Clinical and molecular implications of antipsychotics in MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has emerged as a major comorbidity among patients with severe mental illness (SMI), particularly those treated with second-generation antipsychotics (SGAs). These agents induce systemic metabolic disturbances through mechanisms involving adipose tissue dysfunction, mitochondrial injury, and dysregulation of hepatic lipid metabolism. Increasing evidence identifies SGAs as significant contributors to hepatic dysfunction, acting through activation of sterol regulatory element-binding proteins (SREBPs), impairment of mitochondrial respiratory function, low-grade inflammation, alterations in the AMPK signaling pathway, and gut microbiota dysbiosis. Collectively, these processes promote hepatic lipid accumulation, insulin resistance, and progression toward non-alcoholic steatohepatitis (NASH). Furthermore, non-invasive biomarkers such as the Fatty Liver Index (FLI) and FIB-4 score have demonstrated potential utility for early screening and risk stratification in psychiatric populations. Overall, SGAs play a central role in the pathogenesis of MASLD by disrupting mitochondrial homeostasis, lipid metabolism, and gut-liver axis communication. Routine liver monitoring should be integrated into psychiatric care, and future research must focus on preventive and therapeutic strategies that protect hepatic function without compromising mental stability.