Drugs & Aging

, Volume 26, Issue 12, pp 997–1012 | Cite as

Proarrhythmic Risk with Antipsychotic and Antidepressant Drugs

Implications in the Elderly
  • W. Victor R. Vieweg
  • Mark A. Wood
  • Antony Fernandez
  • Mary Beatty-Brooks
  • Mehrul Hasnain
  • Anand K. Pandurangi
Review Article


The quinidine-like effects of some antidepressant drugs (particularly tricyclic antidepressants) and many antipsychotic drugs (particularly the phenothiazines) confound treatment of psychosis and depression in patients with major mental illness. This is especially true among elderly patients with existing risk factors for corrected QT (QTc) interval prolongation.

We used PubMed, previously reported review articles and the extensive personal files of the authors to identify cases of subjects aged ≥60 years who developed QTc interval prolongation, polymorphic ventricular tachycardia (PVT)/torsade de pointes (TdP) and/or sudden cardiac death while taking antipsychotic or antidepressant drugs or a combination of these medications. We identified 37 patients who had taken, in total, 46 antipsychotic or antidepressant drugs.

Our most striking finding was that almost four-fifths of our cases involved women. When the 14 critically ill subjects receiving haloperidol intravenously were excluded, 91.3% of our subjects were women. Almost three-quarters of our study subjects had cardiovascular disease.

Intravenous administration of haloperidol in the critically ill and profoundly agitated elderly warrants particular comment. Of the 14 subjects in this category identified, six were men and eight were women. In 13 cases, the drug dose far exceeded the 2 mg necessary to produce an antipsychotic effect. These clinicians were using an agent to achieve sedation that usually requires very high doses in the critically ill and profoundly agitated elderly to achieve this effect.

Inclusion criteria for our literature review required antipsychotic and/or antidepressant drug-induced QTc interval prolongation. Even so, our finding that 31 of our 37 subjects developed PVT is sobering. However, the reader should not conclude that drug-induced QTc interval prolongation is highly predictive of PVT or its TdP subtype. All of our study subjects had at least two risk factors for TdP, with age and sex being the most common. We included the rare case of a patient with congenital long QT syndrome who developed further lengthening of the QTc interval and TdP when prescribed an antidepressant drug well known to produce QTc interval prolongation.

We conclude with recommendations for clinicians not expert in the specialty of cardiology to deal with the many questions raised in this review. Specifically, such clinicians treating elderly patients with antipsychotic and antidepressant drugs that may prolong the QTc interval should aggressively obtain a baseline ECG for elderly female patients with additional risk factors such as personal or family history of pre-syncope or syncope, electrolyte disturbances or cardiovascular disease. Elderly male patients are also subject to QTc interval prolongation when such risk factors are present. It is important that the clinicians themselves inspect ECGs. If the QT interval is more than half the RR interval, QTc interval prolongation is likely to be present. In such cases, a cardiology colleague interested in QTc interval issues and TdP should be asked to review the ECG. Finally, nothing in our recommendations replaces meticulous attention to US FDA guidelines in the package insert of each drug.


