CanJPsychiatry 2015;60(5):206214
In Review
Impact of Age andSex onQTProlongation in
Patients Receiving Psychotropics
Simon W Rabkin, MD, FRCPC, FACC1
1
Professor of Medicine (Cardiology), Department of Medicine (Cardiology), University of British Columbia, Vancouver, British Columbia.
Correspondence: Department of Medicine, Division of Cardiology, University of British Columbia, Level 9, 2775 Laurel Street, Vancouver, BC V5Z 1M9;
rabkin@mail.ubc.ca.
Key Words: QT interval, age,
sex, psychotropics, cardiac
sudden death
Received November 2014 and
accepted February 2015.
206 W La Revue canadienne de psychiatrie, vol 60, no 5, mai 2015
Objective: To assess older age and female sex, 2 of the major risk factors for potentially fatal
cardiac arrhythmias or sudden cardiac death in patients prescribed psychotropics, within the context
of electrocardiographic evidence of time between start of Q wave and end of T wave (QT) interval
prolongation, which is an indicator of an increased risk for potentially fatal cardiac arrhythmias.
Method: The literature on the relation between age, sex, and QT interval with respect to
psychotropic drugs was reviewed.
Results: The QT interval must be corrected (QTc) for heart rate. Because slower heart rates
prolong and faster heart rates shorten the QT interval, people with faster heart rates may have
a prolonged QT interval that is not apparent until the correction is performed. QTc values for
apparently healthy post-pubertal people are less than 450 ms for males and less than 470 ms for
females. The longer QT intervals in women may account for their increased risk of potentially fatal
cardiac arrhythmias on psychotropics. QTc increases with increasing age. Assessment of QTc in
older people is especially important to identify people with a longer QTc who are more likely to
attain a serious QT level with drugs that prolong QTc. The age-related increase in QTc is more
evident in men than women, suggesting that male sex does not afford protection against potentially
fatal arrhythmias at older age.
Conclusion: The association of increasing age and female sex with greater QT intervals indicates
the need to have an increased awareness of the QTc prior to use of these psychotropics and to
evaluate the QTc after initiation of therapy.
WWW
Leffet de lge et du sexe sur lallongement de lintervalle QT chez des
patients recevant des psychotropes
Objectif: valuer lge avanc et le sexe fminin, 2 des facteurs de risque majeurs pour
des arythmies cardiaques potentiellement fatales ou une mort subite dorigine cardiaque
chez des patients qui lon a prescrit des psychotropes, dans le contexte dune preuve
lectrocardiographique du temps de lallongement de lintervalle (QT) entre le dbut de londe Q et
la fin de londe T, ce qui est un indicateur du risque accru darythmies cardiaques potentiellement
fatales.
Mthode: La littrature sur la relation entre lge, le sexe, et lintervalle QT en ce qui conerne les
psychotropes a t recense.
Rsultats: Lintervalle QT doit tre corrig (QTc) pour la frquence cardiaque. Parce que des
frquences cardiaques plus lentes allongent lintervalle QT et que des frquences cardiaques plus
rapides le racourcissent, les personnes dont la frquence cardiaque est plus rapide peuvent avoir
un intervalle QT allong qui nest pas apparent jusqu lexcution de la correction. Les valeurs
QTc pour des personnes postpubertaires apparemment en sant sont moins que 450 ms pour les
hommes et moins que 470 ms pour les femmes. Les intervalles QT plus longs chez les femmes
peuvent expliquer leur risque accru darythmies cardiaques potentiellement fatales avec les
psychotropes. Lintervalle QTc saccrot avec lge. Lvaluation du QTc ches les personnes ges est
particulirement importante pour identifier les personnes au QTc allong qui sont plus susceptibles
datteindre un niveau de QT svre avec des mdicaments qui prolongent le QTc. Laugmentation
du QTc lie lge est plus vidente chez les hommes que chez les femmes, suggrant que le sexe
masculin noffre pas de protection contre les arythmies potentiellement fatales en ge avanc.
Conclusion: Lassociation de lge avanc et du sexe fminin avec de plus grands intervalles QT
indique le besoin dtre plus conscient du QTc avant dutiliser ces psychotropes, et dvaluer le QTc
aprs le dbut de la thrapie.
www.LaRCP.ca

