BREAKING GROUND, BREAKING THROUGH: 

THE STRATEGIC PLAN FOR

MOOD DISORDERS RESEARCH OF

THE NATIONAL INSTITUTE OF MENTAL HEALTH
Table of Contents 

EXECUTIVE SUMMARY .........................................................................................5

The Nature and Impact of Mood Disorders............................................. 5 

 The Scope of the Problem............................................................... . 6 

 Scientific Opportunities for Research on Mood Disorders........................... 9 

Developing the NIMH Strategic Plan for Mood Disorders Research.................9

 Basic and Clinical Neuroscience: Foundation for Discovery.........................10 

Neuroscience............. ...................................................................11 

 Dimensions of Age and Disease......................................................... 12 

 Treatment, Prevention, and Services: Improving Outcomes........................ 13 

Expanding and Strengthening the Research Foundation........................... 14 

INTRODUCTION ...................................................................................................16

 The Nature and Impact of Mood Disorders............................................. 16 

Mood Disorders Research at NIMH: A 50-Year Perspective..................... ... 17 

About Strategic Planning at NIMH...................................................... 20 

BASIC AND CLINICAL NEUROSCIENCE: FOUNDATION FOR DISCOVERY...22

Current Status of the Field............................................................................................. 22

Triggering the Mood Changes in Depression and Bipolar Illness................................ 22 

The Connection Between Neurochemistry and Mood Disorders ............................ 22 

Specific Brain Regions Are Affected in Mood Disorders ....................................... 24 

Thought Processes Affect Mood Disorders ............................................................. 24 

Using Computers to Model Mood Disorders........................................................... 26 

Finding the Genes Involved in Mood Disorders........................................................... 26 

Gene-Environment Interactions............................................................27 

Animal Models......................................................................................................... 27 

Behavioral Models of Mood Disorders......................................................................... 29 

Studying Depression in Rodents.............................................................................. 30 

Non-Human Primate Models of Depression............................................................ 31 

Animal Models of Mania......................................................................................... 32 

Neurobiology and Drug Action .................................................................................... 33 

Communication Between Cells................................................................................ 34 

Communication Within a Cell ................................................................................. 35 

Opportunities for Progress............................................................................................. 37

Opportunities to Discover a Genetic Basis of Mood Disorders.................................... 37 

Opportunities to Understand the Neural Basis of Mood and Emotion ......................... 39 

Brain Structure and Mood Disorders ....................................................................... 40 

Opportunities to Discover New Drug and Physiologic Treatments.............................. 42 

Biomarkers............................................................................................................... 43 

Pharmacogenetics and Its Contributions to Drug Discovery and Drug Utilization. 43 

Research Priorities.......................................................................................................... 44
DIMENSIONS OF AGE AND DISEASE ................................................................50

Current Status of the Field............................................................................................. 51

Mood Disorders in Children ......................................................................................... 51 

Developmental Factors ............................................................................................ 51 

Hormones................................................................................................................. 51 

Anxiety..................................................................................................................... 51 

Family Risk Factors for Early-Onset Depression .................................................... 52 

The Influence of Gender on Mood Disorders............................................................... 53 

Aging and Depression................................................................................................... 54 

Cognition and Depression in the Elderly................................................................. 54 

Psychosocial Factors in Geriatric Depression.......................................................... 55 

Depression and Caregiving...................................................................................... 56 

Depression and Illness in the Elderly....................................................................... 56 

Comorbidity: Depression and Other Medical Illnesses ................................................ 57 

Coronary Heart Disease ........................................................................................... 57 

Diabetes.................................................................................................................... 58 

Neurological Disorders and Stroke.......................................................................... 58 

Cancer ...................................................................................................................... 59 

HIV/AIDS................................................................................................................ 59 

Opportunities for Progress............................................................................................. 60

Opportunities to Identify Depression and Bipolar Disorder During Development ...... 60 

Opportunities to Develop New Therapies for Children and Adolescents..................... 62 

Opportunities to Understand the Influence of Gender................................................. 63 

Depression and the Reproductive Cycle.................................................................. 65 

Opportunities to Improve Mental Health for the Elderly.............................................. 65 

Opportunities to Understand Mood Disorders as Diseases of the Brain and Body...... 67 

Research Priorities.......................................................................................................... 68

TREATMENT, PREVENTION, AND SERVICES: IMPROVING OUTCOMES ......75

Current Status of the Field............................................................................................. 75

Clinical Trials................................................................................................................ 75 

Pharmacological Therapy ............................................................................................. 77 

Depression................................................................................................................ 77 

Bipolar Disorder....................................................................................................... 78

 Somatic Treatments for Mood Disorders......................................................79 

Psychosocial Therapy Development............................................................................. 80 

Depression................................................................................................................ 80 

Bipolar Disorder....................................................................................................... 81 

Issues for Treatment...................................................................................................... 81 

Measurement............................................................................................................ 81 

Prevention of Suicidal Behavior .............................................................................. 82 

Delivery of Services...................................................................................................... 83 

Primary Care ............................................................................................................ 83 
Barriers to Care........................................................................................................ 83 

Issues Facing Racial and Ethnic Minority Groups .................................................. 85 

Children and Adolescents ........................................................................................ 86 

Opportunities for Progress............................................................................................. 86

 Opportunities to Improve and Expand Clinical Trials.......................................87 

Increasing Participation Diversity in Clinical Trials ............................................... 88 

Opportunities to Develop New Psychosocial and Behavioral Therapies ..................... 88 

Opportunities for the Prevention of Mood Disorders ................................................... 89 

Using Non-Traditional Dissemination Methods to Increase Accessibility to 

Psychosocial Interventions.................................................................................... 91 

Research Priorities.......................................................................................................... 92

EXPANDING AND STRENGTHENING THE RESEARCH FOUNDATION ... 96 

 Research Training................................................................................97 

 Disseminating Research Results...............................................................97 

Research Priorities................................................................................98 

APPENDICES....................................................................................101 

 Appendix A: National Advisory Mental Health Council................................101 

 Appendix B: Mood Disorder Workgroups.................................................104 

 Appendix C: NIMH Staff Participants............ ........................................ 112 
EXECUTIVE SUMMARY 

Mood disorders, the foci of this strategic plan for research, are serious medical 

illnesses that affect more than 20 million Americans of every race and ethnic group and 

at every stage of life, from childhood through old age. Mood disorders are “brain 

disorders,” meaning they are mediated through the brain, yet they disrupt every facet of a 

person’s life: emotions, thought processes, behavior, and physical health. Left untreated, 

or inappropriately treated, mood disorders are potentially fatal; nearly one in six persons 

with severe, untreated depression will die by suicide. Short of this tragic outcome, mood 

disorders are immensely disabling. A landmark study sponsored by the World Health 

Organization and the World Bank reports that in the United States and other nations with 

developed economies, major depression is the leading cause of disability. The same study 

projects that by the year 2020, depression will be the second leading cause of disability 

worldwide. The mission of the National Institute of Mental Health (NIMH) is to reduce 

the burden of mental illness and behavioral disorders through research on mind, brain, 

and behavior. Clearly, improved understanding, recognition, treatment, and prevention of 

mood disorders are critical scientific and public health priorities. 

The Nature and Impact of Mood Disorders 

Breaking Ground, Breaking Through: The Strategic Plan for Mood Disorders 

Research of the National Institute of Mental Health addresses two types of mood 

disorder—major depression and bipolar disorder, also known as manic-depressive illness. 

The term depression, of course, refers not only to an illness, but also to moods and 

behaviors that occur in the normal course of life. Unlike the normal shifts in mood that 

most people experience, however, the symptoms of depression are more extreme and 

frequently incapacitating. These symptoms include a persistent sad mood; loss of interest 

or pleasure in activities that were once enjoyed; significant change in appetite or body 

weight; difficulty sleeping or oversleeping; physical slowing or agitation; loss of energy; 

feelings of worthlessness or inappropriate guilt; difficulty thinking or concentrating; and 

recurrent thoughts of death or suicide. A diagnosis of depression is made if an individual 

has five or more of these symptoms every day during a 2-week period. In bipolar 

disorder, episodes of depression alternate with episodes of mania, a condition marked by 

periods of abnormally and persistently elevated mood or irritability accompanied by at 

least three of the following symptoms: overly inflated self-esteem; decreased need for 

sleep; increased talkativeness; racing thoughts; distractibility; increased goal-directed 

activity or physical agitation; and excessive involvement with pleasurable activities that 

have a high potential for risky consequences. 

By far the more common of the two, major depression affects approximately 19 

million American adults at any given time and an estimated 6 percent of children ages 9 

to 17. For reasons that are not clearly understood, depression occurs twice as often among 

women as men. Five to 14 percent of women will have an episode of depression at some 

point in their lives in contrast to 2 to 4 percent of men. Bipolar disorder affects some 2.3 
million American adults, or approximately 1 percent of the population, and distributes 

roughly equally between men and women. Although firm data are lacking on the extent 

to which bipolar disorder affects children and adolescents, clinical experience suggests 

that some proportion of children and adolescents who have major depression eventually 

will be found to have bipolar disorder; this likelihood increases if the depressed young 

person has a family member with bipolar disorder. 

Today, the intense and disabling symptoms of depression and bipolar disorder 

often can be relieved through treatment involving combinations of medications and 

psychotherapy. Yet even with appropriate treatment, both depression and bipolar disorder 

tend to be episodic and recurrent; that is, after a person has been depressed once and 

recovers, he or she is likely to have in the future one or more episodes of depression, 

and/or mania in the case of bipolar disorder. Single episodes are the exception. This 

pattern of illness implies high, and sustained, personal, family, and societal costs—costs 

that can and will be reduced substantially through an accelerated program of research and 

discovery. 

The Scope of the Problem 

As described below, and in greater detail in the Introduction, the strategic 

planning process began in late 2000 when NIMH established nine workgroups, each with 

expertise in an area of research relevant to some facet of mood disorders, to develop 

comprehensive reviews of the state-of-the-science in a given area. That such a large 

number of workgroups were judged necessary to assess research needs and opportunities 

associated with mood disorders should not be surprising. Mood disorders occur across the 

life span, affecting children, adults, and the elderly. They affect people of all races and 

ethnicities, across cultures. Although the brain is the organ most directly implicated in 

mood disorders, these illnesses often are described as “systemic illnesses,” meaning that 

they affect the body in its entirety; that is, mood disorders can affect—and be affected 

by—one’s general health, behavior, and environment. While responsibility for treating 

mood disorders commonly is assigned to psychiatrists, psychologists, psychiatric nurses, 

social workers, and counselors, in fact, the preponderance of treatment of mood disorders 

occurs in the general health care sector. Accordingly, the reader of this strategic plan who 

pores through each of its major sections will find all of the following topics addressed. 

• Brain Science—Neuroscientists are gaining the ability to determine just how 

brain cells and circuits function to enable cognition, emotion, and behavior. 

Advances in brain imaging technologies are enhancing the practicality of 

approaches that will image brain function in real time and over periods of 

development. The challenge is to apply this fundamental knowledge, along with 

information about how the brain changes as it develops and ages, to reveal the 

exact brain regions that function incorrectly in depression and bipolar disorder. 

• Genetics—The completion of the Human Genome provides enormous impetus to 

ongoing efforts to identify the genes responsible for vulnerability and resilience to 

depression and bipolar disorder. When combined with growing knowledge of how 

these disorders are inherited within families and with information about the 

environmental triggers needed to activate vulnerability, the genetics revolution 
permits us to anticipate one day using the word “cure” in the context of the mood 

disorders. 

• Behavior—The explosion in new knowledge about genetics, structure, and 

function of the brain has challenged behavioral scientists to radically expand the 

traditional boundaries and methods of their discipline to determine how specific 

behaviors are directed and modified by genes, how behavior can modify the brain, 

how behavioral therapies for mental disorders can be strengthened, and how 

behavioral strategies for preventing the onset or recurrence of depression and 

bipolar disorder can be refined. 

• Treatment—With greater understanding about the brain mechanisms involved in 

memory, decision making, and emotional responses to traumatic events, 

researchers are revisiting and redesigning many of the treatments currently in use 

for mental disorders. Translation of basic science findings into innovative 

behavioral and pharmacological treatments that can either correct or compensate 

for brain dysfunctions will yield more effective treatments. 

• Prevention—Though genetic factors may play some role in predisposing 

individuals to developing depression, it is clear that the triggers for depression are 

largely environmental. As a result, studies aimed at identifying and understanding 

the environmental risk factors for depression should provide insights for 

developing novel behavioral, educational, and pharmacological methods for 

preventing depressive symptoms from occurring or reducing their duration and 

severity when they do recur. 

• Service Systems and the Delivery of Treatment—Understanding and correcting 

disparities in access to and quality of mental health treatment not only will benefit 

individuals who have mood disorders, but also will help to raise the overall 

quality and effectiveness of health care services. 

In addition, during the development of the strategic plan, the need for research 

focused on the particular needs of special segments of the population—women, children, 

elderly persons, members of racial and ethnic minority groups, and persons who 

simultaneously have a mood disorder and another general medical illness—became 

glaringly apparent. Accordingly, these issues come up repeatedly in both the scientific 

reviews and the listing of research priorities and objectives, and warrant special mention. 

• Women and Depression—There is evidence that women are at least twice as 

likely as men to experience a depressive episode within a lifetime, a fact that 

would suggest the need for the development of gender-specific therapies and 

prevention strategies, but also may provide important biological insights into the 

causes of depression. For example, women are more likely than men to 

experience the symptoms of depression on a seasonal basis. They are also more 

likely than men to have a prior history of anxiety disorder and to experience 

physical symptoms along with depressive symptoms. Childhood-onset depression 

appears to confer similar risk of subsequent depression for girls and boys. 

However, earlier onset in boys is associated with comorbidity and suggests a 

“purer” form of depressive disorder. Depressed girls report higher levels of mood 

disturbance, while boys report more irritability. Since gender differences in rates 
of depression emerge in early adolescence, there are obvious questions about the 

role of biological factors, specifically sex hormones, as well as social and cultural 

influences in the development of depression. For women, the age of onset of 

depression also often coincides with the age period of childbearing, and there is 

evidence that pregnancy and the postpartum state are associated with heightened 

risk for bipolar depression. 

• Children—One of the most fundamental advances in mood disorders research 

has been to demonstrate that depression and bipolar disorder are as much illnesses 

of childhood and adolescence as they are of adulthood. Now, researchers need to 

better understand the childhood precursor forms of depression and bipolar 

disorder and how and when to intervene preventively in children who are most at 

risk of developing these illnesses. Designing the most effective mental health care 

services for children and adolescents is also a critical task for the future. 

• Elderly Persons—Although depression is strikingly prevalent among older 

people, its assessment and diagnosis can be especially challenging. The clinical 

presentation of depression in older adults may differ from that seen in young 

adulthood and midlife. For example, many older people tend to report to their 

health care provider somatic complaints rather than psychological problems, and 

often do not present with the full range of symptoms that constitute the threshold 

for diagnosis of clinical depression. In addition to the complications associated 

with social isolation and loss, detection of depression in late life can be obscured 

by other co-occurring general medical disorders. 

• Comorbidity—The occurrence of depression and other mood disorders in the 

context of other illnesses is particularly common among elderly people, yet it is 

increasingly clear that depression may play a role in both the cause and 

progression of many other ailments across the life span. Research has shown that 

treatment of co-occurring, or comorbid, depression can often improve health 

outcomes for many people with a wide variety of diseases. Not only may relief 

from depression help a person adhere to complex treatment plans and improve his 

or her quality of life, but also researchers are tracing the biological aspects of 

depression at the physiological and cellular levels that could affect these other 

illnesses. 

• Race, Ethnicity, and Culture—America draws its strength from its cultural 

diversity, but the full potential of our diverse, multicultural society cannot be 

realized until all Americans gain access to quality health care that meets their 

needs, particularly when those needs include treatment for depression or bipolar 

disorder. Unfortunately, there exists a striking disparity in the quality of mental 

health services and the underlying knowledge base as it pertains to Americans 

who are members of a racial or ethnic minority group. The U.S. Surgeon General 

recently found that racial and ethnic minority groups bear a greater burden from 

unmet mental health needs and thus suffer a greater loss to their overall health and 

productivity (http://www.mentalhealth.org/cre/default.asp). Addressing this 

disparity will take equal action in two areas: training a scientific workforce for 

research on mood disorders that reflects the full racial and ethnic diversity of the 

Nation, and requiring researchers to conduct investigations using study groups 

that reflect the full racial and ethnic diversity of the Nation. Both steps are vital 
because culture influences so many aspects of mood disorders, including how 

individuals from a given culture communicate and manifest their symptoms, their 

style of coping, their family and community supports, and their willingness to 

seek treatment. Likewise, the cultures of researchers, clinicians, and the service 

system influence diagnosis, treatment, and service delivery. Cultural and social 

influences are not the only determinants of mood disorders and patterns of service 

use, but they do play critically important roles. 

Scientific Opportunities for Research on Mood Disorders 

Advances in the capability to investigate brain function at multiple levels have 

been among the signal achievements of health science over the past decade. NIMH 

collaborates with multiple, diverse scientific disciplines to utilize the tools of molecular 

and cellular biology, genetics, epidemiology, and cognitive and behavioral science to 

gain a more thorough and comprehensive understanding of the factors that influence 

brain function and behavior in normal as well as abnormal states, including mental 

illness. Evidence from neuroscience, genetics, and clinical investigation has demonstrated 

unequivocally that the brain is the primary organ affected in depression and bipolar 

disorder. Modern brain imaging technologies are revealing that in both disorders, neural 

circuits responsible for the regulation of moods, thinking, sleep, appetite, and behavior 

fail to function properly and that critical neurotransmitters—chemicals used by nerve 

cells to communicate—are out of balance. Genetics research indicates that vulnerability 

to depression and bipolar disorder results from the interaction of multiple genes and 

environmental factors. Ongoing research examining brain chemistry and the mechanisms 

of action of antidepressant medications and mood stabilizers, as well as psychosocial 

interventions, continues to inform efforts to develop new and better treatments. As this 

work progresses, NIMH is placing greater emphasis on mental health services and service 

systems research with the aim of improving the field’s capability to deliver existing 

evidence-based treatments with a high degree of fidelity to standards developed and 

evaluated in research settings. 

Looking to the future, scientists agree that advances in multiple arenas will 

continue to frame, at an increasingly rapid pace, remarkable opportunities for mood 

disorders research. 

Developing the NIMH Strategic Plan for Mood Disorders Research 

To ensure an investment of resources that will take maximal advantage of 

proliferating opportunities, NIMH last year convened nine workgroups to examine the 

status of key areas of research relevant to mood disorders. Workgroup foci included 

genetics, neural and behavioral substrates of mood regulation, preclinical models, 

pharmacologic and somatic treatment development, psychosocial intervention 

development, development and natural history, aging and medical comorbidity, clinical 

trials and translation, and overcoming barriers to care/reducing public burden. Leading 

researchers in the field, a broad cross-section of consumer and advocacy group members, 

NIMH staff, and members of the National Advisory Mental Health Council (NAMHC) 

were invited to participate in the workgroups. Nearly 200 people were engaged in an 

iterative process that resulted in a series of in-depth reviews to be used by NIMH staff to 

help guide the Institute’s research on mood disorders (Appendices A-C). 
Drawing on the workgroup reports and other sources, NIMH professional staff 

aggregated the assessments of current knowledge and conclusions regarding scientific 

needs and opportunities into three major sections, described and summarized below. 

In a final phase of the strategic planning process, NIMH staff used the 

consolidated scientific reviews that were endorsed by the NAMHC as the foundation, 

along with other resources, for developing specific research priorities and objectives for 

the Institute. In its entirety, the NIMH Strategic Plan for Mood Disorders Research lists 

52 research objectives buttressed by specific implementation steps; these objectives form 

the core of the plan. This executive summary of the strategic plan presents selected shortand long-term research priorities that represent the scope of the plan. 

Basic and Clinical Neuroscience: Foundation for Discovery 

Advances in basic neuroscience over the past two decades have provided a rich 

and increasingly mature knowledge base for understanding pathophysiology and 

developing rational therapies— pharmacologic and psychosocial—for treating brain 

diseases. Progress in the Human Genome Project actually has been faster than predicted 

and is expected to contribute exponentially to the identification of genes that produce 

vulnerability and resilience to mood disorders, information that will lend itself in rapid 

order to greater diagnostic precision and to the identification of novel drug targets. 

Neuroimaging technologies such as positron emission tomography, or PET 

scanning, and magnetic resonance imaging (MRI) have emerged as invaluable tools for 

research that seek to identify specific brain regions that are involved in and affected by 

mood disorders. The ability to observe regional blood flow in the brain and patterns of 

brain metabolism during specific tasks and events is enabling investigators to recognize 

alterations in particular brain regions that are associated with illness. Some of these 

persist regardless of a subject’s immediate mood state; others can be seen to reverse when 

a subject is responding positively to antidepressant medications or other forms of 

treatment. Piecing together such glimpses of brain activity with what is known of the 

neural circuits and neurochemical pathways associated with specific brain structures and 

regions implicated in mood disorders affords researchers a more comprehensive 

understanding of how existing medications exert therapeutic effect and, in turn, to 

consider novel targets for treatment development studies. 

As neuroscientists delineate with both precision and cross-laboratory consistency 

the brain regions involved in modulating mood, they are achieving a much finer 

appreciation of the role of various neurotransmitter systems, including those using 

glutamate, gamma-aminobutyric acid, serotonin, norepinephrine, and dopamine, that are 

involved in depression and mania. Recent work has identified other neurochemical 

systems that also may be involved in mood disorders, including cell membrane-bound 

signal transduction elements and intracellular signaling systems that modulate gene 

transcription and protein synthesis. Such insights are providing important clues that point 

to neurochemical targets for novel selective pharmacologic manipulation. By 

encouraging investigators to think differently about drug targets, this concentration of 

new knowledge will contribute progressively to new therapeutics. 

Approaching the question of mood from another perspective, research conducted 

over recent decades has yielded an increasingly coherent picture of the critical roles that 
behavioral and learning processes assume in the development, maintenance, and 

treatment of depression. Findings that certain cognitive styles—for example, a person’s 

tendency to make negative global attributions when confronted with discrete, stressful 

life events—have been associated with vulnerability to relapse in depression and bipolar 

disorder, and offer leads for refining and developing new psychosocial therapies. 

Advances in genetics and molecular biological technologies have ushered in a 

new era in the use of animal models for research on mood disorders. Over the years, 

much informative research has drawn inferences about clinical depression on the basis of 

animal models of “depression.” As an alternative approach, investigators today are 

finding it useful to identify intermediate components—for example, sleep disruption in 

depression—that occur somewhere between genes and clinical syndromes. Called 

“endophenotypes,” such components offer a means of parsing out with considerable 

precision a particular feature of a disorder that can be measured in animal behavior—

another example might be a physiological response to a stressful stimulus. Such strategies 

simplify the task of identifying the genetic basis for the feature in question, and they 

facilitate the translation of findings among various animal models and from animals to 

humans. 

What makes this a particularly promising time is the manner in which information 

is converging from genetics, neurobiology, animal models of mood disorders, basic 

behavioral research, and cognitive neuroscience. Seemingly unrelated advances in each 

of these areas collectively are pushing the field toward the discovery of biological 

markers for mood disorders, which in turn will yield improved diagnostic measures and 

point to the ultimate biological causes and environmental triggers for mood disorder 

symptoms. This information, scientists anticipate, will culminate in the development of 

new behavioral and pharmacological treatments. 

Selected Research Priorities and Objectives: Basic and Clinical Neuroscience 

Opportunities to Discover a Genetic Basis of Mood Disorders: 

• Enhance the broad availability and coordination of core research resources in 

extramural and intramural genetics research programs for use in future genetic 

studies of mental disorders. 

Opportunities to Understand the Neural Basis of Mood and Emotion

• Identify measures of core symptoms of depression and mania that can be modeled 

in animals (e.g., indices of cognitive processes, sleep disturbances, or reward 

mechanisms) as an essential first step in model development. 

• Establish how experiential and genetic factors interact to modulate neural and 

behavioral indicators of mood disorders. 

• Expand resources in support of greater quality, availability, and use of 

postmortem brain tissues for studies of brain structure and circuitry related to 

mood disorders. 

Opportunities to Discover New Drug and Physiologic Treatments

• Establish quantitative outcome measures and biological markers for the diagnosis 

and assessment of disease progression and treatment of mood disorders. 
• Establish long-term partnerships between government, academia, and industry to 

accelerate innovative drug discovery and the development of behavioral assays 

for evaluating novel therapeutics. 

Dimensions of Age and Disease 

A central consideration in developing the strategic plan was that the prevalence of 

mood disorders is not constant throughout the human life span. Not only do rates of 

depression vary, but the types of depression that occur early in life are likely to be 

different than those that occur late in life, when comorbid illnesses often play a 

significant role in psychological well-being. Prior to the 1980s, most clinical research and 

virtually all epidemiologic research on depression was confined to adult samples. Only as 

research involving children and adolescents has been undertaken in recent decades have 

clinical investigators begun to appreciate that many—perhaps most—individuals with a 

depressive disorder began to experience serious symptoms early in adolescence and that 

their vulnerability to develop these conditions may have been established even earlier. 

An equally important and researchable insight has been that depression is not a 

normal feature of aging and that late-life depression principally affects individuals with 

other medical and psychosocial problems, including cognitive dysfunction, disability, 

medical illnesses, and social isolation. The prospect of a rapidly expanding “old-old” 

population in the United States over the next decades portends significantly increased 

rates of comorbid depression and cognitive impairment, a malign duo that will drive up 

health care costs while diminishing substantially the quality of life for affected 

individuals. These clinical associations are guiding the development of hypotheses 

regarding mechanisms that predispose, initiate, and perpetuate specific mood syndromes 

in late life. 

Yet another arena of robust research activity in recent years has examined gender 

disparities in depression. Issues under study include the question of a marked gender-byage change during adolescence; prepubertally, boys and girls have comparable rates of 

depression, but beginning in early adolescence, the rate in girls rapidly increases to the 

point where women’s lifetime rates of depression are twice those experienced by men. 

Some early evidence suggests that genes play a larger role in the development of 

depression in women than they do in men. Also, investigators are attentive to the 

possibility of subtle interactions among neurotransmitters such as serotonin that are 

known to be involved in depression and neuroendocrine rhythmicity associated with the 

menstrual cycle or reproduction; such interaction, scientists believe, may be associated 

with the possibility of greater sensitivity on the part of some women to environmental, 

psychosocial, and psychological risk factors for depression. 

Awareness is growing, too, throughout the medical and health care fields, of the 

frequent co-occurrence of depression with a broad array of illnesses—coronary heart 

disease, diabetes, stroke, cancer, and HIV/AIDS, to name but a few. In the course of 

developing the strategic plan, it became evident that a major obstacle to research is the 

lack of attention that existing diagnostic systems give to the recognition and diagnosis of 

depression in the context of medical illness. Depression, investigators now know, should 

not be viewed as—or, worse, somehow dismissed as—an understandable consequence of 

one’s having a life-threatening or chronic illness; rather, depression should be recognized 
as a discrete condition usually amenable to appropriate treatment. A nascent body of 

research, moreover, points to clinical depression as a factor that, left untreated, can have 

an active and negative impact on the course and outcome of general medical illness. 

Selected Research Priorities and Objectives: Dimensions of Age and Disease 

Opportunities to Identify Depression and Bipolar Disorder During Development

• Determine the developmental pathophysiology of mood disorders. 

• Improve the diagnostic validity of mood disorders in children and adolescents. 

• Develop effective treatments for children and adolescents with mood disorders. 

• Understand the effects of sex and gender on etiology, diagnosis, treatment, and 

prevention of depression and bipolar disorder in women. 

Opportunities to Improve Mental Health for the Elderly

• Expand the knowledge base of safe and effective treatments for late-life 

depression and associated suicide risk. 

Opportunities to Understand Mood Disorders as Diseases of the Brain and Body

• Identify the mechanisms and processes that have a relatively large influence on 

the development of comorbid disorders (i.e., explain a relatively large amount of 

variance in the outcomes) and can also be modified through intervention. 

Treatment, Prevention, and Services: Improving Outcomes 

The scientists and consumer advocates alike who participated in the workgroups 

acknowledged that although refinements in pharmacological, behavioral, and 

psychosocial interventions are of immense benefit to many persons with mood disorders, 

all too many people with depression or bipolar disorder go untreated or receive less than 

optimal treatment. Even when persons with these illnesses receive treatment, only 

slightly more than half of all of them respond well to therapy, which typically is defined 

as experiencing a 50 percent or greater reduction from baseline symptom severity. If 

complete symptom remission or restoration of function is the outcome criterion, then the 

proportion is even lower. 

Most of what is known about the efficacy of pharmacological and behavioral 

treatments is derived from research conducted in academic settings involving relatively 

homogeneous populations of almost exclusively Caucasian people without co-occurring 

general medical or mental illnesses. Thus, in addition to translating information newly 

acquired from basic research into clinical applications, urgent need exists for research to 

assess the effectiveness of existing treatments in actual urban and rural community 

settings. This is a challenge that calls, in turn, for studies that will identify and validate 

markers of treatment outcome—physiological, cognitive, functional, and behavioral—

that extend well beyond acute symptom remission. Research also is needed that will 

focus on innovative strategies for improving the delivery of care to diverse populations, 

particularly racial and ethnic minority groups. A related challenge common to all mood 

disorders, but particularly nettlesome in the management of bipolar disorder, is the need 

for new approaches to encouraging adherence to treatment regimens. 
The high risk for suicidality in the context of mood disorders makes imperative 

the need for innovative research despite such formidable obstacles as the ethical concerns 

that surround the inclusion of actively or potentially suicidal subjects in controlled 

clinical trials. 

In today's world of constantly shifting health care organizations and a rapidly 

expanding array of treatments, a central challenge for intervention research in mood 

disorders is to select research priorities and design trials that will have high public health 

significance while promising to yield information relevant to continuously evolving 

service delivery and reimbursement systems. In clinical trials and prevention studies, 

researchers must actively strive to reach out to diverse communities and populations to 

ensure that persons representative of all Americans will participate in research, so that the 

findings will reflect the best outcomes for all groups. 

Selected Research Priorities and Objectives: Treatment, Prevention, and Services 

Opportunities to Expand and Improve Clinical Trials

• Assess the long-term effects of treatment interventions on physiological and 

functional status. 

Opportunities to Develop New Psychosocial and Behavioral Therapies

• Determine the basic mechanisms by which psychosocial interventions operate to 

produce therapeutic change to increase opportunities for innovative 

developments. 

Opportunities for the Prevention of Mood Disorders

• Determine what interventions are needed during various phases of an illness to 

help prevent the recurrence and relapse of mood disorders. 

Opportunities to Improve Delivery of Services

• 

• 

• 

Understand the processes by which theoretically based research information on 

mood disorders is effectively disseminated and implemented or utilized by 

clinicians or delivery systems. 

Increase the development of practice-level interventions that are based on 

research tested theoretical models. 

Identify the individual, social, and cultural determinants of stigma and develop 

interventions to change these determinants. 

Expanding and Strengthening the Research Foundation 

The utility of the scientific agenda that holds center stage throughout the pages of 

this mood disorders research strategic plan ultimately will be measured in the extent to 

which it improves the lives of individuals who themselves have a mood disorder or who 

deal with the impact of mood disorders in the context of family, work, or other social 

groupings. The centrality of the human element in planning, conduct, and application of 

research was recognized by every workgroup that contributed to the strategic plan. 

Clearly, the needs of individuals with mood disorders are a driving force behind 
development of the plan. But many other persons are equally critical: educators who play 

a vital role in training young scientists in the techniques and nuances of research relevant 

to mood disorders; researchers and communicators whose primary responsibility is to 

disseminate the knowledge generated through research; and clinicians and other health 

and social service professionals who apply the products of research in diverse settings. 

Challenges in two particular arenas—training tomorrow’s researchers and putting 

the fruits of research in the hands of public health practitioners, clinicians, and members 

of the general public—cross-cut the entire strategic planning process. Absent a solid 

foundation in these areas, even the most innovative scientific agenda becomes a sterile 

exercise. In compiling this final document, NIMH staff culled from the workgroup 

reports an array of implicit and explicit recommendations for research training that 

encompass disciplinary as well as demographic gaps in the contemporary research 

community and, importantly, that anticipate the impact of future scientific advances and 

shifts in the Nation’s age and racial/cultural composition in the years ahead. A second 

category of needs and opportunities involves educating front-line clinicians and the 

public-at-large about mood disorders, using a mix of media and language and formats 

that will be broadly accessible. An example of a more specific educational challenge is 

that of informing interested individuals—clinicians as well as patients—how to learn 

about and participate in clinical services and prevention trials. 

Selected Research Priorities and Objectives: Expanding and Strengthening the 

Research Foundation 

Opportunities to Expand and Strengthen the Research Foundation in Training

• Address the shortage of new and established investigators in various disciplines to 

conduct mood disorders research, particularly racial and ethnic minority 

investigators, and those focusing on child and elderly populations. 

