Seltorexant for major depressive disorder.

Introduction: Preclinical and clinical pharmacologic evidence indicates that orexin systems are relevant to sleep-wake cycle regulation and dimensions of reward and cognition, providing the basis for hypothesizing that they may be effective as therapeutics in mental disorders. Due to the limited efficacy and tolerability profiles of existing treatments for Major Depressive Disorder (MDD), investigational compounds in novel treatment classes are needed; seltorexant, an orexin receptor antagonist, is a potential new treatment currently under investigation.

Areas covered: Mechanisms implicated in MDD, including reward and sleep, are first overviewed. Then, the safety, tolerability, and efficacy profiles of seltorexant and the wider context of orexin receptor antagonism for depression are discussed in focus. Preclinical and clinical data are also discussed. PubMed, Medline, Cochrane Library, Embase, Scopus, and Web of Science were systematically searched from inception to 10 October 2024, in accordance with PRISMA guidelines.

Expert opinion: Early clinical evidence suggests that seltorexant is effective in treating MDD, both in individuals diagnosed with insomnia and those not, although greater antidepressant effects are observed in individuals with severe sleep disturbance. Results from large phase III clinical trials are needed to confirm efficacy and safety.