Clinical usefulness of dual orexin receptor antagonism beyond insomnia: Neurological and psychiatric comorbidities

Orexin is a neurotransmitter produced by a small group of hypothalamic neurons. Besides its well-known role in the regulation of the sleep-wake cycle, the orexin system was shown to be relevant in several physiological functions including cognition, mood and emotion modulation, and energy homeostasis. Indeed, the implication of orexin neurotransmission in neurological and psychiatric diseases has been hypothesized via a direct effect exerted by the projections of orexin neurons to several brain areas, and via an indirect effect through orexin-mediated modulation of sleep and wake. Along with the growing evidence concerning the use of dual orexin receptor antagonists (DORAs) in the treatment of insomnia, studies assessing their efficacy in insomnia comorbid with psychiatric and neurological diseases have been set in order to investigate the potential impact of DORAs on both sleep-related symptoms and disease-specific manifestations. This narrative review aimed at summarizing the current evidence on the use of DORAs in neurological and psychiatric conditions comorbid with insomnia, also discussing the possible implication of modulating the orexin system for improving the burden of symptoms and the pathological mechanisms of these disorders. Target searches were performed on PubMed/MEDLINE and Scopus databases and ongoing studies registered on Clinicaltrials.gov were reviewed. Despite some contradictory findings, preclinical studies seemingly support the possible beneficial role of orexin antagonism in the management of the most common neurological and psychiatric diseases with sleep-related comorbidities. However, clinical research is still limited and further studies are needed for corroborating these promising preliminary results.