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Psychopharmacology (2011) 216:916

DOI 10.1007/s00213-011-2188-5

ORIGINAL INVESTIGATION

Sex difference in QTc prolongation in chronic


institutionalized patients with schizophrenia on long-term
treatment with typical and atypical antipsychotics
Fu De Yang & Xiang Qun Wang & Xiu Ping Liu & Ke Xin Zhao & Wei Hong Fu &
Xue Ru Hao & Xing Li Zhang & Guo Shu Huang & Sheng Cai Qu & Jing Shen Bai &
Xu Feng Huang & Thomas R. Kosten & Xiang Yang Zhang

Received: 12 August 2010 / Accepted: 16 January 2011 / Published online: 9 February 2011
# Springer-Verlag 2011

Abstract Materials and methods Electrocardiograms were obtained


Objective The rate-corrected electrocardiographic QT (QTc) from age- and sex-matched 456 controls and 1,006
interval may significantly increase in patients with schizo- inpatients with schizophrenia (male/female=689/317) tak-
phrenia taking antipsychotics. The objective of this natural- ing antipsychotics. QTc prolongation was defined as a
istic study was to assess the prevalence of prolonged QTc mean value of two standard deviations above the controls.
interval in a large population of inpatients with chronic The adjusted relative risk was calculated using logistic
schizophrenia and to explore QTc relationship with demo- regression analysis.
graphic variables and prescribed treatments. Results QTc prolongation was present in 45 (4.5%) of
1,006 patients overall. Fewer men (3.2%, 22 of 689) than
women (7.3%, 23 of 317) displayed QTc prolongation
F. D. Yang (*) : X. Q. Wang : X. P. Liu : K. X. Zhao : (p<0.004). Moreover, QTc intervals were shorter in male
W. H. Fu : X. R. Hao : X. L. Zhang : G. S. Huang : S. C. Qu : (39131 ms) than female subjects (40037 ms) (p<0.001).
J. S. Bai
Beijing HuiLongGuan Hospital,
Clozapine was found to produce a longer QTc intervals
Beijing 100096, Peoples Republic of China compared to risperidone and typical antipsychotics. Fur-
e-mail: yangfd200@126.com thermore, multiple regression analysis showed that signif-
icant predictors for QTc prolongation were comorbid
X. F. Huang
Centre for Translational Neuroscience, School of Health Sciences,
cardiovascular disease, antipsychotic types, sex, and age
University of Wollongong, (all p<0.01).
Wollongong, Australia Conclusion Our present findings suggest that there are sex
differences in the prevalence of QTc prolongation and QTc
T. R. Kosten : X. Y. Zhang
lengthening in schizophrenia. Antipsychotic types are risk
Menninger Department of Psychiatry and Behavioral Sciences,
Baylor College of Medicine, factors for QTc prolongation, and risks are substantially
Houston, TX, USA higher for clozapine.

T. R. Kosten (*)
Keywords Schizophrenia . Antipsychotics .
VA Medical Center,
Research Building 110, Room 229, 2002 Holcombe Boulevard, QT prolongation . Electrocardiography
Houston, TX 77030, USA
e-mail: kosten@bcm.edu

X. Y. Zhang (*) Introduction


VA Medical Center,
Research Building 109, Room 130, 2002 Holcombe Boulevard,
Houston, TX 77030, USA The QT interval is the sequence of the electrocardiogram
e-mail: xyzhang@bcm.edu (ECG) from the beginning of the QRS complex to the end
10 Psychopharmacology (2011) 216:916

