Safety, tolerability, and preliminary efficacy of seltorexant versus quetiapine extended release as adjunctive therapy in major depressive disorder: a randomized, flexible-dose, 6-month, parallel-group, exploratory study

Int J Neuropsychopharmacol. 2026 Mar 9:pyag009. doi: 10.1093/ijnp/pyag009. Online ahead of print.

ABSTRACT

IMPORTANCE: Seltorexant, a selective orexin-2 receptor (OX2R) antagonist, has demonstrated antidepressant effects in major depressive disorder (MDD), particularly among patients with higher baseline insomnia symptoms.

OBJECTIVE: To investigate flexibly dosed seltorexant vs flexibly dosed quetiapine extended release (quetiapine-XR) as adjunctive treatment to a selective serotonin (SSRI) or serotonin-norepinephrine (SNRI) reuptake inhibitor.

SETTING: Outpatient.

DESIGN: Randomized, active-controlled, multicenter, exploratory phase 2 study with screening (≤4 weeks), double-blind treatment (24 weeks), and post-treatment follow-up (2 weeks) phases.

PARTICIPANTS: Patients with MDD and inadequate response to 1-3 SSRIs/SNRIs, including an ongoing SSRI/SNRI, in the current depressive episode.

INTERVENTIONS: Flexibly dosed seltorexant (20 or 40 mg) or quetiapine-XR (150 or 300 mg, with 2-day initial dosing of 50 mg) once daily as adjunctive therapy to an SSRI/SNRI. Randomization (1:1) was stratified by baseline Insomnia Severity Index total score (≥15 vs <15). Safety, tolerability, and preliminary efficacy were evaluated.

MAIN OUTCOMES AND MEASURES: Primary efficacy endpoint was time to all-cause study drug discontinuation. Secondary efficacy endpoints included change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Subgroup analyses included MADRS change by mode dose (MD; most frequent daily dose received by a patient during the study). Safety and tolerability also were assessed.

RESULTS: Time to all-cause discontinuation (estimated 25th percentile [80% CI]: seltorexant, 62 [38, 83] days vs quetiapine-XR, 42 [35, 61] days; hazard ratio [80% CI]: 0.83 [0.6, 1.2]) and all-cause discontinuation (seltorexant, 41.2% vs quetiapine-XR, 47.1%; 2-sided p=.5355) did not differ significantly between treatment groups. For the seltorexant 20-mg MD group, MADRS total scores consistently improved over time and reductions were numerically greater at Weeks 18 and 24 versus the seltorexant 40-mg MD and the combined quetiapine-XR groups, and patients with higher baseline insomnia symptoms had greater improvement in MADRS total score, consistent with prior studies showing efficacy at 20 but not 40 mg (Savitz, et al. 2019; Mesens, et al. 2025). Treatment-emergent adverse event rates were 65.4% for seltorexant and 80.8% for quetiapine-XR.

CONCLUSIONS AND RELEVANCE: Results support the favorable tolerability and preliminary efficacy of seltorexant 20 mg daily as adjunctive treatment in patients with MDD, especially those with insomnia symptoms, and suggest potential approaches to differentiate seltorexant from quetiapine-XR in future adequately powered studies. Trial registration. Clinicaltrials.gov identifier: NCT03321526.

PMID:41795948 | DOI:10.1093/ijnp/pyag009