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. Roland Kuhn, deputy medical director of the cantonal psychiatric clinic at Münsterlingen, near Lake Constance, had tested Geigy compounds before, and after chlorpromazine's success he asked the Swiss firm for new drugs of the same family to try in psychotic patients. In early 1956 he received G 22355, later named imipramine: a three-ring compound with the same side chain as chlorpromazine, made by Franz Häfliger and Walter Schindler in 1948.

Kuhn's initial results with schizophrenic patients were disappointing: imipramine did not suppress psychosis, and some patients became agitated. But three patients with depressive psychosis improved markedly within a few weeks, and on February 4, 1956, Kuhn wrote to Geigy that the drug might be an antidepressant. He gave it to 37 more depressed patients and presented the results from all 40 at the Second International Congress of Psychiatry in Zurich in September 1957, to an audience of about a dozen people; his report appeared in the Schweizerische Medizinische Wochenschrift that year. In the American Journal of Psychiatry in 1958 he described his experience with about 500 patients, reporting no serious side effects.

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 launched imipramine as Tofranil in Switzerland at the end of 1957 and in the rest of Europe in the spring of 1958, and the FDA approved it in 1959. 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 approved in the United States, received FDA approval in December 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. An earlier SSRI, zimelidine, had been sold in Europe for 16 months before cases of Guillain-Barré syndrome ended its use. Tricyclics did not disappear from practice; they kept a role in neuropathic pain, migraine prophylaxis, and treatment-resistant depression.