GLP-1 Receptor Agonists Show Psychiatric Safety Signals in FAERS Analysis; Semaglutide Higher Than Tirzepatide
Background
The global expansion of glucagon-like peptide-1 (GLP-1) receptor agonist use for conditions like type 2 diabetes and obesity has coincided with an increase in reported psychiatric adverse events (AEs). While these reports exist in spontaneous reporting databases, the specific case-level characteristics associated with these patterns remain poorly understood. This knowledge gap necessitates a deeper investigation into the safety profile of these widely prescribed medications, especially concerning mental health outcomes, to inform clinical practice and patient counseling.
Study Design
Researchers analyzed data from the FDA Adverse Event Reporting System (FAERS) spanning from 2021 Q2 to 2025 Q3. A comparator-based approach was employed, contrasting GLP-1 receptor agonists with other antidiabetic and anti-obesity agents. Disproportionality analyses using PRR, ROR, and IC were conducted to identify consolidated safety signals at the Preferred Term (PT) level. Drug-specific analyses focused on individual GLP-1 receptor agonists, specifically semaglutide and tirzepatide. Three classification models (logistic regression, XGBoost, and LightGBM) were developed, and SHAP values were utilized to pinpoint case-level features linked to psychiatric AE reporting patterns.
Results
The study included a substantial 211,195 unique cases, with 111,105 attributed to GLP-1 receptor agonists and 100,090 to comparators. A total of 16 Preferred Terms met the criteria for consolidated safety signals, indicating a clear association between GLP-1 RA use and psychiatric AEs. Suicidal ideation emerged as the most frequently reported psychiatric adverse event, demonstrating a significant disproportionality with an ROR of 2.95. Drug-specific analyses consistently showed that the signal magnitudes for psychiatric AEs were higher for semaglutide compared to tirzepatide. The XGBoost model achieved a strong predictive performance with an AUROC of 0.816. > SHAP analysis revealed that age ≥65 years had the highest mean |SHAP| value (0.57), indicating a negative association with psychiatric AE reporting, meaning older adults had a lower predicted probability. Semaglutide use ranked second with a mean |SHAP| value of 0.35, showing a positive direction, suggesting increased reporting probability. The absence of concomitant medications (0.20) and a diabetes indication (0.10) were negatively associated, while younger age (19-44 years, 0.08) showed a positive association with psychiatric AE reporting.
Key Findings
- 16 psychiatric Preferred Terms showed safety signals associated with GLP-1 receptor agonists.
- Suicidal ideation was the most frequently reported psychiatric AE, with an ROR of 2.95.
- Psychiatric AE signal magnitudes were consistently higher for semaglutide than tirzepatide.
- Age ≥65 years was associated with a lower probability of psychiatric AE reporting (mean
|SHAP|0.57). - Semaglutide use was associated with a higher probability of psychiatric AE reporting (mean
|SHAP|0.35).
Why It Matters
This pharmacovigilance study provides critical real-world data on the psychiatric safety profile of GLP-1 receptor agonists, offering a more nuanced understanding beyond clinical trial settings. Clinicians should exercise heightened vigilance for psychiatric adverse events, particularly suicidal ideation, when prescribing GLP-1 RAs, especially in younger patients and those on semaglutide. The differential signal magnitudes between semaglutide and tirzepatide suggest that specific GLP-1 RAs might carry varying risk profiles, which could influence prescribing decisions. While this study does not provide a direct protocol, it strongly informs risk-benefit discussions and emphasizes the need for personalized patient monitoring and counseling regarding mental health, particularly when initiating or continuing GLP-1 RA therapy.
glp-1-receptor-agonists
semaglutide
tirzepatide
psychiatric-adverse-events
suicidal-ideation
pharmacovigilance