1957: Discovery of Imipramine and Antidepressant Drug Therapy (1957)

Major depressive disorder affected millions of people worldwide, yet in the 1950s no pharmacological
treatment existed. The discovery of antidepressants followed, in part, an accidental observation.

Roland Kuhn, a Swiss psychiatrist working at the Münsterlingen psychiatric hospital, was testing
a series of iminodibenzyl compounds provided by the Geigy pharmaceutical company for potential
antipsychotic activity. One compound—G 22355, later named imipramine—failed to show antipsychotic
effects but instead produced a marked elevation of mood and increased drive in depressed patients.
Kuhn's 1957 report in the Schweizerische Medizinische Wochenschrift described 40 patients treated
with imipramine, documenting a true antidepressant effect rather than mere sedation or stimulation.
Geigy launched imipramine as Tofranil in 1958.

Imipramine's mechanism—blockade of neuronal monoamine reuptake transporters, principally
norepinephrine and serotonin transporters—was elucidated by Julius Axelrod and colleagues.
This observation, combined with the earlier discovery that the antituberculosis drug iproniazid
was a monoamine oxidase inhibitor (MAOI) that elevated mood, crystallised the monoamine hypothesis
of depression: that the disorder involves deficiency of norepinephrine or serotonin in synaptic
clefts. The monoamine hypothesis, though incomplete, guided antidepressant development for
decades and led directly to the design of selective serotonin reuptake inhibitors (SSRIs)
in the 1970s–1980s.

Imipramine also turned out to be effective for panic disorder, enuresis in children, and chronic
pain—illustrating how psychiatric drug discoveries often reveal unexpected pharmacological principles.