Psychiatric Adverse Events Associated with GLP-1 Receptor Agonists: Evidence of Intraclass Heterogeneity in the WHO VigiBase Global Database
Semaglutide and liraglutide show higher psychiatric ADR reporting, suggesting the need for careful monitoring of patients using these GLP-1 RAs.
Where it sits
this study against the rest of the exenatide corpusSummary and findings
This study analyzed psychiatric adverse drug reactions associated with GLP-1 receptor agonists using the WHO VigiBase database. It found significant heterogeneity in psychiatric event reporting among different GLP-1 RAs, with semaglutide and liraglutide showing higher disproportionality. Exenatide, tirzepatide, and dulaglutide did not show significant signals.
Abstract
<h4>Background: </h4> /Objectives: Concerns regarding the psychiatric safety profile of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have increased since the 2023 European Medicines Agency (EMA) and U.S. Food and Drug Administration (FDA) reviews. However, it remains unclear whether this signal is uniform across the drug class or concentrated in specific compounds. This study aimed to characterize and compare, in a systematic manner, the global reporting patterns of psychiatric adverse drug reactions (ADRs) associated with the main GLP-1 RAs using the World Health Organization (WHO) VigiBase global pharmacovigilance database. <h4>Methods:</h4> A descriptive, cross-sectional pharmacovigilance study was conducted on individual case safety reports (ICSRs) retrieved from VigiAccess (January 2000–2026) for semaglutide, liraglutide, dulaglutide, exenatide, tirzepatide, and lixisenatide. A disproportionality analysis was performed within the MedDRA “Psychiatric disorders” System Organ Class (SOC) using the Reporting Odds Ratio (ROR) with 95% confidence intervals (CI). The study adhered to the STROBE and READUS-PV guidelines. <h4>Results:</h4> A total of 537,519 ADR reports were analyzed across the five drugs with sufficient reporting volume (lixisenatide was excluded owing to n = 22 psychiatric events). Psychiatric disorders accounted for 19,899 reports, with marked intraclass heterogeneity in both the proportion of psychiatric reports (6.73% for semaglutide versus 3.12% for tirzepatide) and in disproportionality estimates. Signals of disproportionate reporting were identified exclusively for semaglutide (ROR 1.55; 95% CI 1.50–1.59) and liraglutide (ROR 1.19; 95% CI 1.15–1.23), whereas tirzepatide, dulaglutide, and exenatide showed point estimates below unity. <h4>Conclusions:</h4> The psychiatric safety profile of GLP-1 RAs is not homogeneous within the therapeutic class. The disproportionality signal is concentrated on semaglutide and, to a lesser extent, liraglutide. These findings extend previous WHO-based analyses limited to suicidality and support active clinical surveillance of psychiatric symptoms in patients treated with these specific agents.
Background
The study addresses concerns about the psychiatric safety of GLP-1 receptor agonists, which have been under scrutiny by regulatory agencies. Previous analyses have focused on suicidality, but this study aims to provide a broader understanding of psychiatric adverse events across the drug class. Understanding intraclass differences is important for patient safety and informed prescribing.
Methods
A descriptive, cross-sectional pharmacovigilance study was conducted using the WHO VigiBase database. Individual case safety reports from January 2000 to 2026 for semaglutide, liraglutide, dulaglutide, exenatide, tirzepatide, and lixisenatide were analyzed. Disproportionality analysis was performed using the Reporting Odds Ratio (ROR) within the MedDRA 'Psychiatric disorders' System Organ Class.
Results
The study analyzed 537,519 ADR reports, identifying 19,899 related to psychiatric disorders. Semaglutide had a disproportionality signal with an ROR of 1.55 (95% CI 1.50–1.59), and liraglutide had an ROR of 1.19 (95% CI 1.15–1.23). Exenatide, tirzepatide, and dulaglutide did not show significant disproportionality signals.
Interpretation
The findings suggest that the psychiatric safety profile of GLP-1 RAs varies significantly within the class, with semaglutide and liraglutide showing higher risks. This contrasts with previous analyses focused on suicidality alone. The study's reliance on pharmacovigilance data limits its ability to establish causality, but it highlights the need for active clinical monitoring of psychiatric symptoms in patients using these drugs.
Key findings
- 537,519 ADR reports analyzed.
- 19,899 psychiatric disorder reports identified.
- 6.73% psychiatric reports for semaglutide vs 3.12% for tirzepatide.
- Semaglutide ROR 1.55; 95% CI 1.50–1.59.
- Liraglutide ROR 1.19; 95% CI 1.15–1.23.
Limitations
- pharmacovigilance data may have reporting bias
- lacks clinical context
- excludes lixisenatide due to low event count
- cross-sectional design limits causality inference