Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials

Am J Psychiatry. 2004 Feb;161(2):217-22. doi: 10.1176/appi.ajp.161.2.217.


Objective: The authors sought to determine the efficacy and acceptability of lithium for relapse prevention in bipolar disorder.

Method: A systematic review and meta-analysis of randomized controlled trials comparing lithium with placebo in the long-term treatment of bipolar disorders was conducted. Data were obtained from searching the registers of the Cochrane Collaboration; reviewing reference lists, journals, and conference abstracts; and contacting authors, experts, and pharmaceutical companies. Outcomes investigated included risk of relapse (manic, depressive, and total) as well as risk of specific adverse effects and total withdrawal rates.

Results: Five randomized controlled trials (770 participants) were included. Lithium was more effective than placebo in preventing all relapses (random effects relative risk=0.65, 95% CI=0.50 to 0.84) and manic relapses (relative risk=0.62, 95% CI=0.40 to 0.95). The protective effect of lithium on depressive relapses was smaller and was less robust (relative risk=0.72, 95% CI=0.49 to 1.07).

Conclusions: Lithium treatment reduces the risk of relapse in bipolar disorder. The preventive effect is clear for manic episodes, although it is equivocal for depressive episodes.

Publication types

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

MeSH terms

  • Antimanic Agents / therapeutic use*
  • Bipolar Disorder / drug therapy*
  • Humans
  • Lithium Carbonate / therapeutic use*
  • Randomized Controlled Trials as Topic
  • Secondary Prevention
  • Time


  • Antimanic Agents
  • Lithium Carbonate