Ketamine and esketamine for suicidal ideation in depression: a systematic review and meta-analysis of randomized controlled trials

Background Suicidal ideation is a major clinical problem in depressive disorders, while conventional antidepressants have delayed effects. Ketamine and esketamine may provide rapid relief, but their effects on suicidal ideation, durability, suicidal behavior, and safety remain uncertain. Aim To evaluate the efficacy, durability, suicidal-behavior outcomes, acceptability, and safety of ketamine and esketamine for suicidal ideation in adults with depression. Methods PubMed/MEDLINE, Scopus, Web of Science Core Collection, and the Cochrane Library were searched from inception through 23 August 2026. Twelve randomized controlled trials (RCTs), involving 1,127 randomized participants, were included. Ketamine and esketamine were analyzed separately. The primary outcome was suicidal-ideation severity at the earliest post-treatment assessment within 24 h. A 72-hour fallback was used for suicidal-ideation remission when no earlier eligible assessment was available. Random-effects meta-analyses used restricted maximum likelihood (REML), with Hartung–Knapp confidence intervals for analyses including at least three trials and classic Wald-type confidence intervals for two-trial analyses. Results Ketamine was associated with lower suicidal-ideation severity in the primary acute analysis (5 trials; 247 participants; Hedges g = − 0.76, 95% CI − 1.14 to − 0.38; I² = 6%; moderate-certainty evidence). Esketamine showed a smaller and imprecise effect (2 trials; 286 participants; g = − 0.21, 95% CI − 0.44 to 0.02; low-certainty evidence). Evidence for suicidal-ideation remission and suicide attempts was imprecise. The acute effect of ketamine on depressive-symptom severity was uncertain, whereas esketamine reduced Montgomery–Åsberg Depression Rating Scale (MADRS) scores. Dissociation was more frequent with both interventions; dizziness and increased blood pressure were also more frequent with esketamine. These safety findings were limited by sparse data and variation in outcome ascertainment. Conclusion Ketamine showed a short-term reduction in suicidal-ideation severity in a small, methodologically limited RCT evidence base, but the magnitude of the drug-specific effect remains uncertain. Evidence for esketamine, remission, durability, prevention of suicidal behavior, and comparative safety remains limited or imprecise. Larger, better-masked trials using standardized suicidality measures and longer follow-up are needed.