of the T wave and represents the temporal equivalent of patients with schizophrenia. The current study sought to
ventricular depolarization and repolarization. Its value further investigate sex differences in the rates and correlates
corrected for heart rate is referred as corrected QT interval of QTc interval prolongation with schizophrenia, while
(QTc) (Sumi et al. 2007). Prolongation of this interval is using a genetically more homogeneous Han Chinese
considered a marker of the arrhythmogenic potential of a inpatient population.
drug specifically linked to an increased risk of ventricular
tachyarrhythmia torsade de pointes (TdP) leading to
sudden cardiac death (SCD) (Zemrak and Kenna 2008). Materials and methods
Antipsychotic drugs are among medications associated
with prolongation of the QTc interval (Glassman and Subjects
Bigger 2001; Mackin and Young 2005; Stllberger et al.
2005; Zemrak and Kenna 2008; Van Noord et al. 2009). For In a cross-sectional naturalistic study, all inpatients were
example, Warner et al. (1996) found QTc prolongation approached in the Beijing HuiLongGuan Hospital, a
(>420 ms) in 23% of inpatients with chronic schizophrenia Beijing City-owned psychiatric hospital. The recruitment
compared with 2% of age-matched, drug-free controls. criteria of the patients included (1) meeting DSM-IV
Reilly et al. (2000) reported an 8% prevalence for QTc schizophrenia criteria, (2) duration of illness for at least
prolongation in 495 psychiatric patients, the majority of 2 years, (3) receiving stable oral doses of antipsychotic
whom were prescribed antipsychotics. Furthermore, there drugs for at least 6 months, and (4) the stable clinical
are marked differences in QTc prolongation caused by symptoms. Patients with first-episode or acute exacerba-
different antipsychotic agents (Haddad and Anderson tion were excluded.
2002). For example, typical antipsychotics are recognized All together, 1,006 Chinese Han patients (male/female=
as having a greater risk of QTc interval prolongation than 689/317) meeting the inclusion criteria were recruited,
are atypical antipsychotics (Vieweg 2003; Zemrak and without a sex selection bias. Diagnoses were made by two
Kenna 2008). Harrigan et al. (2004) reported the effects of investigating psychiatrists after reviewing all medical
six antipsychotics on the QTc interval both in the absence records available, which usually included many years of
and presence of metabolic inhibition using a prospective, treatment. The study was approved by the ethics committee
randomized design. All treatment groups in the study had a of the hospital, and patients signed a written informed
mean increase in QTc interval from baseline. The mean consent.
QTc interval change was greatest in the thioridazine group, All patients were chronic, with a mean duration of illness
following by ziprasidone, haloperidol, quetiapine, risper- of 24.011.3 years and aged between 25 and 75 years
idone, and olanzapine. A most recent study cross- (mean 50.211.6 years). Antipsychotic drug treatment the
sectionally examined the risk of QTc prolongation of patients have been taking consisted mainly of monotherapy
antipsychotic drugs in a large clinical sample from Japan, with clozapine (n=365), risperidone (n=184), and typical
showing that chlorpromazine, intravenous haloperidol, and antipsychotics (n=457). Among patients on typical anti-
sultopride were associated with an increased risk of QTc psychotics, 158 were on perphenazine, 89 on chlorproma-
prolongation, whereas the second-generation antipsychotic zine, 67 on sulpiride, 66 on haloperidol, and 77 on other
drugs (i.e., olanzapine, quetiapine, risperidone, and zote- typical antipsychotics. A mean daily dose of antipsychotics,
pine), mood stabilizers, benzodiazepines, and antiparkinso- including both the first- and the second-generation anti-
nian drugs did not prolong the QTc interval (Ozeki et al. psychotics, was converted to approximate daily mean
2010). However, another recent cross-sectional study found chlorpromazine milligram equivalents for each subject
that only 10 patients (6%) had a prolonged QTc interval in using standard guidelines (Woods 2003). Mean antipsy-
all inpatients (n=171) in a Spanish long-term psychiatric chotic dose (in chlorpromazine equivalents) was 324
hospital. After controlling for significant variables, the 239 mg/day. The average body mass index of the patients
effects of antipsychotic compound or class on the mean was 24.15.0 kg/m2.
QTc interval were not evident (Ramos-Ros et al. 2010). Subjects aged 2575 years living in one of the small
Thus, the picture emerges that the effects of typical and communities in Chang-Ping district in Beijing, China were
atypical antipsychotics on QTc prolongation deserve further eligible for the present study. Those responding to local
investigations. media advertisements for free ECG test and to physician
There are well-known sex-related differences in QTc referrals were screened for eligibility. Following a tele-
interval in normal human population (Vieweg et al. 2009). phone interview to evaluate eligibility, potential participants
However, no study has examined sex differences in QTc were invited for baseline screening. A complete medical
interval in schizophrenia. Furthermore, few studies address history was taken at baseline. All participants were
the prevalence of QTc interval prolongation in Chinese interviewed by trained investigators, using a detailed
Psychopharmacology (2011) 216:916 11

