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History and Evolution of the Monoamine Hypothesis of Depression

Robert M. A. Hirschfeld, MD

Published: March 31, 2000

Article Abstract

The symptoms of depression can be improved by agents that act by various mechanisms to increasesynaptic concentrations of monoamines. This finding led to the adoption of the monoamine hypothesisof depression, first put forward over 30 years ago, which proposes that the underlying biologicalor neuroanatomical basis for depression is a deficiency of central noradrenergic and/orserotonergic systems and that targeting this neuronal lesion with an antidepressant would tend to restorenormal function in depressed patients. The hypothesis has enjoyed considerable support, since itattempts to provide a pathophysiologic explanation of the actions of antidepressants. However, in itsoriginal form it is clearly inadequate, as it does not provide a complete explanation for the actions ofantidepressants, and the pathophysiology of depression itself remains unknown. The hypothesis hasevolved over the years to include, for example, adaptive changes in receptors to explain why thereshould be only a gradual clinical response to antidepressant treatment when the increase in availabilityof monoamines is rapid. Still, the monoamine hypothesis does not address key issues such as whyantidepressants are also effective in other disorders such as panic disorder, obsessive-compulsive disorder,and bulimia, or why all drugs that enhance serotonergic or noradrenergic transmission are notnecessarily effective in depression. Despite these limitations, however, it is clear that the developmentof the monoamine hypothesis has been of great importance in understanding depression and in thedevelopment of safe and effective pharmacologic agents for its treatment.

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