Invited review: the evolution of antidepressant mechanisms

Present antidepressants are all descendents of the serendipitous findings in the 1950s that the monoamine oxidase inhibitor iproniazid and the tricyclic antidepressant imipramine were effective antidepressants. The identification of their mechanism of action, and those of reserpine and amphetamine, in the 1960s, led to the monoamine theories of depression being postulated; first, with noradrenaline then 5-hydroxytryptamine being considered the more important amine. These monoamine theories of depression predominated both industrial and academic research for four decades. Recently, in attempts to design new drugs with faster onsets of action and more universal therapeutic action, downstream alterations common to current antidepressants are being examined as potential antidepressants. Additionally, the use of animal models has identified a number of novel targets some of which have been subjected to clinical trials in humans. However, monoamine antidepressants remain the best current medications and it may be some time before they are dislodged as the market leaders.