Adjunctive antidepressants for the acute treatment of bipolar depression: A systematic review and meta-analysis

Psychiatry Res. 2022 May;311:114468. doi: 10.1016/j.psychres.2022.114468. Epub 2022 Feb 22.


Background: The depressive phase of bipolar disorder causes significant functional impairment and disease burden. The efficacy and safety of antidepressants in the treatment of bipolar depression has long been a subject of debate.

Aims: To synthesize evidence of the effectiveness, risk of mood switching, and tolerability of adjunctive antidepressants in acute bipolar depression compared to using mood stabilizers or antipsychotics alone.

Method: Multiple databases were searched for randomized controlled trials, including open label and double-blinded, for patients ages 18 or older with acute bipolar depression, comparing efficacy and adverse events in those who used adjunctive antidepressants versus without. Risk of bias and outcomes were assessed using the Cochrane Risk of Bias Tool. This study has PROSPERO registration CRD42016037701.

Results: Nineteen studies met inclusion criteria. Adjunctive antidepressants showed no significant effect on improving response rate (RR=1.10, 95%CI: 0.98-1.23). Subgroup analysis showed that adjunctive antidepressants with antipsychotics had a small but significantly better response rate compared to antipsychotics alone, which was not seen with adjunctive antidepressants with mood stabilizers. However, that finding was limited by studies predominantly using olanzapine as the antipsychotic medication. Adjunctive antidepressants had no clinically significant impact (but a small statistically significant impact) on improving depressive symptoms (SMD=-0.13, 95%CI: -0.24 to -0.02). There was no association with increased mood switch (RR=0.97, 95%CI: 0.68-1.39) and there was an association with lower dropout due to inefficacy (RR=0.66, 95%CI: 0.45∼0.98).

Conclusions: There is no evidence of adjunctive antidepressants clinically improving response rate or depressive symptoms for acute bipolar depression. They are well tolerated, without increasing the risk of short-term mood switch.

Publication types

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

MeSH terms

  • Adolescent
  • Antidepressive Agents / therapeutic use
  • Antimanic Agents / therapeutic use
  • Antipsychotic Agents* / pharmacology
  • Antipsychotic Agents* / therapeutic use
  • Bipolar Disorder* / drug therapy
  • Depression / drug therapy
  • Humans


  • Antidepressive Agents
  • Antimanic Agents
  • Antipsychotic Agents