Psychotropics and sudden cardiac death

University of Rhode Island
Psychotropics and Sudden Cardiac DeathJessica L. GorenUniversity of Rhode Island, [email protected] Follow this and additional works at: Terms of UseAll rights reserved under copyright.
Citation/Publisher AttributionDinh, Tuan Anh and Jessica L. Goren. "Psychotropics and Sudden Cardiac Death" Rhode Island Medical Journal. 96(3):38-41. March2013.
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Psychotropics and Sudden Cardiac Death
TUAN ANH DINH; JESSICA L. GÖREN, PHARMD, BCPP
ABSTRACT
Prolonged QTc intervals can lead to ventricular tachy- Over the past two decades there has been a large increase arrhythmia and TdP. While the true incidence of TdP is un- in the number of patients prescribed psychotropic med- known, the number of reported cases is low. Over a period ications. Many of these agents are associated with QTc of 15 years only 761 cases were reported to the World Health prolongation which is considered a marker for increased Organization.5 Therefore, prolonged QTc has become a risk of sudden cardiac death due to malignant arrhyth- surrogate marker for TdP.1,5 mias such as Torsades de pointes (TdP). Psychotropics It is important to note that drug induced QTc prolonga- rarely lead to sudden death in healthy individuals on a tion alone rarely leads to TdP. A review of population studies single QTc prolonging medication. However, factors such reported prolonged QTc was associated with TdP in pa- polypharmacy, recent initiation of a QTc prolonging med- tients with preexisting cardiovascular disease, but not with ication, bradycardia, electrolyte abnormalities and preex- healthy patients.6 Rather TdP is most likely to occur when isting arrhythmias increase the likelihood of psychotro- prolonged QTc is combined with at least two risk factors pic-induced sudden cardiac death. Therefore, clinicians such as electrolyte abnormalities, bradycardia or congeni- must recognize which psychotropics and risk factors are tal cardiac abnormalities. The most important risk factors associated with increased risk in order to minimize the appear to be preexisting heart disease, age >65 years, and risks of psychotropic QTc prolongation.
female sex. 6,7 Torsades de pointes may be increased in hos-pitalized patients because hospitalized patients are more KEYWORDS: psychotropic, side effect, cardiac, QTc,
likely to have risk factors such as heart disease, advanced age, Torsades, arrhythmia 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. INTRODUCTION
There has been increasing concern regarding the cardiac side
Psychotropics and QTc
effects of psychotropics. Some psychotropic medications in- Psychotropics, such as antidepressants and antipsychotics, crease the risk of sudden cardiac death. However, these drugs affect the heart by blocking certain potassium channels. are important for many patients. Therefore, it is important This leads to a blockade of type I (a fast potassium chan- to assess cardiac risks associated with psychotropics. This nel in the heart), causing a delay in repolarization and thus article will summarize these effects and provide recommen- QTc prolongation.1,2 This is accomplished via either HERG dations on cardiac risk assessment for patients treated with (Human ether-a-go-go Related Gene) blockade or abnormal psychotropic medications. protein trafficking for HERG. Almost all drugs which can induce TdP block HERG, while a few indirectly affect HERG The QT interval and Torsades de pointes
function.1,2 Drugs which prolong the QTc by alternate means The QT interval is the measure of cardiac conduction speed are less likely to result in TdP.
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 Table 1. Average QTc1-3
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.
M A R C H 2 0 1 3
Population-based studies indicate there is a two- to three- with preexisting risk factors or those with elevated blood fold increased risk of sudden cardiac death in patients taking concentrations due to over dose, high doses or drug inter- non-cardiac QTc prolonging medications.6,7 Antidepressants actions. Bupropion, mirtazapine and trazodone all appear to are the psychotropic class most commonly associated with have minimal risk of QTc prolongation at typical doses.15 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- Table 2. Mean QTc prolongation and psychotropics12-15
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.13-16 Antidepressants and QTc
Large 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 M A R C H 2 0 1 3
Psychotropic Polypharmacy and QTc
medication is increased, a pre- and post-baseline ECG will The risk of QTc prolongation with antipsychotics and be useful in determining risk of the dose increase.
antidepressants is typically dose related.1,4,5,10 Therefore any For patients with a prolonged QTc of ≥ 500 milliseconds, combination of medications which results in elevated con- consider discontinuing any QTc prolonging medications centrations of antidepressants or antipsychotics increases and/or substituting with medications less likely to prolong the likelihood of QTc prolongation. Conversely, any psycho- the QTc. Also, consider consulting a cardiologist. 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 Since psychotropic-induced QTc prolongation is typically medications, whether the psychotropics are combined with dose related, patients should be maintained on the lowest other QTc prolonging psychotropic or non-psychotropic effective doses of psychotropics. Additionally, careful review medications. Thus careful consideration should be given to for drug interactions should be conducted prior to adding any utilization of psychotropic polypharmacy and combinations medications to ongoing psychotropic treatment. The risk of of psychotropics and non-psychotropic medications.
