Prediction of Ventricular Arrhythmias by QRS/QTc - Ratio in Citalopram or Escitalopram Intoxication

Abstract

BackgroundThe U.S. Food and Drug Administration (FDA) has stated that citalopram and escitalopram should not be used at daily doses above 40 mg/20 mg due to risk for development of fatal ventricular arrhythmias like torsade de pointes (TdP). Yet, supratherapeutic serum concentrations of citalopram are common and predicting patients at risk for TdP is of high clinical value. Accordingly, we investigated whether QRS/QTc; developed for predicting TdP in hypothermic patients could be used in citalopram intoxication.MethodsA total of 16 publications describing patients suffering from complications due to citalopram or escitalopram treatment, or intoxication with the same substances, were included after a systematic search. The main criterion for inclusion was admission ECG, either with given QRS and QTc values or with attached ECG-files that enabled calculation.ResultsQRS/QTc rather that QTc alone emerged as a marker of ventricular arrhythmia in the 16 included case reports, with highly significant (p < 0.0005) lower values in patients displaying ventricular arrhythmias.ConclusionCitalopram and escitalopram are extensively used in treatment of depressive disorders, and a large proportion of patients have supratherapeutic serum concentrations. Calculation of QRS/QTc in available case reports show that this novel ECG-marker has potential to predict patients at risk for developing ventricular arrhythmias.

Pro-arrhythmic effect of escitalopram and citalopram at serum concentrations commonly observed in older patients – a study based on a cohort of 19,742 patients

“…Although not posing a considerable risk at therapeutic concentrations, both R- and S-demethylcitalopram gave a dose-dependent increase in triangulation and could be ascribed to an increased risk of TdP in patients with escitalopram- or citalopram-intoxication. 11 , 21 Different from all other tested substances, both demethylcitalopram-metabolites did also affect cycle length, which reduced with between 3.8 and 9.9 percent from baseline for the different concentrations. This could be enhanced in patients with CYP-enzyme variants driving metabolism toward the demethylcitalopram-metabolites.…”

“…It has already proved more accurate than QTc to predict ventricular arrhythmias after escitalopram or citalopram intoxication. 21 …”

“… 20 According to common pharmacological practice, we have therefore investigated higher concentrations (10× and 100× estimated free fraction in risk patients) of the compounds. This range is clinically relevant according to a recent paper on escitalopram and citalopram intoxications 21 and allowed us to account for the possibility that the total drug concentration could have cardiotoxic effect. In a large therapeutic drug monitoring (TDM) study 60 nM was the average total concentration in patients with normal escitalopram metabolism through CYP2C19, and 136 nM was below the average total concentration in poor metabolizers.…”