P harmacologic agents have dramatically advanced
the treatment of patients with psychiatric disorders
in their widest scope. The use of any drug needs to be
weighed against its adverse effects, which, in turn, need
to be understood, minimized, or avoided. The potential
seriousness of drug-induced adverse effects is highlighted
by the capacity of some psychotropics to increase the risk of
cardiac sudden death. Estimates are that a large number of
people are prescribed drugs that have the potential to have
adverse cardiac effects.1 There are well-defined risk factors
for sudden cardiac death in patients prescribed these agents;
foremost among them is age. Another leading risk factor
is the female sex. The QT interval on the routine 12-lead
ECG is an important indicator of a potential adverse effect
of drugs on the heart and one that predicts the development
of potentially fatal cardiac arrhythmias. The purpose of this
article is to examine the ability of psychotropics to induce
adverse cardiac effects, the effect on the QT interval, the
impact of age and sex, and their interaction with other
factors.
Antipsychotics Increase the Risk of
Cardiac Sudden Death
Antipsychotic use has been reported to be associated
with a 2- to 3-fold increase in sudden death. The use of
antipsychotics was associated with a 2.4-fold increase in the
occurrence of cardiac sudden death, compared with nonuse
of these kinds of drugs, in a cohort of 481744 people,
enrolled in a US Medicaid-based study.2 Sudden death
occurrence was greater in people receiving higher, compared
with low, doses of traditional antipsychotics.2 In another
study, patients with schizophrenia treated with clozapine,
HPD, risperidone, or thioridazine had a 1.7- to 3.2-fold
higher rates of cardiac arrest and ventricular arrhythmia,
compared with a control group of patients with glaucoma
or psoriasis.3 Sudden death rates were higher in users of
typical as well as atypical antipsychotics, compared with
nonusers of antipsychotics.4 Specifically, cardiac sudden
death rates were increased in people receiving clozapine,
Abbreviations
ECG electrocardiogram
FDA Food and Drug Administration
HPD haloperidol
QT time between start of Q wave and end of T wave
QTc corrected QT
QTcBZT QTc calculated with Bazetts formula
QTcDMT QTc calculated with Dmitrienkos formula
QTcFRD QTc calculated with Fridericias formula
QTcFRM QTc calculated with Framinghams formula
QTcHDG QTc calculated with Hodges formula
QTcRTH QTc calculated with Rautaharjus formula
SSRI selective serotonin reuptake inhibitor
TdP torsade de pointes
www.TheCJP.ca
Impact of Age andSex onQTProlongation in Patients Receiving Psychotropics
Clinical Implications
The QT interval must be corrected for heart rate
otherwise prolonged QT intervals at faster heart rates
will not be recognized.
Women and older people have longer QTc, which
may explain higher rates of fatal arrhythmias on
psychotropics.
Women and older people can reach critical QTc levels
more readily on psychotropics because of their intrinsic
longer QTc.
Limitations
Lack of randomized clinical trials limits the ability to
establish absolute levels of QTc risk for potentially fatal
cardiac arrhythmias with each psychotropic drug for
each age and sex.
olanzapine, quetiapine, and risperidone, as well as HPD or
thioridazine.4 In a casecontrol study in primary care groups
in the Netherlands, use of antipsychotics was associated
with a 3-fold increase in risk of sudden cardiac death.5
While studies of association are not proof of causality, they
nevertheless are a component of the evidence essential for
establishing causality. Regardless, data on association raise
concerns about the potential for cardiac sudden death in
patients on antipsychotics.
Influence of Age and Sex on Risk of
Cardiac Sudden Death With Antipsychotics
The Swedish pharmacovigilance database evaluated the
occurrence of the potentially fatal kind of ventricular
tachycardia called TdP and found that the most common
risk factor for drug-induced TdP was age over 65 years,
which occurred in 72% of cases.6 The second leading
causes was female sex, which was present in 70% of cases.6
These findings were substantiated in another study, which
reported that increasing age, female sex, concomitant
diseases, and co-administration of other drugs increased
the risks for TdP.7 A greater proportion of women but not
older people was suggested but not significant in a case
control study in family practice.5 If one considers only older
people, an increase in risk of death has been noted in men
after institution of antipsychotic treatment.8 Although this
study did not separate cardiac from noncardiac deaths,8 it
does suggest that men, especially older men are not spared
the risk of adverse effects of antipsychotics.
There are numerous factors that may explain the increased
occurrence of potentially fatal cardiac arrhythmias or cardiac
sudden death in older people receiving psychotropics (Table1).
QT Interval and Heart RateImportance of
Adjusting for Heart Rate but Which One
The QT interval is measured from the onset of the Q wave of
the QRS complex to the end of the T wave. It encompasses
both electrical depolarization and repolarization of the
heart. As the duration of repolarization is longer than
The Canadian Journal of Psychiatry, Vol 60, No 5, May 2015 W 207
In Review

