Reevaluating Clozapine-Induced QT Prolongation

Abstract

Background and hypothesis: Clozapine is the most effective medicine for treatment-resistant schizophrenia, but is limited by adverse events, including potential QT prolongation which can lead to life-threatening arrhythmias. Studies linking clozapine and corrected QT (QTc) prolongation may overestimate this risk due to high rates of clozapine-associated tachycardia. We investigated whether trough clozapine plasma levels are independently associated with QT prolongation after accounting for heart rate.

Study design: We conducted a retrospective, cross-sectional analysis of inpatients treated with clozapine at a tertiary hospital between 2017 and 2023. Trough clozapine plasma levels, and 12-lead electrocardiograms were extracted from electronic medical records. QT intervals were manually measured and corrected using Bazett's, Fredericia, Hodges' formulae, and the QT nomogram. Multivariable regression and causal mediation were used to test the association between clozapine plasma level, heart rate, and QTc.

Study results: Among 313 patients, Bazett's correction classified 27.5% as having prolonged QTc, whereas only one patient (0.3%) exceeded the at-risk threshold using Fredericia, Hodges, or the QT nomogram. Clozapine plasma level correlated with Bazett's-corrected QT (QTcB) (P = .02), but not after adjustment for heart rate (P = .75). Mediation analysis showed that heart rate significantly mediated the relationship between clozapine plasma level and QTcB intervals (P < .001).

Conclusions: Apparent clozapine-induced QTc prolongation is largely an artifact of tachycardia and over-correction by Bazett's formula. The Fredericia and Hodges formulae, and the QT nomogram provide a more reliable assessment of torsadogenic risk and prevent unnecessary discontinuation or dose reductions of clozapine.

Keywords: QT interval; schizophrenia; torsades de pointes.