Side Effects of Ziprasidone

To the Editor: The following case report pertains to the use and side effects of ziprasidone. In particular, this vignette relates to the prolongation of the QTc interval in the face of abnormal electrolyte levels.

The issue of ziprasidone lengthening the QTc interval has demanded a good deal of attention and created substantial anxiety among clinicians since the drug was recently introduced (1). Considerable scrutiny of ziprasidone’s cardiac effects regarding the inception of arrhythmias has been ongoing (2). While thioridazine received a “black box” warning concerning its QTc-interval disturbances, other conventional antipsychotics, such as haloperidol, have also been associated with this risk (3, 4). Glassman and Bigger (1) estimated the rate of occurrence of torsade de pointes with this group of older antipsychotics as “10–15 such events in 10,000 person-years of observation.” To our knowledge, no case of torsade de pointes during ziprasidone use has emerged, despite the drug’s growing use at doses in excess of 160 mg/day. Moreover, we know of no appearance of arrhythmia in reported cases of intentional overdose (5, 6).

This absence of negative information has not cooled the general fear that, at least in special cases, ziprasidone may yet engender significant arrhythmia, including potentially fatal ventricular disturbances. No study, to our knowledge, has yet addressed either general considerations concerning drug interactions and metabolic interference potentially causing QTc-interval prolongation or specific metabolic inhibitors of aldehyde oxidase, an important mediator of ziprasidone metabolism (7). Recently, Biswas et al. (8) reported a case of cardiac arrhythmia without fatality yet “requiring aggressive cardiac monitoring” in a 17-year-old adolescent who overdosed with ziprasidone and bupropion in combination. Although authors’ opinions differ widely (9–13), bupropion in overdose may alone engender cardiotoxicity, including QTc-interval prolongation.

Apart from congenital anomalies, the risk of QTc prolongation increases dramatically in the presence of hypokalemia and hypomagnesemia (14–16). The following case report addresses how ziprasidone behaves in the presence of severe hypokalemia and accompanying hypomagnesemia, significant causes of ventricular abnormalities.

Our patient’s case illustrates ziprasidone’s effect on the QTc interval in the presence of a provocative state, severe hypokalemia, and hypomagnesemia. In the present instance, our patient’s abnormal electrolyte levels were alone sufficient to account for the prolongation of her QTc interval. While there was evidence to demonstrate the QTc-lengthening effects of ziprasidone, we know of no prior case reports that have discussed its effects under these circumstances. It appears that, at least in this instance, ziprasidone’s cardiac action is less dramatic than one might anticipate. These data lend further credibility to the idea that the drug’s effect on the myocardium is less dire than is widely feared. Certainly, further investigation into this matter is necessary before one can determine the true margin of safety for ziprasidone use. Unfortunately, such data will have to emerge from fortuitous events. Decisions to use this drug ought to result from our appreciation of the facts, which have so far shown little in the way of significant clinical data regarding cardiac impairment. In the meantime, one ought to remain cautious but not unduly critical of ziprasidone.