Risperidone and Corrected QT-interval Prolongation in Surface Electrocardiogram
Risperidone is an antipsychotic medication suspected of causing
QT prolongation and several cases are reported in this regard. However, available
information with respect to its effect on QT interval is limited especially
from different settings. The aim of this study was to assess the effect of risperidone
in lengthening QT interval among psychotic patients referred to a psychiatric
ward in North West of Iran. A controlled cohort study was conducted on psychotic
patients referred to Razi Hospital from April 2010-2011. The treatment cohort
groups were 120 patients receiving risperidone for the first time during their
treatment. The comparison cohort included 60 control patients who were not receiving
risperidone. An electrocardiogram was obtained from all the study participants
at admission time, one week afterwards and at discharge. Corrected QT interval
(QTc) was determined using Bazetts
formula. QTc dispersion was calculated as MaxQTc-MinQTc.
Data were analyzed using SPSS statistical software package. The mean change
in QTc measures over time was not statistically significant in control group.
However, QTc increment was statistically significant over time in V1 and V3
leads in risperidone group. Multivariate longitudinal data analysis, using between-effects
model, to manage multiple measurements over time found the overall QTc trend
to be different between the groups (p<0.01). Risperidone may have significant
effects on QT interval and QT dispersion. Physicians and psychiatrists should
be aware that prolonged QTc interval is a potential indicator of cardiovascular
risk and should be cautious in prescribing potentially QT-prolonging medications,
at least to certain patients.
Received: January 25, 2012;
Accepted: August 11, 2012;
Published: October 06, 2012
The QT interval is defined as a measure of the time between the start of the
Q wave and the end of the T wave in the heart's electrical cycle. It was in
1957 that the first case of Long QT syndrome (LQTS) was presented from Norway
(Jervell and Lange-Nielsen, 1957). It is characterized
by a prolonged QT interval in the electrocardiogram, syncope and sudden cardiac
death due to ventricular tachyarrhythmias, typically torsades de pointes (Morita
et al., 2008). The QT interval is the duration of ventricular depolarization
and repolarization, caused by trans-membrane flow of ions. It should be taken
into account that QT interval prolongation is not necessarily associated with
torsades de pointes. Other etiologies include antiarrhythmic drugs such as amiodarone
and procainamide (Bernardi et al., 1998; Welch
and Chue, 2000). Potential lengthening of the QT interval induced by atypical
antipsychotic drugs have been the source of much concern, nevertheless, the
conventional antipsychotic medications available nowadays are significantly
more cardiotoxic, particularly agents in the butyrophenone and phenothiazine
classes (Welch and Chue, 2000). These effects may be
significant in the presence of predisposing factors. Risperidone is an antipsychotic
medication suspected of causing QT prolongation and several cases are reported
in this regard. However, available information with respect to its effect on
QT interval is limited especially from different settings (Campbell
et al., 1999; Suzuki et al., 2012).
The aim of this study was to assess the effect of risperidone in lengthening
QT interval among psychotic patients referred to a psychiatric ward in North
West of Iran.
MATERIALS AND METHODS
A controlled cohort study was conducted on psychotic patients referred to Razi
Hospital from April 2010-2011. All the patients were admitted to Psychiatry
Ward of the Razi Hospital in Tabriz, Iran. The treatment cohort groups were
120 patients receiving risperidone for the first time during their treatment.
The comparison cohort included 60 control patients who were not receiving risperidone.
The comparative group was made up of psychiatric patients presumed of lacking
changes in their medication during the course of the study. They were frequency
matched for gender and age. Both the test and control group lacked a known history
of cardiovascular diseases or electrolyte imbalance disorders. Patient received
a dose of 3-8 mg risperidone based on clinical decision making. An electrocardiogram
was obtained from all the study participants at admission time, one week afterwards
and at discharge. QT interval was measured using 10X zoom screen caliper software.
