insurance plan could be designed which

would more closely resemble those for other physical ailments.

In fact, since the mid-1970s, the treatment of

severe mental disorders has increasingly reflected

the medical model, with short-term hospitalization,

the use of prescription drugs, and the development

of a more reliable diagnostic classification system

(63).

As indicated in this report, data point increasingly

to the importance of biological factors in certain

mental disorders. However, some mental health

policy experts and advocates question whether

labeling as such is necessary or appropriate, asserting that emphasizing the underlying causes of

mental disorders is not necessary to gain care and

will not guarantee adequate care; rather, what is

needed is political will.

To accomplish some form of parity for insurance

reimbursement of mental disorders requires no

reliance on the brain disease theory or, indeed, on

any theory of the cause or nature of mental disorders

(60).

While the general view of what causes a disorder or

problem can impact on policy approaches in dealing

with it (58), simply renaming a condition may not be

adequate for achieving such a goal. The court case

previously described is illustrative: After the court

ordered Arkansas Blue Cross and Blue Shield to pay

for treatment of the daughter’s bipolar disorder, the

company rewrote its contract so that this disorder

was specifically identified as a mental disorder,

subject to the usual coverage limitations (42).

Another factor in this debate is the heightened

concern about the cost of health care in general (30),

which has led to an environment of restricting, not

expanding, insurance benefits. For example, during

the 1980s, the States began to mandate some type of

mental health insurance coverage; the more recent

trend in State legislatures is to waive mandates

requiring such coverage (18). Concern also exists

about what will happen to coverage of the other

‘‘nonphysical’ disorders (26). Increased coverage
Chapter 7--Public Attitudes and Policy . 163

of biological disorders could reduce even further

coverage of psychological disorders that cannot

demonstrate a clear biological foundation. Preventive efforts and stress-related disorders, for example,

might be neglected (70). Another concern focuses on

the definition of medical management, even for

biologically based mental disorders.

Skeptics view it as a prelude to eliminating

insurance coverage for psychotherapy and fear that

it will encourage unnecessary drug treatment and

create an incentive to diminish the time spent talking

to patients (63).

Although researchers are developing more effective

biological approaches, psychosocial interventions

are an important component of treatment and

rehabilitation. Given the problems faced in obtaining adequate coverage for the care of severe mental

disorders, as well as the complexities of the issues

impacting on the health care and mental health care

finance debate, a full consideration of these issues,

which is beyond the scope of this report, is warranted.

SUMMARY AND CONCLUSIONS

While the last 30 years have seen an improvement

in the public’s knowledge of and attitudes toward

mental disorders, stigma still abounds. People with

mental disorders and their family members suffer

acutely from that stigma. And negative public

attitudes contribute to discrimination in research

support, treatment availability, financing of care,

housing, and employment.

The stigma attached to mental disorders, while

compelling and undeniable, has manifold aspects.

The notion of stigma embraces everything from

willful denigration of those who are different to fear

and ignorance. The social and public policy effects

of stigma are also complex, being influenced by

many different factors, including laws, the structure

of service delivery, and economic constraints. Because of the complex nature of the stigma attached

to mental disorders and the many relevant areas of

public policy, OTA finds that a wide-ranging

strategy will be necessary to bring about public

policies that benefit persons with severe mental

disorders. Educating the public about the nature of

these conditions is one important tactic; vigilance in

relevant policy areas, such as that evidenced in the

passage of the Americans With Disabilities of Act,

is another.

Concepts of what causes mental disorders influence public attitudes and policy. Modem neuroscience, which is undergoing revolutionary and rapid

advances, is the primary influence on current understanding of the mental disorders considered in this

report. Some skeptics point out that this trend is but

another reincarnation of biological psychiatry, which

historically has wielded influence from time to

time-not always to the advantage of those with

mental disorders. While many factors play a role,

including professional self-interest, the perennial

hope for a cure, and the optimism traditionally

attached to biomedical research, the broad base of

research into the function of the human brain

distinguishes today’s search for biological factors

associated with mental disorders.

OTA identfied several ways in which the data

from biological research into mental disorders and

perceptions of that data can affect public attitudes

and policy. Biological explanations of mental disorders are used to counter the view that these

conditions result from moral turpitude, thus exculpating individuals whose disorders may lead to

unusual, erratic, or tightening behavior. Also, the

assertion that biological factors contribute to the

development of mental disorders debunks the stigmatizing notion that bad parenting is the essential

cause. Biological data have been viewed as exonerating family members from blame and thus helping

them to deal with stigma.

The increased emphasis on biological aspects of

mental disorders, while helpful in dismantling some

negative attitudes, is not without its limitations. As

mentioned, perceptions of what causes mental disorders are not the sole reason for stigma. For example,

fear of violent behavior, a simplistic image of mental

disorders reinforced by the media, also shapes public

attitudes. Furthermore, publicized data may be

misinterpreted. The specious notion that a biological, especially a genetic, substrate for human behavior dissolves moral agency can be especially dehumanizing to persons with mental disorders. Also,

while reproachful theories of causation, such as the

schizophrenogenic mother, have been largely refuted, it is important to note that biological research

has not ruled out the role of psychosocial factors in

the development, course, and treatment of mental

disorders. Finally, with rapid advances in molecular

genetics, some sort of genetic test for mental

disorders may become possible in the future; such a

test-or simply the perception that these conditions
164 . The Biology of Mental Disorders

are inherited--could prove to be a powerful tool for

discrimination.

The emphasis on biological aspects of severe

mental disorders is intimately linked to the hope that

biomedical research will lead to new treatments and,

ultimately, cures. While hopes for a cure have long

accompanied new eras of mental health policy, this

period bears the distinctive mark of the new age of

brain research. A realistic viewpoint requires that we

be patient and stay the course of what is likely to be

a slow unraveling of the secrets of the brain.

Similarly, policymakers must not be seduced into

simplifying their consideration of mental disorders

and focusing solely on research while ignoring the

care needs of those currently afflicted with these

disorders.

By highlighting the biological components of

mental disorders, advocates seek more than treatment advances. As exemplified by recent court cases

and State laws, attempts to obtain increased financial support for care also drive this trend. Identification of biological markers for certain mental disorders, along with effective treatments, can assist

third-party payers for health care by enabling them

to identify objectively an insurable event. However,

other questions are raised by this trend, including

concerns about the coverage of “nonbiologica1”

disorders or interventions. A full consideration of

mental health care and its finance is required to

answer this issue.

1.

2.

3.

4.

5.

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Appendixes
Appendix A

Decade of the Brain

Public Law 101-58

101st Congress Joint Resolution

Whereas it is estimated that 50 million Americans are

affected each year by disorders and disabilities that

involve the brain, including the major mental illnesses;

inherited and degenerative diseases; stroke; epilepsy;

addictive disorders; injury resulting from prenatal events,

environmental neurotoxins and trauma; and speech,

language, hearing and other cognitive disorders;

Whereas it is estimated that treatment, rehabilitation

and related costs of disorders and disabilities that affect

the brain represents a total economic burden of $305

billion annually;

Whereas the people of the Nation should be aware of

the exciting research advances on the brain and of the

availability of effective treatment of disorders and disabilities that affect the brain;

Whereas a technological revolution occurring in the

brain sciences, resulting in such procedures as positron

emission tomography and magnetic resonance imaging,

permits clinical researches to observe the living brain

noninvasively and in exquisite detail, to define brain

systems that are implicated in specific disorders and

disabilities, to study complex neuropeptides and behaviors as well as to begin to learn about the complex

structures underlying memory;

Whereas scientific information on the brain is amassing

at an enormous rate, and the field of computer and

information sciences has reached a level of sophistication

sufficient to handle neuroscience data in a manner that

would be maximally useful to both basic researchers and

clinicians dealing with brain function and dysfunction;

Whereas advances in mathematics, physics, computational science, and brain imaging technologies have made

possible the initiation of significant work in imaging brain

function and pathology, modeling neural networks, and

simulating their dynamic interactions;

