Effects of Antipsychotics on Skeletal Muscle Molecular Pathways: A Systematic Review

Antipsychotics increase metabolic risk, but the contribution of skeletal muscle molecular alterations remains incompletely defined. We systematically reviewed evidence describing antipsychotic-associated molecular effects in skeletal muscle across human, animal, and cell-based models. MEDLINE, Embase, and PsycINFO were searched through June 2026 for primary, peer-reviewed studies reporting molecular measurements in skeletal muscle after antipsychotic exposure. Risk of bias was assessed using design-appropriate tools, and evidence was synthesized narratively because of substantial heterogeneity. Of 2292 records screened, 34 studies met inclusion criteria. The evidence base comprised predominantly animal studies, with a smaller number of cell/ex vivo experiments and five human biopsy studies. Antipsychotic exposure was associated with alterations in insulin signaling and glucose uptake, lipid composition, mitochondrial respiration and substrate metabolism, calcium handling, gene expression, DNA methylation, and myotube integrity. Olanzapine and clozapine most often showed adverse muscle-related effects, although findings varied by agent, model, dose, and exposure duration. Certainty was generally low to very low with moderate certainty for selected, controlled experimental findings. Major limitations included heterogeneity, limited human evidence, and frequent risk-of-bias concerns. Antipsychotic exposure may alter skeletal muscle molecular pathways but the implications for clinical outcomes remain unknown. Larger, longitudinal human studies are needed to establish causality, clinical relevance, and potential therapeutic targets.