  1. 1.
    Vieweg WVR, Nicholson CS. Antidepressant drugs and the cardiovascular system. Med Update Psychiatrists 1996; 1: 154–60CrossRefGoogle Scholar
  2. 2.
    Vieweg WVR, Nicholson CS. Torsade de pointes ventricular tachycardia, QT interval, and psychotropic drugs. Med Update Psychiatr 1997; 2(2): 48–54CrossRefGoogle Scholar
  3. 3.
    Vieweg V, Driscoll R, Silber C. Long-term cardiovascular safety of sertindole. 49th Institute of Psychiatric Services; 1997 Oct 24–28; Washington, DCGoogle Scholar
  4. 4.
    Khan SP, Dahlvani S, Vieweg WVR, et al. Electrocardiographic QT interval in a geropsychiatric inpatient population: a preliminary study. Med Psychiatr 1998; 1: 71–4Google Scholar
  5. 5.
    Vieweg WVR. Mechanisms and risks of electrocardiographic QT interval prolongation when using antipsychotic drugs. J Clin Psychiatry 2002; 63Suppl. 9: 18–24PubMedGoogle Scholar
  6. 6.
    Vieweg WVR. Strategies to prevent fatal arrhythmias with antipsychotics. Curr Psychiatry 2002; 1(5): 10–21Google Scholar
  7. 7.
    Ames D, Camm J, Cook P, et al. Minimizing the risks associated with significant QTc prolongation in people with schizophrenia: a consensus statement by the Cardiac Safety in Schizophrenia Group. Australas Psychiatry 2002 Jun; 10(2): 115–24CrossRefGoogle Scholar
  8. 8.
    Vieweg WVR, McDaniel NL. Drug-induced QT interval prolongation and torsade de pointes in children and adolescents: part I of a four-part series. Child Adolesc Psychopharmacol News 2003; 8(1): 1–7CrossRefGoogle Scholar
  9. 9.
    Vieweg WVR, McDaniel NL. Drug-induced QT interval prolongation and torsade de pointes in children and adolescents: part II of a four-part series. Child Adolesc Psycho-pharmacol News 2003; 8(2): 1–5CrossRefGoogle Scholar
  10. 10.
    Vieweg WVR, McDaniel NL. Drug-induced QT interval prolongation and torsade de pointes in children and adolescents: part III of a four-part series. Child Adolesc Psycho-pharmacol News 2003; 8(3): 1–4CrossRefGoogle Scholar
  11. 11.
    Vieweg WVR, McDaniel NL. Drug-induced QT interval prolongation and torsade de pointes in children and adolescents: part IV of a four-part series. Child Adolesc Psychopharmacol News 2003; 8(4): 1–4CrossRefGoogle Scholar
  12. 12.
    Vieweg WVR. New generation antipsychotic drugs and QTc interval prolongation. Prim Care Companion J Clin Psychiatry 2003; 5: 205–15PubMedCrossRefGoogle Scholar
  13. 13.
    Vieweg WVR, Wood MA. Tricyclic antidepressants, QT interval and torsade de pointes. Psychosomatics 2004; 45: 371–7PubMedCrossRefGoogle Scholar
  14. 14.
    Vieweg WVR, 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: 319–23Google Scholar
  15. 15.
    Vieweg WVR, Pandurangi A, Anum EA, et al. Toxicology findings in child and adolescent suicides in Virginia: 1987–2003. Prim Care Companion J Clin Psychiatry 2006; 8: 142–6PubMedCrossRefGoogle Scholar
  16. 16.
    Fernandez A, Bang SE, Srivathsan K, et al. Cardiovascular side effects of newer antidepressants. Anadolu Kardiyol Derg 2007; 7: 305–9PubMedGoogle Scholar
  17. 17.
    Garratt CJ, Griffith MJ. Electrocardiographic diagnosis of tachycardias. In: Camm AJ, editor. Clinical approaches to tachyarrhythmias. Amonk (NY): Futura Publishing Company, Inc., 1994: 1–53Google Scholar
  18. 18.
    Postema PG, De Jong JSSG, Van der Bilt IAC, et al. Accurate electrocardiographic assessment of the QT interval: teach the tangent. Heart Rhythm 2008; 5: 1015–8PubMedCrossRefGoogle Scholar
