REVIEW ARTICLE Drugs 2002; 62 (11): 1649-1671

0012-6667/02/0011-1649/$30.00/0

© Adis International Limited. All rights reserved.

Antipsychotic-Related QTc Prolongation,

Torsade de Pointes and Sudden Death
Peter M. Haddad1 and Ian M. Anderson2
1 Bolton, Salford and Trafford Mental Health Partnership, Eccles, Salford, UK
2 Neurosciences and Psychiatry Unit, University of Manchester, Manchester, UK

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1650
1. Sudden Unexplained Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1652
2. Mechanisms for QTc Prolongation and Proarrhythmia . . . . . . . . . . . . . . . . . . . . . . . . . 1653
2.1 QTc Interval . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1653
2.2 QTc Prolongation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1655
2.3 Torsade de Pointes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1655
3. QTc Prolongation and Specific Antipsychotic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . 1655
3.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1655
3.2 Conventional Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1657
3.2.1 Thioridazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1657
3.2.2 Pimozide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1657
3.2.3 Droperidol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1658
3.2.4 Haloperidol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1658
3.2.5 Chlorpromazine and Sulpiride . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1658
3.3 Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1659
3.3.1 Sertindole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1659
3.3.2 Ziprasidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1659
3.3.3 Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1660
3.3.4 Clozapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1660
3.3.5 Zotepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1660
3.3.6 Other Atypical Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1661
4. Risk Factors for Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1661
4.1 Nonpharmacological Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1661
4.1.1 Congenital Long QT Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1661
4.1.2 Individual Predisposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1662
4.1.3 Cardiac Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1662
4.1.4 Electrolyte Imbalance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1662
4.1.5 Overdose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1662
4.1.6 Female Sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1663
4.1.7 Restraint and Psychological Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1663
4.1.8 Substance Misuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1663
4.1.9 Miscellaneous Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1663
4.2 Pharmacological Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1664
4.2.1 Pharmacokinetic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1664
4.2.2 Pharmacodynamic Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1665
5. Managing the QTc Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1666
5.1 Antipsychotic Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1666
5.2 Patient Selection and Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1666
1650 Haddad & Anderson

5.3 Advice for Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1666

5.4 Use of High Dosages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1667
5.5 Rapid Tranquillisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1667
5.6 Adopting a Coherent Policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1667
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1668

Abstract Sudden unexpected deaths have been reported with antipsychotic use since
the early 1960s. In some cases the antipsychotic may be unrelated to death, but
in others it appears to be a causal factor. Antipsychotics can cause sudden death
by several mechanisms, but particular interest has centred on torsade de pointes
(TdP), a polymorphic ventricular arrhythmia that can progress to ventricular fi-
brillation and sudden death. The QTc interval is a heart rate-corrected value that
represents the time between the onset of electrical depolarisation of the ventricles
and the end of repolarisation. Prolongation of the QTc interval is a surrogate
marker for the ability of a drug to cause TdP. In individual patients an absolute
QTc interval of >500 msec or an increase of 60 msec from baseline is regarded
as indicating an increased risk of TdP. However, TdP can occur with lower QTc
values or changes.
Concern about a relationship between QTc prolongation, TdP and sudden
death applies to a wide range of drugs and has led to the withdrawal or restricted
labelling of several. Among antipsychotics available in the UK, sertindole was
voluntarily suspended, droperidol was withdrawn, and restricted labelling intro-
duced for thioridazine and pimozide. The degree of QTc prolongation is dose
dependent and varies between antipsychotics reflecting their different capacity
to block cardiac ion channels. Significant prolongation is not a class effect.
Among currently available agents, thioridazine and ziprasidone are associated
with the greatest QTc prolongation. Virtually all drugs known to cause TdP block
the rapidly activating component of the delayed rectifier potassium current (Ikr).
Arrhythmias are more likely to occur if drug-induced QTc prolongation coex-
ists with other risk factors, such as individual susceptibility, presence of congen-
ital long QT syndromes, heart failure, bradycardia, electrolyte imbalance,
overdose of a QTc prolonging drug, female sex, restraint, old age, hepatic or renal
impairment, and slow metaboliser status. Pharmacodynamic and pharmacokinetic
interactions can also increase the risk of arrhythmias.
Further research is needed to quantify the risk of sudden death with antipsy-
chotics. The risk should be viewed in the context of the overall risks and benefits
of antipsychotic treatment. It seems prudent, where possible, to select antipsy-
chotics that are not associated with marked QTc prolongation. If use of a QTc-
prolonging drug is warranted, then measures to reduce the risk should be adopted.

‘In recent years many clinicians have become
increasingly troubled over reports of sudden, unex-
pected death occurring in psychiatric patients be-
ing treated with phenothiazine tranquillising
drugs. Most cases reported are young, in apparent
good health, on fairly high doses of one or more
phenothiazines’ Leestma & Koenig, 1968.[1]
Abnormalities on the electrocardiograph (ECG)
and cases of sudden death in patients prescribed
antipsychotics were first noted in the 1960s.[1-4]
The possibility of a causal link has been an area of
controversy since that time and was the subject of
a report in 1987 by the American Psychiatric Asso-
ciation[5] and in 1997 by the Royal College of Psy-

 Adis International Limited. All rights reserved. Drugs 2002; 62 (11)

Antipsychotic-Related Arrhythmias 1651

chiatrists.[6] Both reports concluded that there was Table I. Drugs associated with QT prolongation[7,8]a

insufficient epidemiological evidence to prove that Antiarrhythmic drugs Class 1a

Disopyramide
sudden death was more likely in those treated with Procainamide
antipsychotics than in the general population, but Quinidine
accepted that there was indirect evidence of a pos- Class 3
Amiodarone
sible link and that further research was warranted.
Bretylium
In recent years it has become apparent that a Dofetilide
wide range of drugs, including antipsychotics, can Sotalol
prolong the QT interval (table I). In extreme cases Antihistamines Astemizole (withdrawn in the UK)
Terfenadine (withdrawn in the USA)
or susceptible individuals, QT prolongation is as-
Antimicrobial agents Fluoroquinolone antibiotics
sociated with torsade de pointes (TdP), a polymor- Grepafloxacin
phic ventricular arrhythmia that can progress to Levofloxacin
ventricular fibrillation and sudden death.[7] A re- Sparfloxacin
Macrolide antibiotics
cent report by the European Society of Cardiol- Clarithromycin
ogy[7] listed 66 drugs associated with QT-interval Erythromycin
prolongation, 54 of which had been associated Imidazoline antifungals
Ketoconazole
with TdP. With many of the drugs, the association
Antimalarials
with QT prolongation and/or TdP was only recog- Chloroquine
nised after several years of clinical use. Halofantrine
The clinical relevance of QT prolongation de- Quinine
Miscellaneous antimicrobials
pends on its frequency, magnitude and association Cotrimoxazole
with adverse clinical events, and for many drugs Pentamidine
these issues are unclear. However, with certain Spiramycin
Calcium antagonists Prenylamine (withdrawn in the UK)
class Ia and class III antiarrhythmic agents, esti-
Terodiline (withdrawn in the UK)
mates of risk are available and are significant. For Miscellaneous Cisapride (withdrawn in the UK)
example, the incidence of TdP in patients treated nonpsychotropic drugs Probucol
with quinidine, a class Ia antiarrhythmic, has been Tricyclic and related Amitriptyline
antidepressant drugs Clomipramine
reported to be between 2 and 8.8%.[9-12] With Desipramine
sotalol, a class III antiarrhythmic and potassium Doxepin
channel blocker, an incidence of between 1.8 and Imipramine
4.8% was reported.[13-15] The SWORD (Survival Maprotiline
Nortriptyline
With ORal D-sotalol) study showed that, contrary Typical antipsychotic Chlorpromazine
to expectation, sotalol increased overall mortality drugs Droperidol (withdrawn in the UK)
when used in patients after a myocardial infarction, Fluphenazine
Haloperidol
presumably by increasing the incidence of fatal ar-
Mesoridazine
rhythmia.[16] Pimozide
Although the risks of TdP and sudden death Sulpiride
with most QTc prolonging drugs are unclear, con- Thioridazine
Trifluoperazine
cern has been sufficient so that several drugs have Atypical antipsychotic Sertindole (voluntarily suspended in Europe)
been withdrawn worldwide, or at least in some drugs Ziprasidone
countries, or have had their labelling restricted. In Miscellaneous Chloral hydrate
psychotropic drugs Lithium
the UK sertindole[17] was voluntarily suspended,
a This list is not comprehensive and is given to indicate the diver-
droperidol[18] was withdrawn and restricted pre- sity of drugs involved. The drugs listed differ with regard to
scribing guidelines introduced for pimozide[19] and their effect on QT prolongation. Some have marked effects
while others have minor effects.
thioridazine.[18] Nonpsychotropic drugs that have

 Adis International Limited. All rights reserved. Drugs 2002; 62 (11)

