Esketamine vs Midazolam in Boosting the Efficacy of Oral Antidepressants for Major Depressive Disorder

Abstract

ImportanceLoss 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.ObjectiveTo 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 ParticipantsThis 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.InterventionsAll 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 MeasuresThe 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.ResultsA 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 RelevanceThis 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 RegistrationChinese Clinical Trial Registry Identifier: ChiCTR2100050335

Case report: Dezocine’s rapid and sustained antidepressant effects

“…Given the clinical observation that the efficacy of serotonin-norepinephrine reuptake inhibitors, blocking the activity of NET and SERT, is often delayed, the rapid antidepressant effect of dezocine may be associated with opioidergic modulation rather than monoaminergic systems alone. Synergistic potentiation between the opioidergic and monoaminergic systems cannot be excluded, especially given the evidence that ketamine can expedite the antidepressant onset of escitalopram and boost its efficacy ( Xiao et al, 2023 ). The sustained antidepressant effects of dezocine, with an average terminal half-life of approximately 2.4 h, raise questions as to whether this reflects placebo effects, reactivation of antidepressants, slow metabolism subsequent to receptor occupancy similar to ketamine ( Ma et al, 2023 ), warranting further investigation.…”