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

Abstract

Introduction: Approximately 30-40% of patients with major depressive disorder fail to respond to conventional antidepressants. Ketamine and esketamine are increasingly used in maintenance protocols extending months to years, yet synthesized data on cumulative safety remain limited. This systematic review evaluated long-term safety of both agents with follow-up ≥12 weeks.

Methods: MEDLINE, PsycINFO, Embase, and Cochrane Library were searched via OVID from inception through January 29, 2026. Eligible studies enrolled adults with depressive disorders receiving ketamine or esketamine with ≥12-week follow-up and extractable safety data. Risk of bias was assessed using RoB 2 (RCTs) and ROBINS-I v2 (nonrandomized studies). Safety outcomes were synthesized narratively across nine domains: neurocognitive, dissociative/psychotomimetic, sedation, cardiovascular, hepatic, urinary, misuse/dependence, suicidality, and serious adverse events (SAEs).

Results: Thirty-two studies (11 RCTs, 21 nonrandomized) 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 h 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: Over follow-up durations typically ranging from 3 to 12 months, 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.