CNS Spectrums

Review Articles

A systematic review of the evidence for the treatment of acute depression in bipolar I disorder

Michael A. Cerulloa1 c1 and Stephen M. Strakowskia1

a1 Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, USA


In this article, we examined evidence for the acute treatment of depression in bipolar I disorder, focusing on double-blind, placebo-controlled studies with a definite primary outcome measure and published in peer review journals. Quetiapine and olanzapine/fluoxetine are currently approved by the FDA for the treatment of bipolar depression, and a number of additional agents (including other atypical antipsychotics, mood stabilizers, antidepressants, and novel compounds) have been studied with varying degrees of efficacy. The medication with the most evidence for efficacy in bipolar depression is quetiapine, with five studies showing positive efficacy compared to placebo. In contrast, five studies of lamotrigine were negative, although meta-analyses of the pooled have found some treatment effects. Two studies of olanzapine and olanzapine/fluoxetine and three small studies of divalproex showed significant efficacy in treating bipolar depression. Two studies of aripiprazole found no differences compared to placebo. Early research on lithium in bipolar depression had significant methodological flaws, and only one study of lithium met our primary search criteria. To better understand the role of antidepressants, we also examined studies of antidepressants as adjunctive treatment of bipolar depression in participants taking mood stabilizers or atypical antipsychotics. These studies reported mixed results for a variety of antidepressants, but the majority found no differences compared to placebo. Other studies of adjunctive treatment were also discussed. There has been one positive adjunctive study each of lamotrigine, omega-3 fatty acids, modafinil, and armodafinil, while there was one negative trial each of omega-3 fatty acids, ziprasidone, and levetiracetam.

(Received November 15 2012)

(Accepted January 24 2013)

(Online publication March 18 2013)


  • Bipolar disorder;
  • fMRI;
  • Bipolar depression;
  • treatment


c1 Address for correspondence: Michael Cerullo, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati COM, 260 Stetson Street, Suite 3200, Cincinnati, OH 45219-0516, USA. Email


  This study was supported by NIMH grants K23MH081214 (Cerullo) and P50MH077138 and R01MH071931 (Strakowski).