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Meta-Analysis
. 2022 Dec 1;79(12):1162-1172.
doi: 10.1001/jamapsychiatry.2022.3352.

Efficacy and Safety of Ketamine vs Electroconvulsive Therapy Among Patients With Major Depressive Episode: A Systematic Review and Meta-analysis

Taeho Greg Rhee  1   2   3 , Sung Ryul Shim  4 , Brent P Forester  5   6 , Andrew A Nierenberg  5   7 , Roger S McIntyre  8   9 , George I Papakostas  5   7   10 , John H Krystal  1 , Gerard Sanacora  1 , Samuel T Wilkinson  1
Affiliations
Meta-Analysis

Efficacy and Safety of Ketamine vs Electroconvulsive Therapy Among Patients With Major Depressive Episode: A Systematic Review and Meta-analysis

Taeho Greg Rhee et al. JAMA Psychiatry. .

Erratum in

  • Error in Figure.
    [No authors listed] [No authors listed] JAMA Psychiatry. 2022 Dec 1;79(12):1241. doi: 10.1001/jamapsychiatry.2022.4135. JAMA Psychiatry. 2022. PMID: 36477141 Free PMC article. No abstract available.

Abstract

Importance: Whether ketamine is as effective as electroconvulsive therapy (ECT) among patients with major depressive episode remains unknown.

Objective: To systematically review and meta-analyze data about clinical efficacy and safety for ketamine and ECT in patients with major depressive episode.

Data sources: PubMed, MEDLINE, Cochrane Library, and Embase were systematically searched using Medical Subject Headings (MeSH) terms and text keywords from database inception through April 19, 2022, with no language limits. Two authors also manually and independently searched all relevant studies in US and European clinical trial registries and Google Scholar.

Study selection: Included were studies that involved (1) a diagnosis of depression using standardized diagnostic criteria, (2) intervention/comparator groups consisting of ECT and ketamine, and (3) depressive symptoms as an efficacy outcome using standardized measures.

Data extraction and synthesis: Data extraction was completed independently by 2 extractors and cross-checked for errors. Hedges g standardized mean differences (SMDs) were used for improvement in depressive symptoms. SMDs with corresponding 95% CIs were estimated using fixed- or random-effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed.

Main outcomes and measures: Efficacy outcomes included depression severity, cognition, and memory performance. Safety outcomes included serious adverse events (eg, suicide attempts and deaths) and other adverse events.

Results: Six clinical trials comprising 340 patients (n = 162 for ECT and n = 178 for ketamine) were included in the review. Six of 6 studies enrolled patients who were eligible to receive ECT, 6 studies were conducted in inpatient settings, and 5 studies were randomized clinical trials. The overall pooled SMD for depression symptoms for ECT when compared with ketamine was -0.69 (95% CI, -0.89 to -0.48; Cochran Q, P = .15; I2 = 39%), suggesting an efficacy advantage for ECT compared with ketamine for depression severity. Significant differences were not observed between groups for studies that assessed cognition/memory or serious adverse events. Both ketamine and ECT had unique adverse effect profiles (ie, ketamine: lower risks for headache and muscle pain; ECT: lower risks for blurred vision, vertigo, diplopia/nystagmus, and transient dissociative/depersonalization symptoms). Limitations included low to moderate methodological quality and underpowered study designs.