1652
been withdrawn in the UK include prenylamine,
terodiline, astemizole and cisapride, while the an-
tihistamine terfenadine was restricted to prescrip-
tion only status.[7] This paper examines the possi-
ble relationship between antipsychotic drugs, QTc
prolongation, TdP and sudden death.
1. Sudden Unexplained Death
Schizophrenia is associated with increased mor-
tality. This results not only from an increased sui-
cide rate but also from increased mortality due to
‘natural causes’ including cardiovascular dis-
ease.[20] There are many possible explanations for
this association which should be regarded as being
multifactorial. Central to this paper is the possibil-
ity that antipsychotic drugs may contribute to the
excess mortality by causing sudden, unexpected,
unexplained death, defined by Jusic and Lader[21]
as ‘death within the hour of symptoms (excluding
suicide, homicide and accident) which is both un-
expected in relation to the degree of disability be-
fore death and unexplained because clinical inves-
tigation and autopsy failed to identify any plausible
cause’. Of course, the accuracy of the finding of
‘autopsy negative’ death depends on the extent of
the examination and the skill and experience of the
pathologist.
Case reports from the 1960s to the present day
have documented sudden death in patients receiv-
ing antipsychotics.[1-4,21,22] An association is also
evident in data collected by regulatory bodies. For
example, from the date of first marketing to May
1996 the UK database of spontaneous adverse drug
reaction reports, maintained by the Medicines Con-
trol Agency (MCA), received 31 reports of unex-
plained sudden death and 63 reports of fatal cardiac
arrest or arrhythmia in association with 11 antipsy-
chotic agents.[6]
Sudden unexplained death occurs in the general
population and so, even if antipsychotics exerted
no harmful effect, such deaths would occur among
patients receiving medication by coincidence.
However, the details of some case reports (such as
a close temporal link between starting an antipsy-
chotic and death or lack of other risk factors)
 Adis International Limited. All rights reserved.
Haddad & Anderson
strongly implicate the antipsychotic as either the
main factor, or at least a contributory factor, in
causing death.
Only a few studies have specifically addressed
the issue of sudden unexplained death and antipsy-
chotic medication. In a series of autopsy negative
deaths in Finland, Mehtonen et al.[23] found that
phenothiazines, particularly thioridazine, were
over-represented compared to their population use.
The main limitation of the study is that it was de-
scriptive and did not control for potential con-
founding factors such as age and cardiovascular
disease. Two recent studies overcome this weak-
ness.
Reilly et al.[24] conducted a retrospective case-
control study of UK psychiatric in-patients dying
suddenly and surviving controls matched for age,
gender and psychiatric diagnosis. Logistic regres-
sion analysis showed that probable sudden unex-
plained death was significantly associated with
current use of thioridazine (adjusted odds ratio =
5.3; 95% confidence interval [CI] 1.7 to 16.2; p =
0.004) as well as hypertension and ischaemic heart
disease. There was no significant association with
other individual antipsychotic drugs, although this
may reflect the small study size.
Ray et al.[25] conducted a retrospective cohort
study of approximately half a million Tennessee
Medicaid enrolees, many of whom were prescribed
antipsychotics. The data related to the period 1988
to 1993, prior to the introduction of atypical anti-
psychotics other than clozapine. The cohort had
1487 confirmed sudden cardiac deaths and multi-
variate rate ratios were calculated controlling for
potential confounding factors including age, sex,
race, non-cardiac and cardiac illness. The risk of
sudden cardiac death in those currently receiving a
moderate-dose antipsychotic drug (>100mg thio-
ridazine equivalents per day) was 2.39 times
greater than for non-users (95% CI 1.77 to 3.22; p
< 0.001). This was greater than the risk for current
low-dose antipsychotic use (p = 0.003). The risk
among former antipsychotic-users was not signifi-
cantly different to that of non-users.
Drugs 2002; 62 (11)
Antipsychotic-Related Arrhythmias
Among current moderate-dose antipsychotic
users, an increased risk of sudden cardiac death
existed for both sexes and for both of two age
groups, but was greater in females and in those
aged 65 years or older.[25] Among cohort members
with severe cardiovascular disease, current moder-
ate-dose antipsychotic users had a 3.53-fold in-
creased risk of sudden cardiac death compared
with non-users (the risk ratio in the absence of car-
diac disease was 1.60). An increased risk existed
for subgroups defined by current use of haloperi-
dol, thioridazine, chlorpromazine and thiothixene.
Absolute rates of sudden cardiac death per 10 000
person-years of follow-up were calculated (stand-
ardised to the age and sex distribution of the co-
hort).[25] Within the entire cohort the rate per 10 000-
person years was 26.9 for users of moderate-dose
antipsychotics compared with 11.3 for non-users
i.e. for every 10 000 person-years of follow-up
antipsychotic use was associated with 15 addi-
tional deaths. In those with no cardiovascular dis-
ease and severe cardiovascular disease, respec-
tively, use of moderate-dose antipsychotics was
associated with 4 and 367 additional sudden car-
diac deaths.
All three studies[23-25] indicate an association
between antipsychotic use and sudden death but
none prove causality. Several factors could ex-
plain, or contribute to, the association. For exam-
ple, the higher rate of sudden death in antipsy-
chotic users may reflect under-diagnosis and
under-treatment of cardiovascular disease or higher
rates of smoking within this group, factors that
were not assessed in any of the studies. However,
these explanations are weakened by the fact that
thioridazine was the only antipsychotic associated
with increased risk of death in the study by Reilly
et al.[24] and in the study by Ray et al.[25] the in-
creased risk associated with antipsychotics was
dose related and specific to current antipsychotic
use, rather than former use. In addition, Ray et
al.[25] completed a secondary analysis that sug-
gested that the additional risk of sudden death con-
ferred by smoking was already largely accounted
for by controlling for diagnosed cardiovascular
 Adis International Limited. All rights reserved.
1653
disease. In summary, although each study has its
weaknesses, a review of the whole evidence base
provides a strong case that certain antipsychotic
drugs can increase the risk of sudden unexplained
death.
Arrhythmias have long been regarded as the
most plausible mechanism by which antipsychot-
ics could cause sudden unexplained death, al-
though other mechanisms have been proposed.
These include peripheral vasodilation leading to
hypotension and cardiovascular collapse,[26] respi-
ratory dyskinesias that impair co-ordination of re-
spiratory muscles leading to asphyxia[27] and oral-
laryngeal-pharyngeal dystonia leading to acute
airway obstruction.[28]
Acute myocarditis[29] and cardiomyopathy[30]
have been implicated in sudden deaths associated
with clozapine but these should be recognised at
the postmortem examination. Prolongation of the
QTc interval is a surrogate marker or signal for the
risk of arrhythmias associated with prolongation of
cardiac repolarisation.[31] However, arrhythmias
may develop though other pathways, for example
suppression or acceleration of atrioventricular
nodal conduction. Clearly, the cardiac safety of a
drug can not be assessed solely on the basis of its
effects on the QTc interval.
2. Mechanisms for QTc Prolongation
and Proarrhythmia
2.1 QTc Interval
The normal QT interval runs from the beginning
of the QRS complex to the end of the T wave (fig-
ure 1). It represents the time between the onset of
electrical depolarisation of the ventricles and the
end of repolarisation, that is, it reflects the duration
of individual action potentials in the cardiac myo-
cytes. The QT interval shortens with increasing
heart rate and correcting for this variation gives the
QTc or rate-corrected value. Various formulae ex-
ist for making this correction with some contro-
versy regarding which is the most appropriate. One
of the most widely used, and that recommended by
the European Medicines Evaluation Agency,[31] is
Drugs 2002; 62 (11)
1654
R interval is subject to variation within the myocar-
P T
Q S
PQ QRS
QT
Fig. 1. Schematic electrocardiographic trace showing the QT
interval.
Bazett’s formula (QTc = QT/RR1/2). Others include
the Fridericia and Framingham formulae.
A disadvantage of all universal correction for-
mulae is that they can over or under correct the QT
interval when the heart rate extends beyond a nar-
row physiological range. The Bazett formula in
particular tends to overestimate the QTc interval at
higher heart rates. Consequently when applied to a
drug that accelerates the heart rate it can result in
artificial QTc (Bazett) prolongation. The Fridericia
formula (QTc = QT/RR1/3) is less sensitive to this
effect. Conversely, the Bazett formula underesti-
mates the QTc when applied to drugs, such as β-
blockers, that slow the heart rate.
These correction problems reflect the assump-
tion that a single mathematical formula will de-
scribe the QT to RR relationship satisfactorily in
all individuals and this is not the case. In clinical
pharmacology studies improved heart rate correc-
tion can be achieved by employing a data-specific
correction formula but even this is liable to distor-
tions. The most reliable method of heart rate cor-
rection is to devise a correction formula for each
study participant. This approach requires large
numbers of ECGs for each individual, is expensive
and is largely restricted to academic research work.
These issues, and others related to the assessment
of drug-induced QT prolongation, are comprehen-
sively dealt with in a recent review by Malik and
Camm.[32]
Multiple sources of variability in the measure-
ment of the QTc interval exist. For example, the QT
 Adis International Limited. All rights reserved.
Haddad & Anderson
dium and differs between ECG leads, a phenome-
non referred to as QT dispersion.[33] The QTc inter-
val seen in a 12 lead ECG is the averaged measure
of repolarisation across most of the ventricles. The
QT interval is also subject to diurnal and prandial
variation, and increases during sleep[34] and after
food consumption. Increases of 16 to 23 msec have
been reported during the 60 minutes following a
meal.[35] Obesity is often associated with QTc pro-
longation and a 10kg increase in fat mass has been
linked to a >5 msec increase in QTc.[36,37] Further-
more, the mean QTc interval is longer in females
than in males.[38] Difficulty in identifying the end
of the T-wave can introduce further variability in
the measurement of the QTc interval, and manual
and automatic measurements may not correlate
well.[39] These factors have the potential to intro-
duce inconsistencies within and across studies
The marked intraindividual variability in the QT
interval makes a strict divide between normal and
abnormal QTc values problematic. In 1997 the
Committee for Proprietary Medicinal Products
(CPMP) published a report on the assessment of
QT-interval prolongation by noncardiovascular
drugs.[31] This suggested normal, borderline and
prolonged values for the QTc after Bazett’s correc-
tion (table II).
The problems of measuring the QTc interval and
the lack of a direct relationship between the QTc
interval and the potential for developing arrhyth-
mias has led to ongoing research into alternative
measures of cardiac repolarisation including T-
wave changes.[32] At present such work is at an ex-
perimental level.
Table II. Standard values for the QTc interval (Bazett correction)
suggested by the Committee For Proprietary Medicinal Products[31]a
Women (msec) Men (msec)
Normal <450 <430
Borderline 451-470 431-450
Prolonged >470 >450
a These values assume the absence of any drug or disease.
Drugs 2002; 62 (11)
Antipsychotic-Related Arrhythmias
2.2 QTc Prolongation
The cardiac action potential is generated by the
transmembranal movement of various ion currents
in cardiac cells. These include sodium, calcium and
potassium, and a variety of ion channel subtypes
exist. Depolarisation is primarily the result of the
inward movement of sodium ions. The repolarisa-
tion phase is primarily the result of the outward
movement of potassium ions. One of the most stud-
ied potassium currents is the delayed rectifier po-
tassium current (Ik), which is the sum of two kin-
etically and pharmacologically distinct potassium
currents, a rapidly-activating (Ikr) and a slowly-ac-
tivating (Iks) component.
Virtually all drugs known to cause TdP have
been shown to block Ikr; the relevant ion channel
is encoded by the human ether-a-go-go-related
gene (HERG).[40] TdP that is attributable solely to
the disruption of other ion channels has not been
reported.[32] However, such a possibility cannot be
ruled out. In particular, inhibition of potassium
currents other than Ikr may be proarrhythmic, while
effects on other ion channels may counteract this
tendency. For example, it has been postulated that
combined calcium and potassium channel block-
ade may reduce the proarrhythmic risk associated
with QTc prolongation.[41] This may explain why
verapamil, a combined potassium and calcium
channel antagonist, has not been reported to cause
TdP despite causing QTc prolongation in a dose-
dependent manner.[42]
The different propensity of antipsychotic agents
to cause QTc prolongation and TdP reflects their
differential effects on cardiac ion channels at ther-
apeutic dosages. Haloperidol,[43] droperidol,[44] thio-
ridazine,[45] pimozide[46] and sertindole[47] have all
been shown to be high affinity antagonists of Ikr.
2.3 Torsade de Pointes
TdP is a ventricular arrhythmia characterised by
QRS complexes of changing amplitude that appear
to ‘twist’ around the isoelectric line. It is believed
to be triggered by the occurrence of early after-
 Adis International Limited. All rights reserved.
1655
depolarisations in combination with increased het-
erogeneity of cardiac repolarisation.
Although TdP may be asymptomatic or cause
self-limiting palpitations, dizziness or syncope, in
rare cases it may progress to ventricular fibrillation
and sudden death. The risk of TdP increases with
increasing length of the QTc interval but the rela-
tionship is not linear.
The 1997 CPMP document provided guidance
on ‘signal’ values for QT measurements.[31] The
values refer to individual QTc changes (after
Bazett’s correction) and not to mean values for
study populations. Individual changes of less than
30 msec were regarded as unlikely to raise signif-
icant concerns about the proarrhythmic potential
of a drug. In contrast, two changes were high-
lighted as raising ‘clear concerns’ about the poten-
tial risk of a drug to induce arrhythmias including
TdP:
• an individual change in the QTc of greater than
60 msec relative to drug-free baseline measure-
ments;
• an absolute QTc value, or at lower heart rates an
uncorrected QT value, greater than 500 msec.
Of these two indicators, the absolute QTc value
was regarded as having greater prognostic signifi-
cance. Two other parameters relating to QTc dis-
persion across a 12 lead ECG were regarded as
raising ‘concern’ about the potential for arrhyth-
mias:
• dispersion greater than 100 msec;
• a change in dispersion of more than 100%.[31]
It is important to emphasise that QTc prolon-
gation is only a surrogate marker or signal of ar-
rhythmic risk and not the risk itself. Some drugs,
including amiodarone, cause significant QTc pro-
longation but rarely cause TdP.[13]
3. QTc Prolongation and Specific
Antipsychotic Drugs
3.1 Overview
QTc prolongation with antipsychotic agents, as
with other drugs, is dose related.[48,49] Warner et
al.[48] showed that QTc prolongation was signifi-
Drugs 2002; 62 (11)
1656 Haddad & Anderson