  19. 19.
    Goldenberg I, Moss AJ, Zareba W. QT interval: how to measure it and what is “normal”. J Cardiovasc Electrophysiol 2006; 17: 333–6PubMedCrossRefGoogle Scholar
  20. 20.
    Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7: 353–70Google Scholar
  21. 21.
    Fu EY, Clemo HF, Ellenbogen KA. Acquired QT prolongation: mechanisms and implications. Cardiol Rev 1998; 6: 319–24PubMedCrossRefGoogle Scholar
  22. 22.
    Viskin S, Justo D, Halkin A, et al. Long QT syndrome caused by noncardiac drugs. Prog Cardiovasc Dis 2003; 45: 415–27PubMedGoogle Scholar
  23. 23.
    Tan HL, Hou CJY, Lauer MR, et al. Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995; 122: 701–14PubMedGoogle Scholar
  24. 24.
    Yap YG, Camm J. Risk of torsade de pointes with non-cardiac drugs. BMJ 2000; 320: 1158–9PubMedCrossRefGoogle Scholar
  25. 25.
    Boehnert MT, Lovejoy Jr FH. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 1985; 313: 474–9PubMedCrossRefGoogle Scholar
  26. 26.
    Bednar MM, Harrigan EP, Anziano RJ, et al. The QT interval. Prog Cardiovas Dis 2001; 43: 1–45Google Scholar
  27. 27.
    Abdelmawla N, Mitchell AJ. Sudden cardiac death and antipsychotics. Part 1: risk factors and mechanisms. Adv Psychiatr Treat 2006; 12: 35–44CrossRefGoogle Scholar
  28. 28.
    Abdelmawla N, Mitchell AJ. Sudden cardiac death and antipsychotics. Part 2: monitoring and prevention. Adv Psychiatr Treat 2006; 12: 100–9CrossRefGoogle Scholar
  29. 29.
    Sicouri S, Antzelevitch C. Sudden cardiac death secondary to antidepressant and antipsychotic drugs. Expert Opin Drug Saf 2008; 7: 181–94PubMedCrossRefGoogle Scholar
  30. 30.
    Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med 2004; 350: 1013–22PubMedCrossRefGoogle Scholar
  31. 31.
    Psychopharmacological Drugs Advisory Committee. Briefing document for Zeldox® capsules (ziprasidone HCl). 2000 Jul 19 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1.htm [Accessed 2009 Sep 15]
  32. 32.
    Su HM, Chiu HC, Lin TH, et al. Longitudinal study of the ageing trends in QT interval and dispersion in healthy elderly subjects. Age Ageing 2006; 35: 636–8PubMedCrossRefGoogle Scholar
  33. 33.
    US Food and Drug Administration. E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs [online]. Available from URL: http://www.fda.gov/RegulatoryInformation/Guidances/ucm129335.htm [Accessed 2009 Sep 15]
  34. 34.
    Camm AJ, Malik M, Yap YG. Acquired long QT syndrome. London: Blackwell Futura, 2004CrossRefGoogle Scholar
  35. 35.
    Browne K, Prystowsky E, Heger JJ, et al. Prolongation of the Q-T interval in man during sleep. Am J Cardiol 1983; 52: 55–9PubMedCrossRefGoogle Scholar
  36. 36.
    Morganroth J, Brozovich FV, McDonald JT, et al. Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991; 67: 774–6PubMedCrossRefGoogle Scholar
  37. 37.
    Woosley R, Sketch MH. Gender and drug-induced torsade de pointes. ACCEL 30, No. 2. Bethesda (MD): American College of Cardiology, 1998Google Scholar
  38. 38.
    Compton SJ, Lux RL, Ramsey MR, et al. Genetically defined therapy of inherited long-QT syndrome: correction of abnormal repolarization by potassium. Circulation 1996; 94: 1018–22PubMedCrossRefGoogle Scholar
  39. 39.
    Hatta K, Takahashi T, Nakamura H, et al. Hypokalemia and agitation in acute psychotic patients. Psychiatry Res 1999; 86: 85–8PubMedCrossRefGoogle Scholar