Whereas comprehending the reality of the nervous

system is still on the frontier of technological innovation

requiring a comprehensive effort to decipher how individual neurons, by their collective action, give rise to human

intelligence;

Whereas fundamental discoveries at the molecular and

cellular levels of the organization of the brain are

clarifying the role of the brain in translating neurophysiologic events into behavior, thought, and emotion;

Whereas molecular biology and molecular genetics

have yielded strategies effective in preventing several

forms of severe mental retardation and are contributing to

promising breakthroughs in the study of inheritable

neurological disorders, such as Huntington’s disease, and

mental disorders, such as affective illnesses;

Whereas the capacity to map the biochemical circuitry

of neurotransmitters and neuromodulators will permit the

rational design of potent medications possessing minimal

adverse effects that will act on the discrete neurochemical

deficits associated with such disorders as Parkinson’s

disease, schizophrenia, and Alzheimer’s disease;

Whereas the incidence of necrologic, psychiatric,

psychological, and cognitive disorders and disabilities

experienced by older persons will increase in the future as

the number of older persons increases;

Whereas studies of the brain and central nervous

system will contribute not only to the relief of necrologic,

psychiatric, psychological, and cognitive disorders, but

also to the management of fertility and infertility,

cardiovascular disease, infectious and parasitic diseases,

developmental disabilities and immunologic disorders, as

well as to an understanding of behavioral factors that

underlie the leading preventable causes of death in this

Nation;

Whereas the central nervous and immune systems are

both signaling systems which serve the entire organism,

are direct connections between the nervous and immune

system, and whereas studies of the modulatory effects of

each system on the other will enhance our understanding

of diseases as diverse as the major psychiatric disorders,

acquired immune deficiency syndrome, and autoimmune

disorders;

Whereas recent discoveries have led to fundamental

insights as to why people abuse drugs, how abused drugs

affect brain function leading to addiction, and how some

of these drugs cause permanent brain damage;

Whereas studies of the brain will contribute to the

development of new treatments that will curtail the

craving for drugs, break the addictive effects of drugs,

prevent the brain-mediated “high” caused by certain

abused drugs, and lessen the damage done to the

developing minds of babies, who are the innocent victims

of drug abuse;

Whereas treatment for persons with head injury,

developmental disabilities, speech, hearing, and other

cognitive functions is increasing in availability and

effectiveness;

–169-
170 ● The Biology of Mental Disorders

Whereas the study of the brain involves the multidisciplinary efforts of scientists from such diverse areas as

physiology, biochemistry, psychology, psychiatry, molecular biology, anatomy, medicine, genetics, and many

others working together toward the common goals of

better understanding the structure of the brain and how it

affects our development, health, and behavior;

Whereas the Nobel Prize for Medicine of Physiology

has been awarded to 15 neuroscientist within the past 25

years, an achievement that underscores the excitement

and productivity of the study of the brain and central

nervous system and its potential for contributing to the

health of humanity;

Whereas the people of the Nation should be concerned

with research into disorders and disabilities that affect the

Approved July 25, 1989.

brain, and should recognize prevention and treatment of

such disorders and disabilities as a health priority;

Whereas the declaration of the Decade of the Brain will

focus needed government attention on research, treatment, and rehabilitation in this area: Now, therefore, be it

Resolved by the Senate and House of Representatives of

the United States of America in Congress Assembled, that

the decade beginning January 1, 1990, hereby is designated the “Decade of the Brain,” and the President of the

United States is authorized and requested to issue a

proclamation calling upon all public officials and the

people of the United States to observe such decade with

appropriate programs and activities.

Legislative History-H.J. Res. 174 (S.J. Res. 173):

Congressional Record, vol. 135 (1989):

June 29, 1989, considered and passed House

July 13, 1989, considered and passed Senate
Appendix B

Acknowledgments

The Office of Technology Assessment would like to thank the members of the advisoxr panel who commented on drafts

of this report, the contractors who provided material for this assessment, and the many individuals and organizations that supplied

information for the study. In addition, OTA acknowledges the following individuals for their review of drafts of this report.

John Ambrose

National Mental Health Association

Alexandria, VA

Joyce Barham

Rockville, MD

Kate Berg

National Institute of Mental Health

Rockville, MD

Floyd E. Bloom

Scripps Research Institute

La Jolla, CA

William T. Carpenter, Jr.

Maryland Psychiatric Research Center

Baltimore, MD

Bernard J. Carroll

Duke University Medical Center

Durham, NC

Dennis S. Charney

Connecticut Mental Health Center

New Haven, CT

Roland D. Ciaranello

Stanford University School of Medicine

Stanford, CA

Philip Cohen

Huntington’s Disease Society of America,

New York, NY

Robert M. Cook-Deegan

Institute of Medicine

Washington, DC

James H. Cromwell

National Alliance for the Mentally Ill

Arlington, VA

William S. Custer

Employee Benefit Research Institute

Washington, DC

Isabel Davidoff

National Institute of Mental Health

Rockville, MD

Steven C. Dilsaver

Ohio State University

Columbus, OH

Inc.

Susan Dime-Meenan

National Depressive and Manic Depressive Association

Chicago, IL

Nancy (Mrs. Pete) Domenici

Family Member

Washington, DC/New Mexico

Morgan Downey

The National Foundation for Brain Research

Washington, DC

Allen Feezor

North Carolina Insurance Department

Raleigh, NC

Laurie Flynn

National Alliance for the Mentally Ill

Arlington, VA

J. David Gallager

American Diabetes Association

Alexandria, VA

Rohan Ganguli

University of Pittsburgh

Pittsburgh, PA

David George

Hill Crest Hospital

Birmingham, AL

Elliot S. Gershon

National Institute of Mental Health

Bethesda, MD

Irving I. Gottesman

University of Virginia

Charlottesville, VA

Anthony A. Grace

University of Pittsburgh

Pittsburgh, PA

Gerald N. Grob

Rutgers University

New Brunswick, NJ

Samuel B. Guze

Washington University School of Medicine

St. Louis, MO

Susan Hoechstetter

National Association of Social Workers

Silver Spring, MD

–171–
172 . The Biology of Mental Disorders

Neil Holtzman

Johns Hopkins University

Baltimore, MD

Philip S. Holzman

Harvard University

Cambridge, MA

John M. Kane

Long Island Jewish Medical Center

Glen Oaks, NY

Ingo Keilitz

National Center for State Courts

Williamsburg, VA

Samuel J. Keith

National Institute of Mental Health

Rockville, MD

Charles H. Kellner

Medical University of South Carolina

Charleston, SC

Ronald Kessler

University of Michigan

Ann Arbor, MI

Kenneth Kidd

Yale University School of Medicine

New Haven, CT

Darrell G. Kirch

National Institute of Mental Health

Rockville, MD

Joel Kleinman

National Institute of Mental Health

Washington, DC

Stephen H. Koslow

National Institute of Mental Health

Rockville, MD

Chris Koyanagi

National Mental Health Association

Alexandria, VA

Alan I. Leshner

National Institute of Mental Health

Rockville, MD

Carl Leventhal

National Institute of Neurological Disorders and Stroke

Bethesda, MD

Beverly B. Long

World Federation for Mental Health

Atlanta, GA

Laura L. Mancuso

National Association of State Mental Health Program

Directors

Alexandria, VA

Jack D. Maser

National Institute of Mental Health

Rockville, MD

Noel A. Mazade

National Association of State Mental Health Program

Directors

Alexandria, VA

Thomas H. McGlashan

Yale Psychiatric Institute

New Haven, CT

David Mechanic

Rutgers University

New Brunswick, NJ

Laurane G. Mendelssohn

Lilly Research Laboratories

Indianapolis, IN

M.-Marsel Mesulan

Harvard Medical School

Boston, MA

John Monahan

University of Virginia

Charlottesville, VA

Eve K. Moscicki

National Institute of Mental Health

Rockville, MD

Loren R. Mosher

Department of Addiction, Victim, and Mental Health

Services, Montgomery County

Rockville, MD

Richard A. Mulivor

Coriell Cell Repositories

Camden, NJ

Charles B. Nemeroff

Duke University Medical Center

Durham, NC

Grayson S. Norquist

National Institute of Mental Health

Rockville, MD

Enid Peschel

Yale University School of Medicine

Woodbridge, CT

Harold A. Pincus

American Psychiatric Association

Washington, DC

Robert Plomin

Pennsylvania State University

University Park, PA

Stephanie Poe

Washington Business Group on Health

Washington, DC
Appendix B--Acknowledgments ● 173

Michael I. Posner

University of Oregon

Eugene, OR

Dominick P. Purpura

Albert Einstein College of Medicine

Bronx, NY

Mark A. Randolph

Institute of Medicine

Washington, DC

Judith L. Rapoport

National Institute of Mental Health

Bethesda, MD

Ralph R. Reed

American Medical Association

Washington, DC

Darrel A. Regier

National Institute of Mental Health

Rockville, MD

Philip R. Reilly

Shriver Center for Mental Retardation, Inc.