Table III. Mean change in QTc and heart rate from baseline to steady
state. Results of Pfizer Study 054[8]
Drug QTc (Bazett) QTc (Fridericia) Heart rate
[msec] [msec] (beats per min)
Thioridazine +35.8 +29.6
Ziprasidone +20.6 +15.6
Quetiapine +14.5 +4.8
Risperidone +10.0 +3.0
Olanzapine +6.4 +1.1
Haloperidol +4.7 +7.3
cantly more likely to occur in patients receiving
dosages of antipsychotics above 2000mg chlor-
promazine equivalents per day. Reilly et al.[49] as-
sessed ECGs from 495 psychiatric patients in order
to determine predictors of QTc lengthening (de-
fined from a healthy control group as >465 msec).
Antipsychotic dosage was defined as standard (0 to
1000mg chlorpromazine equivalents per day), high
(1001 to 2000mg chlorpromazine equivalents per
day) and very high (>2000mg chlorpromazine
equivalents per day). In a logistic regression anal-
ysis, antipsychotic dosage emerged as a robust pre-
dictor of QTc lengthening (adjusted odds ratio for
high dosage 5.3; 95% CI 1.2 to 24.4; p = 0.03;
adjusted odds ratio for very high dosage 8.2; 95%
CI 1.5 to 43.6; p = 0.01).
Although most antipsychotic agents can cause
QTc prolongation, there are marked differences be-
tween specific agents in their potential for this ef-
fect. This is well demonstrated in a recent study
conducted by Pfizer (study 054) which was de-
signed to assess the effects of specific antipsy-
chotic drugs on the QT interval.[8] Patients had
schizophrenia and normal baseline ECGs (QTc
Bazett and Fridericia correction formulae. Quet-
iapine was the only drug that consistently raised
heart rate throughout the study (mean increase 11.2
+5.7 beats per minute) and the Bazett QTc value may be
+4.6 artificially high as a result; the Fridericia QTc value
+11.2 was lower (table III). Irrespective of which correc-
+6.4
tion formula is used, thioridazine and ziprasidone
+6.5
–2.9 caused the most marked QTc prolongation. Fur-
thermore, the mean QTc increase for ziprasidone
was approximately 15 msec less than that seen with
thioridazine and approximately 12 msec greater
than the average of the other four comparator drugs
(haloperidol, olanzapine, quetiapine and
risperidone). It is unclear to what extent the in-
creases in QTc from baseline seen with these latter
four drugs are drug-related effects or a placebo ef-
fect. However, when reviewing this study, the US
Food and Drug Administration (FDA) assessor re-
garded the effects of these four agents on cardiac
repolarisation to be minimal or absent.[50] Figure 2
shows the percentage of patients with QTc (Bazett)
changes from baseline of ≥60 msec and ≥75 msec
at steady state. Only thioridazine and ziprasidone
were associated with increases in the QTc interval
of ≥75msec. There were no patients with an in-
crease in QTc interval of ≥500 msec in the study,
irrespective of the antipsychotic agent adminis-
tered.
30 29 ≥60 msec
≥75 msec
25
21
20
Patients (%)

<450 msec). The study had a non-blind, parallel

group design with patients receiving one of six an- 15
11
tipsychotics. Each patient received an antipsy- 10
10
chotic dosage that was titrated to the highest that
5 4 4 4
they could tolerate within a specified dose range 3
0 0 0 0
for each agent. For thioridazine the maximum dose 0
was 300 mg/day. Repeat ECGs were obtained at the
= e

=3 e

=2 e

=2 e

=2 e

=2 ol
(n azin

(n don

(n pin

(n on

(n pin

(n id
Zi 30)

Q 3)

7)

la )

al )

0)
8

er
rid
tia

time of the estimated maximum plasma concentra-

i
rid

as

nz

op
pe
ue
io

pr

is
Th

tion (tmax).
R

Table III shows the mean changes in QTc from Fig. 2. Percentage of patients with QTc (Bazett) prolongation of
baseline to steady state from this study using the ≥60 msec and ≥75 msec at steady state (data from study 054[8]).

 Adis International Limited. All rights reserved. Drugs 2002; 62 (11)

