{"title":"Investigating antidiabetic drug targets as potential therapeutic modulators for schizophrenia.","authors":"Yu-Sheng Huang, Xu Lin, Ya-Juan Xu, Gui-Bing Chen","doi":"10.1007/s00213-025-06951-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Rationale: </strong>Certain types of antidiabetic drugs (ADs) have been proven to improve cognitive functions and symptom dimensions in schizophrenia (SCZ).</p><p><strong>Objectives: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":20783,"journal":{"name":"Psychopharmacology","volume":" ","pages":"2055-2067"},"PeriodicalIF":3.3000,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601183/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00213-025-06951-3","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/11/10 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Rationale: Certain types of antidiabetic drugs (ADs) have been proven to improve cognitive functions and symptom dimensions in schizophrenia (SCZ).
Objectives: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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