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

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

Stevan Nikolin  1   2 , Anthony Rodgers  3 , Andreas Schwaab  4 , Anees Bahji  5   6 , Carlos Zarate Jr  7 , Gustavo Vazquez  7 , Colleen Loo  1   2   3
Affiliations

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

Stevan Nikolin et al. EClinicalMedicine. .

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.

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Conflict of interest statement

AB has been awarded doctoral studies research funding from the Canadian Institutes of Health Research Fellowship and research funding through the Calgary Health Trust. AB receives a small honorarium for teaching undergraduate and postgraduate medical trainees in the Cumming School of Medicine at the University of Calgary. AB is an unpaid member of the Canadian Network for Mood and Anxiety Treatments editorial committee, the International Society of Addiction Journal Editors, the Canadian Society of Addiction Medicine policy committee, and the Addiction Psychiatry section of the Canadian Psychiatric Association. AB is also an unpaid associate editor of the Canadian Journal of Addiction and a mental health educator for TED-Ed, where he receives a small honorarium for supporting online educational content. CZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R, 6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R, S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a 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 post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties the government may receive. GV has received grants from the Canadian Institute of Health Research; Canadian Biomarker Integration Network in Depression; Canadian Ontario Ministry of Health and Long-Term Care; Queen's University Medical School (RIG and Dean's Doctoral Award); Research Innovation Fund (Providence Care Hospital); Women's Giving Circle UHKK. GV is a speaker or member of the advisory board for: Abbvie, Allergan, Janssen, Lundbeck/Otsuka, NeonMind Biosciences, Asofarma, Raffo, Gador, Eurofarma, Elea/Phoenix, Psicofarma, Tecnofarma, Sunovion, Janssen. CL is supported by an NHMRC (Australian National Health and Medical Council) investigator Grant (1195651). CL has served on an advisory board for Janssen Cilag and a scientific advisory committee for Douglas Pharmaceuticals. She is the Medical Director of Neurostimulation/Interventional Psychiatry at the Ramsay Northside Clinic. The remaining authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Study selection.
Fig. 2
Fig. 2
Acute effects following the single/first dose of ketamine to a control condition. Data points represent random effects aggregate meta-analyses conducted separately for each combination of ketamine formulation (Racemic vs Esketamine) and dose (High vs Low) at specific time points; baseline, as well as 4 h, and days 1 and 3 following the initial dose. Error bars denote the 95% confidence interval. Dashed lines indicate findings from the mixed effects multivariable meta-regression incorporating 1st and 2nd order fixed effects of time (linear and quadratic, respectively) as well as factors of ketamine formulation and dosage as fixed effects, and ‘study’ as a random effect. Plots are separated to show results for High (top panel) and Low (bottom panel) dose categories. Negative standardised mean differences (SMDs) indicate reduced scores on standardised depression scales (e.g., MADRS or HDRS) for participants receiving ketamine compared to a control condition. Differences between groups at baseline (day 0) are included for visual reference and were not incorporated in the meta-regression analysis. RAC: racemic; S: esketamine.
Fig. 3
Fig. 3
Repeated administrations as part of a treatment course. Data points represent random effects aggregate meta-analyses conducted separately for each combination of ketamine formulation (Racemic vs Esketamine) and dose (High vs Low) at specific time points; days 7, 14, 21, and 28 during a treatment course. Due to differences in data collection times between studies, findings were aggregated for results reported within ±3 days from these time points (e.g., findings at day 25 were aggregated into day 28). Error bars denote the 95% confidence interval. Dashed lines indicate findings from the mixed effects multivariable meta-regression incorporating 1st and 2nd order fixed effects of time (linear and quadratic, respectively) as well as factors of ketamine formulation and dosage as fixed effects, and ‘study’ as a random effect. Plots are separated to show results for High (top panel) and Low (bottom panel) dose categories. Negative standardised mean differences (SMDs) indicate reduced scores on standardised depression scales (e.g., MADRS or HDRS) for participants receiving ketamine compared to a control condition. RAC: racemic; S: esketamine.
Fig. 4
Fig. 4
Effects following the final dose. Data points represent random effects aggregate meta-analyses conducted separately for each combination of ketamine formulation (Racemic vs Esketamine) and dose (High vs Low) at specific time points; baseline, as well as days 7, 14, 21, and 28 following the final dose in a treatment course. Error bars denote the 95% confidence interval. Dashed lines indicate findings from the mixed effects multivariable meta-regression incorporating 1st and 2nd order fixed effects of time (linear and quadratic, respectively) as well as the factor of ketamine formulation as a fixed effect, and ‘study’ as a random effect. Model findings are only provided for the High dose category because all but one study contributing to the meta-regression outcomes used a high dose. Plots are separated to show results for High (top panel) and Low (bottom panel) dose categories. Negative standardised mean differences (SMDs) indicate reduced scores on standardised depression scales (e.g., MADRS or HDRS) for participants receiving ketamine compared to a control condition. Time is represented as the number of days since the final dose of a treatment course. RAC: racemic; S: esketamine.
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