Antipsychotic-Related Arrhythmias
Specific antipsychotics, particularly those where
QTc prolongation has been highlighted as a poten-
tial problem, are discussed in more detail in sec-
tions 3.2 and 3.3.
3.2 Conventional Antipsychotics
3.2.1 Thioridazine
QTc prolongation appears a particular problem
with thioridazine with evidence accumulating
from several sources.
• Reilly et al.[49] showed an increased risk of QTc
prolongation with thioridazine compared with
other antipsychotic drugs (adjusted odds ratio
5.4; 95% CI 2.0 to 13.7; p < 0.001). In this study
15 of 64 patients treated with thioridazine had
a prolonged QTc interval.
• In a large series of consecutive patients present-
ing to hospital with antipsychotic drug over-
doses, compared with other drugs thioridazine
was more likely to cause tachycardia (odds ratio
1.7; 95% CI 1.1 to 2.9; p = 0.03), a prolonged QTc
interval (>450 msec) [odds ratio 4.7; 95% CI 2.7
to 7.9; p = 0.001] and arrhythmias (odds ratio
infinity; 95% CI 2.4 to infinity; p = 0.004).[51]
• A study of medico-legal autopsies conducted by
Mehtonen et al.[23] in Finland over a 3-year pe-
riod (1985 to 1988) identified 49 cases of sud-
den death associated with the therapeutic use of
antipsychotic or antidepressant drugs. Pheno-
thiazines, especially thioridazine, were over
represented when compared with estimates of
antipsychotic use in the population (based on
defined daily dosages per 1000 population per
day). Phenothiazines were associated with 46 of
the 49 cases (94%) of sudden death and were
estimated to account for 60% of total antipsy-
chotic use in the population. Thioridazine was
involved in over half of the total deaths (28 of
49) and 75% of deaths that involved the use of
a single antipsychotic (15 of 20). However, it
was estimated that thioridazine accounted for
only 18% of antipsychotic use in the population.
• In a retrospective matched case-control study of
UK psychiatric in-patients dying suddenly,
probable sudden unexplained death was signif-
 Adis International Limited. All rights reserved.
1657
icantly associated with current use of thiorida-
zine (adjusted odds ratio = 5.3; 95% CI 1.7 to
16.2; p = 0.004).[24]
• Since 1964 the Committee on the Safety of
Medicines (CSM)/MCA has received 42 reports
of suspected arrhythmias associated with thio-
ridazine in the UK.[18] Of the cases where the
outcome was known 21 of 39 were fatal. These
reports included patients receiving low dosages
of thioridazine or with a history of dementia.
• Multiple case reports have documented TdP and
sudden death in patients prescribed thioridazine
at therapeutic dosages and following over-
dose.[1,2,52-56] This includes a case published in
1963 that was the first report of sudden death in
a patient prescribed an antipsychotic agent.[2]
• Thioridazine causes significant blockade of
Ikr.[45]
Despite these data, thioridazine has often been
used as an anxiolytic or hypnotic in the UK, even
though there is little evidence for such use.[57] In
the year 2000, following a review by the CSM, the
MCA in the UK restricted the indications for thio-
ridazine.[58] The CSM concluded that the risk to
benefit ratio would be favourable only when thio-
ridazine was used as a second-line treatment in
schizophrenia in adults under the supervision of a
consultant psychiatrist.[18] Previous indications
which included anxiety, mania, impulsive behavi-
our and agitation in the elderly were deemed inap-
propriate. In addition, new contraindications and
precautions for safely using thioridazine were de-
tailed. These are summarised in table IV. In the
year 2000 the FDA took similar action with regard
to thioridazine[59] and mesoridazine.[60]
3.2.2 Pimozide
In a randomised, controlled trial the QTc inter-
val was significantly prolonged by pimozide but
not haloperidol or placebo.[62] In the UK, between
1971 and 1995, 16 deaths and 24 other cases of
serious cardiac events (predominantly arrhyth-
mias) in patients prescribed pimozide were re-
ported to the CSM.[19] This led to recommenda-
tions in the UK and the US that patients prescribed
pimozide periodically undergo ECGs. If the QTc
Drugs 2002; 62 (11)
1658
Table IV. Principal changes to the UK Summary of Product Char-
acteristics for thioridazine as introduced in the year 2000[61]
Indications
Only as second-line treatment of schizophrenia in adults
Precautions for use
Baseline ECG <450 msec in men and <470 msec in women
Baseline serum potassium, magnesium and calcium levels
should be within normal limits
Regular ECG and electrolyte monitoring
Discontinue treatment if QTc >500 msec
Contraindications
Clinically significant cardiac disorders (e.g. cardiac failure,
angina, cardiomyopathy)
QTc prolongation
History of ventricular arrhythmias or Torsade de Pointes
Bradycardia or 2nd or 3rd degree heart block
Family history of QTc prolongation
Uncorrected hypokalaemia or hypomagnesaemia
Decreased CYP 2D6 activity
Administration of a substrate or inhibitor of CYP 2D6
Administration of another QTc prolonging drug
CYP = cytochrome P450.
interval is prolonged, doctors are advised to con-
tinue treatment under close supervision or to con-
sider withdrawing the drug.[63]
3.2.3 Droperidol
Outside of psychiatry, droperidol has been used
as a pre-anaesthetic agent. Dose-dependent in-
creases in the QTc interval have been observed in
surgical patients treated with droperidol[64] and
also in in vitro heart perfusion models.[44] Among
psychiatric patients, Reilly et al.[49] showed an in-
creased risk of QTc prolongation with droperidol
compared with other antipsychotic drugs (adjusted
odds ratio 6.7; 95% CI 1.8 to 24.8; p = 0.004). In
this study, six of the 37 droperidol-treated patients
had a prolonged QTc interval. Between 1993 and
1999 the manufacturers received reports of 72
cases worldwide of QT prolongation, serious ven-
tricular arrhythmia or sudden death in association
with droperidol.[18] In the UK the manufacturer
voluntarily discontinued distribution of droperidol
from 31 March 2001.[18]
 Adis International Limited. All rights reserved.
Haddad & Anderson
3.2.4 Haloperidol
Haloperidol has been associated with QTc pro-
longation, TdP and sudden death in single case re-
ports and small series. This occurred at normal
therapeutic dosages with both oral[65,66] and intra-
venous administration,[67] and also in overdose.[68]
When sudden death occurs in psychiatric patients
there is often no ECG evidence, thus making it dif-
ficult to determine whether the cause was an ar-
rhythmia. In this respect haloperidol is interesting,
as it has been widely used on medical wards, in-
cluding intensive care units (ICU), to control agi-
tation. Patients in ICUs usually have frequent, if
not continuous, ECG monitoring and this provides
a valuable source of information. Over 24 cases of
haloperidol-induced TdP have been reported from
ICUs, and in one study, 8 of 223 consecutive ICU
patients (3.6%) treated with intravenous haloperi-
dol developed TdP.[69] The severe medical prob-
lems of some these patients could have acted as
additional risk factors for TdP.
Although haloperidol can cause TdP and sudden
death, the risk of these outcomes appears far less
than with thioridazine. In the Finish autopsy study
conducted by Mehtonen et al.[23] there were 46 sud-
den deaths associated with antipsychotics of which
only 6 (13%) involved haloperidol compared with
28 (61%) that involved thioridazine. In none of the
6 haloperidol-related deaths was haloperidol the
sole drug used. In contrast, thioridazine was the
only drug prescribed in 15 of the 28 thioridazine-
related deaths. At the time of the study both halo-
peridol and thioridazine accounted for a similar
proportion of total antipsychotic use in Finland
(approximately 18% for each drug). In the UK the
recommended maximum dosage of haloperidol has
recently been substantially lowered.[63]
3.2.5 Chlorpromazine and Sulpiride
TdP has been reported in association with chlor-
promazine[70] and sulpiride[71] but the degree of
risk is uncertain.
Drugs 2002; 62 (11)
Antipsychotic-Related Arrhythmias
3.3 Atypical Antipsychotics
3.3.1 Sertindole
Sertindole was introduced on the market in
1997, being launched in several European coun-
tries. It was associated with dose-dependent QTc
prolongation with an average increase of 21 msec
at the maximum recommended dosage of 24 mg/
day.[72] The proportion of patients with QTc values
≥500 msec has been reported as 3.1 to 4.0%[73] and
7.8%[8] in different documents. In a randomised
trial of sertindole versus haloperidol, 8% of the
sertindole-treated patients had QTc intervals ≥500
msec compared with none in the haloperidol group
(p < 0.05).[74] During the clinical trials programme
there were two documented cases of TdP; both
were associated with overdose and neither was fa-
tal.[75] By the end of November 1998, the MCA/
CSM had been notified that sertindole had been
associated with 36 fatalities, nine of which had oc-
curred in the UK.[17] In addition, there were 13
reports of serious but nonfatal arrhythmias in the
UK over the same time period. The manufacturers
of the drug voluntarily suspended its European
marketing in December 1998, pending a full eval-
uation of its risks and benefits.
3.3.2 Ziprasidone
Ziprasidone recently entered clinical use in the
US. Its approval was initially delayed because of
concerns over effects on the QTc interval. Study
054, discussed previously in section 3.1, indicated
that ziprasidone had a greater effect on the QTc
interval than did risperidone, olanzapine, quetiap-
ine or the conventional antipsychotic haloperidol,
but a lesser effect than did thioridazine (table III,
figure 2).[8,50]
Comparisons with sertindole are complicated
by the need to compare across studies but suggest
that ziprasidone has a less marked effect on
repolarisation. In ECGs obtained at random inter-
vals during short-term trials of ziprasidone, the
mean increase in the QTc (Bazett) was 9.7 msec at
the maximum licensed dosage of 160 mg/day.[8]
ECG data gathered in a similar way for sertindole
showed a mean QTc increase of 21 msec at the
maximum licensed dosage of 24 mg/day.[72] The
 Adis International Limited. All rights reserved.
1659
incidence of QTc ≥500 msec in the ziprasidone
clinical programme was two of 3095 patients
(0.06%) compared with 1 of 440 patients (0.23%)
receiving placebo.[8] In comparison, the incidence
of QTc ≥500 msec with sertindole was 3.1[73] to
8%,[74] which is approximately 50 or 100 times
higher than that of ziprasidone.
To date no cases of TdP have been reported
with ziprasidone. However, the manufacturer’s
prescribing information in the US states that when
selecting an antipsychotic drug the prescriber
should consider the greater capacity of ziprasidone
to prolong the QT/QTc interval compared with sev-
eral other antipsychotic drugs.[76] It also specifies
that ziprasidone is contraindicated in patients with
a known history of QT prolongation, recent acute
myocardial infarction or uncompensated heart fail-
ure, and should not be co-prescribed with other
QT-prolonging drugs.
A variety of data suggest that TdP may not be a
serious problem with ziprasidone. These include
the following:
• ziprasidone has not been associated with an in-
creased rate of syncope, sudden death or TdP in
clinical trials;[8]
• the effects on QTc prolongation with zipra-
sidone are less than those observed with thiorid-
azine[8] (figure 2, table III) and sertindole;[72]
• QTc prolongation of ≥500 msec is relatively
rare with ziprasidone;[8]
• ten cases of overdose with ziprasidone have
been reported.[8] None were associated with se-
rious cardiac events or death. This includes one
patient who ingested 4.6g of ziprasidone which
is nearly 29 times the daily maximum dosage;
• in study 054, QTc prolongation with zipra-
sidone was not significantly increased in the
presence of a metabolic inhibitor suggesting
that pharmacokinetic interactions are unlikely
to be a major problem.[8]
However, a repeated message in the literature
regarding QTc prolongation and noncardiac drugs
is that the risk of TdP and sudden death often only
became apparent several years after licensing.
There are two key reasons for this. Firstly, TdP and
Drugs 2002; 62 (11)
1660
sudden death are often rare complications. For ex-
ample, based on adverse drug reaction data for
cisapride, it has been estimated that there was one
report of a serious disorder of cardiac rhythm for
approximately every 110 000 prescriptions and one
reported fatality for approximately every 430 000
prescriptions (on average each patient was pre-
scribed the drug on three occasions).[32] A far
higher incidence was reported with QTc-prolong-
ing antiarrhythmic agents, such as sotalol,[13-15]
partly because these drugs were targeted at a highly
vulnerable group, that is, those with cardiac dis-
ease. The second reason why sudden death often
becomes apparent several years after licensing is
that clinical trials have highly selective entry cri-
teria and will exclude patients who are susceptible
to the induction of TdP, such as the elderly, those
with comorbid substance misuse or comorbid
physical disorders (e.g. heart disease) and those
prescribed multiple medications. In this respect it