  40. 40.
    Hatta K, Takahashi T, Nakamura H, et al. Prolonged QT interval in acute psychotic patients. Psychiatry Res 2000; 94: 279–85PubMedCrossRefGoogle Scholar
  41. 41.
    US Food and Drug Administration Advisory Committee. Zeldox capsules (ziprasidone): summary of efficacy and safety and overall benefit risk relationship. Bethesda (MD): US Food and Drug Administration, 2000 Jul 19Google Scholar
  42. 42.
    Vincent GM. Long QT syndrome. Cardiol Clin 1999; 18: 309–25CrossRefGoogle Scholar
  43. 43.
    Schwartz PJ, Periti M, Malliani A. The long QT syndrome. Am Heart J 1975; 89: 378–90PubMedCrossRefGoogle Scholar
  44. 44.
    Schwartz PJ. Idiopathic long QT syndrome: progress and questions. Am Heart J 1985; 109: 399–411PubMedCrossRefGoogle Scholar
  45. 45.
    Ray WA, Meredith S, Thapa PB, et al. Antipsychotics and the risk of sudden cardiac death. Arch Gen Psychiatry 2001; 58: 1161–7PubMedCrossRefGoogle Scholar
  46. 46.
    Ray WA, Meader KG. Antipsychotics and sudden death: is thioridazine the only bad actor? Br J Psychiatry 2002; 180: 483–4PubMedCrossRefGoogle Scholar
  47. 47.
    Ray WA, Chung CP, Murray KT, et al. Atypical anti-psychotic drugs and the risk of sudden cardiac death. N Engl J Med 2009; 360: 225–35PubMedCrossRefGoogle Scholar
  48. 48.
    Fowler NO, McCall D, Chou T, et al. Electrocardiographic changes and cardiac arrhythmias in patients receiving psychotropic drugs. Am J Cardiol 1976; 37: 223–30PubMedCrossRefGoogle Scholar
  49. 49.
    Ko PT, Gulamhusein S, Kostuk WJ, et al. Torsade de pointes, a common arrhythmia, induced by medication. CMAJ 1982; 127: 368–72Google Scholar
  50. 50.
    Flugelman MY, Pollack S, Hammerman H, et al. Congenital prolongation of Q-T interval: a family study of three generations. Cardiology 1982; 69: 170–4PubMedCrossRefGoogle Scholar
  51. 51.
    Herrmann HC, Kaplan LM, Bierer BE. QT prolongation and torsade de pointes ventricular tachycardia produced by the tetracyclic antidepressant agent maprotiline. Am J Cardiol 1983; 51: 904–6PubMedCrossRefGoogle Scholar
  52. 52.
    Davison ET. Amitriptyline-induced torsade de pointes: successful therapy with atrial pacing. J Electrocardiol 1985; 18: 299–302PubMedCrossRefGoogle Scholar
  53. 53.
    Jerjes Sanchez Diaz C, Garcia Hernandez N, Gonzalez Carmona VM, et al. Helicoidal ventricular tachycardia caused by amitriptyline. Arch Inst Cardiol Mex 1985; 55: 353–6PubMedGoogle Scholar
  54. 54.
    Zee-Cheng CS, Mueller CE, Seifert CF, et al. Haloperidol and torsades de pointes. Ann Intern Med 1985; 102: 418PubMedGoogle Scholar
  55. 55.
    Casazza F, Fiorista F, Rustici A, et al. Torsade de pointes caused by tricyclic antidepressive agents: description of a clinical case. G Ital Cardiol 1986; 16: 1058–61PubMedGoogle Scholar
  56. 56.
    Fayer SA. Torsade de pointes ventricular tachyarrhythmia associated with haloperidol. J Clin Psychopharmacol 1986; 6: 375–6PubMedCrossRefGoogle Scholar
  57. 57.
    Wilt JL, Minnema AM, Johnson RF, et al. Torsade de pointes associated with the use of intravenous haloperidol. Ann Intern Med 1993; 119: 391–4PubMedGoogle Scholar
  58. 58.
    Metzger E, Friedman R. Prolongation of the corrected QT and torsade de pointes cardiac arrhythmia associated with intravenous haloperidol in the medically ill. J Clin Psychopharmacol 1993; 13: 128–32PubMedCrossRefGoogle Scholar
