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QTc Interval Prolongation and Torsade de Pointes Associated with Second-Generation Antipsychotics and Antidepressants: A Comprehensive Review

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Abstract

We comprehensively reviewed published literature to determine whether it supported the link between corrected QT (QTc) interval prolongation and torsade de pointes (TdP) for the 11 second-generation antipsychotics and seven second-generation antidepressants commonly implicated in these complications. Using PubMed and EMBASE, we identified four thorough QT studies (one each for iloperidone, ziprasidone, citalopram, and escitalopram), 40 studies specifically designed to assess QTc interval prolongation or TdP, 58 publications based on data from efficacy and safety trials, 18 toxicology studies, and 102 case reports. Thorough QT studies, QTc prolongation-specific studies, and studies based on efficacy and safety trials did not link drug-associated QTc interval prolongation with TdP. They only showed that the drugs reviewed caused varying degrees of QTc interval prolongation, and even that information was not clear and consistent enough to stratify individual drugs for this risk. The few toxicology studies provided valuable information but their findings are pertinent only to situations of drug overdose. Case reports were most informative about the drug–QTc interval prolongation–TdP link. At least one additional well established risk factor for QTc prolongation was present in 92.2 % of case reports. Of the 28 cases of TdP, six (21.4 %) experienced it with QTc interval <500 ms; 75 % of TdP cases occurred at therapeutic doses. There is little evidence that drug-associated QTc interval prolongation by itself is sufficient to predict TdP. Future research needs to improve its precision and broaden its scope to better understand the factors that facilitate or attenuate progression of drug-associated QTc interval prolongation to TdP.

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References

  1. Vieweg WV. New generation antipsychotic drugs and QTc interval prolongation. Prim Care Companion J Clin Psychiatry. 2003;5:205–15.

    PubMed  PubMed Central  Google Scholar 

  2. Vieweg WV, Wood MA, Fernandez A, Beatty-Brooks M, Hasnain M, Pandurangi AK. Proarrhythmic risk with antipsychotic and antidepressant drugs: implications in the elderly. Drugs Aging. 2009;26:997–1012.

    PubMed  CAS  Google Scholar 

  3. Hasnain M, Vieweg WV, Breden Crous EL, Hancox JC. Methadone and torsade de pointes: how can we better understand the association? Am J Med. 2013;126:757–8.

    PubMed  Google Scholar 

  4. Hasnain M, Vieweg WV, Howland RH, Kogut C, Breden Crouse EL, Koneru JN, et al. Quetiapine and the need for a thorough QT/QTc study. J Clin Psychopharmacol. 2014;34:3–6.

    PubMed  Google Scholar 

  5. Vieweg 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.

    PubMed  CAS  Google Scholar 

  6. Vieweg WV, Hasnain M, Hancox JC, Baranchuk A, Digby GC, Kogut C, et al. Risperidone, QTc interval prolongation, and torsade de pointes: a systematic review of case reports. Psychopharmacology (Berl). 2013;228:515–24.

    CAS  Google Scholar 

  7. Hasnain M, Vieweg WV, Howland R.H., Kogut C, Crouse E.L.B., Koneru JN, et al. Quetiapine, QTc interval prolongation, and torsade de pointes: a review of case reports. Ther Adv Psychopharmacol. 2014;4(3):130-8.

  8. FDA. FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses. http://www.fda.gov/drugs/drugsafety/ucm297391.htm. Accessed 29 July 2014.

  9. AstraZeneca. Quetiapine (Seroquel) Prescribing Information. http://www1.astrazeneca-us.com/pi/Seroquel.pdf. Accessed 29 July 2014.

  10. Arizona University-Based Center for Education and Research on Therapeutics (AZCERT). CredibleMeds—A Trusted Partner Providing Reliable Information on Medicines. http://www.crediblemeds.org/everyone/. Accessed 29 July 2014.

  11. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. The clinical evaluation of Qt/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs (E14). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Guideline.pdf. Accessed 29 July 2014.

  12. E14 Implementation Working Group. ICH E14 Guideline: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Questions & Answers (R2). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_QAs_R2_Step4.pdf. Accessed 29 July 2014.

  13. Astrom-Lilja C, Odeberg JM, Ekman E, Hagg S. Drug-induced torsades de pointes: a review of the Swedish pharmacovigilance database. Pharmacoepidemiol Drug Saf. 2008;17:587–92.

    PubMed  Google Scholar 

  14. Bednar MM, Harrigan EP, Anziano RJ, Camm AJ, Ruskin JN. The QT interval. Prog Cardiovasc Dis. 2001;43:1–45.

    PubMed  CAS  Google Scholar 

  15. Viskin S, Justo D, Halkin A, Zeltser D. Long QT syndrome caused by noncardiac drugs. Prog Cardiovasc Dis. 2003;45:415–27.

    PubMed  CAS  Google Scholar 

  16. Agelink MW, Majewski T, Wurthmann C, Lukas K, Ullrich H, Linka T, et al. Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine. J Clin Psychopharmacol. 2001;21:8–13.

    PubMed  CAS  Google Scholar 

  17. Isbister GK, Balit CR, Macleod D, Duffull SB. Amisulpride overdose is frequently associated with QT prolongation and torsades de pointes. J Clin Psychopharmacol. 2010;30:391–5.

    PubMed  Google Scholar 

  18. Joy JP, Coulter CV, Duffull SB, Isbister GK. Prediction of torsade de pointes from the QT interval: analysis of a case series of amisulpride overdoses. Clin Pharmacol Ther. 2011;90:243–5.

    PubMed  CAS  Google Scholar 

  19. Coulouvrat C, Dondey-Nouvel L. Safety of amisulpride (Solian): a review of 11 clinical studies. Int Clin Psychopharmacol. 1999;14:209–18.

    PubMed  CAS  Google Scholar 

  20. Stevenson RJ. Amisulpride overdose: suggested management of prolonged QTc. Emerg Med J. 2010;27:565.

    PubMed  Google Scholar 

  21. Chung AK, Chua SE. Torsade de pointes associated with low-dose amisulpride: a case report. J Psychopharmacol. 2010;24:433–5.

    PubMed  CAS  Google Scholar 

  22. Isbister GK, Murray L, John S, Hackett LP, Haider T, O’Mullane P, et al. Amisulpride deliberate self-poisoning causing severe cardiac toxicity including QT prolongation and torsades de pointes. Med J Aust. 2006;184:354–6.

    PubMed  Google Scholar 

  23. Ward DI. Two cases of amisulpride overdose: a cause for prolonged QT syndrome. Emerg Med Australas. 2005;17:274–6.

    PubMed  Google Scholar 

  24. O’Shea M, Sazhin V, Collins A. Ventricular ectopics during crossover of atypical antipsychotics. Aust N Z J Psychiatry. 2003;37:773–4.

    PubMed  Google Scholar 

  25. Pedrosa GF, Grohmann R, Ruther E. Asymptomatic bradycardia associated with amisulpride. Pharmacopsychiatry. 2001;34:259–61.

    Google Scholar 

  26. Grande I, Pons A, Baeza I, Torras A, Bernardo M. QTc prolongation: is clozapine safe? Study of 82 cases before and after clozapine treatment. Hum Psychopharmacol. 2011;26:397–403.

    PubMed  CAS  Google Scholar 

  27. Kang UG, Kwon JS, Ahn YM, Chung SJ, Ha JH, Koo YJ, et al. Electrocardiographic abnormalities in patients treated with clozapine. J Clin Psychiatry. 2000;61:441–6.

    PubMed  CAS  Google Scholar 

  28. Cohen H, Loewenthal U, Matar M, Kotler M. Association of autonomic dysfunction and clozapine. Heart rate variability and risk for sudden death in patients with schizophrenia on long-term psychotropic medication. Br J Psychiatry. 2001;179:167–71.

    PubMed  CAS  Google Scholar 

  29. Yang FD, Wang XQ, Liu XP, Zhao KX, Fu WH, Hao XR, et al. Sex difference in QTc prolongation in chronic institutionalized patients with schizophrenia on long-term treatment with typical and atypical antipsychotics. Psychopharmacology (Berl). 2011;216:9–16.

