Dinh, Tuan Anh

Gören, Jessica L.

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Dinh,  Anh

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University of Rhode IslandDigitalCommons@URIPharmacy Practice Faculty Publications Pharmacy Practice2013Psychotropics and Sudden Cardiac DeathJessica L. GörenUniversity of Rhode Island, jgoren@challiance.orgTuan Anh DinhUniversity of Rhode IslandFollow this and additional works at: https://digitalcommons.uri.edu/php_facpubsTerms of UseAll rights reserved under copyright.This Article is brought to you for free and open access by the Pharmacy Practice at DigitalCommons@URI. It has been accepted for inclusion inPharmacy Practice Faculty Publications by an authorized administrator of DigitalCommons@URI. For more information, please contactdigitalcommons@etal.uri.edu.Citation/Publisher AttributionDinh, T.A., & Gören, J. L. (2013). Psychotropics and Sudden Cardiac Death. Rhode Island Medical Journal, 96(3), 38-41. Retrievedfrom http://www.rimed.org/rimedicaljournal/2013/03/2013-03-38-cont-psychotropics.pdfAvailable at: http://www.rimed.org/rimedicaljournal/2013/03/2013-03-38-cont-psychotropics.pdfProlonged QTc intervals can lead to ventricular tachy- arrhythmia and TdP. While the true incidence of TdP is un-known, the number of reported cases is low. Over a period of 15 years only 761 cases were reported to the World Health Organization.5 Therefore, prolonged QTc has become a surrogate marker for TdP.1,5 It is important to note that drug induced QTc prolonga-tion alone rarely leads to TdP. A review of population studies reported prolonged QTc was associated with TdP in pa-tients with preexisting cardiovascular disease, but not with healthy patients.6 Rather TdP is most likely to occur when prolonged QTc is combined with at least two risk factors such as electrolyte abnormalities, bradycardia or congeni-tal cardiac abnormalities. The most important risk factors appear to be preexisting heart disease, age >65 years, and female sex. 6,7 Torsades de pointes may be increased in hos-pitalized patients because hospitalized patients are more likely to have risk factors such as heart disease, advanced age, bradycardia or electrolyte disturbances than outpatients.8 QTc prolongation is often dose dependent but the max-imal effect of many drugs is limited.6 Therefore, massive drug overdoses of QTc prolonging medications do not necessarily result in severe QTc prolongation or TdP. Psychotropics and QTcPsychotropics, such as antidepressants and antipsychotics, affect the heart by blocking certain potassium channels. This leads to a blockade of type IKr (a fast potassium chan-nel in the heart), causing a delay in repolarization and thus QTc prolongation.1,2 This is accomplished via either HERG (Human ether-a-go-go Related Gene) blockade or abnormal protein trafficking for HERG. Almost all drugs which can induce TdP block HERG, while a few indirectly affect HERG function.1,2 Drugs which prolong the QTc by alternate means are less likely to result in TdP.ABSTRACT Over the past two decades there has been a large increase in the number of patients prescribed psychotropic med-ications. Many of these agents are associated with QTc prolongation which is considered a marker for increased risk of sudden cardiac death due to malignant arrhyth-mias such as Torsades de pointes (TdP). Psychotropics rarely lead to sudden death in healthy individuals on a single QTc prolonging medication. However, factors such polypharmacy, recent initiation of a QTc prolonging med-ication, bradycardia, electrolyte abnormalities and preex-isting arrhythmias increase the likelihood of psychotro-pic-induced sudden cardiac death. Therefore, clinicians must recognize which psychotropics and risk factors are associated with increased risk in order to minimize the risks of psychotropic QTc prolongation.KEYWORDS:  psychotropic, side effect, cardiac, QTc, Torsades, arrhythmiaINTRODUCTIONThere has been increasing concern regarding the cardiac side effects of psychotropics. Some psychotropic medications in-crease the risk of sudden cardiac death. However, these drugs are important for many patients. Therefore, it is important to assess cardiac risks associated with