questionnaire including general information, sociodemo- as the return to TP isoelectric baseline by the tangential
graphic characteristics, smoking behavior, and medical and method (Perkimki et al. 1995). At least two consecutive
psychological conditions. Four hundred and fifty-six cycles were measured in each of the 12 leads, and the mean
normal controls (male/female=306/150; mean age, 50.0 value of the consecutive cycles of each lead was calculated.
12.1 years) were recruited, and matched for age and sex. The mean QT interval was calculated from the mean value
We used this group to establish values for the upper limits of the consecutive cycles of each lead. Bazetts formula
of normal for measurements of QTc interval. Inclusion (QTc=QT/RR) was used to obtain heart rate-corrected (c)
criteria were an absence of cardiovascular disease. These values of QT intervals (Bazett 1920), where QTc is the QT
participants were studied by the same methods as for interval corrected for heart rate, and RR is the interval from
patients. Psychiatric disorders were ruled out among the onset of one QRS complex to the onset of the next QRS
controls by psychiatric review evaluation conducted by a complex, measured in seconds, often derived from the heart
psychiatrist. They also had a negative history of psychiatric rate (HR) as 60/HR (here, QT is measured in milliseconds).
disorder in their first-degree relatives. To estimate intra-observer variability, two copies of a
All subjects were Han Chinese being recruited at the random sample of ten ECGs were taken and the QT
same period from Beijing area. A complete medical history interval was measured again. The relative difference (mean
and physical examination and laboratory tests were absolute difference in percentage of mean measured value)
obtained from patients and control subjects. All subjects was 3.8% for the mean QT interval.
were in physical health, and any subjects with abnormalities
were excluded. Neither the patients with schizophrenia nor Statistical analyses
the control subjects suffered from illegal drug substance
abuse/dependence. All subjects gave signed, informed A threshold figure for QTc lengthening was defined as two
consent to participate in the study, which was approved standard deviations above the mean value seen in the
by the Institutional Review Board, Beijing HuiLongGuan healthy reference group (Reilly et al. 2000). All electro-
Hospital. Demographic data for patients and normal cardiograms showing QTc lengthening on initial analysis
controls are summarized in Table 1. and all electrocardiograms identified by the automated
machine analysis alone as showing lengthened QTc were
Procedure reanalyzed twice and only included in the QTc-lengthening
group if the mean of the two readings was above or equal to
An ECG was recorded in the morning between 9:00 and the threshold value. The overall point prevalence of QTc-
11:00 after the subjects had rested for about 10 min in the interval lengthening was calculated in psychiatric patients.
supine position: 12-lead recording on a MAC 1200 ST The prevalence of QTc prolongation by sex was
ECG machine (GE Medical System, Germany) with 10- analyzed by the MantelHaenzsel common odds ratio
mm/mV amplitude, paper speed of 25 mm/s, and standard (OR) test. T tests for the continuous variables and chi-
lead positions. Only ECGs with sinus rhythm were used in square tests for the categorical variables were performed. A
the study, and a minimum of nine leads were required. The stepwise selection logistic regression model with the
measurements were performed manually with a calibrator response variable QTc prolongation was used to examine
by an experienced observer blinded to the clinical data of the all significant predictors of the presence of QTc
the patients. The QT intervals were measured from the prolongation. Furthermore, relationships between length of
onset of the QRS complex to the end of the T wave, defined QTc interval and the independent variables such as sex,
age, duration of illness, type, comorbid cardiovascular
disease (CVD) and dose (chlorpromazine equivalent) of
Table 1 Electrocardiograms in schizophrenia and normal controls antipsychotic drugs, combined antipsychotics, and com-
grouped by sex bined antidepressants used multivariate regression analyses
Groups Sex RR (ms) QTc (ms) with dummy variable coding for categorical variables like
sex. Two-tailed significant values were used, and statistical
Schizophrenia Male (n=689) 1,310220 391.230.9 significance was defined as p<0.05.
Female (n=317) 1,330230 399.736.6
Normal controls Male (n=306) 1,200150 404.319.9
Female (n=150) 1,210200 409.518.4 Results

