Investigating antidiabetic drug targets as potential therapeutic modulators for schizophrenia

Certain types of antidiabetic drugs (ADs) have been proven to improve cognitive functions and symptom dimensions in schizophrenia (SCZ).

Schizophrenia is a major contributor to social functional impairment, and antipsychotics (APs) remain the cornerstone of its treatment. Investigating the potential of antidiabetic drugs as APs could significantly advance therapeutic strategies for schizophrenia.

To assess this potential, we employed an integrated analytical framework that included two-sample Mendelian randomization (MR) using genetic proxies for antidiabetic drug targets, multivariable MR (MVMR), and colocalization analyses. Furthermore, gene and drug enrichment analyses alongside molecular docking studies were performed to elucidate underlying mechanisms and identify candidate drugs. The analysis utilized summary statistics from genome-wide association meta-analyses (GWAS) of schizophrenia, as well as gene expression data from the eQTLGen consortium.

A total of fourteen drug targets were identified among eight major antidiabetic drugs. Notably, RXRB, a target of thiazolidinediones (TZDs), exhibited a strong inverse association with schizophrenia risk (OR: 0.28, 95% CI: 0.21-0.38, P < 0.001). Other significant targets included GPD1 (targeted by metformin), LRP2 (insulin), SLC5A2 (SGLT2 inhibitors), and ABCC8/KCNJ11 and INS (sulfonylureas). Primary and secondary MR analyses confirmed the associations of RXRB, INS, LRP2, and SLC5A2 with gene expression levels. Drug enrichment and molecular docking analyses identified bezafibrate as a promising candidate for repurposing as an AP.

Antidiabetic drugs may possess therapeutic potential in schizophrenia by modulating specific drug-related pathways.These findings provide new theoretical support for the selection of ADs in patients with schizophrenia comorbid with diabetes, and also offer new insights for the future development of APs.