Neuropsychiatric Safety of GLP-1 Receptor Agonists and Tirzepatide in Adults with Type 2 Diabetes Mellitus or Obesity.
- 1Master of Public Health Program, Long Island University, Brooklyn, New York, USA.
- 2Frank H. Netter MD School of Medicine, Quinnipiac University, North Haven, Connecticut, USA.
- 3St. Vincent's Medical Center, Hartford HealthCare, Bridgeport, Connecticut, USA.
Abstract
Neuropsychiatric safety concerns about glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and tirzepatide prompted regulatory review by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). We synthesized the contemporary evidence in adults with type 2 diabetes mellitus or obesity, emphasizing study design, risk of bias, and the distinction between signal detection and causal inference. The PubMed/MEDLINE, Embase, Web of Science, and Scopus databases were searched without a lower date limit through March 15, 2026 (English, adults ≥18 years). The review was reported with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020, and the PRISMA-S and PRISMA-Harms extensions. Evidence was grouped into prespecified categories: randomized syntheses, comparative observational studies and target-trial emulations, outlier non-active-comparator studies, pharmacovigilance analyses, and regulatory reviews. Risk of bias was appraised with the Cochrane Risk of Bias 2 tool and with Risk of Bias in Non-randomised Studies of Interventions; certainty was summarized using Grading of Recommendations Assessment, Development and Evaluation. Twenty studies and two regulatory reviews met the inclusion criteria. Randomized evidence, including two large 2025 meta-analyses and post hoc pooled analyses of semaglutide and tirzepatide, showed no increased risk of suicidality, depression, or anxiety, though psychiatric exclusion criteria limited generalizability. Active-comparator cohorts from the United States, Scandinavia, and the United Kingdom likewise showed no clear increase after confounding control. Passive-comparator and disproportionality analyses generated signals but could not separate drug effects from baseline psychiatric risk, obesity-related distress, or reporting bias. The EMA and FDA conclusions do not support a causal class-wide association between GLP-1 RAs and suicidal ideation or behavior. Evidence does not support a clinically meaningful increase in neuropsychiatric harm with GLP-1 RAs or tirzepatide in the populations studied. Surveillance remains warranted for patients with substantial psychiatric morbidity, for obesity-only populations, and for long-term rare outcomes.
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BibTeX
@article{jani2026neuropsychiatric,
title = {{Neuropsychiatric Safety of GLP-1 Receptor Agonists and Tirzepatide in Adults with Type 2 Diabetes Mellitus or Obesity.}},
author = {Het Tushar Jani and Helisse Levine and Abhiraj Patel and Richa Trivedi and Xitij Dineshkumar Patel},
journal = {Rambam Maimonides medical journal},
year = {2026},
month = oct,
doi = {10.5041/rmmj.10585},
url = {https://europepmc.org/article/MED/42957176},
note = {CC BY},
}
RIS
TY - JOUR
TI - Neuropsychiatric Safety of GLP-1 Receptor Agonists and Tirzepatide in Adults with Type 2 Diabetes Mellitus or Obesity.
AU - Het Tushar Jani
AU - Helisse Levine
AU - Abhiraj Patel
AU - Richa Trivedi
AU - Xitij Dineshkumar Patel
PY - 2026
DA - 2026/10/26
JO - Rambam Maimonides medical journal
DO - 10.5041/rmmj.10585
UR - https://europepmc.org/article/MED/42957176
AB - Neuropsychiatric safety concerns about glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and tirzepatide prompted regulatory review by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). We synthesized the contemporary evidence in adults with type 2 diabetes mellitus or obesity, emphasizing study design, risk of bias, and the distinction between signal detection and causal inference. The PubMed/MEDLINE, Embase, Web of Science, and Scopus databases were searched without a lower date limit through March 15, 2026 (English, adults ≥18 years). The review was reported with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020, and the PRISMA-S and PRISMA-Harms extensions. Evidence was grouped into prespecified categories: randomized syntheses, comparative observational studies and target-trial emulations, outlier non-active-comparator studies, pharmacovigilance analyses, and regulatory reviews. Risk of bias was appraised with the Cochrane Risk of Bias 2 tool and with Risk of Bias in Non-randomised Studies of Interventions; certainty was summarized using Grading of Recommendations Assessment, Development and Evaluation. Twenty studies and two regulatory reviews met the inclusion criteria. Randomized evidence, including two large 2025 meta-analyses and post hoc pooled analyses of semaglutide and tirzepatide, showed no increased risk of suicidality, depression, or anxiety, though psychiatric exclusion criteria limited generalizability. Active-comparator cohorts from the United States, Scandinavia, and the United Kingdom likewise showed no clear increase after confounding control. Passive-comparator and disproportionality analyses generated signals but could not separate drug effects from baseline psychiatric risk, obesity-related distress, or reporting bias. The EMA and FDA conclusions do not support a causal class-wide association between GLP-1 RAs and suicidal ideation or behavior. Evidence does not support a clinically meaningful increase in neuropsychiatric harm with GLP-1 RAs or tirzepatide in the populations studied. Surveillance remains warranted for patients with substantial psychiatric morbidity, for obesity-only populations, and for long-term rare outcomes.
SN - 2076-9172
ER -