Association between Intravenous Ketamine Treatment and Cognitive Function in Patients with Treatment-Resistant Depression: A Double-Blind, Randomized, Placebo-Controlled Trial
Kie Nomoto, Yohei Ohtani, Taisuke Yatomi, Kengo Yonezawa, Sota Tomiyama, Nobuhiro Nagai, Keisuke Kusudo, Shiori Honda, Sotaro Moriyama, Shinichiro Nakajima, Mié Matsui, Takashige Yamada, Hiroshi Morisaki, Kimio Yoshimura, Tsuyoshi Eiro, S Tsugawa, Sadamitsu Ichijo, Yu Fujimoto, Tomoyuki Miyazaki, Takuya Takahashi, Hiroyuki Uchida, Hideaki Tani
Pharmacopsychiatry July 7, 2026 Peer reviewed DOI: 10.1055/a-2894-5681 via OpenAlex
Summary
Ketamine treatment did not significantly affect cognitive function compared to a placebo in patients with treatment-resistant depression (TRD). In this study involving 34 Japanese patients, both objective and subjective cognitive scores showed no notable changes post-treatment. However, ketamine responders reported improved subjective cognitive function relative to non-responders. Additionally, those with lower baseline inhibitory control experienced greater reductions in depression symptoms after treatment.
Study at a glance
| Design | double-blind, randomized, placebo-controlled trial |
|---|---|
| Sample size | 34 |
| Population | Japanese patients with treatment-resistant depression |
| Key finding | Repeated ketamine administration did not significantly deteriorate cognitive function compared to placebo. |
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.