INTRODUCTION: 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.
METHODS: 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.
RESULTS: 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: 2.13, 1.52, 1.07) and (adjusted ROR: 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.
CONCLUSION: 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.