Neuro-Metabolic Disruption Underlying Olanzapine-Induced Obesity

Olanzapine remains a cornerstone to treat schizophrenia and bipolar disorder. However, its clinical utility is constrained by high propensity to induce obesity and metabolic dysfunction. Despite decades of clinical use, olanzapine-induced weight gain is still framed as secondary and largely unavoidable adverse effect. The present review is needed to consolidate emerging evidence demonstrating that olanzapine disrupts energy homeostasis through effects on central appetite-regulating circuits, peripheral endocrine and metabolic pathways, and gut microbiome–mediated signaling. We explore current knowledge on hypothalamic and reward-related neural mechanisms, insulin and leptin dysregulation, adipose tissue remodeling, and microbiome-derived metabolic modulation. In addition, we evaluate experimental models, including rodent and zebrafish systems that have been instrumental in dissecting these mechanisms and identifying translational opportunities. By integrating clinical relevance with mechanistic and model-based insights, this review aims to reframe olanzapine-induced obesity as a tractable, drug-induced metabolic condition. Such approach is essential for guiding early risk stratification, informing personalized antipsychotic selection, and accelerating development of metabolically safer therapeutic strategies without compromising psychiatric efficacy.