Neuropsychiatric adverse events related to the use of GLP-1 receptor agonists
A systematic review
DOI:
https://doi.org/10.59487/2965-1956-4-16811Keywords:
Glucagon-Like Peptide-1 Receptor Agonists, rug-Related Side Effects and Adverse Reactions, Mental DisordersAbstract
Objective: To evaluate the main neuropsychiatric adverse events associated with the use of GLP-1 receptor agonists. Methods: This systematic review analyzed articles published between 2019 and 2025 in the PubMed and Medline databases, using the search terms “GLP-1 agonist,” “mental disorders,” and “adverse effects.” Observational and experimental study designs were included. Nine articles were selected, encompassing diverse methodologies such as pharmacovigilance studies, retrospective cohorts, Mendelian randomization, and post-hoc analyses of randomized clinical trials. Results: Pharmacovigilance studies identified a possible association between GLP-1 receptor agonists and neuropsychiatric adverse events. Analyses involving semaglutide showed adjusted reporting odds ratios of 1.70 for depression, 1.26 for anxiety, and 1.45 for suicidal behavior. Another study reported a ratio of 2.55 for suicidal ideation among semaglutide users for weight loss, as well as cases of eating disorders. In contrast, post hoc analyses of clinical trials did not reveal significant differences in depressive symptoms or suicidal ideation compared with placebo. Mendelian randomization studies suggested a reduced risk of GLP-1 receptor activation for schizophrenia, bipolar disorder, and bulimia nervosa, while one cross-sectional study associated semaglutide with decreased symptoms of anxiety and depression. Conclusion: A direct causal relationship between GLP-1 receptor agonists and severe neuropsychiatric adverse events has not been fully established. Methodological heterogeneity and confounding factors account for the discrepancies: while pharmacovigilance studies raise concerns, more controlled study designs do not confirm causality. Active clinical monitoring of patients is recommended, and larger randomized clinical trials are needed to clarify the risk–benefit profile of these drugs.
Downloads
References
Zayed MF, Khyat NO, Alsibyani RW, Alshami RZ, Alsubahi RA, Alamoudi MK. An insight into pharmaceutical design and pharmacokinetic characteristics of GLP-1 RAs. Curr Pharm Des. 2025;CPD-EPUB-150007. doi:10.2174/0113816128375766250720234005
Lyseng-Williamson KA. Glucagon-like peptide-1 receptor analogues in type 2 diabetes: their use and differential features. Clin Drug Investig. 2019;39(8):805-819. doi:10.1007/s40261-019-00826-0
Gonzalez-Rellan MJ, Drucker DJ. New molecules and indications for GLP-1 medicines. JAMA. 2025;2838996. doi:10.1001/jama.2025.14392
Al Qassab M, Mneimneh M, Jradi A, Derbas B, Dabboussi D, Khoury Baini J, et al. The expanding role of GLP-1 receptor agonists: advancing clinical outcomes in metabolic and mental health. Curr Issues Mol Biol. 2025;47(4):285. doi:10.3390/cimb47040285
Chen W, Cai P, Zou W, Fu Z. Psychiatric adverse events associated with GLP-1 receptor agonists: a real-world pharmacovigilance study based on the FDA Adverse Event Reporting System database. Front Endocrinol (Lausanne). 2024;15:1330936. doi:10.3389/fendo.2024.1330936
Lu W, Wang S, Tang H, Yuan T, Zuo W, Liu Y. Neuropsychiatric adverse events associated with glucagon-like peptide-1 receptor agonists: a pharmacovigilance analysis of the FDA Adverse Event Reporting System database. Eur Psychiatry. 2025;68(1):e20. doi:10.1192/j.eurpsy.2024.1803
Chen W, Cai P, Zou W, Fu Z. Psychiatric adverse events associated with GLP-1 receptor agonists: a real-world pharmacovigilance study based on the FDA Adverse Event Reporting System database. Front Endocrinol. 2024;15:1330936. doi:10.3389/fendo.2024.1330936
Guirguis A, Chiappini S, Papanti GD, Vickers-Smith R, Harris D, Corkery JM, et al. Exploring the association between suicidal thoughts, self-injury, and GLP-1 receptor agonists in weight loss treatments: Insights from pharmacovigilance measures and unmasking analysis. Eur Neuropsychopharmacol. 2024;82:82-91. doi:10.1016/j.euroneuro.2024.02.003
Nishida K, Chrétien B, Dolladille C, Ebina T, Aleksic B, Cabé N, et al. Psychiatric and psychological adverse effects associated with dulaglutide, semaglutide, and liraglutide: A VigiBase study. Clin Nutr. 2025;51:252-265. doi:10.1016/j.clnu.2025.06.011
Schoretsanitis G, Weiler S, Barbui C, Raschi E, Gastaldon C. Disproportionality analysis from World Health Organization data on semaglutide, liraglutide, and suicidality. JAMA Netw Open. 2024;7(8):e2423385. doi:10.1001/jamanetworkopen.2024.23385
