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Which psychotropics carry the greatest risk of QTc prolongation?

Nicole B. Washington, DO, Nancy C. Brahm, PharmD, MS, BCPP, CGP, and Julie Kissack, PharmD, BCPP

rs. A, age 68, has a 40-year history of an ECG measure of ventricular depolar- with comorbid ization and repolarization. The QTc des- M anxiety disorder not otherwise speci- ignation indicates a correction for heart fied, mellitus, and hypertension. rate with increasing heart rate correlating She takes furosemide, 40 mg/d, lisinopril, 20 with a shorter QT interval. Readings of 440 mg/d, and metformin, 2,000 mg/d, for hyperten- milliseconds are considered normal.1 QTc sion and diabetes; , 1.5 mg/d, and par- prolongation is defined as >450 millisec- Vicki L. Ellingrod, oxetine, 40 mg/d, for anxiety; and ex- onds for men and >470 milliseconds for PharmD, BCPP, FCCP tended release, 800 mg/d, for psychotic features women.2 An increase in the QT interval is Series Editor and mood dysregulation with schizoaffective dis- a predictor of serious cardiac events.3 order. Mrs. A’s husband died 5 years ago and she and lives alone in a senior care facility. Mrs. A uses a have been associated with QTc prolonga- weekly pill reminder box because her residential tion. When identifying agents that could facility does not monitor adherence. disrupt cardiac conduction, clinicians need She sees her psychiatrist once a month and her to consider whether the drug’s molecular primary care provider every 3 months. She has no structure, receptor affinity, or pharmaco- history of illicit drug, , or tobacco use. logic effects are most critical.2 Although Two weeks ago, Mrs. A was found leaning these may be important, patient-specific against the wall in a hallway, complaining of variables that increase the risk of QTc pro- and disorientation, and unable to find longation may have greater impact. These her way back to her apartment. In the emer- include: gency department, her serum potassium is low • age >65 (3.0 mEq/L; normal range: 3.5 to 5.0), fasting • female sex glucose is elevated (110 mg/dL; range: 65 to 99), and ECG reveals a prolonged QTc interval of 530 milliseconds. Before this episode, Mrs. Practice Points A had been medically stable without mood or • Screen patients for risk factors for prolonged QTc interval, such as congenital psychotic symptoms, although her daughter long QT syndrome, family history of cardiac reported medication self-administration was conduction abnormalities, and previous becoming difficult. occurrences of medication-mediated QTc prolongation. Exposure to psychotropics carries a risk • Obtain baseline and steady state ECG of QTc prolongation. The QT interval is when initiating high-risk agents, particularly when administering combination therapy. Dr. Washington is Assistant Professor, Department of Psychiatry, School of Community Medicine and Dr. Brahm • Use the lowest effective dose of is Clinical Professor, College of Pharmacy, University of Oklahoma, Tulsa, OK. Dr. Kissack is Professor and Chair, antidepressants and antipsychotics and Current Psychiatry Department of Pharmacy Practice, Harding University College monitor symptoms closely. 36 October 2012 of Pharmacy, Searcy, AR. Savvy Psychopharmacology

