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However, which case-level characteristics are associated with these reporting patterns remains insufficiently characterized. This study aimed to characterize case-level features associated with psychiatric AE reporting in GLP-1 receptor agonist users through pharmacovigilance and explainable machine learning methods. Methods: The FDA Adverse Event Reporting System (FAERS) data (2021 Q2\u20132025 Q3) were analyzed using a comparator-based approach comprising other antidiabetic and anti-obesity agents. Disproportionality analyses (PRR, ROR, and IC) were performed to detect consolidated safety signals at the Preferred Term (PT) level, with additional drug-specific analyses for individual GLP-1 receptor agonists. Three classification models (logistic regression, XGBoost, and LightGBM) were developed, and SHAP values were used to identify case-level features associated with psychiatric AE reporting patterns. Results: A total of 211,195 unique cases were included (111,105 for GLP-1 receptor agonists; 100,090 for comparators). Sixteen PTs met consolidated signal criteria, with suicidal ideation being the most frequently reported (ROR 2.95). Drug-specific analyses indicated that signal magnitudes were consistently higher for semaglutide than tirzepatide. The XGBoost model achieved an AUROC of 0.816. SHAP analysis showed that age \u226565 years had the highest mean |SHAP| value (0.57) with a negative direction, corresponding to a lower predicted probability of psychiatric AE reporting in older adults. Semaglutide use ranked second (0.35) and showed a positive direction. Absence of concomitant medications (0.20) and diabetes indication (0.10) showed negative directions, while younger age (19\u201344 years, 0.08) showed a positive direction. These patterns remained consistent in sensitivity analysis excluding concomitant psychotropic medication users (AUROC 0.797). Conclusions: Older age status was associated with decreased predicted probability of psychiatric AE reporting, while semaglutide use and younger age showed positive contributions. These case-level patterns, identified through pharmacovigilance analysis using a comparator-based approach and explainable machine learning, suggest that reporting patterns may differ across subgroups and that the observed reporting heterogeneity among younger adults and semaglutide users merits further investigation in prospective studies.<\/jats:p>","DOI":"10.3390\/ph19060953","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:06:34Z","timestamp":1782875194000},"page":"953","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Psychiatric Safety Signals of GLP-1 Receptor Agonists: A FAERS-Based Pharmacovigilance Study with Explainable Machine Learning"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7034-2115","authenticated-orcid":false,"given":"Suhyeon","family":"Moon","sequence":"first","affiliation":[{"name":"Department of Biohealth Regulatory Science, Graduate School, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"EunJu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biohealth Regulatory Science, Graduate School, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doyeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biohealth Regulatory Science, Graduate School, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9532-1581","authenticated-orcid":false,"given":"Kyung Hee","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0635-4374","authenticated-orcid":false,"given":"Yeo Jin","family":"Choi","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Institute of Integrated Pharmaceutical Science, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2388-1122","authenticated-orcid":false,"given":"Sooyoung","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Biohealth Regulatory Science, Graduate School, Ajou University, Suwon 16499, Republic of Korea"},{"name":"Department of Pharmacy, College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","first-page":"e984","article-title":"Obesity and cardiovascular disease: A scientific statement from the American Heart Association","volume":"143","author":"Poirier","year":"2021","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102848","DOI":"10.1016\/j.eclinm.2024.102848","article-title":"Burden of disease attributable to high body mass index: An analysis of data from the Global Burden of Disease Study 2021","volume":"76","author":"Zhou","year":"2024","journal-title":"eClinicalMedicine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0140-6736(23)01301-6","article-title":"Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: A systematic analysis for the Global Burden of Disease Study 2021","volume":"402","author":"Ong","year":"2023","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/S0140-6736(23)02750-2","article-title":"Worldwide trends in underweight and obesity from 1990 to 2022: A pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults","volume":"403","author":"Phelps","year":"2024","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, J.-Y., Wang, Q.-W., Yang, X.-Y., Yang, W., Li, D.-R., Jin, J.-Y., Zhang, H.-C., and Zhang, X.-F. 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