Atypical Antipsychotics in Bipolar Depression: Potential Mechanisms of Action
J Clin Psychiatry 2005;66(suppl 5):40-48
© Copyright 2015 Physicians Postgraduate Press, Inc.
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"Conventional" antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), bupropion,
or serotonin-norepinephrine reuptake inhibitors, are not recommended as monotherapy for
bipolar depression. Although they are likely to provide effective symptom relief in combination with
mood stabilizers, the risk of precipitating a switch to mania often complicates their use even as combination
therapy. Recently, 2 psychotropic medications approved for treating acute mania, olanzapine
and quetiapine, have also been shown to possess antidepressant activity without destabilizing mood
and, as such, are potential mood stabilizers. This article aims to review the mechanism of action of
conventional antidepressants and newer agents that are effective in the treatment of bipolar depression.
A number of mechanisms have been postulated to play a role in the effective treatment of bipolar depression,
including targets as diverse as serotonin (5-HT), norepinephrine, dopamine, γ-aminobutyric
acid (GABA), glutamate, and various second messenger signaling pathways. A review of the data reveals
an important point of commonality among the antidepressant treatments, olanzapine, and quetiapine.
Antidepressant treatments, such as norepinephrine reuptake inhibitors, SSRIs, and electroconvulsive
therapy, induce a reduction of 5-HT2A receptors. Both olanzapine and quetiapine not only are
antagonists at this receptor but also induce downregulation of 5-HT2A receptors. It is possible that the
antidepressant efficacy of these agents is mediated by this receptor, while the additional benefit of
olanzapine and quetiapine over unimodal antidepressant treatments, in terms of stabilizing mood, may
be provided by their concomitant dopamine D2 antagonism. Further studies should be conducted to
examine these hypotheses.