• electrolyte imbalances (specifically Table low serum potassium and magnesium Examples of QTc prolongation levels) • high or toxic serum levels of the sus- associated with select a pected drug antipsychotics Approximate QTc • preexisting cardiovascular impair- interval prolongation ment, such as bradycardia.4,5 in millisecondsb Other risk factors include concurrent Aripiprazole4,17 -1 to -4 use of an agent with similar cardiovascular Clozapine4 10 effects or one that competes for metabolism Haloperidol1,2 7 to 15 (either enzymatic or at the binding site), Mesoridazine16 39 to 53 physiologic limitations such as renal insuf- Olanzapine1 2 to 6.5 ficiency, and medication changes that may Clinical Point Paliperidone4 2 to 4 increase or decrease psychotropic clear- Pimozide2 19 QTc prolongation has ance.4,6 Geriatric patients with Quetiapine1,2 6 to 15 have an increased risk for cardiovascular- been reported with 1,2 related death.7,8 3.5 to 10 all SSRIs at plasma Sertindole1 30 concentrations 2,16 Antidepressants 33 to 41 above the Among antidepressants, most Ziprasidone1,2 16 to 21 therapeutic level reports of QTc prolongation involve ami- aList is not comprehensive. Other antipsychotics may be associated with QTc prolongation triptyline and .9 Risk factors bQTc prolongation interval may depend on the route of include demographics (eg, female sex, administration age), personal or family history (congeni- tal long QT syndrome, cardiovascular dis- ease), and concurrent conditions or drug concurrent use of that may use, particularly those associated with QTc prolong QTc interval.14 doses prolongation.3 and nortripty- >300 mg/d may require additional cardiac line also have been identified as high-risk monitoring.5,12 Data from venlafaxine poi- agents.10 soning case reports found a positive cor- QTc prolongation has been reported relation between dose and QTc prolonga- with all selective inhib- tion.15 In a review of toxicology database itors at plasma concentrations above the information, Wenzel-Seifert et al4 found therapeutic level.11 -associated extended QT interval with , QTc prolongation was limited to cases of fluoxetine, and venlafaxine at toxic doses overdose or when additional risk factors or in the presence of additional risk factors were reported.4 QTc prolongation from such as sex, older age, or personal or fam- psychotropics could increase the risk of ily history of congenital long QT syndrome torsades de pointes, according to an analy- or cardiovascular disease. sis of the FDA Adverse Event Reporting System.12 In 2011, the FDA reported an in- Antipsychotics creased risk of abnormal heart rhythms— Case reports, case series, and research tri- Discuss this article at including QTc prolongation—with citalo- als have evaluated the risk of QTc prolon- www.facebook.com/ CurrentPsychiatry pram doses >40 mg/d.13 Although cases gation with antipsychotics (Table).1,2,4,16,17 of QTc prolongation with have The first-generation antipsychotics thio- not been reported,11 the Arizona Center for ridazine,4,16,18 ,16,18 chlorprom- Education and Research on Therapeutics azine,19 and haloperidol3 warrant cardiac lists paroxetine with other agents that may monitoring. The QTc prolongation effects Current Psychiatry increase the risk for QTc prolongation with of thioridazine and its active metabolite Vol. 11, No. 10 37 Savvy Psychopharmacology

change is less than with other agents un- Related Resources less other variables were present, such as: • De Hert M, Detraux J, van Winkel R, et al. Metabolic and car- • concomitant use of medications that diovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114-126. may prolong QTc interval (ie, amanta- 2 • Vieweg WV, Wood MA, Fernandez A, et al. Proarrhythmic risk dine, , or tamoxifen ) with antipsychotic and drugs: implications • preexisting cardiovascular conduction in the elderly. Drugs Aging. 2009;26(12):997-1012. disorders • Sandson NB, Armstrong SC, Cozza KL. An overview of 3,23 psychotropic drug-drug interactions. Psychosomatics. • higher doses (>40 mg/d). 