Efficacy of single and repeated administration of ketamine in unipolar and bipolar depression: a meta-analysis of randomized clinical trials

Pharmacol Rep. 2020 Jun;72(3):543-562. doi: 10.1007/s43440-020-00097-z. Epub 2020 Apr 16.


Background: Due to unmet clinical needs for efficient drugs with a rapid onset of antidepressant effects, we aimed to evaluate the efficacy of single-dose ketamine in different subgroups of patients with major depression and establish whether repeated ketamine administration could be a viable strategy to maintain treatment gains.

Methods: Electronic databases (Medline via PubMed, Embase, Cochrane Library, Trip Database) were systematically searched until February 22, 2019, for published peer-reviewed randomized controlled trials (RCTs) concerning a single and repeated administration of ketamine in patients with major depression. All relevant RCTs were selected and critically appraised, and a meta-analysis of eligible studies was performed.

Results: A total of 20 studies were included in the meta-analysis. The largest effect of ketamine vs. controls in reducing depressive symptoms was observed at 24 h (SMD = - 0.89; 95% CI - 1.24; - 0.53; p < 0.00001); however, a significant difference was shown for up to 7 days after a single dose. Significant differences compared with controls were observed for up to 7 days in treatment-resistant patients and when ketamine was added to ongoing antidepressant treatment, while there were no significant differences at 7 days when ketamine was used as monotherapy. In patients with major depression, initial antidepressant effects of ketamine were maintained during repeated dosing. At 2-3 weeks of repeated ketamine treatment, significant reduction of depression severity scores was observed: SMD = - 0.70; 95% CI - 1.15; - 0.25 or SMD = - 0.81; 95% CI - 1.41; - 0.20 (depending on the dosing regimen used); p ≤ 0.009 vs placebo.

Conclusions: Our meta-analysis revealed rapid and robust antidepressant effects of single-dose ketamine in patients with treatment-resistant depression (TRD). By pooling data from RCTs, we showed for the first time that repeated ketamine administration is effective in sustaining initial antidepressant effects observed after single dosing.

Keywords: Antidepressants; Bipolar disorder; Ketamine; Major depressive disorder; Meta-analysis; RCT.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Antidepressive Agents / therapeutic use
  • Bipolar Disorder / drug therapy*
  • Depressive Disorder, Major / drug therapy*
  • Ketamine / pharmacology*
  • Randomized Controlled Trials as Topic*


  • Antidepressive Agents
  • Ketamine