This issue begins a series of columns on the subject of prolongation of the QT interval and psychiatric medications. This initial installment will focus on a challenging case presented to me by a colleague. The issues underlying this case are central to many of the recurrent themes discussed in this column.
The patient was a 17-year-old female with bipolar and attention-deficit/hyperactivity disorder (ADHD). She had been symptomatic with these disorders from a very young age. She also had familial or congenital prolonged QT interval and a family history of congenital deafness in a grandmother. The patient was currently receiving 1,000 mg of valproate in the ER formulation taken at bedtime and 0.5 mg of clonazepam up to twice a day as needed for agitation. However, the patient's previous physician had treated her with a variety of different medications, some of which, according to her history, had prolonged her QT interval to the point that she passed out. Perhaps for this reason, her previous physician had declined to continue treating her. According to the brief medication history that was supplied, the patient had previously been treated with fluoxetine up to 80 mg/day, atomoxetine up to 20 mg/day, dexmethylphenidate extended release (Focalin XR) up to 10 mg/day, atenelol up to 100 mg/day, alprazolam 0.5 mg/day, and quetiapine up to 400 mg/day. She had been weaned off of quetiapine because of her prolonged QT interval. According to her history, the patient experienced severe tremors on one or more of these medications for almost 6 months. As the quetiapine was being discontinued, she developed hypomania. After 3 days of not sleeping, she was diagnosed with bipolar disorder. She may also have been having akathisia. The patient was euphoric when hypomanic but also had depressive episodes.
The overriding issue for my colleague was whether I had any recommendations as to what medications would be safe to consider. She consulted me on a Monday and needed an answer by Friday when the patient was scheduled to come in for a visit. Specifically, my colleague had considered aripiprazole but was not able to find any information about the risk of QT prolongation with this agent. She also wondered whether it made sense to try benztropine to treat the akathisia and whether there had been any reports of QT prolongation associated with that medication.
Conceptualization of the Case
As the regular reader of this column knows, the conceptualization begins with the following equation:
The effect that is the focus of concern in this case is prolongation of intracardiac conduction, specifically the QT interval. While this may be a desirable effect for anti-arrhthymic medications, it is not so for psychiatric medications, where it is to be avoided because excessive prolongation of the QT interval can cause a fatal arrhythmia known as torsade de pointes.1 This term, French for "twisting around the point," comes from the fact that the EKG in a patient with torsade de pointes is completely disorganized and looks like the tracing is simply twisting in a meandering fashion around a point.2
The clinical adage is that non-sustained torsade presents as dizziness whereas sustained torsade presents as death.3 In the former situation, the patient experiences dizziness as a result of a transient cessation of blood flow to the brain due to the momentary disorganized and hence dysfunctional contraction of the myocardium. If the arrhythmia is sustained, the patient dies. For a drug to be able to cause this effect, it must affect a mechanism of action capable of slowing intracardiac conduction (variable 1 in the equation). The most common mechanism mediating this adverse effect is the potassium rectifying current.4-6 Next, the drug must reach a sufficient concentration (variable 2) to affect this target to a sufficient degree to slow intracardiac conduction to the point of causing arrhythmia. While anti-arrhythmic drugs may have been designed to specifically block this current, that is not the case with psychiatric medications. As discussed in previous columns, psychiatric medications have generally been designed to affect specific receptors or uptake pumps.7-10 However, some of these drugs are capable of inadvertently blocking the potassium rectifying current at nearly the same concentration as they block their desired target.11,12 For this reason, they have the potential to slow intracardiac conduction and thus cause torsade.
While the factors discussed above are all relevant in this case, the primary cause of concern here is variable 3. This patient has a genetic predisposition for a prolonged QT interval.13 Individuals with such a predisposition are at increased risk for torsade de pointes and sudden death for this reason alone. There is also concern that these patients may be more sensitive to the effects of drugs that are capable of causing QT prolongation.
Few empirical data are available to guide the clinician concerning the treatment of this patient. The lack of data is the result of several factors. First, individuals who have familial prolongation of the QT interval are rare and therefore difficult to study. Second, there is little support for undertaking studies in such patients solely to develop generalizable knowledge about their dose-response curve with drugs that can prolong the QT interval. Third, it would be difficult to obtain approval for such a study since one would have to justify exposing such individuals to drugs solely to determine if they are more sensitive to the QT prolonging effects of the drugs than individuals in the general population.
