Cardiac Risk Must Be Weighed For Patients on Antipsychotics
Sudden cardiac death. Recent research shows that even though the number of documented cases in patients taking antipsychotics may be small, the risk is real.
Since the 1960s, case reports have associated antipsychotic use with sudden cardiac death (SCD). While the exact mechanism of action isn't known, SCD is most likely tied to fatal arrhythmias provoked by a drug-induced, prolonged QTc interval—a measure of the heart conduction system's refractory period and subsequent readiness for the next heartbeat.
By the beginning of the QT interval, electrolytes have undergone a drastic shunting from one side of the myocardial cell membrane to the other, creating the electrical stimulus that results in contraction of the cardiac muscle. (A QTc interval is simply a corrected interval length that is calculated from the measured QT interval and then adjusted for the effect of the heart rate; as rate slows, the interval normally lengthens somewhat.) In order for a subsequent electrical stimulus to occur and create the next heartbeat, those electrolytes must return to their starting places during the QT. If the electrolytes do not fully return to their resting states, any subsequent electrical stimulus will not be normal. In fact, the earlier in the QT the next stimulus falls, the more chaotic that stimulus will be. If the stimulus occurs early enough, the result is an uncoordinated fibrillation of the ventricular muscle because the electrolytes are not in the correct intracellular or extracellular positions.
Many drugs, including several antipsychotics, disrupt these transmembrane movements of certain electrolytes, most notably the inward movement of potassium through specific ion channels, marking the beginning of the return to normalcy. Because the potassium cannot return to where it started, the entire cardiac cycle is slowed down, lengthening the QT interval. Research has shown that drugs like terfenadine (Seldane) and cisapride (Propulsid) directly block the potassium current, especially when combined with other medications that slow metabolic processes in the liver, such as ketoconazole (Nizoral).
Some Antipsychotics Guilty
Terfenadine was withdrawn from the U.S. market after documented cases of SCD due to the ventricular arrhythmia, torsades de pointes, or TdP (French for“ twisting of points,” a reference to the twisting of the directions of the complexes on an electrocardiogram that are diagnostic of the rhythm). TdP is a chaotic and rapid ventricular tachycardia that originates in multiple sites within one or both ventricles, causing cardiac output to plummet toward zero quickly. Without intervention, some patients may spontaneously return to a normal rhythm, but the risk of SCD is high.
For years the antipsychotic thioridazine (Mellaril) has been associated with TdP-induced SCD. The newer antipsychotic sertindole, although widely available outside the United States, was never approved for sale by the FDA because of its association with TdP-induced SCD. Most recently, ziprasidone (Geodon) was significantly delayed in its FDA approval process while researchers attempted to determine whether its propensity to prolong the QT interval was clinically significant.
While both thioridazine and sertindole have been linked to cases of SCD, no documented cases of cardiac arrhythmias or SCD have been conclusively linked to ziprasidone.
Evidence Builds
At least two recent reports have looked at antipsychotics and SCD due to prolongation of the QT interval. The first, in the February Journal of Clinical Psychopharmacology, was a randomized, controlled, parallel group study with a fixed sequence for all patients. The senior author, Edmund Harrigan, M.D., and colleagues at Pfizer Global Research and Development in New London, Conn., followed 183 men and women between the ages of 18 and 59 with a stable psychotic disorder. Patients were tapered from their existing therapy and after a washout period were randomized to haloperidol, thioridazine, ziprasidone, quetiapine, olanzapine, or risperidone. Blood levels were taken to establish peak drug concentrations, and ECGs were recorded at the peak level of each drug in each patient and compared with baseline ECGs.
All six antipsychotics were associated with measurable prolongation of the QT interval. The largest change was seen with thioridazine (an increase in the QTc of 30.1 milliseconds), followed by ziprasidone (15.9 ms increase), haloperidol (7.1 ms increase), quetiapine (5.7 ms increase), risperidone (3.9 ms increase) and olanzapine (1.7 ms increase). No adverse events considered to be tied to QTc prolongation were noted in any of the patients.
The protocol was repeated with the addition of a known metabolic inhibitor specific to the cytochromes known to metabolize the individual drugs, and contrary to popular thought, QT intervals were not significantly different between metabolic inhibition and noninhibition.
A second report, in the June 28 Archives of Internal Medicine by Dutch researchers at the Erasmus Medical Center in Rotterdam, used population-based records from a database of patients from 150 general practitioners. While the database has been supported by numerous grants from pharmaceutical companies, this specific study was supported by Erasmus and the University of Groningen in the Netherlands.
The researchers reviewed all cases of death between January 1, 1995, and April 1, 2001. Within the 554 cases of SCD, current use of an antipsychotic was associated with a threefold increase in risk of SCD. Past use of an antipsychotic was not found to be associated with SCD. Of interest, SCD in users of antipsychotics tended to be higher in men and higher in those younger than age 65; however, these tendencies were not statistically significant. Unfortunately, the authors concluded, the number of individuals on specific antipsychotics was not sufficient enough for the researchers to compare rates of SCD between drugs.
Both groups of researchers concluded that potential cardiotoxicity, leading to potentially fatal arrhythmia, is a chemically relevant risk that must be balanced with the benefits of these medications. They stressed the importance of a full medical history and physical examination prior to starting antipsychotic therapy.
An abstract of “A Randomized Evaluation of the Effects of Six Antipsychotic Agents on QTc” can be accessed online at<www.psychopharmacology.com/> by following the prompts to the February issue. “Antipsychotics and the Risk of Sudden Cardiac Death” is posted online at<http://archinte.ama-assn.org/cgi/content/abstract/164/12/1293>.▪
Arch Intern Med 2004 164 1293
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Published online: 17 September 2004
Published in print: September 17, 2004
Notes
Of the common side effects associated with antipsychotic therapy, prolongation of the heart's QTc interval may be one of the least understood.
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