should be noted that most of the safety data on
ziprasidone originates from clinical trials.
In summary, the effect of ziprasidone in pro-
longing the QTc interval is an indication that it
could cause TdP and sudden death - whether or not
it does will only become clear after greater clinical
use and postmarketing surveillance.
3.3.3 Risperidone
In contrast to sertindole and ziprasidone, other
atypical antipsychotics have far less of an effect on
the QTc interval. Risperidone has been shown to
cause minor QTc prolongation at therapeutic dos-
ages,[8,77] and this effect has also been noted in
overdose.[78] There are no reported cases of TdP in
patients prescribed risperidone. A recent report de-
scribed a 34-year-old woman, with no history of
cardiac disease, who had a fatal cardiac arrest sev-
eral days after commencing risperidone.[79] Her
ECG showed mechanical and electrical dissocia-
tion (pulseless electrical activity) and a prolonged
QTc interval (480 msec). However, there was no
evidence of either TdP or ventricular fibrillation.
Although it is possible that risperidone was a ca-
sual factor in this death, it was not the result of TdP.
 Adis International Limited. All rights reserved.
Haddad & Anderson
3.3.4 Clozapine
Clozapine has been shown to increase QTc in a
dose-dependent manner but it is rare for this to be
pathological.[80] In a study of 61 patients treated
with clozapine, a QTc >500 msec was seen in two
patients. Of these, one had a baseline ECG abnor-
mality and in the second the QTc normalised de-
spite the dosage of clozapine being increased.[80]
Thus, it is questionable as to what extent, if any,
clozapine was involved in the effects on QTc.
A preliminary study reported that the sudden
death rate during treatment with clozapine (4/561,
0.71%) was 2.5 times higher than for other psychi-
atric agents.[81] However, the small number of
cases of sudden death and the failure of the re-
searchers to control for potential confounding fac-
tors severely limit the study. An autopsy was avail-
able for only one of the four clozapine recipients
who died suddenly and this revealed death due to
pulmonary emboli. It cannot be assumed that any
of the other three sudden deaths were arrhythmic
in origin. This is particularly relevant as clozapine-
induced myocarditis can cause sudden death.[29]
Clozapine has also been associated with fatal
cardiomyopathy and, in a recent case report, it was
suggested that this might have been a factor con-
tributing to sudden death.[30] In theory, cardiomy-
opathy could increase the proarrhythmic effect of
clozapine. However, to date there are no unequiv-
ocal reports of a fatal cardiac arrhythmia in a pa-
tient prescribed clozapine.
3.3.5 Zotepine
In an analysis of six clinical trials, involving a
total of 537 patients, zotepine caused a small but
statistically significant prolongation of the QTc in-
terval (mean increase 8.3 msec).[82] Of the zotep-
ine-treated patients, 106 (20%) experienced a QTc
prolongation greater than 30 msec and 21 (4%) ex-
perienced a QTc prolongation greater than 60 msec.
In contrast 13 (9%) placebo recipients had a QTc
prolongation greater than 30 msec and none had a
QTc prolongation greater than 60 msec. The prod-
uct monograph concludes that zotepine has a mod-
est effect on QTc interval which probably does not
represent an important pro-arrhythmic effect.
Drugs 2002; 62 (11)
Antipsychotic-Related Arrhythmias
However, caution is advised in the use of zotepine
in patients at risk of arrhythmias (e.g. those with
coronary heart disease or those prescribed other
QTc prolonging drugs) and a pre-treatment ECG is
recommended before initiating treatment in these
patient groups.[82]
3.3.6 Other Atypical Agents
Analyses of ECGs obtained during four ran-
domised, controlled trials (n = 2700) involving
olanzapine showed that the incidence of maximum
QTc ≥450 msec during treatment was approxi-
mately equal to the incidence of QTc ≥450 msec at
baseline.[83] In addition, no patients had a QTc
>500 msec during olanzapine treatment. In a study
of quetiapine, mean QTc increases of up to ≤8 msec
were observed, but again there were no reported
instances of QTc >500 msec.[84] In 12 patients
treated with amisulpride 400 mg/day the mean QTc
interval decreased by 5.9 msec compared with the
pretreatment value.[85]
4. Risk Factors for Arrhythmias
Warner et al.[48] found QTc prolongation (>420
msec) in 23% of inpatients with chronic schizo-
phrenia compared with 2% of age-matched, drug-
free controls. Reilly et al.[49] assessed 495 psychi-
atric patients, the majority of whom were prescribed
antipsychotics, and reported an 8% prevalence for
QTc prolongation (>456 msec, equivalent to a
value 2 standard deviations above the mean value
seen in a healthy reference group). The difference
in the incidence between the two studies may
partly reflect the variations in patient charac-
teristics between the studies and the higher cut-off
value adopted by Reilly et al. Irrespective of this,
it is apparent that QT-interval prolongation occurs
in a significant minority of psychiatric patients
with antipsychotic treatment being a major cause.
However, arrhythmias are rare in patients pre-
scribed antipsychotics, and sudden death rarer still,
so it seems that the presence of one or more other
risk factors are required to precipitate an arrhyth-
mia in an individual with QT prolongation.
These risk factors can be divided into pharma-
cological and nonpharmacological (table V). Key
 Adis International Limited. All rights reserved.
1661
Table V. Risk factors for arrhythmias
Nonpharmacological risk factors
Congenital long QT syndromes
Individual predisposition
Specific cardiac disorders (e.g. ventricular hypertrophy, heart
failure, bradycardia)
Electrolyte imbalance (especially hypokalaemia)
Overdose of antipsychotic drug
Female sex
Restraint and psychological stress
Substance misuse
Miscellaneous factors
elderly
renal and hepatic impairmenta
slow metaboliser statusa
Pharmacological risk factors
Pharmacokinetic factors
inhibition of specific cytochrome P450 enzymes
competition for specific cytochrome P450 enzymes
Pharmacodynamic factors
independent QTc prolongation
electrolyte disturbance
a Depending on metabolism and route of elimination of drug.
nonpharmacological risk factors are reviewed in
sections 4.1 and pharmacological risk factors in
section 4.2. It should be noted that several of these
risk factors are listed in the ‘contra-indications’ or
‘precautions’ section of the Summary of Product
Characteristics (SPC) of pimozide, thioridazine
and ziprasidone.
4.1 Nonpharmacological Factors
4.1.1 Congenital Long QT Syndromes
Two inherited forms of QTc interval prolonga-
tion exist. The Romano-Ward syndrome shows
autosomal dominant inheritance. The Jervell and
Lange-Nielsen syndrome is associated with con-
genital deafness and is very rare. The most com-
mon presentation is with episodes of syncope trig-
gered by emotional or physical stress, although
cardiac arrest or sudden death may be the initial
presentation.[86] The syncopal episodes are some-
times misdiagnosed as epilepsy. Symptoms usually
begin in childhood or adolescence but presentation
may be at any age from a few days after birth to
Drugs 2002; 62 (11)
1662
middle age. The prevalence is unknown but may be
as high as 1 in 5000.[87]
The genetic cause of congenital long QT syn-
dromes (LQTS) is heterogeneous with at least
seven genes being involved.[88] All the genes iden-
tify to date encode ion channel proteins indicating
that the congenital LQTS are an ion-channel-
opathies.
4.1.2 Individual Predisposition
There is strong evidence that those individuals
who develop TdP when prescribed a proarrhythmic
drug have an underlying predisposition to manifest
such a reaction. A study of patients prescribed class
III antiarrhythmics showed that those who devel-
oped TdP had more marked drug-induced QT pro-
longation that those who did not develop TdP.[89]
Furthermore, the degree of QTc prolongation in the
group with TdP was unrelated to drug dosage. In
other words, those patients who developed TdP
showed an abnormal response to the drug. Further
support is provided by the finding that some pa-
tients who experience drug-induced TdP are at high
risk of a further arrhythmic episode if exposed to a
second QTc prolonging drug.[90]
In some patients the susceptibility has a genetic
basis. Molecular analysis has shown that a propor-
tion of patients who develop drug-induced QT pro-
longation and arrhythmia have mutations of genes
that code for cardiac ion channels. In some patients
the mutations involve genes associated with con-
genital LQTS[91,92] suggesting that, in these indi-
viduals, drug-induced TdP represents a ‘forme
fruste’ of the congenital LQTS. In others the ge-
netic abnormality is unrelated to the genes associ-
ated with congenital LQTS.[93]
The ‘susceptibility’ model helps explain the
apparent idiosyncratic nature of drug-induced
TdP.[94] In individuals with a marked repolarisation
abnormality (low repolarisation reserve) TdP will
occur when they are exposed to a drug with a low
proarrhythmic potential. In such persons TdP is
less to do with the drug and more to do with the
underlying susceptibility. In contrast, individuals
with a minor repolarisation abnormality (high
repolarisation reserve) will only develop TdP if ex-
 Adis International Limited. All rights reserved.
Haddad & Anderson
posed to a drug with a marked proarrhythmic po-
tential or if other predisposing factors are present
which reduce the repolarisation reserve (e.g. hypo-
kalaemia, bradycardia). Within this model the dif-
ference in the proarrhythmic potential of drugs re-
lates to the degree of predisposing abnormality
required for TdP to manifest.
The concept of an underlying genetic predispo-
sition is of potential clinical importance as it raises
the possibility of developing screening tests for
mutations of the involved genes and the early iden-
tification of individuals who are at risk.
4.1.3 Cardiac Disorders
Patients with cardiac hypertrophy and cardiac
failure are more susceptible to drug-induced TdP.
This is because both conditions reduce Ikr and pro-
long the action potential.[95] Bradycardia is another
risk factor and the mechanism is straightforward;
the slower the heart rate the longer the repolarisa-
tion phase. Ischaemic heart disease also increases
the pro-arrhythmic risk.[32]
4.1.4 Electrolyte Imbalance
Hypokalaemia, hypomagnesaemia and hypocal-
caemia can cause QT prolongation and so increase
the risk of arrhythmias. Electrolyte disturbances
may result from physical illness and reflect diar-
rhoea, vomiting, malabsorption or limited fluid in-
take. Drugs may also cause electrolyte imbalance,
for example certain diuretics cause hypokalaemia.
4.1.5 Overdose
Suicide and nonfatal overdose are common
among patients with schizophrenia. An association
between antipsychotic dosage and QTc prolonga-
tion has been demonstrated in several studies.[48,49]
It is possible that some deaths following antipsy-
chotic overdose reflect cardiac arrhythmias caused
by dose-related QTc prolongation. In support of
this, ventricular arrhythmias have been reported
with overdoses of thioridazine, haloperidol, sulpir-
ide, mesoridazine, pimozide, chlorpromazine,
sertindole and remoxipride.[96] With pimozide, a
drug known to cause QT prolongation, ten of 13
deaths reported to the CSM by 1990 were associ-
ated with dosages greater than 20mg daily, the up-
Drugs 2002; 62 (11)
Antipsychotic-Related Arrhythmias
per limit recommended in the British National For-
mulary.[97]
4.1.6 Female Sex
Several studies have shown that women are
more prone to drug-induced TdP. For example,
women accounted for 70% of the 323 cases of TdP
related to cardiovascular drugs which were identi-
fied in an extensive survey.[98] The increased inci-
dence in women remained irrespective of the pre-
sence of other risk factors. Female gender was a
major risk factor for increased mortality in patients
treated with sotalol versus those receiving placebo
in the SWORD study.[16] A female predominance
is also apparent in the FDA reports of erythromy-
cin-associated cardiac arrhythmias.[99] The in-
creased vulnerability of women to TdP may reflect
the fact that the QTc interval is longer in women
than in men by about 20 msec.[38]
4.1.7 Restraint and Psychological Stress
Strenuous exercise[100] and psychological
stress[101,102] are associated with sudden death in
the general population. Both factors may be rele-
vant in situations where an agitated or excited pa-
tient is restrained. The underlying mechanism may
relate to increased plasma noradrenaline and
adrenaline levels leading to increased myocardial
instability and fatal arrhythmias.[6] Such a mecha-
nism could account for sudden death during peri-
ods of restraint without implicating the antipsy-
chotic medication. If patients concurrently receive
antipsychotic medication, which causes QTc pro-
longation, then such changes may act in an additive
way to trigger sudden death.[103] Given the rela-
tionship between QTc prolongation and antipsy-
chotic dosage, the risk is likely to be at its greatest