Table 1 Potential reasons for the increased occurrence of potentially fatal cardiac
arrhythmias or cardiac sudden death in older people receiving psychotropics
Increased corrected QT (QTc) interval in older people
Reduced drug metabolism leading to higher blood levels
Increased prevalence of cardiovascular disease (CVD) that may not be clinically apparent
Increased need for medications treatment of CVDs, such as diuretics for hypertension that induce
hypokalemia or hypomagnesaemia
Increased presence of concomitant illnesses that require the use of medications, some of which
may increase QTc interval
Increased presence of concomitant illnesses that require the use of medications, some of which
may inhibit the metabolism of psychotropics leading to their higher blood levels

depolarization, and the QT interval is relatively easy to
measure, the QT interval is used as an index of cardiac
repolarization.
The QT interval changes with heart rateincreasing at
slower heart rates and decreasing at faster heart rates. There
are over 20 formulae that have been proposed or used for
considering the relations between QT and heart rate.9,10
Correction formulae are usually indicated by the lower case
c after the QT.
Several of the more common older as well as some of the
more recent formulae can be named after their principal
author11: Bazett (QTcBZT)12; Fridericia (QTcFRD)13;
Hodges (QTcHDG) (see Hodges et al14); Framingham
(QTcFRM) (see Sagie et al15); Dmitrienko (QTcDMT)
(see Dmitrienko et al16); and Rautaharju (QTcRTH) (see
Rautaharju et al17).
It is important to interpret the QT interval after heart rate
adjustment because slower heart rates prolong and faster
heart rates shorten the QT interval. People with faster heart
rates may have a prolonged QT interval that is not apparent
until after the correction has been performed. It is important
to recognize that there is no perfect adjustment formula.
While the more recent formulae are based on larger numbers
of people and appear to do a better job of adjusting for the
impact of heart rate, the older formulae, mainly QTcBZT
and QTcFRD, are the ones most commonly in use.
Relation Between Age and QTc
There is an increase in QTc with age. Evaluating 2 of the
oldest as well as 2 recent heart rate correction formulae
show the increase in QT with age for both men (Figure1)
and women (Figure 2). The data are based on several large
studies. Dmitrienko et al16 evaluated the ECGs from 13039
men and women and fit a linear model to log-transformed
QT and RR (time between 2 consecutive R waves) data.16
QTcDMT provides an excellent adjustment for the impact
of heart rate on the QT interval, and it shows an increasing
QT with age.16 Mason et al18 reported on a data set of
ECGs from 57595 people participating in drug trials. The
increase in QTc with age was evident for both QTc BZT
and QTcFRD. Rautaharju et al17 used pooled data from 3
different sources2 population studies and the Mason
databaseto derive 2 new equations. QTcRTH also
increased with age17 (figures 1 and 2). Note, the QTc values
are slightly different between all 4 different QTc formulae.
Relation Between Sex and QTc
There are clear differences in QTc between men and women
(figures 1 and 2). Women show a longer QTc than men
across most decades. Combining the data for the 4 different
QTc formulae shows that there are differences between
men and women in QTc (Figure 3). The sex difference is
greatest in people after adolescence and extends to the sixth
decade (Figure 3). However, the difference between men
and women decreases at older ages.
The difference in duration of QTc between men and women
is not only evident on the resting ECG but also found on the
24-hour ECG evaluating the QT interval.19 The between-
sex difference is greater at slower heart rates.19 The latter
observation may explain the increased occurrences of TdP
in women at a slower heart rate.20
Recognizing the sex differences in QTc interval, an
American Heart Association expert committee group
recommended that a QTc over the 99th percentile should
be considered abnormally prolonged, which translated into
QTc values, for apparently healthy post-pubertal people, of
450 ms for males and 470 ms for females.21
The intriguing question is the potential conflict between
normative standards or reference values and biological
differences that may explain differences in predisposition
to potentially fatal cardiac arrhythmias. There remains
much that is unknown about the relation between QT
prolongation, cardiac arrhythmias, and sex differences in
response to psychotropics. One hypothesis is that there is a
threshold QT interval at which risk for TdP is high, and after
which, further increases in QTc markedly increase the risk
of TdP. If such a threshold level exists, then women should
more readily reach this level, as their QTc is longer than
men. Similarly, older people will more readily reach this
level because they have longer QTc than younger people.
Hypothesis to explain sex effects on QT interval would
include genetic (chromosomal) or hormonal differences
that affect QT interval, probably through an action on
the molecular mechanisms that regulate ventricular

