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QTc Prolongation and High-Dose Olanzapine

TO THE EDITOR: The electrocardiographic QT interval is a representation of ventricular depolarization and repolarization. This interval is corrected for heart rate (QTc). It has high normal variability and is rate dependent in an inverse relationship. QT interval prolongation can predispose patients to torsades de pointes and sudden death.¹ A QTc interval of over 440 msec can be of concern, and an interval of 500 msec or greater is associated with a substantial risk of developing dangerous cardiac dysrhythmias.² Antipsychotic drug-related QTc interval prolongations have raised awareness about this potential medication-induced complication.³ At conventional doses, olanzapine is not associated with statistically significant QTc interval changes.^4,5 The following vignette documents QTc interval prolongation in a patient receiving 40 mg/day of olanzapine.

Case Report

Ms. A, a 28-year-old nonobese woman, was hospitalized with a recent history of deteriorating mental status, suicidal thoughts, and auditory hallucinations. She was using cocaine and alcohol before admission. Initial laboratory reports showed normal serum chemistries and a normal hemogram. A baseline ECG revealed a QTc interval of 412 msec and a heart rate of 93 bpm. Olanzapine, 20 mg b.i.d., was initiated the next day because of persistently severe agitation and psychosis. After 11 days, asymptomatic tachycardia was observed; a second ECG revealed a QTc interval of 485 msec and a sinus rhythm of 124 bpm. Thus, there was a lengthening of the QTc interval by 73 msec—an 18% increase.

The results of laboratory profiles, including calcium and magnesium concentrations, were normal; the first two ECGs were obtained at approximately the same time of day. Therefore, other causes of QTc interval prolongation, such as electrolyte imbalance and diurnal variation, were thought unlikely. Thus, olanzapine was deemed to be the most likely etiology of this electrocardiographic change, and the drug was discontinued. Two days later, a repeat ECG showed a sinus tachycardia of 122 bpm and a QTc interval of 424 msec. Thus, after olanzapine discontinuation, Ms. A's QTc interval returned to a safer value, within 12 msec of baseline. Olanzapine, 40 mg/day, was considered at least partially responsible for the QTc interval prolongation.

Discussion

This case suggests that olanzapine may cause QTc interval prolongation at higher-than-conventional doses. Recent literature indicates that olanzapine is not a statistically significant cause of QTc interval prolongation;^4,5 however, the maximum dose studied was usually 20 mg/day. When we consider the paucity of data regarding subjects given 40 mg/day of olanzapine, this report demonstrates the need for monitoring ECGs in such circumstances. There are indications for a linear relationship between olanzapine dose and the lengthening of QTc interval.^4,5 This report also illustrates the importance of assessing a baseline ECG when prescribing a medication or dose that may result in a conduction delay. Had the patient's baseline QTc interval been nearer the normal range, a change of 72 msec would have been insignificant; however, with her QTc interval already at the upper end of normal, this increase resulted in a QTc interval of concern. A long QTc interval confers an enhanced susceptibility to drugs that prolong QT intervals. Though olanzapine-induced fatal arrhythmias secondary to a prolonged QTc interval are rare, the possibility does exist and should be considered, particularly in people taking drugs in higher-than-conventional doses.

REFERENCES

1. Tan HL, Hou CJ, Lauer MR, Sung RJ: Electrophysiologic mechanisms of the long QT interval syndromes and torsades de pointes. Ann Intern Med 1995; 122:701-714[Abstract/Free Full Text]
2. Morganroth J, Brozovich FV, McDonald JT, Jacobs RA: Variability of the QT measurement in healthy men, with implications for selection of an abnormal QT value to predict drug toxicity and proarrhythmia. Am J Cardiol 1991; 67:774-776[CrossRef][Medline]
3. Glassman AH, Bigger JT Jr: Antipsychotic drugs: prolonged QTc interval, torsades de pointes, and sudden death. Am J Psychiatry 2001; 158:1774-1782[Abstract/Free Full Text]
4. Czekalla J, Beasley CM Jr, Dellva MA, Berg PH, Grundy S: Analysis of the QTc interval during olanzapine treatment of patients with schizophrenia and related psychosis. J Clin Psychiatry 2001; 62:191-198[Medline]
5. Czekalla J, Kollack-Walker S, Beasley CM Jr: Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics. J Clin Psychiatry 2001; 62:35-40

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				W. R. Zemrak and G. A. Kenna Association of antipsychotic and antidepressant drugs with Q-T interval prolongation Am. J. Health Syst. Pharm., June 1, 2008; 65(11): 1029 - 1038. [Abstract] [Full Text] [PDF]

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