Evidence for associations between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and mood or suicidality has been inconsistent. The authors set out to clarify reporting patterns of depressed mood and suicidal thoughts linked to GLP-1RAs specifically in patients with type 2 diabetes mellitus (T2DM), where affective vulnerability may be present. The study aimed to compare reports involving GLP-1RAs to reports for other glucose-lowering medications and to explore timing, coexisting depression, concomitant psychotropic use, and causality signals.
The analysis used the WHO VigiBase pharmacovigilance database covering 2010–2024 and restricted to reports in patients with T2DM. Investigators conducted disproportionality analyses, calculated adjusted reporting odds ratios (RORs), and applied a Weibull time-to-event model to evaluate time-to-onset. Analyses incorporated stratification or adjustment for age, sex, dose, time-to-onset, documented comorbid depression, and concomitant antidepressant use. The Bradford Hill criteria were used to explore causality considerations.
A total of 1,183,817 adverse events related to GLP-1RAs were identified in VigiBase for the study period. The authors observed disproportionality signals for reports of depressed mood and suicidal thoughts associated with three agents highlighted in the dataset:
The analysis did not identify a signal for suicide attempts or completed suicide. Absolute reporting frequencies of depressed mood and suicidal thoughts were described as low despite the observed disproportionality.
Median time-to-onset for reports of depressed mood or suicidal thoughts was 96 days after starting the GLP-1RA. Survival analysis using the Weibull model demonstrated an early increase in reporting followed by stabilization over time, indicating that most reports occurred relatively early in the treatment course.
Reports involving GLP-1RAs had higher documented rates of preexisting depression and psychotropic co-treatment compared with reports for other glucose-lowering agents. Specifically, concomitant antidepressant use was 2.3 to 5 times more frequent in GLP-1RA reports. Documented comorbid depression was 25% to 120% higher versus other glucose-lowering medications. When analyses were adjusted for antidepressant use, the strength of the associations was modestly attenuated, suggesting confounding or effect modification by underlying affective illness or its treatment.
The investigators applied Bradford Hill considerations to interpret the signals. Their assessment supported a model in which underlying affective vulnerability and factors related to reporting may explain the observed increased reporting of mood symptoms and suicidal thoughts rather than a single, uniform drug-specific neuropsychiatric effect across all GLP-1RAs. The pattern of early-onset reporting and the higher prevalence of comorbid depression and antidepressant use among reports were salient factors in this interpretation.
The authors concluded that GLP-1RAs are associated with increased reporting of depressed mood and suicidal thoughts in VigiBase among patients with T2DM, particularly in those receiving concomitant antidepressants. However, the absolute frequency of reports was low and no signal for suicide attempts or completed suicide was detected. Given these findings, the study recommends a patient-centered approach: GLP-1RAs remain clinically valuable for glucose management, but clinicians should consider psychiatric monitoring during the early treatment period in patients with known affective vulnerability or who are taking antidepressants.
As a pharmacovigilance disproportionality analysis using VigiBase, the study is subject to limitations inherent to spontaneous reporting systems: underreporting, reporting bias, variable data quality, and inability to calculate true incidence or to confirm causality. Details about clinical severity, standardized psychiatric assessment, or outcomes after drug discontinuation were not reported in the abstract. The authors noted that adjustment for antidepressant use only modestly attenuated associations, but the potential for residual confounding remains. Further prospective and controlled investigations would be required to determine whether the observed reporting patterns reflect causal effects, differential reporting, or confounding by indication and comorbidity.
Overall, this VigiBase analysis highlights an association in reporting between some GLP-1RAs and mood-related adverse events in T2DM and supports closer psychiatric observation early after treatment initiation for patients with affective vulnerability.