A Systematic Review of Long-term Safety Outcomes of Ketamine and Esketamine in Patients with Treatment-resistant Depression.

INTRODUCTION: Approximately 30-40% of patients with major depressive disorder fail to respond to conventional antidepressants. Ketamine and esketamine are increasingly used, yet synthesized data on cumulative safety remain limited. This systematic review evaluated long-term safety of both agents. METHODS: MEDLINE, PsycINFO, Embase, and Cochrane Library were searched from inception through January 29, 2026. Eligible studies enrolled adults with depressive disorders receiving ketamine or esketamine with ≥12-week follow-up. Safety outcomes were synthesized narratively across nine domains: neurocognitive, dissociative/psychotomimetic, sedation, cardiovascular, hepatic, urinary, misuse/dependence, suicidality, and serious adverse events (SAEs). Risk of bias was assessed. RESULTS: Thirty-two studies (11 RCTs, 21 non-randomized) met inclusion criteria, with follow-up ranging from 3 months to 9 years. Across cardiovascular, hepatic, and urinary domains, neither racemic ketamine nor intranasal esketamine demonstrated evidence of cumulative organ toxicity during maintenance treatment. Dissociative and sedative effects were common but consistently transient, resolving within 1-2 hours of administration. No treatment-emergent neurocognitive dysfunction was identified; urologic complications were rare and resolved with treatment discontinuation. No cases of iatrogenic addiction, drug-seeking, or withdrawal were documented for either formulation. Suicidal ideation scores showed reductions from baseline, though suicide attempts and completions occurred during follow-up periods. SAEs attributable to treatment were rare. The comparative analyses suggested essentially equivalent long-term safety profiles between racemic ketamine and intranasal esketamine. CONCLUSION: Current evidence supports the safety of ketamine and esketamine for TRD, with no cumulative organ toxicity or iatrogenic addiction during maintenance treatment. Acute effects remain transient and manageable. However, findings are limited by heterogeneity in safety monitoring across studies.