QTc is the QT interval corrected for heart rate, and RR is the interval
Electrocardiograms were examined from 456 healthy
from the onset of one QRS complex to the onset of the next QRS
complex, measured in milliseconds, often derived from the heart rate volunteers and 1,006 patients. According to the Bazetts
(HR) as 60/HR [here, QT is measured in milliseconds] formula, the RR interval and the QT interval adjusted for
12 Psychopharmacology (2011) 216:916

the length of the RR interval for men and women were receiving high-dose antipsychotic treatment (800 mg/day
shown in Table 1. in chlorpromazine equivalents; n = 63) did not show
Based on the definition of QTc interval prolongation by significant difference in QTc prolongation than those (n=
Reilly et al. (2000) and by Warner et al. (1996), the 943) receiving low-dose antipsychotic treatment (394.7
threshold figure for QTc lengthening was 444.1 ms for men 34.2 vs. 393.933.1 ms, p>0.05).
and 446.3 ms for women in our present study. As presented Logistic regression analysis showed that the antipsy-
in Table 2, QTc prolongation was present in 45 (4.5%) of chotic type was a significant risk factor for QTc prolonga-
1,006 patients overall. Fewer men (3.2%, 22 of 689) than tion (2 =3.76, p<0.05, OR=1.21; 95% CI, .971.56),
women (7.3%, 23 of 317) displayed QTc prolongation (2 = whereas the dose and duration of treatment of antipsychotic
8.39, df=1, p=0.004). This difference remained significant drug, combined antipsychotics, and combined antidepres-
after using logistic regression to adjust for the character- sants were not risk factors for QTc prolongation. Further
istics in Table 2 (2 =6.64, p<0.01; adjusted OR=2.17; analysis showed that there was a significant difference in
95% confidence interval (CI), 1.154.02). Moreover, QTc QTc interval among patients with schizophrenia treated
intervals were shorter in male (39131 ms) than female with clozapine (39728, n=365), risperidone (38937, n=
subjects (40037 ms) by about 9 ms (F=14.6, df=1, 1004, 184), and typical antipsychotics (39235, n=457) (F=3.96,
p<0.001). Table 2 showed that patient with schizophrenia df=2, 1002, p <0.02). Posthoc tests showed that the
had an excess of cardiovascular disease (9.9%). QTc clozapine had higher QTc interval than both the risperidone
interval prolongation was more common in those patients (p<0.009) and typical antipsychotic groups (p<0.04).
with than without cardiovascular disease (F=7.94, p< However, no significant difference in QTc interval was
0.005). Furthermore, almost twice the proportion of patients noted between the risperidone and typical antipsychotic
with QTc prolongation were taking combined antidepres- subgroups (p=0.29). On examination of individual anti-
sant treatment (13.3% vs. 6.2%; 2=3.53, p=0.06). psychotics, clozapine was found to increase the risk of QTc
However, there was no significant difference in any other prolongation, and sulpiride was found to have a trend
variables, including age, duration of illness, type and dose towards a significant QTc prolongation after the variables in
of antipsychotic drugs, combined antipsychotics, and Table 2 including CVD were controlled for (Table 3).
combined antidepressants, between the QTc prolongation However, risperidone, perphenazine, chlorpromazine, and
and non-QTc prolongation groups. In addition, patients haloperidol had no significant effect on the QTc prolonga-

Table 2 Characteristics of patients with schizophrenia with or without QTc prolongation

Characteristic All patients (n=1,006) QTc prolongation (n=45) non-QTc prolongation (n=961) t or 2 P value