    CAS  Google Scholar 

  30. Kramer I, Rauber-Luthy C, Kupferschmidt H, Krahenbuhl S, Ceschi A. Minimal dose for severe poisoning and influencing factors in acute human clozapine intoxication: a 13-year retrospective study. Clin Neuropharmacol. 2010;33:230–4.

    PubMed  Google Scholar 

  31. Nielsen J, Emborg C, Gydesen S, Dybbro J, Aagaard J, Haderup K, et al. Augmenting clozapine with sertindole: a double-blind, randomized, placebo-controlled study. J Clin Psychopharmacol. 2012;32:173–8.

    PubMed  CAS  Google Scholar 

  32. Henderson DC, Fan X, Copeland PM, Sharma B, Borba CP, Forstbauer SI, et al. Ziprasidone as an adjuvant for clozapine- or olanzapine-associated medical morbidity in chronic schizophrenia. Hum Psychopharmacol. 2009;24:225–32.

    PubMed  CAS  Google Scholar 

  33. Zink M, Kuwilsky A, Krumm B, Dressing H. Efficacy and tolerability of ziprasidone versus risperidone as augmentation in patients partially responsive to clozapine: a randomised controlled clinical trial. J Psychopharmacol. 2009;23:305–14.

    PubMed  CAS  Google Scholar 

  34. Anil Yagcioglu AE, Kivircik Akdede BB, Turgut TI, Tumuklu M, Yazici MK, Alptekin K, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry. 2005;66:63–72.

    PubMed  Google Scholar 

  35. Muscatello MR, Pandolfo G, Mico U, Lamberti CE, Abenavoli E, Scimeca G, et al. Augmentation of clozapine with ziprasidone in refractory schizophrenia: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2014;34:129–33.

    PubMed  CAS  Google Scholar 

  36. Sacchetti E, Galluzzo A, Valsecchi P, Romeo F, Gorini B, Warrington L. Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study. Schizophr Res. 2009;110:80–9.

    PubMed  Google Scholar 

  37. Sharma TR, Chahil R. Dose dependent, new onset QTc prolongation in a patient with paranoid schizophrenia receiving clozapine. Asian J Psychiatr. 2011;4:221–2.

    PubMed  Google Scholar 

  38. Dhillon R, Bastiampillai T, Tee K, Vanlint A. Clozapine and associated QTc prolongation. Aust N Z J Psychiatry. 2011;45:1098–9.

    PubMed  Google Scholar 

  39. Tanner MA, Culling W. Clozapine associated dilated cardiomyopathy. Postgrad Med J. 2003;79:412–3.

    PubMed  CAS  PubMed Central  Google Scholar 

  40. Cohen H, Loewenthal U, Matar MA, Kotler M. Reversal of pathologic cardiac parameters after transition from clozapine to olanzapine treatment: a case report. Clin Neuropharmacol. 2001;24:106–8.

    PubMed  CAS  Google Scholar 

  41. Dewan V, Roth BA. Antipsychotic-induced QTc interval prolongation. Can J Psychiatry. 2004;49:646.

    PubMed  Google Scholar 

  42. Potkin SG, Preskorn S, Hochfeld M, Meng X. A thorough QTc study of 3 doses of iloperidone including metabolic inhibition via CYP2D6 and/or CYP3A4 and a comparison to quetiapine and ziprasidone. J Clin Psychopharmacol. 2013;33:3–10.

    PubMed  CAS  Google Scholar 

  43. Kane JM, Lauriello J, Laska E, Di MM, Wolfgang CD. Long-term efficacy and safety of iloperidone: results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol. 2008;28:S29–35.

    PubMed  CAS  Google Scholar 

  44. Cutler AJ, Kalali AH, Weiden PJ, Hamilton J, Wolfgang CD. Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol. 2008;28:S20–8.

    PubMed  CAS  Google Scholar 

  45. Weiden PJ, Cutler AJ, Polymeropoulos MH, Wolfgang CD. Safety profile of iloperidone: a pooled analysis of 6-week acute-phase pivotal trials. J Clin Psychopharmacol. 2008;28:S12–9.

    PubMed  CAS  Google Scholar 

  46. FDA PsychoPharmacological Drugs Advisory Committee. FDA Background on ZeldoxTM (ziprasidone hydrochloride capsules) Pfizer, Inc. http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1b.pdf. Accessed 29 July 2014.

  47. Harrigan EP, Miceli JJ, Anziano R, Watsky E, Reeves KR, Cutler NR, et al. A randomized evaluation of the effects of six antipsychotic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol. 2004;24:62–9.

    PubMed  CAS  Google Scholar 

  48. Suzuki Y, Sugai T, Fukui N, Watanabe J, Ono S, Tsuneyama N, et al. Sex differences in the effect of four second-generation antipsychotics on QTc interval in patients with schizophrenia. Hum Psychopharmacol. 2013;28:215–9.

    PubMed  CAS  Google Scholar 

  49. Suzuki Y, Ono S, Sugai T, Fukui N, Watanabe J, Tsuneyama N, et al. Dose-dependent effects of olanzapine on QT intervals and plasma prolactin levels in Japanese patients with stable schizophrenia. Hum Psychopharmacol. 2011;26:440–3.

    PubMed  CAS  Google Scholar 

  50. Suzuki Y, Sugai T, Ono S, Sawamura K, Fukui N, Watanabe J, et al. Changes in the metabolic parameters and QTc interval after switching from olanzapine to aripiprazole in Japanese patients with stable schizophrenia. J Clin Psychopharmacol. 2011;31:526–8.

    PubMed  Google Scholar 

  51. Suzuki Y, Sugai T, Fukui N, Watanabe J, Ono S, Tsuneyama N, et al. Changes in QT interval after switching to quetiapine in Japanese patients with schizophrenia. Hum Psychopharmacol. 2013;28:94–6.

    PubMed  CAS  Google Scholar 

  52. Watanabe J, Suzuki Y, Fukui N, Ono S, Sugai T, Tsuneyama N, et al. Increased risk of antipsychotic-related QT prolongation during night time: a 24-h holter electrocardiogram recording study. J Clin Psychopharmacol. 2012;32:18–22.

    PubMed  Google Scholar 

  53. Huang CL, Su KP, Hsu HB, Pariante CM. A pilot observational crossover study of QTc interval changes associated with switching between olanzapine and risperidone. J Clin Psychiatry. 2007;68:803–5.

    PubMed  Google Scholar 

  54. de Castro MJ, Fraguas D, Laita P, Moreno D, Parellada M, Pascual D, et al. QTc changes after 6 months of second-generation antipsychotic treatment in children and adolescents. J Child Adolesc Psychopharmacol. 2008;18:381–3.

    PubMed  Google Scholar 

  55. Ozeki Y, Fujii K, Kurimoto N, Yamada N, Okawa M, Aoki T, et al. QTc prolongation and antipsychotic medications in a sample of 1017 patients with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:401–5.

    PubMed  CAS  Google Scholar 

  56. Meyer-Massetti C, Vaerini S, Ratz Bravo AE, Meier CR, Guglielmo BJ. Comparative safety of antipsychotics in the WHO pharmacovigilance database: the haloperidol case. Int J Clin Pharm. 2011;33:806–14.

    PubMed  CAS  Google Scholar 

  57. Ou JJ, Xu Y, Chen HH, Fan X, Gao K, Wang J, et al. Comparison of metabolic effects of ziprasidone versus olanzapine treatment in patients with first-episode schizophrenia. Psychopharmacology (Berl). 2013;225:627–35.

    CAS  Google Scholar 

  58. Simpson GM, Weiden P, Pigott T, Murray S, Siu CO, Romano SJ. Six-month, blinded, multicenter continuation study of ziprasidone versus olanzapine in schizophrenia. Am J Psychiatry. 2005;162:1535–8.

    PubMed  Google Scholar 

  59. Simpson GM, Glick ID, Weiden PJ, Romano SJ, Siu CO. Randomized, controlled, double-blind multicenter comparison of the efficacy and tolerability of ziprasidone and olanzapine in acutely ill in patients with schizophrenia or schizoaffective disorder. Am J Psychiatry. 2004;161:1837–47.

