Comparative safety and tolerability of ketamine and esketamine for major depressive disorder: a systematic review and meta-analysis.
Frontiers in pharmacology – January 01, 2025
Source: PubMed
Summary
Remarkably, serious adverse events are not significantly more common when treating major depressive disorder with certain new therapies. A comprehensive meta-analysis investigated the safety of esketamine and ketamine for unipolar depression. Systematically reviewing many studies, it found both drugs can cause transient side effects like dizziness and temporary blood pressure changes. However, they demonstrate a positive safety profile overall, with no significant long-term issues regarding cognitive function, addiction, or organ health observed. Esketamine showed a potential tolerability advantage over ketamine for short-term use, offering promising options for patients.
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.