Waltham, MA

David A. Rochefort

Northeastern University

Boston, MA

Anthony J. Rothschild

McLean Hospital/Harvard Medical School

Belmont, MA

Leonard S. Rubenstein

Mental Health Law Project

Washington, DC

Melvin Sabshin

American Psychiatric Association

Washington, DC

Leslie Scallet

Mental Health Policy Resource Center

Washington, DC

Greg Scandlen

Scandlen Publishing, Inc.

Alexandria, VA

Sandra Scarr

University of Virginia

Charlottesville, VA

Arnold B. Scheibel

University of California

Los Angeles, CA

Joanne Severe

National Institute of Mental Health

Rockville, MD

Steven S. Sharfstein

Sheppard Pratt Health System, Inc.

Baltimore, MD

Wendy Wilson Sheridan

National Disease Resource Interchange

Philadelphia, PA

David Shore

National Institute of Mental Health

Rockville, MD

Eugene Streicher

National Institute of Neurological Disorders and Stroke

Bethesda, MD

David Tennenbaurn

Blue Cross Blue Shield Association

Chicago, IL

Richard F. Thompson

University of Southern California

Los Angeles, CA

Ron Thompson

National Association of Psychiatric Survivors

Bethesda, MD

E. Fuller Torrey

National Institute of Mental Health

Washington, DC

Ming T. Tsuang

Harvard University

Cambridge, MA

Thomas W. Uhde

National Institute of Mental Health

Bethesda, MD

Daniel P. van Kammen

University of Pittsburgh

Pittsburgh, PA

Otto F. Wahl

George Mason University

Fairfax, VA

Daniel Weinberger

National Institute of Mental Health

Washington, DC

Myrna M. Weissman

Columbia University

New York, NY
Appendix C

List of Contractor Documents

For this report, the Office of Technology Assessment commissioned seven reports on various topics related to mental

disorders. The reports are available in a single volume (NTIS PB 92-216134) from the National Technical Information

Service (NTIS) in Springfield, VA. For additional information, call NTIS at (703) 487-4600.

●

●

●

●

Insuring Health Care: Discrimination Against Men- ●

tal Disorders, G. Scandlen, 1991.

Educating the Public About Severe Mental Disor- ●

ders, J.P. Ambrose and J.D. Gallager, 1991.

Report on Schizophrenia, Part I: The Clinical ●

Phenomenon, W.T. Carpenter, 1991.

Report on Schizophrenia, Part II: Etiology and

Biology, W.T, Carpenter, 1991.

Clinical Trials With Drug Free Subjects, .J.M. Kane,

1991.

The History of Treatment of Mental Illness, J.M.

Quen, 1990.

Molecular Genetics in Psychiatry, R.D. Ciaranello,

1990.

–174-
Appendix D

Acronyms and Glossary of Terms

Acronyms

ADA —Americans with Disabilities Act

ADAMHA —Alcohol, Drug Abuse, and Mental Health

APA

APA

APS

CAT

CDC

CSF

D/ART

DBBBS

DCR

DHHS

DOD

DOE

DSM-III

Administration

—American Psychiatric Association

—American Psychological Association

—American Psychological Society

-computerized axial tomography

—Centers for Disease Control

-cerebrospinal fluid

—DEPRESSION Awareness, Recognition

and Treatment

—Division of Basic Brain and Behavioral

Sciences

—Division of Clinical Research

—U.S. Department of Health and Human

Services

—Department of Defense

—Department of Energy

—Diagnostic and Statistical Manual of

Mental Disorders, 3rd edition

DSM-III-R —Diagnostic and Statistical Manual of

Mental Disorders, 3rd edition, revised

DST -dexamethasone-suppression test

ECA —Epidemiologic Catchment Area

ECT -electroconvulsive therapy

EEG -electroencephalograph

ELSI —Ethical, Legal, and Social Implications

FCCSET —Federal Coordinating Council for Science,

Engineering, and Technology

FDA —U.S. Food and Drug Administration

GABA —gamma aminobutyric acid

IRB —institutional review board

LSD —lysergic acid diethylamide

MAOI —monoamine oxidase inhibitors

MRI —magnetic resonance imaging

NAMI —National Alliance for the Mentally Ill

NARSAD —National Alliance for Research on

NASA

NCI

NE

NEI

NIA

NIAAA

NICHD

NIDA

Schizophrenia and Depression

—National Aeronautics and Space

Administration

—National Cancer Institute

—norepinephrine

—National Eye Institute

—National Institute on Aging

—National Institute on Alcohol Abuse and

Alcoholism

—National Institute on Child Health and

Human Development

—National Institute on Drug Abuse

NIDOCD

NIDR

NIEHS

NIMH

NINDS

NMHA

NSF

OCD

PCP

PET

PHS

PKU

RDC

REM

SAD

SAMHSA

SPECT

SPEM

UAGA

USDA

VA

—National Institute on Deafness and Other

Communication Disorders

—National Institute of Dental Research

—National Institute on Environmental

Health Sciences

—National Institute of Mental Health

—National Institute of Neurological

Disorders and Stroke

—National Mental Health Association

—National Science Foundation

-obsessive-compulsive disorder

—phencyclidine

—positron emission tomography

—U.S. Public Health Service

—phenylketonuria

—Research Diagnostic Criteria

—rapid eye movement

—seasonal affective disorder

—Substance Abuse and Mental Health

Services Administration

—single photon emission computed

tomography

—smooth-pursuit eye movements

—Uniform Anatomical Gift Act

—U.S. Department of Agriculture

—Department of Veterans Affairs

Glossary

Acetylcholine: A chemical messenger in the nervous

system. See neurotransmitter.

Adoption study: The attempt to separate the influence of

genes from that of the environment by comparing the

presence of a trait in biological versus adoptive family

members. Compare family study, twin study.

Affective disorder: See mood disorder.

Agoraphobia: Fear of being in public places from which

escape might be difficult. This condition frequently

accompanies panic disorder. See panic disorder.

Allele: A version of a gene at a particular locus on the

chromosome; one allele is inherited from each parent.

If the two alleles at a locus are identical, the organism

is homozygous for that gene; if they are different,

heterozygous. See genotype, phenotype.

Animal model: An animal that shares, or in which can be

replicated or approximated, features of human disorders and that is used in studies of these disorders.

Although animal models cannot duplicate human

mental disorders completely, they can be used to study

basic brain structure and functions, mechanisms that

may contribute to particular symptoms, hypothesized

–175–
176 ● The Biology of Mental Disorders

causes of a disorder, and drugs for treatment of the

disorder.

Animal rights: The concept that animals have intrinsic

rights that are equal to humans’ rights. Compare

animal welfare.

Animal welfare: In the context of scientific research,

provision of proper food, shelter, care, and treatment

of animals used in experiments. Compare animal

rights.

Antianxiety drug: Medication, such as benzodiazepines,

used to treat symptoms of anxiety disorders.

Antidepressant: Medication used to treat depressive

symptoms. See tricyclic antidepressant, monoamine

oxidase inhibitor (MAOI), fluoxetine.