psychotropics. This article will summarize these effects and provide recommen-dations on cardiac risk assessment for patients treated with psychotropic medications. The QT interval and Torsades de pointesThe QT interval is the measure of cardiac conduction speed that starts from the beginning of a QRS wave and ends with the T wave on an electrocardiogram (ECG). Usually the length of the QT wave decreases as heart rate increases, so a corrected value (QTc) is used to assess cardiac conduction. QTc is measured in milliseconds and the average QTc is be-tween 430 and 450 milliseconds. (Table 1) Females usually have a slower cardiac conduction rhythm than males and thus a longer QTc.1-3 The QTc varies by up to 10 milliseconds during the course of a day with maximal intervals during the first few hours of awakening.4 Table 1. Average QTc1-3R H O D E  I S L A N D  M E D I C A L  J O U R N A L M A R C H  2 0 1 3 38CONTRIBUTIONSPsychotropics and Sudden Cardiac DeathTUAN ANH DINH; JESSICA L. GÖREN, PHARMD, BCPP       MEN WOMEN NORMAL <430 <450 BORDERLINE 431-450 451-470 PROLONGED >450 >470 with preexisting risk factors or those with elevated blood concentrations due to over dose, high doses or drug inter-actions. Bupropion, mirtazapine and trazodone all appear to have minimal risk of QTc prolongation at typical doses.15R H O D E  I S L A N D  M E D I C A L  J O U R N A L M A R C H  2 0 1 3 39CONTRIBUTIONSPopulation-based studies indicate there is a two- to three-fold increased risk of sudden cardiac death in patients taking non-cardiac QTc prolonging medications.6,7 Antidepressants are the psychotropic class most commonly associated with TdP (9%).7,9,10 For antipsychotics, it is estimated there are 10-15 sudden cardiac deaths/10,000 years of observation, and only a small proportion of these deaths are likely attrib-utable to TdP.11 Risk of QTc prolongation with other psycho-tropics such as benzodiazepines and anticonvulsants is low. Risk is of sudden cardiac death is highest in the first 90 days of initiating, increasing the dose or adding an interact-ing medication. Female sex, polypharmacy, congenital long QT syndrome, electrolyte abnormalities, increasing age and higher doses of QTc prolonging medication all increase the likelihood of experiencing drug induced QTc prolongation.10,11 While studies have reported psychotropics increase pa-tients’ average QTc, the QTc interval typically remains less than 500 milliseconds, considered a clinically relevant in-dicator of TdP risk.4,10,11 In patients with schizophrenia a reported history of arrhythmia and other metabolic factors had greater influence on the prolongation of QTc interval than use of psychotropics alone.9 Therefore, it seems likely psychotropic induced QTc prolongation is unlikely to lead to TdP in the absence of other risk factors. Antipsychotics and QTc Although large epidemiologic studies have reported first- and second-generation antipsychotics are associated with increased risk of sudden cardiac death, the absolute risk of death remains quite low.1,3,6,7,9-14 In addition, while numer-ous antipsychotics have been shown to prolong the QTc (Table 2), relatively few antipsychotics have been associated with TdP.1,3,13,14 Thioridazine, pimozide and ziprasidone are known to cause the greatest QTc prolongation while queti-apine, risperidone and clozapine are associated with lower risk.1,12-14 Significant evidence of antipsychotic induced TdP is only associated with mesoridazine, thioridazine and hal-operidol.1,15 While haloperidol has been linked to TdP, risk is much lower than with thioridazine.1,13,14 Aripiprazole appears to have a lower risk of QTc prolongation, although there is one well documented case report of QTc pro- longation with low dose monotherapy aripiprazole.13-16Antidepressants and QTcLarge epidemiologic trials have demonstrated an elevated risk of sudden cardiac death with tricyclic antidepressants (TCAs). TCAs have been shown to prolong the QTc 10-25 ms and cases of TdP have been reported with most, although not all, TCAs.13-15 Newer antidepressants have less risk of QTc prolongation and sudden cardiac death compared with TCAs although QTc prolongation of 5-12 ms and cases of TdP have been reported