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This topic was discussed at the Council's September 2002 meeting. This background paper was prepared by staff solely to aid discussion, and does not represent the official views of the Council or of the United States Government.

Staff Background Paper

On Depression and Antidepressants

This paper summarizes the psychiatrically recognized types of depression, current theories of what causes depression, and the treatment of depression with antidepressants, focusing on the antidepressants' biological action. A complete discussion of topics so complex would require many pages. The goal here is only to orient Council members for whom the subject is unfamiliar, and to give general background information that will further discussion. The selected bibliography attached should aid members interested in exploring these topics more extensively.

We begin not with the neurobiology, but with the human problem of concern. This reflects the ethical orientation of the Council, but also the early stage of biological understanding in this area. As will be seen below, scientific answers to crucial questions - like, "What is going on in the brain when we are depressed?" "What is different about the brains of a chronically depressed and an 'emotionally normal' person?" "Why do antidepressants work?" "Does all depression have a common or even similar biological basis?" - are partial and contested. It is difficult to draw ethically useful conclusions from biological knowledge this incomplete.

I. Types of Depression

No laboratory findings are diagnostic of depression. According to the very helpful review of Nestler et al. (2002): " . . . [T]he diagnosis of depression, as opposed to most diseases of other organ systems (diabetes, cancer, chronic obstructive pulmonary disease, to name a few), is not based on objective diagnostic tests (serum chemistry, organ imaging, or biopsies), but rather on a highly variable set of symptoms. Accordingly, depression should not be viewed as a single disease, but a heterogeneous syndrome comprised of numerous diseases of distinct causes and pathophysiologies." The symptoms are authoritatively set forth in the Diagnostic and Statistical Manual (DSMIV, 2000).

The symptoms of a "Major Depressive Episode" are the touchstone for all diagnoses of depression. Such an episode requires either "depressed mood" or "loss of interest or pleasure" nearly every day for two consecutive weeks, together with at least four other symptoms from a list of seven: weight loss or gain; insomnia or hypersomnia; psychomotor agitation or retardation; fatigue; feelings of worthlessness or excessive or inappropriate guilt; diminished ability to think, concentrate, or make decisions; and recurrent thoughts of death or suicide. (Notably, two instances of depression could have only one symptom in common.) The symptoms can be self-reported or observed by others. They must not be part of another problem, such as substance abuse or a general medical condition. And they must be severe enough to "cause clinically significant distress or impairment in social, occupational, or other important areas of functioning" (this is the only clear link in diagnosis between a state of feeling and the way a life is being lived).

The essential feature of "Major Depressive Disorder" is a clinical course marked by one or more such episodes. Major Depressive Disorder can be chronic - with the symptoms of an episode persisting for two years or more - but more often symptoms come, go away after a few weeks or months of blackness, and come back again. "Dysthymic Disorder," by contrast, is less severe and less episodic. It is the other primary type of depression, and the one likely to be of chief interest to the Council.

The essential feature of Dysthymia (pronounced "dis-THIGH-me-a") is depressed mood most of the day, for more days than not, for at least two years. Otherwise its symptoms largely match those of Major Depression, though there seems to be more of a tendency to irritability, brooding, and feelings of inadequacy. According to the DSMIV, "Because these symptoms have become so much a part of the individual's day-to-day experience (e.g., 'I've always been this way,' 'That's just how I am'), they are often not reported unless directly asked about by the interviewer."

Given that Major Depression and Dysthymia are so continuous, one might ask how far the continuity goes. Interestingly, when the DSMIV tries to distinguish Major Depression from "Bereavement," the difference is not in symptoms, but in the symptoms' source (the loss of a loved one) and duration (if symptoms persist for more than two months, "Bereavement" may be reclassified as "Major Depression"). The DSMIV does note that periods of sadness are part of the human condition, and not medical problems. But is there a qualitative difference? This is the "continuity issue," and a live subject of research. While the matter is unresolved, most findings currently point to continuity from medical conditions to normal emotions. (As a biological matter, there has been little success in finding consistent differences between the brains of depressed and "emotionally normal" people, let alone between the brains of depressed people and those unhappy in a normal way.)

There are other subtypes of depression after the distinction between Major Depressive Disorder and Dysthymia: Psychotic Depression (severe symptoms with delusions), Melancholic Depression (severe symptoms that do not improve when good things happen), Reactive Depression (moderate symptoms apparently in response to external factors), and Atypical Depression (associated with labile mood, hypersomnia, weight gain and increased appetite). Bipolar Disorder and its variations are characterized by alternating manic and depressed states.

II. Theories about the Causes of Depression

The discussion of depression's cause or causes is philosophically and scientifically challenging.