Antipsychotic, antipsychotic drug: Medication used to

treat psychosis, for example in schizophrenia. See

chlorpromazine, clozapine.

Anxiety: Commonly experienced apprehension, tension,

or uneasiness from anticipation of danger, the source

of which is largely unknown or unrecognized. See

anxiety disorder.

Anxiety disorder: Any of several mental disorders

characterized by anxiety, including agoraphobia, obsessivecompulsive disorder, and panic disorder. See agoraphobia, anxiety, obsessive-compulsive disorder, panic

disorder.

Autoreceptor: A protein (receptor) in the wall of a nerve

cell that binds a neurotransmitter released by that cell.

Autoreceptors act as a feedback mechanism to regulate

a neuron’s activity. See neurotransrnitter; compare

receptor.

Axon: The long extension of a nerve cell along which

electrical impulses travel. See neuron.

Basal ganglia: A group of nuclei in the upper part of the

brain that, among other functions, help mediate

movement. See nuclei.

Base pairs: Two complementary nucleotides held together by weak bonds. Two strands of DNA are held

together in the shape of a double helix by the bonds

between base pairs. The base adenine pairs with

thymine, and guanine pairs with cytosine. See DNA.

Behavioral sensitization: The increasing response of a

laboratory animal to repeated administration of the

same dose of a stimulant drug. Compare kindling.

Behavioral therapy: A form of psychotherapy that

focuses on modifying faulty behavior rather than basic

changes in the personality. Instead of probing the

unconscious or exploring the patient’s thoughts and

feelings, behavior therapists seek to eliminate symptoms and to mod@ ineffective or maladaptive patterns

by applying basic learning techniques and other

methods. (Examples: relaxation therapy, sell-control

therapy, social skills training.) This mode of treatment

is used for depression and obsessive-compulsive

disorder.

Benzodiazepines: A class of drugs used to treat some

anxiety disorders by increasing the action of the

inhibitory neurotransmitter GABA. See anxiety disorder, GABA, neurotransmitter.

Biological rhythm: Change in a physiological or behavioral function that repeats at regular intervals and

provides a framework of temporal organization for an

organism. Alterations in biological rhythms have been

associated with mood disorders. See circadian rhythm,

mood disorder.

Bipolar disorder: A severe mood disorder characterized

by manic and major depressive episodes, with periods

of recovery generally separating the mood swings.

Psychosis may be present during manic episodes.

Bipolar disorder usually begins in the mid 20s and is

chronic. See depression, mania, mood disorder; compare major depression.

Candidate gene: A gene suspected of causing or being

otherwise closely linked to a disorder the location of

the gene is then sought by linkage analysis. See linkage

analysis.

Catecholamine: A class of neurotransmitter including

norepinephrine, epinephrine, and dopamine. See dopamine, neurotransmitter, norepinephrine.

Causative factor: The biological substance or activity

that causes a disorder. Compare correlated factor.

Cerebral cortex: The upper portion of the brain, consisting of layers of neurons and the pathways connecting

them. The cerebral cortex is divided into four lobes on

each side and is the part of the brain responsible for

higher-order thinking and decisionmaking.

Cerebrospinal fluid (CSF): Fluid manufactured in the

brain and contained within the brain and spinal cord;

it circulates in the central nervous system.

Chlorpromazine, Thorazine: A traditional antipsychotic

drug, first introduced in the 1950s, used to treat

psychotic symptoms. Chlorpromazine can produce

side effects typical of traditional antipsychotic drugs.

See antipsychotic, traditional antipsychotic drugs.

Chromosome: The rod-shaped body that contains genes

and intervening regions of DNA that do not code for

proteins. Each human cell except gametes (eggs and

sperm) contains 23 pairs of chromosomes: 22 pairs of

autosomes and one set of sex chromosomes. See DNA,

gene.

Circadian rhythm: A biological rhythm, such as body

temperature, that repeats approximately every 24

hours. See biological rhythm.

Clomipramine, Anafranil: A medication commonly used

to treat obsessive-compulsive disorder; it inhibits the

reuptake of the neurotransmitter serotonin. See serotonin.

Clozapine, Clozaril: A newer antipsychotic agent used to

treat symptoms of schizophrenia in persons who do not

respond to traditional antipsychotic drugs. Clozapine

ameliorates both positive and negative symptoms of
Appendix Acronyms and Glossary of Terms ● 177

schizophrenia; it does not seem to produce tardive

dyskinesia. Clozapine can result in agranulocytosis, a

potentially fatal decrease in the number of white blood

cells, which fight infection. See antipsychotic, tardive

dyskinesia, traditional antipsychotic drugs.

Cognition: The processing of information by the brain;

specifically, perception, reasoning, and memory.

Cognitive therapy: A psychotherapeutic approach based

on the concept that emotional problems are the result

of faulty ways of thinking and distorted attitudes

toward oneself and others. The therapist takes the role

of an active guide who helps the patient correct and

revise his or her perceptions and attitudes by citing

evidence to the contrary or eliciting it from the patient.

The therapist uses cognitive and behavioral techniques

to correct distortions of thinking associated with

depression, that is, pessimism about oneself, the world,

and the future. Brief treatment.

Comorbidity: The occurrence of two or more mental

disorders at the same time. The disorders may occur

independently of each other, or one may occur as a

consequence of the other.

Compulsion: An insistent, intrusive, and unwanted

action that is repeated over and over. See obsessivecompulsive disorder.

Computerized axial tomography (CAT): A type of

imaging used to scan the living brain that uses

computers to combine series of x-rays; CAT scans

provide clearer pictures of the brain than x-rays alone.

Correlated factor: A biological substance or activity that

is linked to a disorder and may result in some of its

symptoms. Compare causative factor.

Corticotropin-releasing factor: A hormone produced by

the brain that controls cortisol levels; elevated levels

appear to be associated with depression.

Delusion: A belief that is clearly implausible but compelling and central to an individual’s life.

Dendrite: One of several branched fibers extending out of

a nerve cell that receives impulses from another

neuron. See neuron.

Depression: When used to describe a mood, depression

is characterized by feelings of sadness or dejection.

Depression may be a symptom seen in a variety of

disorders, including bipolar disorder and major depression, and be characterized by extreme feelings of

sadness or irritability, inactivity, withdrawal from

society, and difficulty concentrating. See bipolar

disorder, major depression.

Dexamethasone-suppression test (DST): Developed as

a test of hormone functioning, it has been studied as a

possible diagnostic tool in depression. In healthy

individuals, administration of the drug dexamethasone

suppresses the concentration of cortisol in the blood.

Approximately 40 to 50 percent of persons diagnosed

with major depression have an abnormal DST in that

they do not suppress cortisol in response to dexamethasone. See depression.

DNA (deoxyribonucleic acid): The molecule that encodes genetic information. DNA is a double-stranded

helix held together by weak bonds between base pairs

of nucleotides. See base pairs, chromosome, gene.

Dopamine: A chemical messenger in the brain. This

neurotransmitter appears to play some role in schizophrenia and perhaps other mental disorders. See

neurotransmitter, schizophrenia.

Electroconvulsive therapy (ECT): Electric shock treatments used to treat persons with severe depression.

Electroencephalograph (EEG): An instrument for measuring electrical waves generated by neurons in the

brain.

Eugenics: Attempts to improve inherited qualities

through selective breeding. Positive eugenics is the

systematic attempt to increase the transmission of

desired traits by promoting the reproduction of individuals carrying the genes for such traits; negative

eugenics is the systematic attempt to minimize the

transmission of undesirable traits by preventing or

reducing the reproduction of individuals carrying the

genes for such traits.

Family study: The attempt to determine whether a trait

runs in a family, and thus maybe heritable, by studying

as many members of the family as possible in several

generations. Compare adoption study, twin study.

Fluoxetine, Prozac: The most widely prescribed antidepressant in the United States, it acts on the neurotransmitter serotonin. Prozac produces fewer serious side

effects than MAOIs or tricyclic antidepressants. Side

effects associated with Prozac include nausea, tremor,

insomnia, nervousness, and occasionally agitation or

anxiety. See antidepressant, serotonin.