if patients receive high dosages of parenteral med-
ication.
In a review of deaths in patients detained under
the Mental Health Act 1983 in England and Wales
over a 2-year period, Banerjee et al.[104] identified
two patients who died while being restrained after
receiving antipsychotic medication and concluded
that ‘the risk of sudden cardiotoxic collapse in re-
sponse to neuroleptic medication given during a
period of high physiological arousal should be
 Adis International Limited. All rights reserved.
1663
widely publicised’. However, the risk needs to be
kept in perspective and must be balanced against
the dangers of withholding pharmacological treat-
ment from highly disturbed psychotic individuals.
These risks include patient distress, damage to
property, and injury to self and others.
4.1.8 Substance Misuse
Alcohol and substance misuse are relatively
common in patients with schizophrenia and may
contribute to sudden death. Chronic alcohol mis-
use[105,106] and cocaine misuse[107,108] are both as-
sociated with QT prolongation. Sudden death is
well recognised in people using cocaine[109] and
has been reported in cocaine users who have been
restrained.[110] Some of these deaths appear to be
due to arrhythmias but other mechanisms may con-
tribute. For example, cocaine can cause coronary
artery vasospasm and so lead to myocardial infarc-
tion.[111]
4.1.9 Miscellaneous Factors
Hepatic and renal impairment have the potential
to increase the plasma concentrations of a QTc-
prolonging drug and so increase its cardiotoxic ef-
fect. The size of this effect will vary between drugs,
and will reflect the individual metabolism and
elimination characteristics of the drug. Renal im-
pairment was implicated as a contributory mech-
anism in a case report that documented sudden
death in a psychiatric inpatient who was prescribed
chlorpromazine.[112] The patient was identified as
having renal insufficiency several days before
death. The only relevant autopsy finding was an
elevated serum chlorpromazine concentration, pre-
sumably reflecting accumulation secondary to re-
nal impairment. The authors concluded that the
most likely cause of death was an arrhythmia in-
duced by the high serum chlorpromazine concen-
tration.
The elderly are particularly vulnerable to the
adverse effects of drugs because of their impaired
renal excretion and hepatic metabolism, and the
increased likelihood of physical illnesses and in-
teractions with co-prescribed medications.
Genetic polymorphisms within the hepatic cy-
tochrome P450 (CYP) enzyme system mean that
Drugs 2002; 62 (11)
1664
some individuals, termed ‘slow metabolisers’,
have a decreased ability to metabolise certain
drugs. Different antipsychotics are metabolised by
different cytochrome enzymes. Thioridazine is me-
tabolised by the CYP 2D6 pathway, which is defi-
cient in 7 to 10% of the Caucasian population.[113]
Such individuals may achieve particularly high
plasma concentrations of the drug and be at greater
risk of arrhythmias.
4.2 Pharmacological Factors
If a patient is prescribed an antipsychotic drug
that significantly prolongs the QTc interval, then
additional drugs can increase the risk of arrhythmia
via pharmacokinetic or pharmacodynamic interac-
tions. The likelihood of interaction is high as many
drugs, from a diverse range of classes, can be in-
volved. Furthermore, many patients will be treated
simultaneously by more than one doctor (e.g. psy-
chiatrist, general practitioner and other specialist)
if there is a comorbid physical disorder. Preventing
pharmacological interactions relies not only on
each doctor being familiar with many drugs but
also knowing what colleagues are co-prescribing
for any given patient.
4.2.1 Pharmacokinetic Interactions
A co-prescribed drug may increase the plasma
concentration of a QTc prolonging drug by inhib-
iting its metabolism by a specific CYP enzyme or
by competing as a substrate for that enzyme. The
importance of this mechanism is highlighted by the
experience with the motility stimulant cisapride
and the antihistamine terfenadine. The metabolism
of both drugs is highly dependent on the CYP 3A4
isoenzyme system. When prescribed alone cisapr-
ide and terfenadine cause only minor QTc eleva-
tion. However, if co-prescribed with a potent inhib-
itor of CYP 3A4, there is a marked rise in QTc
values reflecting an increase in plasma cisapride or
terfenadine concentrations.
In most studies terfenadine causes a mean in-
crease in the QTc interval of between 8 and 18
msec.[32] However, in a study in which terfenadine
was co-prescribed with ketoconazole, a CYP 3A4
inhibitor, the QTc interval increased by 82
 Adis International Limited. All rights reserved.
Haddad & Anderson
msec.[114] Cisapride in isolation is associated with
a QTc prolongation of 6 to 18 msec.[115,116] In one
study, monotherapy with cisapride led to a 6 msec
QTc elevation and clarithromycin alone (a CYP
3A4 inhibitor) caused a minimal QTc increase.[115]
However, the combination of cisapride and clar-
ithromycin caused an average QTc increase of 25
msec above pretreatment values in parallel with a
3-fold increase in the plasma cisapride concentra-
tion.
These interactions had serious clinical repercus-
sions. Between 1993 and 1999 the FDA received
341 reports of QT prolongation and ventricular ar-
rhythmias (80 of which were fatal) in association
with cisapride.[117] Concomitant prescriptions of
drugs known to inhibit CYP 3A4 accounted for 126
(37%) of these reports and was the largest single
risk factor. Most of the cardiac arrhythmias and
sudden deaths reported with terfenadine occurred
following overdose or when it was co-prescribed
with a CYP 3A4 inhibitor.[118] The potential for
interactions with CYP 3A4 substrates is also in-
creased with the concurrent intake of grapefruit
juice as it is a potent inhibitor of the enzyme.[116]
Some drugs that inhibit CYP 3A4, for example
imidazole and macrolide antibiotics, also prolong
the QTc interval in their own right. However, when
these drugs were co-prescribed with cisapride or
terfenadine it was the pharmokinetic, rather than a
pharmacodynamic, interaction that appeared most
relevant to the generation of TdP.[115]
Pimozide is largely metabolised by CYP 3A4,
although CYP 2D6 also plays a role. In vitro data
indicate that potent CYP 3A4 inhibitors, such as
macrolide antibiotics, will inhibit the metabolism
of pimozide resulting in a markedly elevated
plasma concentrations of pimozide.[22] A recent
case report[22] detailed the sudden death of a 27-
year-old man 2 days after he was prescribed pimoz-
ide and clarithromycin, a macrolide antibiotic.
Prior to combining these drugs the patient had a
prolonged QT interval. The UK SPC for pimozide
contraindicates the concomitant prescription of
drugs known to inhibit CYP 3A4 or 2D6.[61]
Drugs 2002; 62 (11)
Antipsychotic-Related Arrhythmias
The UK SPC for thioridazine, metabolised by
CYP 2D6, contraindicates concomitant use of CYP
2D6 inhibitors such as selective serotonin reuptake
inhibitors (SSRIs), tricyclic antidepressants
(TCAs) and β-blockers.[61]
Ziprasidone is metabolised by an aldehyde ox-
idase pathway and CYP 3A4. In study 054, concur-
rent administration of ketoconazole, a CYP 3A4
inhibitor, elevated plasma ziprasidone concentra-
tions but did not cause further prolongation of the
mean QTc interval suggesting a flattening of the
dose-QTc response.[8] This finding, plus the exist-
ence of two metabolic pathways and the fact that
there are no known clinically relevant inhibitors of
aldehyde oxidase, suggests that ziprasidone is less
susceptible to pharmacokinetic interactions that in-
crease the QTc to above values seen with mono-
therapy.
4.2.2 Pharmacodynamic Interactions
The effect of an antipsychotic on the QTc inter-
val will be potentiated by the concurrent use of
other drugs that prolong the QTc interval (table I).
Examples of nonpsychotropics that can prolong
the QTc interval include certain antihistamines, an-
tiarrhythmics and antimicrobials. Psychotropic
drugs that can cause QTc prolongation, and have
been associated with TdP, include lithium, chloral
hydrate, certain TCAs (amitriptyline, desipramine,
doxepin and imipramine)[7] and the tetracyclic an-
tidepressant maprotiline.[119] In a study of psychi-
atric patients, TCA use was an independent predic-
tor of QTc prolongation (adjusted odds ratio 4.4,
95%; CI 1.6 to 12.1; p = 0.004).[49] Life-threaten-
ing ventricular arrhythmias[120] and a case of sud-
den death[121] have been reported in patients co-
prescribed imipramine and thioridazine. Sudden
death has also been reported with the combination
of imipramine and chlorpromazine.[121]
The SSRIs are generally regarded as less cardio-
toxic than the TCAs, both at therapeutic dosages
and in overdose.[122] Studies with various SSRIs,
including paroxetine[123] and fluoxetine,[124] have
indicated absent or minimal effects on the QTc in-
terval, and the SSRIs are not generally regarded as
QTc-prolonging agents. However, occasional
 Adis International Limited. All rights reserved.
1665
cases of QTc prolongation with SSRI treatment
have been documented,[125,126] and TdP has been
reported with citalopram.[127] In summary, al-
though safer than TCAs, it would be an oversim-
plification to regard SSRIs as having no cardio-
toxic or proarrhythmic potential.
Antipsychotic polypharmacy (the co-prescrib-
ing of more than one antipsychotic) is common in
clinical practice, although there is little, if any, ev-
idence base to support it. In a 10-year prospective
study of a cohort of 88 psychiatric patients with
schizophrenia (mean age of 63 years) there were
39 deaths with no instances of suicide.[128] This
equated to a 1.33-fold higher relative risk of death
compared to the general population. An inde-
pendent risk factor for death was the concurrent
prescription of more than one antipsychotic drug
(relative risk 2.46; 95% CI 1.1 to 5.47; p = 0.03).
A possible explanation is that there was a toxic
additive effect of the antipsychotics. However, it
cannot be assumed that the mechanism was pro-
arrhythmia. Antipsychotic polypharmacy was re-
garded as present if it had occurred at any point in
the study period, not just at the time of death,[128]
and this is not consistent with a direct effect of
concurrent medications on cardiac repolarisation.
In summary, it is advisable to ensure that anti-
psychotics that cause significant QTc prolongation
are not co-prescribed with other QTc-prolonging
drugs. Advice to this effect appears in the manu-
facturers prescribing information for ziprasi-
done[76] in the US, and in the UK SPCs[61] for
pimozide and thioridazine. For example, the SPC
for thioridazine specifically contraindicates the
concomitant prescribing of TCAs, maprotiline,
phenothiazines and pimozide, as well as a variety
of nonpsychotropic agents.
A second way in which a co-prescribed drug can
increase the risk of arrhythmias is by causing elec-
trolyte disturbance. For example, some diuretics
can cause hypokalaemia. Low extracellular potas-
sium concentrations increase the risk of TdP by
reducing Ikr.
Drugs 2002; 62 (11)
1666
5. Managing the QTc Risk
5.1 Antipsychotic Selection
QTc prolongation is one of many factors that
need to be considered when selecting an antipsy-
chotic. Selection should be on an individual patient
basis. However, given that antipsychotics show lit-
tle difference in efficacy and that QTc prolongation
can have fatal consequences, it seems prudent to
avoid drugs that have a significant effect on the QT
interval where possible.
5.2 Patient Selection and Monitoring
Occasionally there will be good reasons to use
an antipsychotic associated with significant QTc
prolongation, such as when a patient has failed to
respond to other agents or has shown a good re-
sponse to the QTc prolonging drug in the past. Yap
and Camm[129] listed four key principles for safer
prescribing of QTc prolonging drugs:
• not exceeding the upper recommended dose;
• restricting the dosage in patients with pre-
existing heart disease or other risk factors;
• avoiding concomitant prescribing of drugs that
inhibit drug metabolism or excretion, prolong
the QT interval or produce hypokalaemia;
• ensuring that serum potassium levels are regu-
larly checked.
It must be emphasised that these are general
principals. Any specific advice regarding QTc pro-
longation in the SPC should be considered for each
drug. With certain antipsychotics this is extensive
and includes specific contraindications and precau-
tions designed to reduce the risk of cardiac compli-
cations. For example, with pimozide and thiorida-
zine an ECG is recommended prior to
commencement of treatment and at specified inter-
vals thereafter.
The experience with terfenadine[130,131] and
cisapride[132] is that clinicians often failed to follow
prescribing restrictions and monitoring require-
ments. In 1998 concern about QTc prolongation led
the FDA to determine that cisapride was contrain-
dicated in those with medical conditions or pre-
scribed medications that increased the arrhythmic
 Adis International Limited. All rights reserved.
Haddad & Anderson
risk. The prescribing information was changed and
