Indian Journal of Psychological Medicine

: 2016  |  Volume : 38  |  Issue : 2  |  Page : 165--166

Psychotropic drugs and prolonged QTc interval: Does it really that matter?

Ahmed Naguy 
 Al-Manara Centre, Kuwait Centre for Mental Health, Shuwaikh, Kuwait

Correspondence Address:
Ahmed Naguy
Al-Manara Centre, Kuwait Centre for Mental Health, Shuwaikh

How to cite this article:
Naguy A. Psychotropic drugs and prolonged QTc interval: Does it really that matter?.Indian J Psychol Med 2016;38:165-166

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Naguy A. Psychotropic drugs and prolonged QTc interval: Does it really that matter?. Indian J Psychol Med [serial online] 2016 [cited 2019 Oct 20 ];38:165-166
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Psychotropic drug-induced QTc prolongation has become increasingly a clinicians' nightmare, forcing them to refrain from prescribing very efficacious drugs, and hence, depriving patients from potential therapeutic trials.

Herein, I would emphasize some points germane to this topic in an attempt to address my rhetorical query.

QTc prolongation is feared for resultant malignant polymorphic ventricular tachycardia, what Dessertenne coined torsades de pointes (TdP). [1]

As if ruled, acquired QTc prolongation leading to TdP is a rare clinical occurrence (cf. congenital long QT syndromes). [2]

Second, a propensity of a certain drug to prolong QTc interval is different from its torsadogenic effect. An exemplar is amiodarone. [3] And conversely, there are case reports of TdP in patients with apparently normal QT interval. [4]

Third, QTc measurement is fraught with fallacies. It ideally mandates physical rest. Physiologic fluctuations [5] are commonplace, for instance, it increases during the night, the first part of menstrual cycle, and exponentially with weight gain. Correction using Bazzet's versus Fridericia's formula is primarily dependant on heart rate. [6] Automated calculation is reliably unreliable.

Reliance on QTc prolongation as a sole surrogate marker for TdP is highly tricky and misleading. Other markers to consider include, inter alia, QTc dispersion, TPTE, flattened T-waves, postpause U-accentuation, triangulation, and monophasic action potential (MAPs). [7]

Last but not the least, when TdP develops in the setting of QTc prolongation, the underlying mechanism is multifactorial. Mostly, it is a cumulative risk. For instance, female gender, underlying ischemic heart, polypharmacy, overdosage, dyselectrolytemia, etc. [8]

Now, let me show how this has negatively impacted our clinical practice. In my opinion, big pharma abandoned too many promising meds in the pipeline with merely 5-ms increase in QTc above baseline! [9] Although 60 ms increase in practice is deemed meaningful. [10]

Second, clinicians, out of this QTc phobia, relinquished the idea of prescribing some psychotropic drugs with very attractive pharmacologic portfolios. Suffice to mention, Sertindole (Serdolect® ), Ziprasidone (Zeldox® ), and Citalopram (Celexa® ) just to name few.

Sertindole is one of only a few metabolic-friendly atypical antipsychotics, with extrapyramidal symptoms equal to placebo, and promising procognitive actions. [11] Unfortunately, it was withdrawn from US markets for cardiotoxicity concerns. [12] Eckardt et al. [13] refuted it. They have demonstrated that QT and MAP in case of sertindole are cycle-length independent, no effects on transmural or interventricular dispersion of repolarization, and no early after depolarization. This might be ascribed to α1 blockade and/or I Na inhibition pharmacologic properties of sertindole.

Ziprasidone, again, a metabolic-friendly atypical antipsychotic, with MOZART study by Sacchetti et al. showing comparable efficacy to clozapine in resistant schizophrenia. [14] Cardiac concerns were too refuted. Camm et al. revised the topic, including ZODIAC trial, and concluded modest mean increase in QTc from 4.5 to 19.5 ms in a dose-dependent fashion, with <1% QTc prolongation over 60 ms. [15]

Citalopram is a selective serotonin reuptake inhibitor, which Lespérance et al. in CREATE trial found efficacious in depressed patients with coronary artery disease. [16] Wagner et al. [17] conducted a positive RCT of citalopram for major depressive disorder in children and adolescents. Nonetheless, Food and Drug Administration warned about its potential to prolong QTc at high doses and recommended a ceiling dose of 40 mg/d. [18] Hasnain et al. [19] contends that safety warnings should extent to escitalopram (Lexapro® ) too. Zivin et al. [20] refuted these concerns in a large cohort study finding no elevated risks of ventricular arrhythmias or all-cause, cardiac, or noncardiac mortality associated with citalopram dosages over 40 mg/d.

