Abstract
BACKGROUND: Metabolic side effects associated with atypical antipsychotics represent a major challenge in the clinical management of schizophrenia, contributing to poor treatment adherence and an increased risk of relapse. MicroRNAs (miRNAs) have emerged as promising diagnostic biomarkers for schizophrenia, with growing evidence indicating that their expression is modulated by antipsychotic treatment. Dysregulated miRNAs may not only reflect underlying disease mechanisms but also actively contribute to therapeutic response and the development of metabolic side effects. OBJECTIVES: This scoping review critically evaluates the current literature on miRNAs in schizophrenia, focusing on their role in modulating treatment response and antipsychotic-induced metabolic disturbances. Key knowledge gaps are identified to inform future translational research. ELIGIBILITY CRITERIA: We included studies involving adults or animal models with psychotic symptoms (with schizophrenia as the primary diagnosis) treated with atypical antipsychotics. Eligible studies reported associations between miRNA expression, metabolic parameters, and clinical outcomes. SOURCES OF EVIDENCE: A rapid review was conducted using PubMed to identify relevant articles published up to December 1, 2025 and 16 articles were included for final review. CHARTING METHODS: Data charting was performed by one reviewer using a pre-developed and piloted form. The review was reported according to the Preferred Reporting items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR checklist). RESULTS: Atypical antipsychotics, particularly those acting on dopamine and serotonin receptors, were shown to modulate specific dysregulated miRNAs. Several of these miRNAs regulate genes involved in metabolic pathways, such as lipid and glucose metabolism, potentially contributing to the variability in cardiometabolic side effects observed across individuals. CONCLUSION: Emerging evidence suggests that miRNAs may play a dual role in mediating both therapeutic efficacy and metabolic risk in schizophrenia treatment. However, the underlying mechanisms remain incompletely understood. Robust, large-scale studies are urgently needed to validate miRNAs as clinically actionable biomarkers for guiding personalized antipsychotic therapy. TRIAL REGISTRATION: A protocol was not prospectively registered, as the aim of this scoping review was exploratory in nature.