Letters to the Editor
Olanzapine: A Proarrhythmic Drug?
Dear Editor:
A 70-year-old woman presented with an 8-month history of auditory
and visual hallucinations that had developed within 4 weeks of beginning
carbidopa and levodopa (100 mg and 25 mg) 3 times daily for antiparkinsonian
therapy. The patient’s history included parkinsonism for the
last 9 years, essential hypertension for the last 4 years (treated
with tablet Enalapril maleate 7.5 mg once daily), bronchial asthma
for the last 3 years (treated with inhaled Ipratropium bromide,
Salbutamol, and long-acting Theophylline 400 mg once daily), osteoarthritis
of the left knee (treated with tablet Tramadol 50 mg 3 times daily),
and asymptomatic ventricular premature contractions (no active intervention)
for the last 1½ years. Baseline cardiovascular parameters
3 months prior to evaluation were available: heart rate, 88/minute
with occasional ectopic beats; blood pressure, 158/94 mm Hg in right
upper limb; echocardiography, left ventricular diastolic dysfunction;
and Holter, multiple ventricular premature contractions. The baseline
ECG recording showed a pulse rate of 81/minute, PR interval of 160
msec, QRS of 120 msec, and corrected QT (QTc) of 418 msec. We started
her on Olanzapine 2.5 mg (half-tablet) once daily. Follow-up at
1 week showed improvement in her psychotic features. An ECG recording
showed a pulse rate of 107/minute, PR interval of 160 msec, QRS
of 100 msec, and QTc of 428 msec. Olanzapine was immediately discontinued;
all other treatment parameters were unchanged. A repeat ECG recorded
2 days after discontinuation showed pulse rate of 115/minute, PR
interval of 200 msec, QRS of 80 msec, and QTc of 444 msec. A final
ECG, recorded 1 week after discontinuation (to ensure complete washout
of olanzapine from her body), showed pulse rate of 100/minute, PR
interval of 160 msec, QRS of 72 msec, and QTc of 413 msec.
Recently, an increasing number of noncardiac drugs have been reported
to be associated with QT interval prolongation and torsades de pointes
(1). The degree of QT interval prolongation increases in the presence
of organic heart disease and sinus bradycardia, especially in female
subjects (1). Among noncardiac drugs, new (atypical) antipsychotics
can cause QT interval prolongation and potentially fatal arrhythmias
(2). Sertindole (1) and risperidone (3) have been implicated to
a greater degree than have clozapine or olanzapine. However, animal
models have suggested that all atypical antipsychotics, including
olanzapine, prolong QT interval in a concentration-dependent manner
(4). Our case demonstrates a temporal relation of QT prolongation
(although in the normal range) with initiation of olanzapine and
reversal of this QTc prolongation to baseline level on washout of
olanzapine from the body.
One may argue that the ECG recording made just prior to discontinuation
of olanzapine showed less prolongation of QTc interval, compared
with the ECG recording on day 2 of discontinuation. This can be
explained by olanzapine’s pharmacokinetic profile (that is,
its half-life of approximately 30 hours). Additionally, with regard
to effects on the cardiovascular system, the patient’s relatively
long-term concomitant use of multiple other medicines is not associated
with any significant pharmacokinetic or pharmacodynamic interactions
with olanzapine (5). Owing to ethical issues and because informed
consent was not available, we did not attempt rechallenge.
Hence, based on the available information, it can be theorized
that olanzapine led to QTc interval prolongation in an elderly woman
with preexisting heart disease; that is, olanzapine can be a proarrythmic
noncardiac agent. We recommend that atypical antipsychotics, including
olanzapine, should be initiated with caution and with careful monitoring
of the cardiac parameters in elderly patients.
References
1. Yap YG, Camm J. Risk of torsades de pointes with
non-cardiac drugs. BMJ 2000;320:1158–9.
2. Wirshing DA, Erhart SM, Pierre JM, Boyd JA. Nonextrapyramidal
side effects of novel antipsychotics. Curr Opin Psychiatry 2000;13:45–50.
3. Arun P, Gupta N. Symptomatic bradycardia: an adverse
event following risperidone initiation in an elderly male. Hong
Kong J Psychiatry 2001;11 (3):21–2.
4. Drici MD, Wang WX, Liu XK, Woosley RL, Flockhart
DA. Prolongation of QT interval in isolated feline hearts by antipsychotic
drugs. J Clin Psychopharmacol 1998;18:477–81.
5. Karalliedde L, Henry J. Handbook of drug interactions.
London: Arnold; 1998.
Nitin Gupta, MD
Pankaj Malhotra, MD
Chandigarh, India
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