Opportunities to Expand and Strengthen the Research Foundation in Public Education

• Expand the dissemination and translation of mood disorders risk factors, 

diagnosis, and treatment knowledge to the community. 
INTRODUCTION

Mood disorders, the foci of this strategic plan for research, are serious medical 

illnesses that affect more than 20 million Americans of every race and ethnic group and 

at every stage of life, from childhood through old age. Mood disorders are “brain 

disorders,” meaning they are mediated through the brain, yet they disrupt every facet of a 

person’s life: emotions, thought processes, behavior, and physical health. Left untreated, 

or inappropriately treated, mood disorders are potentially fatal; nearly one in six persons 

with severe, untreated depression will die by suicide. Short of this tragic outcome, mood 

disorders are immensely disabling. A landmark study sponsored by the World Health 

Organization and the World Bank reports that in the United States and other nations with 

developed economies, major depression is the leading cause of disability. The same study 

projects that by the year 2020, depression will be the second leading cause of disability 

worldwide. The mission of NIMH is to reduce the burden of mental illness and 

behavioral disorders through research on mind, brain, and behavior. Clearly, improved 

understanding, recognition, treatment, and prevention of mood disorders are critical 

scientific and public health priorities. 

The Nature and Impact of Mood Disorders 

Breaking Ground, Breaking Through: The Strategic Plan for Mood Disorders 

Research of the National Institute of Mental Health addresses two types of mood 

disorder—major depression and bipolar disorder, also known as manic-depressive illness. 

The term depression, of course, refers not only to an illness, but also to moods and 

behaviors that occur in the normal course of life. Unlike the normal shifts in mood that 

most people experience, however, the symptoms of depression are more extreme and 

frequently incapacitating. These symptoms include a persistent sad mood; loss of interest 

or pleasure in activities that were once enjoyed; significant change in appetite or body 

weight; difficulty sleeping or oversleeping; physical slowing or agitation; loss of energy; 

feelings of worthlessness or inappropriate guilt; difficulty thinking or concentrating; and 

recurrent thoughts of death or suicide. A diagnosis of depression is made if an individual 

has five or more of these symptoms every day during a 2-week period. 

In bipolar disorder, episodes of depression alternate with episodes of mania, a 

condition marked by periods of abnormally and persistently elevated mood or irritability 

accompanied by at least three of the following symptoms: overly inflated self-esteem; 

decreased need for sleep; increased talkativeness; racing thoughts; distractibility; 

increased goal-directed activity or physical agitation; and excessive involvement with 

pleasurable activities that have a high potential for risky consequences. The symptoms of 

depression and mania can occur at the same time. The cycles of depression, mania, or 

mixed mania and depressive symptoms usually recur and may become more frequent, 

often interfering with work, school, family, and social life. 

Severe mania or depression can be accompanied by periods of psychosis. 

Psychotic symptoms include hallucinations (hearing, seeing, or otherwise sensing the 

presence of stimuli that are not actually there) and delusions (false, fixed beliefs that are 

not subject to reason or contradictory evidence and are not explained by a person's usual 

cultural concepts). Psychotic symptoms associated with bipolar disorder typically reflect 

the extreme mood state at the time, such as the grandiosity during mania or worthlessness 
during depression. Bipolar disorder with rapid cycling is defined as four or more episodes 

of illness within a 12-month period. This form of the illness tends to be more resistant to 

treatment than non-rapid-cycling bipolar disorder. 

Far more common than bipolar disorder, major depression affects approximately 

19 million American adults at any given time and an estimated 6 percent of children ages 

9 to 17. For reasons that are not clearly understood, depression occurs twice as often 

among women as men. Five to 14 percent of women will have an episode of depression 

at some point in their lives in contrast to 2 to 4 percent of men. Bipolar disorder affects 

some 2.3 million American adults, or approximately 1 percent of the population, and 

distributes roughly equally between men and women. Although firm data are lacking on 

the extent to which bipolar disorder affects children and adolescents, clinical experience 

suggests that some proportion of children and adolescents who have major depression 

eventually will be found to have bipolar disorder; this likelihood increases if the 

depressed young person has a family member with bipolar disorder. 

Today, the intense and disabling symptoms of depression and bipolar disorder 

often can be relieved through treatment involving combinations of medications and 

psychotherapy. Yet, as noted, even with appropriate treatment, both depression and 

bipolar disorder tend to be episodic and recurrent; that is, after a person has been 

depressed once and recovers, he or she is likely to have in the future one or more 

episodes of depression, and/or mania in the case of bipolar disorder. Single episodes are 

the exception. This pattern of illness implies high, and sustained, personal, family, and 

societal costs—costs that can and will be reduced substantially through an accelerated 

program of research and discovery. 

Mood Disorders Research at NIMH: A 50-Year Perspective 

 Because of their high prevalence, morbidity, and mortality, mood disorders, along 

with serious illnesses including schizophrenia, autism, and severe anxiety, historically 

have been important research priorities for NIMH. Nearly half a century ago, shortly after 

NIMH was established, two classes of effective antidepressant medications—the tricyclic 

antidepressants (TCAs) and the monoamine oxidase inhibitors (MAOIs) were introduced 

concurrently with the first antipsychotic medications. These new compounds signaled the 

start of what would be termed the “psychopharmacology revolution.” That these 

compounds were discovered serendipitously did not diminish their utility in research any 

less than in clinical practice. In their clinical effects, the new medications lent themselves 

to early efforts to enhance classification and diagnosis in psychiatry; they invigorated 

clinical research; and they were invaluable tools to pioneering neuroscientists engaged in 

studies of the brain and mental illnesses. By 1970, NIMH investigators were among those 

who had participated in research that influenced the Food and Drug Administration’s 

approval of another compound new to this country—the mood stabilizer lithium 

carbonate, used to manage the mood swings associated with bipolar disorder. 

Psychotropic medications and the burgeoning discipline of neuroscience 

accurately heralded a new era focused on the role of the brain in mood disorders, but 

diverse other areas of research also were thriving. Throughout the 1960s and 1970s, 

following a long period of Freudian-inspired attention to “insight” in both the treatment 

and explanation of mental disorders, many psychologists and others became increasingly 

interested in the behavior of a depressed individual and the role of the environment in 
reinforcing and negating that behavior, lines of research that led to new theories about the 

origins of the illness. Other research was focusing on cognitive aspects of mood 

disorders, with investigators speculating that persons might experience sadness, loss of 

motivation, and suicidal wishes because their thinking was disturbed rather than vice 

versa. In fairly short order, these hypotheses and subsequent research led to 

fundamentally new forms of psychotherapeutic interventions. 

At this time too, preclinical investigators were striving to identify circumstances 

in which depression-like symptoms might be generated in animal models. Approaches 

ranged from separating infant monkeys from their mothers, to psychopharmacologic 

manipulations to deplete brain catecholamines, to “learned helplessness” models which 

suggested that early experience with persistent and uncontrollable trauma could lead to 

the development of a passive, helpless approach to dealing with frustration in later life. 

As work in all of these various areas progressed, NIMH sponsored several large 

multisite research programs on depression. These included, for example, the NIMH 

Collaborative Depression Study, a longitudinal naturalistic follow-up study that began 

recruitment in 1978 and today is the longest-running depression study in the world. At 

the start of the project, the major aim was to further the knowledge on the genetics and 

comparative nosology of depression and related mood disorders. As the research 

developed, the aims broadened to include investigations of risk factors in the onset of 

first episodes of depressive illness, course of illness in subjects and relatives, reliability 

and validity of diagnosis and investigations of the effect of comorbidity, as well as many 

more. Among other NIMH projects begun in the 1970s were the Collaborative Study of 

the Psychobiology of Depressive Disorders, which was designed to explore how 

biological, psychological, and environmental forces combine to create depressive states, 

and the Treatment of Depression Collaborative Research Program, the first multisite, 

coordinated study initiated by NIMH in the field of psychotherapy research. The mid1980s saw release of initial findings from the Epidemiologic Catchment Area (ECA) 

study; while not specific to depression, its quantification of mental disorders in the 

United States was critical to all NIMH research on mental disorders. In the late 1980s, 

NIMH launched its Genetics Initiative, a centralized resource needed to achieve large 

sample sizes of complex genetic disorders. The initiative creates cell lines from blood 

samples and saves detailed behavioral and clinical information on subjects with a variety 

of disorders, including bipolar disorder, and makes these samples broadly available to 

qualified investigators. 

Although the field of mood disorders research remained active, in the absence of 

any fundamentally new insights into pathophysiology or etiology, refinements in 

treatments were hard won, at best. In fact, as is noted later in this document, the 

introduction and apparent effectiveness of lithium in treating bipolar disorder, which 

some observers predicted would become as significant a development as use of insulin 

for diabetes, tended to foster a sense of complacency about the need for new types of 

medications and contributed to a worrisome decline in treatment research and clinical 

trials focused on the disorder. By the late 1980s, sustained progress in neurobiological 

research that was capitalized on and augmented by the pharmaceutical industry had 

contributed to the introduction of fluoxetine, a novel antidepressant that selectively 

increased availability of serotonin at synapses. While the compound proved to be safer 

and easier to use than the TCAs and MAOIs, it and successive compounds like it called 
selective serotonin reuptake inhibitors, again failed to yield fundamentally novel insights 

into the mechanisms of mood disorders. 

Paralleling and, in some instances, outpacing scientific and clinical advances were 

the increased understanding of depression by the public and an increasing receptivity to 

acknowledging mood disorders as a treatable condition. This shift was attributable both 

to the vastly increased access to safe and effective pharmacologic treatment through the 

primary care sector, and to a handful of acclaimed and widely read accounts of 

depression, including William Styron’s Darkness Visible: A Memoir of Madness, Patty 

Duke’s A Brilliant Madness, and Kathy Cronkite’s On the Edge of Darkness. Also, the 

importance of research to improved treatment of mental disorders was benefiting from 

both public and private educational efforts. In 1986, NIMH launched its Depression 

Awareness, Recognition and Treatment (D/ART) program, and the energetic efforts of 

consumer-driven advocacy groups including the National Alliance for the Mentally Ill, 

the National Depressive and Manic-Depressive Association, the Anxiety Disorders 

Association of America, and others were highly supportive of research needs. 

The 1990s, designated by presidential proclamation as the “decade of the brain,” 

was indeed enormously fruitful in basic science. Cognitive neuroscience was maturing 

rapidly. Increasingly sophisticated studies of learning and memory contributed to 

elucidating the mechanisms of brain plasticity, enriching understanding of functional and 

structural brain changes in mood disorders and other serious mental illnesses. A new 

appreciation of neural circuitry, including circuitry putatively involved in mood 

regulation, had grown out of steady progress in tract tracing, physiology, research 

involving lesions in animal models, and neuroimaging in humans. The completion of the 

draft sequence of the human genome was imminent, and as the looming relevance of 

molecular biology and genetics to research on genetically complex mental disorders 

became indisputably evident, the realization added urgency to the need for innovative 

cognitive and behavioral science research that would, ultimately, provide a framework 

for molecular-cellular and systems-level neurobiological discoveries. 

Even as NIMH continued to invest heavily in all of these areas, the pressure for 

increasing scientific attention to the more effective use of existing treatments prompted 

NIMH to launch an unprecedented series of clinical trials designed to move beyond 

traditional randomized, controlled efficacy trials conducted in academic medical settings, 

and to evaluate treatments as they are routinely used in community settings, with 

demographically and diagnostically diverse subjects. Three of these new effectiveness 

trials focus on mood disorders—the Systematic Treatment Enhancement Program for 

Bipolar Disorder (STEP-BD), Sequenced Treatment Alternatives to Relieve Depression 

(STAR*D), and Treatment for Adolescents with Depression Study (TADS). Also, in 

2000, NIMH undertook a major revitalization of its intramural, or in-house, Mood and 

Anxiety Disorders Research Program, recruiting a distinguished roster of senior 

investigators from academia. 

Viewed collectively, the stunningly broad array of scientific activities and 

opportunities, combined with the well-documented public health significance of 

depression and bipolar disorder, impressed the NIMH leadership with the need for a 

systematic analysis of the broadest possible arena of mood disorder-relevant research and 

the timeliness of a major strategic planning effort focused on mood disorders. 
About Strategic Planning at NIMH 

 Strategic planning offers a means of strengthening the traditional formula of 

investigator-initiated research that is a central feature of NIH-funded research. Today, an 

abundance of scientific capabilities and opportunities exists in the areas of brain and 

behavioral research. We are increasingly able to perceive how particular research 

emphases will achieve desired goals or outcomes, whether this is new knowledge about 

basic processes, the design and development of clinical interventions, or other objectives. 

As we refine scientific tools and capabilities for treating and preventing mental illness, 

we also are gaining unprecedented knowledge about the distribution, determinants, and 

costs of mental disorders, information that underscores the urgency of research. 

Development of this strategic plan for mood disorders research has involved 

nearly 200 individuals, including members of the National Advisory Mental Health 

Council (NAMHC) and representatives of scientific and advocacy organizations, working 

in collaboration with NIMH. The participation of knowledgeable advocates, including 

consumers and families who can offer valuable information and insights about issues that 

warrant research, has been a particularly useful source of input to the planning process. 

The strategic planning process began in late 2000 when NIMH established small 

workgroups of scientific leaders and public stakeholders, each focused on a key area of 

research. These areas included genetics, neural and behavioral substrates of mood 

regulation, preclinical models, pharmacologic and somatic treatment development, 

psychosocial intervention development, aging and medical comorbidity, development and 

natural history, clinical trials and translation, and overcoming barriers to care and 

reducing public burden. The Institute invited leading researchers in the field, NIMH staff, 

members of the NAMHC, and a broad cross-section of consumer and advocacy group 

members to participate in the process. Participants were assigned to one of the nine 

workgroups with the following charges: 

1. Genetics and Epidemiology of Mood Disorders: Discover risk genes for mood 

disorders. 

2. Neural and Behavioral Substrates of Mood Regulation: Apply cognitive 

neuroscience, and molecular-cellular and systems-level neurobiology to understand 

representation and regulation of mood states in human and animal models. 

3. Preclinical Models: Develop novel animal models to advance understanding of mood 

disorders. 

4. Development and Natural History: Understand risk factors, course, and expression 

of mood disorders during childhood development through adulthood. 

5. Aging and Medical Comorbidity: Focus on etiology, morbidity, treatment, and 

outcomes of mood disorders associated with aging and other medical conditions. 

6. Pharmacologic and Somatic Treatment Development: Advance the development 

and testing of fundamentally new, rationally designed medications and treatments for 

mood disorders. 

7. Psychosocial Intervention Development: Explore opportunities to advance the 

development of innovative treatments for mood disorders and understand the 

mechanisms underlying change. 

8. Clinical Trials and Translation: Improve methods, speed, and cost of research that 

addresses clinical questions, and translates preclinical to clinical models and clinical 

to service models. 
9. Overcoming Barriers to Care and Reducing Public Burden: Determine means to 

eliminate personal, social, professional, financial, and cultural barriers to treatment 

for mood disorders. 

Each workgroup was asked to answer a series of questions about the state of 

current research findings, gaps in the research, and important scientific opportunities. The 

workgroup chairs determined the delegation of work, timing, and frequency of 

conference calls, and the need for meetings prior to the convening of all workgroup 

members at a major conference held on March 24-25, 2001 in Pittsburgh, Pennsylvania. 

Through a round of well over 60 conference calls, the preparation and circulation of draft 

papers, and the 2-day meeting in Pittsburgh, the nine workgroups produced in-depth 

reviews of the current status, needs, and opportunities in each topic area. In the 12 

months following the Pittsburgh meeting, which was essentially the launch of the 

strategic planning process, NIMH staff have carefully analyzed the findings and 

conclusions contained in the workgroup reports and other source materials, and evaluated 

these in the context of the current NIMH mood disorders research portfolio, including 

planned activities and initiatives. Staff, with the assistance of a science writer, drafted 

multiple versions of a research strategic plan, with each iteration moving closer toward 

consensus on a set of broad priorities and specific research objectives ultimately endorsed 

by the NAMHC. 

NIMH intends that this strategic plan for mood disorders research not only will 

guide the Institute’s funding initiatives in the years ahead, but also will serve as a 

resource for all who take an interest in seeing the burden of depression and bipolar 

disorder become a thing of the past. 
BASIC AND CLINICAL NEUROSCIENCE: FOUNDATION FOR DISCOVERY

Significant advances in basic neuroscience over the past two decades have 

provided a rich and increasingly mature knowledge base for understanding 

pathophysiology and developing rational pharmacotherapy in treating brain diseases. 

New discoveries based on novel experimental techniques have repeatedly provided 

human brain researchers with emerging models of neural mechanisms that will 

potentially contribute to disease understanding, as well as a more comprehensive 

understanding of current drug action. Progress in the Human Genome Project has actually 

been faster than predicted and is expected to contribute exponentially to the identification 

of genes producing vulnerability and resilience to mood disorders, and to the 

identification of novel drug targets. 

With considerable precision and cross-laboratory consistency, neuroscientists are 

delineating the brain regions involved in modulating mood. Research has uncovered 

several neurotransmitter systems, including those using glutamate, gamma-aminobutyric 

acid (GABA), serotonin, norepinephrine, and dopamine, that are involved in depression 

and mania. Recent work has also identified other neurochemical systems that may be 

involved in mood disorders, including membrane-bound signal transduction elements and 

intracellular signaling systems that modulate gene transcription and protein synthesis. 

Such insights have provided important clues that point to neurochemical targets for novel 

selective pharmacologic manipulation. This concentration of new knowledge will 

progressively contribute to new therapeutics and allow scientists interested in mood 

disorders to think differently about drug targets. 

What makes this a particularly promising time is the convergence of information 

from genetics, animal models of mood disorders, basic behavioral research, and 

neuroscience. Together, research from each of these areas is pushing the field toward the 

discovery of biological markers for mood disorders, which in turn will yield improved 

diagnostic measures and the discovery of the ultimate biological causes and 

environmental triggers for mood disorder symptoms. Such knowledge will culminate in 

the development of new pharmacological and behavioral treatments. 

CURRENT STATUS OF THE FIELD

TRIGGERING THE MOOD CHANGES IN DEPRESSION AND BIPOLAR ILLNESS

A critical area of research in the field of mental illness aims to gain a better 

understanding of the factors that influence mood. These factors may reflect changes in 

brain chemistry or even in brain structure, genetic effects, or behavioral characteristics, 

such as a particular style of coping with stress or change. Whatever the underlying cause 

of the mood disorders may prove to be, there is little doubt that multiple factors 

contribute to the development of depression and bipolar illness. 

The Connection Between Neurochemistry and Mood Disorders 

One of the most consistent findings from depression and bipolar disorder research 

is that individuals with mood disorders display a variety of changes in brain chemistry 
and even in brain structure. What is still unclear is whether these abnormalities cause the 

vulnerability to abnormal mood episodes or whether they represent the ways in which the 

brain compensates for other, as yet undiscovered disease processes. Another possibility is 

that these observed changes are consequences of recurrent brain illness. Whatever their 

origin, none of these abnormalities are specific or sensitive enough to be useful as either 

diagnostic measures or prognostic indicators of treatment outcome in routine clinical 

care. 

The brain systems that have received the greatest attention in mood disorders 

research have been those that use the neurotransmitters dopamine, serotonin, and 

norepinephrine to transmit nerve signals between neighboring nerve cells. These 

monoamine neurotransmitter systems are extensively distributed throughout the network 

of limbic, striatal, and prefrontal cortical neuronal circuits thought to support the 

behavioral and visceral manifestations of mood disorders. 

The evidence showing that monoamine neurotransmitter systems play an 

important role in mood disorders comes from two types of studies. One avenue of 

research shows that effective antidepressant drugs exert their primary biochemical effects 

by regulating the action of these neurotransmitters. Along similar lines, drugs used to 

treat high blood pressure that reduce brain levels of these monoamines can trigger major 

depressive episodes. 

There is also evidence suggesting that at least some of the biochemical events 

involved in the normal function of monoamine neurotransmission—the ability of a 

neurotransmitter to bind to its receptor on the ends of nerve cells, for example—differ in 

individuals with mood disorders. Neuroimaging, postmortem, and pharmacological 

challenge studies have all shown, for instance, that abnormalities of serotonin1A receptor 

function and binding and serotonin transporter binding are associated with mood 

disorders. 

The monoamine neurotransmitters are not the only neurochemical system affected 

in individuals with mood disorders. For example, elevated activity of the hypothalamicpituitary-adrenal (HPA) axis, which plays a critical role in the body’s response to stress, 

is one of the most replicated biological findings in major depression. Relative to healthy 

control subjects, individuals with depression have elevated levels of the stress hormone 

cortisol in 24-hour collections of plasma and urine, enlarged adrenal and pituitary glands, 

and exaggerated cortisol response to stimulation by the hormone adrenocorticotropin 

(ACTH). 

While dysfunction within these neurotransmitter and neuroendocrine systems is 

likely to play a role in the disease process, researchers now believe that these 

abnormalities may represent downstream effects of other, more primary neurobiological 

problems. It may be, for example, that the disruption of signaling networks that integrate 

multiple chemical signals and regulate the functional balance between interacting 

neuronal circuits constitute a common downstream abnormality. Such an abnormality 

could account for the abnormalities observed in so many neurotransmitter, 

neuroendocrine, and physiologic systems in mood disorders. 
Specific Brain Regions Are Affected in Mood Disorders 

Neuroimaging studies in people with mood disorders have revealed multiple 

abnormalities of regional cerebral blood flow (CBF) and glucose metabolism—two 

proxies of neuronal activity—in various limbic and prefrontal cortical brain structures. 

Some of the changes observed in specific brain regions persist independent of mood state, 

that is, whether or not a person is experiencing depressive or manic symptoms. In 

addition, some of these abnormalities reverse during antidepressant drug therapy in 

individuals who respond positively to the treatment, while others of these neurobiological 

changes do not vary during treatment. 

Data from unmedicated individuals with depression have shown that CBF and 

metabolism are above normal in brain regions such as the amygdala—a brain region 

involved in acquiring and recalling emotional or arousing memories—and parts of the 

orbital cortex, while those same measures are below normal in parts of the prefrontal 

cortex and anterior cingulate cortex. The overall pattern of these metabolic changes 

during an episode of major depression suggests that structures implicated by other types 

of evidence in mediating emotional and stress responses, such as the amygdala, are 

abnormally activated. These patterns also suggest that areas such as the posterior orbital 

cortex that are thought to modulate or inhibit emotional expression are also activated. At 

the same time, brain regions implicated in attention and sensory processing, including 

parts of the anterior cingulate cortex, are deactivated. 

 Elevated metabolism in the amygdala seen during depression, taken with these 

other observations, suggests that the amygdala may be excessively stimulating cortical 

structures involved in forming certain types of memory and that this chain of events may 

account for the tendency of depressed subjects to ruminate on memories of emotionally 

aversive or guilt-provoking life events. Similarly, abnormal activity in the amygdala 

related to depression may conceivably alter the initial evaluation and memory 

consolidation related to sensory or social stimuli in such a way as to magnify their 

emotional significance, an idea supported by other data. For example, norepinephrine 

release in the amygdala plays a critical role in at least some types of emotional learning, 

and activation of the HPA axis stimulates norepinephrine release. At least some 

depressed subjects have abnormally elevated secretion of both norepinephrine and 

cortisol, which in the presence of amygdala activation might increase the likelihood that 

ordinary social or sensory stimuli are perceived or remembered as being aversive or 

emotionally arousing. 

The hippocampus is another brain region that may play a central role in 

depression. The hippocampus is known to play an important role in context-specific 

emotional responses, and individuals with depression often display normal emotional 

responses but in inappropriate contexts. In individuals with long-term depression, 

magnetic resonance imaging (MRI) studies indicate the hippocampus is reduced in size. 

This reduction may result from hyperactivity of corticotropin releasing hormone (CRH) 

or of other components of the HPA axis. Future studies will examine if therapeutic 

treatments can reverse changes in hippocampal structure or function. 

Thought Processes Affect Mood Disorders 

Over the past 30 years, it has become clear that behavioral and learning processes 

play critical roles in the development, maintenance, and treatment of depression. For 
example, individuals who exhibit negative cognitive styles, such as a tendency to make 

stable, global attributions, are more vulnerable to depression and suicide when they 

experience stressful life events than are individuals with more positive cognitive styles. 

These same cognitive vulnerabilities also may increase risk for symptoms or episodes of 

bipolar disorder in combination with stressful life events. 

Rumination, the tendency for a person to focus repetitively on the symptoms of 

depression and the causes and consequences of those symptoms, can increase the severity 

and duration of a depressive episode. Rumination also mediates the effects of negative 

cognitive styles and other vulnerability factors for depression, including past history of 

depression and personality vulnerabilities, in predicting onsets of major depressive 

episodes. Rumination may worsen depression by enhancing negative thoughts about the 

past, present, and future; by interfering with effective interpersonal problem solving; and 

by impairing social relationships. In fact, rumination may be an early predictor of 

depression. 

Though it is clear that life events play a role in triggering episodes of depression 

and mania or hypomania, various kinds of life events may not be equivalent in their 

propensity to trigger depression or mania. For example, major negative events that 

remove a person from his or her normal social network appear to be potent triggers of 

depression. Events that disrupt circadian rhythms, particularly the sleep/wake cycle, or 

that involve goal attainment or “challenge,” are likely triggers of mania or hypomania. 

Furthermore, events that match specific content areas of vulnerability for individuals 

(e.g., rejection for an individual who is highly dependent) may be particularly likely to 

prompt depressive and manic or hypomanic episodes. 

Each of these life event triggers can be seen as a form of stress, but the precise 

manner in which vulnerability and stress combine to lead to depression, mania, or 

hypomania is unknown. It may be that only high-risk individuals with negative cognitive 

styles who experience high stress develop depression, or that high “doses” of stress can 

precipitate depression in individuals with low cognitive vulnerability and low “doses” of 

stress are sufficient to trigger depression in highly vulnerable individuals. Another 

possibility is that high-risk individuals may be drawn to lifestyles that increase their 

exposure to greater life stress and this greater stress, in turn, precipitates depressive or 

manic symptoms. 

Cognitive research has also shown that hopelessness—the expectation that highly 

desired outcomes will not occur or that highly aversive outcomes will occur and that one 

cannot change this situation—may be an important cause of depression. Certainly, 

hopelessness is the best single psychological predictor of suicidal thoughts, attempts, and 

suicide deaths, but whether hopelessness should be best regarded as an early symptom of 

some other factors that trigger depression requires further study. 

While a lack of social support appears to be one factor involved in triggering 

depression, the presence of a strong social support network appears to protect against 

depression when people experience stressful events. Similarly, social support may protect 

individuals with bipolar disorder from mood swing episodes. Strong social support, 

particularly when it can counter negative events, may in fact make a person more resilient 

by preventing the development of hopelessness. 
Using Computers to Model Mood Disorders 

Computational modeling—using computer programs to mimic brain function and 

behavior—is an important tool that can provide valuable insights into cognitive and other 

behavioral functions, their links to neuronal activity, the nature of disorders of these 

functions, and the interdependency between disorders at the neural and functional levels. 

The behavioral and cognitive sciences use many different kinds of models, but at present 

the most widely used and broadly applicable models treat thinking, or cognition, as 

information processing. 

One valuable aspect of computational models is that they frequently enable the 

design of new solutions to practical problems by virtue of their link to mechanism. As 

with models in other sciences, computational models in the behavioral sciences both 

reduce the complexity of behavioral phenomena and provide testable mechanistic 

accounts of the underlying mental processes causing the behavior. Though there are as 

yet no computational models capable of representing the complex changes that occur in 

mood disorders, models have been developed that focus on some of the learning and 

behavioral aspects of these brain illnesses. In addition, some recent modeling work 

involving so-called executive function—brain processes that integrate basic behavioral 

activities—has shown promise in explaining how deficits in dopamine function may be 

responsible for the most severe cognitive problems experienced by people with 

schizophrenia. 

There are several models available that explore certain aspects of learning, a brain 

function thought to malfunction to at least some degree in mood disorders. Some of these 

models are able to capture the function of various brain circuits involved in learning. 

Others provide insights into how neural circuits in the brain might adapt and change with 

learning, and how slight changes in those processes could lead to maladaptive behaviors, 

including some of the precursors of mood change. These modeling efforts could lead to 

new methods for “retraining” the brain for changing behavior itself. 

FINDING THE GENES INVOLVED IN MOOD DISORDERS

Family, twin, and adoption studies of mood disorders have demonstrated 

conclusively that genetic factors are involved in the susceptibility to mood disorders, 

particularly bipolar disorder. The weighted average risk ratio (comparing the prevalence 

of mood disorders among relatives of patients compared to those of controls) for bipolar 

disorder among relatives of individuals with bipolar disorder is 9.2, whereas the average 

risk ratio of major depression among relatives of individuals with bipolar disorder 

compared to those of controls is 1.9. This indicates a very high magnitude of familial 

aggregation of bipolar disorder, similar to that found for many of the major diseases for 

which the genetic basis has been identified. In contrast, the average risk ratio for major 

depression among relatives of individuals with major depression compared to those of 

controls is 2.0, indicating only a moderate influence of familial aggregation on nonbipolar mood disorders. 

The initial enthusiasm generated by early claims of linkage between bipolar 

disorder and various DNA markers faded when these results were not replicated in 

subsequent studies. In fact, numerous linkage studies of bipolar disorder have 

“identified” putative genes on nearly all chromosomes. Investigators have reported weak 
associations of bipolar disorder to several genes involved in the GABA, serotonin, and 

dopamine systems. Recent studies have also identified genes mediating signal 

transduction and other loci relevant for further genetic analysis. However, none of these 

results have been confirmed upon further study. To date, genomic scans have not been 

conducted in studies of depression, and association studies for specific genes have been 

inconclusive. 

There is, however, good reason to be optimistic about identifying genes that 

increase the vulnerability to mood disorders. Advances in gene identification 

technologies, combined with the completion of the Human Genome Project, have 

provided a new foundation of understanding and the tools to undertake a more meticulous 

analysis of the genetics of mood disorders. Recent successes in detecting susceptibility 

genes for other common but genetically complex disorders, including non-insulin 

dependent, or type II, diabetes and inflammatory bowel syndrome, that also had 

experienced the same type of conflicting analysis raise the real possibility that a 

concerted research effort using the same types of tools will yield similar breakthroughs in 

the genetics of mood disorders. 

Gene-Environment Interactions 

While mood disorders are highly heritable, non-genetic factors are also important and, for 

many depressive syndromes, may be just as significant as genetic factors. To date, the 

most studied non-genetic factor that is believed to contribute to depression or bipolar 

disorder is stress. Many cases of mood disorders seem to be preceded by periods of 

stress, but stress per se is not sufficient to induce depression or bipolar disorder in the 

vast majority of individuals. Accordingly, there has been considerable interest in 

preclinical research in studying the ways in which stress (including early life stress) 

might interact with genetic vulnerabilities to modify behavioral phenotypes. 

Conversely, several forms of psychotherapy, including interpersonal 

psychotherapy (IPT) and cognitive-behavioral therapy (CBT), have been shown to be 

effective treatments for mild to moderate depression and effective additions to 

medications for more severe cases. As a result, there has been interest in understanding 

the neural and molecular mechanisms by which positive environmental experiences (e.g., 

enriched environment, optimized early life) modulate complex behavior. 

Based on studies of different rodent inbred strains or mutants, it is clear that 

genetic factors can dramatically alter an animal’s responses to stress, antidepressant 

treatments, and related perturbations. Conversely, environmental factors can compensate 

for genetic-based abnormalities. These interactions are not surprising, given the fact that 

experience changes the brain, that such changes are mediated by the same signal 

transduction pathways implicated in the long-term actions of psychotropic drugs on the 

brain, and that the functioning of these pathways is heavily dependent on an individual’s 

genetic constitution. One goal of current research, then, is to better understand the precise 

mechanisms of interaction and use a combination of genetic and non-genetic 

perturbations to create improved animal models of mood disorders as well as of the 

effects of positive experiences on stress-related abnormalities. 

Animal Models 
Many studies of inbred strains of laboratory animals have shown that genetic 

factors are important in determining an animal’s responses to stress as well as to 

antidepressant treatments. An understanding of these genetic factors could facilitate 

human genetic studies by suggesting individual genes, and even families of genes, that 

might contribute to mood disorders in humans. Such an understanding might also assist in 

the development of better animal models of mood disorders, discussed later in this 

chapter. However, as with human studies, no specific gene to date has been related to 

naturally occurring differences in mood-related characteristics, or phenotypes, seen in 

animals. 

 One approach to improve the likelihood of identifying such genetic factors is to 

use a more carefully selected phenotype or perhaps intermediate biological traits on the 

pathways from genes to complex observable behavioral outcomes (so-called 

“endophenotypes”) as an endpoint. For example, where depression might be considered a 

complex phenotype, increased physiological responses to a stressful stimulus would be 

considered endophenotypes. A given endophenotype may be a more precisely measured 

biological characteristic with a simpler genetic basis, and as such, identifying an 

endophenotype may make it easer to translate results between different species, including 

humans. As a result, as endophenotypes are identified in humans, it should be possible to 

model these in laboratory animals and attempt to identify any genetic determinants. In the 

case of bipolar disorder, for instance, disturbances in the sleep/wake or rest/activity cycle, 

as well as changes in the level of behavioral arousal during these cycles, could be 

conceptualized as possible endophenotypes that would be easily studied in rodents. Many 

individuals with bipolar disorder show abnormalities in rest/activity patterns and 

sleep/wake cycles that precede the onset of changes in mood, and mood stabilizing 

medications significantly alter the cycling of affective episodes over the longitudinal 

course of these disorders. 

In some cases, endophenotypic traits can be observed in lower organisms, such as 

nematodes, flies, or zebrafish. Studies of such organisms are clearly not going to teach us 

about the detailed neural circuitry underlying complex emotions, but they do have the 

power to reveal new biochemical pathways that modulate basic neural and cellular 

functions that are abnormal in mood disorders. As an example, analyzing the pathways 

underlying carefully selected endophenotypes in model organisms could facilitate gene 

discovery and analysis of gene function in mammalian systems. 

