Antidepressants for bipolar depression: a systematic review of randomized, controlled trials

Am J Psychiatry. 2004 Sep;161(9):1537-47. doi: 10.1176/appi.ajp.161.9.1537.


Objective: This study reviewed the evidence from randomized, controlled trials on the efficacy and safety of antidepressants in the short-term treatment of bipolar depression.

Method: The authors performed a systematic review and meta-analysis of randomized, controlled trials. They searched the Cochrane Collaboration Depression, Anxiety, and Neurosis Controlled Trials Register, incorporating results of searches of MEDLINE, EMBASE, CINAHL, PsycLIT, PSYNDEX, and LILACS. The main outcome measures were the proportion of patients who clinically responded to treatment and the rate of switching to mania.

Results: Twelve randomized trials were included, with a total of 1,088 randomly assigned patients. Five trials compared one or more antidepressants with placebo: 75% of these patients were receiving a concurrent mood stabilizer or an atypical antipsychotic. Antidepressants were more effective than placebo. Antidepressants did not induce more switching to mania (the event rate for antidepressants was 3.8% and for placebo, it was 4.7%). Six trials allowed comparison between two antidepressants. The rate of switching for tricyclic antidepressants was 10%, and for all other antidepressants combined, it was 3.2%.

Conclusions: Antidepressants are effective in the short-term treatment of bipolar depression. The trial data do not suggest that switching is a common early complication of treatment with antidepressants. It may be prudent to use a selective serotonin reuptake inhibitor or a monoamine oxidase inhibitor rather than a tricyclic antidepressant as first-line treatment. Given the limited evidence, there is a compelling need for further studies with longer follow-up periods and careful definition and follow-up of emerging mania and partial remission.

Publication types

  • Clinical Trial
  • Comparative Study
  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adult
  • Aged
  • Anticonvulsants / therapeutic use
  • Antidepressive Agents / therapeutic use*
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / psychology
  • Double-Blind Method
  • Female
  • Humans
  • Lithium / therapeutic use
  • Male
  • Middle Aged
  • Placebos
  • Practice Guidelines as Topic
  • Randomized Controlled Trials as Topic
  • Risk Assessment
  • Treatment Outcome


  • Anticonvulsants
  • Antidepressive Agents
  • Placebos
  • Lithium