    PubMed  Google Scholar 

  60. Brown RR, Estoup MW. Comparison of the metabolic effects observed in patients treated with ziprasidone versus olanzapine. Int Clin Psychopharmacol. 2005;20:105–12.

    PubMed  Google Scholar 

  61. Kwon JS, Mittoux A, Hwang JY, Ong A, Cai ZJ, Su TP. The efficacy and safety of 12 weeks of treatment with sertindole or olanzapine in patients with chronic schizophrenia who did not respond successfully to their previous treatments: a randomized, double-blind, parallel-group, flexible-dose study. Int Clin Psychopharmacol. 2012;27:326–35.

    PubMed  Google Scholar 

  62. Czekalla J, Beasley CM Jr, Dellva MA, Berg PH, Grundy S. Analysis of the QTc interval during olanzapine treatment of patients with schizophrenia and related psychosis. J Clin Psychiatry. 2001;62:191–8.

    PubMed  CAS  Google Scholar 

  63. Street JS, Clark WS, Kadam DL, Mitan SJ, Juliar BE, Feldman PD, et al. Long-term efficacy of olanzapine in the control of psychotic and behavioral symptoms in nursing home patients with Alzheimer’s dementia. Int J Geriatr Psychiatry. 2001;16(Suppl 1):S62–70.

    PubMed  Google Scholar 

  64. Wright P, Birkett M, David SR, Meehan K, Ferchland I, Alaka KJ, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001;158:1149–51.

    PubMed  CAS  Google Scholar 

  65. Lindborg SR, Beasley CM, Alaka K, Taylor CC. Effects of intramuscular olanzapine vs. haloperidol and placebo on QTc intervals in acutely agitated patients. Psychiatry Res. 2003;119:113–23.

    PubMed  CAS  Google Scholar 

  66. Breier A, Meehan K, Birkett M, David S, Ferchland I, Sutton V, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002;59:441–8.

    PubMed  CAS  Google Scholar 

  67. Meehan K, Zhang F, David S, Tohen M, Janicak P, Small J, et al. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol. 2001;21:389–97.

    PubMed  CAS  Google Scholar 

  68. Meehan KM, Wang H, David SR, Nisivoccia JR, Jones B, Beasley CM Jr, et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology. 2002;26:494–504.

    PubMed  CAS  Google Scholar 

  69. Lung DD, Wu AH, Gerona RR. Cardiotoxicity in a citalopram and olanzapine overdose. J Emerg Med. 2013;45:554–8.

    PubMed  Google Scholar 

  70. Ritchie B, Norris ML. QTc prolongation associated with atypical antipsychotic use in the treatment of adolescent-onset anorexia nervosa. J Can Acad Child Adolesc Psychiatry. 2009;18:60–3.

    PubMed  PubMed Central  Google Scholar 

  71. Letsas KP, Sideris A, Kounas SP, Efremidis M, Korantzopoulos P, Kardaras F. Drug-induced QT interval prolongation after ciprofloxacin administration in a patient receiving olanzapine. Int J Cardiol. 2006;109:273–4.

    PubMed  Google Scholar 

  72. Su KP, Lane HY, Chuang CL, Chen KP, Shen WW. Olanzapine-induced QTc prolongation in a patient with Wolff–Parkinson–White syndrome. Schizophr Res. 2004;66:191–2.

    PubMed  Google Scholar 

  73. Imran N, Rampes H, Rosen S. Antipsychotic induced prolongation of QTc interval treated with magnesium. J Psychopharmacol. 2003;17:346–9.

    PubMed  Google Scholar 

  74. Dineen S, Withrow K, Voronovitch L, Munshi F, Nawbary MW, Lippmann S. QTc prolongation and high-dose olanzapine. Psychosomatics. 2003;44:174–5.

    PubMed  Google Scholar 

  75. Hough DW, Natarajan J, Vandebosch A, Rossenu S, Kramer M, Eerdekens M. Evaluation of the effect of paliperidone extended release and quetiapine on corrected QT intervals: a randomized, double-blind, placebo-controlled study. Int Clin Psychopharmacol. 2011;26:25–34.

    PubMed  Google Scholar 

  76. Suzuki Y, Fukui N, Watanabe J, Ono S, Sugai T, Tsuneyama N, et al. QT prolongation of the antipsychotic risperidone is predominantly related to its 9-hydroxy metabolite paliperidone. Hum Psychopharmacol. 2012;27:39–42.

    PubMed  CAS  Google Scholar 

  77. Meltzer HY, Bobo WV, Nuamah IF, Lane R, Hough D, Kramer M, et al. Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week, placebo-controlled studies. J Clin Psychiatry. 2008;69:817–29.

    PubMed  CAS  Google Scholar 

  78. Gopal S, Hough D, Karcher K, Nuamah I, Palumbo J, Berlin JA, et al. Risk of cardiovascular morbidity with risperidone or paliperidone treatment: analysis of 64 randomized, double-blind trials. J Clin Psychopharmacol. 2013;33:157–61.

    PubMed  CAS  Google Scholar 

  79. Balit CR, Isbister GK, Hackett LP, Whyte IM. Quetiapine poisoning: a case series. Ann Emerg Med. 2003;42:751–8.

    PubMed  Google Scholar 

  80. Eyer F, Pfab R, Felgenhauer N, Strubel T, Saugel B, Zilker T. Clinical and analytical features of severe suicidal quetiapine overdoses–a retrospective cohort study. Clin Toxicol (Phila). 2011;49:846–53.

    CAS  Google Scholar 

  81. Isbister GK, Duffull SB. Quetiapine overdose: predicting intubation, duration of ventilation, cardiac monitoring and the effect of activated charcoal. Int Clin Psychopharmacol. 2009;24:174–80.

    PubMed  Google Scholar 

  82. Devlin JW, Roberts RJ, Fong JJ, Skrobik Y, Riker RR, Hill NS, et al. Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med. 2010;38:419–27.

    PubMed  CAS  Google Scholar 

  83. Aghaienia N, Brahm NC, Lussier KM, Washington NB. Probable quetiapine-mediated prolongation of the QT interval. J Pharm Pract. 2011;24:506–12.

    PubMed  Google Scholar 

  84. Barker MJ, Benitez JG, Ternullo S, Juhl GA. Acute oxcarbazepine and atomoxetine overdose with quetiapine. Vet Hum Toxicol. 2004;46:130–2.

    PubMed  Google Scholar 

  85. Beelen AP, Yeo KT, Lewis LD. Asymptomatic QTc prolongation associated with quetiapine fumarate overdose in a patient being treated with risperidone. Hum Exp Toxicol. 2001;20:215–9.

    PubMed  CAS  Google Scholar 

  86. Bodmer M, Burkard T, Kummer O, Beyrau R, Krahenbuhl S, Haschke M. Pharmacokinetics and pharmacodynamics of quetiapine in a patient with a massive overdose. Ther Drug Monit. 2008;30:553–6.

    PubMed  CAS  Google Scholar 

  87. Digby G, Machaalany J, Malik P, Methot M, Simpson CS, Redfearn D, et al. Multifactorial QT interval prolongation. Cardiol J. 2010;17:184–8.

    PubMed  Google Scholar 

  88. Digby GC, Perez Riera AR, Barbosa BR, Simpson CS, Redfearn DP, Methot M, et al. Acquired long QT interval: a case series of multifactorial QT prolongation. Clin Cardiol. 2011;34:577–82.

    PubMed  Google Scholar 

  89. Furst BA, Champion KM, Pierre JM, Wirshing DA, Wirshing WC. Possible association of QTc interval prolongation with co-administration of quetiapine and lovastatin. Biol Psychiatry. 2002;51:264–5.

    PubMed  CAS  Google Scholar 

  90. Gajwani P, Pozuelo L, Tesar GE. QT interval prolongation associated with quetiapine (Seroquel) overdose. Psychosomatics. 2000;41:63–5.