GABA (gamma aminobutyric acid): A major neurotransmitter implicated in anxiety disorders. See anxiety

disorder, neurotransmitter.

Gene: The fundamental physical and functional unit of

heredity. Each gene is made up of an ordered sequence

of base pairs, is located on a particular position on a

particular chromosome, and codes for (determines the

structure of) a particular protein. See base pairs, DNA,

chromosome, protein.

Genetic counseling: A clinical service that provides an

individual, and sometimes his or her family, with

information about heritable conditions. At present,

genetic counseling can provide only a general estimate

of risk for a mental disorder, not an accurate assessment of individual risk.

Genetic heterogeneity: The phenomenon whereby a

disorder is caused by one gene in some individuals but

a different gene in other individuals.

Genotype: The genetic constitution of an organism.

Compare phenotype.
178 ● The Biology of Mental Disorders

Glutamate: A neurotransmitter that stimulates nerve

cells and may play a role in certain mental disorders.

See neurotransmitter.

Hallucination: A perception without an objective basis,

often an imaginary voice, vision, taste, or smell.

Hippocampus: A nucleus in the brain crucial to learning

and memory; part of the limbic system. See limbic

system, nuclei.

Hypothalamus: A group of nuclei in the brain that

regulate hormones and such behaviors as eating,

. . drmkmg, and sex. See nuclei.

Incomplete penetrance: Failure of a trait to be expressed,

even though the gene coding for it is present.

Informed consent: The agreement of a person to

participate as a subject in an experimental procedure

after rationally weighing the possible benefits and

risks of the procedure. The nature of some mental

disorders may render individuals incompetent to give

informed consent and, therefore, unable to participate

in research projects.

Interpersonal psychotherapy: A form of psychotherapy

in which the therapist seeks to help the patient to

identify and better understand his or her interpersonal

problems and conflicts and to develop more adaptive

ways of relating to others. The therapist focuses on

client’s current interpersonal relationships. Helps clients learn more effective ways of relating to others and

coping with conflicts in relationships. Brief, focused

treatment.

Kindling: The creation of seizures in an area of the brain

by subjecting it to repeated, low-level electrical

stimulation; eventually, the area becomes so sensitive

that seizures will occur spontaneously, with no electrical stimulus. Compare behavioral sensitization.

Limbic system: A network of structures in the brain

(including the hippocampus and part of the temporal

lobes) associated with control of emotion and behavior, specifically, perception, motivation, gratification,

memory, and thought. See hippocampus.

Linkage analysis: A technique for determiningg whether

a major gene produces a trait and, if so, where on the

chromosomes that gene is located (but not which gene

it is or what its function is). Linkage analysis uses

markers (such as genetic traits or DNA sequences)

whose loci are known and calculates the probability

that the loci for the marker and the gene being sought

are linked.

Lithium carbonate: The most common medication used

to treat bipolar disorder, lithium is used to diminish

manic symptoms and to prevent future episodes. Side

effects include increased thirst and urination, memory

problems, tremor, and weight gain. Long-term treatment, which is commonly required, can have toxic

effects on the thyroid gland, the kidneys, and the

nervous system; lithium can also cause fetal abnormalities.

Locus ceruleus: A nucleus in the brain that is involved in,

among other things, the body’s response to stressful

situations, such as the fight-or-flight response. See

nuclei.

Magnetic resonance imaging (MRI): A technique that

constructs images of the living human brain by

detecting molecular changes in neurons exposed to a

strong magnetic field.

Major depression: A mood disorder characterized by

profound depression, that is, complete loss of interest

or pleasure in activities. Other common symptoms

include weight gain or loss, insomnia or excessive

sleepiness, slowed or agitated movement, intense

feelings of guilt or worthlessness, diminished ability to

concentrate, and recurrent thoughts of death or suicide.

Bouts of depression commonly recur. Psychosis may

also accompany major depression. The typical age of

onset is the late 20s. See mood disorder; compare

bipolar disorder.

Mania: A mood disorder characterized by expansiveness,

elation, talkativeness, hyperactivity, and excitability.

See bipolar disorder.

Manic depression, manic-depressive disorder: See

bipolar disorder.

Melancholia: A severe form of depression in which there

is a nearly complete loss of interest or pleasure in

activities, accompanied by somatic symptoms such as

weight loss and early morning wakening.

Metabolize: A compound that results from the chemical

breakdown of a neurotransmitter in the space between

nerve cells. See neurotransmitter.

Monoamine: A group of neurotransmitters; namely,

norepinephrine, epinephrine, serotonin, and dopamine. See dopamine, neurotransmitter, norepinephrine, serotonin.

Monoamine oxidase inhibitor (MAOI): A class of

antidepressants that acts by prolonging monoamine

activity; generally used to treat persons who do not

respond to tricyclic antidepressants. MAOIS can interact with certain foods and other medications to produce

potentially fatal hypertension. See monoamine.

Mood disorder: A mental disorder characterized by

extreme or prolonged disturbances of mood, such as

sadness, apathy, or elation. Mood disorders are divided

into two major groups: bipolar, or manic-depressive,

disorders, characterized by depression and mania; and

unipolar, or depressive, disorders, characterized by

depression only. See major depression, bipolar disorder.

Negative eugenics: See eugenics.

Neuroendocrine system: Hormones that influence the

activity of neurons and glands. Many symptoms

associated with depression may be related to changes

in the hormones secreted by these glands, particularly

the pituitary, adrenal, and pineal glands.
AppendixD-- Acronyms and Glossary of Terms ● 179

Neuron, nerve cell: The basic functional unit of the

nervous system, neurons carry on information processing in the brain. The neuron consists of a relatively

compact cell body containing the nucleus, several

branched extensions (dendrites), and a single long

fiber (the axon) with twig-like branches along its

length and at its end. Information in the form of

electrical impulses generally travels from the dendrites, through the cell body, and along the axon to

other cells via neurotransmitters. See axon, dendrite,

neurotransmitter.

Neuroscience: The study of the nervous system and how

it is affected by disease. Neuroscience draws from

numerous fields, including anatomy, physiology, physics, electronics, genetics, biochemistry, optics, pharmacology, psychology, neurology, psychiatry, neurosurgery, and computer science, and is based on the

concept that behavior, thought, and emotion are the

result of nerve cell interaction.

Neurotransmitter: Specialized chemical messenger synthesized and secreted by neurons to communicate with

other neurons. A neurotransmitter is released into the

space between neurons (synapse), moves across that

space, and attaches (binds) to a specific protein

(receptor) in the outer wall of a neighboring neuron.

Some neurotransmitters stimulate the release of neurotransmitters from other neurons (excitatory neurotransmitters), while others inhibit the release of

neurotransmitters from other neurons (inhibitory neurotransmitters). See neuron, receptor.

Non-REM sleep: The four stages of sleep during which

the sleeper does not experience rapid eye movement.

Compare REM sleep.

Norepinephrine: A chemical messenger in the brain.

Alterations in this neurotransmitter have been implicated in several mental disorders. See neurotransmitter.

Nuclei, nucleus: Groups of neurons in the brain that are

located in the same region and that share, to varying

degrees, the same function. Axons extending from

nuclei convey information between and among nuclei

throughout the brain. See neuron.

Obsession: Irrational thought, image, or idea that is

irresistible and recurrent, if unwanted. See obsessivecompulsive disorder.

Obsessive-compulsive disorder (OCD): A mental disorder characterized by recurrent and persistent thoughts,

images, or ideas perceived by the sufferer as intrusive

and senseless (obsessions) and by stereotypic, repetitive, purposeful actions perceived as unnecessary

(compulsions). The average age of onset is 20. OCD is

generally chronic, with symptoms waxing and waning.

The disorder frequently occurs with depression and

Tourette’s syndrome, a neurological disorder. See

anxiety disorder, depression.

