Olanzapine and Peripheral Metabolic Dysregulation: Organ-Resolved Mechanisms, Risk, and MASLD-Aligned Care Pathways

Shuwei WengJinxiu Lin^*Dajun Chai^*

• First Affiliated Hospital of Fujian Medical University, Fuzhou, China

This review examines how olanzapine drives metabolic injury beyond the brain and why an organ-resolved perspective is needed. We synthesize clinical signals of early weight gain, insulin resistance, dyslipidemia, and steatotic liver disease, and integrate translational evidence across liver, adipose tissue, skeletal muscle, pancreatic β-cells, and the gut–liver axis. Mechanistic strands include disordered hepatic lipid handling, suppression of brown-fat thermogenesis, β-cell endoplasmic-reticulum stress with impaired secretion, and skeletal-muscle insulin-signaling defects with altered epigenetic programs that blunt glucose disposal. We summarize modifiers of risk across life stage, treatment exposure, genetic variation, smoking status, and pregnancy, and distill a pragmatic pathway that prioritizes early reassessment, MASLD-aligned liver evaluation, targeted lifestyle treatment, metformin for early deterioration, and GLP-1 receptor agonists when required. We advance the view that weight-independent extra-cerebral mechanisms are central to olanzapine's metabolic liability and that psychiatric practice should adopt metabolic frameworks used in hepatology and endocrinology. We propose an agenda for organ-specific human phenotyping and exposure-aware designs that integrate therapeutic drug monitoring with microbiome, metabolomics, and bile-acid profiling, alongside comparative trials that test stepped algorithms within psychiatric care. This perspective outlines a path to preserve antipsychotic efficacy while reducing preventable systemic metabolic harm.