  59. 59.
    Hunt N, Stern TA. The association between intravenous haloperidol and torsade de pointes. Psychosomatics 1995; 36: 541–9PubMedCrossRefGoogle Scholar
  60. 60.
    Di Salvo TG, O’Gara PT. Torsade de pointes caused by high-dose intravenous haloperidol in cardiac patients. Clin Cardiology 1995; 18: 285–90CrossRefGoogle Scholar
  61. 61.
    Mazur A, Strasberg B, Kusniec J, et al. QT prolongation and polymorphous ventricular tachycardia associated with trazodone-amiodarone combination. Int J Cardiol 1995; 52: 27–9PubMedCrossRefGoogle Scholar
  62. 62.
    Appleby M, Mbewu A, Clarke B. Fluoxetine and ventricular torsade: is there a link? Int J Cardiol 1995; 49: 178–80PubMedCrossRefGoogle Scholar
  63. 63.
    Rialan A, Richard M, Deutsch P, et al. Torsade de pointes in a patient under long-term maprotiline therapy: apropos of a case. Ann Cardiol Angeiol (Paris) 1996; 45: 123–5Google Scholar
  64. 64.
    Sharma ND, Rosman HS, Padhi D, et al. Torsades de pointes associated with intravenous haloperidol in critically ill patients. Am J Cardiol 1998; 81: 238–40PubMedCrossRefGoogle Scholar
  65. 65.
    Iglesias E, Esteban E, Zabala S, et al. Tiapride-induced torsade de pointes. Am J Med 2000; 109: 509PubMedCrossRefGoogle Scholar
  66. 66.
    Douglas PH, Block PC. Corrected QT interval prolongation associated with intravenous haloperidol in acute coronary syndromes. Cathet Cardiovasc Intervent 2000; 50: 352–5CrossRefGoogle Scholar
  67. 67.
    Lentini S, Rao ML, Schroder R, et al. QT prolongation and torsade de pointes tachycardia during therapy with maprotiline: differential diagnostic and therapeutic aspects. Dtsch Med Wochenschr 2001; 126: 1396–400PubMedCrossRefGoogle Scholar
  68. 68.
    Kang M, Lesh B, Tampi R, et al. Spotting a silent killer. Current Psychiatry 2004; 3: 75–88Google Scholar
  69. 69.
    Wilting I, Smals OM, Holwerda NJ, et al. QTc prolongation and torsades de pointes in an elderly woman taking fluoxetine [letter]. Am J Psychiatry 2006; 163: 325PubMedCrossRefGoogle Scholar
  70. 70.
    Letsas K, Korantzopoulos P, Pappas L, et al. QT interval prolongation associated with venlafaxine administration. Int J Cardiol 2006; 109: 116–7PubMedCrossRefGoogle Scholar
  71. 71.
    Klein-Schwartz W, Lofton AL, Benson BE, et al. Prospective observational multi-poison center study of ziprasidone exposures. Clin Toxicol 2007; 45: 782–6CrossRefGoogle Scholar
  72. 72.
    Katagai H, Yasui-Furukori N, Kikuchi A, et al. Effective electroconvulsive therapy in a 92-year-old dementia patient with psychotic feature. Psychiatry Clin Neurosci 2007; 61: 568–70PubMedCrossRefGoogle Scholar
  73. 73.
    Huang BH, Hsia CP, Chen CY. Sulpiride induced torsade de pointes. Int J Cardiol 2007; 118: e100–2PubMedCrossRefGoogle Scholar
  74. 74.
    Raviña R, Guteirrez J, Raviña P. Acquired long QT syndrome: long-term electrocardiographic (Holter) recording of torsades de pointes ending in asystole: II. Int J Cardiol 2007; 116: 272–5PubMedCrossRefGoogle Scholar
  75. 75.
    Mehtonen O-P, Aranko K, Malkonen L, et al. A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland. Acta Psychiatr Scand 1991; 84: 58–64PubMedCrossRefGoogle Scholar
  76. 76.
    Kapur S, Seeman P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001; 158: 360–9PubMedCrossRefGoogle Scholar
  77. 77.
