Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders

Abstract

Orexins comprise two neuropeptides produced by orexin neurons in the lateral hypothalamus and are released by extensive projections of these neurons throughout the central nervous system. Orexins bind and activate their associated G protein-coupled orexin type 1 receptors (OX1Rs) and OX2Rs and act on numerous physiological processes, such as sleep-wake regulation, feeding, reward, emotion, and motivation. Research on the development of orexin receptor antagonists has dramatically increased with the approval of suvorexant for the treatment of primary insomnia. In the present review, we discuss recent findings on the involvement of the orexin system in the pathophysiology of psychiatric disorders, including sleep disorders, depression, anxiety, and drug addiction. We discuss the actions of orexin receptor antagonists, including selective OX1R antagonists (SORA1s), selective OX2R antagonists (SORA2s), and dual OX1/2R antagonists (DORAs), in the treatment of these disorders based on both preclinical and clinical evidence. SORA2s and DORAs have more pronounced efficacy in the treatment of sleep disorders, whereas SORA1s may be promising for the treatment of anxiety and drug addiction. We also discuss potential challenges and opportunities for the application of orexin receptor antagonists to clinical interventions.