History and evolution of the monoamine hypothesis of depression

The symptoms of depression can be improved by agents that act by various me chanisms to increase synaptic concentrations of monoamines. This finding le d to the adoption of the monoamine hypothesis of depression, first put forw ard over 30 years ago, which proposes that the underlying biological or neu roanatomical basis for depression is a deficiency of central noradrenergic and/or serotonergic systems and that targeting this neuronal lesion with an antidepressant would tend to restore normal function in depressed patients . The hypothesis has enjoyed considerable support, since it attempts to pro vide a pathophysiologic explanation of the actions of antidepressants. Howe ver. in its original form it is clearly inadequate, as it does not provide a complete explanation for the actions of antidepressants, and the pathophy siology of depression itself remains unknown. The hypothesis has evolved ov er the years to include, for example, adaptive changes in receptors to expl ain why there should be only a gradual clinical response to antidepressant treatment when the increase in availability of monoamines is rapid. Still. the monoamine hypothesis does not address kev issues such as why antidepres sants are also effective in other disorders such as panic disorder, obsessi ve-compulsive disorder, and bulimia, or why all drugs that enhance serotone rgic or noradrenergic transmission are not necessarily effective in depress ion. Despite these limitations, however, it is clear that the development o f the monoamine hypothesis has been of great importance in understanding de pression and in the development of safe and effective pharmacologic agents for its treatment.