Conclusions and relevance: Findings from this systematic review and meta-analysis suggest that ECT may be superior to ketamine for improving depression severity in the acute phase, but treatment options should be individualized and patient-centered.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rhee reported support from the National Institute on Aging (NIA) through Yale School of Medicine (T32AG019134); funding from the NIA (R21AG070666), National Institute of Mental Health (#R21MH117438), and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut; serving as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA); receiving honoraria payments from PCORI and SAMHSA; having served as a stakeholder/consultant for PCORI and received consulting fees from PCORI; and currently serving as a co–editor-in-chief of Mental Health Science and pending to receive honorarium payments annually from the publisher, John Wiley & Sons. Dr Forester reported research grant funding from Biogen, Eisai, Rogers Family Foundation, Spier Family Foundation and the National Institutes of Health (NIH); serving on the Pharmacy and Therapeutics Committee for CVS Health; and serving as a consultant for Patina Health. Dr Nierenberg reported grants from PCORI (PaCR-2017C2-8169, XPPRN-1512-33786, XPPRN-1512-33786), the Thomas P. Hackett, MD Endowed Chair in Psychiatry at Massachusetts General Hospital, and the Dauten Family Center for Bipolar Treatment Innovation; being a consultant for Abbott Laboratories, Alkermes, American Psychiatric Association, Appliance Computing, Mindsite, Basliea, BrainCells, Brandeis University, Bristol Myers Squibb, Clintara, Corcept, Dey Pharmaceuticals, Dainippon Sumitomo (now Sunovion), Eli Lilly, EpiQ, Mylan, Forest, Genaissance, Genentech, GlaxoSmithKline, Hoffman LaRoche, Infomedic, Intra-Cellular Therapies, Lundbeck, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Medavante, Merck, Methylation Sciences, Naurex, NeuroRx, Novartis, Otsuka, Pamlab, Parexel, Pfizer, PGx Health, Ridge Diagnostics Shire, Schering-Plough, Somerset, Sunovion, Takeda Pharmaceuticals, Targacept, and Teva; consulting through the Massachusetts General Hospital Clinical Trials Network and Institute for AstraZeneca, BrainCells, Dainippon Sumitomo/Sepracor, Johnson & Johnson, Labopharm, Merck, Methylation Science, Novartis, PGx Health, Shire, Schering-Plough, Targacept, and Takeda/Lundbeck Pharmaceuticals; grant, research, or other support from the American Foundation for Suicide Prevention, Agency for Healthcare Research and Quality, Brain and Behavior Research Foundation, Bristol Myers Squibb, Cederroth, Cephalon, Clexio, Cyberonics, Elan, Eli Lilly, Eisai, Forest, GlaxoSmithKline, Janssen Pharmaceuticals, Intra-Cellular Therapies, Lichtwer Pharma, Marriott Foundation, Mylan, Myriad, National Institute of Mental Health, Neuronetics, Pamlab, PCORI, Pfizer, Sage, Shire, Stanley Foundation, Takeda, and Wyeth-Ayerst; honoraria from Belvoir Publishing, University of Texas Southwestern, Dallas, Brandeis University, Bristol Myers Squibb, Hillside Hospital, American Drug Utilization Review, American Society for Clinical Psychopharmacology, Baystate Medical Center, Columbia University, Controlled Risk Insurance Company, Dartmouth Medical School, Health New England, Harold Grinspoon Charitable Foundation, Imedex, Israel Society for Biological Psychiatry, Johns Hopkins University, MJ Consulting, New York State, Medscape, MBL Communications, Massachusetts General Hospital Psychiatry Academy, National Association of Continuing Education, Physicians Postgraduate Press, State University of New York Buffalo, University of Wisconsin, University of Pisa, University of Michigan, University of Miami, University of Wisconsin at Madison, World Congress of Brain Behavior and Emotion, American Professional Society of ADHD and Related Disorders, International Society for Bipolar Disorder, SciMed, Slack Publishing, Wolters Kluwer Publishing, the American Society for Clinical Psychopharmacology (formerly NCDEU), Rush Medical College, Yale University School of Medicine, National Nuclear Data Center, Nova Southeastern University, National Alliance on Mental Illness, Institute of Medicine, Continued Medical Education Institute, and the International Society for CNS Clinical Trials and Methodology; serving currently or formerly on the advisory boards of Appliance Computing, BrainCells, Eli Lilly, Genentech, Johnson & Johnson, Takeda/Lundbeck, Targacept, and InfoMedic; stock options in Appliance Computing, BrainCells, and Medavante; and copyrights to the Clinical Positive Affect Scale and the Massachusetts General Hospital Structured Clinical Interview for the Montgomery-Åsberg Depression Scale exclusively licensed to the Massachusetts General Hospital Clinical Trials Network and Institute. Dr McIntyre reported research grant support from the Canadian Institutes of Health Research/Global Alliance for Chronic Diseases/National Natural Science Foundation of China (NSFC) and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, and Atai Life Sciences; and being chief executive officer of Braxia Scientific Corp. Dr Papakostas reported serving as a consultant, sometimes on behalf of Massachusetts General Hospital, for Abbott Laboratories, Acadia Pharmaceuticals, Alkermes, Alfasigma USA, AstraZeneca, Avanir Pharmaceuticals, Axsome Therapeutics, Boston Pharmaceuticals, Brainsway, Bristol Myers Squibb, Cala Health, Cephalon, Dey Pharma, Eleusis Health Solutions, Eli Lilly, Genentech, Genomind, GlaxoSmithKline, Evotec, H. Lundbeck, Inflabloc