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Figure 1 Mean QT interval for women at different ages
Women
430 QTcDMT
QTcBZT
420 QTcRTH
QTcFRD
QTc, ms
410
400
390
380
0 25 50 75 100
Age, years
The mean QT interval for women at different ages (using the
midpoint of the age group) for 4 different QT correction (QTc)
formulae. The mean data for QTc, calculated with Bazetts formula
(QTcBZT) and QTc calculated with Fridericias formula (QTcFRD),
were the numerical data from Mason et al18; the mean data for QTc,
calculated with Dmitrienkos formula (QTcDMT) and QTc calculated
with Rautaharjus formula (QTcRTH), were graphical extrapolations
of the data from Dmitrienko et al16 and Rautaharju et al.17
repolarization (QT interval). Similarly, aging may alter the
characteristics of one or more of the molecular mechanisms
responsible for the QTc, and render them more sensitive to
the cardiac action of certain psychotropic agents.
Women made up 70% of the 332 reported cases of TdP
associated with the use of cardiovascular drugs that prolong
QT, namely, quinidine, procainamide, disopyramide,
amiodarone, sotalol, bepridil, or prenylamine. Even after
adjusting for other TdP risk factors,22 these studies suggest
that the greater sensitivity of women to potentially fatal
cardiac arrhythmias is not limited to psychotropics. Rather, it
suggests a biological difference in susceptibility to potentially
fatal cardiac arrhythmias for drugs that can prolong QTc.
The basis for the greater sensitivity of women to drug-
induced cardiac arrhythmias may be explained, in part, by
the greater QT interval in women from the age of puberty
to old age. The biological basis for the longer QTc is due in
part to differences between the outward potassium currents in
the heartthe major determinants of the repolarization phase
of the cardiac action potential. Female rabbit ventricular
myocytes have significantly lower outward potassium (IKr and
IK1) currents and current densities than ventricular myocytes
from male rabbits.23 The finding that the QT shortens after
puberty in men but not women suggests that sex hormones
modulate repolarization.24 Drici et al25 evaluated the effects
of ovariectomy followed by estradiol or dihydrotestosterone
treatment on factors responsible for QT duration in isolated
rabbit hearts. Oophorectomy shortened QT interval and
estradiol replacement lengthened the QT interval.25
Kannankeril et al26 concluded that although sex hormones
play a role in QTc differences between men and women, they
explain only part of the observed differences.p 773 While there
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Impact of Age andSex onQTProlongation in Patients Receiving Psychotropics
Figure 2 Mean QT interval for men at different ages
Men
430 QTcDMT
QTcBZT
420 QTcFRD
QTcRTH
QTc, ms
410
400
390
380
0 25 50 75 100
Age, years
The mean QT interval for men at different ages (using the midpoint
of the age group) for 4 different QT correction (QTc) formulae. The
mean data for QTc, calculated with Bazetts formula (QTcBZT)
and QTc calculated with Fridericias formula (QTcFRD), were
the numerical data from Mason et al18; the mean data for QTc,
calculated with Dmitrienkos formula (QTcDMT) and QTc calculated
with Rautaharjus formula (QTcRTH), were graphical extrapolations
of the data from Dmitrienko et al16 and Rautaharju et al.17
is a role of female hormones in modulating QT interval,25 the
concept is conflicted by the data that testosterone can also
lengthen QT interval and may have an action, independent
of its role on QTc, to increase the resistance to ventricular
arrhythmias induced by some drugs.25 Thus sex hormones alter
cellular processes that alter QTc, but the relevant hormones
and their detailed actions requires further study to define more
clearly the mechanism for the sex differences in QTc.27
Other mechanisms, such as hormonal modulation of
pharmacokinetics of psychotropics, and their binding to
potassium channels, may also play a role in the action of
drugs to induce cardiac arrhythmias.28
QT Interval and Sudden Death
The importance of considering the impact of psychotropics
on the QT interval rests on the link between QT prolongation
and cardiac sudden death. A succinct opinion is the FDA
statement:
While the degree of QT prolongation is recognized
as an imperfect biomarker for pro-arrhythmic risk,
in general there is a qualitative relationship between
QT prolongation and the risk of TdP, especially for
drugs that cause substantial prolongation of the QT
interval.29, p 2
The FDA further concluded that
It is difficult to determine whether there is an effect
on the mean QT/QTc interval that is so small as to be
inconsequential, but the risk of arrhythmias appears to
increase with the extent of QT/QTc prolongation.29, p 6
The FDA warned that both for males and females, a QTc
greater than 500 ms is highly abnormal.29
The Canadian Journal of Psychiatry, Vol 60, No 5, May 2015 W 209
In Review
Figure 3 Corrected QT (QTc) for men and women using
the mean values for figures 1 and 2
425
Women
QTc, ms
Men
400
