Nortriptyline serum concentration as a predictor for cardiac risk in amitriptyline-treated patients

Tricyclic antidepressants have been shown to affect electrocardiogram (ECG) parameters, but there is limited evidence in relation to the serum concentrations. Therefore, we aimed to evaluate a prediction of cardiac risk in amitriptyline- and doxepin-treated patients by serum concentrations.

The association between serum concentrations of amitriptyline (n = 100) and doxepin (n = 71) and ECG parameters was retrospectively examined using linear regression analysis. Mann-Whitney U tests were applied to evaluate differences in QTc intervals in patients with serum concentrations above and below the upper limit of the therapeutic reference range, as well as the alert level of each target drug.

The sum serum concentration of amitriptyline and the nortriptyline serum concentration were significantly associated with an increased PQ interval (p = 0.020, p = 0.007), as well as with increased QTcB (p = 0.012, p < 0.001) and QTcF intervals (p = 0.025, p < 0.001). The nortriptyline concentration was significantly associated with the QRS interval (p = 0.003). In patients with active moiety concentrations above the alert level (300 ng/ml) and nortriptyline concentrations above the reference range (170 ng/ml), the QTcB interval was significantly prolonged (p = 0.032, p = 0.007). No significant association with any ECG parameter was detected for doxepin serum concentrations.

The effect of amitriptyline on ECG parameters may be explained by nortriptyline alone. Accordingly, with increasing nortriptyline concentrations, the potential risk for an atrioventricular block, a bundle branch block, and prolongation of QTc interval may increase significantly.