Corrected QT Interval Prolongation in Psychopharmacological Treatment and Its Modulation by Genetic Variation

Abstract

Several antipsychotics and antidepressants have been associated with electrocardiogram alterations, the most clinically relevant of which is the heart rate-corrected QT interval (QT_c) prolongation, a risk factor for sudden cardiac death. Genetic variants influence drug-induced QT_c prolongation and can provide valuable information for precision medicine. The effect of genetic variants on QT_c prolongation as well as the possible interaction between polymorphisms and risk medications in determining QT_c prolongation were investigated. Medications were classified according to their known risk of inducing QT_c prolongation (high-to-moderate, low, and no risk). QT_c duration and risk of QT_c > median value were investigated in a sample of 77 patients with mood or psychotic disorders being treated with antidepressants and antipsychotics, and who had at least 1 ECG recording. A secondary analysis considered QT_c percentage change in patients (n = 25) with 2 ECG recordings. Single-nucleotide polymorphisms previously associated with QT_c prolongation during treatment with psychotropic medications were investigated. No association survived after multiple-testing correction. The best results for modulation of QT_c duration were identified for rs10808071 (the ABCB1 gene, nominal p = 0.007) when at least 1 medication with a moderate-to-high risk was prescribed, and for rs12029454 (the NOS1AP gene) in patients taking at least 1 medication with a cardiovascular risk (nominal p = 0.008). In the secondary analysis, rs2072413 (the KCNH2 gene) was the top finding for the modulation of QT_c percentage change (nominal p = 0.001) when 1 drug with a moderate-to-high risk was added compared to baseline. Despite the limited power of this study, our results suggest that ABCB1, NOS1AP, and KCNH2 may play a role in QT_c duration/prolongation during treatment with psychotropic drugs.