Antipsychotic drugs: Prolonged QTc interval, torsade de pointes, and sudden death

Objective: The authors review the mechanisms and establish the risk of tors ade de pointes and sudden death with antipsychotic drugs. Method: They present a review of original concepts, the distinction between familial and drug-induced cases of torsade de pointes, and the recognition of the role of noncardiac drugs in torsade de pointes and sudden death. Th ey review the evidence linking QTc interval prolongation, potassium channel s, and torsade de pointes from both the long QT syndrome and drugs. They ex amine the risk for torsade de pointes from antipsychotic drugs and estimate the frequency of sudden death on the basis of epidemiological data in norm al and schizophrenic populations. Results. All drugs that cause torsade de pointes prolong the QTc interval a nd bind to the potassium rectifier channel, but the relationships are not p recise. Prediction of torsade de pointes and sudden death can be improved b y examining dose dependency, the percent of QTc intervals higher than 500 m sec, and the risk of drug-drug interactions. Although sudden unexpected dea th occurs almost twice as often in populations treated with antipsychotics as in normal populations, there are still only 10-15 such events in 10,000 person-years of observation. Conclusions: Although pimozide, sertin-dole, droperidol, and haloperidol ha ve been documented to cause torsade de pointes and sudden death, the most m arked risk is with thioridazine. There is no association with olanzapine, q uetiapine, or risperidone. Ziprasidone does prolong the QT interval, but th ere is no evidence to suggest that this leads to torsade de pointes or sudd en death. Only widespread use will prove if ziprasidone is entirely safe, T o date, all antipsychotic drugs have the potential for serious adverse even ts. Balancing these risks with the positive effects of treatment poses a ch allenge for psychiatry.