Alpha Psychiatry. 2025 Dec 22;26(6):49352. doi: 10.31083/AP49352. eCollection 2025 Dec.
ABSTRACT
OBJECTIVE: To explore the molecular mechanisms underlying clozapine-induced metabolic syndrome (MetS) in schizophrenia patients, providing scientific evidence for clinicians to prevent and manage metabolic syndrome during the treatment of psychiatric disorders.
METHODS: Ten schizophrenia patients with MetS and ten matched controls were recruited from Shanghai Mental Health Center according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for schizophrenia and the 2016 Chinese Adult Dyslipidemia Prevention and Treatment Guidelines for MetS. Peripheral blood RNA sequencing was performed to identify differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network were used to pinpoint hub genes. Mendelian randomization (MR) was conducted to validate causal relationship between serum brain-derived neurotrophic factor (BDNF) levels and MetS components.
RESULTS: A total of 1019 DEGs were identified, grouped into eight mRNA modules through WGCNA. Key hub genes included RP11-611O2.6, acid phosphatase-like 2 (ACPL2), T cell receptor alpha variable 12-2 (TRAV12-2), matrix metallopeptidase 8 (MMP8), piggyBac transposable element derived 4 pseudogene 1 (PGBD4P1), transmembrane protein 261 (TMEM261), and BDNF, with BDNF and MMP8 further validated by PPI network analysis. MR analysis confirmed a causal association between BDNF levels and MetS risk, reinforcing its role in metabolic dysregulation. Gene Ontology (GO) annotation and pathway enrichment analysis highlighted immune response, morphological changes, and metabolic processes as key biological processes, with pathways such as biological oxidation and defensins significantly enriched.
CONCLUSION: Significant differences in gene expression are observed between schizophrenia patients with and without MetS. Individual variability in clozapine-induced MetS may be linked to DEGs.
PMID:41523972 | PMC:PMC12781211 | DOI:10.31083/AP49352
