Depression Research at the National Institute of Mental Health

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Depressive disorders affect approximately 19 million American adults. The suffering endured by people with depression and the lives lost to suicide attest to the great burden of this disorder on individuals, families, and society.

Improved recognition, treatment, and prevention of depression are critical public health priorities. The National Institute of Mental Health (NIMH), the world’s leading mental health biomedical organization, conducts and supports research on the causes, diagnosis, prevention, and treatment of depression.

Evidence from neuroscience, genetics, and clinical investigation demonstrate that depression is a disorder of the brain. Modern brain imaging technologies are revealing that in depression, 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 results from the influence of multiple genes acting together with environmental factors. Studies of brain chemistry and of mechanisms of action of antidepressant medications continue to inform the development of new and better treatments.

In the past decade, there have been significant advances in our ability to investigate brain function at multiple levels. NIMH is collaborating with various scientific disciplines to effectively 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, including mental illness. This collaboration reflects the Institute’s increasing focus on "translational research," whereby basic and clinical scientists are involved in joint efforts to translate discoveries and knowledge into clinically relevant questions and targets of research opportunity. Translational research holds great promise for disentangling the complex causes of depression and other mental disorders and for advancing the development of more effective treatments.

Symptoms and Types of Depression

Symptoms of depression 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 major depressive disorder (or unipolar major depression) is made if an individual has five or more of these symptoms during the same two-week period. Unipolar major depression typically presents in discrete episodes that recur during a person’s lifetime.

Bipolar disorder (or manic-depressive illness) is characterized by episodes of major depression as well as episodes of mania – 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 in pleasurable activities that have a high potential for painful consequences. While sharing some of the features of major depression, bipolar disorder is a different illness that is discussed in detail in a separate NIMH publication.

Dysthymic disorder (or dysthymia), a less severe yet typically more chronic form of depression, is diagnosed when depressed mood persists for at least two years in adults (one year in children or adolescents) and is accompanied by at least two other depressive symptoms. Many people with dysthymic disorder also experience major depressive episodes. While unipolar major depression and dysthymia are the primary forms of depression, a variety of other subtypes exist.

In contrast to the normal emotional experiences of sadness, loss, or passing mood states, depression is extreme and persistent and can interfere significantly with an individual’s ability to function. In fact, a recent study sponsored by the World Health Organization and the World Bank found unipolar major depression to be the leading cause of disability in the United States and worldwide.

There is a high degree of variation among people with depression in terms of symptoms, course of illness, and response to treatment, indicating that depression may have a number of complex and interacting causes. This variability poses a major challenge to researchers attempting to understand and treat the disorder. However, recent advances in research technology are bringing NIMH scientists closer than ever before to characterizing the biology and physiology of depression in its different forms and to the possibility of identifying effective treatments for individuals based on symptom presentation.

An NIMH Snapshot

The National Institute of Mental Health (NIMH) is one of 25 components of the National Institutes of Health (NIH), the Government's principal biomedical and behavioral research agency. NIH is part of the U.S. Department of Health and Human Services. The actual total fiscal year 1999 NIMH budget was $859 million.

NIMH Mission

To reduce the burden of mental illness through research on mind, brain, and behavior.

How Does the Institute Carry Out Its Mission?

NIMH conducts research on mental disorders and the underlying basic science of brain and behavior.
NIMH supports research on these topics at universities and hospitals around the United States.
NIMH collects, analyzes, and disseminates information on the causes, occurrence, and treatment of mental illnesses.
NIMH supports the training of more than 1,000 scientists to carry out basic and clinical research.
NIMH communicates information to scientists, the public, the news media, and primary care and mental health professionals about mental illnesses, the brain, mental health, and research in these areas.

One of the most challenging problems in depression research and clinical practice is refractory – hard to treat – depression. While approximately 80 percent of people with depression respond very positively to treatment, a significant number of individuals remain treatment refractory. Even among treatment responders, many do not have complete or lasting improvement, and adverse side effects are common. Thus, an important goal of NIMH research is to advance the development of more effective treatments for depression – especially treatment-refractory depression – that also have fewer side effects than currently available treatments.

Research on Treatments for Depression

Medication

Studies on the mechanisms of action of antidepressant medication comprise an important area of NIMH depression research. Existing antidepressant drugs are known to influence the functioning of certain neurotransmitters in the brain, primarily serotonin and norepinephrine, known as monoamines. Older medications – tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) – affect the activity of both of these neurotransmitters simultaneously. Their disadvantage is that they can be difficult to tolerate due to side effects or, in the case of MAOIs, dietary restrictions. Newer medications, such as the selective serotonin reuptake inhibitors (SSRIs), have fewer side effects than the older drugs, making it easier for patients to adhere to treatment. Both generations of medications are effective in relieving depression, although some people will respond to one type of drug, but not another.

Antidepressant medications take several weeks to be clinically effective even though they begin to alter brain chemistry with the very first dose. Research now indicates that antidepressant effects result from slow-onset adaptive changes within the brain cells, or neurons. Further, it appears that activation of chemical messenger pathways within neurons, and changes in the way that genes in brain cells are expressed, are the critical events underlying long-term adaptations in neuronal function relevant to antidepressant drug action. A current challenge is to understand the mechanisms that mediate, within cells, the long-term changes in neuronal function produced by antidepressants and other psychotropic drugs and to understand how these mechanisms are altered in the presence of illness.

Knowing how and where in the brain antidepressants work can aid the development of more targeted and potent medications that may help reduce the time between first dose and clinical response. Further, clarifying the mechanisms of action can reveal how different drugs produce side effects and can guide the design of new, more tolerable, treatments.

As one route toward learning about the distinct biological processes that go awry in different forms of depression, NIMH researchers are investigating the differential effectiveness of various antidepressant medications in people with particular subtypes of depression. For example, this research has revealed that people with atypical depression, a subtype characterized by reactivity of mood (mood brightens in response to positive events) and at least two other symptoms (weight gain or increased appetite, oversleeping, intense fatigue, or rejection sensitivity), respond better to treatment with MAOIs, and perhaps with SSRIs than with TCAs.

Many patients and clinicians find that combinations of different drugs work most effectively for treating depression, either by enhancing the therapeutic action or reducing side effects. Although combination strategies are used often in clinical practice, there is little research evidence available to guide psychiatrists in prescribing appropriate combination treatment. NIMH is in the process of revitalizing and expanding its program of clinical research, and combination therapy will be but one of numerous treatment interventions to be explored and developed.

Untreated depression often has an accelerating course, in which episodes become more frequent and severe over time. Researchers are now considering whether early intervention with medications and maintenance treatment during well periods will prevent recurrence of episodes. To date, there is no evidence of any adverse effects of long-term antidepressant use.