Pharmacotherapeutic Determinants for QTc Interval Prolongation in Japanese Patients with Mood Disorder

Abstract

Introduction:

An increased incidence of sudden death has been observed among patients treated with antidepressants. A prolonged QTc interval is a known prognostic factor for fatal arrhythmia, and several studies have shown that the use of antidepressants can cause a prolonged QTc interval. However, few studies, especially in Japan, have compared the effects of multiple drugs on QTc interval or examined dose relationships in a clinical setting.

Methods:

We compared the effects of antidepressants on QT interval, corrected to QTc by Bazett's formula, in 729 Japanese patients who were diagnosed with mood disorder.

Results:

Using stepwise multiple linear regression analysis, we found that the use of tricyclic antidepressants (P<0.01) and concomitant use of antipsychotics (P<0.05), as well as advanced age and being female (known factors for prolonged QTc interval; both P<0.01), significantly prolonged the QTc interval. Analysis of individual antidepressants also revealed that the use of clomipramine (P<0.01) and amitriptyline (P<0.05) significantly prolonged the QTc interval.

Conclusion:

Our results reveal that tricyclic antidepressants, especially clomipramine and amitriptyline, confer a risk of prolonged QTc interval in a dose-dependent manner. The selective serotonin reuptake inhibitors investigated (fluvoxamine, paroxetine, sertraline) were not indicated as risk factors for QTc prolongation.

Key words

antidepressants - QTc interval - sudden death - tricyclic antidepressants - selective serotonine reuptake inhibitors

• References

• 1 Sicouri S, Antzelevitch C. Sudden cardiac death secondary to antidepressant and antipsychotic drugs. Expert Opin Drug Saf 2008; 7: 181-194
• 2 Straus SM, Kors JA, De Bruin ML et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol 2006; 47: 362-367
• 3 Reilly JG, Ayis SA, Ferrier IN et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355: 1048-1052
• 4 Vieweg WV, Wood MA, Fernandez A et al. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging 2009; 26: 997-1012
• 5 Whang W, Kubzansky LD, Kawachi I et al. Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses' Health Study. J Am Coll Cardiol 2009; 53: 950-958
• 6 International Registry for Drug-induced Arrhythmias Arizona classification lists January 5 2012 Available at http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm#
• 7 Bazett HC. The time relations of the blood-pressure changes after excision of the adrenal glands, with some observations on blood volume changes. J Physiol 1920; 53: 320-339
• 8 Inada I. Dose equivalence of psychotropic drugs: 2006-version. Jpn J Clin Psychopharmacol 2006; 9: 1443-1447
• 9 Chan A, Isbister GK, Kirkpatrick CM et al. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. QJM 2007; 100: 609-615
• 10 The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E14, The clinical evaluation of qt/qtc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs January 5 2012 Available at http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/the-clinical-evaluation-of-qtqtc-interval-prolongation-and-proarrhythmic-potential-for-non-antiarrh.html
• 11 Blaschke D, Parwani AS, Huemer M et al. Torsade de pointes during combined treatment with risperidone and citalopram. Pharmacopsychiatry 2007; 40: 294-295
• 12 van Noord CSS, Sturkenboom MC, Hofman A et al. Psychotropic drugs associated with corrected QT interval prolongation. J Clin Psychopharmacol 2009; 29: 9-15
• 13 Hamer M, David Batty G, Seldenrijk A et al. Antidepressant medication use and future risk of cardiovascular disease: the Scottish Health Survey. Eur Heart J 2011; 32: 437-442
• 14 Ray WA, Meredith S, Thapa PB et al. Cyclic antidepressants and the risk of sudden cardiac death. Clin Pharmacol Ther 2004; 75: 234-241
• 15 Tie H, Walker BD, Valenzuela SM et al. The heart of psychotropic drug therapy. Lancet 2000; 355: 1825
• 16 Staudacher I, Wang L, Wan X et al. hERG K(+) channel-associated cardiac effects of the antidepressant drug desipramine. Naunyn Schmiedebergs Arch Pharmacol 2011; 383: 119-139
• 17 Obers S, Staudacher I, Ficker E et al. Multiple mechanisms of hERG liability: K⁺ current inhibition, disruption of protein trafficking, and apoptosis induced by amoxapine. Naunyn Schmiedebergs Arch Pharmacol 2010; 381: 385-400
• 18 Jo SH, Hong HK, Chong SH et al. Clomipramine block of the hERG K+ channel: accessibility to F656 and Y652. Eur J Pharmacol 2008; 592: 19-25
• 19 Jo SH, Youm JB, Lee CO et al. Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline. Br J Pharmacol 2000; 129: 1474-1480
• 20 Witchel HJ, Pabbathi VK, Hofmann G et al. Inhibitory actions of the selective serotonin re-uptake inhibitor citalopram on HERG and ventricular L-type calcium currents. FEBS Lett 2002; 512: 59-66
• 21 Thomas D, Gut B, Wendt-Nordahl G et al. The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels. J Pharmacol Exp Ther 2002; 300: 543-548
• 22 Milnes JT, Crociani O, Arcangeli A et al. Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652. Br J Pharmacol 2003; 139: 887-898
• 23 Ozeki Y, Fujii K, Kurimoto N et al. QTc prolongation and antipsychotic medications in a sample of 1 017 patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34: 401-405
• 24 U.S. Food and Drug administration FDA Drug Safety Communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide) on August 24, 2011, January 5, 2012 Available at http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm
• 25 Wenzel-Seifert K, Wittmann M, Haen E. Torsade de Pointes episodes under treatment with selective serotonin reuptake inhibitors. Pharmacopsychiatry 2010; 43: 279-281