Gender 8.39 0.004


Female 317 (31.5%) 23 (51.1%) 294 (30.6%)
Male 689 (68.5%) 22 (48.9%) 667 (69.4%)
Age (years) 50.211.6 51.814.0 50.111.5 0.94 0.35
Duration of illness 24.011.3 24.312.6 24.011.2 0.17 0.87
Antipsychotics 1.16 0.28
Atypicals 549 (54.6%) 21 (46.7%) 528(54.9%)
Typicals 457 (45.4%) 24 (53.3%) 433(45.1%)
Daily AP dose (mg) 324239 301230 325240 0.67 0.61
(CPZ equivalent)
Combined antipsychotics 0.03 0.85
Yes 82 (8.2%) 4 (8.9%) 78 (8.1%)
No 924 (91.8%) 41(91.1%) 883 (91.9%)
Combined antidepressant 3.53 0.06
Yes 66 (6.5%) 6 (13.3%) 60 (6.2%)
No 940 (93.5%) 39 (86.7%) 901 (93.8%)
Comorbid cardiovascular disease
Yes 100 (9.9%) 10 (22.2%) 90 (9.4%) 7.94 0.005
No 906 (90.1%) 35 (77.8%) 871 (90.6%)

Combined antipsychotics means that two or more antipsychotics have been used. Combined antidepressant means an antidepressant with an
additional antipsychotic agent
Psychopharmacology (2011) 216:916 13

Table 3 Result of logistic


regression analysis on the risk of Unadjusted relative risk (95% CI) Adjusted relative risk (95% CI)
QTc prolongation for each
antipsychotic drug Age 1.01(0.991.04) 0.97(0.931.02)
Sex 3.49(1.627.55)* 3.48(1.587.59)*
Duration of illness 0.99 (0.961.02) 0.92(0.881.01)
Dose (CPZ) 1.00 (0.9901.01) 0.96 (0.921.01)
Combined antipsychotics 1.02 (0.871.20) 0.93 (0.761.18)
Combined antidepressants 0.90 (0.362.25) 0.56 (0.152.67)
Clozapine (n=365) 3.50 (1.2110.17)** 3.77 (1.2211.21)**
Risperidone (n=184) 1.16 (0.941.43) 1.19 (0.941.51)
Perphenazine (n=158) 1.08 (0.661.77) 1.18 (0.712.16)
Chlorprozamine (n=89) 1.74 (0.595.16) 1.91 (0.625.89)
Sulpiride (n=67) 1.20 (0.961.49) 1.32 (0.921.81)***
CPZ chlorpromazine
Haloperidol (n=66) 1.03 (0.631.68) 0.98 (0.921.02)
*p<0.01; **p<0.05; ***p=0.08

tion. In addition, Table 4 showed QTc interval measure- 239 mg/day) and a low frequency of antipsychotic poly-
ments for each drug by sex along with the percent that pharmacy (8.2%) and coadministered antidepressant
showed longer QTc interval measurements and the longest (6.5%), which have been found to be associated with QTc
single QTc interval for each drug. prolongation. Furthermore, whether the race or ethnic
In the stepwise selection model of the multiple linear origin is a risk factor is still unknown. In addition, one
regression analysis, CDV and antipsychotic types were found limitation of studies of QTc lengthening is the variation in
to lengthen the QTc interval (t=4.58, p<0.001; t=3.32, p< cut-off values for abnormalityfrom 420 to 470 ms
0.001). Sex and age were also indicated as a risk factor for (Warner et al. 1996; Reilly et al. 2000), which means that
QTc lengthening (t=3.36, p<0.001; t=3.05, p<0.01). different investigators have used different criteria to define
QTc prolongation. Due to the heterogeneity in cut-off
values for the definition of QTc prolongation, as well as
Discussion settings and design, a comparison across studies is limited.
In our present study, patients with schizophrenia have
The prevalence of QTc prolongation in our sample of 4.5% been shown to have an excess of cardiovascular disease
is in the middle of the reported range (0.538%) of existing (9.9%). Furthermore, QTc intervals were more common in
worldwide prevalence estimates (Ramos-Ros et al. 2010). those patients with than without cardiovascular disease (p<
This relatively low frequency of 4.5% is surprising, taking 0.005). Since cardiovascular disease is an important cause
into account that the patients had a high mean age (50.2 of QT interval prolongation and arrhythmia (Khan et al.
11.6 years) and a long duration of illness (24.011.3 years). 1998), this is likely to be a significant factor for QT interval
However, in our current study, the patients had low doses of prolongation in the current study. Also, our study showed
antipsychotic drugs (chlorpromazine equivalent, 324 that female patients had a higher prevalence of QTc

