Atypical antipsychotics in bipolar depression: Potential mechanisms of action

Lakshmi N. Yatham, Jeffrey M. Goldstein, Eduard Vieta, Charles L. Bowden, Heinz Grunze, Robert M. Post, Trisha Suppes, Joseph R. Calabrese

Research output: Contribution to journalArticlepeer-review

148 Scopus citations


"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.

Original languageEnglish (US)
Pages (from-to)40-48
Number of pages9
JournalJournal of Clinical Psychiatry
Issue numberSUPPL. 5
StatePublished - 2005

ASJC Scopus subject areas

  • Psychiatry and Mental health


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