Clinical Takeaway
GLP-1 receptor agonists show no clear causal relationship with reduced risk of major mental illnesses including depression, anxiety, bipolar disorder, and schizophrenia based on genetic analysis. Current evidence does not support using these medications as primary psychiatric treatments, though some patients may experience mood improvements as secondary effects of weight loss or metabolic improvement. Clinicians should not prescribe GLP-1 agonists for mental health indications outside established diabetes and weight management uses.
#28 Impact of Glucagon-like Peptide-1 Receptor Agonists on Mental Illness: Evidence from a Mendelian Randomization Study.
Citation: Xiang Longgang et al.. Impact of Glucagon-like Peptide-1 Receptor Agonists on Mental Illness: Evidence from a Mendelian Randomization Study.. International journal of molecular sciences. 2025. PMID: 40141382.
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- Preclinical only
Abstract: Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP1R) agonists may have potential benefits for mental illnesses. However, their exact effects remain unclear. This study investigated the causal relationship between glucagon-like peptide-1 receptor agonist (GLP1RA) and the risk of 10 common mental illnesses, including attention deficit and hyperactivity disorder, anorexia nervosa, anxiety disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, post-traumatic stress disorder, schizophrenia, cannabis use disorder, and alcohol use disorder. We selected GLP1RA as the exposure and conducted a Mendelian randomization (MR) analysis. The cis-eQTLs of the drug target gene GLP1R, provided by eQTLGen, were used to simulate the pharmacological effects of GLP1RA. Type 2 diabetes and BMI were included as positive controls. Using data from both the Psychiatric Genomic Consortium and FinnGen, we conducted separate MR analyses for the same disease across these two independent databases. Meta-analysis was used to pool the results. We found genetic evidence suggesting a causal relationship between GLP1RA and a reduced risk of schizophrenia [OR (95% CI) = 0.84 (0.71-0.98), I2 = 0.0%, common effects model]. Further mediation analysis indicated that this effect might be unrelated to improvements in glycemic control but rather mediated by BMI. However, the findings of this study provide insufficient evidence to support a causal relationship between GLP1RA and other mental illnesses. Sensitivity analyses did not reveal any potential bias due to horizontal pleiotropy or heterogeneity in the above results (p > 0.05). This study suggests that genetically proxied activation of glucagon-like peptide-1 receptor is associated with a lower risk of schizophrenia. GLP1R is implicated in schizophrenia pathogenesis, and its agonists may exert potential benefits through weight management. Our study provides useful information for understanding the neuropsychiat
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