{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T23:16:37Z","timestamp":1790982997472,"version":"4.1.0"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Oral semaglutide carries a neuropsychiatric safety profile that continues to evolve. Large clinical trials have not, at the group level, demonstrated excess psychiatric adverse events\u2014but pharmacovigilance databases and case reports have documented a signal for depression and suicidal ideation in individual patients. A dose-dependent onset with rechallenge has not, to our knowledge, been previously described for the oral formulation, though such an association cannot be established from a single observation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>We describe a 54-year-old man with type 2 diabetes and no psychiatric history who developed moderately severe major depression (Patient Health Questionnaire-9 [PHQ-9]: 18; Hamilton Depression Rating Scale 17 items [HDRS-17]: 22) within 2 weeks of escalating oral semaglutide from 3 to 7 mg daily. Vortioxetine 10 mg combined with bupropion XL 150 mg produced remission within 4 weeks (PHQ-9: 6). On structured rechallenge, depression returned when the dose was re-escalated to 7 mg (PHQ-9: 17; HDRS-17: 20). Permanent discontinuation was followed by sustained remission.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>As far as we are aware, this is the first reported case of a dose-related, rechallenge-associated depressive episode tied in time to oral semaglutide and treated with a vortioxetine\u2013bupropion combination. A Naranjo score of 7 puts the relationship in the probable range, though that reading is held back by the usual limits of a single case and by an incomplete washout before rechallenge. The step from 3 to 7 mg may be a point of raised psychiatric risk in vulnerable patients, and watching mood during titration looks like a sensible precaution.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fpsyt.2026.1893173","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:10:25Z","timestamp":1784887825000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: Oral semaglutide-associated depression in a patient with type 2 diabetes mellitus: a dose-dependent recurrence confirmed on rechallenge and managed with vortioxetine\u2013bupropion combination therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Abdulrahman S.","family":"Alanazi","sequence":"first","affiliation":[{"name":"College of Pharmacy, University of Hail","place":["Hail, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basmah A.","family":"Alanazi","sequence":"additional","affiliation":[{"name":"Health Holding Company","place":["Hail Health Cluster, Hail, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.14752","article-title":"Effect of oral semaglutide on glycemic control","volume":"318","author":"Davies","year":"2017","journal-title":"JAMA"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1177\/02537176241246744","article-title":"The potential role of GLP-1 agonists in psychiatric disorders","volume":"46","author":"Gunturu","year":"2024","journal-title":"Indian J Psychol Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2024.3193","article-title":"Psychiatric safety of semaglutide (STEP 1,2,3,5)","volume":"184","author":"Wadden","year":"2024","journal-title":"JAMA Intern 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