375
0 25 50 75 100
Age, years
The means for each formulae were averaged and not weighted
according to their sample size because the studies varied
markedly in their sample size and the largest study would bias the
overall result. Further, the graph is useful for illustrative purposes
rather than a precise determination of values as the different
formulae cannot be readily averaged.
Psychotropics and QTc Prolongation
In a survey of 6790 psychiatric inpatients, HPD,
phenothiazines, fluoxetine, and citalopram (including
escitalopram) were significantly more common in patients
with drug-induced long QT and potentially fatal ventricular
arrhythmias.30 In the Kaiser Permanente Medical Care
Program of Northern California, there were significant
increases in QTc for HPD, thioridazine, imipramine,
citalopram, venlafaxine, clozapine, ziprasidone, sertraline
quetiapine, nortriptyline, and risperidone.31
In a meta-analysis, using a Bayesian-framework with both
direct and indirect comparisons of randomized controlled
trials comparing 15 antipsychotics and placebo in the
acute treatment of schizophrenia, Leucht et al32 found that
most antipsychotics were associated with an increase in
QTc. However, there are considerable differences in the
magnitude of the increase in QTc between drugs.32 Most
clinical trials evaluating drugs used for the treatment of
psychiatric conditions enrolled mainly younger people.
Harrigan et al33 compared the change in QTc from baseline
in men and (or) women, aged 18 to 59 years, who required
chronic treatment of a psychotic disorder and reached
steady-state on either HPD 15 mg/day, thioridazine
300mg/day, ziprasidone 160 mg/day, quetiapine
750mg/day, olanzapine 20 mg/day, or risperidone
68mg/day increased to 16 mg/day. Each of the
antipsychotics studied was associated with a measurable
prolongation of the QTc interval.33
Haloperidol
HPD significantly increased QTc in a meta-analysis of
antipsychotics.32 Many of the studies were in younger people.
For example, in 27 people, aged 35.7 years, HPD produced
a 7.1 ms increase in QTc.33 In 18 people, aged 41 years, who
210 W La Revue canadienne de psychiatrie, vol 60, no 5, mai 2015
received 5 to 10mg/day, HPD was associated with a much
greater QTcBZT than a control group.34 The duration of the
QT interval predicted the occurrence of HPD-induced TdP in
patients with critical illness.35
To illustrate the impact of age and sex on HPDs effect on
QTc, data from over 1000 people was used.36 This construct
showed that QTc approaches 500 ms in men in their late 60s
for those whose response to HPD was only 1SD greater
than the mean response (Figure 4).37 This effect is somewhat
more apparent in one ECG database18 than the other.16 The
impact of HPD on QTc was evident in women as well as
men (Figure 4B). These effects of HPD are noteworthy, even
though HPD does not produce as great an increase in QTc as
chlorpromazine (Figure 4).
The effects of HPD on QTc is consistent with the data that
HPD treatment of schizophrenia is associated with a 2.2-fold
higher rate of cardiac arrhythmias, cardiac arrests, or cardiac
deaths.3,38
Olanzapine
Olanzapine significantly increased QTc in a meta-analysis
of antipsychotics.32 The ages of people in studies are often
young. For example, in 17 people, age 34 years who
received 5 to 20mg/day (average 15mg/day), olanzapine
was associated with a much greater QTcBZT than a
control group.34 In 24 people, aged 38.3 years, olanzapine,
20mg/day, produced a minimal 1.7-ms increase in QTc.33
In 13 people aged 35 years (39% men) there was about a
10-ms increase in QTcBZT with olanzapine, which was not
significant but the sample size was very small.39 However,
2 of the 13 patients (15%) showed a very large increase in
QT of more than 75ms.39 The relatively young age of the
people in these trials should be considered when this drug
is used in older people and women who have longer QTc
intervals before treatment.
Olanzapine has electrophysiological effects to increase
cardiac monophasic action potential duration.40 The
mechanism is the property of olanzapine to produce a
concentration-dependent block of the rapid component
(IKr) of the delayed rectifier potassium current in HEK
[Human Embryonic Kidney] 293 cells transfected
with human ether--go-go-related gene,40 which is a
major determinant of cardiac repolarization and the QT
duration.
Sex differences are important for this drug. Olanzapine had
a greater impact on prolonging the QTc interval, compared
with risperidonean effect that is more evident in women
than men.41
Risperidone
Risperidone significantly increased QTc in a meta-analysis
of antipsychotics.32 Although in a small (25-person)
group, aged 38.1 years, risperidone produced a minimal
3-ms increase in QTc.33 Other studies disagree with this
conclusion. Considering age and sex, older people and
women would be expected to show more of a greater QTc
prolongation when receiving this drug.37
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 Impact of Age andSex onQTProlongation in Patients Receiving Psychotropics