Panic disorder: A mental disorder characterized by

sudden, inexplicable bouts, or attacks, of intense fear

and strong bodily symptoms, namely, increased heart

rate, profuse sweating, and difficulty breathing. Panic

attacks occur twice a week, on average. The disorder

is usually chronic, with symptoms waxing and waning,

and the average age of onset is 24. Antidepressants and

antianxiety drugs, as well as psychotherapy, are often

used to treat panic disorder. See anxiety disorder.

Peptides, neuropeptides: Chemicals, including some

hormones, that act as messengers in the brain. Neuropeptides modulate the activity of many other neurotransmitters. See neurotransmitter.

Phenocopy: Nongenetic production of the symptoms of

a disorder that mirror those of the genetically derived

disorder.

Phenotype: The manifestation of a genetic trait. See

allele, genotype.

Positive eugenics: See eugenics.

Positron emission tomography (PET): Imaging technique that creates computerized images of the distribution of radioactively labeled materials in the brain in

order to show brain activity. PET scans of labeled

drugs that attach to specific receptors show the

distribution and number of those receptors.

Protein: A large molecule composed of chains of smaller

molecules (amino acids) in a specific sequence,

proteins are required for the structure, function, and

regulation of the body’s cells, tissues, and organs. Each

protein has a unique function. Examples are hormones,

enzymes, and antibodies.

Psychodynamic psychotherapy: Any form or technique

of psychotherapy that focuses on the underlying, often

unconscious factors (drives and experiences) that

determine behavior and adjustment.

Psychopharmacology: The study of the action of drugs

on the mind.

Psychosis: A mental state characterized by extreme

impairment of the sufferer’s perception of reality,

including hallucinations, delusions, incoherence, and

bizarre behavior. Psychosis is a prominent symptom of

schizophrenia. See delusion, hallucination, schizophrenia.

Raphe nuclei: The major serotonin-containing nuclei in

the brain, they regulate sleep and are involved with

behavior and mood. See nuclei.

Receptor, receptor molecule: Protein embedded in the

wall of nerve cells that binds neurotransmitters. Each

receptor binds a specific neurotransmitter, thereby

turning a particular biochemical or cellular mechanism

on or off. Receptors are generally found in the

dendrites and cell body of neurons. See dendrite,

neuron, neurotransmitter; compare autoreceptor.

Recombination: The exchange of segments of chromosomes during the production of egg and sperm; the

exchange site is called crossover.
180 ● The Biology of Mental Disorders

REM (rapid eye movement) sleep: Stage of sleep during

which the eyes move rapidly, brain activity resembles

that observed during wakefulness, heart rate and

respiration increase and become erratic, and vivid

dreams are frequent. Compare non-REM sleep.

Reuptake: Removal of a neurotransmitter from the

synapse by the neuron that released it. Compare

metabolize; see neurotransmitter, synapse.

Schizoaffective disorder: A mental disorder involving

symptoms of both schizophrenia and mood disorders.

See mood disorder, schizophrenia.

Schizophrenia: A mental disorder characterized by

disturbance of cognition, delusions and hallucinations,

and impaired emotional responsiveness. The disorder

consists of positive symptoms (delusions, hallucinations, illogical thought, and bizarre behavior) and

negative symptoms (blunting of emotion, apathy, and

social withdrawal). The positive symptoms of schizophrenia are also typical of psychosis. Schizophrenia

usually begins in the late teen years or the early 20s.

The disorder cannot now be cured or prevented, but its

symptoms can be treated. See psychosis.

Seasonal affective disorder (SAD): A depressive disorder in which the onset of depression occurs during the

winter months, with remission or mania during the

spring. Symptoms of SAD are generally treated with

phototherapy, that is, bright artificial light in the early

morning, in the evening, or at both times.

Sensitization: See behavioral sensitization, kindling.

Serotonin: A chemical messenger in the brain. This

neurotransmitter has been implicated in several mental

disorders, including mood disorders. See mood disorder, neurotransmitter.

Single photon emission computed tomography (SPECT):

An imaging technique that shows brain activity by

tracking the distribution of radioactively labeled substances in the brain.

Somatic: Physical, as opposed to mental; for example,

somatic symptoms of a mental disorder.

Substance abuse: A maladaptive pattern of psychoactive

substance use indicated by either: 1) continued use

despite knowing that it causes or exacerbates a

persistent or recurrent social, occupational, psychological, or physical problem, or 2) recurrent use in

situations in which it creates a physical hazard (such as

driving when intoxicated). Abuse refers to relatively

mild, transient symptoms. Compare substance dependence.

Substance dependence: Impaired control over use of a

psychoactive substance and continued use of the

substance despite adverse consequences. Dependence

can include physiological tolerance to a substance and

is more serious and persistent than substance abuse.

Compare substance abuse.

Supportive psychotherapy: A treatment technique that

helps a patient reduce stress and cope with his or her

disorder without probing disturbing thoughts or emotions. Compare behavioral therapy, cognitive therapy,

interpersonal psychotherapy, psychodynamic psychotherapy.

Synapse: The site at which an impulse is transmitted from

the axon of one nerve cell to the dendrite of another

nerve cell, typically by a neurotransmitter. See neurotransmitter.

Tardive dyskinesia: A side-effect of traditional antipsychotic drugs. This side-effect, which involves abnormal involuntary movements of the face, tongue,

mouth, fingers, upper and lower limbs, and occasionally the entire body, usually appears after taking the

drug for some time and occurs in at least a mild form

in 25 to 40 percent of patients on antipsychotic agents.

Tardive dyskinesia maybe severe or irreversible in 5

or 10 percent of cases. See traditional antipsychotic

drugs.

Traditional antipsychotic drugs, Typical antipsychotic

drugs: Medication used to treat psychosis, for example

in schizophrenia. These medications can have various

side effects including dry mouth, constipation, blurring of vision, weight gain, restlessness, and tremor.

The most serious side effect is tardive dyskinesia.

Traditional antipsychotic drugs were introduced for

the treatment of psychosis in the 1950s and act by

binding to a dopamine receptor (D2). See chlorpromazine, tardive dyskinesia.

Trait: A genetically determined characteristic. See allele,

genotype, phenotype.

Tricyclic antidepressant: Traditional medication for

depression that acts by blocking reuptake of monoamine. Side effects include dry mouth, constipation,

sedation, nervousness, weight gain, and diminished

sex drive. See monoamine.

