Psychiatric Adverse Events Associated with GLP-1 Receptor Agonists: Evidence of Intraclass Heterogeneity in the WHO VigiBase Global Database

Background/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. Methods: 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 (CIs). This study adhered to the STROBE and READUS-PV guidelines. Results: 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 24,899 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. Conclusions: 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.