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

Aims: Suicide is a global public health concern, accounting for nearly 700,000 deaths annually. Although well-established risk factors, including mental health disorders, are widely recognized, emerging concerns have surfaced regarding a potential association between glucagon-like peptide-1 receptor agonists (GLP-1 RAs), the dual Gastric Inhibitory Polypeptide (GIP)/GLP-1 Receptor Agonist tirzepatide and suicidal behavior. This systematic review aims to synthesize the available evidence on the potential association between these drugs and suicidal behavior. Methods: This review was conducted following PRISMA guidelines. A systematic search was performed in MEDLINE, Embase, and APA PsycInfo up to September 24, 2024, using terms related to GLP-1 RAs/GIP/GLP-1 RAs and suicidal behavior.Three independent reviewers conducted article screening and data extraction. Risk of bias was evaluated using the Newcastle-Ottawa Scale for cohort studies and ROB2 for RCTs. Results: The review identified 16 studies published between 2017 and 2024, consisting of 5 observational studies, 2 randomized controlled trials, 8 pharmacovigilance analyses, and 1 post-hoc analysis of RCTs. No consistent evidence indicated an increased suicide risk among GLP-1 RA users. Pharmacovigilance analyses produced mixed findings; while some disproportionality analyses reported higher rates relative to other antihyperglycemic drugs, no causal link was confirmed. Cohort studies involving diabetic and obese populations generally did not demonstrate a significant increase in suicidal behavior. Conclusions: Although current data do not warrant changes in prescribing practices, further research is needed before definitive conclusions can be drawn. Moreover, the generalizability and reliability of these findings should be interpreted in light of the methodological limitations of the included studies.