Before approving the antipsychotic agent ziprasidone last year, the Food and Drug Administration required specific safety data on whether the drug might cause the life-threatening arrhythmia known as torsade de pointes.
The FDA’s action, which delayed the drug’s approval for 3 years, underscores growing concern about the risk of cardiovascular effects with the use of antipsychotic and other agents known to prolong the cardiac QT interval. This concern has led to withdrawal of some drugs before reaching the market (e.g., the atypical neuroleptic sertindole), the addition of “black box” warnings in the labeling of some antipsychotics, and withdrawal from the market of antihistamines terfenadine and astemizole and the GI stimulant cisapride.
Torsade de pointes is a polymorphic ventricular tachycardia (VT), a rare arrhythmia that can cause sudden death. Because torsade can occur with the use of some antipsychotics, the psychiatrist needs to consider cardiovascular safety when selecting among available agents. To help with these decisions, here is information about the documented and potential electrocardiographic features of commonly prescribed antipsychotic drugs, as well as background on QT interval prolongation and torsade de pointes.
Torsade de pointes
Named for a ballet movement, torsade de pointes describes bursts of “twisting of the points,” a variation of the morphology of the QRS vector about the isoelectric axis from positive to net negative and back again. As seen on an ECG (Figure 1), the first beat of torsade de pointes is a normal ventricular complex preceded by a P wave. This is followed by a premature ventricular contraction (PVC) with a short coupling interval. After a compensatory pause, a second normal beat is followed by a second PVC, which is the first beat of a polymorphic VT. We know tachycardia is present because the ventricular beats appear close together. We know the arrhythmia is ventricular in origin because the ventricular complexes are wide. Finally, we note the ventricular complexes vary in configuration—that is, the shape (morphology) varies from beat to beat.
Figure 1 Typical ECG features of torsade de pointes
Sinus beat with normal ventricular complex (1) followed by premature ventricular contraction (PVC) (2) with short coupling interval. After a long pause (long refractory period), another sinus beat (3) is followed by another PVC (4) with a short coupling interval. The second PVC (4) is the first beat of polymorphic ventricular tachycardiaIn torsade, the stimulus for the VT moves within the ventricle, changing its shape from beat to beat. This multifocal VT differs from the more common unifocal VT, in which all the QRS complexes appear the same.
Drug-induced torsade de pointes
Although the term torsade de pointes was first described in 1966,1 the drug-induced form of this arrhythmia has been recognized for nearly a century.
Quinidine Around 1920, cardiologists first used quinidine to help restore normal sinus rhythm in patients with atrial fibrillation, most commonly due to rheumatic heart disease.2
In 1964, Selzer and Wray3 studied the use of quinidine to convert atrial fibrillation to normal sinus rhythm in more than 200 patients seen during 4 years in a cardiopulmonary clinic. In a subgroup of eight patients, these researchers documented 10 reactions (including five documented episodes of ventricular fibrillation/ventricular flutter) among 36 syncopal episodes that developed within 1 to 6.5 hours of quinidine administration. Symptoms were nonspecific and included nausea, faintness, and feeling ill. It is now recognized that torsade de pointes was the principal rhythm disturbance in those eight patients. Syncope usually occurs early in treatment and may be found in 5% to 10% of patients taking quinidine.
TCAs and antipsychotics Tricyclic antidepressants (TCAs) and antipsychotics that have quinidine-like properties (e.g., thioridazine) also may be associated with QT interval prolongation and torsade de pointes.4-9 In high doses (particularly in overdose), TCAs may induce widening of the QRS complex. Fowler et al reported episodes of VT in five patients taking thioridazine—one of whom died.10
Mehtonen et al reported sudden unexpected deaths associated with antipsychotic or antidepressant drugs among 31 women and 18 men in a survey of autopsies performed from 1985 to 1988 in Finland. The authors documented therapeutic use of phenothiazines in all but 3 of the 49 cases. Thioridazine was involved in more than half the deaths. In 15 of the deaths, thioridazine was the only antipsychotic drug taken. Drugs other than thioridazine were documented in only 5 of the 49 sudden cardiac deaths.11
Figure 2 Normal ECG in sinus rhythm
In this typical lead II of a surface ECG, the P wave (atrial depolarization) leads to right and left atrial contraction and the QRS complex (ventricular depolarization) leads to left and right ventricular contraction. The ST segment represents isoelectric ventricular repolarization, and the T wave represents directional repolarization. The QT interval includes both ventricular depolarization (QRS complex) and ventricular repolarization (JT interval, or ST segment plus T wave).