Comparative safety and tolerability of ketamine and esketamine for major depressive disorder: a systematic review and meta-analysis.

A systematic review and meta-analysis of 47 studies found that both ketamine and esketamine are associated with a higher rate of adverse events than placebo in treating major depressive disorder, but serious adverse events were not significantly increased. Common side effects include dizziness, dissociation, nausea, vertigo, and blurred vision, which are dose-dependent and transient. Esketamine showed a potential tolerability advantage over ketamine, with higher number needed to harm values, meaning fewer people experience side effects per dose. No significant long-term issues were found for cognitive function, bladder symptoms, or addiction-related measures. Direct head-to-head trials are needed to confirm these findings.

Study at a glance

Abstract

Ketamine and esketamine have demonstrated rapid, short-term antidepressant effects in major depressive disorder (MDD), but their relative safety remains unclear. This review aims to update the evidence on the safety of two agents for MDD and indirectly compare their safety and tolerability. We systematically searched PubMed, PsycINFO, Embase, and Cochrane databases up to 1 May 2025. Eligible studies compared ketamine or esketamine with placebo, active psychotropic agents, or electroconvulsive therapy in adults with MDD. We retrieved 5,473 articles, 47 of which met the inclusion criteria. For ketamine versus placebo, both dropout and incidence rates of adverse events (AEs) were statistically significant, with number needed to harm (NNH) values of 12 and 2, respectively. A similar pattern of effect sizes was found for esketamine, but with higher corresponding NNH values. Conversely, neither the meta-analysis nor NNH analyses of the incidence of serious AEs for ketamine and esketamine were statistically significant. A series of AEs like dizziness, dissociation, nausea, vertigo, and vision blurred, with relatively low NNH values, would be more likely to occur in clinical practice and exhibit dose-dependent effects. Moreover, ketamine or esketamine was associated with transient and significant psychiatric side-effects, blood pressure increases, and sedation post-dose. No significant abnormalities were observed in cognitive impairments, laboratory results, bladder symptoms, nasal examination, or addiction-related evaluations for either drug. Although further promising evidence supports the safety of ketamine and esketamine for MDD, the findings of this study highlight a potential tolerability advantage with esketamine over ketamine for short-term use for MDD. These findings require further validation through direct head-to-head clinical trials comparing these two drugs. https://www.crd.york.ac.uk/PROSPERO/view/CRD42023389486.