Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study

Background: Seltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD). Methods: To replicate and extend this observation, a double-blind, adaptive dose-finding study was performed in patients with MDD who had an inadequate response to 1-3 selective serotonin/serotonin-norepinephrine reuptake inhibitors in the current episode. Patients were randomized (2:1:1) to placebo or seltorexant (20 mg or 40 mg) once-daily, administered adjunctively to the antidepressant the patient had been receiving at screening. After an interim analysis (6 weeks postrandomization of 160th patient), newly recruited patients randomly received (3:3:1) placebo or seltorexant 10 mg or 20 mg; the 40-mg dose was no longer assigned. Patients were stratified by baseline Insomnia Severity Index (ISI) scores (ISI >= 15 vs <15). The primary endpoint was change from baseline Montgomery-Asberg Depression Rating Scale (MADRS) total score at week 6. Results: Mixed-Model for Repeated Measures analysis showed a greater improvement in MADRS total score in the seltorexant 20-mg group vs placebo at weeks 3 and 6; least-square means difference (90% CI): -4.5 (-6.96; -2.07), P = .003; and -3.1 (-6.13; -0.16), P = .083, respectively. The improvement in MADRS score at week 6 for seltorexant 20 mg was greater in patients with baseline ISI >= 15 vs those with ISI < 15; least-square means difference (90% CI) vs placebo: -4.9 (-8.98; -0.80) and -0.7 (-5.16; 3.76), respectively. The most common (>= 5%) adverse events with seltorexant were somnolence, headache, and nausea. Conclusions: A clinically meaningful reduction of depressive symptoms was observed for seltorexant 20 mg. In the subset of patients with sleep disturbance (ISI >= 15), a larger treatment difference between seltorexant 20 mg and placebo was observed, warranting further investigation. No new safety signal was identified.