    Reilly JG, Ayis SA, Ferrier IN, et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355: 1048–52PubMedCrossRefGoogle Scholar
  78. 78.
    Antonelli D, Atar S, Freedberg NA, et al. Torsade de pointes in patients on chronic amiodarone treatment: contributing factors and drug interactions. Isr Med Assoc J 2005; 7: 163–5PubMedGoogle Scholar
  79. 79.
    Darpö B. Spectrum of drugs prolonging QT interval and the incidence of torsade de pointes. Eur Heart J Supplements 2001; 3Suppl. K: K70–80CrossRefGoogle Scholar
  80. 80.
    Sala M, Vicentini A, Brambilla P, et al. QT interval prolongation related to psychoactive drug treatment: a comparison of monotherapy versus polytherapy. Ann Gen Psychiatry 2005; 4: 1–6PubMedCrossRefGoogle Scholar
  81. 81.
    Al-Khatib SM, LaPointe NMA, Kramer JM, et al. What clinicians should know about the QT interval. JAMA 2003; 289: 2120–7PubMedCrossRefGoogle Scholar
  82. 82.
    Viskin S, Rosovski U, Sands AJ, et al. Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one. Heart Rhythm 2005; 2: 569–74PubMedCrossRefGoogle Scholar
  83. 83.
    Bai R, Yan GX. Accurate interpretation of the QT interval: a vital task that remains unaccomplished. Heart Rhythm 2005; 2: 575–7PubMedCrossRefGoogle Scholar
  84. 84.
    Hongo RH, Goldschlager N. Overreliance on computerized algorithms to interpret electrocardiograms. Am J Med 2004; 117: 706–8PubMedCrossRefGoogle Scholar
  85. 85.
    Roden DM. Keep the QT interval: it is a reliable predictor of ventricular arrhythmias. Heart Rhythm 2008; 5: 1213–5PubMedCrossRefGoogle Scholar
  86. 86.
    Hondeghem LM. QT prolongation is an unreliable predictor of ventricular arrhythmia. Heart Rhythm 2008; 5: 1210–2PubMedCrossRefGoogle Scholar
  87. 87.
    Malik M. Is there a physiologic QT/RR relationship? J Cardiovasc Electrophysiol 2002; 13: 1219–21PubMedCrossRefGoogle Scholar
  88. 88.
    Malik M, Hnatkova K, Schmidt A, et al. Accurately measured and properly heart-rate corrected QTc intervals show little daytime variability. Heart Rhythm 2008; 5: 1424–31PubMedCrossRefGoogle Scholar
  89. 89.
    Franz MR. Bazett, Fridericia, or Malik? Heart Rhythm 2008; 5: 1432–3PubMedCrossRefGoogle Scholar
  90. 90.
    Phoon CKL. Mathematic validation of a shorthand rule for calculating QTc. Am J Cardiol 1998; 82: 400–2PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • W. Victor R. Vieweg
    • 1
    • 2
    • 3
    • 4
  • Mark A. Wood
    • 4
    • 5
  • Antony Fernandez
    • 1
    • 3
  • Mary Beatty-Brooks
    • 6
  • Mehrul Hasnain
    • 7
    • 8
  • Anand K. Pandurangi
    • 3
  1. 1.Department of PsychiatryHunter Holmes McGuire Veterans Affairs Medical CenterRichmondUSA
  2. 2.Department of MedicineHunter Holmes McGuire Veterans Affairs Medical CenterRichmondUSA
  3. 3.Department of Psychiatry, Medical College of Virginia CampusVirginia Commonwealth UniversityRichmondUSA
  4. 4.Department of Internal Medicine, Medical College of Virginia CampusVirginia Commonwealth UniversityRichmondUSA
  5. 5.Cardiology Division, Medical College of Virginia CampusVirginia Commonwealth UniversityRichmondUSA
  6. 6.Department of Medical MediaHunter Holmes McGuire Veterans Affairs Medical CenterRichmondUSA
  7. 7.Department of Psychiatry, Western Regional Integrated Health AuthoritySir Thomas Roddick HospitalStephenvilleCanada
  8. 8.Department of PsychiatryMemorial University of NewfoundlandSt John’sCanada

Personalised recommendations