Psychiatric News September 17, 2004
Volume 39 Number 18
© 2004 American Psychiatric Association
p. 26
Cardiac Risk Must Be Weighed For Patients on Antipsychotics
Jim Rosack
Of the common side effects associated with antipsychotic therapy,
prolongation of the heart's QTc interval may be one of the least
understood.
Sudden cardiac death. Recent research shows that even though the
number of documented cases in patients taking antipsychotics may be small, the
risk is real.
Since the 1960s, case reports have associated antipsychotic use with sudden
cardiac death (SCD). While the exact mechanism of action isn't known, SCD is
most likely tied to fatal arrhythmias provoked by a drug-induced, prolonged
QTc interval—a measure of the heart conduction system's refractory
period and subsequent readiness for the next heartbeat.
By the beginning of the QT interval, electrolytes have undergone a drastic
shunting from one side of the myocardial cell membrane to the other, creating
the electrical stimulus that results in contraction of the cardiac muscle. (A
QTc interval is simply a corrected interval length that is calculated from the
measured QT interval and then adjusted for the effect of the heart rate; as
rate slows, the interval normally lengthens somewhat.) In order for a
subsequent electrical stimulus to occur and create the next heartbeat, those
electrolytes must return to their starting places during the QT. If the
electrolytes do not fully return to their resting states, any subsequent
electrical stimulus will not be normal. In fact, the earlier in the QT the
next stimulus falls, the more chaotic that stimulus will be. If the stimulus
occurs early enough, the result is an uncoordinated fibrillation of the
ventricular muscle because the electrolytes are not in the correct
intracellular or extracellular positions.
Many drugs, including several antipsychotics, disrupt these transmembrane
movements of certain electrolytes, most notably the inward movement of
potassium through specific ion channels, marking the beginning of the return
to normalcy. Because the potassium cannot return to where it started, the
entire cardiac cycle is slowed down, lengthening the QT interval. Research has
shown that drugs like terfenadine (Seldane) and cisapride (Propulsid) directly
block the potassium current, especially when combined with other medications
that slow metabolic processes in the liver, such as ketoconazole
(Nizoral).
Some Antipsychotics Guilty
Terfenadine was withdrawn from the U.S. market after documented cases of
SCD due to the ventricular arrhythmia, torsades de pointes, or TdP (French for
"twisting of points," a reference to the twisting of the
directions of the complexes on an electrocardiogram that are diagnostic of the
rhythm). TdP is a chaotic and rapid ventricular tachycardia that originates in
multiple sites within one or both ventricles, causing cardiac output to
plummet toward zero quickly. Without intervention, some patients may
spontaneously return to a normal rhythm, but the risk of SCD is high.
For years the antipsychotic thioridazine (Mellaril) has been associated
with TdP-induced SCD. The newer antipsychotic sertindole, although widely
available outside the United States, was never approved for sale by the FDA
because of its association with TdP-induced SCD. Most recently, ziprasidone
(Geodon) was significantly delayed in its FDA approval process while
researchers attempted to determine whether its propensity to prolong the QT
interval was clinically significant.
While both thioridazine and sertindole have been linked to cases of SCD, no
documented cases of cardiac arrhythmias or SCD have been conclusively linked
to ziprasidone.
Evidence Builds
At least two recent reports have looked at antipsychotics and SCD due to
prolongation of the QT interval. The first, in the February Journal of
Clinical Psychopharmacology, was a randomized, controlled, parallel group
study with a fixed sequence for all patients. The senior author, Edmund
Harrigan, M.D., and colleagues at Pfizer Global Research and Development in
New London, Conn., followed 183 men and women between the ages of 18 and 59
with a stable psychotic disorder. Patients were tapered from their existing
therapy and after a washout period were randomized to haloperidol,
thioridazine, ziprasidone, quetiapine, olanzapine, or risperidone. Blood
levels were taken to establish peak drug concentrations, and ECGs were
recorded at the peak level of each drug in each patient and compared with
baseline ECGs.
All six antipsychotics were associated with measurable prolongation of the
QT interval. The largest change was seen with thioridazine (an increase in the
QTc of 30.1 milliseconds), followed by ziprasidone (15.9 ms increase),
haloperidol (7.1 ms increase), quetiapine (5.7 ms increase), risperidone (3.9
ms increase) and olanzapine (1.7 ms increase). No adverse events considered to
be tied to QTc prolongation were noted in any of the patients.
The protocol was repeated with the addition of a known metabolic inhibitor
specific to the cytochromes known to metabolize the individual drugs, and
contrary to popular thought, QT intervals were not significantly different
between metabolic inhibition and noninhibition.
A second report, in the June 28 Archives of Internal Medicine by
Dutch researchers at the Erasmus Medical Center in Rotterdam, used
population-based records from a database of patients from 150 general
practitioners. While the database has been supported by numerous grants from
pharmaceutical companies, this specific study was supported by Erasmus and the
University of Groningen in the Netherlands.
The researchers reviewed all cases of death between January 1, 1995, and
April 1, 2001. Within the 554 cases of SCD, current use of an antipsychotic
was associated with a threefold increase in risk of SCD. Past use of an
antipsychotic was not found to be associated with SCD. Of interest, SCD in
users of antipsychotics tended to be higher in men and higher in those younger
than age 65; however, these tendencies were not statistically significant.
Unfortunately, the authors concluded, the number of individuals on specific
antipsychotics was not sufficient enough for the researchers to compare rates
of SCD between drugs.
Both groups of researchers concluded that potential cardiotoxicity, leading
to potentially fatal arrhythmia, is a chemically relevant risk that must be
balanced with the benefits of these medications. They stressed the importance
of a full medical history and physical examination prior to starting
antipsychotic therapy.
An abstract of "A Randomized Evaluation of the Effects of Six
Antipsychotic Agents on QTc" can be accessed online at
<www.psychopharmacology.com/>
by following the prompts to the February issue. "Antipsychotics and the
Risk of Sudden Cardiac Death" is posted online at
<http://archinte.ama-assn.org/cgi/content/abstract/164/12/1293>.
Arch Intern Med 2004 164 1293[Abstract/Free Full Text]
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