New Data Show Seltorexant Comparable to Quetiapine XR in Major Depressive disorder, Despite Missing Statistical Meaning
SAN DIEGO, CA – September 21, 2025 - A phase 3 trial presented at Psych Congress this week indicates that seltorexant demonstrated comparable efficacy to quetiapine extended-release (XR) as an adjunctive treatment for major depressive disorder (MDD) in patients experiencing insomnia symptoms.While the study did not meet its primary endpoint of statistically significant response rate difference,researchers highlighted seltorexantS enhanced safety and tolerability profile as a potential benefit.
The study compared seltorexant to quetiapine XR in adult participants with MDD and insomnia. participants who discontinued early were classified as nonresponders. The primary endpoint, response rate as measured by a ≥50% reduction from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, showed a numerically higher rate with seltorexant (57.4%) versus quetiapine XR (53.4%), but the difference of 4.0% did not reach statistical significance (95% CI: -3.3, 11.3). Statistical comparison utilized a stratified Cochran-Mantel-Haenszel test adjusted for region, age group, and baseline rumination level.
Secondary efficacy endpoints, assessed via mixed model for repeated measures, included changes from baseline to week 26 in total body weight, MADRS total score, Patient Health Questionnaire-9 (PHQ-9) total score, and patient-Reported Outcome Measurement Details System-Sleep Disturbance (PROMIS-SD) T-score. Mean changes observed were: 0.5 (2.89) kg for seltorexant versus 2.1 (3.93) kg for quetiapine XR in weight; -23.0 (10.12) versus -22.7 (9.54) for MADRS total score; -12.1 (6.36) versus -12.5 (5.95) for PHQ-9; and -20.18 (11.70) versus -21.07 (11.27) for PROMIS-SD T-score.
Investigators reported that overall rates of treatment-emergent adverse events and discontinuation due to adverse events were lower with seltorexant. Specifically, treatment-emergent adverse events occurring at a rate at least two times higher with quetiapine XR compared to seltorexant included somnolence, increased weight, and dry mouth.
“Even though the primary endpoint was not met, seltorexant showed comparable efficacy to quetiapine XR, and with enhanced safety and tolerability, which indicates a favorable benefit-risk balance for further progress as a potential adjunctive treatment option in MDD,” researchers concluded.
These findings build upon previous research, including a phase 2b study published in International Journal of Neuropsychopharmacology in 2021 (Savitz A, et al.). The novel mechanism of action of seltorexant suggests it may address an unmet need in MDD, despite the lack of statistical significance in this trial.