For all of these reasons, data are limited to extrapolations from studies that have been done to assess the QT prolonging effects of drugs in normal controls, which can then be applied to this patient and others like her with familial QT prolongation, based on the assumption that these patients will be even more sensitive to these effects than normal controls. Furthermore, not only are there minimal data concerning drug effects in patients with familial QT prolongation, there are also minimal or no data concerning the QT effects of many older drugs. This is because this effect was only recognized as a significant safety concern during the 1990s, principally because of sudden deaths that occurred when terfenadine (Seldane) was used in combination with a significant cytochrome P450 (CYP) 3A3/4 enzyme inhibitor, such as the azole antifungal ketoconazole.14-19 The inhibition of the CYP 3A3/4 enzyme caused by a drug like ketoconazole prevented the conversion of terfenadine to its active metabolite, fexofenadine (Allegra).20,21 Normally, terfenadine never made it into the systemic circulation when it was taken orally. Instead, it was almost completely converted to fexofenadine during the process of absorption across the bowel wall, since the CYP 3A3/4 on which its metabolism depends is particularly expressed and hence concentrated in enterocytes which form the mucosa of the small bowel and in the hepatocytes. (Although many readers may think that most first-pass metabolism occurs in the liver, it in fact occurs in the bowel wall, due to this expression of CYP 3A3/4 in enterocytes.22)
The irony is that terfenadine was being given as a non-sedating antihistaminic but that, in fact, its metabolite, fexofenadine was actually the active agent. The even greater irony is that fexofenadine, unlike terfenadine, has only minimal effects on the potassium rectifying current.23 For most patients, this distinction was not clinically important because terfenadine never made it into the body to any appreciable degree. However, that situation changed drastically when terfenadine was administered in combination with an azole antifungal such as ketoconazole. As a result of this drug-drug interaction, an estimated 250 individuals, mainly young women, died as a result of torsade de pointes.24-28
When this adverse drug-drug interaction was recognized, terfenadine was pulled from the market and greater attention was paid to the effect of drugs, including psychiatric drugs, on the QT interval.29-34 It was concern over prolongation of the QT interval that prevented the marketing of sertindole,35 that led to the black box warning for thioridazine (Mellaril) 40 years after it was introduced to the U.S. market,36 and that led to concerns about drugs such as ziprasidone (Geodon).37
In upcoming columns in this series, we will discuss how studies concerning the prolongation of the QT interval are done and what we know and do not know about the QT prolonging effects of specific psychiatric medications, before returning to the specific elements of this case and how it might best be approached.
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8. Preskorn SH. The human genome project and modern drug development in psychiatry. J Psych Prac 2000;6:272-6.*
9. Preskorn SH. Antipsychotic drug development in the prehumangenome era: A full circle. J Psych Prac 2001;7:209-13.*
10. Preskorn SH. Drug discovery in psychiatry: Drilling down on the target of interest. J Psych Prac 2001;7:267-72.*
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21. von Moltke LL, Greenblatt DJ, Duan SX, et al. Inhibition of terfenadine metabolism in vitro by azole antifungal agents and by selective serotonin reuptake inhibitor antidepressants: Relation to pharmacokinetic interactions in vivo. J Clin Psychopharmacol 1996;16:104-12.
22. Tsunoda SM, Velez RL, von Moltke LL, et al. Differentiation of intestinal and hepatic cytochrome P450 3A activity with use of midazolam as an in vivo probe: Effect of ketoconazole. Clin Pharmacol Ther 1999;66:461-71.
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29. Buckley NA, Sanders P. Cardiovascular adverse effects of antipsychotic drugs. Drug Safety 2000;23:215-28.
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32. 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.
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35. Eckardt L, Breithardt G, Haverkamp W. Electrophysiologic characterization of the antipsychotic drug sertindole in a rabbit heart model of torsade de pointes: Low torsadogenic potential despite QT prolongation. J Pharmacol Exp Ther 2002;300:64-71.
36. Reilly JG, Ayis SA, Ferrier IN, et al. Thioridazine and sudden death in psychiatric in-patients. Br J Psychiatry 2002;180: 515-22.
37. FDA Pharmacological Drugs Advisory Committe. Pfizer briefing document for ziprasidone mesylate for intramuscular injection. Feb. 15, 2001. (www.fda.gov/ohrms/dockets/ac/01/briefing/3685b2_01_pfizer.pdf
, accessed Mar 6, 2006.)
*The publications by Dr. Preskorn cited here can be accessed at his website (www.preskorn.com).
The deadline for submissions to the Journal of Psychiatric Practice Resident Paper Competition has been extended to April 15, 2006. Entries should be sent to the Managing Editor, Ruth Ross, via email ([email protected]) or regular mail (228 Black Rock Mtn Ln, Independence, VA 24348). The winning paper will be published in a forthcoming issue of the journal and the winner will receive a $500 voucher good towards the purchase of Lippincott Williams & Wilkins books and journals and a certificate in recognition of this achievement.