Ketamine for the treatment of major depression: a systematic review and meta-analysis
This systematic review and meta-analysis (n=3299) investigated the efficacy of ketamine for depression by analysing 49 randomised controlled trials (RCTs). The study found that racemic ketamine had numerically greater effects on depression severity, response, and remission rates compared to esketamine. Higher doses were more effective than low doses, with differences evident in initial effects, ongoing treatment, and lasting effects post-final dose.
Authors
- Carlos Zarate
- Colleen Loo
- Anthony Rodgers
Published
Abstract
Background
Intranasal esketamine has received regulatory approvals for the treatment of depression. Recently a large trial of repeated dose racemic ketamine also demonstrated efficacy in severe depression. However, uncertainties remain regarding comparative efficacy, dosage, and the time course of response.
Methods
In this systematic review and meta-analysis, we searched Embase, Medline, Pubmed, PsycINFO, and CENTRAL up to April 13, 2023, for randomised controlled trials (RCTs) investigating ketamine for depression. Two investigators independently assessed study eligibility and risk of bias and extracted the data on depression severity scores, response and remission rates, and all-cause dropouts. Multivariable mixed-effects meta-regressions incorporated drug formulation (racemic (Rac) or esketamine (Esket)) and dose (Low or High) as covariates. Treatment effects were assessed: immediately following the first dose, during further repeated dosing, and follow-up after the final dose of a treatment course. This study is registered with PROSPERO (CRD42021221157).
Findings
The systematic review identified 687 articles, of which 49 RCTs were eligible for analysis, comprising 3299 participants. Standardised mean differences (95% confidence intervals) immediately following the first/single treatment were moderate-high for all conditions (Rac-High: −0.73, −0.91 to −0.56; Esket-High: −0.48, −0.75 to −0.20; Rac-Low: −0.33, −0.54 to −0.12; Esket-Low: −0.55, −0.87 to −0.24). Ongoing effects during repeated dosing were significantly greater than the control for Rac-High (−0.61; −1.02 to −0.20) and Rac-Low (−0.55, −1.09 to −0.00), but not Esket-Low (−0.15, −0.49 to 0.19) or Esket-High (−0.22, −0.54 to 0.10). At follow-up effects remained significant for racemic ketamine (−0.65; −1.23 to −0.07) but not esketamine (−0.33; −0.96 to 0.31). All-cause dropout was similar between experiment and control conditions for both formulations combined (Odds Ratio = 1.18, 0.85-1.64). Overall heterogeneity varied from 5.7% to 87.6%.
Interpretation
Our findings suggested that effect sizes for depression severity, as well as response and remission rates, were numerically greater for racemic ketamine than esketamine. Higher doses were more effective than low doses. Differences were evident in initial effects, ongoing treatment, and lasting effects after the final dose.
Research Summary of 'Ketamine for the treatment of major depression: a systematic review and meta-analysis'
Introduction
Despite the availability of numerous antidepressant pharmacotherapies, major depressive disorder carries a substantial burden of treatment resistance, with a significant proportion of patients failing to respond to two or more adequate medication trials. Ketamine — a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist — has attracted considerable clinical interest due to its capacity to produce rapid and robust antidepressant effects, including acute reductions in suicidal ideation, within hours of administration. Whilst single-dose intravenous ketamine has been relatively well characterised in controlled trials, the evidence for its use as a longer-term treatment modality across multiple routes of administration remains fragmented across heterogeneous study designs, and a comprehensive synthesis of efficacy, safety, and tolerability data for clinical MDD populations is lacking.
Expert Research Summaries
Go Pro to access AI-powered section-by-section summaries, editorial takes, and the full research toolkit.
Full Text PDF
Full Paper PDF
Pro members can view the original manuscript directly in the browser.
Study Details
- Study Typemeta
- Journal
- Compounds
- Topics
- Authors
- APA Citation
Nikolin, S., Rodgers, A., Schwaab, A., Bahji, A., Zarate, C., Vazquez, G., & Loo, C. (2023). Ketamine for the treatment of major depression: a systematic review and meta-analysis. eClinicalMedicine, 62, 102127. https://doi.org/10.1016/j.eclinm.2023.102127
References (8)
Papers cited by this study that are also in Blossom
Bobo, W. V., Vande Voort, J. L., Croarkin, P. E. et al. · Depression and Anxiety (2016)
Zhu, W., Ding, Z., Zhang, Y. et al. · Neuroscience Bulletin (2016)
Jafarinia, M., Afarideh, M., Tafakhori, A. et al. · Journal of Affective Disorders (2016)
Wilkinson, S. T., Katz, R. B., Toprak, M. et al. · Journal of Clinical Psychiatry (2018)
Andrade, C. · Journal of Clinical Psychiatry (2017)
Jelen, L. A., Young, A. H., Stone, J. M. · Journal of Psychopharmacology (2020)
Zhang, J. C., Yao, W., Hashimoto, K. · Neuropharmacology (2022)
Short, B., Fong, J., Galvez, V. et al. · Lancet Psychiatry (2017)
Cited By (5)
Papers in Blossom that reference this study
Salvetti, G., Saccenti, D., Moro, A. S. et al. · Brain Sciences (2024)
Glue, P., Loo, C., Fam, J. et al. · Nature Medicine (2024)
Meling, D., Ehrenkra, R., Nayak, S. et al. · Psychoactives (2024)
Wong, S., Kwan, A. T. H., Teopiz, K. M. et al. · Journal of Affective Disorders (2024)
Rodgers, A., Bahceci, D., Davey, C. G. et al. · Australian and new-zealand Journal of Psychiatry (2023)
Your Personal Research Library
Go Pro to save papers, add notes, rate studies, and organize your research into custom shelves.