Evaluating seltorexant as a treatment option for major depressive disorder.
INTRODUCTION Major depressive disorder is a leading cause of disability, with a significant rate of patients responding inadequately to antidepressants, and residual symptoms, including insomnia, worsening overall outcomes. Current adjunctive options display partial efficacy and tolerability, motivating the search for different strategies. Beyond regulating the sleep-wake cycle, orexin systems are implicated in reward and cognition, and have emerged as new targets for depressive disorders. AREAS COVERED This Drug Profile summarizes the published peer-reviewed evidence on seltorexant (JNJ-42847922; MIN-202), a selective orexin-2 receptor antagonist, for adjunctive treatment of MDD, covering its pharmacological, preclinical, and clinical profile, efficacy, safety and tolerability, head-to-head comparisons with current adjunctive treatments, regulatory status, and competitive landscape. Relevant literature was identified through structured searches of PubMed/MEDLINE and ClinicalTrials.gov (from database inception to April 2026), complemented by Google Scholar employed solely to identify conference proceedings, using combinations of terms related to seltorexant and depression. EXPERT OPINION Seltorexant 20 mg has shown a promising antidepressant effect, particularly in patients with clinically significant insomnia, and a favorable tolerability profile. The mixed phase-3 results, the modest effect sizes, and gaps on core symptoms of depression, including anhedonia and suicidality, and on long-term safety warrant a measured positive view, pending confirmatory data.