Abstract
Patients with severe mental illness have increased mortality, often linked to cardio-metabolic disease. Non-alcoholic fatty liver disease (NAFLD) incidence is higher in patients with schizophrenia and is exacerbated with antipsychotic treatment. NAFLD is associated with obesity and insulin resistance, both of which are induced by several antipsychotic medications. NAFLD is considered an independent risk factor for cardiovascular disease, the leading cause of death for patients with severe mental illness. Although the clinical literature clearly defines increased risk of NAFLD with antipsychotic therapy, the underlying mechanisms are not understood. Given the complexity of the disorder as well as the complex pharmacology associated with atypical antipsychotic (AA) medications, we chose to use a proteomic approach in healthy mice treated with a low dose of risperidone (RIS) or olanzapine (OLAN) for 28 days to determine effects on development of NAFLD and to identify pathways impacted by AA medications, while removing confounding intrinsic effects of mental illness. Both AA drugs caused development of steatosis in comparison with vehicle controls (p < 0.01) and affected multiple pathways relating to energy metabolism, NAFLD, and immune function. AA-associated alteration in autonomic function appears to be a unifying theme in the regulation of hepatic pathology.
Highlights
Patients with severe mental illness, including schizophrenia, experience a significantly shortened life expectancy with high rates of all-cause mortality [1,2,3], most commonly associated with metabolic dysregulation and cardiovascular disease
Details of animal growth rates, locomotor activity, adiposity, and energy expenditure for this cohort were recently reported in a manuscript describing atypical antipsychotic (AA) effects on the heart [21]
Animals were maintained on standard mouse chow to avoid potentially confounding effects of high-fat feeding, an experimental paradigm associated with diet-induced obesity and Non-alcoholic fatty liver disease (NAFLD) [22,23]
Summary
Patients with severe mental illness, including schizophrenia, experience a significantly shortened life expectancy with high rates of all-cause mortality [1,2,3], most commonly associated with metabolic dysregulation and cardiovascular disease. Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic worldwide and is associated with obesity, insulin resistance, and inflammation [4,5,6,7]. Incidence of NAFLD is elevated in patients with severe mental illness [3] and with atypical antipsychotic (AA) treatment [8]. NAFLD is progressive in nature, characterized by hepatic steatosis and fibrosis, and can culminate in cirrhosis and hepatocarcinoma if not managed [9,10,11]. Understanding drug-associated effects on NAFLD incidence and progression is of growing importance
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