Heterogeneity and concentration-dependence of ionic channel mechanisms underlying ventricular repolarization prolongation induced by atypical antipsychotics

Atypical antipsychotics (AAPs)-induced QT interval prolongation represents a major clinical safety challenge. Traditional mechanisms based solely on hERG (IKr) channel blockade cannot fully explain the heterogeneity of clinical phenotypes and severe arrhythmias during overdose. This study systematically evaluated the effects of representative AAPs at therapeutic and toxic concentrations on cardiomyocyte electrophysiological activities. Using whole-cell patch-clamp techniques, we recorded action potentials and major transmembrane ionic currents (IKr, IKs, IK1, Ito, and INa) in primary adult mouse ventricular myocytes exposed to five AAPs (olanzapine, quetiapine, clozapine, ziprasidone, and risperidone) at a moderate therapeutic concentration. Dose-responses for olanzapine and quetiapine across low, medium, and high concentrations were also analyzed. At therapeutic concentrations, all the five AAPs significantly prolonged 90% action potential duration (APD90). Olanzapine, clozapine, and risperidone also prolonged APD50, which was unlike quetiapine and ziprasidone. Ion current analysis revealed quetiapine and ziprasidone significantly inhibited IKr, whereas olanzapine, clozapine, and risperidone suppressed Ito. Olanzapine and clozapine additionally reduced IK1 and INa. At supratherapeutic concentrations, olanzapine and quetiapine concentration-dependently prolonged APD90 and non-selectively inhibited all measured currents. In conclusion, at therapeutic concentrations, AAPs delay ventricular repolarization via distinct ion channel blockades. At supratherapeutic doses, the loss of channel selectivity and synergistic multi-channel blockade constitute the core mechanism for malignant arrhythmias during drug overdose, highlighting the need to consider drug-specific multi-channel profiles in future clinical cardiac safety evaluations.