Imipramine, amitriptyline, their N-demethyl derivatives, and other similar compounds were the first successful antidepressants and, since the early 1960s, have been widely used for the treatment of major depression. Because of their structures, they are often referred to as the “tricyclic” antidepressants. Their efficacy in alleviating major depression is well established, and support for their use in other psychiatric disorders is growing. Just prior to the discovery of the antidepressant properties of Imipramine in the late 1950s, the ability of monoamine oxidase (MAO) inhibitors to cause mania was noted, and during the early 1960s, both types of agents were studied intensively. Early MAO inhibitors appeared to be limited in efficacy at the doses used and presented both toxic risks and potentially dangerous interactions with other agents, thus limiting their acceptance in favor of the tricyclic agents. Recently, after decades of limited progress, a series of innovative antidepressants has emerged. Most, like fluoxetine, are characterized as inhibitors of the neuronal inactivation of serotonin by active reuptake (transport); others including trazodone, nefazodone and bupropion, have a less well-defined neuropharmacology and can be considered “atypical”. Whereas the efficacy of the newer agents has not been demonstrated to be superior to that of the older agents, their relative safety and tolerability has led to their rapid acceptance as the most commonly prescribedantidepressants.
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