β-Adrenoceptor blockade can augment the torsadogenic action of risperidone

Abstract

Risperidone is a second-generation antipsychotic for treating schizophrenia and bipolar disorder. It can potently inhibit I_Kr, but is classified into conditional risk for torsade de pointes (TdP) by CredibleMeds®. Our previous studies using chronic atrioventricular block dogs showed that risperidone alone did not induce TdP, and that dl-sotalol (β-adrenoceptor blockade plus I_Kr inhibition) induced TdP three times more frequently than d-sotalol (I_Kr inhibition alone). Since risperidone can block α₁-adrenoceptor and decrease blood pressure, the resulting reflex-mediated increase of sympathetic tone on β-adrenoceptor might protect the heart from its I_Kr inhibition-associated TdP. To validate this hypothesis, risperidone was administered to chronic atrioventricular block dogs after β-adrenoceptor blocker atenolol infusion with monitoring J-T_peak and T_peak-T_end, which are proarrhythmic surrogate markers of "substrate" and "trigger" toward TdP, respectively. Atenolol alone induced TdP in 1 out of 5 dogs; moreover, an additional infusion of risperidone induced TdP in 3 out of 4 dogs. Risperidone prolonged QT interval, J-T_peak and T_peak-T_end in animals that induced TdP. These findings indicate that β-adrenoceptor blockade can diminish repolarization reserve to augment risperidone’s torsadogenic potential, thus advising caution when using β-adrenoceptor blockers in patients with I_Kr inhibition-linked labile repolarization.