 One approach to searching for genes involved in endophenotypes associated with 

depression is to start with an animal that has a genetic alteration—a mutation— 

associated with a particular abnormal behavior that is relevant to the mood disorders; 

disturbances in sleep would be one example. Such phenotype-based mutagenesis offers a 

powerful means of genetically dissecting complex behavior. Though these efforts will be 

difficult, several such phenotype-based mutagenesis programs focused on behavioral 

endpoints have been initiated recently. These programs will soon provide researchers 

with a large collection of mutant mice that have specific behavioral abnormalities 

relevant to the study of mood disorders. The power of this approach is its ability to 

generate a series of mice with subtle variants of phenotypes, something that will be 

critical for identifying a specific gene. The availability of the mouse genome sequence 

and rapid development of genomic technologies that enable mapping and positional 
cloning of mutations, combined with development of suitable phenotypic screens, should 

facilitate the search for the genes underlying behavioral traits in mice. 

 Many traits of biomedical interest exhibit continuous, quantitative variation and 

are therefore believed to be under the control of many genes. Simple examples of 

quantitative traits include height and weight; more complex examples would be mood, 

thought processes, and cognitive capacity. Genes controlling such traits can in theory be 

detected using an approach referred to as quantitative trait locus (QTL) analysis. Most 

QTL studies to date have been conducted on inbred mouse or rat strains that differ 

dramatically in a particular phenotype. The parental inbred strains are then mated, and the 

phenotype of individual animals resulting from these crosses are associated with a marker 

in a specific chromosomal region. Recent advances in both statistical methodology and 

molecular genetics have increased the possibility of identifying QTLs involved in several 

complex behavioral traits, such as fear and emotionality, learning and memory, response 

to mood-affecting drugs, and circadian behavior. However, despite these methodological 

advances, there have been no reports to date identifying the specific genes underlying 

QTLs related to behavioral abnormalities. It remains to be seen whether sequencing the 

mouse genome will facilitate successful identification of these genes or whether the traits 

identified involve too many different genes to isolate any individual genetic variation 

using a classical QTL mapping approach. In these circumstances, random mutagenesis 

approaches as described above may prove to be fruitful. 

Several experimental strategies are currently being employed to generate single 

gene mutations in mice, and there are now many instances of such “transgenic” and 

“knockout” mice contributing to our understanding of mood disorders. For example, 

transgenic mice that overproduce the brain peptide CRH show several characteristics 

consistent with enhanced stress responsiveness and anxiety-like behavior. In contrast, 

mice lacking CRH or one of its receptors show the opposite phenotypes. Transgenic mice 

are also playing a critical role in efforts to understand the role that each of the fourteen 

subtypes of serotonin receptors plays in brain function and behavior. Mice lacking the 

5HT1A receptor, for example, show increased anxiety-like behavior, whereas those 

lacking the 5HT1B receptor are more aggressive and more sensitive to mood-stimulating 

drugs. 

 The major limitation with these types of genetic models is that the mutations affect 

all stages of development and often many tissues and brain regions. As a result, it is 

difficult to ascribe a particular phenotype to a brain region of interest or to determine 

whether a phenotype reflects a developmental abnormality caused by the mutation or, 

rather, reflects loss of the adult function of the mutated protein. However, molecular 

biologists have now devised several “inducible” technologies that allow investigators to 

alter gene expression in specific tissues or at specific times during development. Though 

these techniques have only recently been developed, they hold particular promise for 

studying genetic factors involved in behavior and mood. 

 

BEHAVIORAL MODELS OF MOOD DISORDERS

The best model of a disease is theory-driven. In the case of depression, for 

example, researchers could replicate in a laboratory animal the various factors that cause 

depression in humans and, consequently, many of the symptoms as well. A related 
approach is to model a disease mechanism in a laboratory animal and recreate particular 

features of the disorder. Both of these approaches have been used with considerable 

success in recent years in creating animal models for several neurological conditions, 

such as Huntington’s disease and certain forms of familial Alzheimer’s and Parkinson’s 

diseases, for which the underlying genetic abnormalities are known. These models are 

now being used to explore possible medications that can oppose or even reverse the 

fundamental mechanisms of the diseases. However, as stated earlier, we are still in the 

early stages in understanding the etiology and pathophysiology of depression, let alone 

the genetics, and so such approaches are not yet feasible for studying mood disorders. 

Also, many of the core symptoms of depression and mania involve higher brain functions 

that cannot readily be modeled completely in animals. 

 An alternative approach, then, is to reproduce in laboratory animals particular 

symptoms of depression. These models, which include most of those available today, can 

then be used to study the biological mechanisms underlying those symptoms and to 

develop new treatments that alleviate the symptoms. The main limitation of these models 

is that they may poorly reflect mechanisms involved in the human situation and as a 

result, the biological basis of the animal symptoms may differ from the biological basis 

of human symptoms. Drugs that treat the former may not treat the latter. 

Studying Depression in Rodents 

The most widely used animal models of depression involve subjecting rodents to 

a repeated stress and measuring the effects on behavior. For example, the forced swim 

test is the most widely used animal model in depression research, more specifically as a 

screen for antidepressant treatments. The test involves a rat’s response to being forced to 

swim for some period of time. Short-term treatment with most antidepressants increases 

the time a rat will swim. Although this test is used empirically as a proxy for depression, 

one interpretation is that antidepressants may increase active coping responses to swim 

stress. 

The test also provides a useful model in which to study the neurobiological and 

genetic mechanisms underlying stress and antidepressant responses. The test is not 

perfect, however. For example, antidepressants decrease immobility in the test after even 

single doses, despite the fact that the clinical effects of these agents require 

administration for several weeks or longer. Thus, the test is sensitive to the immediate 

effects of these agents and may not be picking up the true "mood-elevating" changes per 

se that these medications produce in the brain. A critical question in the field is whether 

any antidepressant, regardless of its mechanism, would be active in the forced swim test 

or whether the test can only detect drugs with monoamine-based actions. Ultimately, the 

answer to this question must await the development of clinically effective antidepressant 

drugs with novel mechanisms. 

Learned helplessness is another one of a relatively large number of tests that helps 

us understand the stress response and its role in depression. Animals that develop learned 

helplessness show several changes that are reminiscent of depression, such as REM sleep 

alterations, reduced body weight, diminished sexual behavior, and elevated CRH and 

corticosterone levels. Repeated dosing with antidepressants, as well as repeated ECT, 

decreases the number of animals that show learned helplessness. Such treatment is also 

reported to reduce the various neurological changes seen in these animals. 
The attractiveness of learned helplessness as a behavioral model of depression is 

that it is based on a plausible theory that links cognitive function to visceral results. 

Experience of exposure to uncontrollable stress leads the animal to learn that voluntary 

actions are no longer effective. Controversy has centered on whether the effects of 

learned helplessness are truly cognitive or simply products of stress-induced inactivity. 

However, it seems likely that both the cognitive and other behavioral outcomes may well 

be linked, thus helping to provide a reasonably integrated and broad picture of depressive 

symptomatology that is seen in humans. 

Chronic mild stress and social defeat may serve as more naturalistic stress 

models, and thus may represent more accurately the relationship between stress and 

human depression. Stressed animals are reported to exhibit a general loss of pleasure as 

inferred from a reduction in sucrose drinking, as well as a variety of cardiovascular and 

neurochemical changes that may be reversed by longer-term antidepressant treatment. 

The major disadvantage of the chronic stress models is their poor reproducibility. Both 

the behavioral abnormalities produced by chronic stress and the palliative effects of 

antidepressants in these paradigms have been difficult to replicate across laboratories, 

which has reduced their general application. 

 Several models involving manipulation of early life environment have been used, 

including prenatal stress, early postnatal handling, and maternal separation, with 

environmental enrichment used as the opposite stimulus. The early life stress models 

produce neuroendocrine and behavioral changes in rats and mice that persist into 

adulthood. For example, animals subjected to early stress show a hyperactive HPA axis 

in response to stress. They also exhibit increased locomotor responses to novelty and, in 

some studies, greater vulnerability for learned helplessness and drug self-administration. 

The models are generally good in terms of their replicability, and have been successfully 

used with a variety of species, from rodent to non-human primate. In addition, many of 

the resulting abnormalities can be reversed by antidepressant treatment. On the other 

hand, abnormalities in cognitive performance that persist into adulthood have been less 

reliable, perhaps in part because such tests require a more sophisticated level of analysis. 

Studies aimed at understanding the neurobiological mechanisms of the various 

abnormalities seen are just now getting underway. 

Non-Human Primate Models of Depression 

 While rodent models of depression have the obvious advantage of providing 

inexpensive and readily accessible subjects for high throughput studies, there are 

limitations to studying exclusively rodents in animal models of human diseases, 

particularly those that involve a cognitive and emotional component. For this reason, it 

would be particularly useful to have a well-defined primate animal model. 

There is a body of literature, albeit still relatively small, that has explored models 

of depression in primates. The focus of much of this research has been on the effects of 

early life stress in the form of maternal separation. In general, animals reared under these 

conditions show some signs that are similar to those of depressed humans. More recently, 

less extreme forms of early life stress have been explored in non-human primates. For 

example, mothers exposed to unpredictable stress are more likely to raise offspring with 

altered HPA activity and depression-like behavior as adults. These results are largely 

consistent with the rodent literature and are encouraging as potential primate models. 
However, the majority of primate studies has been carried out on macaques, 

which are large animals that take 3 to 5 years to reach sexual maturity, making these 

studies difficult and expensive to carry out. Primate species that are smaller with shorter 

life spans may be more amenable to these studies. Any new primate model of depression 

should take into consideration special behaviors and environmental requirements of the 

particular species used and examine animals living in more naturalistic settings. 

Animal Models of Mania 

 Bipolar disorder is unique among mental illnesses in that it is characterized by 

spontaneously alternating episodes of depression and mania, which often become more 

severe and cycle more rapidly as the syndrome persists. This oscillating pattern of the 

illness introduces a special difficulty in the development of an appropriate animal model 

for the overall syndrome. Traditional animal models for bipolar disorder have 

concentrated on modeling a single manic episode. Several such models have focused on 

the hyperactivity aspect of the disorder, while others are based on measures of motivation 

and reward or the effects of sleep deprivation. Nevertheless, there is as yet no bona fide 

rodent model of mania. There have also been attempts to develop animal models that 

target the progressive and cycling nature of bipolar disorder, including psychostimulantinduced sensitization. These paradigms, too, have failed to provide adequate models of 

the human syndrome; they also lack predictive validity of the efficacy of mood 

stabilizing medications. The lack of an appropriate, reliable model of mania and of 

bipolar disorder continues to greatly hinder attempts to understand the neurobiology of 

the syndrome as well as to develop improved therapeutics. 

 Psychostimulants, such as amphetamines, produce a range of behaviors in animals 

that appear similar to mania, including hyperactivity, heightened sensory awareness and 

alertness, and changes in sleep patterns. Furthermore, psychostimulant-induced 

hyperactivity is reportedly sensitive to lithium. Psychostimulant-induced hyperactivity is 

mediated by increased dopaminergic transmission in striatal regions of the brain, and 

antipsychotic drugs, used in the management of acute mania, are dopamine receptor 

antagonists. Some studies have demonstrated that this model is also sensitive to 

anticonvulsant drugs that are effective against mania. Based on these findings, 

psychostimulant-induced hyperactivity in rodents has become a standard model for the 

screening of drugs to treat mania. However, the relevance of psychostimulant-induced 

hyperactivity to the mechanisms underlying mania remains unproven. 

 Sleep deprivation has a rapid antidepressant effect in approximately one-third of 

individuals, and is also capable of inducing manic episodes in susceptible individuals. 

Similarly, sleep deprivation in rats appears to trigger behaviors reminiscent of those 

characteristic of manic episodes. After 72 hours of sleep deprivation, rats demonstrate a 

period of insomnia lasting about 30 minutes. During this period, they are hyperactive, 

irritable, aggressive, and hypersexual; the insomnia and hyperactivity are reduced by 

lithium treatment. Sleep deprivation appears to enhance dopaminergic function in the 

brain, important for motivation, reward, and incentive drive. Overall, sleep deprivation in 

rats, despite the difficulties in controlling for non-specific stress effects and lack of 

reproducibility, is a potential model of mania that deserves further study. 

 The models described so far are designed to model a single manic episode. These 

models, while they may be valid to an extent, inherently fail to represent the full scope of 
bipolar disorder because they do not model the progressive and cycling nature of the 

syndrome. Such models require that animals display progressive responses that alternate 

between states that are similar, at least in part, to depression and mania. 

 One progressive phenomenon proposed to model aspects of mania is behavioral 

sensitization. The repeated administration of many psychostimulants leads to a gradual 

increase in drug-induced behavioral responses, most typically locomotor activity. The 

development and expression of sensitized behavior may resemble the progression of 

manic episodes in bipolar disorder, with gradual enhancement in severity and onset. 

However, attempts to “treat” behavioral sensitization with antimanic agents have been 

largely unsuccessful: lithium, valproate, and carbamazepine do not reliably inhibit this 

phenomenon. These findings have cast doubt on the usefulness of behavioral sensitization 

as an animal model for bipolar disorder. 

NEUROBIOLOGY AND DRUG ACTION

 There is little doubt that over the next several years researchers will capitalize on 

data from the Human Genome Project and ongoing proteomics efforts to identify a host 

of new targets for drug development efforts. In the meantime, medicinal chemists and 

their colleagues are not at a loss for novel targets. For example, recent work has shown 

that monoamines and other neurotransmitters initiate a cascade of events within the postsynaptic neuron. This cascade can include effects on a variety of so-called second 

messenger systems, including those involving the regulatory molecule known as cyclicadenosine monophosphate (cAMP), that in turn can trigger a wide range of biochemical 

events within the stimulated cell. Evidence suggests that, in general, stimulation of some 

of these pathways is necessary for the action of currently available antidepressants. 

Consequently, medications that act directly on second messenger systems may be 

effective antidepressants. 

There is also evidence that antidepressants stimulate a host of other intracellular 

events that affect gene regulation and expression. Each of these elements is a potential 

target for antidepressant drug development. Already, researchers believe that 

phosphorylation inhibitors active in the central nervous system (CNS) may possess 

antidepressant activity. 

There is evidence, too, that depression and stress may interfere with natural nerve 

cell growth, or neurogenesis, perhaps in part by inhibiting the activity of neurogenic 

factors, such as brain-derived neurotrophic factor (BDNF), or of genes that prevent 

programmed celled death, also known as apoptosis. So far, all somatic treatments known 

to be effective in treating depression, including ECT, have in common the property of 

stimulating the expression of BDNF, and those tested also appear to enhance 

neurogenesis. Thus far, there is evidence that neurogenesis occurs in the hippocampus of 

the mammalian brain. At least one validated animal model of depression, maternal 

depression, is associated with reduced nerve cell growth in the hippocampus. Hence, 

molecules that enhance nerve cell growth could function as antidepressants. 

There is limited and controversial evidence that changes in the expression of the 

signaling molecules known as cytokines, which are usually associated with immune 

function, may be involved in the disease processes that cause depression. Cytokines are 

expressed in the brain, and during development they play important roles in normal brain 
growth during fetal development. A recent study revealed that induction of increased 

cytokine activity was associated with depressed mood in normal volunteers. Should 

further work confirm a relationship between cytokines and depression, medications 

directed at cytokines might represent novel antidepressants. 

Communication Between Cells 

CRH is a major neuropeptide mediator of stress responses in the CNS. It is 

produced in the hypothalamus and causes the pituitary gland to release ACTH. CRH is 

also present in the limbic and cortical areas of the brain. Preclinical studies indicate that it 

plays an important role in a variety of behaviors relevant to anxiety and depression. 

Levels of CRH are increased in the cerebral spinal fluid of individuals with depression. 

Neuroendocrine studies are suggestive of increased CRH drive in the hypothalamus, and 

postmortem investigations have reported an increase in CRH neurons and a likely 

compensatory down-regulation in CRH receptors. This evidence suggests that a CRH 

antagonist might be useful for the treatment of depression or anxiety. CRH antagonists 

capable of reaching the brain have been developed, thereby allowing in the near future 

for an adequate investigation of their clinical utility in the treatment of depression and 

anxiety. 

A class of compounds known as neurokinins, which includes substance P, was 

initially characterized for its potential role in pain control. Preclinical studies have found 

stress increases the release of substance P. Some recent clinical studies have 

demonstrated that an antagonist of the neurokinin-1 (NK1) receptor may be effective for 

the treatment of depression. NK1 receptor activators may dampen serotonin 

neurotransmission, with the antagonist exerting the opposite effect. It is still unclear if 

this is the primary mechanism of action of NK1 antagonists and, indeed, whether NK-1 

antagonists truly possess antidepressant activity in humans. Large-scale clinical trials are 

currently underway to test this hypothesis. 

There has also been interest in the possibility that the serotonin receptor known as 

5-HT7 may be a target for treatment of depression and possibly jet lag, the symptoms of 

which are caused by a disruption of circadian rhythms. The 5-HT7 receptor is expressed 

in limbic brain structures, including the cerebral cortex and hippocampus, and it is also 

expressed in a part of the brain known as the suprachiasmatic nucleus, where it controls 

circadian rhythm. The 5-HT7 receptor is coupled to the cAMP signal transduction 

cascade—antidepressant treatment up-regulates the cAMP-signal transduction cascade in 

the hippocampus. 

Another receptor that may be a good target for antidepressant drug development is 

known as the N-methyl-D-aspartate (NMDA) receptor, one of several that binds to the 

neurotransmitter glutamate. At least one research team has reported that chronic 

antidepressant administration has the effect of reducing this receptor’s activity. In 

addition, NMDA receptor antagonists have antidepressant efficacy in certain animal 

models of depression. This is consistent with a preliminary report demonstrating that the 

anesthetic ketamine, an NMDA receptor antagonist, produces a rapid, but transient 

improvement in individuals with depression. NMDA receptor antagonists are also 

reported to block the atrophy of neurons in the hippocampus as well as the drop-off in 

neuronal growth that occurs in hippocampus response to stress. Further studies are 

needed to determine whether the NMDA receptor is a valid target for antidepressant 
medication. Excessive release of glutamate may be related to the pathophysiology of 

mood disorders. Several drugs that decrease the glutamate release by different 

mechanisms are currently being evaluated as antidepressants. 

Receptors for the neurotransmitter GABA are of interest because of the discovery 

that levels of this neurotransmitter are decreased in the brains of individuals with 

depression and are increased by antidepressant treatment. This would suggest that 

molecules that interact with GABA receptors could have antidepressant efficacy. Since 

there are many different types of GABA receptors in the brain, it may be possible to find 

those that are most important in depression and target them for drug development efforts. 

Communication Within a Cell 

Intracellular signaling pathways, such as those involving cAMP, have many 

components and interact at many levels, forming complex signaling networks that allow the 

cell to receive, process, and respond to information. These networks are involved in integrating 

nerve impulses across different time scales. They also generate distinct nerve-signal outputs 

depending on input strength and duration, and they regulate intricate regulatory loops. Given 

their widespread and crucial role in integrating and fine-tuning physiological processes, it is 

not surprising that abnormalities in signaling pathways have now been identified in numerous 

human diseases. 

Such post-receptor signaling pathways represent the physiological targets for the 

nuclear receptor superfamily of hormones, which include glucocorticoids, thyroid hormones, 

gonadal steroids, and retinoids and that act within the cell nucleus. These actions presumably 

mediate the clinical manifestations of altered hormonal levels in many individuals with mood 

disorders. For example, they may be related to the frequent onset of bipolar disorder in 

puberty, triggering of episodes in the postpartum period, association of depression and possibly 

rapid cycling bipolar disorder with hypothyroidism, and triggering of depression in response to 

prescribed or illicit steroids. In addition, post-receptor signaling pathways have been 

implicated in regulating such complex and diverse behaviors such as mood, appetite, 

wakefulness, reward, learning, and memory consolidation. It is possible, then, that these 

signaling pathways are involved directly or indirectly in the treatment of mood disorders. 

Chronic antidepressant treatment increases the activity of the cAMP cascade in 

the hippocampus and cerebral cortex, suggesting that agents that activate this pathway 

could be useful for the treatment of depression. One enzyme —cAMP-specific 

phosphodiesterase (PDE4)—degrades cAMP in the brain, raising the possibility that 

inhibitors of this enzyme might have antidepressant efficacy. Indeed, one relatively 

selective inhibitor of PDE4 appears to have antidepressant activity in both humans and 

animal models of depression, but this compound also produces intolerable nausea. 

Further work may be able to build off this discovery, however, since there are four 

distinct PDE4 genes in humans, three of which are expressed in the brain. It appears that 

two of these—PDE4A and PDE4B—may be good targets for further drug development 

efforts that could yield effective antidepressants that do not produce nausea. 

Another important intracellular signaling pathway that may be involved in 

depression is the MAP (mitogen activated protein) kinase cascade. Antidepressants 

appear to interact with BDNF, an important molecule in the brain that activates MAP 

kinase and other intracellular cascades. Stress reduces BDNF expression in the 

hippocampus, whereas chronic antidepressant treatments cause neurons to increase their 
expression of BDNF genes. Antidepressant therapy also appears to prevent the stressinduced reductions of BDNF in nerve cells. In addition, BDNF has antidepressant 

efficacy in certain behavioral models of depression, suggesting that the BDNF-MAP 

kinase pathway may play an important role in some of the deleterious effects of stress on 

the hippocampus and that one mechanism by which antidepressants work may include 

increasing the activity of this pathway. Although speculative, this hypothesis forms the 

framework of preclinical antidepressant discovery efforts aimed at identifying small 

molecules that might promote the activity of BDNF and the MAP kinase pathway. 

The mood stabilizer valproate, used to treat bipolar illness, has also been shown to 

activate the MAP kinase cascade, though it is still unclear if this activity has anything to 

do with the mood stabilizing effects of the drug. However, it is clear that valproate and 

lithium both target another signaling pathway involving protein kinase C (PKC). PKC is 

highly enriched in the brain, and plays a major role in regulating neuronal excitability, 

neurotransmitter release, synaptic plasticity (how nerve cell connections change in 

response to a variety of stimuli), and long-term alterations in gene expression. Lithium 

and valproate, despite their completely different chemical structures, exert significant 

effects on PKC in a number of cell systems, including the brain, at therapeutically 

relevant concentrations. In particular, chronic, but not acute, administration of lithium or 

valproate causes selective reductions in the levels of PKC. 

In view of the pivotal role of the PKC signaling pathway in the regulation of 

neuronal excitability, neurotransmitter release, and long-term synaptic events, it may be 

that decreasing the activity of the PKC pathway may contribute to the treatment of acute 

mania. To test this hypothesis clinically, a recent study investigated the potential 

antimanic effects of the breast-cancer therapy tamoxifen, which is a PKC inhibitor in 

addition to an estrogen receptor antagonist. Preliminary results suggest that tamoxifen 

does, indeed, possess antimanic efficacy. Larger double-blind, placebo-controlled studies 

of tamoxifen are currently underway, and it is anticipated that the availability of more 

selective PKC inhibitors will allow for a more direct test of this hypothesis in the future. 

Glycogen synthase kinase-3β (GSK-3β) may be another target for lithium. GSK3β not only controls developmental patterns in diverse organisms, including mammals, 

but also plays an important role in the mature CNS through its involvement in several 

intracellular signaling pathways. GSK-3β has also been implicated in regulating the 

phosphorylation of a protein known as tau, which is implicated in neurodegenerative 

processes such as those characteristic of Alzheimer’s disease. Thus, inhibition of GSK-3β

by lithium may afford protection against cell death that is induced by certain stimuli. 

Researchers have developed several selective GSK-3β inhibitors recently, and are 

currently testing them in rodent models of mood and neurodegenerative disorders. 

Postmortem analyses have shown that recurrent mood disorders and other stressrelated illnesses may be associated with significant reductions in the volume of specific 

regions of brain, as well as in the numbers or sizes of neurons and glia in those regions. 

A new area to explore in this regard is the effect of lithium on neuronal plasticity.
OPPORTUNITIES FOR PROGRESS

The past 15 years have seen an unprecedented advance in our knowledge about 

the biochemical, neural, genetic, and behavioral foundations of depression and mania. 

There is no doubt today that depression and bipolar illness are brain disorders resulting 

from complex interactions among many biochemical, genetic, cognitive, behavioral, and 

environmental factors. Although the task of identifying those factors and how they 

interact to produce the ultimate symptoms of depression and mania is undoubtedly one of 

the more difficult facing biomedical researchers, it is apparent that the past decade and a 

half of research has laid the groundwork for dramatic progress in the near future. 

OPPORTUNITIES TO DISCOVER A GENETIC BASIS OF MOOD DISORDERS

The tremendous progress in molecular biology, neuroscience, and related fields is 

likely to lead to new approaches to the genetics of mental disorders in general and mood 

disorders in particular. Identification of all of the genes in the human genome and their 

functional variation will provide opportunities for studying the impact of those variants 

on phenotypic outcomes of interest. New research tools, such as microarray techniques 

that can detect tissue-specific expression, transgenic mice, expression arrays, and 

proteomics, are allowing researchers to identify gene function. Parallel research across 

numerous species is providing important sources of information regarding gene 

expression, phenotypic models, and gene-environment interaction. 

However, as geneticists move from studying single gene disorders to complex 

disorders, they will require still other tools to dissect the multiple interacting factors. The 

major focus on genetic studies has now shifted from a search for the gene to which genes 

in which contexts lead to the development of mood disorders. The highly restricted 

sampling of the earlier generation of studies is likely to move into the general population 

where the concept of attributable risk will become important. Finally, enhanced 

knowledge regarding genetics will be critical for health care professionals and the public 

alike to ultimately apply genetics findings to human diseases. 

There is widespread agreement among researchers in the field regarding the 

limitations in applying the current nomenclature for mental disorders to biologic studies. 

Mood disorder phenotypes based solely on clinical manifestations without biological 

markers lack conclusive evidence for the validity of classification and reliability of 

measurement. The lack of specificity of biologic and psychosocial risk factors and 

correlates, as well as the lack of longitudinal stability, still suggests etiologic and 

phenotypic heterogeneity. 

It will be critically important to establish population-based samples of mental 

disorders, including members of all the racial and ethnic groups that make up our society. 

Having such populations available for study will be increasingly valuable in validating 

the numerous genetic tests that will emerge from advances in human genetic research and 

the Human Genome Project. It will be necessary to identify more homogenous subtypes 

of mood disorders through family and high-risk research investigating both biologic and 

contextual factors, as well as to investigate familial patterns among affected and 
unaffected individuals to estimate strength and mode of genetic transmission. 

Quantification of risk at the levels of the individual and population will also be an 

important area of study, as will the development of a richer conceptualization of 

environmental factors that may be important mediators of expression of genetic risk for 

mood disorders. 

The lack of public understanding of the concepts of genetics and ethical standards 

employed in mental health/mental illness genetics studies has led to substantial concern 

regarding the possible risks of participating in genetic studies. Accurate information, 

based on solid empirical testing, is the cornerstone of genetic counseling. Even though 

there is still a lack of specific genetic or biologic markers for mood disorders that can be 

employed for pre-diagnostic testing or genetic counseling, familial recurrence risks, 

adjusted for the effects of familial loading, clinical severity, age at onset, mood disorder 

subtype and comorbid disorders, can provide estimates of the probability of mood 

disorders in unaffected relatives. 

Since the majority of studies to date involve families of people in treatment for 

mood disorders, there is generally ample opportunity for explaining the goals, benefits 

and possible risks of participation in genetics studies. As the sampling base expands to 

the community, more attention should be devoted to the development of education 

programs regarding the role of genes in disease in general as well as their current and 

predicted future role in informing our understanding of both individual and populationbased risk. Recruitment, consent procedures, testing, and interpretation remain important 

future areas that must be addressed. 

Similar to different distributions in the prevalence of particular diseases in ethnic 

and racial subgroups, there are now some well-established differences in racial and ethnic 

groups, particularly with respect to drug response. For example, several recent studies 

have demonstrated differences among whites, Asians, Black Americans and African 

Blacks in the frequencies of alleles of CYP2D6, the liver enzyme that metabolizes 

tricyclic antidepressants. Investigators have shown that such differences usually reflect 

differences in the distribution of polymorphic traits, rather than a trait that is unique to a 

particular population subgroup, and that both genetic and environmental factors 

contribute to racial and ethnic differences in drug response. Such differences may have 

important implications for the treatment of mood disorders and may ultimately guide 

selection of pharmacotherapeutic agents. However, the widespread differences within 

racial and ethnic groups should also minimize characterization of these groups based on 

race alone, since geographic origins and other shared cultural factors may be equally 

important in defining diverse population groups. 

Despite proportionate representation of racial and ethnic minority groups in many 

family studies, there is little research on familial aggregation of mood disorders or other 

mental disorders in samples from the wide variety of ethnic and racial populations that 

have sufficient statistical power to investigate sources and patterns of familial 

aggregation. Likewise, despite large ethnic differences in rates of twin births, there has 

been little research on twins of any given ethnicity, with the exception of a small number 

of studies involving Caucasian samples. Yet studies of discordant twins are an ideal 

source of information on cultural and environmental risk factors. Although there is 

substantial fear of misuse of genetic data among members of all population groups, the 
benefits of advances in genetics should be widely available to all individuals, regardless 

of their gender, ethnicity, or racial origin. 

Another issue for future research is the extent to which children should be 

included in genetic linkage and association studies, since few of the genetic studies of 

bipolar disorder include youth under age 18. However, researchers have shown similar 

prevalence rates of bipolar disorder among adolescents and young adults in community 

samples to those seen in adult samples. Other studies have demonstrated the stability of 

bipolar disorder from adolescence to young adulthood; nearly one-third of those with 

bipolar disorder prior to age 18 had additional episodes in early adulthood. Moreover, the 

expression of bipolar disorder was specific since few adolescents with other disorders, 

including depression or subthreshold mania, progressed to bipolar disorder in adulthood. 

This work documents the importance of inclusion of youth in family and genetic studies 

of mood disorders. 

OPPORTUNITIES TO UNDERSTAND THE NEURAL BASIS OF MOOD AND EMOTION

Progress in neuroscience, particularly developmental neuroscience that 

investigates molecular, cellular, and integrative brain functions that are involved in the 

development of mental disorders, will advance our understanding of the complex biologic 

processes underlying mood disorders. The tools of neuroimaging, psychophysiology, and 

preclinical models of emotion are likely to provide information on developmental 

pathways to mood disorders. Likewise, a better understanding of the impact of 

environmental exposures in modifying the development of emotion and mood regulation 

will provide new opportunities to investigate mechanisms underlying changes that occur 

in the brain both before the development of mood disorders and during the appearance of 

symptoms. 

 In the behavioral realm, it is an opportune time for researchers to investigate 

more fully the cognitive and psychosocial processes involved in depression and bipolar 

disorder reviewed herein. For example, given the role that negative cognitive styles and 

information processing play as potential vulnerabilities for depression and possibly for 

bipolar disorder as well, the opportunity exists to determine the precise biological 

mechanisms by which cognitive vulnerability is translated into a mood disorder. 

Perhaps the biggest challenge—and opportunity—facing researchers in the 

coming years is to integrate biological and cognitive approaches to depression and 

bipolar disorder. Indeed, given the major advances that have occurred in understanding 

both the cognitive and psychosocial antecedents of depression and the biological and 

neural bases of emotional and motivational systems, respectively, the time is ripe for an 

integration of the cognitive and biological approaches to depression and bipolar disorder. 

Work on two fundamental psychobiological systems, the behavioral activation system 

that regulates approach behavior to attain rewards and goals, and the behavioral 

inhibition system that regulates withdrawal and/or inhibition of behavior in response to 

threat and punishment, may dovetail with the cognitive vulnerability-stress models of 

depression. For example, when a vulnerable individual experiences a negative life event 

and makes inferences about that event that lead to hopelessness about achieving 

important current and future goals, the neurobiological systems involved in these 

cognitive processes may be those that inhibit the behavioral activation system. 
However, the circuitry that supports the behavioral activation system and the 

behavioral inhibition system is likely to be complicated and distributed across a number 

of interconnected structures, including the prefrontal cortex, anterior cingulate, amygdala, 

and hippocampus. It is therefore overly simplistic to describe merely overall changes in 

the activation of these hypothetical systems. Fortunately, we now have the tools to 

interrogate the detailed circuitry underlying these systems, and future research will need 

to harness these methods to better understand the neural substrates of these hypothesized 

diathesis-stress interactions. 

There is also a need for cross-boundary studies that relate specific abnormalities 

in particular brain regions to objective laboratory tasks that are neurally inspired and 

designed to capture the particular kinds of processing that are hypothesized to be 

implemented in those brain regions. Investigators have conducted relatively few studies 

of this kind, and most studies on people with depression that have tried to relate 

individual differences in neural activity to behavioral phenomena have used self-report or 

interview-based indices of symptoms. In the future, it will be important to complement 

the phenomenological description with laboratory measures that are explicitly designed to 

highlight the processes implemented in different parts of a particular circuit. 

These studies should include measures of both functional and structural 

connectivity to complement the activation measures. It is clear that interactions among 

the various components of the circuitry are likely to play a crucial role in determining 

behavioral output. Moreover, it is possible that connectional abnormalities may exist in 

the absence of abnormalities in specific structures, underscoring the need to include 

measures of connectivity in future research. 