Figure 4 Effects of CPZ and HPD on QTc

A CPZ CPZ
550 Men Women
+CPZ+1 SD 550 +CPD+1 SD
+CPZ +CPZ
99th percentile 99th percentile
500
QTcFRD, ms

500

QTcFRD, ms
450 450

400 400
0 25 50 75 100 0 25 50 75 100
Age, years Age, years

550 550
Men Women

QTcDMT, ms
QTcDMT, ms

500 500

450 450

400 400
0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80
Age, years
Age, years
B

HPD HPD
550
99th+HPD+1 SD 550 99th+HPD+1 SD
99th+HPD Men 99th+HPD
99th percentile 99th percentile Women
500
QTcFRD, ms

500
QTcFRD, ms

450 450

400
400
0 25 50 75 100
0 25 50 75 100
Age, years
Age, years

550 550
Men Women
QTcDMT, ms
QTcDMT, ms

500 500

450 450

400 400
0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80
Age, years Age, years

The 99th percentile of the QT interval for men and women adjusted for heart rate by QTcFRD, according to age, using the midpoint
of each decade, was used for graphical presentation according to the data of Mason et al18 upper panel and Dmitrienko et al16 lower
panel. (A): The data are presented for the 99th percentile, plus the mean change in QTc for CPZ, as well as the change in QTc plus
1 SD with CPZ; (B): The data are presented for the 99th percentile, plus the mean change in QTc for HPD, as well as the change in
QTc plus 1 SD with HPD.
CPZ = chlorpromazine; HPD = haloperidol; QT = time between start of Q wave and end of T wave; QTc = corrected QT;
QTcDMT = QTc calculated with Dmitrienkos formula; QTcFRD = QTc calculated with Fridericias formula
This figure is reproduced, with permission, from Rabkin.37