Measurements were done by two electrophysiology nurses trained for this purpose
with good pretested inter-rater reliability to ensure reproducibility of measurement.
They were kept blind to study purpose and patient grouping. A pilot assessment
reliability study was conducted on 10 patients showing appropriate inter-rater
agreement between the nurses. Measurements were done on three precordial leads
(V1, V3 and V5) and three limb leads (I, aVR and aVF). In three consecutive
cycles with stable baseline without noise, QT measurements were averaged to
represent QT interval in that lead. QTc was determined using Bazetts interval
formula (Bazett, 1920):
where, PR is the interval between wave P and wave R in electrocardiogram, QTc
dispersion was calculated as:
Statistical analysis: Data were entered into computer and analyzed using
SPSS statistical software package version 16. Bivariate tests such as t-test
and chi-square test, as well as longitudinal multivariate data analysis were
used. A p-value lower than 0.05, was considered as statistical significance.
Study protocol was approved by the regional committee of ethics in Tabriz University
of Medical sciences. Written informed consent was obtained from all guardians
legally responsible for giving consent as well as those patients who were not
psychotic at the time of recruitment.
Patients with following conditions were excluded from the study:
||Hypokalemia, hypocalcaemia, or hypomagnesaemia at baseline
||History of malignancy
||History of using amiodarone, antiretroviral agents, antifungal agents,
quinolone antibiotics, antiarrhythmic medications and risperidone
Groups had equal distribution according to gender. Patients in treatment group
were a bit older but had lower diastolic blood pressure, systolic blood pressure
and lower heart rate. Mean body mass index was similar between groups. Further
details are presented in Table 1. The mean change in QTc measures
over time was not statistically significant in control group. But QTc increment
was statistically significant over time in V1 and V3 leads risperidone group.
Descriptive statistics of QTc measurements and bivariate between-group comparison
test results at each time point are given in Table 2. Contrary
to RR, the QTc change trend was found to have significantly different slopes
between the two groups. It can be found in this table that prolonged QTc was
observed more in risperidone group mostly after one week of treatment and after
The correlations among QTc measures on different leads can be assessed in Fig.
1. It can be seen that QTc measurements in various cardiac leads are highly
correlated in pairs. The Risk Ratios (RR) of having QTc>450 at discharge
time for those using risperidone over control group were 1.08, 1.2 and 1.2,
respectively for V1, V3 and V5 leads. None of the RRs were statistically different
from 1 as null effect.
Multivariate longitudinal data analysis, using between-effects model, to manage
multiple measurements over time found the overall QTc trend to be different
between the groups (p<0.01).
|| Background variables compared between the two study groups
|Values are Mean±SD, #values are in numbers
|| Electrocardiographic measures compared between groups at
three time points
|Values are Mean±SD, V(1,3,5): Chest leads in electrocardiogram,
avF and avR: Two of the augmented limb leads in electrocardiogram
||Scatter plots of the QTC measures on different leads of electrocardiogram
from patients receiving risperidone for the first time in Razi Hospital,
Tabriz, Iran, V (1,3,5): Chest leads in electrocardiogram, avF and avR:
Two of the augmented limb leads in electrocardiogram
Long QT syndrome (LQTS) was initially described as a rare inherited disease,
a known cause of sudden death due to torsades de pointes, but many patients
were later identified and the mechanisms responsible for tachyarrhythmias are
common to other sudden death syndromes (Morita et al.,
Risk factors of prolonged QTc interval are studies both in general populations
and specific disease groups (Benoit et al., 2005;
Brown et al., 2001; Giunti
et al., 2007; Grandinetti et al., 2005;
Reinsch et al., 2009). In a large national health
survey in USA 8561 subjects over 40 years of age, underwent an electrocardiographic
examination through which age, female sex, hypocalcemia (men), hypokalemia (women)
and a history of thyroid disease and myocardial infarction (men) were found
to be associated with a prolonged QTc interval. Also, taking QT-prolonging medications
was associated with increased odds of prolonged QTc interval in both men and
women (Benoit et al., 2005; Huq,
2007). Nevertheless, another American cohort also suggested that genetic
factors may play an important role in determining QTc interval length than conventional
biochemical and metabolic CVD risk factors (Grandinetti
et al., 2005).