Table 4 QTc interval


measurements for each drug Drug Sex QTc (ms) Longer QTc (%) Longest single QTc
by sex
Clozapine Male (n=244) 393.527.2 36.9 462
Female (n=121) 405.726.4 43.0 484
Risperidone Male (n=104) 387.032.9 31.7 462
Female (n=80) 393.342.3 32.5 506
Perphenazine Male (n=124) 393.633.2 36.3 484
Female (n=34) 394.445.0 38.2 462
Chlorprozamine Male (n=69) 383.229.9 24.6 451
Female (n=20) 402.145.2 35.0 506
Sulpiride Male (n=45) 404.031.6 48.9 484
Female (n=22) 400.547.6 45.5 484
Haloperidol Male (n=55) 386.235.5 25.5 473
Female (n=11) 405.034.0 45.5 440
14 Psychopharmacology (2011) 216:916

prolongation, as well as longer QTc intervals than male retrospective chart review. However, Warner and Hoffmann
patients, which is consistent with previous studies (Vieweg (2002) reported that at therapeutic doses, all antipsychotics
2002; Lin et al. 2004; Sumi et al. 2007; Ramos-Ros et al. considered except clozapine induced TdP and/or QTc
2010). However, some studies reported no sex difference in interval prolongation. Up to date, however, data regarding
QTc prolongation (Ozeki et al. 2010). Other studies failed the relation of adverse cardiac effects to clozapine dose,
to detect female gender as a significant risk factor (Reilly et rate of dose escalation, or demographic variables are
al. 2000; Chong et al. 2003; Rettenbacher et al. 2005), or lacking. Clozapine use has also been associated with
even QTc prolongation was found more commonly in male substantial weight gain, with an increase in serum triglyc-
patients than in female patients (Ozeki et al. 2010). eride levels, and with an increased risk for diabetes
Female gender is known to be a risk factor for QTc (Flanagan 2008), which may independently augment the
prolongation (Taylor 2003; Vieweg et al. 2009). Several risk of cardiovascular disease (Merrill et al. 2005).
studies have shown that women are more prone to drug- Although, currently, there is no enough evidence to predict
induced TdP. For example, women accounted for 70% with confidence the risk of a significant adverse cardiac
cases of TdP related to cardiovascular drugs which were effect in patients being treated with clozapine (Merrill et al.
identified in an extensive survey (Haddad and Anderson 2005), our current results provide robust evidence that
2002). The increased incidence in women remained clozapine may increase the risk of QTc prolongation. When
irrespective of the presence of other risk factors. The clozapine is prescribed, doctors and patients need to take
increased vulnerability of women to TdP may reflect the precautions to minimize the proarrhythmic risk due to QTc
fact that the QTc interval was longer in women than in men prolongation, and measures to reduce the risk should be
by about 20 ms (Stramba-Badiale et al. 1997). However, adopted.
the possible mechanisms in sex difference in QTc prolon- There are two points that need to be mentioned. First,
gation are still unknown. Some recent studies in humans although the Bazett correction formula was chosen, there is
highlighted a close relationship between the circulating no agreement about the most appropriate formula as
levels of androgens and QTc interval in men (van Noord et different formulae can over- or under-correct for heart rate
al. 2010). For example, the sex differences in the QTc under different circumstances. Second, although QT inter-
interval are not present in young children, whereas at the val prolongation may lead to cardiac arrhythmias, there is
time of onset of puberty the duration of the QTc interval in evidence that some anti-arrhythmic drugs may prolong the
boys shortens, which results in a longer QTc interval in QT interval (Wehrens 2006). Furthermore, although anti-
adult women compared to men (Rautaharju et al. 1992; psychotic drugs are among medications associated with
Stramba-Badiale et al. 1992). These sex differences remain prolongation of the QTc interval, which in turn may be
detectable until around the age of 50 years (Rautaharju et considered to be associated with an increased risk of
al. 1992). Since the period between puberty and 50 years of cardiac arrhythmias TdP and sudden death (Zemrak and
age coincides with the highest circulating levels of Kenna 2008; Van Noord et al. 2009), there is a lack of
androgens in males, male sex hormones may play a role evidence directly linking antipsychotic drugs to TdP and
in the shorter QTc interval in men (van Noord et al. 2010). SCD. The relationship between the antipsychotic treat-
One most recent study also showed that lower QTc intervals ments, ventricular tachyarrhythmia TdP, and SCD in
in men with higher serum testosterone levels could be due schizophrenia warrants further investigation.
to the association of serum testosterone with prolongation Also, it is worthy of mentioning that almost twice the
of the RR interval (van Noord et al. 2010). Taken together, proportion of patients with QTc prolongation were taking
these data suggest that testosterone might be an important combined antidepressant treatment (13.3% vs. 6.2%; 2 =
regulator of QTc interval, which might explain the sex- 3.53, p=0.06). Although a significant value of p=0.06 only
related differences in QTc interval. However, we did not showed a statistical trend, this is possibly due to a small
measure the levels of androgens in our present study. sample size of patients (n=6) with QTc prolongation who
Whether sex difference in QTc interval is associated with were taking combined antidepressant treatment. Some
sex hormonal status deserves further investigation. authors reported that antidepressant drugs, particularly the
Our present study showed a significant difference in QTc tricyclic antidepressants can prolong QTc interval (Elming
prolongation between antipsychotic types. Interestingly, et al. 2003). Furthermore, the combination of antipsychotic
clozapine was found to produce a longer QTc intervals and antidepressant agents seems to have addictive effects
compared to risperidone and typical antipsychotics. Only a on QTc interval (Reilly et al. 2000; Sala et al. 2005). Taken
few investigations reported the effect of clozapine treatment together, combination of antipsychotic agents with an
on electrocardiographic (ECG). Kang et al. (2000) also antidepressant may cause a significant QT prolongation.
found that clozapine may be associated with substantial However, Sumi et al. (2007) did not find significant QT
portion of patients who developed ECG abnormalities in a prolongation in their psychiatric patients after 2 weeks of
Psychopharmacology (2011) 216:916 15

