Seltorexant Well-Tolerated in Adolescents as an Adjunct Treatment for Major Depressive Disorder

New exploratory phase 1b data on seltorexant as an adjunct treatment for adolescents with major depressive disorder showed a favorable safety profile and similar pharmacokinetic exposure compared with adults taking seltorexant.¹ Results of this new study were presented by Johnson & Johnson at the 2025 European College of Neuropsychopharmacology Annual Congress in Amsterdam.

The study presented was an exploratory, double-blind, randomized, placebo-controlled design, with 30 adolescent (aged 12-18) participants. Fifty-two participants were planned to enroll, with 30 ultimately receiving the drug or placebo for the study. Participants had a DSM-5 diagnosis of major depressive disorder, an inadequate response to selective serotonin reuptake inhibitors, and a Children’s Depression Rating Scale-Revised score of 40 or greater. Unstable psychiatric or medical comorbidities (like primary anxiety disorder, autism spectrum disorder, and borderline personality disorder) were considered exclusionary.

Participants were randomized 3:1 to receive seltorexant (10 mg or 20 mg dose based on weight) or placebo for 6 weeks, in addition to baseline standard antidepressant therapy. Twenty-three participants received seltorexant and 7 received placebo. Approximately 56.7% of participants were already taking fluoxetine and 36.7% were taking escitalopram at baseline. Sparse pharmacokinetic sampling was collected for every participant, and optimal pharmacokinetic sampling was set for a subgroup of participants. Safety and tolerability were measured by adverse events, concomitant medications, physical examinations, vital signs, Columbia Suicide Severity Rating Scale, electrocardiogram, and laboratory tests.

Nine participants receiving seltorexant and 2 participants receiving placebo reported treatment emergent adverse events. The most common adverse events were headache, diarrhea, and nausea. One patient receiving seltorexant reported increased suicidal ideation, which investigators noted may have been related to change in the patient’s standard antidepressant therapy. No serious adverse events or deaths were reported.

Plasma concentration of seltorexant was available in 16 participants at interim analysis (n=15 from 20mg seltorexant group and n=1 from 10mg seltorexant group), and data collected were consistent with population pharmacokinetic models. The unbound steady state exposure (AUC0-24h,ss) from the model was comparable between adolescents and adults, with a GMR (90% CI) of 0.91 (0.798;1.04) for free seltorexant.

Seltorexant is a selective orexin-2 receptor antagonist, currently in development as an adjunct to standard antidepressant therapy to treat major depressive disorder with insomnia and suboptimal antidepressant therapy response. Seltorexant has previously been studied for efficacy and safety in adults, with an ongoing phase 3 trial evaluating the drug in adult and older adult populations.²

The study was ultimately terminated early due to low participant enrollment and interim analysis showing similar seltorexant safety and tolerability for adolescents. Results from this study did not yield any new safety information about the drug, and current information supports continued research and development of seltorexant for adolescents.

References

1. Mesens S, Crauwels H, Bartolucci R, et al. Seltorexant: a safe and well-tolerated adjunctive treatment for adolescent major depressive disorder with comparable pharmacokinetics to adults. Poster presented at: 38th European College of Neuropsychopharmacology Annual Congress; October 11-14, 2025; Amsterdam, The Netherlands. Accessed October 13, 2025.

2. Phase 3 study of adjunctive treatment with seltorexant in adult and elderly participants with major depressive disorder and insomnia symptoms. Last updated: October 10, 2025. Accessed October 13, 2025. https://clinicaltrials.gov/study/NCT06559306