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The value of identifying such a medication would be enhanced if it were also generally well-tolerated and addressed depressive symptoms that are less responsive to SSRIs or SNRIs, such as insomnia or anxiety. This narrative review summarizes the investigation of a novel class of medications originally developed to treat insomnia, the Orexin Receptor Antagonists (ORAs), as adjunctive treatments for depressed patients who have been able to tolerate but who do not obtain an adequate response to standard antidepressants. Although it is likely that the currently approved Dual Orexin Receptor Antagonists (DORAs)\u2014suvorexant, lemborexant and daridorexant\u2014are safe and useful options for concomitant therapy of insomnia in antidepressant-treated patients, these medications have not been approved for this indication. Moreover, DORAs have not been extensively studied as adjunctive therapies for MDD. By contrast, the investigational ORA seltorexant, which is a selective Orexin 2 receptor antagonist, has shown significant antidepressant effects in Phase 2 and Phase 3 trials. Although at least one more unequivocally positive pivotal study will be needed to garner FDA approval for clinical use in the United States, this drug shows promise as a novel and well-tolerated option for patients with difficult to treat depressive episodes.<\/jats:p>","DOI":"10.1007\/s00406-025-01999-w","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T07:41:03Z","timestamp":1748418063000},"page":"1611-1619","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A new direction for adjunctive therapy of difficult-to-treat depression: examining the role of orexin receptor antagonists"],"prefix":"10.1007","volume":"275","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6403-0861","authenticated-orcid":false,"given":"Michael E.","family":"Thase","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,28]]},"reference":[{"key":"1999_CR1","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1177\/0269881118822258","volume":"33","author":"S Brooks","year":"2019","unstructured":"Brooks S, Jacobs GE, de Boer P, Kent JM, Van Nueten L, van Amerongen G, Zuiker R, Kezic I, Luthringer R, van der Ark P, van Gerven JM, Drevets W (2019) The selective orexin-2 receptor antagonist seltorexant improves sleep: an exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia. 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