Use of ketamine and esketamine for depression: an overview of systematic reviews with meta-analyses

Eur J Clin Pharmacol. 2022 Mar;78(3):311-338. doi: 10.1007/s00228-021-03216-8. Epub 2021 Oct 27.


Purpose: To summarize the evidence of efficacy and safety of the use of ketamine and esketamine for depression.

Methods: A literature search was performed in Medline, the Cochrane Library, LILACS, and CRD until November 2020. We included systematic reviews with meta-analyses of randomized controlled trials on the use of ketamine and esketamine in adult patients with depression. Two authors independently performed the study selection and data extraction. The AMSTAR-2 tool was used to appraise the quality of included reviews.

Results: A total of 118 records were identified, and 11 studies fully met the eligibility criteria. Compared to control, ketamine improved the clinical response at 40 min to 1 week and clinical remission at 80 min to 72 h, and esketamine improved both outcomes at 2 h to 4 weeks. Ketamine and esketamine also had a beneficial effect on the depression scales score and suicidality. For adverse events, oral ketamine did not show significant change compared to control, while intranasal esketamine showed difference for any events, such as dissociation, dizziness, hypoesthesia, and vertigo. Most reviews were classified as "critically low quality," and none of them declared the source of funding of the primary studies and assessed the potential impact of risk of bias in primary studies.

Conclusion: Ketamine and esketamine showed a significant antidepressant action within a few hours or days after administration; however, the long-term efficacy and safety are lacking. In addition, the methodological quality of the reviews was usually critically low, which may indicate the need for higher quality evidence in relation to the theme.

Keywords: Depression; Esketamine; Ketamine; Mental disorders; Overview; Systematic review.

Publication types

  • Review

MeSH terms

  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / adverse effects
  • Antidepressive Agents / therapeutic use*
  • Depressive Disorder / drug therapy*
  • Humans
  • Ketamine / administration & dosage
  • Ketamine / adverse effects
  • Ketamine / therapeutic use*
  • Meta-Analysis as Topic
  • Randomized Controlled Trials as Topic
  • Suicidal Ideation
  • Systematic Reviews as Topic


  • Antidepressive Agents
  • Esketamine
  • Ketamine