{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T22:07:27Z","timestamp":1793138847489,"version":"4.5.0"},"reference-count":64,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Psychiatry"],"published-print":{"date-parts":[[2026,2,1]]},"abstract":"\n Importance<\/jats:title>\n Individuals with schizophrenia spectrum disorders treated with second-generation antipsychotics (SGAs) are at heightened risk for obesity, prediabetes, and type 2 diabetes, contributing to increased cardiovascular morbidity and premature mortality. Early intervention with glucagon-like peptide\u20131 receptor agonists (GLP-1RAs) may help mitigate long-term cardiometabolic risk.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate the efficacy of adjunctive semaglutide on glycemic control, weight-associated outcomes, and cardiometabolic risk factors in individuals with schizophrenia spectrum disorders receiving clozapine or olanzapine and exhibiting early glycemic abnormalities.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n This was a multicenter, double-blind, placebo-controlled, randomized clinical trial. Participants were enrolled from 3 clinical sites in Denmark between September 2021 and August 2024. Screening individuals were aged 18 to 65 years with schizophrenia spectrum disorders and clozapine or olanzapine treatment initiated within the past 5 years. Participants had early-stage glycemic dysregulation (hemoglobin A\n 1c<\/jats:sub>\n [HbA\n 1c<\/jats:sub>\n ], 5.4%-7.4%) and were not receiving antidiabetic therapy.\n <\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Participants received once-weekly subcutaneous semaglutide (1 mg) or a matching placebo, administered adjunctively to SGA therapy for 26 weeks.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n The prespecified primary outcome was change in HbA\n 1c<\/jats:sub>\n level from baseline to week 26. The primary analysis adhered to the intention-to-treat principle.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Of 104 individuals screened, 73 were randomized and 57 (78%) completed the trial. Baseline characteristics were comparable between groups. Mean (SD) age was 35 (12) years, 48 were female (65%), and mean (SD) body mass index was 36.1 (7.9). At week 26, semaglutide significantly reduced HbA\n 1c<\/jats:sub>\n level compared with placebo (mean difference, \u22120.25%; 95% CI, \u22120.33 to \u22120.16;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001); 43% of participants (12 of 28) treated with semaglutide achieved low-risk HbA\n 1c<\/jats:sub>\n levels (&amp;lt;5.4%) vs 3% with placebo. Greater reductions in body weight (\u22129.2 kg; 95% CI, \u221213.3 to \u22125.1 kg;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001), waist circumference (\u22127.0 cm; 95% CI, \u221210.6 to \u22123.3 cm;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001), and fat mass (\u22126.1 kg; 95% CI, \u221210.2 to \u22121.9 kg;\n P<\/jats:italic>\n \u2009=\u2009.006) were observed with semaglutide. No differences in lipid levels, liver function, blood pressure, or psychiatric symptoms were observed. Gastrointestinal adverse events were common but mild and transient; psychiatric adverse events were similar across groups.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n Results of this randomized clinical trial show that adjunctive semaglutide significantly improved glycemic control and weight outcomes in individuals with schizophrenia spectrum disorders. Secondary outcomes were exploratory. These findings support the use of GLP-1RAs as a potential early intervention strategy to reduce cardiometabolic risk in this vulnerable population.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT04892199<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamapsychiatry.2025.3639","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T16:00:32Z","timestamp":1764777632000},"page":"128","source":"Crossref","is-referenced-by-count":28,"title":["Semaglutide and Early-Stage Metabolic Abnormalities in Individuals With Schizophrenia Spectrum Disorders"],"prefix":"10.1001","volume":"83","author":[{"given":"Marie R.","family":"Sass","sequence":"first","affiliation":[{"name":"Mental Health Center Copenhagen, Mental Health Services in the Capitol Region of Denmark, Copenhagen, Denmark"},{"name":"Now with Novo Nordisk A\/S, Bagsvaerd, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette Kruse","family":"Klausen","sequence":"additional","affiliation":[{"name":"Mental Health Center Copenhagen, Mental Health Services in the Capitol Region of Denmark, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine R.","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Steno Diabetes Center Copenhagen, University of Copenhagen, Herlev, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Line","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Mental Health Center Copenhagen, Mental Health Services in the Capitol Region of Denmark, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte E. 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Medicine, Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Kjaer","sequence":"additional","affiliation":[{"name":"Department of Clinical Physiology and Nuclear Medicine, Cluster for Molecular Imaging, Department of Biomedical Sciences, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bolette","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens J.","family":"Holst","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus T.","family":"Ekstr\u00f8m","sequence":"additional","affiliation":[{"name":"Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maj","family":"Vinberg","sequence":"additional","affiliation":[{"name":"Mental Health Centre, Northern Zealand, Copenhagen University Hospital\u2014Mental Health Services CPH, Copenhagen, Denmark"},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph U.","family":"Correll","sequence":"additional","affiliation":[{"name":"The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, New York"},{"name":"Department of Psychiatry and Molecular Medicine, Zucker School of Medicine at 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