Effects of Ketamine Anesthesia on Efficacy, Tolerability, Seizure Response, and Neurocognitive Outcomes in Electroconvulsive Therapy A Comprehensive Meta-analysis of Double-Blind Randomized Controlled Trials

Electroconvulsive therapy (ECT) remains the most effective treatment for major depressive disorder. Ketamine is an anesthetic gaining attention for its rapid antidepressant effect. Numerous randomized controlled trials have investigated the effect of ketamine anesthesia in ECT on various clinical outcomes. Previous systematic reviews have not found benefit for overall depression response, although some have found evidence of benefit early in the ECT course. Clear quantitative conclusions have not been established regarding other outcomes, particularly while only using data from high-quality studies. We aimed to examine all data from double-blind randomized controlled trials comparing ketamine to other anesthetics via meta-analysis, to make recommendations regarding ECT practice and future research. Data were extracted for depressive symptoms, seizure duration and electrical dose, neuropsychological performance, and adverse effects. Effect sizes were calculated using Hedge'sgand odds ratios. Eighteen studies (n = 915) were included in the meta-analysis. Ketamine was not found to enhance improvement of depressive symptoms, either early in ECT course or at end of study. Ketamine had a large effect on increasing seizure duration both overall (Hedge'sg= 0.71,P= 0.038) and in the subgroup receiving ketamine in combination with another anesthetic (Hedge'sg= 0.78,P< 0.01), and on decreasing electrical dose (Hedge'sg= 1.98,P= 0.039). There was no significant effect of ketamine on any individual neuropsychological domain. Ketamine was not associated with increased adverse effects, except for hypertension in patients receiving ketamine monotherapy. Significant heterogeneity was present for many outcomes, and sensitivity analyses suggested a relation to methodological variation in most cases. This study supports the finding that ketamine does not enhance ECT's antidepressant effect, including on early improvement, but provides substantial evidence for enhancing seizure duration and reducing electrical dose. No significant benefit was found on neurocognitive outcomes, but analysis was limited by small sample sizes and high heterogeneity. Ketamine is generally safe in ECT, particularly as a coanesthetic. Our findings provide meta-analytic support to the recommendations in ECT clinical guidelines for use of coadjuvant ketamine in ECT where seizures are suboptimal. Further studies targeting neurocognitive outcomes are encouraged.