Efficacy of Ketamine and Esketamine in Treatment-Resistant Depression Among Older Adults (≥65 Years): A Systematic Review and Meta-Analysis of Randomised and Real-World Studies (2023–2025).

Late-life treatment-resistant depression (TRD) poses substantial clinical challenges, with limited effectiveness of conventional antidepressants and heightened vulnerability to adverse effects among older adults. Ketamine and esketamine have emerged as rapid-acting antidepressants, but their efficacy and safety in geriatric populations remain incompletely characterised. A systematic review and meta-analysis were conducted to evaluate ketamine and esketamine for TRD in adults aged ≥65 years. Thirteen primary studies published between 2023 and 2025 were included. Standardised mean change (SMC) was used to estimate antidepressant effects, while adverse events (AEs) and discontinuation rates were synthesised using random-effects models. Risk of bias was assessed using ROBINS-I and RoB 2 tools, and publication bias was evaluated through funnel plot analysis. Ketamine and esketamine produced large and clinically meaningful reductions in depressive symptoms, with a pooled SMC of −1.68 (95% CI −1.85 to −1.51). Approximately 47 per cent of older adults experienced at least one AE, although most events were mild. Discontinuation due to AEs was low, with a pooled rate of 16 per cent (95% CI 0.14–0.18). Risk-of-bias assessments varied across studies, but randomised trials demonstrated consistently low risk. Funnel plot analysis revealed no evidence of significant publication bias. Ketamine and esketamine appear to be effective and reasonably well tolerated in older adults with TRD. Further geriatric-focused randomised trials are needed to refine dosing, monitor long-term outcomes, and guide clinical decision-making.