A systematic review and meta-analysis of lithium augmentation of tricyclic and second generation antidepressants in major depression

J Affect Disord. 2014 Oct:168:269-75. doi: 10.1016/j.jad.2014.05.053. Epub 2014 Jun 2.


Background: Lithium augmentation of antidepressants for treatment of unipolar major depression was one of the first adjunctive strategies based on a neuropharmacologic rationale. Randomized controlled trials supported its efficacy but most trials added lithium to tricyclic antidepressants (TCAs). Despite its efficacy, use of lithium augmentation remains infrequent. The current systematic review and meta-analysis examines the efficacy of lithium augmentation as an adjunct to second generation antidepressants as well as to TCAs and considers reasons for its infrequent use.

Method: A systematic search of Medline and the Cochrane Clinical Trials database was performed. Randomized, placebo-controlled trials of lithium augmentation were selected. A fixed-effects meta-analysis was performed. Odds ratios for response were calculated for each treatment-control contrast, for the trials grouped by type of initial antidepressant (TCA or second generation antidepressant), and as a meta-analytic summary for all treatments combined.

Results: Nine trials that included 237 patients were selected. The odds ratio for response to lithium vs. placebo in all contrasts combined was 2.89 (95% CI 1.65, 5.05, z=3.72, p=0.0002). Heterogeneity was very low, I(2)=0%. Adjunctive lithium was effective with TCAs (7 contrasts) and with second generation agents (3 contrasts). Discontinuation due to adverse events was infrequent and did not differ between lithium and placebo.

Limitations: The meta-analysis is limited by the small size and number of trials and limited data for treatment resistant patients.

Conclusions: Adjunctive lithium appears to be as effective for second generation antidepressants as it was for the tricyclics.

Keywords: Lithium augmentation; Major depression.

Publication types

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

MeSH terms

  • Antidepressive Agents / therapeutic use*
  • Antidepressive Agents, Second-Generation / therapeutic use*
  • Antidepressive Agents, Tricyclic / therapeutic use*
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / psychology
  • Drug Therapy, Combination
  • Humans
  • Lithium Compounds / therapeutic use*
  • Treatment Outcome


  • Antidepressive Agents
  • Antidepressive Agents, Second-Generation
  • Antidepressive Agents, Tricyclic
  • Lithium Compounds