Abstract：Escitalopram, a selective serotonin re-uptake inhibitor (SSRI) antidepressant which is the (S)-enantiomer of citalopram, is worldwide used for the treatment of depressive and anxious disorders in clinical practice, however, recent data have indicated that high therapeutic escitalopram doses may cause the potential of QTc prolongation effect, which is a predisposing factor for arrhythmia. Nevertheless, in March 2012, the Food and Drug Administration (FDA) issued a safety bulletin advising the daily dosage of escitalopram should be restricted to a maximum of 20 mg daily in healthy adults and 10 mg maximum in high risk patients (eg>60 years of age). In this review, we aimed to investigate what factors can affect and how escitalopram gives rise to QTc prolongation.
BURKE W J. Escitalopram[J]. Expert Opin Investig Drugs, 2002, 11(10):1477-1486.
[2]
JACQUOT C, DAVID D J, GARDIER A M, et al. Escitalopram and citalopram: the unexpected role of the R-enantiomer[J]. Encephale, 2007, 33(2):179-187.
[3]
POSTEMA P G, WILDE A A. The measurement of the QT interval[J]. Curr Cardiol Rev, 2014, 10(3):287-294.
[4]
RAUTAHARJU P M, SURAWICZ B, GETTES L S, et al. AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram: part Ⅳ: the ST segment, T and U waves, and the QT interval: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation and the Heart Rhythm Society. Endorsed by the International Society for Computerized Electrocardiology[J]. J Am Coll Cardiol, 2009, 53(11): 982-991.
[5]
VISKIN S. The QT interval: too long, too short or just right[J]. Heart Rhythm, 2009, 6(5): 711-715.
[6]
TESTER D J, ACKERMAN M J. Genetics of long QT syndrome[J]. Methodist Debakey Cardiovasc J, 2014, 10(1):29-33.
[7]
U.S. FOOD AND DRUG ADMINISTRATION. FDA Drug Safety Communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide) [EB/OL]. USA: FDA,2011-08 [2019-12-26]. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-abnormal-heart-rhythms-associated-high-doses-celexa-citalopram
[8]
EUROPEAN MEDICINES AGENCY. Pharmacovigilance Working Party (PhVWP) [EB/OL]. EUR: EMA,2011-10 [2019-12-26]. https://www.ema.europa.eu/en/documents/report/monthly-report-pharmacovigilance-working-party-phvwp-october-2011-plenary-meeting_en.pdf
[9]
U.S. FOOD AND DRUG ADMINISTRATION. FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses [EB/OL]. USA: FDA,2011-03 [2019-12-26]. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-revised-recommendations-celexa-citalopram-hydrobromide-related.
[10]
THASE M E, LARSEN K G, REINES E, et al. The cardiovascular safety profile of escitalopram[J]. Eur Neuropsychopharmacol, 2013, 23(11):1391-1400.
[11]
KIM A, LIM K S, LEE H, et al. A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers[J]. Int Clin Psychopharmacol, 2016, 31(4):210-217.
[12]
SCHREFFLER S M, MARRAFFA J M, STORK C M, et al. Sodium channel blockade with QRS widening after an escitalopram overdose[J]. Pediatr Emerg Care, 2013, 29(9):998-1001.
[13]
TURKER I, AI T, ITOH H, et al. Drug-induced fatal arrhythmias: acquired long QT and Brugada syndromes[J]. Pharmacol Ther, 2017, 176:48-59.
[14]
PERRIN M J, SUBBIAH R N, VANDENBERG J I, et al. Human ether-a- go-go related gene (hERG) K+ channels: function and dysfunction[J]. Prog Biophys Mol Biol, 2008, 98(2-3):137-148.
[15]
CUBEDDU L X. Iatrogenic QT abnormalities and fatal arrhythmias: mechanisms and clinical significance[J]. Curr Cardiol Rev, 2009, 5(3):166-176.
[16]
CUBEDDU L X. Drug-induced inhibition and trafficking disruption of ion channels: pathogenesis of QT abnormalities and drug-induced fatal arrhythmias[J]. Curr Cardiol Rev, 2016, 12(2):141-154.
[17]
CHAE Y J, JEON J H, LEE H J, et al. Escitalopram block of hERG potassium channels[J]. Naunyn Schmiedebergs Arch Pharmacol, 2014, 387(1):23-32.