Farr OM, Sofopoulos M, Tsoukas MA, Dincer F, Thakkar B, Sahin-Efe A et al. GLP-1 receptors exist in the parietal cortex, hypothalamus and medulla of human brains and the GLP-1 analogue liraglutide alters brain activity related to highly desirable food cues in individuals with diabetes: a crossover, randomised, placebo-controlled trial. Diabetologia. 2016;59:954-65. doi:10.1007/s00125-016-3874-y
Kornelius E, Huang J-Y, Lo S-C, Huang C-N, Yang Y-S. The risk of depression, anxiety, and suicidal behavior in patients with obesity on glucagon like peptide-1 receptor agonist therapy. Sci Rep. 2024; 14:24433. doi:10.1038/s41598-024-75965-2
Wadden TA, Brown WM, Egebjerg L, Frenkel RE, Goldman B, McGowan B, et al. Psychiatric Safety of Semaglutide for Weight Management in People Without Known Major Psychopathology: Post Hoc Analysis of the STEP 1, 2, 3, and 5 Trials. JAMA Intern Med. 2024;184(9):1019-1028. doi:10.1001/jamainternmed.2024.4346
Chao AM, Wadden TA, Walsh OA, Gruber KA, Alamuddin N, Berkowitz RI, et al. Effects of Liraglutide and Behavioral Weight Loss on Food Cravings, Eating Behaviors, and Eating Disorder Psychopathology. Obesity (Silver Spring). 2019;27(12):2005-2010. doi:10.1002/oby.22653
Di Stefano R, Rindi LV, Baldini V, Rossi R, Pacitti F, Jannini EA et al. Glucagon-like peptide-1 receptor agonists, dual GIP/GLP-1 receptor agonist tirzepatide and suicidal ideation and behavior: a systematic review of clinical studies and pharmacovigilance reports. Diabetes Metab Syndr. 2025;19:103238. doi:10.1016/j.dsx.2025.103238
Xiang L, Peng Y. Impact of glucagon-like peptide-1 receptor agonists on mental illness: evidence from a Mendelian randomization study. Int J Mol Sci. 2025;26(6):2741. doi:10.3390/ijms26062741
Zhang L, Chen X, Xu Y, Liu J, Liu Z. Exploring glucagon-like peptide-1 receptor agonists as potential disease-modifying agent in psychiatric and neurodevelopmental conditions: evidence from a drug target Mendelian randomization. BMC Psychiatry. 2025;25(1):484. doi:10.1186/s12888-025-06413-8
Witaszek T, Kłoda K, Mastalerz-Migas A, Babicki M. Association between symptoms of depression and generalised anxiety disorder evaluated through PHQ-9 and GAD-7 and anti-obesity treatment in Polish adult women. Nutrients. 2024;16(15):2438. doi:10.3390/nu16152438
Leutner M, Dervic E, Bellach L, Klimek P, Thurner S, Kautzky A. Obesity as pleiotropic risk state for metabolic and mental health throughout life. Transl Psychiatry. 2023; 13(1):175. doi:10.1038/s41398-023-02447-w
Meshkat S, Di Luciano C, Swiderski A, Li G, Aguilar RJ, Dunkley BT et al. Efficacy and safety of glucagon-like peptide-1 agonists for psychiatric symptoms: a systematic review. Brain Behav. 2025;15(7):e70661. doi:10.1002/brb3.70661
Ma KJ, Chou MH, Chen JD, Huang MQ, Tseng PY, Su SY et al. Exploring the role of obesity in predicting mental health disorders: analyzing the effects of diagnosis sequence order. BMC Psychiatry. 2025; 25(1):946. doi:10.1186/s12888-025-07427-6
Pantovic-Stefanovic M, Velimirovic M, Jurisic V et al. Exploring the role of TNF-α, TGF-β, and IL-6 serum levels in categorical and noncategorical models of mood and psychosis. *Sci Rep.* 2024;14(1):23117. doi:10.1038/s41598-024-23117
Kirichenko TV, Markina YV, Bogatyreva AI, Tolstik TV, Varaeva YR, Starodubova AV. The role of adipokines in inflammatory mechanisms of obesity. Int J Mol Sci. 2022;23(23):14982. doi:10.3390/ijms232314982
Lin MH, Cheng PC, Hsiao PJ et al. The GLP-1 receptor agonist exenatide ameliorates neuroinflammation, locomotor activity, and anxiety-like behavior in mice with diet-induced obesity through the modulation of microglial M2 polarization and downregulation of SR-A4. Int Immunopharmacol. 2023;115:109653. doi:10.1016/j.intimp.2023.109653
European Medicines Agency (EMA). EMA statement on ongoing review of GLP-1 receptor agonists. EMA. 2023. Available from: [https://www.ema.europa.eu/en/news/ema-statement-ongoing-review-glp-1-receptor-agonists] (https://www.ema.europa.eu/en/news/ema-statement-ongoing-review-glp-1-receptor-agonists)
U.S. Food and Drug Administration (FDA). Update on FDA's ongoing evaluation of reports of suicidal thoughts or actions in patients taking a certain type of medicines approved for type 2 diabetes and obesity. FDA. 2024.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Ana Carolina Parahyba Asfor, Ticihana Ribeiro de Oliveira, Matheus Eugênio de Sousa Lima
This work is licensed under a Creative Commons Attribution 4.0 International License.