    PubMed  CAS  Google Scholar 

  91. Gupta S, Nienhaus K, Shah SA. Quetiapine and QTc issues: a case report. J Clin Psychiatry. 2003;64:612–3.

    PubMed  Google Scholar 

  92. Kurth J, Maguire G. Pediatric case report of quetiapine overdose and QTc prolongation. Ann Clin Psychiatry. 2004;16:229–31.

    PubMed  Google Scholar 

  93. Nelson S, Leung JG. Torsades de pointes after administration of low-dose aripiprazole. Ann Pharmacother. 2013;47:e11.

    PubMed  Google Scholar 

  94. Precourt A, Dunewicz M, Gregoire G, Williamson DR. Multiple complications and withdrawal syndrome associated with quetiapine/venlafaxine intoxication. Ann Pharmacother. 2005;39:153–6.

    PubMed  Google Scholar 

  95. Strachan PM, Benoff BA. Mental status change, myoclonus, electrocardiographic changes, and acute respiratory distress syndrome induced by quetiapine overdose. Pharmacotherapy. 2006;26:578–82.

    PubMed  Google Scholar 

  96. Vieweg WV, Schneider RK, Wood MA. Torsade de pointes in a patient with complex medical and psychiatric conditions receiving low-dose quetiapine. Acta Psychiatr Scand. 2005;112:318–22.

    PubMed  CAS  Google Scholar 

  97. Ranjbar F, Akbarzadeh F, Ahmadi NM, Abbasnejhad M. Risperidone and corrected QT-interval prolongation in surface electrocardiogram. Pak J Biol Sci. 2012;15:496–500.

    PubMed  CAS  Google Scholar 

  98. Yerrabolu M, Prabhudesai S, Tawam M, Winter L, Kamalesh M. Effect of risperidone on QT interval and QT dispersion in the elderly. Heart Dis. 2000;2:10–2.

    PubMed  CAS  Google Scholar 

  99. Chiu CC, Chang WH, Huang MC, Chiu YW, Lane HY. Regular-dose risperidone on QTc intervals. J Clin Psychopharmacol. 2005;25:391–3.

    PubMed  Google Scholar 

  100. Llerena A, Berecz R, Dorado P, de la Rubia A. QTc interval, CYP2D6 and CYP2C9 genotypes and risperidone plasma concentrations. J Psychopharmacol. 2004;18:189–93.

    PubMed  CAS  Google Scholar 

  101. Germano E, Italiano D, Lamberti M, Guerriero L, Privitera C, D’Amico G, et al. ECG parameters in children and adolescents treated with aripiprazole and risperidone. Prog Neuropsychopharmacol Biol Psychiatry. 2014;51:23–7.

    PubMed  CAS  Google Scholar 

  102. Nahshoni E, Spitzer S, Berant M, Shoval G, Zalsman G, Weizman A. QT interval and dispersion in very young children treated with antipsychotic drugs: a retrospective chart review. J Child Adolesc Psychopharmacol. 2007;17:187–94.

    PubMed  Google Scholar 

  103. Page CB, Calver LA, Isbister GK. Risperidone overdose causes extrapyramidal effects but not cardiac toxicity. J Clin Psychopharmacol. 2010;30:387–90.

    PubMed  CAS  Google Scholar 

  104. Margari L, Matera E, Craig F, Petruzzelli MG, Palmieri VO, Pastore A, et al. Tolerability and safety profile of risperidone in a sample of children and adolescents. Int Clin Psychopharmacol. 2013;28:177–83.

    PubMed  Google Scholar 

  105. Lin CH, Kuo CC, Chou LS, Chen YH, Chen CC, Huang KH, et al. A randomized, double-blind comparison of risperidone versus low-dose risperidone plus low-dose haloperidol in treating schizophrenia. J Clin Psychopharmacol. 2010;30:518–25.

    PubMed  Google Scholar 

  106. Kane JM, Potkin SG, Daniel DG, Buckley PF. A double-blind, randomized study comparing the efficacy and safety of sertindole and risperidone in patients with treatment-resistant schizophrenia. J Clin Psychiatry. 2011;72:194–204.

    PubMed  CAS  Google Scholar 

  107. Azorin JM, Strub N, Loft H. A double-blind, controlled study of sertindole versus risperidone in the treatment of moderate-to-severe schizophrenia. Int Clin Psychopharmacol. 2006;21:49–56.

    PubMed  Google Scholar 

  108. Chan HY, Lin WW, Lin SK, Hwang TJ, Su TP, Chiang SC, et al. Efficacy and safety of aripiprazole in the acute treatment of schizophrenia in Chinese patients with risperidone as an active control: a randomized trial. J Clin Psychiatry. 2007;68:29–36.

    PubMed  CAS  Google Scholar 

  109. Lazarczyk MJ, Bhuiyan ZA, Perrin N, Giannakopoulos P. Selective acquired long QT syndrome (saLQTS) upon risperidone treatment. BMC Psychiatry. 2012;12:220.

    PubMed  PubMed Central  Google Scholar 

  110. Rajabi F, Hajsheikholeslami F, Beyraghi N. Sudden cardiac death after treatment with low dose risperidone in combination with cotrimoxazole. Asian J Psychiatr. 2011;4:218–20.

    PubMed  Google Scholar 

  111. Pollak PT, Verjee ZH, Lyon AW. Risperidone-induced QT prolongation following overdose correlates with serum drug concentration and resolves rapidly with no evidence of altered pharmacokinetics. J Clin Pharmacol. 2011;51:1112–5.

    PubMed  Google Scholar 

  112. Blaschke D, Parwani AS, Huemer M, Rolf S, Boldt LH, Dietz R, et al. Torsade de pointes during combined treatment with risperidone and citalopram. Pharmacopsychiatry. 2007;40:294–5.

    PubMed  CAS  Google Scholar 

  113. Ravina T, Ravina P, Gutierrez J. Acquired long QT syndrome: risperidone-facilitated triggered activity and Torsades de Pointes during complete AV block. I. Int J Cardiol. 2007;116:416–20.

    PubMed  Google Scholar 

  114. Tei Y, Morita T, Inoue S, Miyata H. Torsades de pointes caused by a small dose of risperidone in a terminally ill cancer patient. Psychosomatics. 2004;45:450–1.

    PubMed  Google Scholar 

  115. Nandagopal JJ, Craig JM, Lippmann S. QTc prolongation: possible association with risperidone and/or haloperidol. Psychosomatics. 2003;44:521.

    PubMed  Google Scholar 

  116. Ravin DS, Levenson JW. Fatal cardiac event following initiation of risperidone therapy. Ann Pharmacother. 1997;31:867–70.

    PubMed  CAS  Google Scholar 

  117. Brown K, Levy H, Brenner C, Leffler S, Hamburg EL. Overdose of risperidone. Ann Emerg Med. 1993;22:1908–10.

    PubMed  CAS  Google Scholar 

  118. Posey DJ, Walsh KH, Wilson GA, McDougle CJ. Risperidone in the treatment of two very young children with autism. J Child Adolesc Psychopharmacol. 1999;9:273–6.

    PubMed  CAS  Google Scholar 

  119. Atmaca M, Yavuzkir M, Mermi O, Topuz M, Kanmaz E, Tezcan E. Effect of sertindole on QTc interval in patients with schizophrenia. Neurosci Lett. 2008;442:1–3.

    PubMed  CAS  Google Scholar 

  120. Nielsen J, Andersen MP, Graff C, Kanters JK, Hardahl T, Dybbro J, et al. The effect of sertindole on QTD and TPTE. Acta Psychiatr Scand. 2010;121:385–8.

    PubMed  CAS  Google Scholar 

  121. Pezawas L, Quiner S, Moertl D, Tauscher J, Barnas C, Kufferle B, et al. Efficacy, cardiac safety and tolerability of sertindole: a drug surveillance. Int Clin Psychopharmacol. 2000;15:207–14.

    PubMed  CAS  Google Scholar 

  122. Blair J, Scahill L, State M, Martin A. Electrocardiographic changes in children and adolescents treated with ziprasidone: a prospective study. J Am Acad Child Adolesc Psychiatry. 2005;44:73–9.

