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This randomized controlled pilot study examines the differences in response to electroconvulsive therapy (ECT) as defined by an improvement of depressive symptoms between ketamine and methohexital as the primary anesthetic agent. Adverse effects and cognitive tolerability were also examined.Subjects undergoing ECT for unipolar or bipolar depression were randomized to receive ketamine or methohexital as the anesthetic agent. Primary outcome measure includes the Hamilton rating scale for depression (17-item). Secondary outcome measures included the mini-mental status examination and Beck depression inventory. All ratings were conducted masked to anesthetic agent. Because of multiple outcome measures obtained over time, mixed models were used to account for the correlations among the measurements within the subjects. Because outcomes were either normally distributed or approximately normally distributed, general linear mixed models were fit with a random intercept specified.A total of 21 subjects were enrolled, and 16 were randomized (methohexital, n = 8; ketamine, n = 8). The 2 treatment groups did not differ statistically in any demographic characteristic. No statistical difference was found between the ketamine and methohexital groups for an improvement in depressive symptoms (P = 0.6); however, subjects in both groups showed significant improvement in depression over time (ketamine, P < 0.0001; methohexital, P < 0.0001). Mini-mental status examination results did not differ between groups, and fatigue was reported more in subjects receiving ketamine (P = 0.03).The results of this pilot study are inconclusive because they lack power to support an advantage of ketamine anesthesia compared with methohexital in ameliorating depressive symptoms for electroconvulsive therapy.