In addition, there is little argument that depression refers to a heterogeneous 

group of disorders, suggesting that depression-spectrum disorders can be produced by 

abnormalities in many different parts of the brain’s neural circuitry. As a result, it is 

likely that some of the heterogeneity that might be produced by deficits in particular brain 

components will not map precisely onto the diagnostic categories developed from 

descriptive psychiatry. A major challenge for the future will be to build a more 

neurobiologically plausible scheme for characterizing the heterogeneity of depression 

based on the location and nature of the abnormality in particular circuitry. Though 

undoubtedly ambitious, such an effort will lead to considerably more consistent findings 

at the biological level and also will enable us to more rigorously characterize different 

forms of depression. 

Brain Structure and Mood Disorders 

Opportunities now exist to use the various brain imaging technologies, in 

conjunction with longitudinal studies, to determine if neurochemical and structural 

abnormalities precede the onset of the disorder, co-occur with the onset of the disorder, or 

follow by some time the expression of the disorder. It is likely that the timing of the 

abnormalities in relation to the clinical course of the disorder varies for different parts of 

the circuitry. 

However, in vivo neuroimaging does not permit the direct investigation of 

diseased brain tissue. Clearly, postmortem human brain studies are limited in certain 

ways by factors such as confounding variables that cannot be directly controlled. 

However, direct studies of postmortem human brain tissue provide the only vehicle for 
exploring, at molecular and cellular levels, the alterations in neural circuitry that give rise 

to the clinical manifestations of mood and other mental illnesses. In addition, the study of 

human brain tissue is essential for the harnessing of the recent powerful advances in 

functional genomics and of the promise of proteomics to our efforts to understand the 

critical neurobiology of these disorders. Thus, investigations of the postmortem human 

brain represent a critical component of the programmatic study of mood disorders. 

However, as in any area of scientific investigation, such studies must be conducted with 

an astute awareness of their strengths and limitations, and with the inclusion of other 

types of studies that mitigate these limitations. 

 In other brain disorders, such as Alzheimer’s disease, postmortem studies have 

proven to be useful by providing the “gold standard” for diagnosis, delineating 

pathogenesis, producing informative leads for candidate genes, and revealing possible 

relationships between brain abnormalities and the clinical symptoms of the illness. In the 

case of mood disorders, as for most mental illnesses, almost no firm data exist in any of 

these areas. Recent studies from several research groups have produced findings 

suggesting that depression and bipolar disorder are associated with a reduction in glial 

cell density in the multiple regions of the prefrontal cortex. However, this abnormality is 

unlikely to be diagnostic of the disorder, and how it may relate to genetics, pathogenesis, 

or pathophysiology is unclear at present and certainly represents an important gap in our 

understanding of this disorder. Effectively utilizing postmortem studies to address these 

types of questions requires consideration of the following types of resources and research 

strategies. 

 Clearly, adequate sample sizes of postmortem human tissue specimens must be 

available for such studies. But beyond numbers, the success of such investigations rests 

on the extent to which the samples are well-characterized, the studies are well-designed 

and appropriate for the question of interest, and the potential confounds of the studies are 

well-considered. Regarding sample characterization, not only is a full reconstruction of 

the person’s history required for accurate diagnosis, but the outcome of many studies may 

also be dependent on knowing the state of the illness at the time of death. For example, 

published studies typically indicate that subjects met diagnostic criteria for depression, 

but fail to specify whether the diagnosis was based on a single episode or recurrent illness 

and whether the subject was actually depressed at the time of death. Similarly, the phase 

of bipolar illness at time of death is frequently not indicated. Clearly, such information 

may prove critical for testing hypotheses that episodes of illness are precipitated by 

changes in nerve growth in certain brain regions or that structural changes in the 

hippocampus reflect total lifetime duration of depression. 

 Differentiating between the effects of the illness and the consequences of its 

treatment on particular brain structures would ideally be assessed in never-medicated 

subjects. However, since an adequate sample of postmortem brain specimens from nevermedicated subjects with depression or bipolar illness is unlikely to ever be available, 

several less direct approaches must be used to address this question. These approaches 

include comparing data from subjects who were on or off medications at the time of 

death, examining subjects with other disorders who also were treated with these 

medications, and using animal models that mimic the clinical treatment of mood 

disorders. 
Certainly, the first two approaches have obvious, and difficult to control, potential 

confounds. Long-term exposure to medications, as is typical in the treatment of recurrent 

major depression and bipolar illness, may have effects on brain morphology, 

neurochemistry or gene expression that persist for a substantial period of time after the 

drug is discontinued. In the case of animal models of drug effects, many studies have 

been conducted in rodents with dosage and time parameters that do not necessarily reflect 

the human treatment condition. These limitations can be overcome through studies in 

non-human primates that involve extended periods of treatment with doses that produce 

serum drug levels shown to be therapeutic in humans. However, that still leaves the 

problem of potential species differences and the possibility that the medications of 

interest may have different effects on the brain of an individual with depression or bipolar 

disorder than on the normal brain. Despite the limitations of each of these three 

approaches individually, convergent findings across approaches should lead to 

reasonable, if provisional, conclusions about the influence of medications on the brain 

measures of interest. 

 The value of postmortem human studies may be increased when they are 

conducted within the context of animal investigations that have characterized the neural 

circuitry of interest. One obvious gap in this regard is the relatively little knowledge that 

exists about the actual circuitry and functional architecture of the cortical regions in the 

primate brain that are implicated in mood disorders. Both the design and interpretation of 

human postmortem studies will be improved by an integration with parallel animal 

studies of the same systems of interest. 

OPPORTUNITIES TO DISCOVER NEW DRUG AND PHYSIOLOGIC TREATMENTS

With the wealth of potential drug targets now available, the opportunity exists to 

accelerate the process of discovery in mood disorder treatments so as to make quantum 

leaps toward novel treatment techniques. There are, however, questions concerning the 

roles that government, consumer advocacy groups, academia, and industry should play in 

the effort to develop new therapeutics for depression and bipolar disorder. Fortunately, 

NIMH is able to take advantage of the experience of other NIH institutes that have 

wrestled with the identical problem of how best to foster the development of novel and 

better therapeutics. 

For example, the National Cancer Institute (NCI) has had a drug development 

program for over 20 years, started in an era when treatments for cancer were not being 

aggressively pursued by pharmaceutical companies. NCI has recently articulated the goal 

of encouraging mechanistically novel drug development for cancer treatments. The 

institute currently supports a complex set of modular mechanisms including repositories 

of drugs, natural products, research tools and information, as well as preclinical and 

clinical drug development services, all available to NCI grantees and small business 

contractors (http://dtp.nci.nih.gov). The National Institute of Allergy and Infectious 

Diseases (NIAID) has initiated a program for drug development in AIDS in order to 

facilitate new therapies and, when necessary, support preclinical and clinical 

development. NIAID also has a modular, flexible but integrated preclinical/clinical grant 

program for academia, and a contract program for small business researchers, to facilitate 

drug development not only for AIDS but also for its accompanying opportunistic 
infections; they aim to target research to gaps in treatment knowledge 

(http://www.niaid.nih.gov/aidstherapeutics). In the process of these efforts, NCI and 

NIAID have both developed a clinical trials network with well-trained clinical scientists 

who not only conduct scientific trials, but also develop improved rating scales for 

specified clinical endpoints and focus on identifying biomarkers for drug action. 

Biomarkers 

 New methods from cognitive and affective neuroscience provide an 

unprecedented opportunity to use non-invasive techniques to examine the function of 

brain circuitry underlying disturbances of cognitive and affective processing in mood 

disorders. These methods take the general approach of defining behavioral constructs and 

developing valid behavioral probes that are incorporated into studies to reveal activity in 

the relevant brain networks. Reliable methods now exist to examine the brain circuitry 

associated with attentional and executive functions, and to define the abnormal cerebral 

activation patterns in unipolar depression and bipolar disorder. Conceivably, a 

“normalization” of these abnormal cerebral activation patterns could define drug activity, 

and provide new tools for studying the pharmacology of mood disorders. Similarly, 

reliable paradigms have been developed to examine activity in subcortical and limbic 

circuits associated with processing reward, threat and other kinds of emotionally relevant 

information. Deficits in these functional domains are widely reported to be present in 

individuals with mood disorders. 

Despite the dramatic increase in research into the neural basis of normal cognitive 

and emotional processes, not enough has been done to apply these methods to the 

investigation of mood disorders. However, the potential for these tools to provide insights 

into pathophysiology and mechanisms of action of treatment, as well as to serve as 

predictors of outcome, is considerable, and the non-invasiveness and potential wide 

availability of novel imaging technologies, such as functional magnetic resonance 

imaging, make these tools especially attractive. Facilitating the application of cognitive 

and affective neuroscience based imaging methods for use as potential biomarkers could 

lead to significant progress in the diagnosis and treatment of mood disorders. 

The majority of work to date on biomarkers has examined peripheral markers, 

including catecholamine levels in plasma and urine, platelet markers such as the 

serotonin transporter, and plasma measures of the HPA axis such as cortisol and CRH. 

The studies on peripheral biomarkers in mood disorders were initially quite popular and 

well received by the research community. However, a strong counter-reaction to the 

catecholamine and platelet measures subsequently developed, in large part because they 

did not clearly reflect CNS activity or function. In contrast, studies of the HPA axis 

(including plasma cortisol) have continuously flourished, showing the role of extrahypothalamic areas in regulating and being affected by cortisol. 

Pharmacogenetics and Its Contributions to Drug Discovery and Drug Utilization 

Pharmacogenetics seeks to find DNA markers for medication treatment outcome, 

including both response to and the potential for side effects from a particular treatment. 

One goal for pharmacogenetics is to have a set of polymorphisms that predict relative 

response and tolerability to specific classes of antidepressants and/or to specific members 

of classes. The suite of genetic variants could also help predict which people need longerterm maintenance treatment. Identification of polymorphisms predicting medication 
intolerance could help avoid unnecessary exposure to various drugs. Pharmacogenetics 

could also stimulate the development of new agents with even more specific or targeted 

modes of action. Many polymorphisms could be identified in public databases using 

candidate loci chosen based on current understanding of antidepressant mechanisms of 

action. 

RESEARCH PRIORITIES

1. OPPORTUNITIES TO DISCOVER A GENETIC BASIS OF MOOD DISORDERS

Objective 1. Enhance validity of mood disorder phenotypes by the identification of 

more heritable and homogeneous subtypes of mood disorders for use in 

molecular genetic studies. 

Implementation: 

• Use existing and new data sets to identify highly heritable subtypes of mood 

disorders and intermediary biologic phenotypes (e.g., sleep parameters, circadian 

rhythm, hyperactivity, mood regulation, stress reactivity, psycho physiologic 

function, autonomic reactivity, and neural structure and function) for inclusion in 

molecular genetic studies of mood disorders. 

 

• Refine the classification of mood disorders by examining components of mood 

disorders and intermediary biological phenotypes in existing high-risk family 

studies and prospective longitudinal studies of mood disorders and related 

phenotypes. 

Objective 2. Identify genes that produce vulnerability and resilience to mood 

disorders and study gene x environment interactions, by capitalizing on existing 

resources and data sets, particularly population-based data. 

Implementation:

• Pool data and support meta-analyses of existing linkage studies of bipolar 

disorder to determine if positive linkage findings can be replicated using identical 

phenotypes and statistical methods across studies. 

• Identify the most heritable subtypes and endophenotypes of mood disorders (e.g., 

sleep patterns, atypical features, stress reactivity, mood regulation, and 

neuroendocrine function). 

 

Objective 3. Enhance the broad availability and coordination of core research 

resources in extramural and intramural genetics research programs for use in 

future genetic studies of mood disorders.

Implementation: 

• Continue to stimulate broad and free sharing with the scientific community of 

research resources, including clinical data and DNA, collected in genetic studies 

and clinical trials supported by NIMH. 
2. OPPORTUNITIES TO UNDERSTAND THE NEURAL BASIS OF MOOD AND EMOTION

Objective 1. Identify measures of core symptoms of depression and mania that can 

be modeled in animals (e.g., indices of cognitive processes, sleep disturbances, or 

reward mechanisms) as an essential first step in model development. 

Implementation: 

• Identify objective clinical measures, biomarkers, and relevant behavioral 

indicators of depression and mania that are amenable to measurement in both 

clinical populations and animals (i.e., parallel measures). 

- Identify and expand human and non-human experimental paradigms 

measuring processes associated with core cognitive symptoms. 

- Develop other indicators of mood and affect including vegetative 

functions (e.g., sleep measures) and reward assessment, and discussion of 

ways to measure these in humans and in animals. 

- Develop procedures to cross-validate measures employed in animal 

studies in clinical populations. 

• Develop cognitive measures in non-human primates. 

- Develop a targeted initiative to encourage studies employing homologous 

models of neurocognitive deficits of human mood disorders in non-human 

primates. 

• Identify strategies for developing measures relevant to bipolar disorder to be used 

in animal models. 

- Identify clinical markers indicative or predictive of manic and depressive 

episodes and rapid cycling in bipolar disorder that may be modeled in 

animals. 

- Compare and refine desired attributes with existing models of depression 

and psychosis. 

- Identify measures of both positive and negative affect. 

Objective 2. Establish how experiential and genetic factors interact to modulate 

neural and behavioral indicators of mood disorders. 

Implementation: 

• Identify potential causes and compensatory changes in the development of mood 

disorders using longitudinal, prospective studies of brain structure and function, 

as well as examining environmental and psychological factors. Particular attention 

should be paid to an integrative review of risk factors and prospective design 

issues. 

• Identify progressive changes in brain activity and cognitive, emotional, and 

behavioral processes pre-and post- treatment for psychosocial and/or 

pharmacological interventions, and ancillary studies using both short-term 

longitudinal studies and later multisite studies. 
Objective 3. Expand resources in support of greater quality, availability, and use of 

postmortem brain tissues for studies of brain structures and circuitry related to 

mood disorders. 

Implementation: 

• Create a national infrastructure for postmortem studies that promotes tissue 

preparation and clinical characterization, including medical disorders comorbid 

with depression. 

• Develop and apply markers of glial pathology in studies of brain regions 

implicated in mood disorders. 

Objective 4. Evaluate and extend cellular, anatomical, and electrophysiological 

models targeting brain circuits relevant to mood disorders.

Implementation: 

• Engage clinical neuroimaging investigators, along with systems neuroscientists, 

electrophysiologists, and scientists employing in vitro systems to: 

- Identify mechanisms for validating cellular or circuit-based models. 

- Explore circuit-based models for drug development. 

• Develop tools and reagents such as inducible and targeted mutant mice, selective 

ligands, and imaging techniques to facilitate model development and validation. 

- Create pathophysiology-based animal models for mood disorders, 

especially mouse models that take advantage of advances in genomics. 

Objective 5. Develop parallel behavioral and neurobiological measures of affect and 

affect regulation that can be used across species to facilitate new models of mood 

disorders and the search for specific endophenotypes. 

Implementation: 

• Initiate collaborations between animal researchers and clinical scientists to 

study specific model systems (e.g., hedonic and regulation of eating). 

• Increase the number of studies with non-human primates to better understand 

neural activity associated with complex systems of behavior. 

Objective 6. Develop a detailed understanding of the fundamental mental/emotional 

states and processes that characterize mood disorders as well as normal 

functioning. 

Implementation: 

• Distinguish the positive and negative affectivity in emotion, mood, and 

temperament; and differentiate reactivity versus regulation of these processes in 

clinical vs. non-clinical populations. 

• Use multidisciplinary approaches that combine phenomenological, behavioral, 

and neurobiological measures, and explicate the heterogeneity of depressive 

disorders. 
• Develop and validate behavioral tasks to relate behavioral dysfunctions in mood 

disorders to specific aspects of brain function. 

Objective 7. Develop new etiological approaches to understanding bipolar disorder. 

Implementation: 

• Identify the distinctive variations in cognition, social cognition, mood, and mood 

regulation that characterize bipolar disorder. 

Objective 8. Develop models to examine the behavioral and/or neurochemical 

impact of early life stressors on later susceptibility to adverse effects of stress in 

genetic mutant mice. 

Implementation: 

• Phenotype differences in susceptibility and resilience of male and female mutant 

mice. 

 

• Examine the impact of environmental manipulations across several developmental 

periods (e.g., early peri/post natal, pre- and post-puberty). 

3. OPPORTUNITIES TO DISCOVER NEW DRUG AND PHYSIOLOGIC TREATMENTS

Objective 1. Establish quantitative outcome measures and biological markers for 

the diagnosis and assessment of disease progression and treatment of mood 

disorders. 

Implementation: 

• Identify and validate quantitative outcome measures and instruments for assessing 

depression (e.g., cognitive, behavioral, psychometric measures, new rating 

scales). 

- Ensure representative samples of women, children, the elderly, and racial 

and ethnic minority participants in the norming process. 

• Identify biological markers (e.g., imaging and genetic markers) for assessing risk, 

course of illness, and predicting treatment response or relapse. 

- Develop guidelines for the validation of new quantitative outcome 

measures, instruments, and biological markers in clinical effectiveness 

trials in collaboration with representatives from the Food and Drug 

Administration (FDA), academia, and industry. 

Objective 2. Develop neurochemical tools for understanding disease 

pathophysiology and identify molecular targets for drug discovery. 

Implementation: 

• Accelerate the development of novel ligands for PET, single photon emission 

computed tomography (SPECT), and functional brain imaging as probes to 

elucidate pathophysiology, to identify disease targets, and as biological markers to 

assess disease progress and treatment response. 

- Expand chemical repositories to increase the availability of unlabeled 

imaging ligands/precursors for basic and clinical research. 
Objective 3. Model depression/depression-like and mania/mania-like symptoms 

that are side effects of pharmacological treatments for non-psychiatric disorders. 

Implementation: 

• Create models for understanding the mechanisms whereby pharmacological 

treatments (e.g., interferon alpha, tumor necrosis factor (TNF), retinoic acid) for 

non-psychiatric disorders induce depression/depressive-like and mania/mania-like 

symptoms as side effects. 

Objective 4. Establish a drug development program that conducts proof of concept 

studies of innovative compounds for the treatment of mood disorders. 

Implementation: 

• Support a targeted clinical trials network to conduct proof of concept studies of 

therapeutic compounds and to validate novel outcome measures, instruments, and 

biomarkers. 

- Identify therapeutic candidates for proof of concept studies. 

Objective 5. Establish long-term partnerships between government, academia, and 

industry to accelerate innovative drug discovery and the development of 

behavioral assays for evaluating novel therapeutics. 

Implementation: 

• Facilitate partnerships between NIMH, academia, and industry to support 

 innovative approaches for drug discovery and the development of behavioral 

assays using NCI’s National Cooperative Drug Discovery Group program as a 

model. 

Objective 6. Identify novel drug targets to assess differential treatment response. 

Implementation: 

• 

• 

Identify single nucleotide polymorphisms (SNPs) and haplotypes that index both 

therapeutic response and adverse events. 

Collect DNA and other biological samples from ongoing large, multisite NIMH 

clinical trials in mood disorders, and make both DNA and clinical data available 

for pharmacogenomics research by the broader scientific community. 

Objective 7. Explore further development of somatic treatments for mood 

disorders. 

Implementation: 

• Develop guidelines for appropriate control (“sham” or other) conditions, 

including adequate informed consent for the study of somatic treatments in 

collaboration with the FDA and academia. 

• Encourage collaboration among clinical, preclinical, and neurological 

investigators to: (a) delineate the mechanisms of action of new and existing 

somatic treatments; (b) apply knowledge gained from the use of somatic 

treatments for neurological disorders to inform research and practice for mental 
disorder treatments; and (c) develop promising animal model approaches, e.g., 

magnetic seizure induction for use as potential human clinical interventions. 
DIMENSIONS OF AGE AND DISEASE

 The prevalence of mood disorders is not constant throughout the human life span. 

In fact, the types of depression that occur early in life are likely to be different than those 

that occur late in life, when comorbid illnesses can play a significant role in 

psychological well-being. The influence of puberty, pregnancy, childbirth, and 

menopause also has a marked influence on the occurrence of mood disorders. 

One picture of the natural history of mood disorders comes from the National 

Comorbidity Survey (NCS), which assessed a representative United States population 

sample of over 8,000 people, aged 15 through 54. The 30-day prevalence for an episode 

of major depression was 4.9 percent. It was highest (6.1 percent) in the youngest group 

surveyed (15-24 years) and lowest (3.9 percent) in the oldest group surveyed (45-54 

years), suggesting that depression does not occur uniformly in all age groups. Prevalence 

rates also suggested more depression in younger participants; for example, the rate was 

scarcely higher in the oldest group (16.7 percent) than in the youngest (15.7 percent). A 

more detailed breakdown of the NCS data shows the highest 12-month prevalence in 

females during their late teens, and in males during their early 20s. 

Prior to the 1980s, clinical and epidemiologic research on depression was 

confined almost entirely to adults. It was somewhat surprising, then, when national 

surveys noted that adults often reported onset of their depressive disorder in the late teens 

or earlier. Now that studies of children and adolescents are available, it is becoming clear 

that many—perhaps most—individuals with a depressive disorder began to experience 

serious symptoms early in adolescence, and that their vulnerability to develop these 

conditions may have been established even earlier. 

An important aspect of the prevalence of unipolar depression is the marked 

gender-by-age change during adolescence. Until approximately age 13, depression is 

equally common in boys and girls. After that age, the rate increases two- to three-fold in 

females, in whom it continues to occur at a higher rate until after middle age. The rate 

also increases in boys, but not as much as in girls. 

Classically defined bipolar disorder occurs infrequently in young people. The 

NCS estimated the lifetime prevalence of the Diagnostic and Statistical Manual of 

Mental Disorders, 3rd edition revised (DSM-III-R) bipolar I disorder in 15- to 54-yearolds at 0.4 percent, and the 1-year prevalence at just under that figure. Recent surveys of 

adolescents report a 3-month prevalence of bipolar disorders (primarily hypomania) at 

0.25 percent in children ages 9 to 13 and a “lifetime” prevalence of bipolar disorder of 

approximately 1 percent in older adolescents ages 14 through 18. However, these 

estimates are uncertain for various reasons. First, few studies possess adequate population 

samples to estimate prevalence accurately. Second, controversy remains concerning 

possible differences between clinical presentations of childhood versus adult bipolar 

disorder. Few studies have followed the same individuals over time to resolve this 

controversy by providing a careful, developmentally informed bipolar diagnosis. Hence, 

the actual population prevalence of prepubertal bipolar disorder is unknown. 

Bipolar disorder exhibits little gender specificity or gender-by-age variation from 

adolescence to adulthood. Retrospective studies of adults report onset beginning in late 

adolescence. The similarity of 12-month and lifetime rates of bipolar disorder in adults 

from the NCS suggests that once established, this is a chronic disease. For clinically 
referred children and adolescents, it also appears that bipolar disorder is a chronic 

disease. However, the appropriate diagnosis for prepubertal children who may show 

symptoms of mood lability, extreme irritability, or rapid mood cycles remains an 

unresolved question. It is unclear, still, whether this is an early form of bipolar disorder or 

if it should be classified differently. 

 Late-life depression principally affects individuals with other medical and 

psychosocial problems, including cognitive dysfunction, disability, medical illnesses, and 

social isolation. The clinical associations of late-life depression have guided the 

development of hypotheses on mechanisms predisposing, initiating, and perpetuating 

specific mood syndromes. 

CURRENT STATUS OF THE FIELD 

MOOD DISORDERS IN CHILDREN

Developmental Factors 

 Thirty years ago there was doubt about whether children could even experience 

depression; today the question is not whether children can suffer from depression but 

rather how many adult mood disorders are truly “adult onset,” and how many are 

recurrent episodes of a disorder that had its onset in childhood or adolescence. Answering 

these questions is difficult, as there have been no published diagnostic studies of unipolar 

depression in population samples of children below ages 8 or 9. Indeed, there is a need 

for new diagnostic methods useful in children as young as preschool age, and for ways of 

assessing possible early subthreshold manifestations of depression and monitoring their 

persistence over time. 

Hormones 

Puberty seems to be a time when children are most at risk of developing 

depression, particularly for girls. The changing levels of various hormones characteristic 

of puberty, including estrogen and testosterone, may affect brain function. Similarly, 

structural changes in the brain occur during puberty that may influence social roles. Other 

studies suggest that social changes may influence numbers of depression-triggering life 

events, or that mismatches may occur with the norms of the social group, as when some 

girls mature earlier than their peers. Evidence is also emerging that exposure to increased 

levels of testosterone and estrogen at puberty, especially in the context of social stress, 

independently predicts risk for depression among vulnerable girls. Clearly, high levels of 

estrogen and testosterone alone cannot “explain” depression, but understanding the 

manner in which hormones affect the brain could have great potential for preventing 

depression in girls at high risk. 

Anxiety 

Depression during childhood and adolescence is likely to be preceded, 

accompanied, or followed by other mental disorders. For example, anxiety disorders are 

some eight-fold more common in depressed than non-depressed children and adolescents, 

while conduct and oppositional disorders were 6.6 times more common. Similarly, 
attention-deficit/hyperactivity disorder (ADHD) was 5.5 times as common in children 

and adolescents with depression as in their unaffected peers. The onset of depression 

appears to follow the onset of other disorders, with the exception of substance abuse and 

panic disorder, which usually begin in the middle to late teens. The precise mechanisms 

by which comorbidity patterns change during development remain unclear. However, 

successful treatment and prevention programs may depend on a better understanding of 

the relationships of these other disorders and depression. 

There does appear to be a significant association between major depression and 

abuse, maltreatment, and related forms of environmental adversity, though it cannot be 

assumed that because children are depressed that they were abused. Further systematic 

investigation of depressed children with histories of maltreatment and depressed children 

without histories of adversity should help to delineate the unique risk and protective factors 

associated with the onset of depression in children. 

Exposure to stress during childhood and adolescence appears to have the potential 

to produce long-lasting effects on human physiology, brain structure, and brain function. 

In a variety of animals, exposure to adversity during critical periods of pre- or postnatal 

brain development appears to induce changes, leading to permanent alterations of their 

perceptions of and responsiveness to environmental events. Nevertheless, complications 

arise in relating animal behavior to human conditions such as depression. Clinical studies 

have linked stress exposure to various developmental psychopathologies; however, the 

frequent occurrence of two or more comorbid conditions in the wake of such exposure 

has made it difficult to ascertain if there is a specific link to depression. 

 Problems also arise in attempting to understand how genetic vulnerabilities and 

stress exposure interact over the course of development. Although stress may 

differentially affect children at increased genetic risk, family stress may only increase 

risk in children without family history of depression. However, some children may be 

genetically more liable to stress exposure, as well as to depression. 

Family Risk Factors for Early-Onset Depression 

 Studies of families at high risk for depression have shown that there is a 

considerable heritable component to depression. Children of parents with depression are 

three times more likely to have a lifetime episode of depression than offspring of parents 

who did not have depression, and the first-degree relatives (i.e., fraternal twins, siblings, 

parents) of depressed children have been found to have significantly elevated rates of 

major depression. In contrast, two adoption studies and a growing number of twin studies 

provide inconsistent support for the role of genetic factors in the early-onset depressive 

symptoms. In twin studies, for example, while heritability estimates of parent-rated 

depressive symptoms of children tend to be high, heritability estimates based on selfreported depressive symptoms are often substantially lower. 

 Parents may transmit genes that directly predispose toward depression; genes that 

are functional in some environments but confer vulnerability in others; or genes 

associated with cognitive styles, such as ruminating, that can lead to depression. Some 

children may carry a genetic liability to other mental disorders, such as anxiety disorders, 

that increase the risk of depression. Alternatively, depression may represent an early 

manifestation of another disease to which a child has a genetic liability, such as bipolar 
disorder. Parental genes may also influence not just the risk of disease, but the age at 

which the disease occurs. 

Parents also provide the atmosphere in which a child grows up. Aspects of 

parenting and the home environment that may not be directly associated with a genetic 

risk appear to influence the risk of, but not the direct cause for, mental disorders in 

general, including depression. 

THE INFLUENCE OF GENDER ON MOOD DISORDERS 

One of the hallmark observations about depression is that women are twice as 

likely as men to experience a depressive episode within a lifetime. Depression can occur 

at any stage of a woman’s life, and it occurs across educational, economic, and racial and 

ethnic groups. 

Clinicians have long known that mood disorders vary in their expression among 

women and men and during periods of reproductive endocrine change. The reproductiverelated variability should not be surprising, as the reproductive steroids estrogen, 

testosterone, and progesterone not only regulate neural function, but also organize the 

development of the brain. During development, reproductive steroids play a significant 

role in how neurons connect to one another by regulating which neurons and how many 

survive, how they differentiate into different types of neurons and migrate through the 

brain as they grow, and how they form synapses with neighboring nerve cells. 

The effects of the developmental influences of the reproductive hormones do not 

end once the brain’s development is complete, however, for these processes also create 

brain circuitry that remains sensitive to the influence of reproductive hormones. Thus, 

when puberty arrives, the sudden influx of these hormones can activate this circuitry, and 

in turn, influence behavior. It may be that mood disorders affect women and men 

differently at the time of puberty as a result of fundamental differences in neural circuitry 

laid down during brain development. This hypothesis is supported by observations of 

mood changes occurring in some women in concert with three periods of change in 

reproductive hormones: the luteal phase of the menstrual cycle, after the birth of a child, 

and in the initial stages of menopause. 

 Studies involving the artificial manipulation of hormone levels suggest that 

normal changes in reproductive steroids are capable of triggering mood disregulation in 

some, but not all, women. Women with a history of premenstrual dysphoric disorder 

(PMDD), but not women lacking the diagnosis, experience elimination of their dysphoria 

during gonadal suppression and return of their dysphoria when exposed to progesterone 

or estrogen. Similarly, euthymic women with a history of postpartum depression (PPD), 

but not women without a history of PPD, become depressed when exposed to and 

withdrawn from high levels of estrogen and progesterone. In neither of these disorders is 

there compelling evidence for abnormal levels of reproductive steroids; hence, the 

depression that is precipitated appears to represent an abnormal response to otherwise 

normal levels or changes in levels of reproductive steroids. The source of this differential 

response is unknown and represents an area of great promise for future research, one that 

may help identify the biological underpinnings of vulnerability to other, nonreproductive-endocrine-related mood disorders. 
There was a period in the 1970s when researchers believed that the hormonal 

changes occurring during menopause were irrelevant in considering the causes of 

depression that occur during this stage of life. Today, however, we know that 

reproductive function plays a critical role in depression that occurs during menopause. In 

fact, estrogen itself is an effective antidepressant for women who first experience 

depression at the onset of menopause. While it is likely that a variety of psychological, 

environmental, historical, and adaptive factors influence the expression of depressions 

associated with changes in reproductive function, it is no longer tenable to deny the 

importance of reproductive steroids in the regulation of brain and affect. 

 

AGING AND DEPRESSION

 

 Geriatric depression occurs in the context of other events, such as cognitive 

dysfunction, disability, comorbid medical illnesses, and psychosocial adversity. These 

dimensions of health have offered an experimental opportunity for advancing and testing 

hypotheses on the development of geriatric depression. Some of these hypotheses and 

models may also prove to be applicable to depression in younger adults. The clinical 

complexity of geriatric depression has also begun to guide the development of 

comprehensive models of care for elderly people with heterogeneous depressive 

syndromes. The areas described below are examples of topics of interest. 

Cognition and Depression in the Elderly 

A significant percentage of depressed elderly individuals also have cognitive 

impairment. The combination of impaired cognition and depressive symptoms doubles in 

frequency by 5-year intervals after age 70 in those living in the community, so that by the 

time a person reaches 85, they have a 25 percent chance of experiencing both cognitive 

dysfunction and depressive symptoms. Individuals with depression have disturbances in 

attention, speed of processing, and executive function even when they are not demented. 

These clinical associations have generated important hypotheses on the pathophysiology 

of geriatric depression and its relationship to treatment response. 

A limitation to this line of research is the dependence on clinical tests of cognitive 

function. These tests are reliable, but having been developed from clinical traditions, they 

tend to be nonspecific indicators of function. At the moment, the tests and methods that 

are tied closest to brain function have not been adapted for use in clinical studies of late 

life. 

The point prevalence of major depression or clinically significant depressive 

symptomatology is approximately 17 percent for people with Alzheimer’s disease and is 

even higher for those with subcortical dementias. However, discrepancies in reporting 

symptoms of depression contribute to reduced or incorrect identification of depression in 

people with dementia. A history of depression is also associated with increased incidence 

of Alzheimer’s disease, and indeed, depressive symptoms often precede the appearance 

of dementia. Individuals with late-life depression and cognitive impairment frequently 

develop dementia within a few years after the onset of depression. 

There are probably many causes for the cognitive impairment seen in geriatric 

depression, with contributions from neurodegenerative and vascular processes likely 

playing an important role. For example, depression may lead to atrophy of the 
hippocampus, which in turn could contribute to cognitive decline. Given that subcortical 

lesions are common in the elderly who have both depression and vascular disease, it may 

be that some types of depression might come from critical lesions or an accumulation of 

lesions leading to disruption of frontostriatal pathways or their modulating systems. 

Depression onset for the first time later in life may represent a distinct subtype of 

depressive illness. 

Improper functioning in frontal and striatal regions of the brain may be an 

important indicator of the course of geriatric depression. A measure of executive 

dysfunction, the neuropsychological expression of frontostriatal impairment, was shown 

to predict poor or delayed antidepressant response, and has been associated with relapse 

and recurrence in geriatric major depression. Again, the use of more sophisticated 

assessments will help establish this link more precisely. 

