QTc liability

As mentioned earlier, several antipsychotics are associated with prolongation of the cardiac QTc, risk of developing torsade depointes, and sudden cardiac death. Sudden death occurs nearly twice as often in antipsychotic treated patients as in the general population with 10-15 such events in 10000 person-years of observation.59 Pimozide, sertindole, and haloperidol elicit torsade de pointes and sudden death, with thioridazine having the greatest risk. While ziprasidone prolongs the QT interval, there is no evidence that this leads to increased incidence of torsade de pointes or sudden death. There appears to be no sudden death association with olanzapine, quetiapine, or risperidone. In a population-based case-control study of 554 cases of sudden cardiac death, the current use of antipsychotics was associated with a threefold increase in risk of sudden cardiac death.60 QTc prolongation has become a major issue in the drug discovery process such that assessment of NCEs for this property occurs early in the lead optimization process while drugs like cisapride have been removed from the marketplace because of the QTc liability.

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