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Following a double-blind placebo lead-in period (up to 3 weeks), participants were randomized to receive once daily aticaprant 10\u2009mg or continue placebo, added to their ongoing treatment, for 6 weeks. Of 184 participants enrolled, 169 were included in safety analyses (aticaprant\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200985, placebo\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200984) and 166 in full intent-to-treat (fITT) efficacy analyses; 121 placebo lead-in non-responders (&lt;30% reduction in MADRS total score) in fITT were included in enriched ITT (eITT) analyses. Improvement (least squares mean difference [upper limit 1-sided 80% CI] versus placebo) in MADRS total score at week 6 for aticaprant was significant versus placebo (eITT: \u22122.1 [\u22121.09], 1-sided\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.044; effect size (ES) 0.23; fITT \u22123.1 [2.21], 1-sided\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.002; ES 0.36). The between-group difference was larger among participants with Snaith\u2013Hamilton Pleasure Scale (SHAPS) score greater\/equal to versus less than baseline median SHAPS. The most common treatment-emergent adverse events reported for aticaprant (versus placebo) were headache (11.8% versus 7.1%), diarrhea (8.2% versus 2.4%), nasopharyngitis (5.9% versus 2.4%), and pruritus (5.9% versus 0%). One participant (1.2%) in each arm discontinued treatment due to an adverse event. In this study of participants with MDD and inadequate response to SSRI\/SNRI, adjunctive treatment with aticaprant significantly reduced depressive symptoms versus placebo, without resulting in significant safety signals, supporting further investigation in larger trials.\n                  <\/jats:p>","DOI":"10.1038\/s41386-024-01862-x","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T12:02:36Z","timestamp":1713787356000},"page":"1437-1447","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Efficacy and safety of aticaprant, a kappa receptor antagonist, adjunctive to oral SSRI\/SNRI antidepressant in major depressive disorder: results of a phase 2 randomized, double-blind, placebo-controlled study"],"prefix":"10.1038","volume":"49","author":[{"given":"Mark E.","family":"Schmidt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iva","family":"Kezic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanina","family":"Popova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama","family":"Melkote","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Van Der Ark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrel J.","family":"Pemberton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Mareels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla M.","family":"Canuso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Fava","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":[[2024,4,22]]},"reference":[{"key":"1862_CR1","unstructured":"World Health Organization. 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PVDA was an employee of Janssen Research & Development, LLC at the time this study was conducted. Maurizio Fava reports the following disclosures related to the last 3 years: <b>Research Support<\/b> Abbvie; Acadia Pharmaceuticals; Aditum Bio Management Company, LLC; Allergan, Alkermes, Inc.; Altimate Health Corporation; Alto Neuroscience, Inc.; Ancora Bio, Inc.; Angelini S.p.A; Aptinyx; Arbor Pharmaceuticals LLC; Avanir Pharmaceuticals Inc.; Axsome; Benckiser Pharmaceuticals, Inc.; BioClinica, Inc.; Biogen; BioHaven; BioShin Limited; Cambridge Science Corporation; Centrexion Therapeutics Corporation; Cerecor; Cybin IRL Limited; Damona Pharmaceuticals; EmbarkNeuro; Eliem Therapeutics LTD; Gate Neurosciences, Inc.; GenOmind, LLC; Gentelon, LLC; Gerbera Therapeutics, Inc.; Happify; Johnson & Johnson; Lundbeck Inc.; Marinus Pharmaceuticals; Medpace, Inc.; Methylation Sciences, Inc.; Millennium Pharmaceutics, Inc.; Minerva Neurosciences; Neuralstem; Neurocrine Biosciences, Inc.; NeuroRX Inc.; Novaremed; Novartis; Otsuka; Pfizer; Premiere Research International; Praxis Precision Medicines; Protagenic Therapeutics, Inc.; Relmada Therapeutics Inc.; Reckitt; Shenox Pharmaceuticals; Stanley Medical Research Institute (SMRI); Taisho; Takeda; University of Michigan; Vistagen; WinSanTor, Inc.; Xenon Pharmaceuticals, Inc.; National Institute of Drug Abuse (NIDA); National Institutes of Health (NIH); National Institute of Mental Health (NIMH); and PCORI. Dr. Fava has not done any personal consulting. Any consulting he has done has been on behalf of Massachusetts General Hospital, except for Revival Therapeutics and Sensorium Therapeutics. <b>Speaking\/Publishing<\/b> Lecture given at Global Medical Education, Inc. Mood Disorders Summit, November 2020. <b>Stock\/Other Financial Options<\/b> Equity Holdings: Compellis; Neuromity; Psy Therapeutics; Revival Therapeutics; Sensorium Therapeutics. Royalty\/patent, other income: Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven. Patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691). Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Belvior; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte. Ltd.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}