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.
Shim et al. (2026) studied this question.