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The Dual-Action Hypothesis: Does Pharmacology Matter?

Richard C. Shelton, MD

Published: December 15, 2004

Article Abstract

With treatment to remission as the gold standard for depression treatment, there is considerablereassessment of treatment approaches with the view to finding and employing agents capable of rapidlyeliminating all symptoms and returning patients to normalcy. The mechanisms of action intrinsicto different classes of antidepressants are at the center of this review. The selective serotonin reuptakeinhibitors (SSRIs), the most commonly prescribed antidepressants, have a single-action mechanisminvolved in modulating the reuptake of the neurotransmitter serotonin. The selectivity of the SSRIsrenders them safer and more tolerable than the earlier multi-acting monoamine oxidase inhibitors(MAOIs) and the tricyclic antidepressants (TCAs). However, because serotonin is not the onlyneurotransmitter implicated in the pathophysiology of depression, the selectivity that bestows safetyto SSRIs may limit somewhat the antidepressant effect in some patients. A newer class of dual-actionantidepressants acts by inhibiting the reuptake of both serotonin and norepinephrine. These serotonin-norepinephrinereuptake inhibitors (SNRIs) have improved side effect profiles compared withthe earlier multi-action antidepressants, compare favorably with the SSRIs on safety and tolerability,and reduce depression and its associated symptoms with greater rapidity. This review comparesthe neurobiology of single- and dual-action mechanisms.

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