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In Review
Quetiapine
Quetiapine significantly increased QTc in a meta-analysis
of antipsychotics.32 Although there is some concern as
to the strength of the evidence implicating quetiapine,42
a randomized, double-blind, placebo-controlled study
showed a small but definite increase in QTc with quetiapine
treatment.43 In a study in 29 patients (24% female, mean age
39 years), there was a 5.7-ms increase in QTc.33 In a study of
33 people (ages between 18 and 64 years) receiving 375mg
twice daily of quetiapine for less than 2 weeks, there was a
small 1.3-ms increase in QTcFRM.44
In a study of 20 Japanese people who were switched from
olanzapine, aripiprazole, or risperidone to quetiapine, there
was a significant increase in QTc after the switch.45 Of note,
there was considerable variability in the extent of QTc
prolongation after switching to quetiapine, suggesting some
people did not show much of a change, while others showed
a marked increase in QTc.45 Quetiapine had a greater impact
on the QTc interval compared with risperidonean effect
that was more evident in women than men.41
Ziprasidone
Ziprasidone significantly increased QTc in a meta-analysis
of antipsychotics.32 In an open-label, randomized, parallel-
group, fixed-sequence study, 31 people (about 71% men),
aged 38 years, ziprasidone increased QTc by 16 ms.33 In
another study of 32 patients aged 18 to 64 years, receiving
ziprasidone 80 mg twice daily for less than 2 weeks, there
was a 9.6-ms increase in QTcFRD.44 Although, in a series of
high-dose ziprasidone, there was no reported associated QTc
prolongation,46 there has been a case report of ventricular
tachycardia, TdP, in a patient receiving ziprasidone,47
indicating the potential for this agent to produce potentially
fatal arrhythmias.
Most of the clinical trials, as noted above, were done in
younger people. In a retrospective study of 23 consecutive
elderly patients admitted to a neuropsychiatry service with
dementia (Diagnostic and Statistical Manual of Mental
Disorder, Fourth Edition) and who were given intramuscular
ziprasidone, 1 person had a QTc greater than 500ms (25%
over baseline).48 This is a small sample, and retrospectively
collected, but it was done in the elderly whether a 4% rate
of dangerous QT prolongation was noted.48
Citalopram
Citalopram, an SSRI, is useful in the management of
depression, especially in older people.49 Considering the
focus of this article is on older people, it is worthwhile to
examine the effect of citalopram on QTc in more detail.
Although some studies suggested that citalopram did not
increase QT,4951 these studies were deficient because they had
either a small sample size or used a casecomparison design,
making them dependent on the nature of the reference group.
More recent clinical prospective trial data show convincing
evidence of QTc prolongation with citalopram. In the
Citalopram for Agitation in Alzheimer Disease (commonly
212 W La Revue canadienne de psychiatrie, vol 60, no 5, mai 2015
referred to as CitAD) Study 186 patients, mean age 78 years,
of whom 64% were men, with probable Alzheimer disease
and clinically significant agitation, were randomized to
receive a psychosocial intervention plus either citalopram
(n=94) or placebo (n=92) for 9 weeks.52 Citalopram
began at 10 mg/day with planned titration to 30 mg/day
during 3 weeks based on response and tolerability.52, p 683
Citalopram was associated with a significantly greater QTc
increase than placebo, and more people in the citalopram
group showed a QTc increase greater than 30 ms.52,53
Citalopram, at high doses, can induce potentially fatal
cardiac arrhythmias, especially when combined with certain
other drugs.54-59
Other SSRIs
In a meta-analysis of 4292 patients, SSRIs were associated
with a dose-dependent increase in QTc interval, compared
with placebo, with citalopram showing a significantly
greater QTc prolongation than sertraline as well as
paroxetine or fluvoxamine.60 There is less clinical trial data,
but escitalopram can induce QT prolongation.61
Venlafaxine
There is a paucity of specific data on this agent. The data from
a large number (n=2005) of users in a clinic setting found that
venlafaxine use was associated with a significantly increase
in QTc.31 The probability of a person having a dangerously
prolonged QTc is greater in women and older person. The
ability of venlafaxine to increase QTc is supported by cases
of patients with markedly prolonged QT with venlafaxine
treatment,62 and with venlafaxine overdose.63,64
Summary
Psychotropics have the potential to prolong QT interval.
While the changes produced by some agents and at certain
doses can be small, the association of increasing age and
female sex with greater QT intervals highlights the need to
have an increased awareness of QTc prior to use of these
agents and to evaluate the QTc after initiation of therapy in
women and older people.
Acknowledgements
There was no funding for this work.
The Canadian Psychiatric Association proudly sponsors the
In Review series by providing an honorarium to the authors.
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