Association between Intravenous Ketamine Treatment and Cognitive Function in Patients with Treatment-Resistant Depression: A Double-Blind, Randomized, Placebo-Controlled Trial

In a double-blind, randomized, placebo-controlled trial, 34 Japanese patients with treatment-resistant depression received four intravenous doses of either ketamine (0.5 mg/kg) or saline. No significant differences emerged between the groups on objective or subjective cognitive function measures. Among ketamine-treated patients, those who responded to treatment (at least 50% reduction on the Montgomery-Åsberg Depression Rating Scale) showed greater improvement in subjective cognitive function than non-responders. Participants with weaker inhibitory control at baseline experienced larger reductions in depressive symptoms after ketamine. Repeated ketamine administration did not worsen cognitive function compared to placebo, suggesting cognitive safety, and baseline cognitive control deficits may predict better treatment response.

Study at a glance

Abstract

Introduction: While the rapid and robust effects of ketamine on depressive symptoms in treatment-resistant depression (TRD) have been demonstrated, the influence of ketamine treatment on cognitive function has not yet been fully elucidated. We aimed to evaluate the effects of ketamine treatment on cognitive function as part of a study that investigated the efficacy of repeated ketamine administration in patients with TRD. In addition, we conducted an exploratory analysis to examine whether baseline cognitive function was associated with ketamine response. Methods: In this double-blind, randomized, placebo-controlled study, 34 Japanese TRD patients were enrolled and assigned randomly into either ketamine or placebo group. They received ketamine 0.5 mg/kg or saline intravenously for four doses. Objective and subjective cognitive functions were evaluated with a comprehensive assessment battery before and after the intervention. We also assessed depressive symptoms with the Montgomery-Åsberg Depression Rating Scale (MADRS). The response was defined by at least a 50% reduction in the total MADRS score. Results: No significant differences were found between the ketamine and placebo groups on objective or subjective cognitive function scale score changes. Moreover, ketamine responders showed a significant improvement in subjective cognitive function compared to non-responders. The participants who demonstrated less inhibitory control at baseline showed greater MADRS score reductions after the ketamine treatment. Discussion: Repeated ketamine administration did not significantly deteriorate cognitive function compared to placebo, which supports a possible cognitive safety profile in patients with TRD. In addition, baseline impaired cognitive control may be associated with ketamine response.