Effect of Benzodiazepines on Esketamine Nasal Spray for Treating Patients With Major Depressive Disorder With Active Suicidal Ideation and Intent

Aim: To examine potential effects of concomitant benzodiazepines on the safety and efficacy of esketamine nasal spray following first-dose treatment of patients in urgent need of symptom control.

Methods: Post-hoc analyses of pooled data from two randomized, double-blind studies of esketamine (ASPIRE-I, ASPIRE-II) were performed. Adults with major depressive disorder (MDD) and active suicidal ideation with intent were randomized to placebo or esketamine 84mg nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care (initial hospitalization and newly-initiated or optimized oral antidepressant[s]). Efficacy and safety were each analyzed in patients using versus not using benzodiazepines.

Results: Most patients (309/451, 68.5%) used concomitant benzodiazepines. Mean Montgomery-Asberg Depression Rating Scale (MADRS) total score decreased from baseline to 24-hours post-first dose (primary efficacy endpoint) in both treatment groups, with greater improvement in depressive symptoms among patients treated with esketamine/standard-of-care versus placebo/standard-of-care. The between-group difference favored esketamine over placebo among patients using benzodiazepines (difference of least squares, LS, means [95% CI]: -4.3 [-6.63, -1.89]) and also among patients not using benzodiazepines ( 3.1 [-6.62, 0.45]). In the esketamine/standard-of-care group, decrease in MADRS total score was greater among patients not using benzodiazepines (mean [SD]: -16.8 [12.82]) versus using benzodiazepines (-15.8 [11.27]) (difference of LS means [95% CI], 1.1 [-2.24, 4.45]). Among esketamine-treated patients, incidence of sedation was higher with benzodiazepine use (8.1% vs. 1.3%), whereas incidence of dissociation was similar (32.0% vs. 26.6%).

Conclusions: Benzodiazepines do not attenuate or enhance the rapid antidepressant effect of esketamine among MDD patients with active suicidal ideation and intent.