2005;46(5):464-494. In 17 case reports of cardiac changes as- Drug Brand Names sociated with quetiapine use, doses ranged • Symmetrel • Latuda from 100 mg/d24 to an overdose of 36 • Elavil Maprotiline • Ludiomil g/d.25 Only 1 patient death was reported • Abilify Mesoridazine • Serentil Clinical Point • Saphris Metformin • Glucophage secondary to overdose and preexisting • Thorazine • Pamelor dysrhythmia and hypertension.26 QTc pro- QTc prolongation has Citalopram • Celexa • Zyprexa • Clozaril • Invega longation associated with risperidone was been associated with Desipramine • Norpramin Paroxetine • Paxil minor1 based on oral doses in the normal Fluoxetine • Prozac • Orap long-term Furosemide • Lasix Quetiapine • Seroquel therapeutic range and incidences of over- use more often than • Haldol Risperidone • Risperdal dose.10 Paliperidone27 and lurasidone28 Hydroxyzine • Atarax, Tamoxifen • Nolvadex, are associated with clinically insignificant with risperidone, Vistaril Soltamox • Fanapt Thioridazine • Mellaril QTc prolongation. Changes in QTc interval olanzapine, or Lisinopril • Prinivil, Zestril Venlafaxine • Effexor were positively correlated with asenapine Lorazepam • Ativan Ziprasidone • Geodon quetiapine dose, although at the highest dose of 40 Disclosures mg/d, the increase was <5 milliseconds.29 The authors report no financial relationship with any company whose products are mentioned in this article or with manufac- Mrs. A presents with a number of risk turers of competing products. No similar work by the authors is factors for QTc prolongation, including under review or in press. No funding was requested or received in conjunction with this manuscript. older age, female sex, and psychiatric and medical comorbidities that require medica- tion. A pill count revealed that she was tak- ing more than the prescribed daily doses mesoridazine are well-documented and of her medications. During the interview, thioridazine-mediated QTc prolongation Mrs. A said that if she missed her medica- increases are dose-dependent.4,18 ECG tion time, she would take them when she monitoring is recommended with IV hal- remembered. If she could not remember operidol, which is used for delirium in if she took her pills, she would take them adults.20 QTc prolongation has been associ- again. Her physicians will explore strate- ated with long-term ziprasidone use more gies to increase medication adherence. often than with risperidone, olanzapine, or quetiapine.19 Ziprasidone prolongs the References 1. Muscatello MR, Bruno A, Pandolfo G, et al. Emerging QTc interval an average of 20 millisec- treatments in the management of - focus on onds,21 which could represent a clinically . Drug Des Devel Ther. 2010;4:187-201. 2. Taylor DM. Antipsychotics and QT prolongation. Acta significant change. QTc prolongation for Psychiatr Scand. 2003;107(2):85-95. iloperidone is comparable to ziprasidone 3. Alvarez PA, Pahissa J. QT alterations in psychopharmacology: proven candidates and suspects. Curr Drug Saf. 2010;5(1): and haloperidol.22 There is some evidence 97-104. that aripiprazole may shorten, rather than 4. Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of torsade de pointes. Dtsch prolong, the QTc interval.4,17 Arztebl Int. 2011;108(41):687-693. Cardiovascular adverse effects associat- 5. Vieweg WV. New generation antipsychotic drugs and QTc interval prolongation. Prim Care Companion J Clin Psychiatry. ed with clozapine—including QTc prolon- 2003;5(5):205-215. gation—are dose-dependent.3 Olanzapine 6. Nielsen J, Graff C, Kanters JK, et al. Assessing QT interval Current Psychiatry prolongation and its associated risks with antipsychotics. CNS 38 October 2012 prolongs QTc interval, although the mean Drugs. 2011;25(6):473-490. Savvy Psychopharmacology

