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

backgroundSeltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD).

methodsTo 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 post-randomization 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-Åsberg Depression Rating Scale (MADRS) total score at week 6.

resultsMixed-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.

conclusionsA 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. REGISTRATION: ClinicalTrials.gov Identifier: NCT03227224. PREVIOUS PRESENTATION: Poster presented at 58th Annual Meeting of American College of Neuropsychopharmacology (ACNP), December 8-11, 2019, Orlando, FL.