Atypical Antipsychotics in Bipolar Depression: Potential Mechanisms of Action

“Conventional” antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), bupropion,or serotonin-norepinephrine reuptake inhibitors, are not recommended as monotherapy forbipolar depression. Although they are likely to provide effective symptom relief in combination withmood stabilizers, the risk of precipitating a switch to mania often complicates their use even as combinationtherapy. Recently, 2 psychotropic medications approved for treating acute mania, olanzapineand quetiapine, have also been shown to possess antidepressant activity without destabilizing moodand, as such, are potential mood stabilizers. This article aims to review the mechanism of action ofconventional 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-aminobutyricacid (GABA), glutamate, and various second messenger signaling pathways. A review of the data revealsan important point of commonality among the antidepressant treatments, olanzapine, and quetiapine.Antidepressant treatments, such as norepinephrine reuptake inhibitors, SSRIs, and electroconvulsivetherapy, induce a reduction of 5-HT_2A receptors. Both olanzapine and quetiapine not only areantagonists at this receptor but also induce downregulation of 5-HT_2A receptors. It is possible that theantidepressant efficacy of these agents is mediated by this receptor, while the additional benefit ofolanzapine and quetiapine over unimodal antidepressant treatments, in terms of stabilizing mood, maybe provided by their concomitant dopamine D₂ antagonism. Further studies should be conducted toexamine these hypotheses.