    PubMed  Google Scholar 

  123. Emul M, Dalkiran M, Coskun O, Yavuz R, Tosun M, Duran A, et al. P wave and QT changes among inpatients with schizophrenia after parenteral ziprasidone administration. Pharmacol Res. 2009;60:369–72.

    PubMed  CAS  Google Scholar 

  124. Levy WO, Robichaux-Keene NR, Nunez C. No significant QTc interval changes with high-dose ziprasidone: a case series. J Psychiatr Pract. 2004;10:227–32.

    PubMed  Google Scholar 

  125. Miceli JJ, Tensfeldt TG, Shiovitz T, Anziano RJ, O’Gorman C, Harrigan RH. Effects of high-dose ziprasidone and haloperidol on the QTc interval after intramuscular administration: a randomized, single-blind, parallel-group study in patients with schizophrenia or schizoaffective disorder. Clin Ther. 2010;32:472–91.

    PubMed  CAS  Google Scholar 

  126. Miceli JJ, Tensfeldt TG, Shiovitz T, Anziano R, O’Gorman C, Harrigan RH. Effects of oral ziprasidone and oral haloperidol on QTc interval in patients with Schizophrenia or schizoaffective disorder. Pharmacotherapy. 2010;30:127–35.

    PubMed  CAS  Google Scholar 

  127. Klein-Schwartz W, Lofton AL, Benson BE, Spiller HA, Crouch BI. Prospective observational multi-poison center study of ziprasidone exposures. Clin Toxicol (Phila). 2007;45:782–6.

    CAS  Google Scholar 

  128. Biederman J, Mick E, Spencer T, Dougherty M, Aleardi M, Wozniak J. A prospective open-label treatment trial of ziprasidone monotherapy in children and adolescents with bipolar disorder. Bipolar Disord. 2007;9:888–94.

    PubMed  CAS  Google Scholar 

  129. Correll CU, Lops JD, Figen V, Malhotra AK, Kane JM, Manu P. QT interval duration and dispersion in children and adolescents treated with ziprasidone. J Clin Psychiatry. 2011;72:854–60.

    PubMed  PubMed Central  Google Scholar 

  130. Delbello MP, Versavel M, Ice K, Keller D, Miceli J. Tolerability of oral ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder. J Child Adolesc Psychopharmacol. 2008;18:491–9.

    PubMed  Google Scholar 

  131. Findling RL, Cavus I, Pappadopulos E, Vanderburg DG, Schwartz JH, Gundapaneni BK, et al. Ziprasidone in adolescents with schizophrenia: results from a placebo-controlled efficacy and long-term open-extension study. J Child Adolesc Psychopharmacol. 2013;23:531–44.

    PubMed  CAS  Google Scholar 

  132. Findling RL, Cavus I, Pappadopulos E, Vanderburg DG, Schwartz JH, Gundapaneni BK, et al. Efficacy, long-term safety, and tolerability of ziprasidone in children and adolescents with bipolar disorder. J Child Adolesc Psychopharmacol. 2013;23:545–57.

    PubMed  CAS  Google Scholar 

  133. Malone RP, Delaney MA, Hyman SB, Cater JR. Ziprasidone in adolescents with autism: an open-label pilot study. J Child Adolesc Psychopharmacol. 2007;17:779–90.

    PubMed  Google Scholar 

  134. Sallee FR, Miceli JJ, Tensfeldt T, Robarge L, Wilner K, Patel NC. Single-dose pharmacokinetics and safety of ziprasidone in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2006;45:720–8.

    PubMed  Google Scholar 

  135. Centorrino F, MacLean E, Salvatore P, Kidwell JE, Fogarty KV, Berry JM, et al. Ziprasidone: first year experience in a hospital setting. J Psychiatr Pract. 2004;10:361–7.

    PubMed  Google Scholar 

  136. Goff DC, McEvoy JP, Citrome L, Mech AW, Bustillo JR, Gil R, et al. High-dose oral ziprasidone versus conventional dosing in schizophrenia patients with residual symptoms: the ZEBRAS study. J Clin Psychopharmacol. 2013;33:485–90.

    PubMed  CAS  Google Scholar 

  137. Kudla D, Lambert M, Domin S, Kasper S, Naber D. Effectiveness, tolerability, and safety of ziprasidone in patients with schizophrenia or schizoaffective disorder: results of a multi-centre observational trial. Eur Psychiatry. 2007;22:195–202.

    PubMed  Google Scholar 

  138. Mencacci C. Efficacy and tolerability of switching to ziprasidone in italian patients with acute exacerbation of schizophrenia: an open-label trial. Pharmacopsychiatry. 2012;45:236–40.

    PubMed  CAS  Google Scholar 

  139. Preval H, Klotz SG, Southard R, Francis A. Rapid-acting IM ziprasidone in a psychiatric emergency service: a naturalistic study. Gen Hosp Psychiatry. 2005;27:140–4.

    PubMed  Google Scholar 

  140. Zhao T, Park TW, Yang JC, Huang GB, Kim MG, Lee KH, et al. Efficacy and safety of ziprasidone in the treatment of first-episode psychosis: an 8-week, open-label, multicenter trial. Int Clin Psychopharmacol. 2012;27:184–90.

    PubMed  CAS  Google Scholar 

  141. Greco KE, Tune LE, Brown FW, Van Horn WA. A retrospective study of the safety of intramuscular ziprasidone in agitated elderly patients. J Clin Psychiatry. 2005;66:928–9.

    PubMed  CAS  Google Scholar 

  142. Rais AR, Williams K, Rais T, Singh T, Tamburrino M. Use of intramuscular ziprasidone for the control of acute psychosis or agitation in an inpatient geriatric population: an open-label study. Psychiatry (Edgmont). 2010;7:17–24.

    Google Scholar 

  143. Papakostas GI, Petersen TJ, Nierenberg AA, Murakami JL, Alpert JE, Rosenbaum JF, et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry. 2004;65:217–21.

    PubMed  CAS  Google Scholar 

  144. Potkin SG, Ogasa M, Cucchiaro J, Loebel A. Double-blind comparison of the safety and efficacy of lurasidone and ziprasidone in clinically stable outpatients with schizophrenia or schizoaffective disorder. Schizophr Res. 2011;132:101–7.

    PubMed  Google Scholar 

  145. Kane JM, Khanna S, Rajadhyaksha S, Giller E. Efficacy and tolerability of ziprasidone in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol. 2006;21:21–8.

    PubMed  Google Scholar 

  146. Camm 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.

    PubMed  CAS  Google Scholar 

  147. Berling I, Isbister GK, Calver L, Clunas S. Digital Holter measurement of QT prolongation in ziprasidone overdose. Clin Toxicol (Phila). 2011;49:694–6.

    CAS  Google Scholar 

  148. Witsil JC, Zell-Kanter M, Mycyk MB. Single-dose ziprasidone associated with QT interval prolongation. Am J Emerg Med. 2012;30:837.e1–2.

    Google Scholar 

  149. Alipour A, Cruz R, Lott RS. Torsade de pointes after ziprasidone overdose with coingestants. J Clin Psychopharmacol. 2010;30:76–7.

    PubMed  Google Scholar 

  150. Oldham MA, Catalano G, Catalano MC, Ross MM. QTc prolongation associated with ziprasidone overdose. CNS Spectr. 2008;13:E1.

    PubMed  Google Scholar 

  151. Eker SS, Sarandol A, Akkaya C, Sivrioglu EY, Kirli S. The potential relationship between QTc interval prolongation and ziprasidone treatment: three cases. J Psychopharmacol. 2009;23:993–6.

    PubMed  CAS  Google Scholar 

  152. Bentley ML, Biscardi FH, Butcher C, Levitov A. Inadvertent administration of intravenous ziprasidone leading to bradycardia and QT interval prolongation. Ann Pharmacother. 2008;42:902–3.

    PubMed  Google Scholar 

  153. Manini AF, Raspberry D, Hoffman RS, Nelson LS. QT prolongation and Torsades de Pointes following overdose of ziprasidone and amantadine. J Med Toxicol. 2007;3:178–81.

