Rationale <p>Orexins, comprising orexin-A and orexin-B, are neuropeptides with extensive projections throughout the central nervous system. They are implicated in a variety of physiological processes through their receptors, orexin type 1 (OX₁) and orexin type 2 (OX₂) receptors. Among the physiological functions of orexins, their role in sleep/wake regulation has garnered significant attention. Consequently, three orexin receptor antagonists that block both OX₁ and OX₂ receptors (dual orexin receptor antagonist; DORA) are available on the market for the treatment of insomnia. Additionally, another DORA, vornorexant, has been submitted for approval.</p> Objective <p>Beyond sleep disorders, the orexin system is deeply implicated in the pathophysiology of several psychiatric disorders, including depression, anxiety, and substance use disorders.</p> Results <p>Accumulating evidence indicates that orexin receptor antagonists improve behavioral abnormalities that mimic certain psychiatric disorders in animal models and are effective in treating these disorders or their symptoms in humans. Moreover, orexin receptor antagonists are expected not only to alleviate core symptoms of psychiatric disorders but also to improve sleep disturbances, which are often comorbid with these conditions.</p> Conclusion <p>Drug discovery and development targeting orexin receptors should provide novel therapeutic options for the treatment of psychiatric disorders.</p>