Glucagon-like peptide-1 receptor agonists and mental health: a narrative review of emerging benefits and risks

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for type 2 diabetes mellitus and obesity, are increasingly recognized for their significant impact on the central nervous system, leading to reports of both beneficial and adverse mental health effects. This review summarizes the current evidence on the effects of GLP-1 RAs on various psychiatric and neurocognitive conditions to evaluate their clinical benefits and potential risks. The literature has revealed a complex and multifaceted psychiatric profile. For depression and anxiety, the evidence is conflicting, with large observational studies showing contradictory results that are largely attributable to confounding by indication or methodological differences in the study design. In contrast, consistent and positive evidence suggests therapeutic potential for substance use disorders, particularly alcohol use disorders. Furthermore, emerging data indicate a significant neuroprotective role, with several cohort studies indicating a reduced risk of dementia. The major public and regulatory attention regarding suicidality appears to be driven by the methodological limitations of the initial reports, as well-controlled active comparator studies have not found an increased risk. However, the safety of GLP-1 RAs in high-risk psychiatric populations has not been established. In conclusion, while GLP-1 RAs show considerable therapeutic potential, their unresolved safety profile in patients with preexisting psychiatric conditions necessitates a cautious clinical approach. Future large-scale randomized controlled trials that include psychiatric populations are crucial for clarifying the direct neuromodulatory effects of these agents and establishing guidelines for their safe use.