Psychosocial Factors in Geriatric Depression 

 Researchers have known for nearly a decade that social factors are not only 

related to the risk of depression, but may also influence the course of depression and play 

a role in suicide risk among the elderly. Depression is the most common risk factor for 

suicide among the elderly, and the elderly have the highest rates of suicide in the Nation, 

with elderly males having a suicide rate six times the national average. 

Advanced age, history of depression, death of a spouse, health-related factors, and 

comorbid anxiety all show significant associations with late-life depression. Financial 

problems in later life are also associated with increased depressive symptoms. However, 

the effects of stress on depression can be ameliorated by environmental factors such as 

having a marital partner and if unmarried, having a good network of social support. In 

fact, research has shown conclusively that social support significantly reduces the impact 

of functional disabilities on the incidence of depression. 

Older persons who experience a large number of negative life events in the past 

year experience a wide range of depressive symptoms. For example, elders who 

experience a death in their family during the past year tend to experience more symptoms 

of depression than do older adults who did not have a family member die. Approximately 

10 to 20 percent of persons who lose their spouse develop clinically significant 

depression in the first year of bereavement. If left untreated, the depression persists and 

may lead to further chronic disability. Widows in particular experience more depression 

than their married peers, though within a year those symptoms usually resolve 

themselves. In addition, recent widowhood increases the risk for suicide among older 

men, though not among older women. 

Depressed elders are often socially isolated—they often lack confiding 

relationships and perceive their friends as less supportive and reliable. Older adults who 

do not have close social ties report higher depressed mood than elders who are actively 

engaged in a supportive social network. In fact, research has shown that measures of 

social support show a strong correlation with mental health measures in a cross-sectional 

survey of rural elders. The availability of a confidant was found to be the single most 

protective factor for four dimensions of depression—depressed affect, low positive affect, 

medical complaints, and interpersonal problems. 

Cognitive theory suggests that how elders perceive their social contact is more 

important than absolute isolation. Loneliness is associated with social isolation and social 
support, poor or perceived health, and depression, and both depression and loneliness 

compromise quality of life. Older women who experience loneliness, for example, report 

more hopelessness, self-focus, and poor health. 

Depression and Caregiving 

Depression is a common consequence of family caregiving, a burden most often 

borne by women. Depression is most likely to occur during long-term caregiving and 

during transitions such as institutionalization. Research has shown that caregivers are at 

risk for experiencing clinically significant depression and that a significant percentage of 

caregivers have been shown to meet diagnostic criteria for depression. This holds true 

even for caregivers who had never been diagnosed with depression prior to assuming the 

role of taking care of an elderly loved one. Prevalence rates of depression, ranging from 

30 percent to as high as 83 percent, among community dwelling caregivers of persons 

with dementia have consistently been reported. Several studies have shown that increased 

social support from family and friends can decrease the stress placed on caregivers and 

less depressive symptoms. Psychological and educational interventions have helped 

caregivers effectively manage problem behaviors and reduce depression. Individual and 

family counseling sessions, participation in support groups, and availability of counselors 

to assist with crises may also reduce depressive symptoms in caregivers. 

Depression and Illness in the Elderly 

 The prevalence of geriatric depression is higher in medical settings than in the 

community. Epidemiological studies show that major depression occurs in 1 percent of 

the general elderly population, while 3 percent of community residing elderly individuals 

suffer from dysthymia and 8 to 15 percent have clinically significant depressive 

symptoms. In contrast, studies have found that clinically significant depressive symptoms 

occur in 17 to 37 percent of people who are hospitalized. 

 Depression in the elderly is a burden to both the consumer/patient and the 

Nation’s health care system. Depressed medical patients with chronic diseases, such as 

diabetes, arthritis, hypertension, and chronic lung disease, stay in bed more days 

compared to similar patients without depression. In addition to medical morbidity, 

depression increases the perception of poor health and utilization of medical services. 

Depressed primary care patients have almost twice the number of appointments with a 

doctor per year compared to non-depressed patients, and depressed patients have more 

than twice the number of hospital days over the expected length of stay compared to nondepressed patients. In addition, 65 percent of depressed patients receive more than five 

medications compared to 36 percent of non-depressed patients. 

 Research on the association between depression and increased mortality has 

been equivocal. Health may be a confounding factor, as depression is associated with 

poor health in elders. One longitudinal study examining the association between 

depression and mortality in nursing home and apartment residents found that the effects 

of depression on mortality were attributable to the correlation of depression with ill 

health, and another investigation found that major depression increased the likelihood of 

death by 59 percent, independently of medical health parameters. 

 Despite problems associated with depression among hospitalized older adults, the 

detection and treatment of depression in this population is inadequate. One study, for 
example, found that only a quarter of depressed patients were identified as such by their 

physicians, with correspondingly low use of antidepressants even following the diagnosis 

of depression. Detection and treatment of depression in primary care and long-term care 

settings are also poor. These studies suggest that detecting and treating depression 

promptly could have a major effect on the health of the elderly. 

 The reasons for underdiagnosis of depression are complex, but poor reporting of 

depressive symptoms may be a contributing factor. Older individuals report fewer 

symptoms of depression to their family members than younger individuals. Another 

factor may be the time constraints of physicians that prevent in-depth discussion of 

depressive symptoms and related psychosocial factors, and age bias. Underreporting of 

depression is particularly common in traditionally underserved racial and ethnic minority 

communities. 

COMORBIDITY: DEPRESSION AND OTHER MEDICAL ILLNESSES

Coronary Heart Disease 

Depression is common in people with coronary heart disease (CHD) and other 

cardiac illnesses, a dangerous situation since depression increases the risk by as much as 

six-fold of dying from heart disease. Approximately one in five cardiac patients has 

major depression at the time of diagnostic cardiac catheterization or following acute 

myocardial infarction (MI). Another one in five has minor depression at these times. 

Many people who are not depressed in the first few days and weeks following an acute 

MI go on to experience an episode of depression within a year, with approximately one 

out of three developing major depression at some time during the 12 months following an 

MI. Although there have been relatively few follow-up studies of depression in post-MI 

patients, there is evidence that it tends to follow a chronic course during the first year 

after the heart attack. In patients with congestive heart failure, estimates of the prevalence 

of major depression have ranged from 17 to 37 percent. In the first year following heart 

transplantation, an estimated 17 percent of patients have major depression. 

 Depressed CHD patients are slower to return to work and are more likely to return 

to the hospital, to report more stress and emotional instability, to be disabled, and to incur 

higher costs for their medical care than CHD patients who are not depressed. Depression 

is also associated with poorer psychosocial adjustment and less symptom relief following 

coronary bypass surgery. 

Depression increases the risk that patients with newly diagnosed coronary artery 

disease will experience a cardiac event following diagnostic cardiac catheterization. It is 

also a significant risk factor for cardiac mortality and medical morbidity following an 

acute heart attack, in patients with unstable angina, and in patients with a transplanted 

heart. In addition, several large, prospective studies have shown that depressed 

individuals without clinical evidence of coronary disease are more likely to develop CHD 

in the ensuing years than are otherwise comparable individuals who are not depressed. It 

is unclear whether depression contributes to the precipitation of cardiac events, 

contributes directly to the underlying artherosclerotic process, or both. The mechanism or 

mechanisms underlying the relationship between depression and cardiac morbidity and 

mortality are unknown, though investigators have proposed several hypotheses that are 
being tested including alteration in heart rate variability and serotonin-induced platelet 

aggregation. 

Diabetes 

 Depression occurs more frequently in adults with diabetes than in otherwise healthy 

control subjects, and it takes a more serious course in diabetic patients. For example, 

people with comorbid diabetes and depression have an eight times greater relapse rate 

than those with depression but without other medical conditions. Conversely, depression 

is associated with an increased rate of medical complications from diabetes and poor 

control of blood sugar levels. Indeed, the relative severity of depression among elderly 

diabetics, for example, correlates with difficulty controlling blood glucose levels. In 

primary care patients, comorbid depression increases health care costs and the use of 

health services. One estimate pegs the total health care costs for diabetes and comorbid 

depression at $192 million per year. 

 One complication of comorbid depression and diabetes is that both monoamine 

oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) can negatively interfere 

with glucose metabolism, and therefore worsen diabetes. In contrast, the serotonin 

reuptake inhibitors (SSRIs) may actually improve both depressive symptoms and glucose 

control. Researchers have also noted that improvements in mood, regardless of the 

therapy chosen, are associated with better compliance with the dietary and medical 

restrictions needed to treat diabetes. 

Neurological Disorders and Stroke 

 The prevalence of depression in neurological disorders is best characterized in 

patients who have suffered a stroke. In contrast to degenerative diseases such as 

Parkinson’s disease and Alzheimer’s disease in which disease onset is often hard to 

pinpoint, the timing and the location of a stroke make the association of changes in mood 

and onset more exact. The mean prevalence of major depression and minor depression in 

patients after a stroke is approximately 20 percent and 19 percent, respectively. In 

Parkinson’s disease, the best estimate is approximately 15 to 20 percent, and for vascular 

disease it is perhaps 20 to 25 percent, with another 25 percent of patients in each group 

suffering from minor depression. 

 Depression has a significant impact on functional recovery from stroke. While the 

average duration of depression in patients who have suffered a stroke is approximately 

1 year, as many as 25 percent of these patients with minor or major depression at baseline 

may remain depressed for up to 3 years. Further, these depressed patients have a more 

prolonged and limited recovery from the stroke and have an increased mortality. As with 

cardiovascular disease, both minor and major depression have an impact on recovery and 

mortality. 

Depression also has an adverse effect on quality of life, cognitive functioning, and 

motor symptoms in Parkinson’s disease, and it increases functional disability in people 

with Alzheimer’s disease. Although some have argued that depression in Parkinson’s 

disease is simply a reaction to the disability of the illness, the incidence of depression in 

Parkinson’s disease is higher than in other illnesses with similar disability. The 

association of depression and Alzheimer’s disease is complicated by the fact that lateonset depression in cognitively intact individuals may be a risk factor for later 
development of Alzheimer’s disease. In general, researchers have concluded that 

depression in Alzheimer’s disease can occur during any stage of the illness and is a 

source of increased disability and mortality. 

 Researchers have proposed two theories on the etiology of depression in 

neurological disease. The first assumes that depression is a reaction to disability and, as 

pointed out above, this can become a circular argument with depression causing 

increased disability. Clearly, disability has a role in the development of depression, but 

there is evidence that the relationship may not be a simple one. The second theory is that 

depression is the result of the neurodegenerative process. Studies examining glucose 

metabolic rates or blood flow changes in regional brain areas of patients with 

neurological disorders—including stroke, Parkinson's disease, and Huntington's 

disease—and comorbid depression demonstrate that these disorders showed a similar 

pattern to that found in primary depression: decreased activity or brain lesions in the 

orbital frontal cortex and basal ganglia. 

Cancer 

The symptoms of depression are common among cancer patients, occurring in as 

many as half of all cancer patients. There is evidence, though, that depression in 

individuals with cancer has been underdiagnosed and undertreated. In part, this is because 

of the belief that depression is a normal and universal reaction to serious disease, but it 

also arises because physicians mistake physical symptoms such as weight loss and sleep 

disturbance, or the emotional and cognitive signs of depression as symptoms of the 

medical illness itself. 

Factors associated with greater prevalence of depression are pain, a higher level 

of medical disability, and more severe illness. More rapid progression and increased 

symptoms of cancer, especially pain, are associated with more severe depression. Having 

cancer and depression simultaneously is associated with increased functional impairment 

and poorer quality of life over the course of cancer therapy and recovery. 

Studies of cancer patients suggest that the severity of depression may have a 

deleterious effect on the number of leukocytes, a class of immune cell, over short periods 

of time. For example, mood disturbances are associated with lower white blood cell 

counts in women with cancer. Symptoms of depression and a lack of social support also 

predict reduced immune cell activity measured at a 3-month follow-up in breast cancer 

patients. 

The diminished immune system activity experienced by patients with depression 

may explain another grim fact: depressed mood heightens the risk of developing cancer 

and of dying after developing cancer. This finding is stronger in people who have been 

chronically depressed. 

HIV/AIDS 

Depression affects a significant proportion of individuals living with HIV/AIDS, 

with estimates of lifetime rates of depression among persons living with HIV, ranging 

from 22 to 45 percent. There is, however, a dearth of research regarding the intersection 

of depression, HIV/AIDS, and aging, which is particularly troubling because HIV/AIDS 

surveillance data indicate that persons over age 50 represent 10 percent of reported cases 

in the United States. Furthermore, trends in incidence rates suggest that AIDS will 
increasingly affect older adults as people already living with HIV are living longer due to 

advances in antiretroviral treatments. 

Depression may affect disease progression in HIV/AIDS through its influence on 

the immune functioning or through its effects on behavioral issues such as treatment 

adherence. Although a clear causal relationship between depression and disease 

progression has not been demonstrated, researchers have accumulated data suggesting 

that the presence of depressive symptoms and severe life stress may contribute to 

immunosuppression and HIV disease progression. 

Numerous studies have documented the myriad problems with adherence to 

treatment, substance use, and declines in quality of life that are associated with 

depression in HIV disease. The mechanisms responsible for these behaviors in depression 

are complex, but recent conceptual models suggest that cognitive, affective, and 

contextual components, such as simple forgetting, apathy, and isolation, respectively, can 

adversely affect adherence to complicated antiretroviral medications and may also be 

related to general poor health care. There is some initial evidence that maintenance of 

effective antiretroviral therapy may be related to improvement of depressive symptoms, 

and several studies are now underway to test the direct and indirect effects of 

interventions to improve mood on adherence to treatment. 

OPPORTUNITIES FOR PROGRESS

 One of the major gaps in mood disorders research is the need for a more complete 

understanding of the natural history and developmental course of depression and bipolar 

disorder—when they first appear, what course these illnesses take as a person ages, and 

how the manifestations of depression and bipolar disorder change over the course of time. 

A complete picture of these disorders would also include how they affect, and in turn are 

affected by, the various medical problems that a person experiences throughout the 

course of a lifetime. 

OPPORTUNITIES TO IDENTIFY DEPRESSION AND BIPOLAR DISORDER DURING 

DEVELOPMENT 

Advances that are occurring in deciphering the human genome raise exciting 

possibilities for integrative programs of research designed to evaluate developmental 

models of depression in the context of interactions between genetic predispositions and 

environmental stresses. Although no specific set of genes, proteins, or environmental 

factors has been linked unambiguously to the origins of the mood disorders, several 

promising hypotheses have emerged. It appears, for example, that the genetic 

contribution to these diseases is likely to be significant and complex, that perinatal 

complications or exposure to adverse environmental circumstances serve to sensitize 

stress-responsive systems during development, that subsequent exposure to trauma may 

precipitate the expression of these diseases in genetically vulnerable individuals, and that 

specific neurobiological systems are involved at different times of development. 

To date, however, far more research examines these ideas in animal models than 

in developing children. Specifically, there is a clear need to conduct the same structural 
and functional neuroimaging studies in pre-adolescents and adolescents as in adults with 

major depression to determine developmental differences in the neuroanatomical 

correlates of depression across the lifecycle. Indeed, the few neuroimaging studies in 

depressed children and adolescents offer preliminary evidence that some neuroanatomical 

correlates of depression may be evident from early in life, while others may emerge later 

in development or secondary to biological alterations associated with the persistence and 

recurrence of disorder. The wealth of emerging non-invasive neuroimaging techniques 

that are suitable for use in children also make this an ideal time to invest in this area of 

research. 

Because so little is known about the development of bipolar disorder in children, 

and considering that genetic factors significantly increase the risk of developing bipolar 

disorder, it would be useful to conduct longitudinal studies of young offspring of bipolar 

parents. Such studies would enable researchers to spot the earliest symptoms of bipolar 

disorder and to correlate them with other behavioral and physical traits that may precede 

the development of bipolar disorder. This information would be invaluable in 

understanding the origins of bipolar disorder and in determining if this illness, like 

depression, first appears during childhood in many people. 

Longitudinal studies of this sort would also help researchers and clinicians to 

develop more appropriate diagnostic labels for children presenting to clinics with 

symptoms of extreme mood lability or irritability. Indeed, there is considerable 

controversy about the most appropriate means for distinguishing bipolar disorder in 

young children from a range of other possible comorbid conditions, including both 

depression and a disruptive behavior disorder. For example, comorbidity, typically with 

disruptive behavior disorders, usually complicates the diagnosis in many children where 

there is a question of a bipolar disorder diagnosis. Bipolar disorder’s symptomatic 

overlap with ADHD is also a leading source of diagnostic confusion. Systematic studies 

of children and adolescents show that rates of comorbid ADHD range from 60 to 90 

percent in youth classified as bipolar. Conduct disorder is also strongly associated with 

pediatric-onset bipolar disorder, and although anxiety is frequently overlooked in studies 

of pediatric-onset bipolar disorder, studies of youth with panic disorder and youth with 

mania document an important overlap of symptoms. 

Careful family-based and longitudinal studies are needed to clarify diagnostic 

boundaries and the relationships between these disorders. Since the diagnosis of bipolar 

disorder appears easier to make in adolescents or adults than in children, it will be 

important to conduct longitudinal studies examining developmental changes in symptoms 

among children of parents classically defined as bipolar. For example, a developmental 

change in a common symptom, like irritability, needs to be examined in large diverse 

samples of community-identified children as they age into adulthood. 

Recent studies of adult bipolar disorder have also generated important research 

questions. Bipolar disorder is recognized as among the most strongly genetic of the 

complex mental syndromes, which should encourage efforts to identify the earliest stages 

of this disorder during childhood. Recent studies among adults also have begun to 

elucidate neural circuits implicated in bipolar disorder as compared to depression. Future 

longitudinal studies of children at high risk for bipolar disorder should begin as early as 

possible and include measures that monitor these potential early forms of the disorder, as 

well as cognitive and affective mechanisms involved in the behavioral expression of this 
disorder. These studies will complement ongoing genetic studies and may elucidate 

markers of increased biological risk in vulnerable children before they develop symptoms 

of bipolar illness. 

OPPORTUNITIES TO DEVELOP NEW THERAPIES FOR CHILDREN AND ADOLESCENTS

Because there has been general acceptance for less than three decades that 

children can experience mood disorders, the state of knowledge regarding mood disorder 

treatments in children remains quite primitive. What is known is that TCAs do not work 

well in pediatric depression. Studies to date are uniformly negative and are probably 

sufficient to conclude that these agents are likely to be ineffective or much less effective 

in childhood and adolescent depression than they are in acute adult depression. SSRIs, 

however, show more promise in treating pediatric depression. 

CBT and IPT are effective therapies for pediatric depression, as shown by over a 

dozen randomized controlled studies. Ongoing psychotherapy studies on pediatric 

depression include studies of psychotherapy for dysthymic children, the Adolescent 

Coping with Depression course compared to mentoring in adolescents with comorbid 

depression and conduct disorder, and Internet-based approaches to treating adolescent 

depression. 

Several structured psychotherapeutic interventions developed for adults have been 

found effective in treating older children and adolescents who come to clinical settings. 

Data from randomized controlled trials support the use of both CBT and IPT for 

depressed adolescents. On the other hand, systemic family therapy and non-specific 

supportive psychotherapy did not prove as successful at speedily reducing depression. 

The response rates for short-term treatment were comparable to adult psychotherapy and 

pediatric trials with SSRIs; likewise, follow-up studies of psychotherapeutic interventions 

showed a high relapse rate. Thus, as with medication, trials of longer-term, more 

intensive interventions are needed to determine whether it is possible to increase response 

and decrease relapse rates. In addition, there is an urgent need to develop and test ageappropriate psychotherapeutic interventions for depressed pre-pubertal children. 

There are no controlled trials or ongoing studies on treatment of preschool 

depression. Outcomes with available treatments in school-age children are not 

impressive. Development of more robust treatments, both pharmacotherapy and 

psychotherapy, and demonstration of the effectiveness in community settings are 

essential. 

There are ongoing NIMH studies of the combination of psychotherapy and 

pharmacotherapy for pediatric depression. The Treatment for Adolescents with 

Depression Study (TADS), a multisite study, compares placebo, an SSRI, CBT, and an 

SSRI plus CBT in the treatment of acute adolescent depression. Another ongoing study is 

examining a collaborative care model of CBT within a health maintenance organization 

as an adjunct to antidepressant treatment. 

 Work on preventing child and adolescent depression has followed two general 

pathways. One approach has been on treatment or prevention of postpartum and maternal 

depression as a potential risk factor for childhood depression, while the other approach 

has been to develop programs targeted at children specifically at risk of developing 

depression or on all children through school-based programs. The first, more common 
approach has reduced maternal depression, but the effects on depression in children have 

been less clear than the effects on other areas, such as cognitive development or 

behavioral problems. In part this may result from short follow-up periods that do not 

extend into periods when childhood depression becomes most prevalent. As several 

prevention studies are currently underway, longer-term follow-up data should become 

available in the next decade. 

Programs directly targeting children and adolescents at risk of developing 

depression have had some success. However, programs addressed to unselected 

populations, such as classroom interventions designed to prevent suicidal behaviors 

through awareness curriculums, have produced mixed results, in some cases even causing 

potential harm. Some studies have established a temporal relationship between early 

anxiety and later depression, especially in adolescent girls. Since effective cognitivebehavioral and pharmacological treatments for pediatric anxiety disorders are now 

available, the opportunity exists to conduct prevention-intervention trials in adolescents 

with anxiety disorder as a means for heading off future depressive episodes. 

There are few controlled studies on the pharmacotherapy of adolescent bipolar 

disorder. One group found that lithium was superior to placebo in the treatment of 

adolescents with comorbid bipolar disorder and substance dependency. In a study of 

depressed children with a family history of bipolar disorder, there was no evidence of 

lithium efficacy. 

Given that many psychopharmacological treatments for behavior disorders can 

exacerbate mania in adults, research is needed that carefully examines the impact of such 

treatments on children. Although recent studies examining short-term SSRI effects in 

children with depression or anxiety disorders document very low rates of manic 

“switching,” longer-term studies in clinically referred patients suggest that the number of 

depressed children that switch may be high. Moreover, in clinical samples treated acutely 

with SSRIs, a sizable group of children showed signs of “activation” or irritability. These 

findings raise questions regarding the predictive relationship between such responses to 

an SSRI and later risk for bipolar disorder, but the power of these phenomena as risk 

factors for bipolar depression has not yet been tested in representative population 

samples. 

 

OPPORTUNITIES TO UNDERSTAND THE INFLUENCE OF GENDER

 A recent World Health Organization report indicates that depression presents the 

greatest disease burden for women when compared to other diseases. Consequently, it is 

critically important to understand what has been learned from empirical studies about the 

gender influences on the course of depression, its treatment, and prevention; and apply 

that knowledge to reduce the environmental, social, and cultural risk factors for 

depression and to optimize interventions. It also is important to incorporate this new 

knowledge into a research agenda that will advance our understanding of how gender and 

depression influence each other. 

 Biological differences in women and men are likely to play a role in the 

differential development of depressive episodes between genders. There is some evidence 

that genes may play a larger role in the development of depression in women. Studies 

underway present the opportunity to determine whether this initial observation holds true, 
and if so, whether the same genes have a differential impact on women versus men in the 

development of depression. Certainly, the obvious difference in sex hormones between 

women and men, and the link between increased rates of depression for women after 

puberty, as well as the link between mood and the menstrual cycle or reproduction, 

suggest that sex hormones may contribute to differences in the onset of depression. 

One possibility is that a disturbance in the interaction between the HPA axis and 

neurotransmitters such as serotonin is a key contributor to depression in women. Women 

may be vulnerable to such disregulation because the neuroendocrine rhythmicity in the 

menstrual cycle or reproduction may make them more sensitive to psychosocial, 

environmental, and other psychological risk factors. Although the direct and indirect 

effects among these factors have not been clearly linked to the onset of mood disorders, 

ongoing research into these connections should provide important insights into the 

development and treatment of mood disorders in women. 

Psychological and social variables are of particular importance to researchers 

attempting to understand the sex-linked differences in the development of depression. 

Gender differences in the response to stress and the impact of stress are likely to play a 

role in the course of depression, though few studies have examined sex differences in 

regard to stress and depression. However, initial research in this area has demonstrated 

that women are three times more likely than men to experience depression in response to 

stressful events. One cognitive style that confers increased risk for depression and that is 

more common in women is ruminative thinking. Another important cognitive difference 

between genders is that relationships are more central to women’s self-concept than 

men’s, and there is evidence that this may account for some of the gender differences in 

depressive symptoms. Certainly, there are important insights to be learned from studies of 

how gender affects such psychological and social factors. 

There is no clear evidence that women respond less or more positively to 

treatments for depression. However, treatment interventions alone may not be sufficient 

to reduce the high prevalence of major depression in women. Instead, researchers need to 

increase their efforts to develop, evaluate, and implement interventions that will prevent 

the onset of depressive episodes. Future prevention research should target women across 

the life span. Identifying groups at imminent risk for depressive episodes may be 

effective in increasing the utility of preventive interventions. Studies should explicitly 

observe effects on collateral public health problems, such as smoking, other substance 

abuse, unplanned pregnancies, marital problems, school performance, job performance, 

and physical health. These preventive interventions may need to address multiple 

outcomes, including healthy development as well as the prevention of psychopathology, 

and involve the collaboration with community to provide the maximal benefit for 

participants. 

Looking toward the future, there is a tremendous opportunity to advance our 

understanding of depression and how to treat and prevent it by examining, rather than 

ignoring, gender differences. Researchers must begin to consider the effects of gender 

when designing and implementing studies and reporting results. Women are a 

heterogeneous group, and this heterogeneity and the context of women’s lives must also 

be considered in research design and the interpretation of experimental results. 
Depression and the Reproductive Cycle 

PMDD is diagnosed in approximately 5 percent of menstruating women and is 

distinguished from the much more common premenstrual syndrome (PMS) by its more 

severe symptoms and impairment. Clinical trials have consistently shown that SSRIs 

taken during the luteal phase of the menstrual cycle can treat the symptoms of PMDD. 

Little has been done, however, to study the benefits of non-pharmacological therapies, 

including exercise and psychotherapy, in treating or preventing PMDD. 

An ongoing challenge to the women who suffer from moderate to severe 

premenstrual conditions is the detection of the illness and treatment with empirically 

proven therapies. For a variety of reasons, including stigma, women will neglect to 

consult a physician when they have moderate to severe premenstrual symptoms, 

including PMDD. On the other hand, clinicians frequently fail to ask women whether 

moderate to severe premenstrual symptoms are affecting their mood and well-being. 

Given the substantial personal burden of PMDD, increased attention to this illness by the 

primary care community could translate into pronounced personal and societal benefits. 

Depression during and after pregnancy can have serious effects on both mother 

and child. Depression during pregnancy is associated with biological disregulation that 

can be detrimental to fetal development, while depression in the period after birth can 

disrupt the attachment of mother and child. Treatment options usually exclude 

medication, though IPT is effective in both pregnancy and the postpartum period because 

of its focus on role transition and interpersonal functioning. ECT appears to be safe and 

effective and is one of the most important interventions for the most serious depressions, 

especially psychotic depression during the postpartum period. 

 Despite the obvious connection between dramatic changes in hormone levels and 

postpartum depression, relatively few studies have examined the role that hormones play 

in triggering postpartum depression or the place that hormone therapy might have in 

treating or preventing depression after childbirth. This should become an important 

avenue for research. In addition, more work needs to be done to determine how best to 

deliver depression-related services to women during pregnancy and after childbirth. This 

is a time when more women seek out medical care than at any other point in their lives, 

so this may represent a unique opportunity to identify and treat mood disorders regardless 

of their specificity for childbearing-related events. 

 The belief that women suffer severe mood disturbances or depression during the 

period surrounding the onset of menopause is not supported by epidemiological data. 

What remains unanswered, however, is whether some women may be more vulnerable to 

the mood effects of hormonal changes. Some evidence suggests that women with a 

history of PMDD or other premenstrual mood changes may have an increased sensitivity 

to the hormonal changes that occur at perimenopause, and that women with previously 

diagnosed mood disorders that are cyclic or associated with reproductive events may be 

at higher risk for depressive symptoms at the onset of menopause. Further research is 

needed to explore these suggestive findings. 

 

OPPORTUNITIES TO IMPROVE MENTAL HEALTH FOR THE ELDERLY

Overall, there remain numerous significant opportunities for research to help 

reduce the burden of depression in late life. The past decade has seen the emergence of 
primary efficacy studies of antidepressant treatment; yet, we do not know which 

antidepressants are the most appropriate for older adults, when considering both their 

safety and their effectiveness. Studies that provide comparative information of multiple 

medications and studies that try to identify the algorithms for optimal treatment are 

needed. Without this information to guide care, older adults end up receiving variable 

care. These issues are equally applicable to psychosocial treatment research. 

Given that most treatment of late-life depression occurs in primary care settings, 

greater efforts can be made to improve the care received there. To date, there have been 

modest gains establishing the challenges to treating depression in primary care, with the 

emphasis on establishing that an effective treatment, regardless of cost, can be provided. 

Over time, more sustainable programs will require validation. Multilevel studies are 

needed to identify effective and cost-efficient methods for identification and treatment of 

depression in both assisted living facilities and nursing home residents. All of these 

studies can help advance the validation and development of time efficient screening 

instruments for routine clinical care. 

The range and variability of depression appears greater in late life, such that there 

remains a need to better characterize its manifestations. For example, the depression seen 

in Alzheimer’s disease appears different than major depression. This has led to the 

development of provisional diagnostic criteria, which can help foster treatment research. 

Our knowledge of the depressive symptoms that co-occur with other mental illnesses, 

including psychosis in late life and anxiety disorders, is more modest. Longitudinal 

studies that can better characterize mood disturbance will ultimately lead to treatment 

development. Underlying the development of treatments that can reduce these burdens is 

the need to further develop basic models of depression in late life, given the known 

relationship with neurobiological function. 

The variability of depression in late life also includes psychotic depression and 

bipolar disorder. Both of these illnesses, though less common, place a greater burden on 

society and the individual. Our gains in understanding and treating these conditions are 

more limited, in part due to the added challenges that come with treatment. Studies that 

can characterize and validate treatment are most needed. 

To date, research has not been able to determine whether and to what extent 

depression increases disability among the elderly and how much disability contributes to 

depression in the elderly. Longitudinal treatment studies need to clarify these relationships 

and identify the target of interventions focused on both depressive symptoms and 

functional deficits. 

Cognitive aspects of depression may play a significant role, and there is a lack of 

consensus regarding the role of cognition in the severity and treatment of depression. The 

development of more sensitive and meaningful measures of cognition is probably the most 

critical step to making gains in this area. Translational research that integrates cognitive 

neuroscience, neuropsychology, and clinical trials theory would hopefully lead to better 

tools. 

An important research task is to identify the specific mechanisms by which social 

factors promote or protect older adults from depression and influence its longitudinal 

course. The role of stress and its biological correlates, including immune function and 

cardiovascular reactivity, as well as the complex interactions between social factors, 
depression, and medical illness, needs to be better articulated. Such studies can guide the 

development of targeted psychosocial and biological interventions. 

Interventions aimed at improving caregivers’ capabilities and well-being need 

investigation, too. Fostering coping skills, and encouraging use of formal help, including 

adult day care and respite services, and informal help may prove effective. Focused 

studies need to examine whether premature or inappropriate institutionalization can be 

prevented through use of pharmacotherapy for behavioral and cognitive symptoms in 

people with dementia and through psychotherapeutic interventions, including short-term 

cognitive, behavioral, psychodynamic therapy, for caregivers. 

OPPORTUNITIES TO UNDERSTAND MOOD DISORDERS AS DISEASES OF THE BRAIN AND 

BODY

The development of standardized criteria for the diagnosis of depression in the 

DSM was a significant advancement in the treatment of mental illness. The diagnosis of 

depression in the context of comorbid medical disorders is poorly developed within this 

framework, however. Indeed, research in this area is minimal and lacks coordination even 

though it is clear that mood disorders have an effect on and are affected by other medical 

conditions that may alter the symptoms of depression and perhaps bipolar disorder. For 

example, comorbid depression may be a symptom in a patient with a neurological 

disorder that is responsive to treatment and with treatment may have a significant impact 

on functional outcome. Yet, the diagnosis of depression in neurological disorders remains 

challenging, and few trials define the potential risks and benefits of somatic therapies in 

this population. Clearly, new thought—and research—is needed to rectify this situation. 

Depression and depressive symptoms have a profound effect on the longitudinal 

course of neurological disorders. Despite being poorly understood, the diagnosis and 

treatment of comorbid depression could provide immediate improvement to long-term 

functional outcomes of a significant percentage of individuals with neurological disease. 

The diagnosis of depression could be standardized, enabling researchers and clinicians to 

develop easily administered diagnostic scales. These scales could be used to assess 

depression and made available to clinicians in routine practice. Algorithms could be 

developed to determine optimal antidepressant medications, as well as physical and 

rehabilitative therapies and other behavioral treatments of depression. 

Understanding depression in neurological disorders can also increase our 

understanding of the pathophysiology of depression. The ground-breaking work linking 

depression to cerebrovascular disease in the left frontal cortex and specific subcortical 

structures, and the recent findings of depression induced by deep brain stimulators in 

Parkinson’s disease are two examples of critical findings that have increased our 

understanding of depression in neurological disorders. 