all healthcare professional were informed by letter.
A survey of prescribing patterns the year prior to
and after this action showed that there had been no
material effect on contraindicated use of cisapr-
ide.[132] Prior to the regulatory action cisapride use
was contraindicated in 16, 30 and 60% of patients
in the three study sites. In the year after the figures
were 24, 28 and 58%, respectively. This finding
indicates that more effective ways to communicate
and implement safety measures are needed.
ECG monitoring of psychiatric patients raises
certain practical problems. Many psychiatric de-
partments do not have ECG facilities, and patients
may comply poorly with appointments to attend
the ECG department of a neighbouring hospital or
clinic. Even if the ECG is taken in the psychiatric
clinic, many psychiatrists lack the training or ex-
perience to interpret an ECG. A survey of trainee
psychiatrists in three hospitals found that only 20%
could identify prolongation of the QT interval on
an ECG.[133] Thus, improved facilities and training
are necessary.
Doctors need to be alert to symptoms that could
indicate cardiac arrhythmias in any patient pre-
scribed antipsychotic medication. These include
dizziness, palpitations and syncope. Such symp-
toms should prompt examination and an ECG. If a
patient develops TdP, the responsible drug should
be stopped and appropriate treatment for the ar-
rhythmia instigated. Psychiatrists should also re-
ceive regular training in cardiopulmonary resusci-
tation.
5.3 Advice for Patients
Patients prescribed an antipsychotic or other
drugs known to cause clinically significant QTc
prolongation should be advised about which med-
icines to avoid, and should be carefully monitored
to ensure that they comply with these instructions.
Some cardiologists recommend that patients be
provided with a warning card that lists contraindi-
cations for co-prescriptions.[129] If the patient is
seeing more than one doctor (e.g. a general practi-
tioner and a psychiatrist) both doctors need to be
Drugs 2002; 62 (11)
Antipsychotic-Related Arrhythmias
aware of the possible dangers associated with co-
prescribing QTc-prolonging medications.
5.4 Use of High Dosages
Clinical trials do not support the widespread use
of high dosages of antipsychotic drugs, but many
clinicians believe that individual patients occa-
sionally respond to high dosages. Given that QTc
prolongation is dose dependent, particular caution
is needed if exceeding licensed dosages. The Royal
College of Psychiatrists has provided guidance on
using antipsychotic dosages that exceed the upper
limits given in the British National Formulary.[134]
The recommendations include carrying out a base-
line ECG to exclude QT prolongation and other
abnormalities, repeating the ECG periodically, in-
creasing the dosage slowly, being alert to the pos-
sibility of drug interactions and carrying out regu-
lar physical observations (pulse, blood pressure
and temperature).
5.5 Rapid Tranquillisation
The use of antipsychotics in patients who are
struggling and require restraint is a complex and a
poorly researched area. Attempts to ‘talk down’ the
patient should be made, but in certain situations
parenteral medication is a necessity. In such pa-
tients failure to medicate can lead to escalating dis-
turbance, damage to property and injury to self and
others. Where possible it is advisable to use the
intramuscular route rather than intravenous admin-
istration. In several UK studies of prescribing prac-
tice haloperidol has been the antipsychotic of
choice, often being administered in combination
with a benzodiazepine.[135,136] Droperidol was also
frequently used.[135,136] In the UK the maximum
recommended dosage for haloperidol has recently
been reduced from 100mg to 30mg a day for oral
therapy and from 60mg to 18mg a day for intra-
muscular administration.[63,137] Given this, plus the
recent withdrawal of droperidol by the manufac-
turer,[18] it is likely that benzodiazepines will play
a larger part in rapid tranquillisation than they have
in the past. A short-acting intramuscular formula-
tion of olanzapine has recently been approved in
 Adis International Limited. All rights reserved.
1667
several countries and it is likely that short acting
intramuscular formulations of other atypical anti-
psychotics will become available in the near fu-
ture. The place of such agents is as yet unclear but
the favourable cardiac profile of olanzapine sug-
gests that it should be a safer option for rapid
tranquillisation.
5.6 Adopting a Coherent Policy
A coherent policy on drug-induced QTc prolon-
gation is needed to assist health professionals and
patients manage the associated risks. This should
include advice and education for clinicians and pa-
tients, assessment during drug development, post-
marketing surveillance, adverse drug reaction
monitoring and further research.
It is 15 years and 5 years, respectively, since the
American Psychiatric Association[5] and the Royal
College of Psychiatrists[6] published reports on the
association between antipsychotic drugs and sud-
den death. Since that time knowledge of QTc pro-
longation has increased, clinical practice has
changed and the range of antipsychotics available
to clinicians has altered. Given these changes, up-
to-date guidance on good clinical practice in the
management of QTc associated risk is required and
should be regularly updated.
A working party of the European Society of
Cardiology recommended that the pharmaceutical
industry introduce more thorough assessment of
repolarisation effects during the development of
new drugs.[7] They recommended that any conclu-
sion that a drug is ‘safe’ be reserved until the results
of postmarketing surveillance were available.
Clinical trials involve relatively small numbers of
carefully selected patients and TdP may only man-
ifest after a drug has been used by a large number
of patients who have one or more risk factors or
those prescribed medications for which there is a
potential for drug interactions. This explains why
with several drugs, including terfenadine, the link
between QTc prolongation and arrhythmias only
became apparent several years after initial market-
ing and after widespread clinical use.
Drugs 2002; 62 (11)
1668
A recent editorial in the British Medical Jour-
nal[129] recommended that all drugs that signifi-
cantly prolong the QT interval be listed and regu-
larly updated in a national drug catalogue such as
the British National Formulary, and any such ad-
verse events be urgently reported to drug safety
authorities and drug manufacturers.
Methodologically robust epidemiological re-
search is needed to clarify the association between
antipsychotic agents and sudden unexplained
death. A UK multicentre study is currently investi-
gating sudden death in psychiatric inpatients.[138]
Comorbid physical illness, physiological arousal
during restraint, alcohol consumption, misuse of
illicit drugs, the apparent central role of antipsy-
chotic drugs, and possible links to high dosage and
polypharmacy will all be evaluated.
6. Conclusion
As stated in the introduction, sudden, unex-
pected and unexplained deaths have been reported
in patients receiving antipsychotic drugs since the
early 1960s. The aetiology remains uncertain, how-
ever, at least a proportion of cases appear to involve
the antipsychotic causing TdP. Similar deaths are
recognised with other QTc prolonging drugs. It
seems that death is most likely to occur when drug-
induced QTc prolongation occurs simultaneously
with other risk factors, both pharmacological and
nonpharmacological. The size of the risk with an-
tipsychotics is unclear, but needs to be seen in the
context of the overall risks and benefits associated
with antipsychotic treatment. The balancing of
such risks is well recognised as antipsychotics have
a variety of other adverse effects, but nonetheless
deliver considerable benefit to many patients.
The risk of QTc prolongation and arrhythmias
seems to differ markedly among different antipsy-
chotics. This difference should be considered when
selecting a drug and there now seems to be suffi-
cient evidence to conclude that, if possible, an anti-
psychotic agent that does not significantly prolong
the QT interval should be chosen in preference to
one that does. However, selection must be on an
individual patient basis and take account of many
 Adis International Limited. All rights reserved.
Haddad & Anderson
other factors including other aspects of safety as
well as efficacy, tolerability, contraindications,
price and patient preference. If an antipsychotic
that increases the QT interval is prescribed, doctors
and patients need to take precautions to minimise
the proarrhythmic risk.
Acknowledgements
No external funding was used to assist in preparing this
manuscript. In 2001 Dr Haddad was a member of the Cardiac
Safety In Schizophrenia Group, an educational group sup-
ported by Eli Lilly.
References
1. Leestma JE, Koenig KL. Sudden death and phenothiazines.
Arch Gen Psychiatry 1968; 18: 137-48
2. Kelly HG, Fay JE, Laverty SG, et al. Thioridazine hydrochlo-
ride (Mellaril): its effect on the electrocardiogram and a report
on two fatalities with electrocardiographic abnormalities. Can
Med Assoc J 1963; 89: 546-54
3. Hollister LE, Koesk JC. Sudden death during treatment with
phenothiazine derivatives. JAMA 1965; 192: 1035-8
4. Huston JR, Bell GE. The effect of thioridazine hydrochloride
and chlorpromazine on the electrocardiogram. JAMA 1966;
198: 134-8
5. Simpson GM, Davis J, Jefferson JW, et al. Sudden deaths in
psychiatric patients: The role of neuroleptic drugs. Washing-
ton DC: American Psychiatric Association Task Force; 1987.
Report no. 27
6. Royal College of Psychiatrists. The association between anti-
psychotic drugs and sudden death. Report of the Working
Group of the Royal College of Psychiatrists’ Psychopharma-
cology Sub-Group. London: Royal College of Psychiatrists;
1997. Council Report No. CR57
7. Haverkamp W, Breithardt G, Camm J, et al. The potential for
QT prolongation and proarrhythmia by non-antiarrhythmic
drugs: clinical and regulatory implications. Report on a Policy
Conference of the European Society of Cardiology. Eur Heart
J 2000; 21 (15): 1216-31. Published simultaneously in Car-
diovasc Res 2000; 47 (2): 219-33
8. FDA. Psychopharmacological Drugs Advisory Committee. 19
July, 2000. Briefing Document for Zeldox Capsules
(zipriasone hydrochloride) [online]. Available from URL: http:
//www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1a.pdf
[Accessed 2002 Jun 24]
9. Roden DM, Woosley RL, Primm PK. Incidence and clinical
features of the quinidine-associated long QT syndrome: im-
plications for patient care. Am Heart J 1986; 111: 1088-93
10. Selzer A, Wray HW. Quinidine syncope. Paroxysmal ventricu-
lar fibrillation occurring during treatment of chronic atrial
arrhythmias. Circulation 1964; 30: 17-26
11. Kay GN, Plumb VJ, Arciniegas JG, et al. Torsade de pointes:
the long-short initiating sequence and other clinical features:
observations in 32 patients. J Am Coll Cardiol 1983; 2: 806-17
12. Bauman JL, Bauernfeind RA, Hoff JV, et al. Torsade de pointes
due to quinidine: observations in 31 patients. Am Heart J
1984; 107: 425-30
13. Hohnnloser SH. Proarrhythmia with class III antiarrhythmic
drugs: types, risks and management. Am J Cardiol 1997; 80:
G82-9
Drugs 2002; 62 (11)
Antipsychotic-Related Arrhythmias
14. Haverkamp W, Martinez RA, Hief C, et al. Efficacy and safety
of d,l-sotalol in patients with ventricular tachycardia and in
survivors of cardiac arrest. J Am Coll Cardiol 1997; 30: 487-95
15. Lehmann MH, Hardy S, Archibald D, et al. Sex differences in
risk of torsade de pointes with d,l-sotalol. Circulation 1996;
94: 2535-41
16. Waldo AL, Camm AJ, deRuyter H, et al. Effects of d-sotalol on
mortality in patients with left ventricular dysfunction after
recent and remote myocardial infarction. The SWORD Inves-
tigators. Survival with oral d-sotalol. Lancet 1996; 348
(9019): 7-12
17. Committee on Safety of Medicines-Medicines Control Agency.
Suspension of availability of sertindole (serdolect). Current
Problems in Pharmacovigilance 1999; 25: 1
18. Committee on Safety of Medicines-Medicines Control Agency.
QT interval prolongation with antipsychotics. Current Prob-
lems in Pharmacovigilance 2001; 27: 4
19. Committee on Safety of Medicines-Medicines Control Agency.
Cardiac arrhythmias with pimozide (Orap). Current Problems
in Pharmacovigilance 1995; 21: 1
20. Brown S. Excess mortality of schizophrenia. A meta-analysis.
Br J Psychiatry 1997; 171: 502-8
21. Jusic N, Lader M. Post-Mortem antipsychotic drug concentra-
tions and unexplained deaths. Br J Psychiatry 1994; 165: 787-91
22. Flockhart DA, Drici MD, Kerbusch T, et al. Studies on the
mechanism of a fatal clarithromycin-pimozide interaction in
a patient with Tourette syndrome. J Clin Psychopharmacol
2000; 20 (3): 317-24
23. Mehtonen OP, Aranko K, Malkonen L, et al. A survey of sudden
death associated with the use of antipsychotic or antidepres-
sant drugs: 49 cases in Finland. Acta Psychiatr Scand 1991;
84: 58-64
24. Reilly JG, Ayis A, Ferrier IN, et al. Thioridazine and sudden