[18]
BÜYÜKDELIGÖZ M, HOCAOLU N, ORANSAY K, et al. The effects of the adenosine receptor antagonists on the reverse of cardiovascular toxic effects induced by citalopram in-vivo rat model of poisoning[J]. Balkan Med J, 2015, 32(3):303-308.
[19]
NIEMEIJER M N, ANDENBERG M E, EIJGELSHEIM M, et al. Pharmacogenetics of drug-induced QT interval prolongation: an update[J]. Drug Saf, 2015, 38(10):855-867.
[20]
MUSTAFA S J, MORRISION R R, TENG B, et al. Adenosine receptors and the heart: role in regulation of coronary blood flow and cardiac electrophysiology[J]. Handb Exp Pharmacol, 2009, (193):161-188.
[21]
DALAGEORGOU C, GE D, JAMSHIDI Y, et al. Heritability of QT interval: how much is explained by genes for resting heart rate[J]. J Cardiovasc Electrophysiol, 2008, 19(4):386-391.
[22]
VANDAEL E, VANDENBERK B, VANDENBERGHE J, et al. Risk factors for QTc-prolongation: systematic review of the evidence[J]. Int J Clin Pharm, 2017, 39(1):16-25.
[23]
ZHANG Y, OUYANG P, POST W S, et al. Sex-steroid hormones and electrocardiographic QT-interval duration: findings from the third National Health and Nutrition Examination Survey and the Multi-Ethnic Study of Atherosclerosis[J]. Am J Epidemiol, 2011, 174(4):403-411.
[24]
BAI C X, KUROKAWA J, TAMAGAWA M, et al. Nontranscriptional regulation of cardiac repolarization currents by testosterone[J]. Circulation, 2005, 112(12):1701-1710.
[25]
BENOIT S R, MENDELSOHN A B, NOURJAH P, et al. Risk factors for prolonged QTc among US adults: Third National Health and Nutrition Examination Survey[J]. Eur J Cardiovasc Prev Rehabil, 2005, 12(4):363-368.
[26]
TISDALE J E. Drug-induced QT interval prolongation and torsades de pointes: role of the pharmacist in risk assessment, prevention and management[J]. Can Pharm J(Ott), 2016, 149(3):139-152.
[27]
BEACH S R, CELANO C M, NOSEWORTHY P A, et al. QTc prolongation, torsades de pointes, and psychotropic medications[J]. Psychosomatics, 2013, 54(1):1-13,21.
[28]
RAO N. The clinical pharmacokinetics of escitalopram[J]. Clin Pharmacokinet, 2007, 46(4):281-290.
[29]
YU B N, CHEN G L, HE N, et al. Pharmacokinetics of citalopram in relation to genetic polymorphism of CYP2C19[J]. Drug Metab Dispos, 2003, 31(10):1255-1259.
[30]
CHANG M, TYBRING G, DAHL M L. Impact of cytochrome P450 2C19 polymorphisms on citalopram/escitalopram exposure: a systematic review and Meta-analysis[J]. Clin Pharmacokinet, 2014, 53(9):801-811.
[31]
PATEL N, WIS′NIOWSKA B, JAMEI M, et al. Real patient and its virtual twin: application of quantitative systems toxicology modelling in the cardiac safety assessment of citalopram[J]. AAPS J, 2017,20(1):6.
[32]
ITOH H, CROTTI L, AIBA T, et al, The genetics underlying acquired long QT syndrome: impact for genetic screening[J]. Eur Heart J, 2016, 37(18):1456-1464.
[33]
TESTER D J, ACKERMAN M J. Genetics of long QT syndrome[J]. Methodist Debakey Cardiovasc J, 2014, 10(1):29-33.
[34]
SINGH P, MALDONADO-DURAN J M. Drug-induced QT prolongation as a result of an escitalopram overdose in a patient with previously undiagnosed congenital long QT syndrome[J]. Case Rep Med, 2014, 2014:917846.
[35]
TISDALE J E. Drug-induced QT interval prolongation and torsades de pointes/role of the pharmacist in risk assessment, prevention and management[J]. Can Pharm J (Ott), 2016, 149(3):139-152.
2019, Vol. 54 
