Esketamine vs Midazolam in Boosting the Efficacy of Oral Antidepressants for Major Depressive Disorder: A Pilot Randomized Clinical Trial

IMPORTANCE: Loss of a previously effective response while still using adequate antidepressant treatment occurs in a relatively high proportion of patients with major depressive disorder (MDD); therefore, there is a need to develop novel effective treatment strategies. OBJECTIVE: To assess the efficacy and safety of a single subanesthetic dose of esketamine in boosting the efficacy of oral antidepressants for treating fluctuating antidepressant response in MDD. DESIGN, SETTING, AND PARTICIPANTS: This single-center, double-blind, midazolam-controlled pilot randomized clinical trial was conducted at Beijing Anding Hospital, Capital Medical University in China. The study enrolled participants aged 18 years and older with fluctuating antidepressant response, defined as patients with MDD experiencing fluctuating symptoms after symptom relief and stabilization. Patient recruitment was conducted from August 2021 to January 2022, and participants were followed-up for 6 weeks. Data were analyzed as intention-to-treat from July to September 2022. INTERVENTIONS: All participants in the esketamine-treated group received intravenous esketamine at 0.2 mg/kg in 40 minutes. Participants in the midazolam control group received intravenous midazolam at 0.045 mg/kg in 40 minutes. MAIN OUTCOMES AND MEASURES: The primary outcome was the response rate at 2 weeks, defined as a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary outcomes included response rate at 6 weeks, remission rates at 2 and 6 weeks, and change in MADRS and Clinical Global Impression–Severity score from baseline to 6 weeks; remission was defined by a MADRS score of 10 or lower. RESULTS: A total of 30 patients (median [IQR] age, 28.0 [24.0-40.0] years; 17 [56.7%] female) were randomized, including 15 patients randomized to midazolam and 15 patients randomized to esketamine; 29 patients completed the study. Response rates at 2 weeks were significantly higher in the esketamine-treated group than in the midazolam control group (10 patients [66.7%] vs 1 patient [6.7%]; P < .001). Participants treated with esketamine experienced significantly greater reduction in MADRS score from baseline to 2 weeks compared with those treated with midazolam (mean [SD] reduction, 15.7 [1.5] vs 3.1 [1.3]; P < .001). No serious adverse events were observed in this trial, and no psychotogenic effects and clinically significant manic symptoms were reported. CONCLUSIONS AND RELEVANCE: This pilot randomized clinical trial found that a single subanesthetic dose of esketamine could boost the efficacy of oral antidepressants in treating fluctuating antidepressant response, with a good safety profile. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR2100050335