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Efficacy and safety of ketamine-assisted electroconvulsive therapy in major depressive episode: a systematic review and network meta-analysis

Molecular Psychiatry (2023)Cite this article

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Abstract

Objective

To meta-analyze clinical efficacy and safety of ketamine compared with other anesthetic agents in the course of electroconvulsive therapy (ECT) in major depressive episode (MDE).

Methods

PubMed/MEDLINE, Cochrane Library, Embase, GoogleScholar, and US and European trial registries were searched from inception through May 23, 2023, with no language limits. We included RCTs with (1) a diagnosis of MDE; (2) ECT intervention with ketamine and/or other anesthetic agents; and (3) measures included: depressive symptoms, cognitive performance, remission or response rates, and serious adverse events. Network meta-analysis (NMA) was performed to compare ketamine and 7 other anesthetic agents. Hedges’ g standardized mean differences (SMDs) were used for continuous measures, and relative risks (RRs) were used for other binary outcomes using random-effects models.

Results

Twenty-two studies were included in the systematic review. A total of 2322 patients from 17 RCTs were included in the NMA. The overall pooled SMD of ketamine, as compared with propofol as a reference group, was –2.21 (95% confidence interval [CI], –3.79 to –0.64) in depressive symptoms, indicating that ketamine had better antidepressant efficacy than propofol. In a sensitivity analysis, however, ketamine-treated patients had a worse outcome in cognitive performance than propofol-treated patients (SMD, –0.18; 95% CI, –0.28 to –0.09). No other statistically significant differences were found.

Conclusions

Ketamine-assisted ECT is tolerable and may be efficacious in improving depressive symptoms, but a relative adverse impact on cognition may be an important clinical consideration. Anesthetic agents should be considered based on patient profiles and/or preferences to improve effectiveness and safety of ECT use.

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Fig. 1: Network diagram for changes in depressive symptoms.
Fig. 2: Forest plots of ketatmine versus other anesthetic agents in the course of ECT.
Fig. 3: Forest plots of ketatmine versus propofol in the course of ECT.
Fig. 4: Rankograms of surface under the cumulative ranking (SUCRA) curves by each outcome measure.

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Data availability

Data are publicly available.

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Author notes

  1. These authors contributed equally: Taeho Greg Rhee, Sung Ryul Shim.

Authors and Affiliations

  1. Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, USA

    Taeho Greg Rhee & Robert A. Rosenheck

  2. VA New England Mental Illness, Research, Education and Clinical Center (MIRECC), VA Connecticut Healthcare System, West Haven, CT, USA

    Taeho Greg Rhee & Robert A. Rosenheck

  3. Department of Public Health Sciences, School of Medicine, University of Connecticut, Farmington, CT, USA

    Taeho Greg Rhee

  4. Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon, Chungcheongnam-do, Republic of Korea

    Sung Ryul Shim

  5. Center for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, RI, USA

    Jonah H. Popp & Thomas A. Trikalinos

  6. Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA

    Charles H. Kellner

  7. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Stephen J. Seiner & Brent P. Forester

  8. Division of Neurotherapeutics, McLean Hospital, Belmont, MA, USA

    Stephen J. Seiner & Brent P. Forester

  9. Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA, USA

    Randall T. Espinoza

  10. Department of Psychiatry, Tufts University School of Medicine, Boston, MA, USA

    Brent P. Forester

  11. Brain and Cognition Discovery Foundation, Toronto, ON, Canada

    Roger S. McIntyre

  12. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Roger S. McIntyre

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Contributions

Study concept and design: TGR; Data acquisition and statistical analyses: TGR & SRS; Interpretation of data: All authors; Drafting of manuscript: TGR, SRS, & CHK; Critical revision of manuscript for important intellectual content: All authors; Supervision: TGR & RSM. TGR and SRS are co-first authors. TGR had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Taeho Greg Rhee.

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Competing interests

Each author completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and had none directly related to this manuscript. (1) TGR was supported in part by the National Institute on Aging (NIA) through Yale School of Medicine (#T32AG019134) in the past 3 years. TGR has also been funded by the NIA (#R21 AG070666), National Institute of Mental Health (#R21MH117438) and Institute for Collaboration on Health, Intervention, and Policy (InCHIP) of the University of Connecticut. TGR serves as a review committee member for Patient-Centered Outcomes Research Institute (PCORI) and Substance Abuse and Mental Health Services Administration (SAMHSA) and has received honoraria payments from PCORI and SAMHSA. TGR has also served as a stakeholder/consultant for PCORI and received consulting fees from PCORI. TGR serves as an advisory committee member for International Alliance of Mental Health Research Funders (IAMHRF). TGR is currently a co-editor-in-chief of Mental Health Science and is pending to receive honorarium payments annually from the publisher, John Wiley & Sons, Inc. (2) SRS reported none. (3) JHP reported none. (4) TAT reported none. (5) RAR reported none. (6) CHK has received fees from UpToDate, Inc. for writing/editing ECT-related topics, royalties from Cambridge University Press for Handbook of ECT, honoraria from Northwell Health for teaching an ECT course and fees for being an expert witness iin ECT-related legal cases. (7) SJS reported none. (8) RTE has been supported by the National Institute of Mental Health (R01MH128690) and the Muriel Harris Chair of Geriatric Psychiatry, Geffen School of Medicine at UCLA. He has also received royalties from UpToDate, Inc. and is on the Editorial Board of the Journal of ECT. (9) BPF has received research grant funding from Biogen, Eisai, Rogers Family Foundation, Spier Family Foundation and the NIH. He also serves in the Pharmacy and Therapeutics Committee for CVS health and is a consultant for Patina Health and Rippl Care. (10) RSM has received research grant support from CIHR/GACD/National Natural Science Foundation of China (NSFC); speaker/consultation fees from Lundbeck, Janssen, Alkermes, Mitsubishi, Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk,Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie, Atai Life Sciences. RSM is a CEO of Braxia Scientific Corp.

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Rhee, T.G., Shim, S.R., Popp, J.H. et al. Efficacy and safety of ketamine-assisted electroconvulsive therapy in major depressive episode: a systematic review and network meta-analysis. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02366-8

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