7. Gill SS, Bronskill SE, Normand SL, et al. Antipsychotic drug use 18. Dallaire S. Thioridazine (Mellaril) and mesoridazine and mortality in older adults with dementia. Ann Intern Med. (Serentil): prolongation of the QTc interval. CMAJ. 2001; 2007;146(11):775-786. 164(1):91,95. 8. Schneeweiss S, Setoguchi S, Brookhart A, et al. Risk of death 19. Haddad PM, Anderson IM. Antipsychotic-related QTc associated with the use of conventional versus atypical prolongation, torsade de pointes and sudden death. Drugs. antipsychotic drugs among elderly patients. CMAJ. 2007; 2002;62(11):1649-1671. 176(5):627-632. 20. Shapiro BA, Warren J, Egol AB, et al. Practice parameters for 9. Vieweg WV, Wood MA. Tricyclic antidepressants, QT interval intravenous analgesia and sedation for adult patients in the prolongation, and torsade de pointes. Psychosomatics. intensive care unit: an executive summary. Crit Care Med. 2004;45(5):371-377. 1995;23(9):1596-1600. 10. Jeon SH, Jaekal J, Lee SH, et al. Effects of nortriptyline on QT 21. Vieweg WV, Hasnain M. Question regarding ziprasidone prolongation: a safety pharmacology study. Hum Exp Toxicol. and QTc interval prolongation in the ZODIAC Study. Am J 2011;30(10):1649-1656. Psychiatry. 2011;168(6):650-651. 11. Wenzel-Seifert K, Wittmann M, Haen E. Torsade de pointes 22. Caccia S, Pasina L, Nobili A. New atypical antipsychotics episodes under treatment with selective serotonin reuptake for schizophrenia: iloperidone. Drug Des Devel Ther. 2010;4: inhibitors. Pharmacopsychiatry. 2010;43(7):279-281. 33-48. 12. Poluzzi E, Raschi E, Moretti U, et al. Drug-induced torsades de 23. Dineen S, Withrow K, Voronovitch L, et al. QTc prolongation pointes: data mining of the public version of the FDA Adverse and high-dose olanzapine. Psychosomatics. 2003;44(2): Event Reporting System (AERS). Pharmacoepidemiol Drug 174-175. Saf. 2009;18(6):512-518. 24. Vieweg WV, Schneider RK, Wood MA. Torsade de pointes in Clinical Point 13. U.S. Food and Drug Administration. FDA drug safety a patient with complex medical and psychiatric conditions communication: revised recommendations for Celexa receiving low-dose quetiapine. Acta Psychiatr Scand. 2005; Paliperidone (citalopram hydrobromide) related to a potential risk of 112(4):318-322. abnormal heart rhythms with high doses. http://www.fda. 25. Capuano A, Ruggiero S, Vestini F, et al. Survival from coma and lurasidone gov/Drugs/DrugSafety/ucm297391.htm. Published March induced by an intentional 36-g overdose of extended-release 28, 2012. Accessed June 26, 2012. quetiapine. Drug Chem Toxicol. 2011;34(4):475-477. are associated 14. Arizona CERT-QT Center for Education and Research on Therapeutics. QT drug lists by risk groups. http://www.azcert. 26. Fernandes PP, Marcil WA. Death associated with quetiapine with clinically org/medical-pros/drug-lists/drug-lists.cfm. Accessed June 26, overdose. Am J Psychiatry. 2002;159(12):2114. 2012. 27. Sedky K, Nazir R, Lindenmayer JP, et al. Paliperidone insignificant QTc 15. Howell C, Wilson AD, Waring WS. Cardiovascular toxicity due palmitate: once-monthly treatment option for schizophrenia. to venlafaxine poisoning in adults: a review of 235 consecutive Current Psychiatry. 2010;9(3):48-50. prolongation cases. Br J Clin Pharmacol. 2007;64(2):192-197. 28. Citrome L. Lurasidone for schizophrenia: a review of 16. Salih IS, Thanacoody RH, McKay GA, et al. Comparison of the the efficacy and safety profile for this newly approved effects of thioridazine and mesoridazine on the QT interval second-generation antipsychotic. Int J Clin Pract. 2011;65(2): in healthy adults after single oral doses. Clin Pharmacol Ther. 189-210. 2007;82(5):548-554. 29. Chapel S, Hutmacher MM, Haig G, et al. Exposure-response 17. Goodnick PJ, Jerry J, Parra F. Psychotropic drugs and the analysis in patients with schizophrenia to assess the effect ECG: focus on the QTc interval. Expert Opin Pharmacother. of asenapine on QTc prolongation. J Clin Pharmacol. 2009; 2002;3(5):479-498. 49(11):1297-1308.

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