{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:51:23Z","timestamp":1792608683904,"version":"4.5.0"},"reference-count":6,"publisher":"American Medical Association (AMA)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Psychiatry"],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"\n Importance<\/jats:title>\n Consistent results from preclinical and clinical studies indicate that activation of glucagon-like peptide-1 receptors (GLP-1 Rs) affects reward processes; however, to our knowledge, no study has previously evaluated whether a GLP-1 R agonist (GLP-1 RA) affects motivated behavior in individuals with major depressive disorder (MDD) in a randomized clinical trial.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To assess the effects of a GLP-1 RA, semaglutide, on reward-related dysfunction in a population with MDD.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This study was a 16-week, double-blind, placebo-controlled, parallel-group randomized clinical trial. A total of 72 participants with a diagnosis of MDD and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 25 or higher were randomized to oral semaglutide (n\u2009=\u200935) or placebo (n\u2009=\u200937). Participants were recruited from the Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, a university-based mood disorders program. Participants were enrolled between March 14, 2022, and July 26, 2024. Data analysis was performed from January 7, 2025, through February 3, 2025.<\/jats:p>\n <\/jats:sec>\n \n Intervention<\/jats:title>\n Patients were randomized 1:1 to receive placebo or oral semaglutide, 14 mg (initiated at 4 mg and titrated using a 4-week dose-escalation regimen), adjunctive to their treatment as usual.<\/jats:p>\n <\/jats:sec>\n \n Main Outcome and Measure<\/jats:title>\n The preregistered outcome of this secondary analysis was performance on the Effort-Expenditure for Rewards Task (EEfRT).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 72 participants were randomized to oral semaglutide (n\u2009=\u200935 [49.7%]; mean [SD] age, 38.17 [11.79] years; 18 female participants [51.4%]) or placebo (n\u2009=\u200937 [51.3%]; mean [SD] age, 40.27 [9.32] years; 19 female participants [51.3%]). Semaglutide-treated participants exhibited a pattern of increased willingness to exert physical efforts with higher expected values of reward (treatment\u2009\u00d7\u2009visit\u2009\u00d7\u2009expected value interaction: \u03c7\n 2<\/jats:sup>\n \u2009=\u200912.024;\n P<\/jats:italic>\n \u2009=\u2009.02). Computational modeling indicated that semaglutide\u2019s effects on choice behavior were a result of reduced effort discounting. Sensitivity to effort was significantly reduced by treatment with semaglutide (\u03b2\u2009=\u2009\u22121.737;\n P<\/jats:italic>\n \u2009=\u2009.03), whereas there was no treatment effect on sensitivity to probability (\u03b2\u2009=\u2009\u22120.776;\n P<\/jats:italic>\n \u2009=\u2009.51).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n In this secondary analysis of a double-blind randomized clinical trial, treatment with semaglutide significantly improved measures of motivation in patients with MDD. Semaglutide reduced the perceived cost of effort, relative to the monetary reward; the results of this trial have implications for the treatment of multiple neuropsychiatric disorders, which are characterized by varied reward dysfunctions.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT04466345<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamapsychiatry.2026.0594","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T15:30:59Z","timestamp":1777476659000},"page":"751","source":"Crossref","is-referenced-by-count":9,"title":["Semaglutide and Effort-Based Decision-Making in Major Depressive Disorder"],"prefix":"10.1001","volume":"83","author":[{"given":"Hartej","family":"Gill","sequence":"first","affiliation":[{"name":"Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Badulescu","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiya","family":"Shah","sequence":"additional","affiliation":[{"name":"University Health Network Mental Health, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan M.","family":"Brudner","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"},{"name":"University Health Network Mental Health, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Phan","sequence":"additional","affiliation":[{"name":"Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Di Vincenzo","sequence":"additional","affiliation":[{"name":"University Health Network Mental Health, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniqa","family":"Tabassum","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharmili Edwin","family":"Thanarajah","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University Frankfurt, Frankfurt, Germany"},{"name":"Cooperative Brain Imaging Center, Goethe University Frankfurt, Frankfurt, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology, Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian-Daniel","family":"Llach","sequence":"additional","affiliation":[{"name":"University Health Network Mental Health, Toronto, Ontario, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Rosenblat","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"},{"name":"University Health Network Mental Health, Toronto, Ontario, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada"},{"name":"Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger S.","family":"McIntyre","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada"},{"name":"Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo B.","family":"Mansur","sequence":"additional","affiliation":[{"name":"Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada"},{"name":"University Health Network Mental Health, Toronto, Ontario, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"key":"ybr260002r1","doi-asserted-by":"publisher","first-page":"2995","DOI":"10.2147\/NDT.S325954","article-title":"Patient expectations and experiences of antidepressant therapy for major depressive disorder: a qualitative study.","volume":"17","author":"Baune","year":"2021","journal-title":"Neuropsychiatr Dis 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