Twin study: The attempt to determine whether a trait is

genetic by comparing how often identical twins

(sharing the same genes) who are raised in the same

environment share that trait with how often fraternal

twins (having different genes) raised in the same

environment share the trait. A high rate of trait-sharing

among identical, but not among fraternal, twins

usually demonstrates that the trait is genetic. Compare

adoption study, family study.
Index
Index

Acetylcholine activity, mood disorders and, 84

Action Plan for Women’s Health, 137-38

ADA. See Americans With Disabilities Act of 1990

Adoption studies, 105

Affective disorders. See Mood disorders

Agoraphobia, 12,63, 109, 111

Agranulocytosis, clozapine and, 53,93

Alcohol abuse or dependence. See Substance abuse or

dependence

Alcohol, Drug Abuse, and Mental Health Administration

(ADAMHA), 130,138

American Psychiatric Association (APA), 46, 114, 152

Americans With Disabilities Act of 1990, 156, 157

Amish studies of mental disorder genetics, 108

Anafranil. See Clomipramine

Animal models of mental disorders, 134-36

Antianxiety agents, 12, 13,64

Antidepressant medications, 9, 10

classes, and generic and brand names, 58

panic disorder and, 12, 13,63-64

side effects of, 58

therapeutic response to, 58, 83

Antipsychotic medications, 7,52-53, 58,92

Anxiety

animal models of, 135

depression and, 55,59

Anxiety disorders. See also Obsessive-compulsive disorder; Panic disorder

comorbid substance abuse and, 57

DSM-III-R and, 59

genetics of, 11, 13, 108-9

APA. See American Psychiatric Association

Arkansas Blue Cross and Blue Shield v. Doe, 162

Behavioral therapy

definition of, 59

obsessive-compulsive disorder and, 11, 62

panic disorder and, 64

Biochemistry, 72-74

of mood disorders, 10, 82-85

of obsessive-compulsive disorder, 11, 88

of panic disorder, 13, 90-91

of schizophrenia, 7, 77-79, 82

Biological factors, evidence of involvement in mental

disorders, 13,93-94, 101, 112

Biological research of mental disorders, impact of, 18-19,

21, 112-13, 156-63

Biological rhythms. See Circadian rhythms

Bipolar disorder. See also Depression; Mania

age at onset of, 9, 56

animal models of, 10, 135

comorbid substance abuse and, 57

cost of, 93

course of, 9, 56

genetics of, 10, 107-8

kindling and sensitization hypothesis of, 10, 87

medication for, 58-59. See also Lithium, Carbamazepine

prevalence of, 3,9,35,56

psychotherapy and, 9,59

risk of, 113

serotonin receptor, 84, 112

symptoms of, 8-9, 53-54

treatment of, 9, 58-59

Bleuler, Eugen, 50

Brain banks, 17-18, 138-40

Brain chemistry

mood disorders and, 10, 82-85

obsessive-compulsive disorder and, 11, 88-89

panic disorder and, 13,90-91

schizophrenia and, 7, 77-78, 82

study of, 72-74

Brain structure and function, 38-39,74-77

mood disorders and, 85-86

obsessive-compulsive disorder and, 11, 89-90

panic disorder and, 13,91-92

schizophrenia and, 7-8, 79-81, 82

Brain tissue for research, availability of, 17-18, 138-40

Carbamazepine, 9, 10,59

Chlorpromazine, 92

Circadian rhythms, mood disorders and, 10, 87

Clinical research, 136-38, 140-41

Clomipramine, 11,62

Clozapine, 53,93

Cognitive therapy

definition of, 59

for depression, 59

for panic disorder, 64

Comorbidity, 111

bipolar disorder and, 57

depression and, 55

obsessive-compulsive disorder and, 11, 61-62

panic disorder and, 12

Compulsions, 11,60-61

frequency by type, 12,63

Computerized axial tomography (CAT), 76,77,79,86

Congress

interest in neuroscience research, 26, 27, 39

policy issues and options, 21-31

Cost of mental disorders, 3-5, 16,35-36

Courts, definition of mental disorders and, 45, 162

Creativity, mental disorders and, 56, 115

D/ART program. See DEPRESSION Awareness, Recognition and Treatment program

Decade of the Brain resolution, 5-6,26,37, 169

Delusions, 47,50,51

Depression

animal models of, 135

anxiety and, 59

–183–
184 . The Biology of Mental Disorders

heterogeneity of, 54-55

medications for, 58

obsessive-compulsive disorder and, 61

public education about, 27-31, 154-55

DEPRESSION Awareness, Recognition and Treatment

program, 27-29, 154-55

Depression, major

age at onset of, 8,56, 107

comorbid substance abuse and, 57

course of, 56

diagnosis of, 55

disability days from, 35

genetics of, 107-8

personal account of symptoms of, 9,54

prevalence of, 3,8,35,56

risk of, 113

suicide and, 8, 53

symptoms of, 8, 53

treatment of, 8

Developmental factors, schizophrenia and, 8,81

Dexamethasone-suppression test (DST), 85

Diagnostic and Statistical Manual of Mental Disorders,

46-47

criteria for major depression, 55

criteria for mania, 55

criteria for obsessive-compulsive disorder, 62

criteria for panic disorder, 64

criteria for schizophrenia, 47

Discrimination against persons with mental disorders, 24,

153, 157, 161

Division of Basic Brain and Behavioral Sciences (DBBBS),

16, 126-27, 128, 129

Division of Clinical Research (DCR), 16, 127-29

Dopamine

depression and, 83

obsessive-compulsiv e disorder and, 89

receptors, 38, 75,92, 112

schizophrenia and, 7, 77-78, 82

Drugs

action of, 74

development of, 92-93

spending for, 4, 36

treatment of bipolar disorder, 9

treatment of major depression, 8

treatment of obsessive-compulsive disorder, 11,62,89

treatment of panic disorder, 12,63-64

treatment of schizophrenia, 7,52-53

DSM. See Diagnostic and Statistical Manual of Mental

Disorders

ECT. See Electroconvulsive therapy

Electroconvulsive therapy, major depression and, 8,58

Electroencephalograph (EEG), 76,77,80

Employment status

mood disorders and, 56

schizophrenia and, 51

Epidemiologic Catchment Area (ECA) Program, 3,4,35,

36

Ethical issues surrounding neuroscience advances, 23-24,

26,39

Eugenics and mental disorders, 25,39, 104, 161

Family studies, 105

Federal Coordinating Council for Science, Engineering,

and Technology, 131

Federal funding for mental disorders research, 5, 14-17,

21-23,37,39, 123-31

Federal information transfer, 30-31

Fetal abnormalities, lithium and, 59

Fluoxetine:

action of, 83, 93

sales of, 93

side effects of, 58,93

Foundation funding for mental disorders research, 15,132

Freud, Sigmund, 37

Galton, Francis, 25, 103, 104

Gamma-aminobutyric acid (GABA), 84

Genetic counseling for mental disorders, 113-15

Genetic heterogeneity, 109-10

Genetic information, privacy issues, 24,39

Genetic mapping, mental disorders and, 109-12

Genetic research

impact of, 24, 112-13, 161

NIMH investment, 101

Genetics

anxiety disorders and, 108-9

basic concepts of, 101-3

mood disorders and, 10, 107-8

obsessive-compulsive disorder and, 11

panic disorder and, 13

schizophrenia and, 8, 106-7, 111

study and analysis of, 103-5

Hallucinations, 50,51

Hand-washing compulsion, 11,60

Homelessness, mental disorders and, 3,35

Hormonal abnormalities and mood disorders, 10,85

Hospitalization, 3,4, 35,36

costs of, 18,23, 141

for major depression, 8,58

for mania, 58

for schizophrenia, 52

Human Genome Project, 24,39, 101

Imaging technology, 38,71,76-77

Immune and viral factors

mood disorders and, 88

schizophrenia and, 8, 81

Incarceration, mental disorders and, 3,35

Information on mental disorders, 19,20,26-31, 153

Inheritance. See Genetics

Insurance coverage for mental disorders, 18-19, 161-63
Index . 185

Interagency Task Force on Hopelessness and Severe

Mental Illness, 26, 153

Interpersonal psychotherapy, definition of, 59

James, William, 158

Kennedy, Edward M., 39

Kindling and sensitization hypothesis of bipolar disorder,

10,87

Kraepelin, Emil, 45,50

Legal issues surrounding neuroscience advances, 23-24,

26,39

Linkage analysis, 105-6, 109-12

Lithium, 9, 10,56,58,84-85,93

LOD score, 106

LSD (lysergic acid diethylamide), 78

Magnetic resonance imaging (MRI), 76,77,79,86

Major depression. See Depression, major

Mania. See also Bipolar disorder

animal models of, 135

characterization of, 9, 54

course of, 56

diagnosis of, 55

medication for, 9, 58

Manic-depressive illness. See Bipolar disorder

MAOIs. See Monoamine oxidase inhibitors

Marital status

mood disorders and, 56

schizophrenia and, 50

Media portrayals of mental disorders, 20, 153, 159

Melancholia, 55

Mendel, Gregor, 101

Mental disorders. See also Anxiety disorders; Bipolar

disorder Depression, major; Mood disorders;

Obsessive-compulsive disorder, Panic disorder;