    PubMed  PubMed Central  Google Scholar 

  154. Heinrich TW, Biblo LA, Schneider J. Torsades de pointes associated with ziprasidone. Psychosomatics. 2006;47:264–8.

    PubMed  Google Scholar 

  155. Simpson BR, Albanese RP Jr. Ziprasidone and hypokalemia: a case of 2 predisposing factors for QTc prolongation without development of torsades de pointes. Prim Care Companion J Clin Psychiatry. 2005;7:134–6.

    PubMed  PubMed Central  Google Scholar 

  156. Jaffe R, Leavitt R, Wind T. QTc prolongation in multiple drug overdose. J Clin Psychopharmacol. 2004;24:348–50.

    PubMed  Google Scholar 

  157. Biswas AK, Zabrocki LA, Mayes KL, Morris-Kukoski CL. Cardiotoxicity associated with intentional ziprasidone and bupropion overdose. J Toxicol Clin Toxicol. 2003;41:101–4.

    PubMed  Google Scholar 

  158. Castro VM, Clements CC, Murphy SN, Gainer VS, Fava M, Weilburg JB, et al. QT interval and antidepressant use: a cross sectional study of electronic health records. BMJ. 2013;346:f288.

    PubMed  PubMed Central  Google Scholar 

  159. Dubnov-Raz G, Juurlink DN, Fogelman R, Merlob P, Ito S, Koren G, et al. Antenatal use of selective serotonin-reuptake inhibitors and QT interval prolongation in newborns. Pediatrics. 2008;122:e710–5.

    PubMed  Google Scholar 

  160. Grundemar L, Wohlfart B, Lagerstedt C, Bengtsson F, Eklundh G. Symptoms and signs of severe citalopram overdose. Lancet. 1997;349:1602.

    PubMed  CAS  Google Scholar 

  161. Jimmink A, Caminada K, Hunfeld NG, Touw DJ. Clinical toxicology of citalopram after acute intoxication with the sole drug or in combination with other drugs: overview of 26 cases. Ther Drug Monit. 2008;30:365–71.

    PubMed  CAS  Google Scholar 

  162. Hayes BD, Klein-Schwartz W, Clark RF, Muller AA, Miloradovich JE. Comparison of toxicity of acute overdoses with citalopram and escitalopram. J Emerg Med. 2010;39:44–8.

    PubMed  Google Scholar 

  163. Yilmaz Z, Ceschi A, Rauber-Luthy C, Sauer O, Stedtler U, Prasa D, et al. Escitalopram causes fewer seizures in human overdose than citalopram. Clin Toxicol (Phila). 2010;48:207–12.

    CAS  Google Scholar 

  164. Isbister GK, Bowe SJ, Dawson A, Whyte IM. Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol. 2004;42:277–85.

    PubMed  CAS  Google Scholar 

  165. Kelly CA, Dhaun N, Laing WJ, Strachan FE, Good AM, Bateman DN. Comparative toxicity of citalopram and the newer antidepressants after overdose. J Toxicol Clin Toxicol. 2004;42:67–71.

    PubMed  CAS  Google Scholar 

  166. Waring WS, Graham A, Gray J, Wilson AD, Howell C, Bateman DN. Evaluation of a QT nomogram for risk assessment after antidepressant overdose. Br J Clin Pharmacol. 2010;70:881–5.

    PubMed  CAS  PubMed Central  Google Scholar 

  167. Rasmussen SL, Overo KF, Tanghoj P. Cardiac safety of citalopram: prospective trials and retrospective analyses. J Clin Psychopharmacol. 1999;19:407–15.

    PubMed  CAS  Google Scholar 

  168. Agosti S, Casalino L, Bertero G, Burrone A, Brunelli C, Morelloni S. Citalopram and levosulpiride: a dangerous drug combination for QT prolongation. Am J Emerg Med. 2013;31:1624.e1–2.

    Google Scholar 

  169. Deshmukh A, Ulveling K, Alla V, Abuissa H, Airey K. Prolonged QTc interval and torsades de pointes induced by citalopram. Tex Heart Inst J. 2012;39:68–70.

    PubMed  PubMed Central  Google Scholar 

  170. Unterecker S, Warrings B, Deckert J, Pfuhlmann B. Correlation of QTc interval prolongation and serum level of citalopram after intoxication–a case report. Pharmacopsychiatry. 2012;45:30–4.

    PubMed  CAS  Google Scholar 

  171. Liotier J, Coudore F. Drug monitoring of a case of citalopram overdosage. Drug Chem Toxicol. 2011;34:420–3.

    PubMed  CAS  Google Scholar 

  172. Fayssoil A, Issi J, Guerbaa M, Raynaud JC, Heroguelle V. Torsade de pointes induced by citalopram and amiodarone. Ann Cardiol Angeiol (Paris). 2011;60:165–8.

    CAS  Google Scholar 

  173. de Gregorio C, Morabito G, Cerrito M, Dattilo G, Oreto G. Citalopram-induced long QT syndrome and torsade de pointes: role for concomitant therapy and disease. Int J Cardiol. 2011;148:226–8.

    PubMed  Google Scholar 

  174. Venkatraman N, O’Neil D, Hall AP. Life-threatening overdose with lamotrigine, citalopram, and chlorpheniramine. J Postgrad Med. 2008;54:316–7.

    PubMed  CAS  Google Scholar 

  175. Tarabar AF, Hoffman RS, Nelson L. Citalopram overdose: late presentation of torsades de pointes (TdP) with cardiac arrest. J Med Toxicol. 2008;4:101–5.

    PubMed  PubMed Central  Google Scholar 

  176. Kanjanauthai S, Kanluen T, Chareonthaitawee P. Citalopram induced torsade de pointes, a rare life threatening side effect. Int J Cardiol. 2008;131:e33–4.

    PubMed  Google Scholar 

  177. Engebretsen KM, Harris CR, Wood JE. Cardiotoxicity and late onset seizures with citalopram overdose. J Emerg Med. 2003;25:163–6.

    PubMed  Google Scholar 

  178. Catalano G, Catalano MC, Epstein MA, Tsambiras PE. QTc interval prolongation associated with citalopram overdose: a case report and literature review. Clin Neuropharmacol. 2001;24:158–62.

    PubMed  CAS  Google Scholar 

  179. Bucklin MH, Gorodetsky RM, Wiegand TJ. Prolonged lipemia and pancreatitis due to extended infusion of lipid emulsion in bupropion overdose. Clin Toxicol (Phila). 2013;51:896–8.

    CAS  Google Scholar 

  180. Altin T, Ozcan O, Turhan S, Ozdemir AO, Akyurek O, Karaoguz R, et al. Torsade de pointes associated with moxifloxacin: a rare but potentially fatal adverse event. Can J Cardiol. 2007;23:907–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  181. van Gorp F, Duffull S, Hackett LP, Isbister GK. Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal. Br J Clin Pharmacol. 2012;73:402–10.

    PubMed  PubMed Central  Google Scholar 

  182. Hanash JA, Hansen BH, Hansen JF, Nielsen OW, Rasmussen A, Birket-Smith M. Cardiovascular safety of one-year escitalopram therapy in clinically nondepressed patients with acute coronary syndrome: results from the DEpression in patients with Coronary ARtery Disease (DECARD) trial. J Cardiovasc Pharmacol. 2012;60:397–405.

    PubMed  CAS  Google Scholar 

  183. Thase ME, Larsen KG, Reines E, Kennedy SH. The cardiovascular safety profile of escitalopram. Eur Neuropsychopharmacol. 2013;23:1391–400.

    PubMed  CAS  Google Scholar 

  184. Mohammed R, Norton J, Geraci SA, Newman DB, Koch CA. Prolonged QTc interval due to escitalopram overdose. J Miss State Med Assoc. 2010;51:350–3.

    PubMed  Google Scholar 

  185. Baranchuk A, Simpson CS, Methot M, Gibson K, Strum D. Corrected QT interval prolongation after an overdose of escitalopram, morphine, oxycodone, zopiclone and benzodiazepines. Can J Cardiol. 2008;24:e38–40.

