Safety of semaglutide on depressive symptoms among people with HIV in routine clinical care

Background: – Semaglutide, widely used for diabetes and obesity, has raised concerns about neuropsychiatric risks, including depression and suicidality. Given the high burden of depression among people with HIV (PWH), we assessed whether semaglutide initiation worsens depressive symptoms. Methods: – We conducted a within-person pre–post study of PWH initiating semaglutide at nine Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) sites between April 2018 and October 2024. Depressive symptoms were measured using the Patient Health Questionnaire-9 (PHQ-9) collected during routine care before and after semaglutide initiation. We estimated changes in PHQ-9 scores after semaglutide initiation using linear mixed models, overall and stratified by baseline depression severity (0–4 no/minimal, 5–9 mild, 10–14 moderate, and ≥15 moderately-severe to severe), body mass index (BMI), diabetes, and antidepressant use. Results: – Among 354 PWH (mean age 54; 77% male; 38% non-Hispanic White; 78% obesity; 60% diabetes), baseline PHQ-9 scores were 0–4 in 53%, 5–9 in 28%, 10–14 in 10%, and ≥15 in 9%. Semaglutide was not associated with overall changes in depressive symptoms (ΔPHQ-9 −0.1 [95% confidence interval (CI) −0.7, 0.5]). Scores increased slightly in those with no/minimal baseline depression (+1.2 [95% CI 0.5, 1.8]), were stable in mild/moderate depression, and decreased in moderately-severe to severe depression (−4.7 [95% CI −7.3, −2.2]). No worsening was observed across BMI, diabetes, or antidepressant subgroups. Conclusion: – Semaglutide initiation was not associated with worsening depressive symptoms among PWH in care. While individual responses may vary, these findings add to evidence on semaglutide safety regarding mood in a high-risk population.