Quo Vadis? Clinicians should be vigilant, mindful, and cognizant of psychotropic-induced QTc prolongation, but in the absence of other risk factors and as long as the cut-off point of 500 ms [21] has not been reached, they should better pursue with the same medication, while keeping monitoring and not depriving patients from often-times valuable pharmacologic options for largely unsubstantiated concerns.

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Conflicts of interest

There are no conflicts of interest.


1Fabiato A, Coumel P. Torsades de pointes, a quarter of a century later: A tribute to Dr. F. Dessertenne. Cardiovasc Drugs Ther 1991;5:167-9.
2Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart 2003;89:1363-72.
3Foley P, Kalra P, Andrews N. Amiodarone - Avoid the danger of torsade de pointes. Resuscitation 2008;76:137-41.
4Paltoo B, O′Donoghue S, Mousavi MS. Levofloxacin induced polymorphic ventricular tachycardia with normal QT interval. Pacing Clin Electrophysiol 2001;24:895-7.
5Can I, Aytemir K, Köse S, Oto A. Physiological mechanisms influencing cardiac repolarization and QT interval. Card Electrophysiol Rev 2002;6:278-81.
6Funck-Brentano C, Jaillon P. Rate-corrected QT interval: Techniques and limitations. Am J Cardiol 1993;72:17B-22B.
7Sauer AJ, Newton-Cheh C. Clinical and genetic determinants of torsade de pointes risk. Circulation 2012;125:1684-94.
8Benoit SR, Mendelsohn AB, Nourjah P, Staffa JA, Graham DJ. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey. Eur J Cardiovasc Prev Rehabil 2005;12:363-8.
9Shah RR. The significance of QT interval in drug development. Br J Clin Pharmacol 2002;54:188-202.
10Van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol 2010;70:16-23.
11Spina E, Zoccali R. Sertindole: Pharmacological and clinical profile and role in the treatment of schizophrenia. Expert Opin Drug Metab Toxicol 2008;4:629-38.
12Pezawas L, Quiner S, Moertl D, Tauscher J, Barnas C, Küfferle B, et al. Efficacy, cardiac safety and tolerability of sertindole: A drug surveillance. Int Clin Psychopharmacol 2000;15:207-14.
13Eckardt L, Breithardt G, Haverkamp W. Electrophysiologic characterization of the antipsychotic drug sertindole in a rabbit heart model of torsade de pointes: Low torsadogenic potential despite QT prolongation. J Pharmacol Exp Ther 2002;300:64-71.
14Sacchetti E, Galluzzo A, Valsecchi P, Romeo F, Gorini B, Warrington L; MOZART Study Group. Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: The MOZART study. Schizophr Res 2009;113:112-21.
15Camm AJ, Karayal ON, Meltzer H, Kolluri S, O′Gorman C, Miceli J, et al. Ziprasidone and the corrected QT interval: A comprehensive summary of clinical data. CNS Drugs 2012;26:351-65.
16Lespérance F, Frasure-Smith N, Koszycki D, Laliberté MA, Van Zyl LT, Baker B, et al. Effects of citalopram and interpersonal psychotherapy on depression in patients with coronary artery disease: The Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial. JAMA 2007;297:367-79.
17Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM, Heydorn WE. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry 2004;161:1079-83.
18Vieweg WV, Hasnain M, Howland RH, Hettema JM, Kogut C, Wood MA, et al. Citalopram, QTc interval prolongation, and torsade de pointes. How should we apply the recent FDA ruling? Am J Med 2012;125:859-68.
19Hasnain M, Howland RH, Vieweg WV. Escitalopram and QTc prolongation. J Psychiatry Neurosci 2013;38:E11.
20Zivin K, Pfeiffer PN, Bohnert AS, Ganoczy D, Blow FC, Nallamothu BK, et al. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry 2013;170:642-50.
21Johnson JN, Ackerman MJ. QTc: How long is too long? Br J Sports Med 2009;43:657-62.