    PubMed  PubMed Central  Google Scholar 

  186. Scharko AM, Schumacher J. Prolonged QTc interval in a 14-year-old girl with escitalopram overdose. J Child Adolesc Psychopharmacol. 2008;18:297–8.

    PubMed  Google Scholar 

  187. Tseng PT, Lee Y, Lin YE, Lin PY. Low-dose escitalopram for 2 days associated with corrected QT interval prolongation in a middle-aged woman: a case report and literature review. Gen Hosp Psychiatry. 2012;34:210–5.

    Google Scholar 

  188. Beyenburg S, Schonegger K. Severe bradycardia in a stroke patient caused by a single low dose of escitalopram. Eur Neurol. 2007;57:50–1.

    PubMed  Google Scholar 

  189. Schreffler SM, Marraffa JM, Stork CM, Mackey J. Sodium channel blockade with QRS widening after an escitalopram overdose. Pediatr Emerg Care. 2013;29:998–1001.

    PubMed  Google Scholar 

  190. Zhao Q, Wojcik MA, Parier JL, Pesco-Koplowitz L. Influence of coadministration of fluoxetine on cisapride pharmacokinetics and QTc intervals in healthy volunteers. Pharmacotherapy. 2001;21:149–57.

    PubMed  CAS  Google Scholar 

  191. Baker B, Dorian P, Sandor P, Shapiro C, Schell C, Mitchell J, et al. Electrocardiographic effects of fluoxetine and doxepin in patients with major depressive disorder. J Clin Psychopharmacol. 1997;17:15–21.

    PubMed  CAS  Google Scholar 

  192. Adetunji B, Basil B, Mathews M, Osinowo T. Should the Physician’s Desk Reference contraindicate the use of chlorpromazine-fluoxetine combination? A case report. J Clin Psychopharmacol. 2006;26:438.

    PubMed  Google Scholar 

  193. Wilting I, Smals OM, Holwerda NJ, Meyboom RH, de Bruin ML, Egberts TC. QTc prolongation and torsades de pointes in an elderly woman taking fluoxetine. Am J Psychiatry. 2006;163:325.

    PubMed  Google Scholar 

  194. Dubnov G, Fogelman R, Merlob P. Prolonged QT interval in an infant of a fluoxetine treated mother. Arch Dis Child. 2005;90:972–3.

    PubMed  CAS  PubMed Central  Google Scholar 

  195. Suchard JR. Fluoxetine overdose-induced seizure. West J Emerg Med. 2008;9:154–6.

    PubMed  PubMed Central  Google Scholar 

  196. Varriale P. Fluoxetine (Prozac) as a cause of QT prolongation. Arch Intern Med. 2001;161:612.

    PubMed  CAS  Google Scholar 

  197. Nykamp DL, Blackmon CL, Schmidt PE, Roberson AG. QTc prolongation associated with combination therapy of levofloxacin, imipramine, and fluoxetine. Ann Pharmacother. 2005;39:543–6.

    PubMed  Google Scholar 

  198. Appleby M, Mbewu A, Clarke B. Fluoxetine and ventricular torsade–is there a link? Int J Cardiol. 1995;49:178–80.

    PubMed  CAS  Google Scholar 

  199. Michalets EL, Smith LK, Van Tassel ED. Torsade de pointes resulting from the addition of droperidol to an existing cytochrome P450 drug interaction. Ann Pharmacother. 1998;32:761–5.

    PubMed  CAS  Google Scholar 

  200. Graudins A, Vossler C, Wang R. Fluoxetine-induced cardiotoxicity with response to bicarbonate therapy. Am J Emerg Med. 1997;15:501–3.

    PubMed  CAS  Google Scholar 

  201. Martin DE, Zussman BD, Everitt DE, Benincosa LJ, Etheredge RC, Jorkasky DK. Paroxetine does not affect the cardiac safety and pharmacokinetics of terfenadine in healthy adult men. J Clin Psychopharmacol. 1997;17:451–9.

    PubMed  CAS  Google Scholar 

  202. Kuhs H, Rudolf GA. Cardiovascular effects of paroxetine. Psychopharmacology (Berl). 1990;102:379–82.

    CAS  Google Scholar 

  203. Edwards JG, Goldie A, Papayanni-Papasthatis S. Effect of paroxetine on the electrocardiogram. Psychopharmacology (Berl). 1989;97:96–8.

    CAS  Google Scholar 

  204. Nelson JC, Lu PY, Martynov O, Yu JY, Mallinckrodt CH, Detke MJ. The safety and tolerability of duloxetine compared with paroxetine and placebo: a pooled analysis of 4 clinical trials. Prim Care Companion J Clin Psychiatry. 2006;8:212–9.

    PubMed  PubMed Central  Google Scholar 

  205. Krulewicz S, Carpenter DJ, Fong R, Horrigan JP, Lipschitz A, Perera P, et al. Analysis of electrocardiographic data following use of paroxetine in pediatric depression and obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 2006;45:422–30.

    PubMed  Google Scholar 

  206. Alderman J. Coadministration of sertraline with cisapride or pimozide: an open-label, nonrandomized examination of pharmacokinetics and corrected QT intervals in healthy adult volunteers. Clin Ther. 2005;27:1050–63.

    PubMed  CAS  Google Scholar 

  207. Glassman AH, O’Connor CM, Califf RM, Swedberg K, Schwartz P, Bigger JT Jr, et al. Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA. 2002;288:701–9.

    PubMed  CAS  Google Scholar 

  208. Wilens TE, Biederman J, March JS, Wolkow R, Fine CS, Millstein RB, et al. Absence of cardiovascular adverse effects of sertraline in children and adolescents. J Am Acad Child Adolesc Psychiatry. 1999;38:573–7.

    PubMed  CAS  Google Scholar 

  209. Guy S, Silke B. The electrocardiogram as a tool for therapeutic monitoring: a critical analysis. J Clin Psychiatry. 1990;51(Suppl B):37–9.

    PubMed  Google Scholar 

  210. Patane S, Marte F, Di BG. QT interval prolongation and torsade de pointes. Int J Cardiol. 2009;131:e51–3.

    PubMed  Google Scholar 

  211. de Boer RA, van Dijk TH, Holman ND, van Melle JP. QT interval prolongation after sertraline overdose: a case report. BMC Emerg Med. 2005;5:5.

    PubMed  PubMed Central  Google Scholar 

  212. Mbaya P, Alam F, Ashim S, Bennett D. Cardiovascular effects of high dose venlafaxine XL in patients with major depressive disorder. Hum Psychopharmacol. 2007;22:129–33.

    PubMed  CAS  Google Scholar 

  213. Johnson EM, Whyte E, Mulsant BH, Pollock BG, Weber E, Begley AE, et al. Cardiovascular changes associated with venlafaxine in the treatment of late-life depression. Am J Geriatr Psychiatry. 2006;14:796–802.

    PubMed  Google Scholar 

  214. Isbister GK. Electrocardiogram changes and arrhythmias in venlafaxine overdose. Br J Clin Pharmacol. 2009;67:572–6.

    PubMed  CAS  PubMed Central  Google Scholar 

  215. Chan AN, Gunja N, Ryan CJ. A comparison of venlafaxine and SSRIs in deliberate self-poisoning. J Med Toxicol. 2010;6:116–21.

    PubMed  PubMed Central  Google Scholar 

  216. Batista M, Dugernier T, Simon M, Haufroid V, Capron A, Fonseca S, et al. The spectrum of acute heart failure after venlafaxine overdose. Clin Toxicol (Phila). 2013;51:92–5.

    CAS  Google Scholar 

  217. Bosse GM, Spiller HA, Collins AM. A fatal case of venlafaxine overdose. J Med Toxicol. 2008;4:18–20.

    PubMed  PubMed Central  Google Scholar 

  218. Letsas K, Korantzopoulos P, Pappas L, Evangelou D, Efremidis M, Kardaras F. QT interval prolongation associated with venlafaxine administration. Int J Cardiol. 2006;109:116–7.

