EFFICACY AND SAFETY OF INTRAVENOUS KETAMINE TREATMENT IN JAPANESE PATIENTS WITH TREATMENT-RESISTANT DEPRESSION: A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL
Authors: Ohtani *Yohei , Tani Hideaki , Nomoto-Takahashi Kie , Yatomi Taisuke , Yonezawa Kengo , Tomiyama Sota , Nagai Nobuhiro , Kusudo Keisuke , Honda Shiori , Nakajima Shinichiro , Eiro Tsuyoshi , Miyazaki Tomoyuki , Takahashi Takuya , Uchida Hiroyuki 
Published: February 2025

Abstract

Background
Whereas ketamine's antidepressant effect for treatment-resistant depression (TRD) has been consistent in the literature from the North American and European countries (1-3), its evidence is scarce among the Asian population (4-6).

Aims & Objectives
We aimed to evaluate the efficacy and safety of intravenous ketamine treatment in Japanese patients with TRD.

Method
In this double-blind randomized placebo-controlled trial, 34 Japanese patients (41.4±9.4 years, 23 men [67.6%]) with TRD were randomized to receive either intravenous ketamine (0.5 mg/kg) or placebo, administered over 40 minutes, twice a week, for two weeks. The primary outcome measure was the change from baseline to post-treatment in the Montgomery-Å sberg Depression Rating Scale (MADRS) total score. Moreover, changes and percent changes in depressive symptomatology scores measured with 17-item Hamilton Depression Rating Scale (HDRS-17), Quick Inventory of Depressive Symptoms Self-Rated (QIDS-SR), 6-item Hamilton Depression Rating Scale (HDRS-6), and rates of remission (i.e., a 10 or less on the MADRS total score), response (i.e., a 50% or more reduction from baseline in the MADRS total score), and partial response (i.e., a 25% or more reduction from baseline in the MADRS total score) were compared between the groups. The values of interest were analyzed on an intention-to-treat (ITT) or per-protocol (PP) basis. Baseline values were used as endpoint values for dropouts in ITT analysis whereas only completers were analyzed in PP analysis. Multiple and logistic regression analyses were conducted to explore the demographic and clinical characteristics associated with the change in the MADRS total score and presence of remission, response, and partial response to ketamine, respectively.

Results
There was no significant reduction in the MADRS total score between the ketamine (n=17) and placebo (n=17) groups on ITT analysis (-8.1 ± 10.0 vs -2.5 ± 5.2, p=0.052); however, there was a significant reduction in the ketamine group (n=15) compared to the placebo group (n=16) on PP analysis (-9.1 ± 10.2 vs -2.7 ± 5.3, p=0.034). Moreover, the ketamine group showed superiority in the percent change in the MADRS score on PP analysis and the HDRS-17 and HDRS-6 scores on ITT and PP analysis. No significant superiority was observed in other outcome measures in the ketamine group compared to the placebo group. Treatment-emergent adverse events were more frequent in the ketamine group than in the placebo group, whereas no serious adverse events were reported. Multiple regression analysis revealed that body mass index and MADRS total score at baseline were negatively associated with the change in the MADRS total score (beta=-0.42, p=0.045; beta=-0.31, p=0.039, respectively). Logistic regression analysis did not find any factor in association with presence of remission, response, nor partial response.

Discussion & Conclusion
The present study demonstrated that the intravenous ketamine treatment outperformed the placebo in alleviating depressive symptoms in Japanese patients with TRD who completed the study, especially in patients with high body mass index and severe symptomatology at baseline. This study suggests that the intravenous ketamine treatment may benefit Asian patients with TRD. Since ethnic differences could impact clinical response (7, 8), further investigations are warranted in populations with various ethnic backgrounds.

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