Association of glucagon-like peptide-1 receptor agonists and seven common mental disorders: A drug target and mediation Mendelian randomization

May 30, 2025Journal of affective disorders

Links Between Glucagon-Like Peptide-1 Receptor Drugs and Seven Common Mental Illnesses Using Genetic Analysis

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Abstract

GLP1RA is associated with reduced risk of Major Depression Disorder (MDD), Bipolar Disorder (BID), and Autism Spectrum Disorder (ASD).

Genetically predicted levels of GLP1R expression correspond to physiological effects such as reduced blood glucose and appetite suppression.
A reduction in the risk of MDD is observed with an odds ratio of 0.6831, indicating a protective effect.
BID shows a similar reduction in risk with an odds ratio of 0.8019.
ASD is associated with a risk reduction indicated by an odds ratio of 0.7115.
Mendelian Randomization results suggest GLP1RA may be a risk factor for Anorexia Nervosa.
Serum glucagon and insulin levels are implicated in the causal effects between GLP1R expression and certain disorders.

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BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP1RA) have been associated with psychiatric symptoms; however, the causal relationships between GLP1RA and seven common mental disorders remain unknown.

METHODS: Mendelian Randomization (MR) were employed to explore the causalities between GLP1RA and seven common mental disorders using genome-wide association study (GWAS) data from 3 million individuals. Type 2 diabetes, blood glucose levels, insulin levels, and appetite was used as positive control. Multiple validations were performed based on the Psychiatric Genomics Consortium (PGC), UK Biobank (UKB), and FinnGen databases. A two-step MR analysis was used to assess the mediating effects. Finally, a systematic review was conducted to validate the psychotropic side effects of GLP1RA.

RESULTS: Positive control analysis indicated that the genetically predicted levels of GLP1R expression accurately reflect the physiological effects of GLP1RA, encompassing the reduction of blood glucose, fat reduction, endocrine regulation, and appetite suppression. GLP1RA reduced the risk of Major Depression Disorder (MDD) (OR = 0.6831 (0.6412-0.7277), FDR < 0.05), Bipolar Disorder (BID) (OR = 0.8019 (0.7504-0.857), FDR < 0.05), and Autism Spectrum Disorder (ASD) (OR = 0.7115 (0.6448-0.7852), FDR < 0.05). Meta results of MR support GLP1RA being a risk factor for Anorexia Nervosa (AN). The mediating MR results showed that serum glucagon and insulin levels were involved in the causal effects between GLP1R expression levels and AN (5.58 %) and BID (6.37 %) (P < 0.05). Finally, 16 observational studies were included in systematic review, most of which supported GLP1RA as a protective factor for MDD.

CONCLUSIONS: Our study suggests that GLP1RA can reduce the risk of MDD, ASD, and BID. This study has significant implications for the safe application of GLP1RAs.

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Association of glucagon-like peptide-1 receptor agonists and seven common mental disorders: A drug target and mediation Mendelian randomization

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