{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T13:20:10Z","timestamp":1793193610388,"version":"4.5.0"},"reference-count":46,"publisher":"American Medical Association (AMA)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Intern Med"],"published-print":{"date-parts":[[2024,11,1]]},"abstract":"<jats:sec><jats:title>Importance<\/jats:title><jats:p>Obesity is associated with numerous psychosocial complications, making psychiatric safety a consideration for treating people with obesity. Few studies have investigated the psychiatric safety of newly available antiobesity medications.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To evaluate the psychiatric safety of subcutaneous semaglutide, 2.4 mg, once weekly in people without known major psychopathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This post hoc analysis of pooled data from the randomized, double-blind, placebo-controlled, multicenter phase 3a STEP 1, 2, and 3 trials (68 weeks; 2018-2020) and phase 3b STEP 5 trial (104 weeks; 2018-2021) included adults with overweight or obesity; STEP 2 participants also had type 2 diabetes. Trial designs have been published previously.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interventions<\/jats:title><jats:p>Semaglutide, 2.4 mg, vs placebo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>Depressive symptoms and suicidal ideation\/behavior were assessed using the Patient Health Questionnaire (PHQ-9) and Columbia\u2013Suicide Severity Rating Scale, respectively. Psychiatric and nervous system disorder adverse events were investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>This analysis included 3377 participants in the STEP 1, 2, and 3 trials (2360 women [69.6%]; mean [SD] age, 49 [13] years) and 304 participants in STEP 5 (236 women [77.6%]; mean [SD] age, 47 [11] years). In the STEP 1, 2, and 3 trials, mean (SD) baseline PHQ-9 scores for the semaglutide, 2.4 mg, and placebo groups were 2.0 (2.3) and 1.8 (2.3), respectively, indicating no\/minimal symptoms of depression. PHQ-9 scores at week 68 were 2.0 (2.9) and 2.4 (3.3), respectively; the estimated treatment difference (95% CI) between groups was \u22120.56 (\u22120.81 to \u22120.32) (<jats:italic>P<\/jats:italic>\u2009&amp;amp;lt;\u2009.001). Participants treated with semaglutide vs placebo were less likely to shift (from baseline to week 68) to a more severe category of PHQ-9 depression (odds ratio, 0.63; 95% CI, 0.50-0.79; <jats:italic>P<\/jats:italic>\u2009&amp;amp;lt;\u2009.001). Based on the Columbia\u2013Suicide Severity Rating Scale, 1% or fewer of participants reported suicidal ideation\/behavior during treatment, with no differences between semaglutide, 2.4 mg, and placebo. Psychiatric disorder adverse events were generally balanced between groups. Similar results were observed in STEP 5.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Relevance<\/jats:title><jats:p>The results of this post hoc analysis suggest that treatment with semaglutide, 2.4 mg, did not increase the risk of developing symptoms of depression or suicidal ideation\/behavior vs placebo and was associated with a small but statistically significant reduction in depressive symptoms (not considered clinically meaningful). People with obesity should be monitored for mental health concerns so they can receive appropriate support and care.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>ClinicalTrials.gov Identifiers: STEP 1 (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT03548935\">NCT03548935<\/jats:ext-link>), 2 (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT03552757\">NCT03552757<\/jats:ext-link>), 3 (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT03611582\">NCT03611582<\/jats:ext-link>), and 5 (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT03693430\">NCT03693430<\/jats:ext-link>)<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamainternmed.2024.4346","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T15:01:12Z","timestamp":1725375672000},"page":"1290","source":"Crossref","is-referenced-by-count":101,"title":["Psychiatric Safety of Semaglutide for Weight Management in People Without Known Major Psychopathology"],"prefix":"10.1001","volume":"184","author":[{"given":"Thomas A.","family":"Wadden","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory K.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, 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