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-bupropion combination therapy.

BACKGROUND: 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-but 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. CASE PRESENTATION: 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. CONCLUSION: 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-bupropion 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.