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Neuroleptic Use in a Patient With a Prolonged QTc Interval

Key Words: Neuroleptics • Long QT Interval

TO THE EDITOR: The use of neuroleptics has been shown to produce QTc prolongation, an ECG change that correlates with ventricular arrhythmias such as torsades de pointes.¹ Current recommendations suggest discontinuing neuroleptics when a patient’s QTc interval exceeds 500 msec in order to lessen the risk of developing these potentially fatal arrhythmias. There are no recommendations regarding treatment of patients with a baseline interval greater than 500 msec. We present a patient with a QTc interval >500 msec who required a neuroleptic in order to participate in his care.

Case Report
"Mr. H" is a 61-year-old homeless African American man who was found unresponsive in a homeless shelter. EMS brought him to the emergency room, where he was intubated and transferred to the Medical ICU. There, he sustained a non–ST-elevation myocardial infarction, and serial ECGs revealed a peak QTc interval length of 654 msec. He was started on a cardiac regimen, including a beta-blocker. His ECG stabilized with a QTc interval in the range of 507 msec–595 msec. On awakening, he was delusional and agitated, refusing all medications and blood draws. The consultation psychiatrists recommended transfer to a psychiatry inpatient unit for further evaluation and management.

Initially, the differential diagnosis for Mr. H included delirium. After several days without neuroleptics, however, he continued to be delusional despite being fully alert. He did not have waxing and waning of his symptoms, and a work-up for causes of delirium was negative. After review of previous records, the treatment team determined that his presentation was most consistent with disorganized schizophrenia. Given Mr. H’s psychotic symptoms, we wanted to initiate a neuroleptic, but were concerned about adding to his risk of developing an arrhythmia, given his prolonged QTc interval and recent myocardial infarction. Finally, it was decided that the risk of Mr. H’s death from refusal to take his cardiac medications was greater than the risk of arrhythmia secondary to drug-induced QTc prolongation. He was prescribed haloperidol and titrated up to a dose of 10 mg bid. An ECG was checked daily in order to monitor his QTc interval, which remained between 503 and 532 msec. Follow-up medical consultation determined that there was no change in his ECGs. He improved significantly and began taking his cardiac medications voluntarily.

Discussion
The QT interval reflects the time required for ventricular depolarization and repolarization. The upper limit of normal for a QTc interval (a QT interval corrected for heart rate) is 440 msec. If depolarization occurs before the end of repolarization, so-called "early after-depolarizations" can provoke torsades de pointes, a potentially lethal ventricular arrhythmia that has been associated with cardiac arrest and sudden death.² Other factors that contribute to the risk of torsades de pointes include female sex, older age, heart disease, electrolyte abnormalities, hypothyroidism, intracranial disorders, and nutritional deficiencies.

Medications that cause QTc prolongation and torsades de pointes (including neuroleptics) most commonly interrupt the delayed rectifier potassium channel I_Kr, preventing potassium from exiting the cell and thus allowing early after-depolarization.³ Haloperidol also increases the risk of QTc prolongation, although it has been shown to block—not I_Kr—but other channels encoded by the HERG gene.⁴ There have been two trials comparing neuroleptic effect on QTc interval. Pfizer Inc., U.S. Pharmaceuticals Group⁵ found that, among six neuroleptics, thioridazine had the greatest mean QTc prolongation, at 35.6 msec, and haloperidol had the least mean prolongation, at 4.7 msec. Harrigan and colleagues⁶ performed a similar trial in 2004 and found the longest mean QTc prolongation with thioridazine, at 30.1 msec; mean prolongation with haloperidol at 7.1 msec; and the lowest mean prolongation with olanzapine, at 1.7 msec.

The current recommendation is to withdraw neuroleptics when the QTc interval is over 500 msec. As with any intervention, however, the risks of treatment must be weighed alongside the benefits. In the patient described above, baseline QTc interval should have been enough to preclude treatment, and his age and considerable cardiac comorbidities were additional risk factors for the development of arrhythmia. The risk of arrhythmia, however, was offset by the fact that the use of a beta-blocker after myocardial infarction has been shown to lead to a 26%–33% decrease in mortality after myocardial infarction⁷ and by our recognition that Mr. H would continue to refuse this potentially life-saving medication while he remained psychotic. Although we do not recommend the cavalier use of neuroleptics in patients at high risk for cardiac arrhythmia, these patients should not be denied access to treatment without a careful assessment of risks and benefits.

REFERENCES

1. Laasko M, Aberg A, Savola J, et al: Diseases and drugs causing prolongation of the QT interval. Am J Cardiol 1987; 59:862–865[CrossRef][Medline]
2. Crouch M, Limon L, Cassano A: Clinical relevance and management of drug-related QT-interval prolongation. Pharmacotherapy 2003; 23:881–908[CrossRef][Medline]
3. Yap Y, Camm J: Risk of torsades de pointes with noncardiac drugs. BMJ 2000; 320:1158–1159[Free Full Text]
4. Suessbrich H, Schonherr R, Heinemann S, et al: The inhibitory effect of the neuroleptic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes. Br J Pharmacol 1997; 120:968–974[CrossRef][Medline]
5. Pfizer Inc.: FDA Briefing Document for Zeldox Capsules (Ziprasidone). New York, Pfizer Inc., U.S. Pharmaceuticals Group, July 18, 2000
6. Harrigan E, Miceli J, Anziano R, et al: A randomized evaluation of the effects of six neuroleptic agents on QTc, in the absence and presence of metabolic inhibition. J Clin Psychopharmacol 2004; 24:62–69[CrossRef][Medline]
7. Thattassery E, Gheorghiade M: Beta-blocker therapy after acute myocardial infarction in patients with heart failure and systolic dysfunction. Heart Failure Review 2004; 9:107–113[CrossRef]

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