Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become first-line pharmacotherapy for eligible patients with type 2 diabetes mellitus and obesity. Soon after their broad uptake, spontaneous reports of suicidal ideation, depression, and anxiety prompted regulatory investigations and a contentious debate about the neuropsychiatric safety of the class. Objective: We aimed to synthesize emerging evidence on psychiatric adverse outcomes associated with GLP-1 RAs by integrating mechanistic, pharmacovigilance, observational, and regulatory data; to trace how the evidence and regulatory assessments evolved chronologically from initial signal detection toward subsequent controlled refutation; and to translate the current balance of evidence into practical clinical guidance. Methods: We conducted a narrative integrative synthesis of peer-reviewed pharmacovigilance studies, cohort and case–control analyses, systematic reviews and meta-analyses, mechanistic literature, and regulatory communications identified through targeted searches of the published record through early 2026. Results: Disproportionality analyses of spontaneous-reporting databases have generated modest, semaglutide-predominant signals for depression and suicidality, whereas liraglutide and tirzepatide have generally not. Anxiety signals parallel those for depression, and emerging data also indicate potential benefits for substance-use, binge-eating, and sleep-disordered breathing. In contrast, large propensity-matched cohort studies, a nationwide case–time–control analysis, an administrative-claims cohort exceeding two million users, and a meta-analysis of 91 placebo-controlled trials enrolling 107,910 participants found no increased risk and, in some analyses, lower risk of suicidal ideation. The principal exception is an amplified reporting signal among patients co-prescribed antidepressants or benzodiazepines, indicating effect modification by psychiatric vulnerability. Conclusions: The preponderance of controlled evidence has not demonstrated a causal relationship between GLP-1 RAs and suicidality or major psychiatric harm, a conclusion reflected in 2024–2026 regulatory determinations. Residual uncertainty persists for psychiatrically vulnerable subgroups, justifying continued individualized monitoring rather than restriction of access.
Batra et al. (2026) studied this question.