Pharmaceuticals, Janssen Global Services, Jazz Pharmaceuticals, Johnson & Johnson, Methylation Sciences, Monopteros Therapeutics, Mylan, Novartis Pharma, One Carbon Therapeutics, Osmotica Pharmaceutical, Otsuka Pharmaceuticals, Pamlab, Pfizer, Pierre Fabre Laboratories, Praxis Precision Medicines, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sage Therapeutics, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Taisho Pharmaceutical, Takeda Pharmaceutical Company, Theracos, and Wyeth; receiving honoraria (for lectures or consultancy) from Abbott Laboratories, Acadia Pharmaceuticals, Alkermes, Alfasigma USA, Asofarma America Central Y Caribe, AstraZeneca, Avanir Pharmaceuticals, Bristol Myers Squibb, Brainsway, Cephalon, Dey Pharma, Eli Lilly, Evotec, Forest Pharmaceuticals, GlaxoSmithKline, Inflabloc Pharmaceuticals, Grunbiotics, Hypera, Jazz Pharmaceuticals, H. Lundbeck, Medichem Pharmaceuticals, Meiji Seika Pharma, Novartis Pharma, Otsuka Pharmaceuticals, Pamlab, Pfizer, Pharma Trade, Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company, Theracos, Titan Pharmaceuticals, and Wyeth; receiving research support (paid to hospital) from Alfasigma USA, AstraZeneca, Bristol Myers Squibb, Cala Health, Forest Pharmaceuticals, the National Institute of Mental Health, Mylan, Neuralstem, Pamlab, PCORI, Pfizer, Johnson & Johnson, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sunovion Pharmaceuticals, Tal Medical, and Theracos; and having served (not currently) on the speaker’s bureau for Bristol Myers Squibb and Pfizer. Dr Krystal reported serving as a consultant for Aptinyx, Biogen, Idec, Bionomics, Boehringer Ingelheim, Clearmind Medicine, Cybin, Enveric Biosciences, Epiodyne, EpiVario, Janssen Research & Development, Jazz Pharmaceuticals, Otsuka America Pharmaceutical, Perception Neuroscience, Praxis Precision Medicines, Spring Care, and Sunovion Pharmaceuticals; serving as a scientific advisory board member for Biohaven Pharmaceuticals, BioXcel Therapeutics, Cerevel Therapeutics, Delix Therapeutics, Eisai, EpiVario, Freedom Biosciences, Jazz Pharmaceuticals, Neumora Therapeutics, Neurocrine Biosciences, Novartis, Praxis Precision Medicines, PsychoGenics, Tempero Bio, and Terran Biosciences; having in the past 3 years the patent “Mavoglurant in treating gambling and gaming disorders” (application 63/125,181 filed by the Yale University Office of Cooperative Research); and having stock options from Biohaven Pharmaceuticals Medical Sciences, Clearmind Medicine, EpiVario, Neumora Therapeutics, Tempero Bio, and Terran Biosciences. Dr Sanacora reported receiving personal fees and serving as a consultant to Allergan, Alkermes, Ancora, Aptinx, AstraZeneca, Avanier Pharmaceuticals, Axsome Therapeutics, Biogen, Biohaven Pharmaceuticals, Boehringer Ingelheim International, Bristol Myers Squibb, Cowen, EMA Wellness, Engrail Therapeutics, Clexio, Denovo Biopharma, Freedom, Gilgamesh, Hoffmann La-Roche, Intra-Cellular Therapies, Janssen Pharmaceuticals, Koa Health, Levo, Lundbeck, Merck, miCure Therapeutics, Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Relmada Therapeutics, Sage Pharmaceuticals, Servier Pharmaceuticals, Seelos Pharmaceuticals, Taisho Pharmaceuticals, Teva, Transend, Valeant, Vistagen Therapeutics, and XW Labs; receiving research contracts from AstraZeneca, Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Merck, and Usona over the past 36 months; holding equity in Biohaven Pharmaceuticals; being a co-inventor on a US patent (8,778,979) held by Yale University and a co-inventor on US Provisional Patent Application 047162-7177P1 (00754) filed by the Yale University Office of Cooperative Research. Dr Wilkinson reported receiving contract funding from Janssen Pharmaceuticals, Sage Therapeutics, and Oui Therapeutics for the conduct of clinical trials administered through Yale University as well as consulting fees from Biohaven Pharmaceuticals, Sage Therapeutics, Janssen Pharmaceuticals, and Oui Therapeutics. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Severity of Depressive Symptoms Between Electroconvulsive Therapy (ECT) and Ketamine in Patients With Major Depressive Episode
Analyses were done using a fixed-effects model and inverse variance. For the study by Kheirabadi et al (2020), we distinguish intramuscular ketamine and oral ketamine without duplications. A 2-stage model was used in B. In the first stage, we obtained the overall effect size estimate of multiple measures within the studies by Ghasemi et al, Sharma et al, and Kheirabadi et al (2020) using a 3-level meta-analysis. In the second stage, we pooled and obtained the overall effect size estimate using 1 effect size from each study. BDI indicates Beck Depression Inventory; HDRS, Hamilton Depression Rating Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; SMD, standardized mean difference.
Figure 2.
Figure 2.. Individual Safety Outcomes Between Electroconvulsive Therapy (ECT) and Ketamine in Patients With Major Depressive Episode
Fixed indicates fixed-effects model; MH, Mantel-Haenszel method; random, random-effects model; RR, relative risk.
Figure 3.
Figure 3.. Risk-of-Bias Assessment for Individual Studies
The risk-of-bias domains are described as follows: D1 indicates bias arising from the randomization process; D2, bias due to deviations from the intended intervention; D3, bias due to missing outcome data; D4, bias in measurement of the outcome; D5, bias in selection of the reported result. (See eTable 3 in the Supplement for details.)
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