AbstractIntroductionSeltorexant, a potent and selective orexin-2 receptor antagonist is being developed as an adjunctive treatment for major depressive disorder (MDD). On-road driving performance was evaluated in adults and elderly with MDD taking an antidepressant (SSRI/SNRI) and in healthy elderly participants following bedtime administration of seltorexant.MethodsThis was a randomized, double-blind, placebo- and positive-controlled 4 way crossover study in 37 adults with MDD taking an antidepressant (SSRI/SNRI) and 26 elderly participants (n=19 with MDD; n=7 healthy). Study treatments were administered at bedtime for eight consecutive days: 2 dose levels of seltorexant (20-or 40-mg), zopiclone 7.5-mg on Days 1 and 8, or placebo. Driving performance was assessed on days 2 and 9 (9h post-dose) using a 1-hour standardized highway driving test (~100 km) in normal traffic, measuring standard deviation of lateral position (SDLP, weaving of car). Drug–placebo difference in SDLP of ≥2.4 cm was considered to reflect clinically meaningful driving impairment.ResultsMean SDLP differences between drug and placebo following seltorexant 20-mg and 40-mg on days 2 and 9 were very small and the upper limits of the 2-sided 95%CI were below the threshold of 2.4 cm (least-square mean [95%CI] 20 mg: −0.1 [−0.80, 0.57] cm, Day 2; −0.2 [−0.81, 0.46], Day 9; 40-mg: 0.4 [−0.27, 1.12], Day 2; 0.6 [−0.14, 1.25], Day 9), suggesting no clinically relevant changes in driving performance in adults and elderly with MDD. Similar results for SDLP were noted for other populations (adults with MDD, elderly, all participants). Assay sensitivity was demonstrated using the positive control, zopiclone, which caused impaired on-road driving performance as measured by the SDLP (least-square mean [95%CI] Day 2: 2.8 [1.99, 3.59] cm, Day 9: 2.7 [1.76, 3.60] cm; lower limits of the 2-sided 95% CI were >0 cm). Most TEAEs were mild or moderate in severity and no new safety issues emerged.ConclusionSeltorexant 20-mg and 40-mg administered as single and multiple doses had no clinically meaningful negative effects on next morning driving performance in adults and elderly with MDD taking an antidepressant (SSRI/SNRI) and healthy elderly participants as assessed by mean changes in SDLP relative to placebo.Support (if any)