First, given current research, it appears highly unlikely that any one thing causes or is even implicated in all depression, as a psychological, genetic or neurobiological matter. It seems likely, in fact, that the term "depression" refers to a number of heterogeneous conditions sharing some - though sometimes very few - symptoms. There is little reason to think one thing causes such a disparate collection.

Second, whatever causes a particular depressive episode might be amenable to multiple descriptions. Psychological accounts (say, a traumatic experience) are ordinarily considered in opposition to biological accounts (say, decreased serotonin production). Yet they might not be in opposition at all. The one could be a mind- or brain-based way of talking about the same thing as the other, two equally accurate or even equivalent descriptions, stated in different languages that accord to different conceptual frameworks. Indeed, to think one could have a psychological experience in which the brain is inactive implies a sort of dualism (the sort of latent dualism one sees when astonished headlines declare that scientists have found anger, or intelligence, or some other aspect of mental life to have a basis in the brain).1 The question remains, of course, of whether the biological or psychological/experiential phenomenon is primary. But the answer is almost always unknown.

Third, even when depression has a genetic basis (which is of course more specific than a biological basis), it is probably inaccurate to say the depression is genetically caused. Genetics appears to confer a susceptibility or sensitivity to environmental stressors. Genetics might account for why one person becomes depressed at a rejection that does not depress another person. But it is not obvious whether to call the genetics or the rejection or some unity of the two the cause.

That said, the following description of existing scientific knowledge on the matter, again from Nestler et al.'s review (2002), is difficult to improve upon. It is quoted in full, both on this topic and on the separate matter of the treatment of depression.

"Genetic and Environmental Causes of Depression

Epidemiologic studies show that roughly 40-50% of the risk for depression is genetic (Sanders et al., 1999; Fava and Kendler, 2000). This makes depression a highly heritable disorder, at least as heritable as several common complex medical conditions (type II diabetes, hypertension, asthma, certain cancers), which are often thought of as genetic. Yet, the search for specific genes that confer this risk has been frustrating, with no genetic abnormality being identified to date [March, 2002] with certainty. The difficulty in finding depression vulnerability genes parallels the difficulty in finding genes for other psychiatric disorders and, in fact, for most common complex diseases. There are many reasons for this difficulty, which are reviewed elsewhere (Burmeister, 1999), including the fact that depression is a complex phenomenon with many genes possibly involved. Thus, any single gene might produce a relatively small effect and would therefore be difficult to detect experimentally. It is also possible that variants in different genes may contribute to depression in each family, which further complicates the search for depression genes.

In addition, vulnerability to depression is only partly genetic, with nongenetic factors also being important. Nongenetic factors as diverse as stress and emotional trauma, viral infections (e.g., Borna virus), and even stochastic (or random) processes during brain development have been implicated in the etiology of depression (Akiskal, 2000; Fava and Kendler, 2000). Depressive syndromes - indistinguishable from major depression defined by DSMIV and by their response to standard antidepressant treatments - occur in the context of innumerable medical conditions such as endocrine disturbances (hyper- or hypocortisolemia, hyper- or hypothyroidism), collagen vascular diseases, Parkinson's disease, traumatic head injury, certain cancers, asthma, diabetes, and stroke.

The role of stress warrants particular comment. Depression is often described as a stress-related disorder, and there is good evidence that episodes of depression often occur in the context of some form of stress. However, stress per se is not sufficient to cause depression. Most people do not become depressed after serious stressful experiences, whereas many who do become depressed do so after stresses that for most people are quite mild. Conversely, severe, horrendous stress, such as that experienced during combat, rape, or physical abuse, does not typically induce depression, but instead causes post-traumatic stress disorder (PTSD) that is distinct from depression based on symptomatology, treatment and longitudinal course of illness. This underscores the view that depression in most people is caused by interactions between a genetic predisposition and some environmental factors, which makes the mechanism of such interactions an important focus of investigation."

III. Treatment of Depression and Biology of Antidepressants

"In contrast to our limited understanding of depression, there are many effective treatments. The large majority (~80%) of people with depression show some improvement with any of several antidepressant medications or electroconvulsive seizures (ECS). In addition, several forms of psychotherapy (in particular, cognitive and behavioral therapies) can be effective for patients with mild to moderate cases, and the combination of medication and psychotherapy can exert a synergistic effect.

The treatment of depression was revolutionized about 50 years ago, when two classes of agents were discovered - entirely by serendipity - to be effective antidepressants: the tricyclic antidepressants and the monoamine oxidase inhibitors. The original tricyclic agents (e.g., imipramine) arose from antihistamine research, whereas the early monoamine oxidase inhibitors (e.g., iproniazid) were derived from work on antitubercular drugs. The discovery that depression can be treated with these medications provided one of the first clues into the types of chemical changes in the brain that regulate depressive symptoms. Indeed, much depression research over the last half-century was based on the notion that understanding how these treatments work would reveal new insight into the causes of depression.