    PubMed  Google Scholar 

  219. Wang Y, Pan G, Balch A. Bias and variance evaluation of QT interval correction methods. J Biopharm Stat. 2008;18:427–50.

    PubMed  Google Scholar 

  220. Malik M. Problems of heart rate correction in assessment of drug-induced QT interval prolongation. J Cardiovasc Electrophysiol. 2001;12:411–20.

    PubMed  CAS  Google Scholar 

  221. Hingorani P, Karnad DR, Natekar M, Kothari S, Narula D, Lokhandwala Y. QTc interval and its variability in patients with schizophrenia and healthy subjects: implications for a thorough QT study. Int J Neuropsychopharmacol. 2012;15:1535–40.

    PubMed  Google Scholar 

  222. Nielsen J. QTc prolongation and clozapine: fact or artefact? Aust N Z J Psychiatry. 2012;46:793–4.

    PubMed  Google Scholar 

  223. Law D, Mohan T, Bastiampillai T, Dhillon R. Clozapine rechallenge following QTc prolongation. Aust N Z J Psychiatry. 2013.

  224. Chung AK, Chua SE. Effects on prolongation of Bazett’s corrected QT interval of seven second-generation antipsychotics in the treatment of schizophrenia: a meta-analysis. J Psychopharmacol. 2011;25:646–66.

    PubMed  Google Scholar 

  225. van Driel ML, De SA, De MJ, Christiaens T. Searching for unpublished trials in Cochrane reviews may not be worth the effort. J Clin Epidemiol. 2009;62:838–44.

    PubMed  Google Scholar 

  226. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet. 2013;382:951–62.

    PubMed  CAS  Google Scholar 

  227. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. The non-clinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals (S7B). http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7B/Step4/S7B_Guideline.pdf. Accessed 29 July 2014.

  228. Farkas AS, Nattel S. Minimizing repolarization-related proarrhythmic risk in drug development and clinical practice. Drugs. 2010;70:573–603.

    PubMed  CAS  Google Scholar 

  229. Panikkath R, Reinier K, Uy-Evanado A, Teodorescu C, Hattenhauer J, Mariani R, et al. Prolonged Tpeak-to-Tend interval on the resting ECG is associated with increased risk of sudden cardiac death. Circ Arrhythm Electrophysiol. 2011;4:441–7.

    PubMed  PubMed Central  Google Scholar 

  230. Hondeghem LM. QT prolongation is an unreliable predictor of ventricular arrhythmia. Heart Rhythm. 2008;5:1210–2.

    PubMed  Google Scholar 

  231. Davey P. How to correct the QT interval for the effects of heart rate in clinical studies. J Pharmacol Toxicol Methods. 2002;48:3–9.

    PubMed  CAS  Google Scholar 

  232. Luo S, Michler K, Johnston P, Macfarlane PW. A comparison of commonly used QT correction formulae: the effect of heart rate on the QTc of normal ECGs. J Electrocardiol. 2004;37 Suppl:81–90.

    PubMed  Google Scholar 

  233. Nielsen J, Graff C, Kanters JK, Toft E, Taylor D, Meyer JM. Assessing QT interval prolongation and its associated risks with antipsychotics. CNS Drugs. 2011;25:473–90.

    PubMed  CAS  Google Scholar 

  234. Postema PG, De Jong JS, Van der Bilt IA, Wilde AA. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Heart Rhythm. 2008;5:1015–8.

    PubMed  Google Scholar 

  235. Chan A, Isbister GK, Kirkpatrick CM, Dufful SB. Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram. QJM. 2007;100:609–15.

    PubMed  CAS  Google Scholar 

  236. Straus SM, Kors JA, de Bruin ML, van der Hooft CS, Hofman A, Heeringa J, et al. Prolonged QTc interval and risk of sudden cardiac death in a population of older adults. J Am Coll Cardiol. 2006;47:362–7.

    PubMed  Google Scholar 

  237. Allen LaPointe NM, Curtis LH, Chan KA, Kramer JM, Lafata JE, Gurwitz JH et al. Frequency of high-risk use of QT-prolonging medications. Pharmacoepidemiol Drug Saf 2006; 15:361-368.

  238. Curtis LH, Ostbye T, Sendersky V, Hutchison S, Allen LaPointe NM, Al-Khatib SM, et al. Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients. Am J Med. 2003;114:135–41.

    PubMed  CAS  Google Scholar 

  239. Mason JW, Ramseth DJ, Chanter DO, Moon TE, Goodman DB, Mendzelevski B. Electrocardiographic reference ranges derived from 79,743 ambulatory subjects. J Electrocardiol. 2007;40:228–34.

    PubMed  Google Scholar 

  240. Carella MJ, Mantz SL, Rovner DR, Willis PW III, Gossain VV, Bouknight RR, et al. Obesity, adiposity, and lengthening of the QT interval: improvement after weight loss. Int J Obes Relat Metab Disord. 1996;20:938–42.

    PubMed  CAS  Google Scholar 

  241. Soydinc S, Davutoglu V, Akcay M. Uncomplicated metabolic syndrome is associated with prolonged electrocardiographic QTc interval and QTc dispersion. Ann Noninvasive Electrocardiol. 2006;11:313–7.

    PubMed  Google Scholar 

  242. Tasolar H, Balli M, Bayramoglu A, Otlu YO, Cetin M, Altun B, et al. Effect of Smoking on Tp-e interval, Tp-e/QT and Tp-e/QTc ratios as indices of ventricular arrhythmogenesis. Heart Lung Circ. 2014.

  243. Erbas O, Yilmaz M. Metoprolol and diltiazem ameliorate ziprasidone-induced prolonged corrected QT interval in rats. Toxicol Ind Health. 2013.

  244. Ng TM, Olsen KM, McCartan MA, Puumala SE, Speidel KM, Miller MA, et al. Drug-induced QTc-interval prolongation in the intensive care unit: incidence and predictors. J Pharm Pract. 2010;23:19–24.

    PubMed  Google Scholar 

  245. Mahida S, Hogarth AJ, Cowan C, Tayebjee MH, Graham LN, Pepper CB. Genetics of congenital and drug-induced long QT syndromes: current evidence and future research perspectives. J Interv Card Electrophysiol. 2013;37:9–19.

    PubMed  Google Scholar 

  246. Gouas L, Nicaud V, Berthet M, Forhan A, Tiret L, Balkau B, et al. Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population. Eur J Hum Genet. 2005;13:1213–22.

    PubMed  CAS  Google Scholar 

  247. Al-Zaiti SS, Fallavollita JA, Wu YW, Tomita MR, Carey MG. Electrocardiogram-based predictors of clinical outcomes: A meta-analysis of the prognostic value of ventricular repolarization. Heart Lung. 2014.

  248. Nielsen J, Graff C, Hardahl T, Andersen MP, Kristoffersen J, Struijk JJ, et al. Sertindole causes distinct electrocardiographic T-wave morphology changes. Eur Neuropsychopharmacol. 2009;19:702–7.

    PubMed  CAS  Google Scholar 

  249. Axelsson R, Aspenstrom G. Electrocardiographic changes and serum concentrations in thioridazine-treated patients. J Clin Psychiatry. 1982;43:332–5.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Psychiatry, Memorial University, St John’s, NL, Canada

    Mehrul Hasnain

  2. Department of Psychiatry and Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA

    W. Victor R. Vieweg

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  1. Mehrul Hasnain
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  2. W. Victor R. Vieweg
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Correspondence to Mehrul Hasnain.

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W. Victor Vieweg, MD, an author on this article, died on 7 October 2013, in Charlottesville, VA, USA. Dr Vieweg, who began his career as a cardiologist, later specialized in psychiatry. He was a prolific researcher, especially in the interface of psychiatry and medicine and often ahead of the times in conceptualizing disease and treatment models. In his death, both psychiatry and medicine have lost a great scholar and teacher.

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Hasnain, M., Vieweg, W.V.R. QTc Interval Prolongation and Torsade de Pointes Associated with Second-Generation Antipsychotics and Antidepressants: A Comprehensive Review. CNS Drugs 28, 887–920 (2014). https://doi.org/10.1007/s40263-014-0196-9

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