treatment with antipsychotics and/or antidepressants, and population and extremely rare among patients with schizo-
the QTc interval length did not differ significantly in the phrenia. Furthermore, the patients in our present study had
monotherapy and the polytherapy groups. Therefore, the been hospitalizing for quite a long time and could not get
effects of a combined treatment of antipsychotic and access to illicit substances.
antidepressant agents on QTc interval deserve further In conclusion, our findings showed sex differences in the
investigation. prevalence of QTc prolongation, and female patients had a
On the other hand, it is commonly believed that higher prevalence of QTc prolongation, as well as longer
combined antipsychotic treatment increases QT interval QTc intervals than male patients. Antipsychotic types were
compared to monotherapy. However, in our present study, risk factors for QTc lengthening, showing that clozapine
we found that polytherapy with two or more antipsychotics was associated with increased risk of QTc prolongation and
did not seem to lead to significant QTc prolongation longer QTc intervals compared to risperidone and typical
compared to monotherapy. Based on a PubMed literature antipsychotics. Hence, in the range of the antipsychotic
search, data on the effects of antipsychotic polytherapy on drugs that we examined, the data may be useful in clinical
the QT interval appear to be limited, which were assessed decision making concerning the choice of antipsychotic
in a trial of combined therapy with clozapine and medication.
risperidone (Yagcioglu et al. 2005), in a casecontrol study
of various antipsychotic combinations (Mackin and Young Acknowledgments This study was funded by the Stanley Medical
Research Institute (03T-459 and 05T-726) and the United States
2005) and in a casecontrol study of polytherapy with two
National Institute of Health (K05-DA0454, P50-DA18827, and
atypical antipsychotics compared to atypical antipsychotic U01-MH79639).
monotherapy (Correll et al. 2009). These studies indicated
that treatment with antipsychotic polytherapy does not
appear to be associated with a significantly elevated QTc
interval or QTc dispersion. Taken together, these results References
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