Case Report

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American Journal of Emergency Medicine

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Citalopram and levosulpiride: a dangerous drug combination for QT prolongation

Abstract

We report the case of an 89-year-old female patient who presented to the emergency department after out-of-hospital cardiac arrest due to Polymorphic ventricular tachycardia treated by public access defibrillation. The admission electrocardiogram (ECG) showed extreme QT prolongation (650 milliseconds) with Recurrent episodes of nonsustained polymorphic ventricular tachycardia. intravenous magnesium sulfate therapy was instituted. After History taking, it was found that the patient was on citalopram and that, 2 days prior to admission, she had begun treatment with levosulpiride. This drug combination resulted in marked prolongation of the QT interval that triggered the Electrical storm.

We report the case of an 89-year-old female patient who presented to the emergency department after an episode of out- of-hospital cardiac arrest due to polymorphic ventricular tachy- cardia treated by public access defibrillation. She had no history of cardiac problems other than hypertension under home therapy with ramipril 2.5 mg.

On admission, she was hemodynamically stable with normal blood pressure. The ECG showed normal sinus rhythm, extreme QT prolongation (650 milliseconds) with T-wave notching (Fig. 1), and recurrent episodes of nonsustained polymorphic ventricular tachy- cardia with Torsades de pointes-like features initiated by an R-on-T phenomenon (Fig. 2).

Blood count and biochemistry values were within the reference range (negative troponin levels, hemoglobin 13.6 g/dL, creatinine 1.0 mg/dL, creatinine clearance N 60 mL/min, potassium 3.9 mEq/L, magnesium 1.7 mEq/L, sodium 137 mEq/L, normal thyroid function). Echocardiography revealed no evidence of significant structural heart disease.

Cardiac arrest was suspected to be due to bradycardia-dependent QT prolongation; and therapy with intravenous magnesium sulfate was initiated (3-mg/min infusion), resulting in termination of arrhythmia episodes and progressive normalization of QT interval.

From the history, we learned that the patient was on citalopram 40 mg/d for 12 months for reactive depression. Two days before admission, she had begun treatment with levosulpiride

25 mg tid for functional dyspepsia; and since then, she experi- enced palpitations followed by frequent collapsing episodes and 2 syncopal events. This dangerous association was suspected to be the cause of QT prolongation, and administration of both drugs was discontinued.

In the next 36 hours, no further ventricular arrhythmias were observed, and intravenous magnesium sulfate therapy was with- drawn. The ECG showed normal sinus rhythm with a QTc interval of 450 milliseconds.

The patient was discharged fully asymptomatic 4 days after admission without any antiarrhythmic medication, with the indica- tion of not taking citalopram in combination with levosulpiride. After a few weeks, in agreement with the neurologist, antidepressant

Fig. 1. Electrocardiogram showing extreme QT prolongation (QTc 600 milliseconds).

0735-6757/$ - see front matter (C) 2013

Fig. 2. Electrocardiogram with the initiation of torsades de pointes. Note the marked QT prolongation in the first beat of sinus rhythm.

therapy was resumed with escitalopram at incremental doses up to a maximum of 10 mg/d.

No evidence of QT prolongation was observed on repeated ECG recorded at regular follow-up intervals.

Citalopram is a selective serotonin reuptake inhibitor that is used for the treatment of major depression, with a better Cardiac safety profile than triCyclic antidepressants [1]. Over the last years, numerous case reports of QT prolongation induced by citalopram have been published, mainly occurring in the presence of citalopram overdose, electrolyte disturbances, or renal/Liver failure, or when administered in combination with other Antidepressant medications that prolong the QT interval or in patients with concealed long QT syndrome [2].

In animal studies, citalopram has also been shown to inhibit delayed rectifier outward potassium current [3], which is the most common mechanism responsible for drug-induced prolongation of the QT interval in humans [3]. However, different from tricyclic antidepressants that exert a selective blockade of delayed rectifier potassium current, this effect is counteracted by the inhibition of depolarizing current mediated by L-type Calcium channels.

In our patient, citalopram as monotherapy did not produce any cardiac adverse effects; but when administered in combination with levosulpiride, it triggered the electrical storm as a result of QT prolongation. Levosulpiride is a substituted benzamide derivative and a selective dopamine D2-receptor antagonist that is widely used for the management of functional gut disorders. No cases of ventricular dysrhythmias or lengthening of the QT interval have been previously reported with this drug. However, levosulpiride may also act as a moderate antagonist at 5-HT₃ receptors as well as a moderate agonist at serotonin 5-HT₄ receptors. In addition, it has, at least in part, similar effects as the benzamide derivative cisapride, which also possesses class III antiarrhythmic activity [4]. These pharmacodynamic proper- ties may ultimately provide a potential mechanism for arrhythmo- genicity, especially in patients concomitantly treated with QT- prolonging drugs (eg, citalopram).

Evidence from experimental studies suggests that both the 5- HT_4(a) and 5-HT_4(b) receptor splice variants are expressed in human atrium and ventricle and have nearly identical pharmacology [5]. It is well known that levosulpiride may trigger atrial dysrhythmias through stimulation of 5-HT₄ receptors. We hypothesize that levosulpiride may express partial 5-HT₄ receptor agonist activity also at the ventricular level, thus favoring the development of electrical storm if an underlying proarrhythmic mechanism is present, as occurred with citalopram-induced QT prolongation in our patient.

To the best of our knowledge, this is the first report describing the occurrence of QT prolongation following the coadministration of citalopram with levosulpiride. The possibility of pharmacodynamic interactions between these 2 widely used drugs may pose a higher risk of cardiac adverse effects. Therefore, patients receiving this potentially dangerous drug combination should be prescribed the lowest effective dosage, should undergo regular ECG monitoring, and should be offered an alternative pharmacological treatment.

Acknowledgments

We wish to thank L. Arena (MD) for his important contribution in the intuition of the dangerous combination (citalopram and levosul- piride) for QT prolongation.

Sergio Agosti MD, PHD

Department of Cardiology, San Giacomo Hospital, Novi Ligure (AL), Italy

E-mail address: [email protected]

Laura Casalino MD, PhD Giovanni Bertero MD Alessandro Burrone MD Claudio Brunelli MD

Department of Cardiology, University of Genoa School of Medicine,

Genoa, Italy

Silvana Morelloni MD

Department of Cardiology, San Giacomo Hospital, Novi Ligure (AL), Italy

http://dx.doi.org/10.1016/j.ajem.2013.06.030

References

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