ROS-induced degradation of hERG potassium channels contributes to aripiprazole-induced prolongation of the QTc interval.

As antipsychotic administration often persists for a lifetime, antipsychotic-induced cardiotoxicity (AIC) becomes a significant and potentially life-threatening side effect. Owing to the lack of an appropriate human cardiomyocyte experimental model, current research on AIC is primarily based on clinical case reports. In this study, we generated human iPSC-derived cardiomyocytes (iPSC-CMs) and characterized the cardiotoxicity of 6 antipsychotics (clozapine, haloperidol, quetiapine, olanzapine, risperidone, and aripiprazole) used in clinical practice. Multielectrode array analysis revealed that all 6 antipsychotics, when used within their respective clinical plasma concentration (CPC) ranges, were likely to cause a significantly prolonged field potential duration (FPD) in iPSC-CMs. Moreover, administration of the third-generation antipsychotic aripiprazole (10 mg/kg, i.g.) led to marked QT interval prolongation in beagle dogs. We demonstrated that aripiprazole administration resulted in mitochondrial damage and oxidative stress, which accelerated protein degradation of human ether-à-go-go-related gene (hERG) channels, generating a rapid delayed rectifying potassium current (I