Glucagon-like peptide-1 receptor activators as possible treatments that change psychiatric and neurodevelopmental disorders: evidence from genetic drug target analysis
Genetically proxied GLP-1RA exposure was associated with a lower risk of several psychiatric and neurodevelopmental conditions.
A lower risk of schizophrenia ( 0.72) was found in association with GLP-1RA exposure.
Bipolar disorder showed a reduced risk, with an odds ratio of 0.91.
Bulimia nervosa risk was significantly lower, indicated by an odds ratio of 0.34.
Post-traumatic stress disorder (PTSD) was associated with a reduced risk (odds ratio 0.45).
Autism risk was also lower with GLP-1RA exposure (odds ratio 0.55).
In contrast, higher GLP-1R expression was linked to an increased risk of obsessive-compulsive disorder (OCD) with an odds ratio of 2.30.
Simplified
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have recently received Food and Drug Administration (FDA) approval for obesity management. However, the causal relationship between GLP-1RAs and psychiatric and neurodevelopmental conditions remains unclear.
METHODS: We used (MR) to investigate the association between genetically proxied GLP-1RA exposure and 12 psychiatric and neurodevelopmental conditions. Genetic instruments were derived from cis-eQTLs for GLP-1R, and analyses were conducted using large-scale GWAS datasets. Type 2 diabetes was included as a positive control (107,133 cases, 656,672 controls). Findings were assessed across multiple independent datasets, including FinnGen, Psychiatric Genomics Consortium (PGC), and UK Biobank, and were synthesized through meta-analysis.
RESULT: Genetically proxied GLP-1RA exposure was associated with a lower risk of schizophrenia ( = 0.72, 95% CI [0.61-0.86]), bipolar disorder (OR = 0.91, 95% CI [0.88-0.94]), bulimia nervosa (OR = 0.34, 95% CI [0.23-0.52]), post-traumatic stress disorder (PTSD) (OR = 0.45, 95% CI [0.31-0.67]), and autism (OR = 0.55, 95% CI [0.32-0.93]), all P < 0.001. Conversely, higher GLP-1R expression was associated with an increased risk of obsessive-compulsive disorder (OCD) (OR = 2.30, 95% CI [1.26-4.22], P < 0.001). No significant associations were observed for anorexia nervosa, broad depression, major depressive disorder (MDD), or suicide and intentional self-harm. Sensitivity analyses and heterogeneity assessments supported the robustness of these findings across multiple cohorts.
LIMITATIONS: GLP-1RAs reduced some psychiatric and neurodevelopmental conditions but lacked extensive evidence. Bulimia nervosa and PTSD evidence was limited to one database. Bipolar disorder and OCD results varied, with significant OCD findings in one database. The study's European ancestry focus limits generalizability. Rare disorders and disease progression were not examined. Future research needs diverse populations, long-term follow-ups, and treatment exploration.
CONCLUSIONS: Our study suggests that GLP-1RAs may decrease the risk of schizophrenia, anxiety disorders, bipolar disorder, bulimia nervosa, PTSD, and autism, but may increase the risk of OCD. Larger randomized controlled trials with long-term follow-up are necessary to confirm these associations and evaluate the risk-benefit ratios.
CLINICAL TRIAL NUMBER: Not applicable.
Key numbers
0.72
Lower risk of schizophrenia
() for schizophrenia
2.30
Lower risk of OCD
() for OCD
0.34
Lower risk of bulimia nervosa
() for bulimia nervosa
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