Evidence regarding depression and suicidality with glucagon-like peptide-1 receptor agonists (GLP-1RAs) remains inconsistent, particularly in patients with type 2 diabetes mellitus (T2DM) and underlying affective vulnerability. We conducted a disproportionality analysis of the WHO VigiBase (2010–2024), including T2DM patients. Reports of depressed mood and suicidal thoughts associated with GLP-1RAs were compared with other glucose-lowering medications. Analyses incorporated age, sex, time-to-onset, dose, comorbid depression, and concomitant antidepressant use. Adjusted reporting odds ratios (RORs) and a Weibull time-to-event model were applied. Causality was explored using Bradford Hill criteria. A total of 1,183,817 adverse events related to GLP-1RA were identified. Depressed mood and suicidality signals were observed with semaglutide, liraglutide, and tirzepatide (adjusted ROR 0.25 : 2.13, 1.52, 1.07) and (adjusted ROR 0.25 : 6.76, 2.43, 3.39), respectively. No signal was identified for suicide attempts or completed suicide. Absolute reporting frequencies were low. Concomitant antidepressant use was 2.3–5 times more frequent, and comorbid depression 25%–120% higher, compared with other glucose-lowering medications. Median time-to-onset was 96 days. Survival analysis demonstrated an early increase in reporting followed by stabilization over time. Adjustment for antidepressant use modestly attenuated associations. GLP-1RAs were associated with increased reporting of depressed mood and suicidal thoughts, particularly in patients receiving concomitant antidepressants. These findings support a patient-centered model in which underlying affective vulnerability or reporting factors drive reported mood symptoms rather than a uniform drug-specific effect. GLP-1RAs remain clinically valuable, but psychiatric monitoring during early treatment in vulnerable patients is warranted. • GLP-1 receptor agonists (GLP-1RAs) are drugs for type 2 diabetes and obesity currently being studied in the treatment of neuropsychiatric disorders. • We found that, specifically, semaglutide, liraglutide, and tirzepatide may be linked to mood symptoms and suicidal thoughts but not completed suicide in type 2 diabetes patients. • We note that these adverse events often occur within about three months after starting treatment. • Patients with comorbid depression who are taking antidepressants seem particularly susceptible to reporting mood symptoms. Monitoring psychiatric patients for these adverse events in patients with affective vulnerability is essential.
Aboukaoud et al. (Wed,) studied this question.