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J Clin Psychiatry. 1999;60 Suppl 14:16-20; discussion 31-5.

Models of antidepressant action.

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Department of Psychiatry, Yale University School of Medicine, and Connecticut Mental Health Center, New Haven 06519, USA.


Although immediate pharmacologic targets can be identified for most antidepressant treatments, elucidation of the critical biological mechanisms leading to symptom relief has defied decades of research. In this review, selected neurotransmitter, biochemical, and anatomic models of antidepressant action are considered with regard to their explanatory power and therapeutic applicability. Monoamine models have been a focus of research attention on antidepressant action, an appropriate emphasis in that virtually all antidepressant medications have high affinity for monoamine substrates. Furthermore, prevailing monoamine models have suggested some promising therapeutic strategies. Nevertheless, these models are ultimately incomplete and do not fully explain important clinical limitations of current treatment: delayed response, incomplete efficacy, and unsustained remissions. Continued therapeutic advancements will likely require the development of models of antidepressant action that extend beyond the monoamines.

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