There also is a need to coordinate clinical research with basic science research in 

areas such as neuropathology of well-characterized neurological diseases. There are few 

animal models of depression and neurological disorders even though animal models 

could provide important insights into such interactions as the role of degeneration of 

specific subcortical nuclei and depression in neurological disorders. 

Numerous studies have provided preliminary evidence for a directional 

relationship between depressive symptoms and aspects of the immune system in groups 
homogeneous for gender and type of disease. However, the link between such measures 

of immunity and clinically meaningful immune function is unclear. More research with 

cancer patients is needed that examines specific functional aspects of cellular immunity 

in association with depression. There is an intriguing recent report in a small sample of 

cancer patients showing a correlation between response to pharmacological treatment for 

depression and natural killer cell counts. 

Similarly, more research is needed that examines specific endocrine and 

immunological correlates of depression for their effects on the health status of cancer 

patients. Gross measures of disease progression do not show an association with 

depression; however, a recent study demonstrated an association between severe 

depression and subsequent risk of being diagnosed with breast cancer. More prospective 

research could begin to systematically identify any effects of depression on the health 

status of cancer patients that may have an impact on disease incidence, course, and 

longevity. 

For persons living with HIV/AIDS, mental health issues have proven to be an 

integral part of adaptation to illness, and an unfortunate but powerful predictor of 

maladaptive coping with the disease, poor adherence to treatment, and decreased quality 

of life. Integrated mental health and HIV/AIDS treatment is the exception rather than the 

norm. Research is needed to test various structural interventions, such as how best to 

encourage and integrate service delivery that could improve access and adherence to 

treatments for both HIV/AIDS and depression. 

 Although there has been excellent work on developing effective treatments for 

depression in HIV/AIDS patients, this research needs to be extended to develop, adapt, 

and assess theory-based interventions for treating depression among underserved, highrisk, or special need populations with HIV/AIDS. Few trials, for example, have included 

representative samples of women, children, ethnic and racial minorities, or older persons 

living with HIV. 

More translational research would enhance our understanding of the mechanisms 

for depression to affect the course of HIV disease, which might also improve our 

selection of treatments. Such studies would help to disentangle the influence of affective 

and cognitive dimensions on mood in HIV disease, including the effects of apathy, lack 

of initiation, neurocognitive problems, and fatigue. 

Effective tools are needed to screen for depressive disorders among patients 

already in care for HIV/AIDS and those at high risk for HIV, such as patients at clinics 

for sexually transmitted diseases. Strategies are also needed to increase the incentives for 

appropriate diagnosis and treatment of mood disorders in medical treatment, since such 

approaches would likely increase appropriate identification and treatment. 

RESEARCH PRIORITIES

1. OPPORTUNITIES TO IDENTIFY DEPRESSION AND BIPOLAR 

DISORDER DURING DEVELOPMENT 

Objective 1. Expand basic preclinical and human research on the development of 

neurobiological, cognitive, emotional, and social processes associated with 

temperament and mood regulation. 
Implementation: 

• Identify critical gaps and research opportunities in current knowledge about the 

development of these basic processes in normative and high-risk populations. 

Objective 2. Improve the diagnostic validity of mood disorders in children and 

adolescents. 

Implementation:

• Improve assessment and treatment of mood disorders in primary care settings and 

school settings.

• Assess functioning levels in children and adolescents with diagnosed mood 

disorders.

• Delineate differential diagnosis, causes, course, treatment, and prevention of 

early-onset bipolar and depressive disorders using collaborative multidisciplinary 

networks of researchers. 

Objective 3. Understand the effects of sex and gender on etiology, diagnosis, 

treatment, and prevention of depression and bipolar disorder in women.

Implementation: 

• Investigate periods for high risk for mood disorders in women (e.g., puberty, the 

childbearing years, the postpartum period, and perimenopause), traumatic life 

events (e.g., childhood sexual assault), and other conditions placing women at 

higher risk. 

• Explore role of hormones (e.g., cortisol, estrogen, progesterone, and dehydroepiandrosterone) in relation to the neurobiology of depression in women 

throughout the life span and integrate biological and psychosocial models of 

depression. 

• Examine the role of stress, including early trauma and stressors throughout the 

life span of women, in mood disorders. 

• Examine the relationship between substance use/abuse and mood disorders in 

women. 

• Investigate the effectiveness of short- and longer-term gender-specific treatments 

and secondary initiatives to reduce relapse, recurrent depression, and refractory 

depression. 

• Determine effective strategies to increase access to services, particularly for 

ethnic and racial minority women and for populations who underutilize available 

services (e.g., older women). 
Objective 4. Determine the developmental pathophysiology of mood disorders. 

Implementation: 

• Identify the neurobiological mechanisms underlying the development of mood 

disorders, and clinical and biological predictors of relapse in children and 

adolescents. 

• Determine the neurobiological mechanisms underlying differential 

pharmacological responsiveness in child and adult mood disorders. Structural and 

functional neuroimaging are among the suggested tools to be used. 

Objective 5. Improve identification of precursors to, and subsyndromes of, mood 

disorders. 

Implementation: 

• Conduct longitudinal studies aimed at young children with prominent early mood 

symptoms (e.g., negative affect, mood lability, extreme irritability, explosiveness, 

chronic anger) that do not meet DSM diagnostic criteria for mood disorders. 

• Study acute and long-term consequences (positive and negative) associated with 

acute, recurrent, and chronic exposure of pharmacological interventions used for 

mood disorders on the developing brain. 

• Expand longitudinal studies of diagnosed and high-risk children to incorporate 

genetic, brain imaging, and other neurobiological and basic behavioral measures. 

• Assess the acute and long-term mental health effects of exposure to trauma in 

children and adolescents. 

Objective 6. Determine when changes in interventions are needed to accommodate 

psychological or physiological life phase changes. 

Implementation: 

• Identify potential differences in treatment response at major developmental and 

life transitional points (e.g., pre-puberty to puberty; pregnancy; biological changes 

with aging). 

• Support secondary analyses of funded treatment trials to explore predictors of 

treatment response during life phases (e.g., studies comparing individual 

developmental history with prior treatment history and outcomes). 

Objective 7. Develop effective treatments for children and adolescents with mood 

disorders. 

Implementation:

• Support studies of long-term maintenance treatments (pharmacological, 

psychosocial, and family psychoeducational) to determine the course of the 

disorder (e.g., affect on relapse) and the development of comorbid conditions, etc. 
• Establish the efficacy and effectiveness of adding manualized CBT and IPT to 

pharmacological treatment and management of adolescent bipolar disorder. 

• Identify and determine the differential effectiveness of pharmacotherapies for 

children and adolescents with mood disorders. 

• Develop and test promising combination and sequenced treatment strategies for 

child and adolescent mood disorders, including strategies to address common 

comorbid disorders. 

• Develop interventions or service delivery models that are sensitive to differences 

in the neuropathophysiology of pre-pubertal children who are depressed or have 

mania, with attention to factors such as cognitive capacity, family culture, 

environmental adversity, comorbid conditions, or other factors that may influence 

treatment and outcome course. 

Objective 8. Prevent mood disorders in children and adolescents. 

Implementation: 

• Determine the long-term impact of successful treatment of juvenile depression 

and anxiety disorders on functioning and on the subsequent development of new 

episodes and other disorders. 

• Establish whether pharmacological agents used to treat ADHD and mood 

disorders increase the risk of hypomania and bipolar disorder. 

• Identify benefits of parent education and parent-mediated interventions to 

improve outcomes and prevent relapse in childhood mood disorders. 

• Ascertain the acute and long-term effects of interventions for depression on 

children and adolescents exposed to trauma. 

2. OPPORTUNITIES TO IMPROVE MENTAL HEALTH FOR THE ELDERLY 

Objective 1. Develop a comprehensive understanding of the risk and protective 

factors in late-life mood disorders that can lead to new preventive and treatment 

interventions. 

Implementation: 

• Determine well-established risk factors that can be used for rapid development of 

new interventions through support of secondary analyses of epidemiological data 

sets. 

• Support trans-institute longitudinal studies to reveal the roles and interactions of 

specific life history, psychosocial, and neurobiological risk factors in morbidity 

and course of disorder. 
Objective 2. Establish the role of cognitive functioning in late-life mood disorders. 

Implementation: 

• Delineate specific behavioral and neurobiological aspects of cognitive 

dysfunction in late-life mood disorders, including the use of new measures 

development. 

• Validate diagnoses and treatments for cognition-related disease models (e.g., 

depression in Alzheimer’s disease, depression in Parkinson’s disease).

Objective 3. Establish the factors involved in the pathophysiology of late-life mood 

disorders. 

Implementation:

• Identify subtypes of depression that are heavily characterized by large- and smallartery disease, and related cardiovascular morbidity such as hypertension (in 

conjunction with the National Institute on Aging and the National Heart, Lung, 

and Blood Institute). 

• Identify other biological factors that contribute to depression 

(e.g., neurodegenerative diseases that affect the midbrain dopaminergic system). 

• Develop innovative and precisely targeted therapeutics that would address the 

vascular mechanisms involved in the depressive disorder. 

• Develop novel interventions that target both neurobiological and psychosocial 

factors contributing to depression. 

Objective 4. Expand the knowledge base of safe and effective treatments for late-life 

depression and associated suicide risk. 

Implementation: 

• Establish “Treatment Research Units – Geriatric” network (TRU-G), similar to 

the child RUPP program. Areas of emphasis could include: 

- Effectiveness 

- Relapse prevention 

- Determining maintenance algorithms 

- Understudied areas (bipolar, dysthymia, psychotic depression, suicide) 

• Validate treatments for acute efficacy while simultaneously exploring factors that 

contribute to sustained remission, reduced relapse, and recurrence. 

• Actively expand research into nursing home, assisted living facilities, and broader 

community settings. 
3. OPPORTUNITIES TO UNDERSTAND MOOD DISORDERS AS DISEASES 

OF THE BRAIN AND BODY 

Objective 1. Improve the ability to diagnose and assess depression comorbid with 

other medical disorders. 

Implementation: 

• Establish the criteria and decision rules used to diagnose major depression, 

dysthymia, and adjustment reactions in persons with other medical illnesses. 

• Based on gaps and needs identified, support development of reliable and valid 

measures for depression in persons with other medical illnesses. 

Objective 2. Identify the mechanisms and processes that have a relatively large 

influence on the development of comorbid disorders (i.e., explain a relatively 

large amount of variance in the outcomes) and can also be modified through 

intervention. 

Implementation: 

• Discover potentially modifiable biological substrates that link comorbid disorders, 

including research on neurotransmitters, neuropeptides, neuromodulators, 

hormones and other proteins, neural circuits, and neural systems (to include 

nervous, endocrine, and immune system pathways, e.g., the HPA axis). 

• Elucidate the genetic, other biological, behavioral, psychosocial, and environmental risk and protective processes that contribute to these comorbid disorders, 

especially the most potent (those that account for the most variance in outcomes) 

and potentially modifiable processes so interventions may be designed to alter 

them. 

Objective 3. Determine variations in prevalence and incidence rates on comorbid 

depression and other medical disorders in women, members of racial and ethnic 

minority groups, children and adolescents, and the elderly. 

Implementation: 

• Determine prevalence and incidence rates by age, gender, racial/ethnic 

background, and income level for mood, anxiety, and psychotic disorders comorbid with the leading causes of death in the United States, such as heart 

disease, cancers, strokes, chronic obstructive pulmonary diseases, and diabetes. 

• Promote epidemiologic studies of depression comorbid with other medical 

disorders to facilitate knowledge of prevalence; to identify potentially modifiable 

risk and protective processes; and to monitor trends in prevention, treatment, and 

rehabilitation. 

 
Objective 4. Support innovative pharmacological, behavioral, psychosocial, or 

environmental interventions aimed at comorbid disorders (e.g., discover 

potentially modifiable biological substrates that link comorbid mental and other 

medical disorders; target functional and symptomatic outcomes; study impact of 

separate organizational and financial systems for mental and general medical 

illnesses). 

Implementation: 

• Expand research on the efficacy, effectiveness, long-term outcome, and safety of 

preventive, treatment, and rehabilitative interventions across the life span on the 

potent, modifiable risk and protective processes contributing to comorbid disorders. 

• Increase the number of clinical trials and intervention studies on pharmacological, 

psychosocial, behavioral, or environmental approaches (individually or in 

combination) that target functional and symptomatic outcomes in depressed 

individuals with comorbid disorders. 
TREATMENT, PREVENTION, AND SERVICES: IMPROVING OUTCOMES

For people suffering from a mood disorder, the outlook has never been better. 

Effective therapies, both pharmacological and behavioral, can help them recover from 

potentially devastating episodes of depression or mania and prevent possible relapses. 

Why, then, is NIMH putting such a heavy emphasis on the development and 

dissemination of new therapies for mood disorders? The answer is that despite 

acknowledged progress, many people with depression or bipolar disorder go untreated. 

Despite the availability of a reasonably safe and effective therapeutic armamentarium, 

untreated and less-than-optimally-treated depression, for example, are both common and 

associated with profound societal costs. Only half of individuals with anxiety and 

depressive disorders are accurately diagnosed, and of those diagnosed, only 25 to 50 

percent receive guideline-level pharmacotherapy and less than 10 percent receive 

evidence-based psychotherapeutic treatments. Even when they do receive treatment, only 

slightly more than half of all of them respond well to therapy, defined as experiencing a 

50 percent or greater reduction from baseline symptom severity. If complete symptom 

remission or restoration of function is the outcome, then the proportion is even lower. 

Investigators have learned a good deal about the efficacy of pharmacological and 

behavioral treatments applied in academic settings to relatively homogeneous populations 

of almost exclusively Caucasian people without complicated general medical or mental 

disorders. Now, researchers need to determine which treatments are effective and costeffective among all members of our society in real-life settings. There is also a dramatic 

need for a better understanding of how to deliver effective therapies to the very people 

who need them most, regardless of their socioeconomic, racial, or ethnic background. 

In today's world of constantly shifting health care organizations and a rapidly 

expanding array of treatments, the challenge for intervention research in mood disorders 

is to select research priorities and design trials that will have high public health 

significance. Public health-based intervention trials prove the value of new treatments 

and show how to translate the delivery of treatments to best meet the needs of all people 

who seek care for a disorder that interferes with their healthy functioning. To accomplish 

these goals, researchers must develop and validate markers of treatment outcome— 

genetic, neuroimaging, physiological, cognitive, functional, and behavioral—that 

represent the mental health status of all members of our society. To include all members 

of society, researchers will have to work with community members to engage them in 

research so that persons representative of all Americans will want to participate in such 

trials. 

CURRENT STATUS OF THE FIELD

CLINICAL TRIALS 

The modern standard for clinical trials used to determine the intrinsic efficacy of 

any treatment (whether pharmacological or psychotherapeutic) is the randomized, double 

blind, placebo-controlled trial. These are usually carried out in academic settings by welltrained clinical investigators, and to maximize the likelihood of a finding, the participants 
under study are invariably narrowly defined. For example, in a trial of a treatment for 

depression, the age range of the subjects would be limited—the elderly might be 

excluded, for example—and individuals with a medical illness such as heart disease or 

diabetes would be excluded, as would anyone who used more than a specified amount of 

alcohol. In addition, the endpoints are usually limited to symptom reduction based on 

well-validated rating scales. 

Such “efficacy” trials are crucial if we are to know that a treatment has value and 

is worth pursuing. Such trials are not, however, enough. When the testing of an 

intervention is limited to such classic clinical trials, we should not be surprised to find 

that the intervention may not work as expected when applied in broad community 

populations, in “real world” settings, and among diverse practitioners operating under 

real world constraints. The results often fail to meet the intent of providers, the 

expectations of consumers, or the demands of health care payers. We regard this gap as a 

reflection of the difference in the yield of research that follows a “regulatory” model and 

research that adheres to a “public health” model of studying interventions for mental 

disorders. One of NIMH’s most important goals in the years ahead is to collaborate with 

the clinical and health services research communities, in consultation with basic 

scientists, advocates, and other federal agencies, to bridge that gap. 

The outcomes of real world patient care often hinge on questions that are not 

addressed in studies based on a regulatory model. Payers want to know the best ways to 

determine what interventions work for what populations and which are the most costeffective. Clinicians want data that will help them plan and implement treatment for 

consumers who may present with co-occurring mental disorders, substance abuse, or 

medical problems; who can be at various stages of an illness; and who are culturally, 

ethnically, or racially diverse. Health care consumers, who are increasingly savvy about 

treatment options and often carry high expectations, want to know what treatment is best 

for their particular condition while presenting clinicians with varying concerns about 

adherence to a treatment regimen. 

The public health model attempts to address these needs. In this type of trial, age, 

gender, co-occurring illnesses, and many other characteristics are no longer the basis for 

exclusion, but rather present important dimensions to ensure that studies are 

representative of the American population and will generalize to many clinical and 

community settings. Treatment intervention is defined to encompass a full range of 

pharmacotherapy and other somatic interventions, psychotherapy and other psychosocial 

approaches, and mixed modality approaches. It can extend to research on rehabilitative 

interventions and preventive interventions, including those focused on prevention of 

relapse and recurrence. Outcomes are not limited to symptom remission but can 

encompass performance, family and interpersonal relationships, disability, health care 

resource use, and quality of life. Settings are selected from a full range of academic and 

nonacademic institutions, specialty and primary care, public and private facilities, with 

sample sizes sufficiently large to ensure adequate power. In these ways, the public health 

model permits studies to be designed to evaluate the effectiveness of clinical 

interventions, as they are likely to be delivered in community and specialized practice. 

These new types of treatment intervention studies will require the development of 

studies that combines the designs of traditional clinical and services research. This will 

necessitate a compromise between the strict randomized studies traditionally used in 
clinical research and the more observational designs used in services research. One 

attempts to maximize internal validity while the other tries to ensure external validity. In 

order to bridge this gap, there is a need to bring together methodologists with expertise 

across these fields to delineate what we currently know and what we don't. A great deal 

of knowledge exists, but it has not been applied to the types of studies proposed here in 

the mental health field. It is also quite likely that new methods and statistical analytic 

approaches will need to be developed to address studies in the mental health area. NIMH 

is committed to fostering development of this new methodology and is exploring the best 

ways to proceed with this endeavor. 

PHARMACOLOGICAL THERAPY

Depression 

Medications for the treatment of depression were introduced in the late 1950s and 

early 1960s as part of what is commonly referred to as the “psychopharmacology 

revolution.” Two classes of antidepressant medications were developed, TCAs and 

MAOIs. A second major wave of new antidepressants occurred in 1988 with the 

introduction of the first SSRI, a class of drugs that prevents neurons from removing 

serotonin from the synapse, which has the effect of increasing the duration of a nerve 

signal. However, at best only 65 percent of individuals with depression or bipolar illness 

respond adequately to available drugs, and many experience intolerable side effects. 

Furthermore, for both antidepressants and mood stabilizers, there is a time lag of weeks 

to months in the desired therapeutic response. 

The SSRIs have become the clear drug treatment of choice for all forms of 

depression. Five are now available and these drugs are approximately equivalent to each 

other. The SSRIs have a much more benign side-effect profile, including safety after 

overdose, than the TCAs and largely for this reason have replaced the earlier drugs as 

first-line therapy. Sexual dysfunction is a major problem of the SSRIs—and indeed of all 

drugs that block the reuptake of serotonin and may affect treatment adherence. 

There are several other effective antidepressants that are frequently used but do 

not fall conveniently into any single category. One, for example, is a dual serotonin and 

norepinephrine reuptake inhibitor, while another increases presynaptic release of both 

serotonin and norepinephrine and is also a serotonin receptor antagonist. Because of 

advantages in the side-effect profile and possibly in efficacy, these drugs are often used 

as first-line agents. 

 Most people with depression do not exhibit a therapeutic response until they have 

taken the drug for at least several weeks. A number of agents have been used as add-ons 

to established antidepressants in an attempt to reduce this latency to response. So far, 

systematic evidence that any such agent is effective in this regard is lacking. 

Slightly more than half the people receiving antidepressant therapy achieve 

adequate response to treatment. NIMH has launched a very large, multisite public healthoriented trial, “Sequenced Treatment Alternatives to Relieve Depression” (STAR*D), to 

identify the most effective approaches using available drugs and psychotherapy to 

address treatment-resistant depression. 

“Off the shelf” herbal remedies are self-prescribed by many individuals for the 

relief of depression, but they are not regulated by the FDA. Therefore, there is virtually 
no information on efficacy, adverse events, or drug-drug interactions of these agents, nor 

is there any regulation of drug composition. Moreover, in most cases the possible 

mechanism of action of these compounds is obscure. Recently, a controlled study failed 

to demonstrate that one of these herbal preparations, St. John’s Wort, was any more 

effective than placebo in the treatment of major depression of moderate severity. 

There is some limited evidence that drugs that enhance dopaminergic 

neurotransmission may have antidepressant properties. For example, one dopamine 

receptor agonist has been reported to be as effective as an SSRI in treating depression. 

Other dopamine reuptake inhibitors, including some that are also serotonin and/or 

norepinephrine reuptake inhibitors, are under development, however. 

Bipolar Disorder 

 Until about 10 years ago, bipolar disorder was in danger of becoming an orphan 

disorder with respect to treatment research and clinical trials. A period of enormous 

complacency had followed the introduction of lithium carbonate in the United States and 

only a tiny number of trials were conducted between its introduction and the early 1990s, 

when both new clinical trial and naturalistic data indicated surprisingly poor outcomes 

showing that fewer than half of all individuals go 2 years without a new episode of mania 

or depression. This has led to a resurgence of interest in the treatment of this devastating 

disorder, including the recognition that psychosocial interventions, virtually absent from 

prior research endeavors, might have a role to play as adjunct treatments. 

 Efforts to develop new pharmacologic strategies for bipolar disorder have included 

trials of a variety of different compounds with different biochemical activities, such as 

anticonvulsants. Although some evidence is available to support the use of each of these 

agents in lithium-resistant bipolar disorder, few studies have carefully evaluated the 

maintenance efficacy of such strategies. Only scant research attention has been given to 

the possibility that psychosocial interventions may be useful adjuncts to maintenance 

pharmacotherapy. 

 Most recently, NIMH has funded the Systematic Treatment Enhancement Program 

for Bipolar Disorder (STEP-BD), a large multicenter, multifaceted long-term clinical 

trial. By following thousands of people over several years in a semi-naturalistic “best 

practices” design, STEP-BD investigators will provide the field with an unprecedented 

amount of data on the longitudinal course and effectiveness of modern, multimodal acute 

and maintenance interventions for different phases of bipolar disorder. A subset of the 

participants maintained on pharmacotherapy will be randomized to one of three specific 

adjunctive psychosocial treatment arms (cognitive therapy, family-focused therapy, or 

interpersonal and social rhythm therapy), and its effectiveness at reducing residual 

symptoms and promoting the recovery of adults with bipolar illness will be compared to 

that afforded by more usual, minimal psychosocial intervention. Embedded randomized 

trials will permit the controlled evaluation of common clinical practices, e.g., combined 

antidepressant and mood stabilizer versus mood stabilizer alone for bipolar depression. 

Related women’s health studies within STEP-BD will examine the relationship of 

valproate to polycystic ovary syndrome and the effectiveness and safety of omega-3 fatty 

acids for mood stabilization in women with bipolar disorder who discontinue traditional 

medications due to planned or actual pregnancy. 
SOMATIC TREATMENTS FOR MOOD DISORDERS 

In many respects the study of somatic treatments is comparable to that of other 

interventions for mental disorders, utilizing clinical trials methodology that includes 

specified treatment parameters, duration, and standard outcome measures. However, 

certain characteristics of somatic treatments distinguish them, to varying degrees, from 

standard drug and psychotherapeutic interventions, and present special challenges to the 

performance of scientific research. 

Because of the relatively invasive nature of some somatic therapies, their use is 

skewed toward sicker mood disorder populations and studies involving random 

assignment to treatment are problematic. For example, ECT is specifically indicated in 

cases of severe depression accompanied by psychosis or catatonia. This also means that a 

disproportionate number of individuals available for study or clinical treatment using 

ECT will be treatment-resistant. The need to study very ill people also means that it is 

difficult to establish a medication-free baseline, which would be ideal to study the true 

effects of a somatic intervention, and essential for meaningful mechanism of action 

research. This has been less of an obstacle to pharmacotherapy research, where the use of 

multiple medications has become the norm in severe mood disorders. The only controlled 

trial of ECT in mania, for example, was published more than a dozen years ago. Some 

investigators have moved instead toward combined treatment studies of somatic 

treatments plus drug treatment. 

However, NIMH-supported research has found ways of improving the outcome of 

ECT while minimizing side effects. For example, placing electrodes on one side of the 

head and using a stronger electrical pulse reduces the memory loss usually associated 

with ECT while retaining its efficacy. A variety of ongoing studies are aimed at further 

increasing the safety of ECT while maximizing its therapeutic effects. Recent NIMHsupported research demonstrated that aggressive pharmacotherapy following successful 

completion of a course of ECT can substantially reduce the common problem of relapse 

in the year following ECT. The first controlled trial of maintenance ECT is currently 

underway. 

Researchers are currently exploring another promising somatic therapy known as 

regional transcranial magnetic stimulation (rTMS). In contrast to ECT, which applies an 

electrical stimulation to the scalp, rTMS generates a more precisely localized 

electromagnetic pulse by using a magnetic coil placed over the person’s head. To date, 

the antidepressant effect of rTMS has been modest, but studies continue in an attempt to 

improve this therapy, which does not require anesthesia and has rarely been associated 

with adverse effects beyond a mild headache. Other more invasive somatic treatments, 

including vagus nerve stimulation and deep brain stimulation, are under study, but have 

not yet shown efficacy in refractory depression in controlled trials. At the milder end of 

the depressive spectrum, a structured aerobic exercise program has shown efficacy 

similar to that of antidepressant medication in one NIMH-supported trial. Research over 

the past two decades supports the efficacy of daily exposure to bright artificial light in 

individuals with an exclusive and repeated seasonal pattern of mood disturbance over 

multiple years. 
PSYCHOSOCIAL THERAPY DEVELOPMENT

Depression 

Depression responds to several different psychotherapies. IPT and CBT have the 

strongest empirical support. Both have demonstrated efficacy in the acute treatment of 

depressed outpatients, although questions remain about the efficacy of CBT among 

people with more severe depression. Traditional psychodynamic and experiential 

interventions, including eclectic approaches to therapy, have been tested in relatively few 

studies and have not proven particularly effective in most of these trials. 

Both IPT and CBT appear to reduce risk for relapse or recurrence so long as they 

are continued. Moreover, CBT appears to have an enduring effect that extends beyond 

the end of treatment. Acute treatment with CBT has been shown to reduce risk for 

subsequent relapse, and adding CBT to medications during continuation treatment 

reduced risk for both relapse and recurrence. There are also indications that CBT can 

prevent the initial onset of the disorder in persons at risk. These indications deserve to be 

pursued; it would be important to determine if CBT has a preventive effect. 

IPT may have a specific effect on interpersonal functioning and the quality of 

relationships. Given that interpersonal relationships are themselves important and that 

problems in this domain may contribute to onset and prolongation of mood disorders, 

these preliminary findings suggest that further research is needed to determine whether 

IPT improves the quality of social and vocational life for those with mood disorders. 

Combined treatment involving medication and evidence-based psychotherapy 

typically provides a modest increment over either single type of treatment alone with 

respect to the reduction of acute distress, and appears to retain the specific additional 

advantages produced by each. For example, medications typically produce more rapid 

symptom relief than IPT, whereas IPT has the broader effect on the quality of 

interpersonal life. Similarly, combining CBT with medication appears to compensate for 

any relative limitations CBT may have in the treatment of more severely depressed 

people while retaining its enduring effects. 

As with antidepressant medications, not all individuals respond to psychosocial 

therapy, and only a minority achieve full remission. Incomplete response increases the 

risk of relapse, and many will have chronic or recurring problems if they do not stay in 

ongoing treatment. Even with such treatment, some individuals will suffer relapse or 

recurrences. Individuals with a history of chronic depression or long-standing personality 

disorders appear to be particularly unlikely to respond to brief interventions. Moreover, 

little is known about the effects of existing treatments on work disabilities and other 

dysfunction that often constitute the primary concerns of people with depression. Clearly, 

new treatments must be developed and existing interventions strengthened to deal with 

these limitations. 

Work is underway on adapting existing evidence-based interventions for use with 

chronic or treatment-resistant forms of depression and in other more specific indications 

around prophylaxis or relapse prevention. Other research is directed toward adapting 

existing therapeutic approaches for new applications, such as dialectical behavior therapy 

for depressed elders with personality disorders, problem-solving approaches for 

depression in the primary care setting, and behavioral activation as a more simply 
behavioral form of CBT. Additional research is needed to further develop and establish 

the properties and optimal uses of new psychotherapeutic approaches that have shown 

initial promise in the treatment of mood disorders, such as supportive-expressive 

psychodynamic psychotherapy, Cognitive Behavioral Analysis System of Psychotherapy 

in treatment of chronic forms of depression, and mindfulness-based cognitive therapy in 

prevention of depressive relapse and recurrence. 

Bipolar Disorder 

The treatment of bipolar disorder remains problematic. The pharmacological 

guidelines for treating people with bipolar disorder during acute, continuation, and 

maintenance phases are well established. Nonetheless, most individuals have breakthrough episodes or significant residual symptoms even while on medications. Problems 

with adherence further undermine the stability of response. Episodes of the illness are 

associated with significant social and occupational problems, and functional deficits often 

remain even when the person is not having an occurrence of the illness. 

Though there is little evidence as yet that these approaches can forestall the 

emergence of mania, over recent years researchers have shown a renewed interest in 

applying psychosocial therapies to the treatment of individuals on medication for bipolar 

disorder. Family-focused therapy aimed at reducing high levels of emotion, especially 

criticism, and enhancing the frequency of positive family or marital interactions appears 

to reduce the risk for subsequent relapse in people on medication. Similarly, IPT 

modified to incorporate attention to stabilizing people’s social rhythms has shown 

considerable promise. Likewise, CBT has demonstrated potential for reducing the 

frequency of depressive relapse and delaying manic relapses, when aimed at early 

recognition and treatment of prodromal symptoms in medicated individuals. 

More must be done to refine existing treatments and develop novel interventions 

for bipolar disorder. The fact that many people do poorly even while on medications 

speaks to the importance of developing or extending other types of treatment. This might 

include developing brief educational interventions for young people at risk for early onset 

by virtue of family history or mood fluctuations. Psychosocial interventions also should 

be developed to enhance individuals’ adherence to mood stabilizing medication regimens 

and their ability to cope with stress that contributes to illness recurrence. Such 

interventions have the potential to alleviate impairments in social and occupational 

functioning not addressed by medication. Sequential models need to be developed that 

parallel the changing course of the illness. Research is needed to determine the optimal 

composition and sequencing of an overall, empirically based treatment approach and to 

validate preliminary clinical observations that behavioral activation, family support, and 

cognitive restructuring may be useful during the depressed phase, whereas medication 

regularity and social rhythm stabilization may be particularly important to prevent cycles 

into mania. 

ISSUES FOR TREATMENT

Measurement 

 Advances in depression research and treatment development are highly dependent 

on the quality of research procedures to measure, assess, or classify the pathology and its 
expressed symptomatology. No reliable biological markers or valid behavioral tests exist 

to define the exact nature of depression and disentangle issues of comorbid pathologies, 

or co-occurring syndromes or clusters of symptoms; accordingly, diagnostic and 

classification systems have principally relied upon clinical description and the naming of 

behavioral signs and symptoms to define the syndrome (e.g., sad mood, sleep difficulties, 

diminished interest). The traditional assessment and diagnosis of depression has proved 

insensitive for the identification of likely responders to existing psychosocial and 

psychopharmacological treatments. 

 Historically, diagnostic measures of depression have utilized two modes: patient 

self-report of symptoms or clinician rating of patient symptoms. Measures in each of 

these traditions have been widely used for multiple purposes with broad public health 

implications, including validating the use of new medications for treatment and 

identifying people who might respond to various treatments of depression. However, the 

most widely used instruments in clinical settings have generally failed to provide clear 

documentation of the symptoms experienced by individuals and instead typically have 

offered only global indices of depression. 

 Assessment tools (both self-report and clinician administered) need to deal 

effectively with the heterogeneity of depression for several reasons. First, different forms 

of depression may respond differentially to various treatment modalities, or have a 

different course. Second, the complete mapping of the human genome raises the 

possibility of relating disorder subtypes to specific genetic vulnerabilities. Third, 

advances in techniques to study neuropathophysiological processes facilitate the study of 

associations between clinical phenomena and the neural substrates and circuitry of mood 

and emotion. Refined measurement is a prerequisite for studies that examine such 

associations, link genetic diatheses to particular forms of disorder, or guide the precise 

tailoring of future therapeutics. 

The tools developed will need to be tailored to a wide audience of consumers and 

should reflect validated components of depression such as: depressed mood, 

hopelessness, psychomotor retardation, sleep disruption, fatigue or loss of energy, 

diminished ability to think or concentrate, disturbed self-image (i.e., feelings of 

worthlessness or excessive guilt), and suicidal ideation. They also need to be appropriate 

for individuals of diverse cultural backgrounds, valid for individuals at various stages of 

development (i.e., children, adults, elderly), suitable for use in diverse settings (e.g., 

clinical trials based in academic centers and community-based mental health), and 

sensitive to individuals with various comorbid medical conditions. 

Prevention of Suicidal Behavior 

Suicide is a complex behavior usually caused by a combination of factors. 

