Ketamine and Esketamine for Late-Life Depression: A Systematic Review of Efficacy, Safety, and Tolerability

Ketamine has emerged as a promising treatment for major depression, though its efficacy and safety remain incompletely characterized in older adults. This systematic review synthesizes current evidence for ketamine in geriatric depression. A search of PubMed, EMBASE, and PsycINFO was conducted. Prospective clinical trials were included, with age restriction to participants ≥60 years applied at full-text review to capture subgroup data. Thirteen studies met inclusion criteria, comprising 757 adults. Studies examined intranasal (n = 5), intravenous (n = 4), subcutaneous (n = 1), and oral (n = 1) ketamine formulations, as well as ketamine combined with ECT (n = 2). Antidepressant efficacy findings were mixed; with preliminary findings of symptomatic improvement in this difficult to treat disease state, although not all studies reported out positive outcomes. Adverse events were generally mild to moderate and discontinuation due to side effects was rare. Cognitive outcomes were mostly stable or improved, though long-term studies noted small declines in reaction time. Ketamine as an ECT anesthetic did not enhance antidepressant outcomes. Evidence certainty was very low to low; findings were limited by small samples, open-label designs, and inconsistent age-stratified reporting.