New Poster Data: Seltorexant Compared With Quetiapine XR as Adjunctive Treatment for MDD With Insomnia Symptoms

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CONFERENCE REPORTER

Investigators presented new phase 3 data on seltorexant compared with quetiapine extended release (XR) as adjunctive treatment for major depressive disorder (MDD) with insomnia symptoms at the 2025 Psych Congress in San Diego, CA. While seltorexant did not meet the primary endpoint of a recent phase 3 study, it may still effectively address an important unmet medical need in MDD.¹

Seltorexant is a first-in-class, selective, high-affinity, orexin-2 receptor antagonist that treats depression symptomsby normalizing manifestations of hyperarousal and promoting physiological sleep. According to results of a recent phase 2 study, seltorexant demonstrated antidepressant effects compared placebo in participants with MDD, particularly in those with insomnia symptoms.²

In the phase 3, international, double-blind, active-controlled trial (NCT04513912), investigators evaluated the use of seltorexant 20 mg or quetiapine XR (labeled dosage) once daily for 26 weeks, in participants with MDD and insomnia symptoms and inadequate response to 1 to 2 antidepressants. Participants aged 18-74 were randomly assigned (1:1) to receive either seltorexant or quetiapine XR while continuing use of their background SSRI/SNRI. The primary efficacy endpoint was response rate defined as ≥50% improvement from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 26. Participants who discontinued early were counted as nonresponders. Comparison between treatment groups was based on stratified Cochran–Mantel–Haenszel test adjusted for region, age group, and baseline rumination level.

Other efficacy endpoints included change from baseline to week 26 in total body weight, in MADRS total score, change from baseline to week 26 in Patient Health Questionnaire-9 (PHQ-9) total score, and change from baseline to week 26 in Patient-Reported Outcome Measurement Information System-Sleep Disturbance (PROMIS-SD) T- score. Investigators based comparison between treatment groups on mixed model for repeated measures with treatment, country, age group, baseline rumination level, time, and time-by-intervention interaction as factors and baseline weight, MADRS total score, PHQ-9 total score, or PROMIS-SD T-score as a covariate.

At week 26, seltorexant showed a numerically greater response rate (57.4%) than quetiapine XR (53.4%), but this difference was not statistically significant (4.0% [95% CI: -3.3, 11.3]). As to secondary endpoints, mean change from baseline to week 26 in total body weight (kg) was 0.5 (2.89) for seltorexant and 2.1 (3.93) for quetiapine XR; mean change from baseline to week 26 in MADRS total score was -23.0 (10.12) for seltorexant and -22.7 (9.54) for quetiapine XR; mean change from baseline to week 26 in PHQ-9 was -12.1 (6.36) for seltorexant and -12.5 (5.95) for quetiapine XR; and mean change from baseline to week 26 in PROMIS-SD T-score was -20.18 (11.70) for seltorexant and -21.07 (11.27) for quetiapine XR.

Although 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 development as a potential adjunctive treatment option in MDD.

As to safety profile, the overall rates of treatment-emergent adverse event and treatment-emergent adverse events leading to study intervention discontinuation were lower for seltorexant compared with quetiapine XR. Treatment-emergent adverse events (≥5% of participants) that were 2 times as common with quetiapine XR compared with seltorexant were somnolence, increased weight, and dry mouth.

Overall, these and prior findings, alongside the novel targeted mechanism of action, suggest that seltorexant may still effectively address an important unmet medical need in MDD, despite not achieving statistical significance.

References

1. Flossbach Y, Mesens S, Pandina G, et al. Seltorexant versus quetiapine extended release as adjunctive treatment in major depressive disorder with insomnia symptoms: phase 3 trial. Poster presented at: Psych Congress; September 17-21, 2025; San Diego, CA. Accessed September 18, 2025.

2. Savitz A, Wajs E, Zhang Y, et al. Efficacy and safety of seltorexant as adjunctive therapy in major depressive disorder: a phase 2b, randomized, placebo-controlled, adaptive dose-finding study. Int J Neuropsychopharmacol. 2021;24(12):965-976.