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Participants were randomized to receive seltorexant (20\u2009mg or 40\u2009mg) or placebo. The treatment effect was assessed by changes in the Hamilton Rating Scale for Depression-17 item (HDRS<jats:sub>17<\/jats:sub>) from treatment-period baseline to week 5 in lead-in placebo non-responders (\u201cenriched\u201d intent-to-treat analysis set). As a secondary outcome, the effect of seltorexant on HDRS<jats:sub>17<\/jats:sub> was assessed in patients with and without subjective insomnia. Seltorexant\u2019s effects on polysomnography, serum cortisol, and cortisol waking response were also measured. In total, 128 participants were enrolled, including 86 in the enriched sample (lead-in placebo non-responders). The mean changes from baseline (SD) in HDRS<jats:sub>17<\/jats:sub> score at week 5 differed significantly across arms: \u22127.0 (5.04) for seltorexant 20\u2009mg, \u22125.5 (4.34) for seltorexant 40\u2009mg, and \u22124.4 (3.67) for placebo (p\u2009=\u20090.0456), which was attributable to the difference between the 20\u2009mg and placebo arms (p\u2009=\u20090.0049). Improvement in depression severity at week 5 for seltorexant 20\u2009mg was greater in patients with higher baseline insomnia severity (nominal p\u2009=\u20090.0059). The treatment benefit in the 20\u2009mg arm remained significant when HDRS scores were adjusted by removing the sleep items (nominal p\u2009=\u20090.0289). The mean HDRS<jats:sub>17<\/jats:sub> change versus placebo was numerically larger in the 20\u2009mg than the 40\u2009mg arm, consistent with data from a previous study in which seltorexant was administered adjunctively to conventional antidepressants. In secondary analyses, the waking cortisol response decreased in the 20\u2009mg arm but not the 40\u2009mg or placebo arms, and while total sleep increased more in the 40\u2009mg arm, this arm also showed reduced REM onset latency and increased stage N1 sleep, which were not evident in the 20\u2009mg arm. These biomarker data suggest mechanistic hypotheses that may account for the apparent curvilinear dose-response relationship of seltorexant. Trial Registration: ClinicalTrials.gov, NCT03374475.<\/jats:p>","DOI":"10.1038\/s41380-024-02846-5","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T07:28:24Z","timestamp":1733902104000},"page":"2427-2435","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Treatment effect and safety of seltorexant as monotherapy for patients with major depressive disorder: a randomized, placebo-controlled clinical trial"],"prefix":"10.1038","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8236-986X","authenticated-orcid":false,"given":"Sofie","family":"Mesens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iva","family":"Kezic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Van Der Ark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mila","family":"Etropolski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gahan","family":"Pandina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Benes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Savitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne C.","family":"Drevets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,11]]},"reference":[{"key":"2846_CR1","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1111\/bph.12415","volume":"171","author":"J Li","year":"2014","unstructured":"Li J, Hu Z, de Lecea L. 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SM, IK, PV, WD, and GP, and are employees of Janssen Research and Development and may hold company stock or stock options. AS and ME are a former employee of Janssen Research and Development and holds stock in the company. HB has received study honoraria from Janssen R&D for conducting the study and is a member of AB for Idorsia, not related to the submitted work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}