for citalopram, fluoxetine and paroxetine.13-15 Reports of QTc prolongation are mixed with the serotonin norepinepherine reuptake inhibitors (SNRIs). However, for both SSRIs and SNRIs, risk appears to be greatest in patients Table 2. Mean QTc prolongation and psychotropics12-15DRUG MEAN QTc  (msec) ANTIDEPRESSANTS TCAs >16 Mirtazapine 5-8 Trazodone 5-8 Venlafaxine 4.7 Duloxetine 0 Fluoxetine 9-16 Citalopram  8-10 Escitalopram 4.5 Paroxetine 1 – 4 Fluvoxamine 0-2 Sertraline 0 Bupropion 0 ANTIPSYCHOTICS Thioridazine 25-30 Ziprasidone 5-22 Pimozide 13 Clozapine 8-10 Iloperidone 9 Haloperidol 7 Quetiapine 6 Risperidone  0-5 Olanzapine 2 Asenapine 2-5 Aripiprazole 0  medication is increased, a pre- and post-baseline ECG will be useful in determining risk of the dose increase.For patients with a prolonged QTc of ≥ 500 milliseconds, consider discontinuing any QTc prolonging medications and/or substituting with medications less likely to prolong the QTc. Also, consider consulting a cardiologist. SUMMARYSince psychotropic-induced QTc prolongation is typically dose related, patients should be maintained on the lowest effective doses of psychotropics. Additionally, careful review for drug interactions should be conducted prior to adding any medications to ongoing psychotropic treatment. The risk of psychotropic-induced QTc prolongation is highest when a medication is started, reaches steady state or after dose in-creases. Therefore, patients successfully treated for >90 days are less likely to experience psychotropic induced arrhyth-mias unless there are changes in medication treatment or new risk factors. Sudden cardiac death is unlikely in patients without preexisting risk factors and is a rare outcome for those with risk factors. Even for patients with risk factors who may have a prolonged QTc that is < 500 milliseconds, treatment with a psychotropic may be reasonable with appropriate monitoring. Physicians should not be discouraged from psy-chotropic use unless patients have a contraindication, such as a cardiac arrhythmia or congenital long QT syndrome. References1. Huffman JC, Stern TA. QTc Prolongation and the Use of Anti-psychotics: A Case Discussion. Prim Care Companion J Clin Psychiatry. 2003;5(6):278-281.2. Ponte ML, Keller GA, Di Girolama G. Mechanism of Drug Induced QT Interval Prolongation. Current Drug Safety. 2010;5:44-53.3. Yap YG, Cramm AJ. Drug Induced QT Prolongation and tor-sades de pointes. Heart. 2003;89(11):1363-1372.4. Nielsen J, Graff C, Kanters JK, Toft E, Taylor D, Meyer JM. As-sessing the QT interval prolongation and its associated risks with antipsychotics. CNS Drugs. 201;25(6):473-490.5. Darpo B. Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes. Eur Heart J (Suppl K). 2001;3:K70-K80.6. Montanez A, Ruskin JN, Herbert PR, et al. Prolonged QTc in-terval and risk of total and cardiovascular mortality and sud-den death in the general population: a review and qualitative overview of the prospective cohort studies. Arch Int Med. 2004;164(9):943-948.7. Astrom-Lilja C, Odeberg JM, Ekman E, Hagg S. Drug-induced torsades de pointes: a review of the Swedish pharmacovigilence database. Pharmacoepidemiol Drug Saf. 2008;17:587-592. 8. Tisdale JE, Wroblewski HA, Overholser BR, Kingery JR, Tru-jillo TN, Kovacs RJ. Prevalence of QT interval prolongation in patients admitted to cardiac care units and frequency of subse-quent administration of QT interval prolonging drugs. Drug Saf. 2012;35(6):459-470. 9. De Bruin ML, Langendijk PN, Koopmans RP, et al. In-hospi-tal cardiac arrest is associated with use of non-antiarryhthmic QTc-prolonging Drugs. Br J Clin Pharmacol. 