Research shows that almost all people who kill themselves have a diagnosable mental or 

substance abuse disorder or both, and that the majority have depressive illness. 

Researchers know little about the prevention of suicidal behavior. Suicidal people are 

routinely excluded from controlled trials, and few studies have targeted such behavior. 

While it is practice to reduce imminent risk for suicide through hospitalization, few 

studies have examined whether this practice reduces suicidality over the long term. 

Existing interventions for depression have done little to reduce the incidence of death by 

suicide, although this may be changing with the advent of newer and safer medications. 
Psychosocial interventions that target suicidal behaviors may reduce risk for 

morbidity and mortality. There are indications that the availability of crisis intervention 

services can reduce risk for suicidal behaviors for some subgroups, and simply 

maintaining a correspondence with people who refuse treatment has been found to reduce 

rates of suicide. Further research is needed to determine whether suicide is best prevented 

by reducing the general level of distress, by targeting the suicidal behaviors directly, or 

both. 

DELIVERY OF SERVICES

Primary Care 

Primary care represents a strategically important setting for the identification and 

treatment of depression and other mental disorders, especially for children and older 

adults. It offers the advantages of continuity of health care, early identification and, 

importantly, coordination of care for mental and somatic disorders given the frequency of 

comorbidity. 

Research indicates that approximately one-third of depressed patients in primary 

settings receive inadequate treatment, and more than half (55 percent) receive no 

treatment. The deficiencies are attributable to a complex set of factors. Primary care 

physicians are hampered by an inability to address multiple problems and concerns in a 

time-limited visit; the lack of clear biological markers with diagnostic utility; and 

limitations in necessary knowledge and skills in mental health care. Patients contribute to 

the problem by an inability or unwillingness—the latter often prompted by the person’s 

beliefs about mental illness and stigma—to articulate their reasons for seeking care; and 

by lack of appreciation of the importance of treatment adherence. The health care system 

also erects multiple barriers to effective diagnoses and treatment; these include: lack of 

availability of providers and treatments; limitations of third-party insurance coverage, 

including restrictions on specialists, medication, and psychotherapeutic care; and 

competing demands of other medical illnesses in terms of costs for procedures and drugs. 

Often cross-cutting these physician, patient, and system obstacles are cultural and 

language barriers in expressing and translating symptoms. 

The reality that the preponderance of treatment for mental disorders occurs in the 

general medical/primary care sector, and the limitations of that care, underscore the need 

for more intensive research addressing these issues. The complex interplay between 

financial/economic incentives, health care provider and patient behavior, and its impact 

on the delivery of effective treatment for depression or bipolar disorder must be 

understood to improve clinical outcomes and realize the full potential of the primary care 

setting. 

Barriers to Care 

Too often, clinical practices and service system innovations validated by research 

are not fully adopted in treatment settings and service systems for individuals with mood 

disorders. Health services must be improved by focusing on a continuum of knowledge 

translation: from basic science to development of new treatments, from treatment 

development to clinical trials, and from clinical trials to practice. The model, in its most 

extreme form, seems to assume that the universe of patient care rotates around the earth 
of scientific knowledge, but clinical practice must proceed even in the absence of data 

from randomized controlled trials. The process of translating science to practice is neither 

a one-way flow from basic to services research, nor a linear process but instead a process 

that has a series of loops whereby at one point practice may stimulate the ideas for 

treatment development and at another time be the recipient of the change. 

The more serious problem is that there also are many common clinical situations 

where people require treatment and there is clear experimental evidence to indicate what 

the clinician should do, but that treatment is not provided. Research funds fail to improve 

public health unless research results become part of routine practice through education or 

re-education of practitioners, administrators, policymakers, and consumers/patients. 

The mood disorders research field can no longer ignore the mounting evidence 

that new information—the central product of research—has only a very limited impact on 

the decision-making behavior of those who receive it. This fact and the resultant chasm 

between treatments selected and carried out in clinical trials and those selected and 

carried out in real world settings have led to considerable tension between clinical 

researchers and practitioners and between clinical trials or “efficacy” and “effectiveness” 

researchers. This chasm must be bridged if we are to improve the health of the Nation. In 

an ideal world, researchers would choose to study highly efficacious treatments that are 

also very generalizable, but this has rarely occurred. 

The data on the efficacy of a few carefully studied psychotherapies and of 

appropriately dosed medication treatment support both forms of therapy for most 

unipolar mood disorders. How have patterns of care shifted as this information became 

available? It is evident that the introduction of the SSRIs has had dramatic and pervasive 

effects on care for depression. The impact of the evidence on the effectiveness of CBT, 

IPT, and other empirically supported psychotherapies is equivocal at best. However, this 

is hardly surprising since neither form of treatment is efficacious with all persons 

suffering from depression, and there are almost no data on how to select among 

treatments when faced with a given patient. It is difficult to know what contribution is 

made through the advertising created by drug companies on the positive effects of their 

products; an advantage, if it is one, that the psychotherapies do share. 

To date, treatment research priorities have not balanced new knowledge 

generation with questions about information needs, and opportunities and mechanisms to 

improve care. Future research priorities will need to emphasize “how” to deliver the 

treatment as well as “what” treatment. They will also need to emphasize the costeffectiveness of treatments across populations and care settings. 

The burden of an illness refers to its total direct and indirect consequences across 

stakeholders of interest—consumers and their families, clinicians, payers, and society. 

Different stakeholders face different consequences of mood disorders and benefit 

differentially from interventions to reduce the burden of these disorders. As a result, 

“externalities” exist, where the consequences of decisions are experienced by 

stakeholders other than the decision maker. For example, pain and suffering is largely 

borne by affected individuals and their families, while health care costs may be borne 

initially by providers, payers, and plans. In this situation, providers and purchasers may 

be reluctant to support the level of care that might be desired by families. More generally, 

externalities can result in substantial barriers to treatment and to changing consumer and 

provider behavior. Information on how costs and benefits of an illness and marginal 
effects of interventions are distributed across stakeholders can be used to formulate 

policies to correct incentives. 

It is likely that barriers to care contribute significantly to the unmet needs for 

appropriate care. For example, low socioeconomic status and poverty increase the risk for 

mood disorders and reduce access to specialty or general medical and mental health 

services. In studies of perceived unmet need, financial barriers predominate. One study 

found that 14 percent of the National Depressive and Manic-Depressive Association 

(NDMDA) members with bipolar disorder indicated they might discontinue medication 

due to costs. Other factors that erect barriers to care include: family dysfunction; lack of 

family resources; comorbid general medical and mental disorders; consumer attitudes, 

knowledge, and behavior; clinician and practice factors; lack of insurance coverage; 

community factors; and societal stigma. Breaking down these barriers in effective ways 

will require new interventions developed through research. 

Issues Facing Racial and Ethnic Minority Groups 

Among the many challenges facing our Nation in the 21st century, one of the 

most urgent is to address health and health care disparities experienced by many citizens 

and disproportionately by members of racial and ethnic minority groups. Racial and 

ethnic minority groups make up 29 percent of the U.S. population and by 2050 will 

account for nearly 50 percent of the population. Yet despite having similar needs for 

mental health care, members of the Nation’s racial and ethnic minority groups often fail 

to receive appropriate care. For example, two national studies found that racial and ethnic 

minority treatment populations were less likely to receive appropriate care for depression 

or anxiety than were Caucasians. 

Americans of ethnically and racially diverse backgrounds also face unique 

cultural barriers to care. For example, although African Americans make up nearly 12 

percent of the U.S. population, only 2 percent of psychiatrists and 2 percent of 

psychologists are African Americans; a similar pattern applies to other racial and ethnic 

minority groups. Racially and ethnically diverse Americans are also more apt than 

Caucasians to be uninsured. Studies have also shown that African Americans are 

terminated sooner from treatment by Caucasian therapists, and are also more likely to be 

perceived stereotypically by inpatient staff as violent or dangerous. 

African Americans with bipolar disorder are at higher risk for being misdiagnosed 

as having schizophrenia than are Caucasians, are less likely to receive lithium therapy, 

and are more likely to have lithium side effects. African Americans are also more likely 

than Caucasians to receive antipsychotics across diagnostic groups and to receive higher 

doses, contributing to high risk for tardive dyskinesia. 

In late 2001, NIMH in collaboration with consultants and public comment 

developed a 5-year strategic plan to address mental health outcome disparities through 

research that aims to describe, understand, and remedy the disproportionate impact on 

minority populations of mental disorders and behaviorally influenced medical conditions 

such as HIV/AIDS (http://www.nimh.nih.gov/strategic/strategicplanmenu.cfm). This 

research takes into consideration relevant contextual frameworks, including interpersonal, 

socio-cultural, and organizational factors. The plan prioritizes ongoing research, research 

training/capacity building, and public information outreach and dissemination activities 

as well as new initiatives. NIMH has also created an additional plan for mental health 
research career development of racial/ethnic minority investigators 

(http://www.nimh.nih.gov/council/diversity.pdf). 

Children and Adolescents 

The literature on burden of mood disorders is undeveloped for children and 

adolescents. The conceptualization and evaluation of barriers is complicated by the 

diversity of service systems for youths, including schools, foster care, and juvenile justice 

systems, in addition to general medical, mental health, and substance abuse systems. 

Professionals differ within and across systems in training, experience, and responsibility 

for youths with mood disorders. 

One of the chief problems is that there is no consensus on diagnostic criteria for 

youth mood disorders. Provider recognition is lower for internalizing disorders, such as 

depression and anxiety, than externalizing disorders, such as conduct disorder, in youth, 

and parents may be less likely to seek services for children with internalizing problems. 

Barriers to referral and treatment in primary care include delays in obtaining 

appointments, lack of specialists, payment problems, managed care restrictions, and 

complex appeal processes. Among children seeking behavioral health care under 

managed Medicaid, 25 percent of their families reported not getting enough approved 

visits and 15 to 20 percent reported waiting more than 4 weeks for an appointment. 

Children are also over-represented among the uninsured. Some initiatives offer 

promise, but benefits vary across states and enrollment rates are low. In the private 

sector, most children are covered by managed specialty carve-out companies. Variation 

in financing and management may affect use of mental health services for children, but 

effects of specific policies are unknown. One consumer survey suggests that children 

with severe mental illness frequently end up in the juvenile justice or child welfare 

systems due to unavailable or inadequate treatment under limits imposed by managed 

care. While achieving parity of annual and lifetime dollar limits for mental health and 

medical health services could increase mental health service use by children, the effects 

of mandated coverage on this age group have not been studied. Policy initiatives affecting 

mental health care for children are implemented with few efforts to track results. 

OPPORTUNITIES FOR PROGRESS

Novel interventions may be created from scratch or refined from existing 

treatments. Innovation often builds on existing knowledge and theory about the processes 

that initiate and maintain the disorders of interest. This knowledge may come from basic 

research on normal populations or psychopathology research on clinical populations; 

efforts to use this information for clinical purposes have come to be called translational 

research. Similarly, basic research on the change process can be used to test theory and 

refine existing interventions, as can efforts to examine mechanisms of change within the 

confines of controlled clinical trials. Finally, innovation can arise from the experience of 

clinical practitioners. 

OPPORTUNITIES TO IMPROVE AND EXPAND CLINICAL TRIALS 
In recent years there has been an increasing emphasis on extending clinical trials 

research—research that examines how well treatments work in people—from tightly 

controlled, academic settings out into community settings. Many past studies have 

established the safety and efficacy of various treatments for mental disorders—that is, 

how well they work in very specific groups of people under ideal conditions. However, 

few studies have adequately tested the effectiveness of particular treatments or treatment 

strategies—how well they work, for example, in people who live in the community, come 

from diverse backgrounds, have co-occurring disorders, or experience atypical patterns of 

illness. In addition, quality of life, ability to work, social functioning, treatment 

adherence, and treatment cost-effectiveness are among the important, real world issues 

that only effectiveness research can adequately assess. In contrast to efficacy research, 

effectiveness studies have very few exclusionary criteria and enroll large numbers of 

participants—several hundred to thousands—so that the findings will be representative of 

and broadly applicable to an entire population group. 

To improve the standards of treatment for mental disorders, NIMH has taken the 

lead in developing treatment effectiveness research on a number of clinical issues of 

major public health significance. Three major, multisite, NIMH-funded effectiveness 

trials that relate to mood disorders are ongoing. 

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEPBD) is the largest and longest treatment study for bipolar disorder ever conducted. STEPBD focuses on finding the most effective strategies for treating episodes of depression 

and mania and for preventing recurrent episodes over time. Almost anyone with bipolar 

disorder who is age 15 or older and living near a study center can participate. There are 

currently 15 STEP-BD study centers recruiting individuals, with an expected total 

enrollment of 5000 participants. STEP-BD is evaluating all the best-practice treatment 

options used for bipolar disorder: mood-stabilizing medications, antidepressants, atypical 

antipsychotics, and psychosocial interventions—or “talk” therapies. Findings from STEPBD will help improve the treatment standards for bipolar disorder used by doctors in 

everyday clinical practice. 

Sequenced Treatment Alternatives to Relieve Depression (STAR*D) focuses on 

non-psychotic major depressive disorder in adults who are seen in outpatient settings. 

The primary purpose of this research study is to determine which treatments work best if 

the first treatment with medication does not produce an acceptable response. There are 

currently more than 30 STAR-D sites recruiting, with an expected total enrollment of 

4000. Participants will first receive citalopram, an SSRI medication; if symptoms remain 

after 8-12 weeks of treatment, up to four other levels of treatment will be offered, 

including cognitive therapy and other medications. There are no placebo treatments. 

Some individuals may require a combination of two or more treatments to obtain full 

benefit. Participation could last from 15 to 27 months and involve up to 30 clinic visits. 

Participants will be interviewed by telephone throughout the study about their symptoms, 

daily functioning, treatment side effects, use of the health care system, and satisfaction 

with treatment. There will be a 1-year follow-up for participants once their depression has 

been successfully treated. 

The Treatment for Adolescents with Depression Study (TADS) is a research study 

of treatments for major depressive disorder in teenagers. TADS will compare the shortand long-term effectiveness of an antidepressant medication (fluoxetine), psychotherapy 
(CBT), and the combination of these treatments in teens ages 12-17 with major 

depression. This is a 36-week study with a 1-year follow-up period. There are 12 TADS 

sites currently recruiting participants, for a total expected enrollment of 432. 

Increasing Participation Diversity in Clinical Trials 

The participation of racial and ethnic minority groups in clinical and public health 

research is essential for addressing disparities in health status. However, for many 

different reasons, racial and ethnic minority group participation is low in most research 

studies. Many authors have documented numerous barriers to participation in research. 

Those barriers fall into four categories: broader health care system issues; cultural and 

social attitudes; public knowledge, perceptions, and attitudes toward researchers and 

research; and behaviors and attitudes of providers and researchers. Most research takes 

place at university medical centers that tend to have an underrepresentation of racial and 

ethnic minority faculty, researchers, students, and patients who ordinarily comprise the 

research scenario. The absence of familiar social and cultural accommodations could 

account for the sense of discomfort racial and ethnic minorities feel in the medical 

research center, and hence their reluctance to enter this setting, particularly as clinical 

trial participants. Several authors describe researcher and physician biases as barriers to 

recruitment of racially and ethnically diverse participants. Despite ethical standards that 

would prohibit such actions, researchers may limit racial and ethnic minority group 

participation in clinical trials because of their beliefs that these participants will prove 

difficult because of linguistic or other social and cultural barriers and impediments. 

Failure to accommodate cultural and economic diversity of potential study 

participants, failure to recognize that restrictive studies do not fully assess safety and 

efficacy of new treatments or preventive interventions for all populations, claims that 

statistical power will be reduced if racial and ethnic minority participants are included, 

inaccurate beliefs that certain populations are not at risk for specific conditions or 

illnesses, and failure to establish research clinics in institutions that have historically 

served racially and ethnically diverse populations, all limit the generalizability of results 

and perpetuate health disparities. With the encouragement of NIMH, clinical researchers 

must dramatically increase the ethnic and racial diversity of their clinical trials 

populations. At the very least, all trials must reflect the diversity of the communities in 

which clinical research is being conducted. NIMH has recently formed partnerships with 

institutions that have historically served predominantly racial and ethnic minority groups, 

such as Howard University. 

OPPORTUNITIES TO DEVELOP NEW PSYCHOSOCIAL AND BEHAVIORAL THERAPIES

Basic research in the areas of cognitive science, neuroscience, behavioral science, 

and developmental psychopathology provides an obvious source of innovation, largely by 

suggesting possible targets for intervention. This has clearly been the case, for example, 

for the existing evidence-based psychosocial interventions for depression: IPT drew 

heavily on attachment theory and CBT was strongly influenced by social-cognitive 

theories of emotion and information processing. It is striking that the two psychosocial 

interventions with the strongest empirical support so closely parallel two of the major 

animal models of depression, separation-loss and learned helplessness. 
The recent report of the National Advisory Mental Health Council’s Behavioral 

Science Workgroup Translating Behavioral Science into Action

(http://www.nimh.nih.gov/tbsia/tbsiatoc.cfm) describes ways in which basic research can 

inform clinical innovation. Better understanding how people process emotionally relevant 

information can be used to identify “what” to target and recent advances in 

developmental psychopathology that have identified periods of risk for mood disorders 

and suicide can tell us “when” to intervene. Much has been learned about the structure 

and function of the nervous system in the last several decades, and the development of 

imaging technologies allows studies of human neural function in vivo. These advances 

and others yet to come may be parlayed into new and more powerful psychosocial 

interventions by linking basic research to intervention development. 

Research on the structure of affect parallels the growing understanding of the 

structure and function of brain neural systems. For example, one new model suggests that 

anxiety and depression share a common core of negative affect, whereas depression is 

further distinguished by an absence of positive affect. Whether this distinction proves 

helpful in refining interventions remains to be seen. One line of research has extended 

CBT to include greater attention to positive affect and a sense of well-being. 

Cognitive science also suggests a number of targets for intervention development. 

For example, research has shown that people with histories of depression think 

differently under stress or in states of mild distress—they become more negative and 

rigid in their thinking and have difficulty generating solutions to the problems they face. 

These propensities are shaped in part by negative life experiences, and both predict risk 

for symptom onset and appear to mediate the preventive effects observed for CBT. Work 

is underway to better understand how these cognitive propensities relate to underlying 

neural mechanisms and how they are shaped by early interpersonal context. 

Research on the mechanisms that underlie interpersonal attachment and 

vulnerability to disruptions in those bonds may illuminate additional ways to intervene. 

Interpersonal loss and disappointment can play an important role in the onset and 

maintenance of depression, and criticism from important others has been shown to 

increase the risk for relapse. As an example, one group is using MRI techniques to 

explore the brain regions that are activated among recovered depressed persons in 

response to maternal criticism. 

Finally, understanding better the protective mechanisms that allow resilience in 

the face of life stress may facilitate the development of innovative interventions. For 

example, researchers need to study the development of emotion regulation, for new 

knowledge about the mechanisms that underlie these phenomena may allow investigators 

to develop new and more effective interventions for depression, bipolar illness, and 

suicide. 

OPPORTUNITIES FOR THE PREVENTION OF MOOD DISORDERS

Depression has come to be recognized as a chronic recurrent disorder in which the 

majority of people with the illness will experience multiple episodes across their 

lifetimes. Clinical practice is evolving toward maintaining such individuals on 

medications indefinitely to reduce the risk of relapse. Given that life-long treatment 

regimens are costly, as well as the costs in human misery and lost productivity when 
people do not obtain treatment, there is much to gain by preventing the onset of the 

disorder and providing the tools to slow its progression. Perhaps it is not surprising, then, 

that the Institute of Medicine Committee on the Prevention of Mental Disorders identified 

depression as the most preventable disorder and called for a substantial increase in 

prevention research in high-risk samples. 

Extending the duration of evidenced-based interventions appears to reduce 

subsequent risk of recurrence—IPT, CBT, and antidepressant medication all reduce risk 

for relapse or recurrence so long as they are continued. Moreover, CBT appears to have 

an enduring effect that lasts beyond the end of treatment. This enduring effect appears to 

be robust regardless of whether the intervention is provided during acute or continuation 

treatment and with or without medications. Clearly, some mechanism must be operating 

that reduces subsequent risk and research should be directed to determining the nature of 

that mechanism. 

For bipolar disorder, brief psycho-educational interventions should be developed 

for younger persons who have not yet been diagnosed but are at risk because of family 

history or dramatic mood fluctuations. Components of these preventive interventions 

might include education about the disorder and its triggers, mood charting, identification 

of early warning signs, sleep/wake cycle monitoring, cognitive restructuring, and other 

tools. Similarly, there may be a role for psychosocial interventions whose primary focus 

is on medication adherence, particularly during the maintenance phase. Components 

might include teaching people how to recognize drug side effects and how to 

communicate with their mental health providers about them. Such preventive therapies 

could address beliefs regarding the meaning of taking medications or the tendency to 

over-glamorize the “high” periods or provide useful discussions about family conflicts 

pertinent to medication taking. 

Research that leads to a detailed account of how cognitive, behavioral, and 

affective vulnerabilities influence the onset and prolongation of mood disorders can 

contribute to the development of effective preventive interventions. For example, 

adolescence is associated with a striking increase in the incidence of depression and 

associated suicide attempts, as well as the emergence of sex differences in depression 

rates, with females greatly outnumbering males. Better understanding of the mechanisms 

underlying these changes might provide clues to the nature and timing of preventive 

interventions. 

Prevention research should also test theories about normal development, the 

course of psychopathology, and change processes that alter the course of mood disorders. 

Well-designed prevention studies can test whether high- and low-risk groups actually 

differ in targeted risk factors, whether and how interventions change these factors, and 

whether these changes are related to improved mood regulation and reduction in episode 

incidence. Prevention trials provide an opportunity to test theories regarding the 

mechanisms that lead to onset and the strategies that avert it. 

Preventive interventions need not be targeted directly at depression to reduce its 

incidence. For example, exposure to job-search skills and inoculation against setbacks not 

only resulted in higher levels of reemployment and monthly income, it also reduced 

levels of depression and the onset of diagnosable depressive episodes among the recently 

unemployed. Similarly, programs designed to increase reading in grade school youngsters 

also reduced symptoms of depression. 
Many depressed and suicidal individuals do not receive efficacious treatment. The 

problem is most severe for members of racial and ethnic minority groups, individuals 

with low incomes, people with different sexual orientations, and children and the elderly. 

In fact, as mentioned above, members of racial and ethnic minority groups are so poorly 

represented in randomized controlled trials that we know very little about the 

effectiveness of “evidence-based interventions” in these groups. Efforts must be made, 

then, to sample populations in a representative fashion, determine whether heterogeneity 

influences outcomes, and identify the responsible mechanisms. Although this might be 

done through conventional means, it likely will require developing new interventions, 

adapting existing ones, and utilizing novel delivery methods, whether targeted at 

prevention or treatment. It will also require new partnerships, more grassroots 

participation, and working with the community. 

It is unclear whether interventions efficacious in controlled trials generalize to 

everyday clinical practice; sometimes they do and sometimes they do not. If an 

intervention is efficacious under controlled conditions but is less effective in applied 

settings, researchers need to ask if that resulted from the patients, therapists, 

implementation, or other aspects of the context and setting. Such variability represents an 

opportunity to explore the processes that lie behind that treatment’s effect or lack of it. 

Transporting interventions to new populations may require new modes of 

delivery. A growing body of literature suggests that interventions for racial and ethnic 

minority groups need to be culturally sensitive so that they take into consideration the 

role of culture and context, with the result that culturally enhanced or adapted treatments 

may differ significantly from the original treatments. For example, involving families in 

treatment decisions appears to be especially important when working with Latino 

populations, while adding a case management component to deal with concrete real-life 

problems may be necessary to reduce attrition in low income, medically ill populations, 

regardless of race or ethnic background. When treatments must be modified to retain their 

effects, it provides an opportunity to explore relevant processes and deepen our 

understanding of the mechanisms involved. The complexity in assessing what will work 

best for whom is both a science and an art that is going to require the development of new 

methods of assessment and the creation of new scientific disciplines. 

Using Non-Traditional Dissemination Methods to Increase Accessibility to Psychosocial 

Interventions 

Non-traditional dissemination methods hold special promise for increasing access 

to effective interventions. Various non-traditional methods have been employed in 

community settings, but they have not been studied systematically. Strategies that have 

been tested include telephone contacts, community-wide television programming, and 

use of computers and web-based questionnaires and teaching modules. 

The Internet affords the opportunity to make psychosocial interventions that can 

be implemented appropriately, reliably, and with proper security available to large 

segments of the public. Web-based educational and assessment tools can be developed 

that could be used for interventions such as acquainting people with bipolar disorder with 

the early warning signs of manic episodes, and providing access to early intervention and 

self-monitoring forms commonly used in clinical practice. Self-rated assessment scales 

can be used to screen widely for bipolar spectrum disorders, as the web site of the 
NDMDA is currently doing. A similar approach could be used to educate families and 

friends about suicide risk and suggest ways to obtain crisis intervention. 

The web and other non-traditional dissemination methods also can be used to 

reach providers. It can provide training in evidence-based methods, information about the 

latest research findings, collegial support to clinicians who are leading the way in the 

provision of evidence-based methods in their professional community, scales useful for 

monitoring patient progress, and even consultation on difficult cases. 

Researchers often think about development of new psychosocial interventions in 

terms of “market segmentation.” By developing a variety of alternative delivery 

methods, we should be able to tailor interventions for increasing segments of the 

population in need, including those in rural areas and non-English-speakers. None of 

these methods will reach everyone, and none will be universally effective, but together 

they can expand prevention and treatment of mood disorders to a larger proportion of the 

population and provide a framework for prioritizing resources.

RESEARCH PRIORITIES

1. OPPORTUNITIES TO IMPROVE AND EXPAND CLINICAL TRIALS 

Objective 1. Determine the efficacy of interventions in populations 

underrepresented in previous trials and determine the effectiveness and costeffectiveness of already proven efficacious treatments for mood disorders. 

Implementation: 

• Determine in what underrepresented populations clinical trials may be needed 

based on evidence of potential differential response by those populations 

compared to the general population. 

• Test the efficacy of psychosocial and pharmacological treatment interventions in 

underrepresented populations and clinical subgroups suspected of having a 

differential response from the general population (e.g., racial and ethnic minority 

populations, prepubertal children with unipolar depression, children and 

adolescents with bipolar disorder, women with postpartum depression, people 

with depression and medical comorbidity). 

• Determine specific approaches to enhance recruitment, participation, and 

retention of underrepresented populations to expand the generalizability of 

findings from clinical trials. 

• Initiate trials to test the effectiveness and cost-effectiveness of treatment 

interventions in mood disorders that have been little studied or are not currently 

under investigation (e.g., major depressive disorder with psychotic features, 

depression with comorbid substance abuse and/or personality disorder). 
Objective 2. Develop new methodology and statistical analytic procedures to 

enhance the ability of clinical trials to provide data relevant to community 

populations. 

Implementation: 

• Incorporate epidemiological strategies and sampling approaches to better 

characterize those who do not participate in clinical trials and dropouts from a 

trial. 

• Develop new methodologies for trial designs that improve relevance of the trial 

results to community populations. 

• Test ways of incorporating preferences and needs of community providers and 

consumers into treatment designs. 

• Evaluate the adequacy of current assessment tools for measurement of mood 

disorders as outcomes in treatment trials across the life span. 

• Increase communication and interaction between clinicians treating individuals 

with mood disorders and basic and clinical researchers to enhance two-way 

exchange of information regarding researchable problems and applicability of 

findings to settings. 

Objective 3. Assess the long-term effects of treatment interventions on physiological 

and functional status. 

Implementation: 

• Monitor long-term beneficial and adverse effects of treatment interventions in 

currently funded clinical trials (e.g., possible changes in brain structure due to 

therapies). 

• Determine the long-term effects of treatments in selected populations with 

particular vulnerabilities to disease recurrence or adverse effects (e.g., racial and 

ethnic minority groups, woman, children, and the elderly). 

2. OPPORTUNITIES TO DEVELOP NEW PSYCHOSOCIAL AND 

BEHAVIORAL THERAPIES 

Objective 1. Determine the basic mechanisms by which psychosocial interventions 

operate to produce therapeutic change to increase opportunities for innovative 

developments. 

Implementation: 

• Test proposed theories of change that have been drawn from identified common 

key dimensions and potential mechanism of action in currently used mood 

disorder intervention protocols. 
• Support translational research on emotion as a means of stimulating development 

of treatments that draw on the interplay between emotion, cognitive functioning, 

and motivational systems. 

 

• Use advances in cognitive neuroscience, imaging, emotion, memory, and learning 

to develop targeted interventions that address known deficits in cognitive 

functioning in depression and bipolar disorder. 

• Identify dimensions of the mood disorders spectrum (e.g., affect regulation, 

irritability, neuroticism, rumination) that may be features of other diseases (e.g., 

Parkinson’s) where the psychosocial treatments already developed might be 

transportable to mental disorders. 

Objective 2. Establish for whom and under what conditions therapy is likely to be 

most effective. 

Implementation: 

• Identify and develop non-traditional outcome targets that reflect the extent of 

functional impairment (e.g., work and social disability) and use these to guide 

treatment development.

 

3. OPPORTUNITIES FOR THE PREVENTION OF MOOD DISORDERS 

Objective 1. Expand studies that test interventions for the prevention of suicide. 

Implementation: 

• Establish consensus on measurement of suicidality (or proxies such as 

hopelessness) and protective factors that will increase consistent use of measures 

across trials. 

• Establish safe and ethical approaches to screening and referral for suicidality 

across settings, including schools, primary care, prisons, and internet web sites. 

• Determine service use patterns and long-term suicidality outcomes in already 

funded clinical trials. 

• Determine interventions to reduce suicidality in community settings (e.g., 

emergency departments, primary care, psychiatric day treatment programs, 

residential treatment facilities, home visiting nurse services). 

Objective 2. Increase and strengthen preventive interventions research. 

Implementation: 

• Promote prevention design methodologies that utilize defined populations to 

provide a more complete analysis of mediators and moderators of intervention 

impact. 

• Study models of emotion regulation (e.g., recovery from emotionally activating 

events) in bipolar disorder and depression as a prevention strategy for relapse. 
• Explore the potential of nontraditional psychosocial interventions delivered by 

nontraditional means (e.g., mood management campaigns or courses via 

television or the web) for both treatment and preventive interventions. 

Objective 3. Determine what interventions are needed during various phases of an 

illness to help prevent the recurrence and relapse of mood disorders. 

Implementation: 

• Expand definitions of treatment outcome (e.g., durable recovery, partial 

response). 

• Test acute interventions that produce longer recovery periods for those most at 

risk for relapse in community populations. 

• Determine optimal combinations and sequencing of interventions over time, to 

address questions such as: 

- What approaches are most effective after inadequate response to acute 

treatment for alleviating residual symptoms and dysfunctions in treated 

individuals?, and 

- What approaches are most effective for integrating multiple treatments for 

individuals with substance abuse or other comorbid disorders? 

• Identify predictors to treatment response at various points throughout illness 

course (e.g., address questions such as what are the best approaches to treat a 3rd

episode). 

• Conduct secondary analyses of funded treatment trials to explore predictors of 

treatment response by individual illness history, life events, treatment preferences, 

and prior treatment history. 

4. OPPORTUNITIES TO IMPROVE DELIVERY OF SERVICES 

Objective 1. Increase the development of practice-level interventions that are based 

on research tested theoretical models. 

Implementation: 

• Test theoretically informed practice-level interventions for mood disorders (e.g., 

interventions based on sociological theories of family-centered care, interventions 

based on economic theories that inform how incentives might reduce bipolar 

disease burden and improve care), including existing trials. 

Objective 2. Understand the processes by which theoretically based research 

information on mood disorders is effectively disseminated and implemented or 

utilized by clinicians or delivery systems. 

Implementation: 
• Assess providers’ perspectives on mood disorders, beliefs about efficacy and 

treatments, and studies of approaches that increase the use of research-based 

treatments (e.g., study of what motivates mental health care practice decisions).

• Use models from research in disciplines that are rarely used in mental health to 

develop new approaches to dissemination and implementation (e.g., engineering, 

social marketing).

• Develop and test dissemination strategies that increase the understanding of basic 

behavioral processes such as motivation, decision making, adherence, emotion, 

cognition, and social interactions between health care providers and consumers. 

Objective 3. Translate multidisciplinary decision theories into community 

interventions to reduce the burden of mood disorders. 

Implementation: 

• 

• 

Specify how mental health policy decisions are made at higher organizational and 

funding levels (e.g., insurers, employers, state mental health directors, legislators) 

to identify levers and barriers to using research evidence by decision makers. 

Objective 4. Identify the individual, social, and cultural determinants of stigma and 

develop interventions to change these determinants. 

Implementation: 

• Based on review of stigma research in other health areas, apply relevant findings 

and models to new research on people with mood disorders. 

• Enlist interdisciplinary group of researchers, health care organization decision 

makers (e.g., employers, insurers, state officials), and other Federal groups (e.g., 

Center for Mental Health Services) to develop unique strategies and 

collaborations in this area to change the individual, social, and cultural 

determinants of stigma against mood disorders. 

EXPANDING AND STRENGTHENING THE RESEARCH FOUNDATION

The utility of the scientific agenda that holds center stage throughout the pages of 

this mood disorders research strategic plan ultimately will be measured in the extent to 

which it improves the lives of individuals who themselves have a mood disorder or who 

deal with the impact of mood disorders in the context of family, work, or other social 

groupings. The centrality of the human element in planning, conduct, and application of 

research was recognized by every workgroup that contributed to the strategic plan. 

