Atypical antipsychotics impair the lipid-lowering and pleiotropic effects of simvastatin via activation of the ADMA-NOX-ROS pathway

Patients with schizophrenia receiving atypical antipsychotics have an increased risk of metabolic syndrome; however, the efficacy of statins in mitigating cardiovascular risks in these patients remains unclear. This study examined the effects of typical and atypical antipsychotics on the lipid-lowering efficacy of statins in schizophrenia patients and investigated the underlying mechanisms of simvastatin action in hepatocytes and endothelial cells (ECs). A retrospective analysis revealed that statins were less effective in lowering LDL levels in patients on atypical antipsychotics. In vitro, olanzapine attenuated the beneficial effects of simvastatin in hepatocytes and ECs. Mechanistically, olanzapine downregulated dimethylarginine dimethylaminohydrolase 1 (DDAH1) and/or DDAH2, leading to elevated asymmetric dimethylarginine (ADMA) levels in both cell types. In hepatocytes, olanzapine suppressed low-density lipoprotein receptor (LDLR) expression and reduced LDL binding by activating the NOX-ROS pathway via PPARγ-PCSK9- and LXRα-IDOL-dependent signaling. Inhibition of the NOX-ROS pathway restored LDLR expression, LDL binding, and the lipid-lowering effects of simvastatin. In ECs, olanzapine impaired simvastatin-induced nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) phosphorylation through NOX-ROS pathway activation. Blocking this pathway reversed eNOS inhibition, restoring the endothelial benefits of simvastatin. Collectively, atypical antipsychotics impair statin efficacy in schizophrenia patients by activating the ADMA-NOX-ROS pathway, which downregulates LDLR in hepatocytes and inhibits eNOS activity in ECs. These findings underscore the need for tailored cardiovascular risk management strategies and identify potential molecular targets to enhance statin effectiveness in patients on atypical antipsychotics.