Antipsychotics in routine treatment are minor contributors to QT prolongation compared to genetics and age

Background: Drug-induced prolongation of cardiac repolarization limits the treatment with many psychotropic drugs. Recently, the contribution of polygenic variation to the individual duration of the QT interval was identified. Aims: To explore the interaction between antipsychotic drugs and the individual polygenic influence on the QT interval. Methods: Retrospective analysis of clinical and genotype data of 804 psychiatric inpatients diagnosed with a psychotic disorder. The individual polygenic influence on the QT interval was calculated according to the method of Arking et al. Results: Linear regression modelling showed a significant association of the individual polygenic QT interval score (ss(std) = 0.176, p < 0.001) and age (ss(std) = 0.139, p < 0.001) with the QTc interval corrected according to Fridericia's formula. Sex showed a nominal trend towards significance (ss(std) = 0.064, p = 0.064). No association was observed for the number of QT prolonging drugs according to AZCERT taken. Subsample analysis (n = 588) showed a significant association of potassium serum concentrations with the QTc interval (ss(std) = -0.104, p = 0.010). Haloperidol serum concentrations were associated with the QTc interval only in single medication analysis (n = 26, ss(std) = 0.101, p = 0.004), but not in multivariate regression analysis. No association was observed for aripiprazole, clozapine, quetiapine and perazine, while olanzapine and the sum of risperidone and its metabolite showed a negative association. Conclusions: Individual genetic factors and age are main determinants of the QT interval. Antipsychotic drug serum concentrations within the therapeutic range contribute to QTc prolongation on an individual level.