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Psychiatric Safety Signals of GLP-1 Receptor Agonists: A FAERS-Based Pharmacovigilance Study with Explainable Machine
Suhyeon Moon1, EunJu Lee1, Doyeon Kim1
1Department of Biohealth Regulatory Science, Graduate School, Ajou University, Suwon 16499, Republic of Korea.
Pharmaceuticals (Basel, Switzerland)
|June 26, 2026
Summary
Glucagon-like peptide-1 (GLP-1) receptor agonist use is linked to psychiatric adverse events, with older adults showing lower reporting probability. Younger patients and semaglutide use were associated with increased reporting of these events.
Area of Science:
- Pharmacovigilance
- Machine Learning
- Drug Safety
Background:
- Growing global use of glucagon-like peptide-1 (GLP-1) receptor agonists has coincided with increased psychiatric adverse event (AE) reports.
- Limited understanding exists regarding case-level factors influencing these reporting patterns.
Purpose of the Study:
- To characterize case-level features associated with psychiatric AE reporting in GLP-1 receptor agonist users.
- To employ pharmacovigilance and explainable machine learning for this analysis.
Main Methods:
- Analysis of FDA Adverse Event Reporting System (FAERS) data (2021 Q2-2025 Q3) using a comparator-based approach.
- Disproportionality analyses (PRR, ROR, IC) and drug-specific analyses for GLP-1 receptor agonists.
- Development of classification models (logistic regression, XGBoost, LightGBM) with SHAP values for feature importance.
Main Results:
- 16 Preferred Terms (PTs) met consolidated signal criteria; suicidal ideation was most frequent (ROR 2.95).
- Semaglutide showed higher signal magnitudes than tirzepatide.
- XGBoost model achieved an AUROC of 0.816; older age (≥65 years) decreased reporting probability, while semaglutide use and younger age (19-44 years) increased it.
Conclusions:
- Older age is associated with decreased predicted psychiatric AE reporting probability.
- Semaglutide use and younger age are associated with increased reporting probability.
- Reporting heterogeneity across subgroups, particularly younger adults and semaglutide users, warrants further investigation.
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