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 Psychotropic drugs are known to affect the QTc interval are less likely to experience psychotropic induced arrhyth- and should be utilized with caution in patients with risk mias unless there are changes in medication treatment or factors such as age >65, female gender, congenital long QTc new risk factors. Sudden cardiac death is unlikely in patients syndrome, electrolyte abnormalities, polypharmacy and pre- without preexisting risk factors and is a rare outcome for those existing cardiac disease.1,13-15 For relatively healthy patients with risk factors. Even for patients with risk factors who may without preexisting risk factors, routine ECG monitoring have a prolonged QTc that is < 500 milliseconds, treatment should be considered for those with episodes of blackouts, with a psychotropic may be reasonable with appropriate fainting, seizures, or with unexplained lightheadedness, monitoring. Physicians should not be discouraged from psy- palpitations or dizziness.15 A baseline ECG should be consid- chotropic use unless patients have a contraindication, such ered in patients who are on multiple QTc prolonging medi- as a cardiac arrhythmia or congenital long QT syndrome. 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. 1. Huffman JC, Stern TA. QTc Prolongation and the Use of Anti- If the QTc is mildly elevated consider lowering the dose or psychotics: A Case Discussion. Prim Care Companion J Clin utilizing another agent with less potential for QTc prolon- gation. In patient whose QTc exceeds 500 milliseconds or 2. Ponte ML, Keller GA, Di Girolama G. Mechanism of Drug whose QTc increases >60 milliseconds when starting a new Induced QT Interval Prolongation. Current Drug Safety. psychotropic consider discontinuation of QTc prolonging 3. Yap YG, Cramm AJ. Drug Induced QT Prolongation and tor- psychotropics or switching to agents with a lower propensi- sades de pointes. Heart. 2003;89(11):1363-1372.
ty for QTc prolongation. Electrolytes should be monitored 4. Nielsen J, Graff C, Kanters JK, Toft E, Taylor D, Meyer JM. As- in patients taking diuretics or those with severe diarrhea, sessing the QT interval prolongation and its associated risks with antipsychotics. CNS Drugs. 201;25(6):473-490.
vomiting or other risk factors for electrolyte imbalances. 1,13-14 5. Darpo B. Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes. Eur Heart J (Suppl K). 6. Montanez A, Ruskin JN, Herbert PR, et al. Prolonged QTc in- The risk of TdP is low in patients who are relatively healthy terval and risk of total and cardiovascular mortality and sud- den death in the general population: a review and qualitative without cardiac disease. Therefore, for patients who do not overview of the prospective cohort studies. Arch Int Med. have other risk factors, it is reasonable to use psychotropic medications that may prolong the QTc. For patients with pro- 7. Astrom-Lilja C, Odeberg JM, Ekman E, Hagg S. Drug-induced torsades de pointes: a review of the Swedish pharmacovigilence longed QTc of <500 milliseconds at baseline, psychotropic database. Pharmacoepidemiol Drug Saf. 2008;17:587-592. medications are a reasonable treatment with ECG monitoring. 8. Tisdale JE, Wroblewski HA, Overholser BR, Kingery JR, Tru- Since the risk is highest during the first 90 days after start- jillo TN, Kovacs RJ. Prevalence of QT interval prolongation in ing a medication, healthy patients on a stable regimen with patients admitted to cardiac care units and frequency of subse- quent administration of QT interval prolonging drugs. Drug Saf. a prolonged QTc of < 500 milliseconds can be continued 2012;35(6):459-470. on their current medication regimen. If the patient devel- 9. De Bruin ML, Langendijk PN, Koopmans RP, et al. In-hospi- ops other risk factors, ECG is a useful tool for reevaluat- tal cardiac arrest is associated with use of non-antiarryhthmic ing the medication regimen. If the dose of a QTc prolonging QTc-prolonging Drugs. Br J Clin Pharmacol. 2007;63:216-223. M A R C H 2 0 1 3
10. Strauss S, Sturkenboom M, Bleumink G, et al. Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. Eur *Jessica L. Gören, PharmD, BCPP is Associate Professor, Depart- Heart J. October 2005;26(19):2007-2012. ment of Pharmacy Practice, College of Pharmacy, University 11. Nielsen J. The safety of atypical antipsychotics: does QTc pro- of Rhode Island; Instructor in Psychiatry, Harvard Medical vide all the answers? Exp Opin. 2011;10(3):341-344. School, Boston, MA; Senior Pharmacist Specialist, Cambridge 12. Harrigan EP, Micelli JJ, Anziano R, et al. A Randomized Evalu- Health Alliance, Cambridge, MA ation of the Effects of Six Antipsychotic Agents on QTc, in the Absence and Presence of Metabolic Inhibition. J Clin Psycho- Tuan Anh Dinh is a Doctor of Pharmacy Student, College of Pharmacy, University of Rhode Island. He is a candidate for 13. Wenzel-Seifert K, Wittmann M, Haen E. QTc prolongation by graduation in 2014.
psychotropic drugs and the risk of Torsades de Pointes. Deutch- es Arzteblatt. 2011;108(41):667-697.
Jessica L. Gören, PharmD, BCPP 14. Alvarexz PA, Pahissa J. QT alterations in psychopharmacology: proven candidates and suspects. Curr Drug Saf. 2010;5(1):97- University of Rhode Island 7 Greenhouse Road 15. http://www.torsades.org accessed August 27, 2012 Kingston RI 02881 16. Nelson S, Leung JG. Torsades de Pointes after administration of low dose aripiprazole. Ann Pharmacother. 2013 [Epub ahead of M A R C H 2 0 1 3

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Conservation of fresh ram spermatozoa at 5°C in the presence of seminal plasma A. Morrier1, F. Castonguay1,2, and J. L. Bailey1,3 Centre de Recherche en Biologie de la Reproduction,1Département des sciences animales, Université Laval, Québec City, Québec, Canada G1K 7P4; 2Dairy and Swine Research and Development