Comparative Efficacy of Racemic Ketamine and Esketamine for Depression

Journal of Affective Disorders, Volume 281, 15 February 2021, Pages 1001

Anees Bahjiab Gustavo H.Vazqueza Carlos A. Zarate Jr

a Department of Psychiatry, Queen’s University, Kingston, ON, Canada
b Department of Public Health Sciences, Queen’s University, Kingston, ON, Canada
c Section Neurobiology and Treatment of Mood Disorders, Division of Intramural Research Program, National Institute of Mental Health, 10 Center Drive, MSC 1282 Building 10CRC, Room 7-5342, Bethesda, MD 20892, USA


Ketamine appears to have a therapeutic role in certain mental disorders, most notably depression. However, the comparative performance of different formulations of ketamine is less clear.


This study aimed to assess the comparative efficacy and tolerability of racemic and esketamine for the treatment of unipolar and bipolar major depression.


Systematic review and meta-analysis.

Data sources

We searched PubMed, MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for relevant studies published since database inception and December 17, 2019.

Study eligibility criteria

We considered randomized controlled trials examining racemic or esketamine for the treatment of unipolar or bipolar major depression.


Primary outcomes were response and remission from depression, change in depression severity, suicidality, retention in treatment, drop-outs, and drop-outs due to adverse events.


Evidence from randomized controlled trials was synthesized as rate ratios (RRs) for treatment response, disorder remission, adverse events, and withdrawals and as standardized mean differences (SMDs) for change in symptoms, via random-effects meta-analyses.


24 trials representing 1877 participants were pooled. Racemic ketamine relative to esketamine demonstrated greater overall response (RR = 3.01 vs. RR = 1.38) and remission rates (RR = 3.70 vs. RR = 1.47), as well as lower dropouts (RR = 0.76 vs. RR = 1.37).


Intravenous ketamine appears to be more efficacious than intranasal esketamine for the treatment of depression.

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