The acute mechanisms of action of antidepressant medications were identified: inhibition of serotonin or norepinephrine reuptake transporters by the tricyclic antidepressants2 , and inhibition of monoamine oxidase (a major catabolic enzyme for monoamine neurotransmitters) by monoamine oxidase inhibitors (see Frazer, 1997). These discoveries led to the development of numerous second generation medications (e.g., serotonin-selective reuptake inhibitors [SSRIs]3 and norepinephrine-selective reuptake inhibitors) which are widely used today. The availability of clinically active antidepressants also made it possible to develop and validate a wide range of behavioral tests with which to study depression-like phenotypes in animal models. Moreover, these medications and behavioral tests represent important tools with which to study brain function under normal conditions and to identify a range of proteins in the brain that might serve as targets for novel antidepressant treatments.

That's the good news. The bad news is that progress in developing new and improved antidepressant medications has been limited. The SSRIs, for example, have a better side effect profile for some patients, and are easier for physicians to prescribe, compared with the older agents. This explains their astonishing financial success, now a world-wide market of >$10 billion a year in sales. However, these newer medications have essentially the same mechanism of action as the older tricyclic antidepressants and, as a result, the efficacy of the newer agents and the range of depressed patients they treat are no better than the older medications. Today's treatments remain sub-optimal, with only ~50% of all patients demonstrating complete remission, although many more (up to 80%) show partial responses.

Furthermore, the mechanism of action of antidepressant medications is far more complex than their acute mechanisms might suggest. Inhibition of serotonin or norepinephrine reuptake or catabolism would be expected to result in enhanced actions of these transmitters. However, all available antidepressants exert their mood-elevating effects only after prolonged administration (several weeks to months), which means that enhanced serotonergic or nonadrenergic neurotransmission per se is not responsible for the clinical actions of these drugs. Rather, some gradually developing adaptations to this enhanced neurotransmission would appear to mediate drug action. Important progress has been made in the search for such drug-induced plasticity . . . but definitive answers are still out of reach. Moreover, several generations of research have failed to provide convincing evidence that depression is caused by abnormalities in the brain's serotonin or norepinephrine systems. This is consistent with the ability of 'antidepressant' medications to treat a wide range of syndromes, far beyond depression, including anxiety disorders, PTSD, obsessive-compulsive disorder, eating disorders, and chronic pain syndromes. It also is consistent with the fact that many medications used in general medicine work far from the molecular and cellular lesion underlying a disease."



  1. Such a dualism may be, it should be said, appropriate or correct. And to make this philosophical point about the possible equivalence of the biological and the psychological/experiential is not to imply that the two ways of speaking will have equivalent cultural effects.
  2. [A gloss might be helpful here. Serotonin and norepinephrine are neurotransmitters. Because they are manufactured in the brain, it is efficient for the brain to "recycle" them. So after they are released into the synaptic cleft, reuptake transporters gather the unused portion up and store it for the next use. Antidepressants function by binding to and thus inhibiting those transporters, which leaves a higher average concentration of serotonin or norepinephrine in the synaptic cleft. Ideally, an antidepressant would be specific in its action, targeting only those neurotransmitters implicated in the depression. Thus selective reuptake inhibitors.]
  3. [Prozac was the first of these SSRIs. Its discovery was announced in 1974. An outpouring of writing on the science, clinical use, and ethics of neuropharmacology immediately followed.]


Selected Bibliography

On the types of and diagnosis of depression, see:

Diagnostic and Statistical Manual IV. (2000). American Psychiatric Press, Washington, D.C., pp. 345-428.

On the neurobiology of depression and for general background information, see:

Nestler, E.J. et al. (2002). Neurobiology of depression. Neuron 34, 13-25.

Manji, H.K. et al. (2001). The cellular neurobiology of depression. Nat. Med. 7, 541-547.

On the history and prescription of antidepressants, see:

Kramer, Peter (1993). Listening to Prozac. (New York: Viking), pp. 47-66.

References in quoted text:

Akiskal, H.S. (2000). Mood disorders: introduction and overview. In Comprehensive Textbook of Psychiatry, B.J. Sadock and V.A. Sadock, eds. (New York: Lippincott, Williams & Wilkins), pp. 1284-1298.

Burmeister, M. (1999). Basic concepts in the study of diseases with complex genetics. Biol. Psychiatry 45, 522-532.

Fava, M., and Kendler, K.S. (2000). Major depressive disorder. Neuron 28, 335-341.

Frazer, A. (1997). Pharmacology of antidepressants. J. Clin. Psychopharmacol. 17 Suppl. 1, 2S-18S.

Sanders et al. (1999). Molecular genetics of mood disorders. In Neurobiology of Mental Illness, D.S. Charney, E.J. Nestler and B.S. Bunney, eds. (New York: Oxford), pp. 299-316.

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