Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis

ABSTRACT

Background

Racemic ketamine and esketamine have demonstrated rapid antidepressant effects. We aimed to review the efficacy and safety of racemic and esketamine for depression.

Research design and methods

We conducted a PRISMA-guided review for relevant randomized controlled trials of racemic or esketamine for unipolar or bipolar major depression from database inception through 2021. We conducted random-effects meta-analyses using pooled rate ratios (RRs) and Cohen’s standardized mean differences (d) with their 95% confidence intervals (CI).

Results

We found 36 studies (2903 participants, 57% female, 45.1 +/- 7.0 years). Nine trials used esketamine, while the rest used racemic ketamine. The overall study quality was high. Treatment with any form of ketamine was associated with improved response (RR=2.14; 95% CI, 1.72-2.66; I2=65%), remission (RR=1.64; 95% CI, 1.33-2.02; I2=39%), and depression severity (d=-0.63; 95% CI, -0.80 to -0.45; I2=78%) against placebo. Overall, there was no association between treatment with any form of ketamine and retention in treatment (RR=1.00; 95% CI, 0.99-1.01; I2<1%), dropouts due to adverse events (RR=1.56; 95% CI, 1.00-2.45; I2<1%), or the overall number of adverse events reported per participant (OR=2.14; 95% CI, 0.82-5.60; I2=62%) against placebo.                             

Conclusions

Ketamine and esketamine are effective, safe, and acceptable treatments for individuals living with depression.

KEYWORDS:

• esketamine
• ketamine
• depressive disorder
• major
• bipolar disorder
• depression
• randomized controlled trials
• meta-analysis

Declaration of interests

CA Zarate Jr. is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation. In addition, they are listed as co-inventor on a patent for the use of (2R,6R)- hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R, S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and posttraumatic stress disorders. He has assigned his patent rights to the US government but will share a percentage of any government<apos;>s royalties. The NIH had no further role in study design, data collection, data analysis, data interpretation, the writing of the report, or the decision to submit the paper for publication. A Bahji reports research grants from the National Institutes of Health/National Institute on Drug Abuse (NIDA) [R25-DA037756, R25DA033211] through the International Collaborative Addiction Medicine Research Fellowship and the Research in Addiction Medicine Scholars Program through Boston University School of Medicine. In addition, they are a recipient of the 2020 Friends of Matt Newell Endowment from the University of Calgary Cumming School of Medicine. They also received financial support from a 2020 Research Grant on the Impact of COVID-19 on Psychiatry by the American Psychiatric Association and the American Psychiatric Association Foundation. G Vazquez has received consulting and speaking honoraria from AbbVie, Allergan, CANMAT,

Elea/Phoenix, Eurofarma, Gador, Janssen, Lundbeck, NeonMind Biosciences, Tecnofarma, Raffo, Otsuka, Psicofarma, and Sunovion, and research grants from CAN-BIND, CIHR, PCH and Queen<apos;>s University. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A peer reviewer on this manuscript has disclosed that they have a patent awarded for development of a controlled release ketamine tablet for TRD. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementry material

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Additional information

Funding

Funding for this work was provided in part by the Intramural Research Program at the National Institute of Mental Health and the National Institutes of Health (IRP-NIMH-NIH; ZIAMH002857).