Short-term efficacy and safety of intravenous ketamine for major depressive disorder in adolescents: a systematic review and metaanalysis of randomized and open-label studies

Background: Adolescent major depressive disorder (MDD) is associated with substantial impairment, suicide risk, and limited response to standard treatments. Intravenous ketamine has rapid antidepressant effects in adults, but pediatric evidence remains limited. This systematic review and meta-analysis evaluated the short-term efficacy and safety of intravenous ketamine for adolescents with MDD, including treatment-resistant depression (TRD). Methods: This Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020-based review was registered in PROSPERO (CRD420251123304). PubMed, Web of Science, and Google Scholar were searched from inception to October 2025. Eligible studies included patients aged 18 years or younger treated with intravenous ketamine for MDD or TRD. Outcomes included changes in Montgomery–Åsberg Depression Rating Scale (MADRS), Children’s Depression Rating Scale–Revised (CDRS-R), Children’s Depression Inventory (CDI), and adverse events. Risk of bias (RoB) was assessed using RoB 2 and methodological index for non-randomized studies. Random-effects meta-analyses were performed where appropriate. Results: Four prospective studies were included: two randomized controlled trials and two open-label studies, involving 77 adolescents. Intravenous ketamine was associated with significant reductions in depressive symptoms. Pooled MADRS scores decreased by 15.90 points [95% confidence interval (CI), -19.16 to -12.64; p < 0.001; I² = 5.9%]. CDRS-R scores decreased by 21.17 points (95% CI, -29.11 to -13.24; p < 0.001; I² = 0%), and CDI scores decreased by 6.55 points (95% CI, -11.78 to -1.31; p = 0.01; I² = 0%). Improvements occurred within 2 hours and persisted up to 14 days in controlled studies. Adverse events were mild and transient, including dissociation, dizziness, nausea, headache, and brief hemodynamic changes. No serious adverse events were reported. Conclusion: Intravenous ketamine may produce antidepressant effects in adolescents with MDD or TRD. Evidence remains limited by small samples, functional unblinding, open-label designs, and brief follow-up. Larger randomized trials with standardized suicidal ideation outcomes and longer safety monitoring are required before clinical adoption.