Exploring mechanisms of increased cardiovascular disease risk with antipsychotic medications: Risperidone alters the cardiac proteomic signature in mice

Abstract

Atypical antipsychotic (AA) medications including risperidone (RIS) and olanzapine (OLAN) are FDA approved for the treatment of psychiatric disorders including schizophrenia, bipolar disorder and depression. Clinical side effects of AA medications include obesity, insulin resistance, dyslipidemia, hypertension and increased cardiovascular disease risk. Despite the known pharmacology of these AA medications, however, the mechanisms contributing to adverse metabolic side-effects are not well understood. To evaluate drug-associated effects on the heart, we assessed changes in the cardiac proteomic signature in mice administered for 4 weeks with clinically relevant exposure of RIS or OLAN. Using proteomic and gene enrichment analysis, we identified differentially expressed (DE) proteins in both RIS-and OLAN-treated mouse hearts (p <0.05), including proteins comprising mitochondrial respiratory complex I and pathways involved

Understanding Mechanisms Underlying Non-Alcoholic Fatty Liver Disease (NAFLD) in Mental Illness: Risperidone and Olanzapine Alter the Hepatic Proteomic Signature in Mice

“…Similarly, significantly depressed levels of cytochrome oxidase subunit VI B (COX6B) during both RIS and OLAN treatment would lead to profound changes in oxidative phosphorylation and metabolic rate that may not be reflected as level changes of downstream proteins because differentially phosphorylated states are not detected. However, metabolic changes in AA-treated patients and our previous report phenotypically demonstrate mitochondrial dysfunction that is highly consistent with reduced oxidative phosphorylation [21]. Finally, DE by both RIS and OLAN of proteins whose function depends on their phosphorylation state are highly likely to be relevant in the absence of posttranslational modification detection when the predicted phenotype is consistent with known AA-induced side effects.…”

“…All animals used in this study were healthy and displayed no adverse effects of daily gavage for the 28-day study duration. Details of animal growth rates, locomotor activity, adiposity, and energy expenditure for this cohort were recently reported in a manuscript describing AA effects on the heart [ 21 ]. Overall, the animals in this study showed normal feeding behavior, weight gain, and locomotor activity.…”

“…Overall, the animals in this study showed normal feeding behavior, weight gain, and locomotor activity. Although there was no treatment effect on body weight gain, animals treated with RIS or OLAN showed a significant increase in adiposity compared to VEH treatment as well as a reduction in plasma-free fatty acid concentrations [ 21 ]. Importantly, 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 NAFLD [ 22 , 23 ].…”

“…The autonomic nervous system (ANS) exerts control over multiple physiological pathways in the liver, including those relating to insulin resistance and NAFLD [ 48 ]. Furthermore, AA medications have been implicated in regulating sympathetic nervous system (SNS) tone, and AA effects on heart and bone appear to be due at least in part to enhanced SNS activity [ 21 , 49 , 50 , 51 ]. In addition to pathways relating to insulin resistance, energy metabolism, fibrosis, and regeneration/repair described above, AA treatment altered the expression of proteins in other pathways known to be regulated by the ANS, including those relating to biliary physiology [ 48 , 52 ].…”

Risperidone Exacerbates Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Renal Impairment in Obese Mice

“…The groups were subsequently separated to form two subgroups: one receiving 1 mg/kg oral risperidone (Sigma-Aldrich, St. Louis, MO, USA) and the other (control group) receiving saline through daily gavage for the final 56 days of the diet period (36.71 ± 0.69 g in risperidone-treated mice and 36.69 ± 0.61 g in control mice (vehicle treated), p > 0.05). Literature on risperidone as a potential drug for application, in studies on behavior, antipsychotic disease, immunosuppression, and cardiovascular disease in a mouse model was referenced when selecting the risperidone dose [ 68 , 69 , 70 ]. During the study, mice were separately kept in microisolation cages placed on racks ventilated by air filtered by high-efficiency particulate air filters under temperature and humidity controlled at 22 ± 1 °C and 55% ± 5%, respectively, under a 12:12-h light/dark cycle, all with free water and food access.…”