Catecholamine Hypothesis of Depression

   (1965)

   In the most frequently cited article ever published in the American Journal of Psychiatry, Harvard psychiatrist Joseph Schildkraut (1934–) argued that depression was an illness linked to the catecholamine neurotransmitters (those having a "catechol" portion, such as dopamine and norepinephrine; these and the "indolamines" such as serotonin are collectively referred to as "monoamines").* Schildkraut had graduated with an M.D. from Harvard in 1959, Catecholamine Hypothesis of Depression trained in psychiatry at the Massachusetts Mental Health Center, then between 1963 and 1967 went down to the National Institute of Mental Health (NIMH) to study neuropsychopharmacology (returning then to "Mass Mental," where he spent the rest of his career). At NIMH, Schildkraut’s awareness of several circumstances began to crystallize into the belief that disordered neurochemistry was the cause of depression: Already at Mass Mental he had been impressed at the response of depressed patients to the monoamine oxidase inhibitor phenelzine (Parke-Davis’s Nardil). (See Iproniazid; Neurotransmitter.) This pointed the gun at the monoamines as implicated in depression: if one could inhibit the enzyme that broke them down, the patients got better. Then, in an experiment he determined that phenelzine acted on norepinephrine (a monoamine), and discovered at NIMH that the tricyclic antidepressant imipramine did so as well. It was thus clear from this and other evidence, he reasoned, that norepinephrine played a key role in depression. "There is good evidence," he concluded, "to support the thesis that the antidepressant effects of both the monoamine oxidase inhibitors and the imipramine-like drugs are mediated through the catecholamines, and that, by different biochemical mechanisms of action, both of these classes of drugs increase the active catecholamines at adrenergic receptor sites." "The catecholamine hypothesis currently seems to be the strongest and most useful pathophysiological hypothesis of affective disorders" (pp. 516, 517). This represented the "catecholamine" theory of depression that would dominate drug discovery research and academic psychopharmacology for years to come. An exclusive role for norepinephrine in mood disorders, however, is no longer credited. (See Selective Serotonin Reuptake Inhibitors.) Yet, the hypothesis sparked much research. Psychiatric historian David Healy refers to Schildkraut’s 1965 article as "the 1960s equivalent to Freud’s Interpretation of Dreams."

   * It is widely forgotten that in 1959 psychiatrist Abram Hoffer (1917–), director of psychiatric research in the Department of Public Health in Saskatchewan, noted at a conference at McGill University on depression: "The evidence suggests that the catecholamines must play a vital and perhaps villanous role in the causation of depression," and adduced the biochemical evidence on which this hypothesis was based (Canadian Psychiatric Association Journal, suppl., pp. S118–S119).