Neurology & Psychiatry · 1958
Imipramine, the first tricyclic antidepressant (Kuhn)
Psychiatry in the mid-1950s had almost nothing to offer patients with severe depression other than electroconvulsive therapy, barbiturate sedation, or admission to a long-term facility. The Swiss pharmaceutical firm Geigy was searching for new compounds in the phenothiazine class after chlorpromazine's success in schizophrenia. Imipramine, a dibenzazepine derivative with a three-ring structure similar to chlorpromazine, looked promising on paper. The compound was forwarded to Roland Kuhn, a psychiatrist at the Munsterlingen Cantonal Hospital on the Swiss shore of Lake Constance, who agreed to evaluate it clinically.
Kuhn's initial results with schizophrenic patients were disappointing: imipramine did not suppress psychosis. But in early 1956, a nurse at Munsterlingen drew Kuhn's attention to a handful of depressed patients who appeared to be brightening, moving more, and engaging more with the ward environment. Kuhn systematically expanded the trial to depressed inpatients. Over approximately two years, he tested imipramine in more than 300 patients and found that those with endogenous depression, characterized by psychomotor retardation, early morning wakening, and diurnal mood variation, responded consistently. Patients with neurotic depression or anxiety did not respond, and neither did those with schizophrenia. He reported these findings in the American Journal of Psychiatry in 1958.
The mechanism was not known at the time of these clinical observations. Subsequent laboratory work by Julius Axelrod and others demonstrated that imipramine blocked the presynaptic reuptake of norepinephrine and serotonin, prolonging their dwell time in the synaptic cleft. That finding gave the monoamine hypothesis of depression its most direct clinical support: a drug that raised synaptic catecholamine and serotonin levels lifted mood in people with depressive illness. The hypothesis was not without critics, and it has been substantially revised and complicated since, but it organized psychopharmacological research for decades.
Geigy marketed imipramine as Tofranil, and it entered widespread clinical use in the early 1960s. The tricyclic class expanded quickly: amitriptyline, nortriptyline, desipramine, and clomipramine followed, each with a somewhat different receptor profile but the same core mechanism and a similar side-effect burden. That burden, which included significant anticholinergic effects (dry mouth, constipation, urinary retention, cognitive slowing) and cardiac conduction slowing, limited their use in elderly patients and made overdose particularly dangerous, since a tricyclic taken in excess could cause fatal arrhythmia.
Fluoxetine, the first selective serotonin reuptake inhibitor, received FDA approval in 1987 and rapidly displaced the tricyclics as first-line antidepressants because of its far more favorable safety profile in overdose and its reduced anticholinergic burden. Tricyclics did not disappear from practice; they retained a role in neuropathic pain, migraine prophylaxis, and treatment-resistant depression. Kuhn's original 1958 report described a drug found by attending carefully to a patient population that had been offered very little, and it supplied the empirical foundation for an entire branch of pharmacology.
Key People
- Roland Kuhn — Swiss psychiatrist who conducted the clinical trial and reported imipramine's antidepressant effects.
- Julius Axelrod — Pharmacologist who elucidated catecholamine reuptake, explaining imipramine's mechanism.
Am J Psychiatry, 1958
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- 1952 · Chlorpromazine in psychosis (Delay & Deniker) (Neurology & Psychiatry)
- 1965 · Methadone maintenance treatment for heroin addiction (Dole and Nyswander) (Neurology & Psychiatry)
- 1949 · Cade's lithium for mania (Neurology & Psychiatry)
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