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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