Ketamine for the treatment of major depression: a systematic review and meta-analysis

Stevan Nikolin; Anthony Rodgers; Andreas Schwaab; Anees Bahji; Carlos Zarate Jr; Gustavo Vazquez; Colleen Loo

doi:10.1016/j.eclinm.2023.102127

Ketamine for the treatment of major depression: a systematic review and meta-analysis

EClinicalMedicine. 2023 Aug 3:62:102127. doi: 10.1016/j.eclinm.2023.102127. eCollection 2023 Aug.

Authors

Stevan Nikolin^{1

2}, Anthony Rodgers³, Andreas Schwaab⁴, Anees Bahji^{5

6}, Carlos Zarate Jr⁷, Gustavo Vazquez⁷, Colleen Loo^{1

2

3}

Affiliations

¹ Discipline of Psychiatry and Mental Health, University of New South Wales, Sydney, Australia.
² Black Dog Institute, Sydney, Australia.
³ The George Institute for Global Health, University of New South Wales, Sydney, Australia.
⁴ Maastricht University, Maastricht, Netherlands.
⁵ Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
⁶ Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
⁷ 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.

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.

Funding: None.

Keywords: Depression; Ketamine; Meta-analysis; Systematic review.

Grants and funding

R25 DA037756/DA/NIDA NIH HHS/United States