Two drugs have the Food and Drug Administration boxed warning for prolonged QTc and TdP: thioridazine and mesoridazine. In addition, six medications carry a warning/precaution about prolonged QTc: ziprasidone, paliperidone, IV haloperidol, iloperidone, quetiapine, and asenapine. “Even though haloperidol is not approved for IV administration, FDA created a label warning for IV haloperidol knowing that many clinicians are using it,” she said. “The label advises clinicians to use particular caution in treating patients who have high risk for QTc prolongation and TdP.”
All antipsychotics prolong the QTc by some amount, but differences exist between agents. One prospective, randomized trial showed that ziprasidone and thioridazine prolonged the QTc more than four other antipsychotic drugs (J Clin Psychopharmacol. 2004;24:62-9). “I think the important point is that nobody had a QTc over 500 milliseconds and nobody had TdP,” Dr. Ernst said. “Some data estimate that even if the QTc is 600 milliseconds, the rate of a life-threatening event is probably no more than one in 4,000, so it’s very rare.”
In a more recent meta-analysis, researchers compared 15 antipsychotics among 43,049 adults participating in 212 clinical trials (Lancet. 2013;382:951-62). They found that the following drugs were not associated with QTc prolongation, compared with placebo: lurasidone, aripiprazole, paliperidone, and asenapine. A separate meta-analysis comparing numerous different antipsychotics in children found that ziprasidone was the only one to be associated with an increased risk of QTc prolongation (J Am Acad Child Adolesc Psychiatry. 2015:54:25-36).
There are also data to suggest an association between antipsychotic use and an increased risk of ventricular arrhythmia or sudden cardiac death. The relationship between prolonged QTc and sudden cardiac death is unclear. One large retrospective cohort study found that all antipsychotics carried a 2.5-fold increased risk of sudden cardiac death, compared with the general population not taking those agents (N Eng J Med. 2009;360[3]:225-35). “Risk seemed to be dose related,” Dr. Ernst said. All antipsychotics carry a boxed warning for increased mortality in elderly patients with dementia-related psychosis. Most of the deaths reported appear related to cardiovascular and infectious causes.