Clearly, the needs of individuals with mood disorders are a driving force behind 

development of the plan. But many other persons are equally critical: educators who play 

a vital role in training young scientists in the techniques and nuances of research relevant 

to mood disorders; researchers and communicators whose primary responsibility is to 

disseminate the knowledge generated through research; and clinicians and other health 

and social service professionals who apply the products of research in diverse settings. 
Challenges in two particular arenas—training tomorrow’s researchers and putting 

the fruits of research in the hands of public health practitioners, clinicians, and members 

of the general public—cross-cut the entire strategic planning process. Absent a solid 

foundation in these areas, even the most innovative scientific agenda becomes a sterile 

exercise. In compiling this final document, NIMH staff culled from the workgroup 

reports an array of implicit and explicit recommendations for research training that 

encompass disciplinary as well as demographic gaps in the contemporary research 

community and, importantly, that anticipate the impact of future scientific advances and 

shifts in the Nation’s age and racial/cultural composition in the years ahead. A second 

category of needs and opportunities involves educating front-line clinicians and the 

public-at-large about mood disorders, using a mix of media and language and formats 

that will be broadly accessible. An example of a more specific educational challenge is 

that of informing interested individuals—clinicians as well as patients—how to learn 

about and participate in clinical services and prevention trials. 

Research Training 

At these promising times for research on the brain and its disorders, we are faced 

with unparalleled scientific opportunities and the consequent need to attract and retain the 

best and the brightest individuals to research careers aimed at understanding mood 

disorders and developing efficacious treatments and prevention strategies. NIMH is 

committed to creating viable career paths for junior investigators whose research training 

and career goals are in areas of program relevance. To accomplish its goal of training 

future generations of mental health researchers, NIMH has long been among the leading 

NIH institutes in supporting National Research Service Award (NRSA) training and 

Research Career Development programs (K-awards). 

As a proportion of its budget, the NIMH investment in NRSA institutional 

training grants, individual fellowships, and career development awards is the highest 

among NIH institutes that support research on the brain and its disorders. This fact 

requires us to look at training and career development issues from a broader NIH and 

national needs perspective. NIMH is committed to training that prepares junior, early-tomid-career, and to a certain extent more established scientists, in multidisciplinary and 

interdisciplinary research on mental health and mental illness. 

To train future generations of mental health researchers, several issues need 

particular attention: focusing on research areas most likely to hold promise in the future; 

ensuring that training and career development support meet future needs in terms of the 

research work force; encouraging and helping women scientists in their chosen research 

career track; and attracting and retaining underrepresented racial and ethnic minority 

groups in research fields relevant to mental health and mental illness. 

Disseminating Research Results 

The goal of dissemination and implementation research is to bridge the gap 

between clinical research and everyday practice by building a knowledge base about how 

mental health care information and new practices are transmitted and translated for health 

care service use in specific settings. One of the major issues about the applicability of 

basic and clinical research to mental health practice settings surrounds how research 

findings spread throughout the field. Research is needed to understand how and why 
information on mental health treatments reaches stakeholders within the field, as a 

necessary prerequisite to determining how the information leads to practice change. 

Dissemination research relates specifically to research topics underlying the creation, 

transmission, and reception of “messages” providing information on 

psychopharmacological and psychosocial treatments. 

 Research is needed, too, on factors that influence the adoption of new 

psychopharmacological and psychosocial interventions within real world mental health 

care systems. Previous efforts to understand implementation have often assumed that 

interventions can be successfully implemented into specific contexts, and have relied on 

an assessment of patient outcomes instead of examining whether implementation was 

faithful to the originally conceived treatment. In addition, previous research has often 

quite effectively demonstrated the ability of a specific treatment to fit into a specific 

setting, but has not explored more fundamental issues that can be generalized beyond a 

specific treatment paradigm. 

Dissemination and implementation research can utilize theories and empirical 

findings from a variety of fields, many not often traditionally associated with mental 

health research. Relevant fields include: information science, clinical decision-making, 

organizational theory, finance, strategic and behavioral change, anthropology, learning 

theory, and marketing. In addition, meaningful research will likely include collaboration 

with stakeholders from multiple mental health settings. 

RESEARCH PRIORITIES 

1. OPPORTUNITIES TO EXPAND AND STRENGTHEN THE RESEARCH 

FOUNDATION 

IN TRAINING: 

Objective 1. Address the shortage of new and established investigators in various 

disciplines to conduct mood disorders research, particularly racial and ethnic 

minority investigators, and those focusing on child and elderly populations. 

Implementation: 

• Develop a trans-institute plan to support the multidisciplinary training of clinical 

and preclinical investigators interested in pursuing research careers in the fields of 

childhood-onset mood disorders and late-life mood disorders. 

• Develop a mood disorders mentorship program devoted to training racial and 

ethnic minority investigators. 

Objective 2. Create training programs and interdisciplinary opportunities to foster 

precision and validity in investigations that extend beyond the boundaries of 

individual disciplines. 

Implementation: 
• Encourage individual career enhancement and training in molecular genetics, 

genetic epidemiology, statistical genetics, and population genetics for researchers 

with basic and clinical research expertise in mood disorders. 

• Increase efforts to recruit basic scientists representing a range of disciplines (from 

molecular genetics to behavioral and systems neuroscience) to mood disorders 

research. Emphasis should be placed on training individuals in an 

interdisciplinary manner and on integrating disease-oriented research with basic 

neuroscience. 

• Further endorse translational research centers through development of specialized 

initiatives to attract new scholars to rapidly test new targets implicated by basic 

research. 

- Sponsor conferences in which junior investigators generate proposals for 

translational research that are reviewed by senior researchers in the field. 

- Provide administrative supplements modeled on minority supplements to 

place junior investigators (postdoctoral) with a basic research background 

in clinical research settings and vice versa. 

• Establish interdisciplinary training programs to develop clinical and social science 

investigators skilled in conducting applied research for populations with mood 

disorders in communities and community-based delivery settings. Such programs 

would include training in interdisciplinary methods; qualitative and quantitative 

methodologies; and application of diverse theoretical approaches to changing 

behavior of individuals, institutions, and communities.

IN PUBLIC EDUCATION: 

Objective l. Expand the dissemination and translation of mood disorders risk 

factors, diagnosis, and treatment knowledge to the community. 

Implementation: 

• Develop evidence-based web sites that focus on information on mood disorders in 

specific populations (e.g., late life, childhood, women) to serve as resource 

clearinghouses for researchers, clinicians, and other individuals. 

• Coordinate with NIMH’s Office of Communications and Public Liaison and 

relevant providers to develop materials that can be used to improve recognition of 

depression and bipolar disorder in community settings. 

• Support efforts by investigators to increase dissemination efforts. 

• Coordinate with the Substance Abuse and Mental Health Services Administration 

and the services community to instantiate new practice models in both primary 

care and institutional settings. 
Objective 2. Enhance public awareness, understanding, and participation in genetic 

risk factor research on mood disorders. 

Implementation: 

• Develop an initiative with the Ethical, Legal, and Social Implications Program of 

the National Human Genome Research Institute to produce guidelines for the 

inclusion of children in genetic studies of mood disorders. 

Objective 3. Provide information about clinical trials to evaluate prevention and 

treatment regimens that will enable individuals and their health care providers 

to make informed choices.

Objective 4. Develop culturally sensitive public awareness information on mood 

disorders for consumers, families, and health care providers of diverse races and 

ethnicities. 
Appendix A 

NATIONAL ADVISORY MENTAL HEALTH COUNCIL (NAMHC) 

Chairperson Executive Secretary

Richard Nakamura, Ph.D. Jane Steinberg, Ph.D.

Acting Director Director, Division of Extramural Activities 

National Institute of Mental Health National Institute of Mental Health 

Bethesda, Maryland Bethesda, Maryland 

Members 

Robert Boorstin Norwood W. Knight-Richardson, M.D. 

Vice President Medical Director 

Greenberg Quinlan Research, Inc. CareMark Behavioral Health Services 

Washington, DC Portland, Oregon 

Mary L. Durham, Ph.D. Henry A. Lester, Ph.D. 

Vice President/Research Professor 

Kaiser Foundation Hospitals Department of Biology

Director, Center for Health Research California Institute of Technology

Northwest and Hawaii Pasadena, California 

Portland, Oregon 

Jeffrey A. Lieberman, M.D. 

Javier I. Escobar, M.D. Professor and Vice Chairman 

Professor and Chairman Department of Psychiatry

Department of Psychiatry School of Medicine 

University of Medicine and Dentistry of University of North Carolina, Chapel Hill 

 New Jersey Chapel Hill, North Carolina 

Robert Wood Johnson Medical School 

Piscataway, New Jersey James L. McClelland, Ph.D. 

Co-Director 

Susan Folkman, Ph.D. Center for the Neural Basis of Cognition 

Professor of Medicine Pittsburgh, Pennsylvania 

Osher Foundation Distinguished Professor 

 in Integrative Medicine James McNulty

Director, Osher Center for Integrative President 

Medicine Manic Depressive and Depressive Association of 

University of California San Francisco Rhode Island 

San Francisco, California Providence, Rhode Island 

Megan R. Gunnar, Ph.D. Charles B. Nemeroff, M.D., Ph.D. 

Distinguished McKnight University Professor Reunette W. Harris Professor and Chair 

 of Child Development and Adjunct Professor Department of Psychiatry and Behavioral Sciences 

 of Adolescent Psychiatry Emory University School of Medicine 

Institute of Child Development Atlanta, Georgia 

University of Minnesota 

Minneapolis, Minnesota 

101
Eric J. Nestler, M.D., Ph.D. 

Lou and Ellen McGinley Distinguished Professor 

& Chairman 

Department of Psychiatry

The University of Texas Southwestern Medical 

Center at Dallas 

Dallas, Texas 

Elaine Sanders-Bush, Ph.D. 

Professor 

Vanderbilt University School of Medicine 

Nashville, Tennessee 

Edward Scolnick, M.D. 

President 

Merck Research Laboratories 

West Point, Pennsylvania 

Larry R. Squire, Ph.D. 

Professor and Research Career Scientist 

Department of Psychiatry

University of California School of Medicine 

Veterans Affairs Medical Center 

San Diego, California 

Ming T. Tsuang, M.D., Ph.D. 

Professor and Director 

Department of Psychiatry

Harvard Medical School 

Massachusetts Mental Health Center 

Boston, Massachusetts 

Roy C. Wilson, M.D. 

Associate Vice Chancellor of Behavioral Health 

 for Policy, Planning and Development 

University of Missouri Health Care 

St. Louis, Missouri 

Special Consultant 

Mitchell S. Rosenthal, M.D. 

President 

Phoenix House Foundation 

New York, New York 

Ex Officio Members

Office of the Secretary, DHHS Department of Defense

Tommy G. Thompson, J.D. Elspeth Cameron Ritchie, M.D. 

Secretary LTC, MC, USA 

Department of Health and Human Services Program Director, Mental Health Policy and 

Washington, DC Women’s Issues 

 OSD/HA 

Falls Church, Virginia 

National Institutes of Health Department of Veterans Affairs 

Elias A. Zerhouni, M.D. Robert Freedman, M.D. 

Director Medical Director 

National Institutes of Health Center for Basic and Clinical Studies in 

Bethesda, Maryland Schizophrenia 

Colorado Veterans Administration Hospital 

Professor of Psychiatry/Pharmacology

University of California Health Sciences Center 

Denver, Colorado 

102
Liaison Representative 

Center for Mental Health Services

Michael J. English, J.D. 

Director 

Division of Knowledge Development and Systems Change 

Center for Mental Health Services 

Substance Abuse and Mental Health Services Administration 

Rockville, Maryland 

 

103
Appendix B 

MOOD DISORDERS WORKGROUPS 

Genetics: Epidemiology and Genetics of Mood 

Disorders

Doreen Koretz, Ph.D.

National Institute of Mental Health 

Bethesda, Maryland 

Co-Chair: Kathleen R. Merikangas, Ph.D. 

National Institute of Mental Health/Intramural 

Research Program (IRP) 

William Lichtenstein 

Lichtenstein Creative Media 

Bethesda, Maryland New York, New York 

Co-Chair: Aravinda Chakravarti, Ph.D. Emmanuel Mignot, M.D., Ph.D. 

Johns Hopkins University School of Medicine Stanford University

Baltimore, Maryland Stanford, California 

 

Members: Steven Moldin, Ph.D. 

Houmam Araj, Ph.D. National Institute of Mental Health 

National Institute of Mental Health Bethesda, Maryland 

Bethesda, Maryland 

Allan Reiss, M.D. 

John Blangero, Ph.D. Stanford University

Southwest Foundation for Biomedical Stanford, California 

 Research 

San Antonio, Texas Neil Risch, Ph.D. 

Stanford University School of Medicine 

Margit Burmeister, Ph.D. Stanford, California 

Mental Health Research Institute 

University of Michigan Peter Sheridan, Ph.D. 

Ann Arbor, Michigan National Institute of Mental Health 

Bethesda, Maryland 

John C. Crabbe, Ph.D. 

Oregon Health Sciences University and Joseph S. Takahashi, Ph.D.* 

Veterans Affairs Medical Center Howard Hughes Medical Institute and 

Portland, Oregon Northwestern University

Evanston, Illinois 

J. Raymond DePaulo, Jr., M.D. 

Neural and Behavioral Substrates of Mood 

Regulation

Johns Hopkins Hospital 

Baltimore, Maryland 

Edward Foulks, M.D., Ph.D. Chair: Richard Davidson, Ph.D. 

Tulane University University of Wisconsin, Madison School of Medicine 

New Orleans, Louisiana Madison, Wisconsin 

Nelson Freim Co-Chair: David Lewis, M.D. er, M.D., Ph.D. 

University Western Psychiatric Institute and Clinic of California, Los Angeles 

Los Angeles, California Pittsburgh, Pennsylvania 

Kathy Kopnisky, Ph.D. 

National Institute of Mental Health 

Bethesda, Maryland 

104 
Members: Molly Oliveri, Ph.D. 

Lauren Alloy, Ph.D. National Institute of Mental Health 

Temple University Bethesda, Maryland 

Philadelphia, Pennsylvania 

Bradley Peterson, M.D. 

David Amaral, Ph.D. Yale University

University of California, Davis New Haven, Connecticut 

Davis, California 

Suzanne Vogel-Scibilia, M.D.

Allan George Bush, M.D. Beaver, Pennsylvania 

Massachusetts General Hospital 

Charleston, Massachusetts Preclinical Models

Jonathan Cohen, M.D., Ph.D. Chair: Eric J. Nestler, M.D., Ph.D.** 

Princeton University University of Texas Southwestern 

Princeton, New Jersey Medical Center at Dallas 

Dallas, Texas 

Bruce Cuthbert, Ph.D. 

National Institute of Mental Health Co-Chair: Elizabeth Gould, Ph.D. 

Bethesda, Maryland Princeton University 

Princeton, New Jersey

Antonio Damasio, M.D., Ph.D. 

University of Iowa College of Medicine Co-Chair : Husseini Manji, M.D. 

Iowa City, Iowa National Institute of Mental Health/IRP 

Bethesda, Maryland 

Wayne Drevets, M.D. 

National Institute of Mental Health/IRP Members:

Bethesda, Maryland Maja Bucan, Ph.D. 

University of Pennsylvania 

Martha Farah, Ph.D. Philadelphia, Pennsylvania 

University of Pennsylvania 

Philadelphia, Pennsylvania Ronald Duman, Ph.D. 

Yale University

Timothy Hays, Ph.D. New Haven, Connecticut 

National Institute of Mental Health 

Bethesda, Maryland Howard Gershenfeld, M.D., Ph.D. 

University of Texas Southwestern 

Jerome Kagan, Ph.D. Medical Center at Dallas 

Harvard University Dallas, Texas 

Cambridge, Massachusetts 

Rene Hen, Ph.D.

James L. McClelland, Ph.D.** Columbia University

Center for Neural Basis of Cognition New York, New York 

Mellon Institute 

Pittsburgh, Pennsylvania Susan Koester, Ph.D. 

National Institute of Mental Health/IRP 

Susan Nolen-Hoeksema, Ph.D. Bethesda, Maryland 

University of Michigan 

Ann Arbor, Michigan Irwin Lucki, Ph.D. 

University of Pennsylvania 

Philadelphia, Pennsylvania 

105 
Michael Meaney, Ph.D. Ronald Dahl, M.D. 

Douglas Hospital Research Centre University of Pittsburgh Medical Center 

Quebec, Canada Pittsburgh, Pennsylvania 

Trevor W. Robbins, Ph.D. Felton Earls, M.D. 

University of Cambridge Harvard University

Cambridge, United Kingdom Cambridge, Massachusetts 

Robert Sapolsky, Ph.D. Hill Goldsmith, Ph.D. 

Stanford University University of Wisconsin, Madison 

Stanford, California Madison, Wisconsin 

Beth Anne Sieber, Ph.D. Connie Hammen, Ph.D. 

National Institute of Mental Health University of California, Los Angeles 

Bethesda, Maryland Los Angeles, California 

Susan Weiss, Ph.D. Martha Hellander, J.D.

National Mental Health Association Child and Adolescent Bipolar Foundation 

Alexandria, Virginia Wilmette, Illinois 

Lois Winsky, Ph.D. Kimberly Hoagwood, Ph.D. 

National Institute of Mental Health National Institute of Mental Health 

Bethesda, Maryland Bethesda, Maryland 

Steve Zalcman, M.D. Joan Kaufman, Ph.D. 

National Institute of Mental Health Yale University

Bethesda, Maryland New Haven, Connecticut 

Development and Natural History Doreen Koretz, Ph.D. 

National Institute of Mental Health 

Chair: James Leckman, M.D. Bethesda, Maryland 

Yale University

New Haven, Connecticut Peter Lewinsohn, Ph.D. 

Oregon Research Institute 

Co-Chair: Charles A. Nelson, Ph.D. Eugene, Oregon 

University of Minnesota 

Minneapolis, Minnesota John S. March, M.D., M.P.H. 

Duke Child and Family Study Center 

Members: Durham, North Carolina 

Joseph Biederman, M.D. 

Massachusetts General Hospital Editha Nottelmann, Ph.D. 

Boston, Massachusetts National Institute of Mental Health 

Bethesda, Maryland 

Mary Blehar, Ph.D. 

National Institute of Mental Health Daniel Pine, M.D.

Bethesda, Maryland National Institute of Mental Health/IRP 

Bethesda, Maryland 

E. Jane Costello, Ph.D. 

Duke University Medical Center 

Durham, North Carolina 

106 
Paul Plotsky, Ph.D. Peter Kaufmann, Ph.D. 

Emory University School of Medicine National Heart, Lung, and 

Atlanta, Georgia Blood Institute, NIH 

Bethesda, Maryland 

Benedetto Vitiello, M.D. 

National Institute of Mental Health Helena Kraemer, Ph.D.

Bethesda, Maryland Stanford University

Stanford, California 

Myrna Weissman, Ph.D.* 

New York State Psychiatric Institute Rick Martinez, M.D.

 New York, New York Janssen Pharmaceuticals 

Titusville, New Jersey 

Aging and Medical Comorbidity

William McDonald, M.D. 

Chair: K. Ranga Krishnan, M.B., Ch.B. Emory University

Duke University Medical Center Atlanta, Georgia 

Durham, North Carolina 

Guy McKhann, M.D. 

Co-Chair: Mahlon DeLong, M.D. National Institute of Neurological 

Emory University School of Medicine Disorders and Stroke, NIH 

Atlanta, Georgia Bethesda, Maryland 

Members: Peter Muehrer, Ph.D. 

George Alexopoulos, M.D. National Institute of Mental Health 

Weill Medical College of Bethesda, Maryland 

 Cornell University

White Plains, New York Jason Olin, Ph.D. 

National Institute of Mental Health 

Kathleen Buckwalter, Ph.D. Bethesda, Maryland 

University of Iowa 

Iowa City, Iowa Emeline Otey, Ph.D. 

National Institute of Mental Health 

Robert Carney, Ph.D. Bethesda, Maryland 

Washington University

St. Louis, Missouri Charles Reynolds, III, M.D. 

Western Psychiatric Institute and Clinic 

Perry D. Cohen, Ph.D. Pittsburgh, Pennsylvania 

Parkinson’s Disease Foundation 

Washington, DC David Spiegel, M.D. 

Stanford University School of Medicine 

Mary Amanda Dew, Ph.D. Stanford, California 

Western Psychiatric Institute and Clinic 

Pittsburgh, Pennsylvania Cynthia Wainscott 

National Mental Health Association of 

Dwight Evans, M.D. Georgia 

University of Pennsylvania Atlanta, Georgia 

Philadelphia, Pennsylvania 

Christopher Gordon, Ph.D.

National Institute of Mental Health 

Bethesda, Maryland 

107 
Pharmacologic and Somatic Treatment Robert Innis, M.D.

Development National Institute of Mental Health/IRP 

Bethesda, Maryland 

Co-Chair: Carol A. Tamminga, M.D. 

Maryland Psychiatric Research Center John Killen, M.D. 

Baltimore, Maryland National Institute of Allergy and 

 Infectious Diseases, NIH 

Co-Chair: Charles B. Nemeroff, M.D., Ph.D.** Bethesda, Maryland 

Emory University School of Medicine 

Atlanta, Georgia Thomas P. Laughren, M.D. 

Food and Drug Administration 

Members: Rockville, Maryland 

Randy Blakely, Ph.D. 

Vanderbilt University Husseini Manji, M.D. 

Nashville, Tennessee National Institute of Mental Health/IRP 

Bethesda, Maryland 

Linda Brady, Ph.D. 

National Institute of Mental Health Steven M. Paul, M.D.

Bethesda, Maryland Eli Lilly and Company

Indianapolis, Indiana 

Cameron S. Carter, M.D. 

Western Psychiatric Institute and Clinic Matthew Rudorfer, M.D. 

Pittsburgh, Pennsylvania National Institute of Mental Health 

Bethesda, Maryland 

Kenneth L. Davis, M.D. 

Mount Sinai School of Medicine Edward Sausville, M.D., Ph.D., F.A.C.P. 

New York, New York National Cancer Institute, NIH 

Rockville, Maryland 

Raymond Dingledine, Ph.D.

Emory University School of Medicine Alan Schatzberg, M.D. 

Atlanta, Georgia Stanford University School of Medicine 

Stanford, California 

Wayne Fenton, M.D. 

National Institute of Mental Health Edward Scolnick, M.D.** 

Bethesda, Maryland Merck Research Laboratories 

West Point, Pennsylvania 

Jack M. Gorman, M.D. 

Columbia University Patricia Suppes, M.D., Ph.D. 

New York, New York University of Texas Southwestern 

 Medical Center at Dallas 

Dimitri Grigoriadis, Ph.D. Dallas, Texas 

Neurocrine Biosciences, Inc. 

San Diego, California Psychosocial Intervention Development

David Henderson, M.D. Chair: Steven D. Hollon, Ph.D. 

Harvard University and Vanderbilt University

Massachusetts General Hospital Nashville, Tennessee 

Boston, Massachusetts

Co-Chair: Ricardo Muñoz, Ph.D. 

Ira Herskowitz, Ph.D. University of California, San Francisco 

University of California, San Francisco San Francisco, California 

San Francisco, California 

108 
Members: David Miklowitz, Ph.D. 

David Barlow, Ph.D. University of Colorado 

Boston University Boulder, Colorado 

Boston, Massachusetts 

Jacqueline Persons, Ph.D. 

William Beardslee, M.D. San Francisco Bay Area Center for 

Children’s Hospital/Department of Cognitive Therapy

 Psychiatry Oakland, California 

Boston, Massachusetts 

Paul Sirovatka, M.S. 

Carl C. Bell, M.D. National Institute of Mental Health 

Community Mental Health Council Bethesda, Maryland 

Chicago, Illinois 

David Sommers, Ph.D. 

Guillermo Bernal, Ph.D. National Institute of Mental Health 

University of Puerto Rico Bethesda, Maryland 

San Juan, Puerto Rico 

Clinical Trials and Translation

Gregory Clarke, Ph.D. 

Kaiser Permanente Center for Chair: Ellen Frank, Ph.D.* 

 Health Research Western Psychiatric Institute and Clinic 

Portland, Oregon Pittsburgh, Pennsylvania 

Robert Desimone, Ph.D. Co-Chair: A. John Rush, M.D.* 

National Institute of Mental Health/IRP University of Texas Southwestern 

Bethesda, Maryland Medical Center at Dallas 

Dallas, Texas 

Regina Dolan-Sewell, Ph.D. 

National Institute of Mental Health Members:

Bethesda, Maryland Mary Blehar, Ph.D. 

National Institute of Mental Health 

L. Patt Franciosi, Ph.D. Bethesda, Maryland 

World Federation for Mental Health 

Milwaukee, Wisconsin Susan Essock, Ph.D. 

Mount Sinai School of Medicine 

Alan Kazdin, Ph.D. New York, New York 

Yale University

New Haven, Connecticut Holly Giesen 

National Institute of Mental Health/IRP 

Laura Kohn, Ph.D. Bethesda, Maryland 

University of Michigan 

Ann Arbor, Michigan William Hargreaves, Ph.D.

University of California, San Francisco 

Marsha Linehan, Ph.D., ABPP Mill Valley, California 

University of Washington 

Seattle, Washington Michael Hogan, Ph.D.* 

Ohio Department of Mental Health 

John Markowitz, M.D. Columbus, Ohio 

Weill Medical College of 

 Cornell University

New York, New York 

109 
Robin Jarrett, Ph.D. Overcoming Barriers to Care and Reducing 

University of Texas Southwestern Public Burden 

 Medical Center at Dallas 

Dallas, Texas Chair: Kenneth B. Wells, M.D., M.P.H. 

University of California Neuropsychiatric 

Robert L. Johnson, M.D.* Research Institute 

New Jersey Medical - UMDNJ Los Angeles, California 

Newark, New Jersey

Co-Chair: Jeanne Miranda, Ph.D. 

Wayne J. Katon, M.D. Georgetown University Medical Center 

University of Washington Washington, DC 

Seattle, Washington 

Members:

Philip Lavori, Ph.D. Mark Bauer, M.D. 

Stanford University School of Medicine Brown University School of Medicine 

Stanford, California Providence, Rhode Island 

James P. McNulty** Martha Bruce, Ph.D., M.P.H.

National Manic-Depressive and Depressive Weill Medical College of 

Association of Rhode Island Cornell University

Bristol, Rhode Island White Plans, New York 

George Niederehe, Ph.D. Mary Durham, Ph.D.** 

National Institute of Mental Health Kaiser Foundation Hospitals 

Bethesda, Maryland Portland, Oregon 

Neal Ryan, M.D. Javier Escobar, M.D.**

Western Psychiatric Institute and Clinic University of Medicine and Dentistry of 

Pittsburgh, Pennsylvania New Jersey

Robert Wood Johnson Medical School 

Gail Stuart, Ph.D., R.N., C.S., F.A.A.N. Piscataway, New Jersey

Medical University of South Carolina 

Charleston, South Carolina Wayne Fenton, M.D. 

National Institute of Mental Health 

Stephen B. Thomas, Ph.D. Bethesda, Maryland 

Center for Minority Health 

University of Pittsburgh Daniel Ford, M.D., M.P.H.

Pittsburgh, Pennsylvania Johns Hopkins Hospital 

Baltimore, Maryland 

Gary D. Tollefson, M.D., Ph.D. 

Eli Lilly and Company Junius Gonzales, M.D. 

Indianapolis, Indiana National Institute of Mental Health 

Bethesda, Maryland 

Benedetto Vitiello, M.D. 

National Institute of Mental Health Kimberly Hoagwood, Ph.D. 

Bethesda, Maryland National Institute of Mental Health 

 Bethesda, Maryland 

Clarissa Wittenberg 

National Institute of Mental Health Sarah M. Horwitz, Ph.D. 

Bethesda, Maryland Yale School of Public Health 

New Haven, Connecticut 

110 
111 

William Lawson, M.D., Ph.D.

Howard University Hospital 

Washington, DC 

Lydia Lewis 

National Depressive and Manic-Depressive 

Association 

Chicago, Illinois 

Thomas McGuire, Ph.D. 

Boston University 

Boston, Massachusetts 

Serene Olin, Ph.D. 

National Institute of Mental Health 

Bethesda, Maryland 

Karen Anderson Oliver, Ph.D. 

National Institute of Mental Health 

Bethesda, Maryland 

Harold Pincus, M.D.

Western Psychiatric Institute and Clinic and 

RAND-University of Pittsburgh Health Institute 

Pittsburgh, Pennsylvania 

Richard Scheffler, Ph.D.

University of California, Berkeley 

Berkeley, California 

William A. Smith, Ed.D. 

Academy for Educational Development 

Washington, DC 

Jurgen Unutzer, M.D., M.P.H.

University of California, Los Angeles 

Los Angeles, CA 

_____________________________ 

* Former member of the NAMHC 

** Current member of the NAMHC 
 112

Appendix C 

NIMH STAFF PARTICIPANTS 

Mood Disorders Executive Committee 

Steven E. Hyman, M.D. 

Former Director, NIMH 

Richard Nakamura, Ph.D. 

Acting Director, NIMH 

Dennis Charney, M.D. 

Chief, Mood and Anxiety Disorders Research 

Program, NIMH/IRP and 

Scientific Director, Mood Disorders Strategic 

Research Plan 

Karen Babich, Ph.D., R.N. 

Health Scientist Administrator, Office of Science 

Policy and Program Planning, NIMH and 

Project Director, Mood Disorders Strategic 

Research Plan 

Robert Desimone, Ph.D. 

Scientific Director, Division of Intramural 

Research Programs, NIMH 

Wayne Fenton, M.D. 

Acting Deputy Director, NIMH and 

Acting Director, Office of Science Policy and 

Program Planning, NIMH 

Stephen Foote, Ph.D. 

Director, Division of Neuroscience and 

Basic Behavioral Science, NIMH 

Grayson Norquist, M.D., M.S.P.H. 

Director, Division of Services and Intervention 

Research, NIMH 

Jane Steinberg, Ph.D. 

Director, Division of Extramural Activities, 

NIMH 

Ellen Stover, Ph.D. 

Director, Division of Mental Disorders, 

Behavioral Research and AIDS, NIMH 

Division of Neuroscience and Basic Behavioral 

Science 

Debra Babcock, Ph.D. 

Linda Brady, Ph.D. 

Hemin Chin, Ph.D. 

Walter Goldschmidts, Ph.D. 

Michael Huerta, Ph.D. 

Israel Lederhendler, Ph.D. 

Douglas Meinecke, Ph.D. 

Steven Moldin, Ph.D. 

Molly Oliveri, Ph.D. 

Kevin Quinn, Ph.D. 

Judith Rumsey, Ph.D. 

Beth Anne Sieber, Ph.D. 

Lois Winsky, Ph.D. 

Steven Zalcman, M.D. 

Division of Mental Disorders, Behavioral 

Research and AIDS

Karen Bourdon, M.S. 

Cheryl Boyce, Ph.D. 

Lisa Colpe, Ph.D. 

Bruce Cuthbert, Ph.D. 

Regina Dolan-Sewell, Ph.D. 

Christopher Gordon, Ph.D. 

Robert Heinssen, Ph.D. 

Kathy Kopnisky, Ph.D. 

Doreen Koretz, Ph.D. 

Peter Muehrer, Ph.D. 

Editha Nottelmann, Ph.D. 

Emeline Otey, Ph.D. 

Farris Tuma, Sc.D. 

Division of Services and Intervention 

Research

Jean Baum 

Elizabeth Bowers 

Junius Gonzales, M.D. 

Ann Hohmann, Ph.D. 

John Hsiao, M.D. 

Barry Lebowitz, Ph.D. 
 113

Jason Olin, Ph.D. 

Karen Anderson Oliver, Ph.D. 

Jane Pearson, Ph.D. 

Matthew Rudorfer, M.D. 

Benedetto Vitiello, M.D. 

Division of Extramural Activities

Houmam Araj, Ph.D. 

Henry Haigler, Ph.D. 

Michael Kozak, Ph.D. 

Peter Sheridan, Ph.D. 

Joel Sherrill, Ph.D. 

David Sommers, Ph.D. 

Division of Intramural Research Programs

Jacqueline Crawley, Ph.D. 

Wayne Drevets, M.D. 

Holly Giesen 

Robert Innis, M.D. 

Susan Koester, Ph.D. 

Husseini Manji, M.D. 

Kathleen Merikangas, Ph.D. 

Daniel Pine, M.D. 

Judith Rapoport, M.D. 

David Rubinow, M.D. 

Trey Sunderland, M.D. 

Office for Special Populations

Mary Blehar, Ph.D. 

Ernest Marquez, Ph.D. 

Robert A. Mays, Jr., Ph.D.* 

Office of Communications and Public Liaison

Clarissa Wittenberg 

Office of the Director

Timothy Hays, Ph.D. 

Kimberly Hoagwood, Ph.D. 

Serene Olin, Ph.D. 

Office of Science Policy and Program 

Planning

Joan Cole 

Logistics Coordinator, Mood Disorders 

 Strategic Research Plan 

Science Writers

Joseph Alper, M.S. 

Louisville, Colorado 

Paul Sirovatka, M.S. 

Office of Science Policy and Program Planning 

Graphic Design

Catherine West 

Office of Communications and Public Liaison 

Penny Kisner 

Office of Communications and Public Liaison 

___________________________________ 

*Special expert and former ex officio member of 

the NAMHC