Comparative efficacy and side-effect profile of ketamine and esketamine in the treatment of unipolar and bipolar depression: protocol for a systematic review and network meta-analysis

BMJ Open. 2021 Feb 12;11(2):e043457. doi: 10.1136/bmjopen-2020-043457.


Introduction: Despite a range of antidepressant drugs and therapies, approximately one-third of patients fail to achieve meaningful recovery, prompting the urgent need for more effective treatment for depression. Several open-label studies randomised controlled trials (RCTs) and meta-analyses have been conducted to confirm the therapeutic efficacy and side effects of ketamine and esketamine. Esketamine is (S)- enantiomer of ketamine; however, there is limited evidence comparing esketamine and ketamine in treating unipolar and bipolar depression have been published so far.

Methods and analysis: We will include all double-blind RCTs comparing efficacy and side-effect profile of ketamine and esketamine in the treatment of unipolar and bipolar depression. Our primary outcomes will be study-defined response at endpoint assessment; dropouts due to adverse events and other adverse drug reactions. Published studies will be retrieved through relevant database searches. Reference selection and data extraction will be independently completed by two investigators, resolving inconsistencies by consensus or a discussion with the third investigator. For each outcome, we will undertake a network meta-analysis to synthesise all evidence. Local and global methods will be used to evaluate consistency. We will assess the quality of evidence contributing to network estimates with the Confidence in Network Meta-Analysis web application.

Ethics and dissemination: This work does not require ethics approval as it will be based on published studies. This review will be published in peer-reviewed journals.

Prospero registration number: CRD42020201559.

Keywords: depression & mood disorders; mental health; psychiatry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bipolar Disorder*
  • Drug-Related Side Effects and Adverse Reactions*
  • Humans
  • Ketamine* / adverse effects
  • Meta-Analysis as Topic
  • Network Meta-Analysis
  • Randomized Controlled Trials as Topic
  • Review Literature as Topic


  • Esketamine
  • Ketamine