2007;63:216-223. R H O D E  I S L A N D  M E D I C A L  J O U R N A L M A R C H  2 0 1 3 40CONTRIBUTIONSPsychotropic Polypharmacy and QTcThe risk of QTc prolongation with antipsychotics and antidepressants is typically dose related.1,4,5,10 Therefore any combination of medications which results in elevated con-centrations of antidepressants or antipsychotics increases the likelihood of QTc prolongation. Conversely, any psycho-tropic that increases the concentration of non-psychotropic QTc prolonging medications increases the risk of drug in-duce arrhythmia. Additionally, the risk of sudden cardiac death is increased in patients on multiple QTc prolonging medications, whether the psychotropics are combined with other QTc prolonging psychotropic or non-psychotropic medications. Thus careful consideration should be given to utilization of psychotropic polypharmacy and combinations of psychotropics and non-psychotropic medications.MonitoringPsychotropic drugs are known to affect the QTc interval and should be utilized with caution in patients with risk factors such as age >65, female gender, congenital long QTc syndrome, electrolyte abnormalities, polypharmacy and pre-existing cardiac disease.1,13-15 For relatively healthy patients without preexisting risk factors, routine ECG monitoring should be considered for those with episodes of blackouts, fainting, seizures, or with unexplained lightheadedness, palpitations or dizziness.15 A baseline ECG should be consid-ered in patients who are on multiple QTc prolonging medi-cations or on high risk medications such as thioridazine. An ECG recording should be obtained for patients with any risk factors before treatment with a QTc prolonging psychotro-pic is started and once the medications are at steady state. If the QTc is mildly elevated consider lowering the dose or utilizing another agent with less potential for QTc prolon-gation. In patient whose QTc exceeds 500 milliseconds or whose QTc increases >60 milliseconds when starting a new psychotropic consider discontinuation of QTc prolonging psychotropics or switching to agents with a lower propensi-ty for QTc prolongation. Electrolytes should be monitored in patients taking diuretics or those with severe diarrhea, vomiting or other risk factors for electrolyte imbalances. 1,13-14 TREATMENT RECOMMENDATIONSThe risk of TdP is low in patients who are relatively healthy without cardiac disease. Therefore, for patients who do not have other risk factors, it is reasonable to use psychotropic medications that may prolong the QTc. For patients with pro-longed QTc of <500 milliseconds at baseline, psychotropic medications are a reasonable treatment with ECG monitoring. Since the risk is highest during the first 90 days after start-ing a medication, healthy patients on a stable regimen with a prolonged QTc of < 500 milliseconds can be continued on their current medication regimen. If the patient devel-ops other risk factors, ECG is a useful tool for reevaluat-ing the medication regimen. If the dose of a QTc prolonging R H O D E  I S L A N D  M E D I C A L  J O U R N A L M A R C H  2 0 1 3 4110. Strauss S, Sturkenboom M, Bleumink G, et al. Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. Eur Heart J. October 2005;26(19):2007-2012. 11. Nielsen J. The safety of atypical antipsychotics: does QTc pro-vide all the answers? Exp Opin. 2011;10(3):341-344. 12. Harrigan EP, Micelli JJ, Anziano R, et al. A Randomized Evalu-ation of the Effects of Six Antipsychotic Agents on QTc, in the Absence and Presence of Metabolic Inhibition. J Clin Psycho-pharmacol. 2004;24:62-69.13. Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by psychotropic drugs and the risk of Torsades de Pointes. Deutch-es Arzteblatt. 2011;108(41):667-697.14. Alvarexz PA, Pahissa J. QT alterations in psychopharmacology: proven candidates and suspects. Curr Drug Saf. 2010;5(1):97-104. 15. http://www.torsades.org accessed August 27, 201216. Nelson S, Leung JG. Torsades de Pointes after administration of low dose aripiprazole. Ann Pharmacother. 2013 [Epub ahead of print, Jan 29]Authors*Jessica L. Gören, PharmD, BCPP is Associate Professor, Depart-ment of Pharmacy Practice, College of Pharmacy, University of Rhode Island; Instructor in Psychiatry, Harvard Medical School, Boston, MA; Senior Pharmacist Specialist, Cambridge Health Alliance, Cambridge, MATuan Anh Dinh is a Doctor of Pharmacy Student, College of Pharmacy, University of Rhode Island. He is a candidate for graduation in 2014.CorrespondenceJessica L. Gören, PharmD, BCPPUniversity of Rhode Island7 Greenhouse RoadKingston RI 02881617-806-8514jgoren@uri.eduCONTRIBUTIONS

Psychotropics and Sudden Cardiac Death

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Psychotropics and Sudden Cardiac Death

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