Antipsychotics are not always harmless medications. Other than its well knows
side effects it may affect lipid profile it have even been reported to cause
priapism. Also, these drugs are not made only for psychotic diseases (Idonije
et al., 2012; Hosseini and Polonowita, 2009;
Kilic et al., 2012). Some antipsychotics are shown
to be associated with QTc prolongation. However, methodological considerations
preclude considering any antipsychotic to be free of the risk of QTc prolongation
and dysrhythmia (Taylor, 2003).
Ravina et al. (2007) described full exposure
of an acquired Long QT Syndrome in an elderly female patient on long-term risperidone
treatment just when bradycardia due to complete AV block developed. They stated
that a combined block of the rapid and delayed components of the Ik current
and concluded that risperidone should be used with caution in female patients
prone to bradycardia (Ravina et al., 2007). Other
cases are also reported in literature. Goyal and Goyal (2003)
reported a case of symptomatic bradycardia secondary to risperidone in a young
man undergoing alcoholic withdrawal. This occurred after moderately high levels
of risperidone. Later in 2004 another case was described of acute sinus bradycardia
with frequent premature ventricular bigeminy complexes in a geriatric patient
taking an initial low starting dose of risperidone. He had normal sinus rhythm
before the risperidone was started (Tran et al.,
In a randomized clinical trial risperidone was compared with aripiprazole and
placebo for efficacy. However, the researchers also compared QTc in risperidone
with placebo. In their study three out of 100 patients in risperidone group
developed QTc prolongation (QTc>450 or 10% increase in QTc compared to baseline),
while, no one in aripiprazole or placebo groups developed such an event. The
difference was not statistically different (Potkin et
al., 2003). Considering the figures provided by the authors, the main
explanation could be sought in low statistical power of the trial. Similarly
in our study using dichotomized assessments, prolonged QTc was observed more
in risperidone group without statistical significance. Due to low incidence
of the event the study turns underpowered, but as found in our results, using
longitudinal multivariate analysis found the trend of QTc change over time to
be statistically different between groups.
In line with our hypothesis, animal studies have shown that risperidone is
a potent IKr blocker. It prolongs cardiac repolarization at clinically relevant
drug concentrations and should not be considered a no-risk alternative to older
neuro leptic agents (Drolet et al., 2003). Therefore,
clinical attention to QT prolongation should be warranted when prescribing risperidone.
Similarly, with previous studies we used Bazetts formula to adjust the
QT interval. The QT interval varies with heart rate, becoming shorter as heart
rate increases. Various correction factors have been suggested, the most commonly
used being Bazetts correction which has a wide acceptability. However,
the effect of drug itself on heart rate should be considered in interpreting
the results (Malik and Camm, 2001). Results of this
research provided consistent information that can be of help in improving the
generalizability of available evidence considering the higher variability of
clinical settings. To provide more reliable and beneficial evidence with equivalent
applicability to various clinical settings, future research in recommended to
focus on precision improvement considering larger scale studies, external validity
improvement targeting higher heterogeneity of various clinical setting as well
as long-term effectiveness studies. Investigating better alternatives of Bazetts
correction to be more appropriate for interventional studies can be another
recommendation for future research.
Risperidone may have significant effects on Q-T interval and Q-T dispersion.
Physicians and psychiatrists should be aware that a prolonged QTc interval is
a potential indicator of cardiovascular risk and should be cautious in prescribing
potentially QT-prolonging medications at least to certain patients. Before prescribing
antipsychotics that may increase the QTc interval, the clinician should ask
about family and personal history of sudden cardiac death, presyncope, syncope
and cardiac arrhythmias and recommend cardiology consultation if history is
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