QT Interval Duration and Dispersion in Children and Adolescents Treated With Ziprasidone

Ziprasidone is a second-generation antipsychotic with proven effectiveness for pediatric bipolar disorder Tourette’s syndrome, pervasive developmental disorder and obsessive-compulsive disorder (1–3). In addition to high-affinity antagonist activity at 5HT2A and dopamine D2 receptors, this antipsychotic has partial agonist activity at 5-HT1A receptors and affinity for norepinephrine and serotonin transporters (4). Ziprasidone is associated with substantially less weight gain and adverse metabolic effects than most other widely used atypical antipsychotics, both in adults (5), and in youth (1,6) and is considered a reasonable treatment choice for minimizing these metabolic complications (6). However, ziprasidone has the potential to prolong the rate-corrected QT interval (QTc) in the electrocardiogram. This effect is greater than the QTc prolongation observed during treatment with haloperidol, risperidone, olanzapine and quetiapine (7,8). Significant prolongation of QTc is generally considered a risk factor for torsades de pointes (TdP), ventricular fibrillation and sudden death, particularly when the QTc is greater than 500 msec (9–11). Antipsychotics produce QTc prolongation by blocking the rapid component of the delayed rectifier current, which promotes potassium efflux from the ventricular myocytes during repolarization (10,11). The mechanism is similar to the QTc prolongation produced by many widely used drugs, such as the antiarrhythmic agents amiodarone and sotalol, quinolone and macrolide antibiotics, and methadone (11). The incidence of TdP in patients treated with these drugs is extremely low, a fact that raises doubts about the value of QTc prolongation as the single electrocardiographic predictor for the risk of TdP. One the other hand, the risk of TdP is clearly increased when the QTc prolongation is associated with a concurrent prolongation of the intramyocardial dispersion of repolarization (10). A larger difference between the action potential duration in adjacent regions of the ventricular myocardium enables circular reentry activity between areas with delayed repolarization and those with excitable myocytes (10,12). The phenomenon is assessed by measuring the QTc dispersion, i.e., the inter-lead variability of QTc on the electrocardiogram. A QTc dispersion >120 msec was shown to be a strong correlate of inducible ventricular tachycardia and its predictive value was not influenced by gender, mean QTc, and left ventricular systolic function (13). QTc dispersion is also a stronger predictor for cardiovascular mortality than QTc duration in the general population (14), patients with myocardial infarction (15), subjects with congenital long QT syndromes (16) and patients who developed TdP after intravenous administration of haloperidol (17). A four-year post-marketing evaluation (4) and a one-year randomized comparison between ziprasidone and olanzapine in 18,000 adult patients, resulting in similar non-suicide related death rates of 0.9% in both groups (18), have indicated that the ziprasidone-induced QTc prolongation is not linked to the occurrence of TdP in adults, and only one case of TdP related to treatment with ziprasidone has been reported in the literature (19). Although one case of sudden death in a child treated with ziprasidone was reported, the authors made it clear that they believed after extensive investigation that this death was unrelated to the ziprasidone treatment (20). In contrast to the large adult databases (4,18), the effect of ziprasidone on myocardial repolarization in children and adolescents has been reported only in a total of 102 patients who were included in five published, open-label studies (1–3,21–22). In these studies, the mean QTc change ranged from −3 msec to +28 msec, and none of these pediatric patients was reported to have experienced syncope or other cardiovascular events. The QTc dispersion was not assessed in any of these studies. In this prospective study, we evaluated the QTc duration and QTc dispersion in 29 children and adolescents monitored carefully during treatment with ziprasidone. Based on the absence of ziprasidone related TdP cases after 8 years of clinical use, we hypothesized that ziprasidone has a low torsadogenic potential because the drug-induced QTc prolongation is not accompanied by a concomitant increase in QTc dispersion.