Schizophrenia

animal models of, 134-36

brain structure and function and, 74-77

challenges for genetic mapping of, 14, 109-12

classification of, 39,4647

comorbid substance abuse and, 57

cost of, 3-5, 16, 35-36

creativity and, 56, 115

definition of, 4546

eugenics and, 25, 104

evidence of biological factors involved in, 13, 93-94,

101

genetic counseling for, 113-15

hopelessness and, 35

impact of biological research, 18-19, 21, 156-63

media portrayals of, 20, 153, 159

medical model of, 162

methods of study of, 71-77

prevalence of, 3,35

psychosocial factors and, 13,71, 112, 161

risk of, 113

stigma attached to, 3,5,26, 151-53, 163

study of genetics of, 103-5, 113-16, 161

suicide and, 6-7, 52

treatment of, 92-93

violence and, 20, 158, 159

Mental health care, insurance coverage for, 18-19,161-63

Mental health professionals, 45

cost of care provided by, 4,36

D/ART program training for, 28, 154

negative attitudes toward persons with mental disorders, 26, 152

shortage and training of clinician-researchers, 18,23,

141-44

Mental health services

cost of, 4, 36

government funding for, 5,37

Microscopy, 38

Molecular biology, 38,71,74

Monoamine oxidase inhibitors

action of, 82

generic and brand names, 58

Monoamines. See also Norepinephrine; Serotonin

mood disorders and, 10, 82-84

Mood disorders. See also Bipolar disorder; Depression,

major

biochemistry of, 10,82-85

brain structure and function and, 85-86

characterization of, 8, 53

circadian rhythms and, 10, 87

classification of, 54-55

comorbidity and, 56, 57

genetics of, 10, 107-8

hormonal abnormalities and, 10, 85

immune and viral factors, 88

prevalence of, 8-9,56

sleep disturbances and, 10, 86-87

social correlates of, 56

suicide and, 7, 52

symptoms of, 10, 53-55

treatment of, 8-9,56,58-59

National Advisory Mental Health Council, 39, 130

National Alliance for Research on Schizophrenia and

Depression (NARSAD), 15, 132

National Alliance for the Mentally Ill (NAMI), 15,37,

132, 154, 156, 160, 161

National Depressive and Manic Depressive Association,

132

National Institute of Mental Health (NIMH)

D/ART program, 27-29, 154-55

genetic counseling and, 114

genetic research investment, 101

mental disorder research funding, 14-17,21-22,123-29

neuroscience research and, 6, 21-22, 38, 123-30

research budget, 14-15, 17, 39, 124-25

National Institute on Aging, 124

National Institutes of Health (NH-I), 130-31, 138
186 ● The Biology of Mental Disorders

National Mental Health Association, 132

National Science Foundation (NSF), 133

Neuroendocrine systems, mood disorders and, 85

Neuropeptides, 38, 84

Neuroscience

ethical, legal, and social issues, 23-24, 26, 39

federal funding for research, 5,21-23,37,39, 130-132

growth and advances in field of, 5-6, 37-38, 156, 163

research, 38-39

Neurotransmitters, 38

action of, 72-74

mood disorders and, 82-85

schizophrenia and, 77-79

NIMH. See National Institute of Mental Health

Norepinephrine receptors, 84

Obsessions, 60-61

frequency by type, 12,63

Obsessive-compulsive disorder

age at onset of, 11, 62

animal models of, 135

biochemistry of, 88-89

brain structure and function and, 11, 89-90

comorbidity and, 57, 61

course of, 11, 62

genetics of, 108-9

individual experience of, 60-61

manifestations of, 11, 60-61, 88

prevalence of, 3, 11,35,62

risk of, 113

Tourette’s syndrome and, 11,62, 89-90, 109, 111

treatment for, 11, 62

OCD. See Obsessive-compulsive disorder

Panic disorder

age at onset of, 12, 63

brain chemistry of, 13,90-91

brain structure and function and, 13,91-92

comorbid substance abuse and, 57

course of, 12, 63

genetics of, 13, 108-9

prevalence of, 3, 12,35,63

risk of, 113

suicide and, 7, 52

symptoms of, 11-12, 62-63

theories of origin of, 12-13, 90

treatment of, 12, 63-64

Penfield, Wilder, 38

Personality disorders, schizophrenia and, 50, 106

Pharmacogenetics, 111

Phencyclidine (PCP), 79

Phenotype, 111

Phenylketonuria (PKU), 112

Positron emission tomography (PET), 74,76,77,79, 80

postmortem brain tissue availability, 17-18, 138-40

Prescription drugs. See Drugs

President’s Commission on Mental Health, 5,37

Productivity losses and mental disorders, 4, 35, 36

Prozac. See Fluoxetine

Psychodynamic psychotherapy, definition of, 59

Psychological tests, 38,76

Psychopharmacology. See Drugs

Psychosis

bipolar disorder and, 9

major depression and, 53

mania and, 54

schizophrenia and, 6, 50

Psychosocial factors and mental disorders, 13,71, 112,

161

Psychotherapy

bipolar disorder and, 9,59

major depression and, 8, 58

modalities of, 59

obsessive-compulsive disorder and, 11, 62

panic disorder and, 12,63-64

schizophrenia and, 52

Public attitudes toward mental disorders, 3,5,26,151-56,

163

Public education about depression, 27-29, 154-55

Public Health Service (PHS) Guidelines for Animal Care

and Use, 134-35

Reproductive hormonal alterations, mood disorders and,

10,55, 85

Research into mental disorders

animal models for, 134-36

barriers to, 16-18

brain tissue and, 17-18, 138-40

clinical studies, 136-38, 140-41

federal funding for, 5, 14-17,21-23,37,39, 123-31

impact of, 18-19, 21, 156-63

public concern and, 14-16

Responsibility for mental disorders, perceptions of,

19-20, 156, 158, 160-61

Risk of mental disorders, 113

SAD. See Seasonal affective disorder

Schizoaffective disorder, 50, 108

Schizophrenia

age at onset of, 8, 51

animal models of, 135

biochemistry of, 7,77-79, 82

brain structure and function and, 7-8,79-81, 82

comorbid substance abuse and, 57

conceptualization of, 50

course of, 8, 50-51

developmental factors and, 8, 81

DSM-III-R criteria for, 47

genetics of, 8, 106-7, 111

hypothesized causes of, 8,50

immune and viral factors, 8, 81

individual experience of, 48-49, 158

prevalence of, 3,6,35,50-51

risk of, 106, 113
Index . 187

smooth-pursuit eye movements and, 111-12

socioeconomic correlates of, 51

suicide and, 6-7, 52

symptoms of, 6-7, 47, 50, 51-52, 77

treatment of, 7,52-53

“Schizophrenogenic” mother, 112, 160

Scottish Rite Foundation, 132

Seasonal affective disorder

characteristics of, 55, 87

treatment of, 8, 58

Serotonin

mood disorders and, 83

obsessive-compulsive disorder and, 11, 62, 88-89

receptors, 84, 112

suicide and, 83

Single-photon-emission computed tomography (SPECT),

76-77

Sleep disturbances, mood disorders and, 10,86-87

Smooth-pursuit eye movements (SPEM) and schizophrenia, 111-12

Social issues surrounding neuroscience advances, 23-24,

26,39

Society for Neuroscience, membership of, 5,37

Socioeconomic status

mood disorders and, 56

schizophrenia and, 50, 56

State and local government funding for mental health

services, 5, 37, 131-32

Sterilization, compulsory, and eugenics, 25, 104, 113

Stigma attached to mental disorders, 3,5,26,151-53,163

Styron, William, account of depression, 9,54

Substance abuse or dependence, 3,35

mental disorders and, 57

obsessive-compulsive disorder and, 11, 61-62

prevalence of, 57

Suicide

major depression and, 8, 53

mental disorders and, 6-7, 52

schizophrenia and, 7, 51-52

serotonin and, 83

Tardive dyskinesia, 53

Tourette’s syndrome and obsessive-compulsive disorder,

11,62, 89-90, 109, 111

Tricyclic antidepressants

action of, 82

generic and brand names, 58

Twin studies, 105

U.S. Department of Agriculture, regulation of biomedical

research on animals, 135

U.S. Department of Veterans Affairs

hospital care for persons with mental disorders, 3,4,36

mental disorders research by, 22-23, 130

Uniform Anatomical Gift Act of 1987, 140

VA. See U.S. Department of Veterans Affairs

Violence and mental disorders, 20, 158, 159

Viral factors

mood disorders and, 88

schizophrenia and, 8, 81