History And Discovery

Although iminodibenzyl had been synthesized in 1889 (Byck 1975), it was not until after 1948 that derivatives of this compound were investigated for their potential usefulness in human subjects. Ironically, the properties that were of interest—the antihistaminic and sedative actions—would later be viewed as the "side effects" of these compounds. In the 1950s, investigation of one of these compounds led to the serendipitous observation that chlorpromazine had "antipsychotic" effects (Delay and Deniker 1952). The tricyclic compound imipramine was closely related to chlorpromazine, differing only in the substitution of an ethylene linkage for sulfur. In 1957, Roland Kuhn, a Swiss psychiatrist, investigated the clinical effects of imipramine in human subjects in part to determine if its sedative properties would be useful (Kuhn 1958, 1970). He found that imipramine was not useful for calming agitated patients; however, he observed that it did appear to ameliorate symptoms in depressed patients. As with lithium and chlorpromazine earlier, the discovery of the psychotropic effects of the tricyclics was a chance observation.

After imipramine was introduced, several other antidepressant compounds were developed and marketed. These compounds had a basic tricyclic structure and also shared many of the secondary effects for which the tricyclics came to be known. Later, other heterocyclic compounds, such as maprotiline, were also marketed. These agents had somewhat similar structures and secondary effects.

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