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Yale University School of Medicine

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JAMA Psychiatry, May 06 2026, | https://doi.org/10.1001/jamapsychiatry.2026.0612 Ketamine Infusions and Rapid Reduction of Suicidal and Depressive Symptoms in Major Depressive Episode: A Systematic Review and Meta-Analysis

Sung Ryul Shim, PhD, MPH¹; Hye Su Jeong, PhD²; Tanner J. Bommersbach, MD, MPH³; Andrew A. Nierenberg, MD^4,5; Carlos A. Zarate Jr, MD⁶; Tyler S. Kaster, MD, PhD^7,8; Christoph U. Correll, MD^{9,10,11,12,13}; Roger S. McIntyre, MD⁸; John H. Krystal, MD¹⁴; Taeho Greg Rhee, PhD^14,15

¹Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon, Republic of Korea
²BK21 FOUR R&E Center for Learning Health Systems, Korea University, Seoul, Republic of Korea
³Department of Psychiatry, University of Wisconsin School of Medicine and Public Health, Madison
⁴Dauten Family Center for Bipolar Treatment Innovation, Massachusetts General Hospital, Boston
⁵Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
⁶Experimental Therapeutics and Pathophysiology Branch, Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health, Bethesda, Maryland
⁷Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
⁸Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
⁹Zucker Hillside Hospital, Psychiatry Research, Northwell Health, Glen Oaks, New York
¹⁰Zucker School of Medicine, Hofstra/Northwell, Hempstead, New York
¹¹Center for Neurosciences, The Feinstein Institute for Medical Research, Manhasset, New York
¹²Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany
¹³German Center for Mental Health, Berlin, Germany
¹⁴Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
¹⁵Department of Public Health Sciences, University of Connecticut School of Medicine, Farmington

Abstract

Importance: While intravenous ketamine is not approved by the US Food and Drug Administration, it is increasingly used with off-label indications as a novel treatment for suicidal and depressive symptoms.

Objective: To systematically review and metasynthesize the efficacy and safety data for intravenous ketamine in treating major depressive episodes (MDEs).

Data sources: PubMed, PsycInfo, Cochrane Library, and Embase were systematically searched from database inception through November 7, 2025, with no language limits.

Study selection: Randomized clinical trials (RCTs) with (1) diagnosis of an MDE; (2) intervention and comparator groups consisting of intravenous ketamine and controls (eg, saline or midazolam); and (3) suicidal and depressive symptoms as efficacy outcomes were included.

Data extraction and synthesis: Hedges g standardized mean differences (SMDs) were used to analyze improvement in suicidal and depressive symptoms using random-effects models. Multiple subgroup analyses were also conducted.

Main outcomes and measures: The main outcomes included the following: (1) changes in suicidal and depressive symptoms; (2) response and remission rates of depressive symptoms; and (3) safety measures (eg, adverse events and serious adverse events).

Results: A total of 26 RCTs comprising 1166 patients with an MDE (n = 626 receiving ketamine and n = 540 as control patients) were included. For suicidal symptoms, patients receiving a single ketamine infusion, compared with control patients, had significantly lower symptoms at 24 hours (SMD, -0.69 [95% CI, -0.98 to -0.40]) and at 1 month (SMD, -0.70 [95% CI, -1.17 to -0.24]). Those with repeated ketamine infusions showed a similar reduction of suicidal symptoms at the end of the treatment (SMD, -0.72 [95% CI, -1.00 to -0.43]). For depressive symptoms, significant reductions were shown at 4 hours (SMD, -1.74 [95% CI, -2.43 to -1.06]), 24 hours (SMD, -1.15 [95% CI, -1.58 to -0.72]), 3 days (SMD, -0.97 [95% CI, -1.73 to -0.20]), and 1 week (SMD, -0.89 [95% CI, -1.65 to -0.13]) after a single ketamine infusion and at the end of the treatment after repeated infusions (SMD, -0.81 [95% CI, -1.16 to -0.46]). Reported serious adverse events (eg, hospitalizations and deaths) were unrelated to the interventions, and other adverse events (eg, headache) were transient and resolved during the trials.

Conclusions and relevance: The findings of this systematic review and meta-analysis suggest that single and repeated intravenous ketamine infusions are efficacious in reducing suicidal and depressive symptoms in patients with an MDE in the acute phase, while longer-term outcomes are not well established.

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