Antipsychotic drugs and QT interval prolongation

The QTc prolongation by antipsychotic drugs is of major concern, especially in light of the data indicating an increased risk of sudden death in psychiatric patients taking these drugs. Sudden death in psychiatric patients could be partially attributed to drug-induced torsades de pointes and for this reason careful evaluation of QTc prolonging properties of antipsychotic drugs is needed. Antipsychotic drugs prolong QT interval usually by blocking the potassium I-Kr current. Improved understanding of ion channel structure and kinetics and its role in repolarization has tremendous impact on understanding of the mechanisms of drug-induced QT prolongation and torsades de pointes. Proarrhythmia caused by a QT-prolonging drug occurs infrequently, and usually multiple factors need to operate to precipitate such an event including a combination of two or more drugs affecting the same pathway, hypokalemia, and possibly genetic predisposition. Currently prescribed antipsychotics might cause QT prolongation ranging from 4-6 ms for haloperidol and olanzapine to 35 ms for thioridazine. The response of a patient to a drug is very individual and therefore an individualized system of drug administration and monitoring needs to be developed which takes into account baseline QTc duration and its changes after a drug was introduced. A systematic approach while stratifying psychiatric patients as those with short QTc (QTc less than or equal to 0.41 sec), borderline QTc QTC = 0.42-0.44 sec), and prolonged QTc (0.45 sec) is being proposed to improve the safety of administering antipsychotic drugs and to decrease the risk of drug-related sudden death in psychiatric patients.