unexplained death in psychiatric in-patients. Br J Psychiatry
2002; 180: 515-22
25. Ray WA, Meredith S, Thapa PB, et al. Antipsychotics and the
risk of sudden cardiac death. Arch Gen Psychiatry 2001; 58:
1161-7
26. Cancro R, Wilder R. A mechanism of sudden death in chlor-
promazine therapy. Am J Psychiatry 1970; 127: 368-71
27. Weiner WJ, Goetz CG, Nausieda PA, et al. Respiratory dyski-
nesias: extrapyramidal dysfunction and dyspnea. Ann Intern
Med 1978; 88: 327-31
28. Modestin J, Krapf R, Boker W. A fatality during haloperidol
treatment: mechanism of sudden death. Am J Psychiatry
1981; 138: 1661-17
29. Kilian JG, Kerr K, Lawrence C, et al. Myocarditis and cardio-
myopathy associated with clozapine. Lancet 1999; 354:
1841-5
30. Hoehns JD, Fouts MM, Kelly MW, et al. Sudden cardiac death
with clozapine and sertraline combination. Ann Phar-
macother 2001; 35: 862-6
31. Committee For Proprietary Medicinal Products (CPMP) Points
to consider: The assessment of the potential for QT interval
prolongation by non-cardiovascular medicinal products. Lon-
don: 1997 Dec
32. Malik M, Camm AJ. Evaluation of drug-induced QT interval
prolongation. Implications for drug approval and labelling.
Drug Saf 2001; 24: 323-51
33. Higham PD, Campbell RWF. QT dispersion. Br Heart J 1994;
71: 508-10
34. Ong JJ, Sarma JS, Venkataraman K, et al. Circadian rhythmicity
of heart rate and QTc interval in diabetic autonomic neurop-
athy: implications for the mechanism of sudden death. Am
Heart J 1993; 125: 744-52
 Adis International Limited. All rights reserved.
1669
35. Nagy D, DeMeersman R, Gallagher D, et al. QTc interval (car-
diac repolarisation): Lengthening after meals. Obes Res
1997; 5: 531-7
36. Carella MJ, Mantz SL, Rovner DR, et al. Obesity, adiposity, and
lengthening of the QT interval: improvement after loss. Int J
Obes Relat Metab Disord 1996; 20: 938-42
37. El-Gamal A, Gallagher D, Nawras A, et al. Effects of obesity
on QT, RR, and QTc intervals. Am J Cardiol 1995; 75: 956-9
38. Stramba-Badiale M, Locati EH, Martinelli A, et al. Gender and
the relationship between ventricular repolarisation and car-
diac cycle length during 24-hour Holter recordings. Eur Heart
J 1997; 18: 1000-6
39. Funck-Bretano C, Jaillon P. Rate-corrected QT interval: tech-
niques and limitations. Am J Cardiol 1993; 72: B17-22
40. De Ponti F, Poluzzi E, Montanaro N. QT-interval prolongation
by non-cardiac drugs: lessons to be learned from recent ex-
perience. Eur J Clin Pharmacol 2000; 56: 1-18
41. Bril A, Gout B, Bonhomme M, et al. Combined potassium and
calcium channel blocking activities as a basis for antiarrhyth-
mic efficacy with low proarrthymic risk: experimental profile
of BRL-32872. J Pharmacol Exp Ther 1996; 276: 637-46
42. De Cicco M, Marcor F, Robieux I, et al. Pharmacokinetic and
pharmacodynamic effects of high-dose continuous intrave-
nous verapamil infusion: clinical experience in the intensive
care unit. Crit Care Med 1999; 27: 332-9
43. Suessbrich H, Schonherr R, Heinemann SH, et al. The inhibi-
tory effect of the antipsychotic drug haloperidol on HERG
potassium channels expressed in Xenopus oocytes. Br J Phar-
macol 1997; 120: 968-74
44. Drolet B, Zhang S, Deschenes D, et al. Droperidol lengthens
cardiac repolarisation due to block of the rapid component of
the delayed rectified potassium current. J Cardiovasc Elec-
trophysiol 1999; 10: 1597-604
45. Drolet B, Vincent F, Rail J, et al. Thioridazine lengthens
repolarisation of cardiac ventricular myocytes by blocking
the delayed rectifier potassium current. J Pharmacol Exp Ther
1999; 288: 1261-8
46. Kang J, Wang L, Cai F, et al. High affinity blockade of the
HERG cardiac K+ channel by the neuroleptic pimozide. Eur
J Pharmacol 2000; 392: 137-40
47. Rampe D, Murawsky MK, Grau J, et al. The antipsychotic agent
sertindole is a high affinity antagonist of the human cardiac
potassium channel HERG. J Pharmacol Exp Ther 1998; 286:
788-93
48. Warner JP, Barnes TR, Henry JA. Electrocardiographic changes
in patients receiving neuroleptic medication. Acta Psychiatr
Scand 1996; 93: 311-3
49. Reilly JG, Ayes SA, Ferrier IN, et al. QTc interval abnormalities
and psychotropic drug therapy in psychiatric patients. Lancet
2000; 335: 1048-52
50. FDA Psychopharmacological Drugs Advisory Committee. 19
July, 2000. Background on Zeldox (ziprasidone hydrochlo-
ride capsules) Pfizer, Inc [online]. Available from URL: http:
//www.fda.gov/ohrms/dockets/ac/00/backgrd/3619b1b.pdf
[Accessed 2002 Jun 24]
51. Buckley NA, Whyte IM, Dawson AH. Cardiotoxicity more
common in thioridazine overdose than with other neurolep-
tics. J Toxicol Clin Toxicol 1995; 33: 199-204
52. Hulisz DT, Dasa SL, Black LD, et al. Complete heart block and
torsade de pointes associated with thioridazine poisoning.
Pharmacotherapy 1994; 14: 239-45
53. Paoloni P, Ciliberti D, Blasi N, et al. Iatrogenic torsade de
pointes induced by thioridazine. Minerva Cardioangiol 1992;
40: 245-9
54. Bastecky J, Kvasnicka J, Vortel J, et al. Suicidal ingestion of
thioridazine as a cause of severe impairment of heart rhythm-
Drugs 2002; 62 (11)
1670
polymorphic ventricular tachycardia. Cesk Psychiatr 1990;
86: 264-8
55. Flugemlman MY, Tal A, Pollock S, et al. Psychotropic drugs
and long QT syndromes: case reports. J Clin Psychiatry 1985;
46: 290-1
56. Kiriike N, Maeda Y, Nishiwaki S, et al. Iatrogenic torsade de pointes
induced by thioridazine. Biological Psychiatry22: 99-103
57. Kirchner V, Kelly CA, Harvey RJ. A systematic review of the
evidence for the safety and efficacy of thioridazine in demen-
tia. Available in The Cochrane Library [database on disk and
CD ROM]. Updated The Cochrane Collaboration; issue 4.
Oxford: Update Software, 1998
58. Dear Healthcare Professional letter. Thioridazine: restricted in-
dications and new warnings on cardiotoxicity. London: Com-
mittee on Safety of Medicines, 2000 Dec 11
59. Dear Healthcare Professional letter. Thioridazine. New Jersey:
Novartis Pharmaceuticals Corporation, 2000 Jul 7
60. Dear Healthcare Professional letter. Mesoridazine. New Jersey:
Novartis Pharmaceuticals Corporation, 2000 Sep 22
61. Association of the British Pharmaceutical Industry (ABPI)
Medicines Compendium 2002. London: Datapharm Commu-
nications Limited, 2002
62. Fulop G, Phillips RA, Shapiro AK, et al. ECG changes during
haloperidol and pimozide treatment of Tourette’s disorder.
Am J Psychiatry 1987; 144: 673-5
63. British Medical Association and Royal Pharmaceutical Society
of Great Britain. Antipsychotic Drugs. Section 4.2.1. London:
British National Formulary, 2002 Mar: 174-84
64. Lischke V, Behne M, Doelken P, et al. Droperidol causes dose-
dependent prolongation of the QT interval. Anesth Analg
1994; 79: 983-6
65. Fayer SA. Torsades de pointes ventricular tachyarrhythmia as-
sociated with haloperidol [letter]. J Clin Psychopharmacol
1986; 6: 375-6
66. Kriwisky M, Perry GY, Tarchitsky D, et al. Haloperdiol-induced
torsades de pointes. Chest 1990; 98: 482-4
67. Hunt N, Stern TA. The association between intravenous
haloperdiol and torsades de pointes: three cases and a litera-
ture review. Psychosomatics 1995; 36: 541-9
68. Hernderson RA, Lane S, Henry JA. Life-threatening ventricular
arrhythmia (torsade de pointes) after haloperdiol overdose.
Hum Exp Toxiciol 1991; 10: 59-62
69. Sharma ND, Rosman HS, Padhi ID, et al. Torsade de pointes
associated with intravenous haloperidol in critically ill pa-
tients. Am J Cardiol 1998; 81: 238-40
70. Ochiai H, Kashiwagi M, Usui T, et al. Torsade de pointes with
T wave alternans in a patients receiving moderate dose of
chlorpromazine: a report of a case [in Japanese]. Kokyu To
Junkan 1990; 38: 819-22
71. Lande G, Drouin E, Gauthier C, et al. Arrhythmogenic effects
of sultopride chlorhydrate: clinical and cellular electrophysi-
ological correlation [in French]. Ann Fr Anesth Reanim 1992;
11: 629-35
72. Zimbroff DL, Kane JM, Tamminga CA, et al. Controlled, dose-
response study of sertindole and haloperidol in the treatment
of schizophrenia. Am J Psychiatry 1997; 154: 782-91
73. Serdolect (sertindole) [product monograph], revised. Copenha-
gen, Denmark: Lundbeck, 1997 Jan: 39-43
74. Daniel DG, Wozniak P, Mack RJ, et al. Long-term efficacy and
safety comparison of sertindole and haloperidol in the treat-
ment of schizophrenia. The sertindole study group. Psy-
chopharmacol Bull 1998; 34: 61-9
75. Fritze J, Bandelow B. The QT interval and the atypical antipsy-
chotic, sertindole. Int J Psych Clin Pract 1998; 2: 265-73
76. Pfizer. Geodon (Ziprasidone hydrochloride) [summary of prod-
uct characteristics]. Pfizer US Pharmaceuticals. Issued 2001 Feb
 Adis International Limited. All rights reserved.
Haddad & Anderson
77. Yerrabolu M, Prabhudesai S, Tawam M, et al. Effect of
risperidone on QT interval and QT dispersion in the elderly.
Heart Dis 2000; 2: 10-2
78. Lo Vecchio F, Hamilton RJ, Hoffman RJ. Risperidone overdose.
Am J Emerg Med 2000; 14: 95-6
79. Ravin DS, Levenson JW. Fatal cardiac event following initiation
of risperidone therapy. Ann Pharmacother 1997; 31: 867-70
80. Kang UG, Kwon JS, Ahn YM, et al. Electrocardiographic ab-
normalities in patients treated with clozapine. J Clin Psychi-
atry 2000; 61: 441-6
81. Modai I, Hirschmann S, Rava A, et al. Sudden death in patients
receiving clozapine treatment: a preliminary investigation. J
Clin Psychopharmacol 2000; 20: 325-7
82. Product Monograph for Zoleptil (zotepine). Knoll AG. Ger-
many 1999, 37
83. Czekalla J, Beasley CM, Dellva MA, et al. Analysis of the QTc
interval during olanzapine treatment of patients with schizo-
phrenia and related psychosis. J Clin Psychiatry 2001; 62:
191-8
84. Arvanitis LA, Miller BG, the Seroquel Trial 13 Study Group.
Multiple fixed doses of ‘seroquel’ (quetiapine) in patients
with exacerbation of schizophrenia: a comparison with halo-
peridol and placebo. Biol Psychiatry 1997; 42: 233-46
85. Agelink MW, Majewski T, Wurthmann C, et al. Effects of newer
atypical antipsychotics on autonomic neurocardiac function:
a comparison between amisulpride, olanzapine, sertindole
and clozapine. J Clin Psychopharmacol 2001; 21: 8-13
86. Viskin S. Long QT syndromes and torsade de pointes. Lancet
1999; 354: 1625-33
87. Sudden Arrhythmia Death Syndromes (SADS) Foundation. An
overview of the inherited long QT syndrome. Available from
URL: http://www.sads.org/LQTS.html [Accessed 2002 Jun 24]
88. Towbin JA, Vatta M. Molecular biology and the prolonged QT
syndromes. Am J Med 2001; 110: 385-98
89. Houltz B, Darpo B, Edvardsson N, et al. Electrocardiographic
and clinical predictors of torsades de pointes induced by al-
mokalant infusion in patients with chronic atrial fibrillation
or flutter: a prospective study. Pacing Clin Electrophysiol
1998; 124: 663-8
90. Jackman WNM, Friday KJ, Anderson JL, et al. The long QT
syndromes: a critical review, new clinical observations and a
unifying hypothesis. Prog Cardiovascular Dis 1988; 31: 115-72
91. Napolitano C, Schwartz PJ, Brown AM, et al. Evidence for a
cardiac ion channel mutation underlying drug induced QT
prolongation and life threatening arrhythmias. J Cardiovasc
Electrophysiol 2000; 6: 691-6
92. Sesti F, Abbott GW, Wei J, et al. A common polymorphism
associated with antibiotic-induced cardiac arrhythmia. Proc
Natl Acad Sci U S A 2000; 97: 100613-8
93. Clancy CE, Rudy Y. Linking a genetic defect to its cellular
phenotype in a cardiac arrhythmia. Nature 1999; 400: 566-9
94. Roden DM. Taking the ‘idio’ out of ‘idiosyncratic’: Predicting
torsade de pointes. Pacing Clin Electrophysiol 1998; 21:
1029-34
95. Tomasselli GF, Marban E. Electrophysiological remodelling in
hypertrophy and heart failure. Cardiovasc Res 1999; 42: 270-83
96. Buckley NA, Sanders P. Cardiovascular adverse effects of anti-
psychotic drugs. Drug Saf 2000 Sep; 23 (3): 215-28
97. Committee on Safety of Medicines. Cardiotoxic effects of
pimozide. Current problems in Pharmacovigilance 1990; 29:
11-2, 35
98. Makkar RR, Fromm BS, Steinman RT, et al. Female gender as
a risk factor for torsade de pointes associated with cardiovas-
cular drugs. JAMA 1993; 270: 2590-7
Drugs 2002; 62 (11)
Antipsychotic-Related Arrhythmias
99. Drici MD, Knollmann BC, Wang WX, et al. Cardiac actions of
erythromycin: influence of female sex. JAMA 1998; 280:
1774-6
100. Hillis WS, McIntyre PD, Maclean J, et al. Sudden death in sport.
BMJ 1994; 309: 657-60
101. Engel GL. Sudden and rapid death during psychological stress:
folklore or folk wisdom? Ann Intern Med 1971; 74: 771-82
102. Malik MA. Emotional distress as a precipitating factor in sud-
den deaths due to coronary insufficiency. J Forensic Sci 1973;
18: 47-52
103. Kumar A. Sudden unexplained death in a psychiatric patient -
a case report: the role of phenothiazines and physical re-
straint. Med Sci Law 1997; 37: 170-5
104. Banerjee S, Bingley W, Murphy E. Deaths of detained patients:
a review of reports to the Mental Health Act Commission.
London: Mental Health Foundation, 1995
105. Koide T, Ozeki K, Kaihara S, et al. Etiology of QT prolongation
and T wave changes in chronic alcoholism. Jpn Heart J 1981;
22: 151-66
106. Yokoyama A, Ishii H, Takagi T, et al. Prolonged QT interval in
alcoholic autonomic nervous dysfunction. Alcohol Clin Exp
Res 1992; 16: 1090-2
107. Perera R, Kraebber A, Schwartz MJ. Prolonged QT interval and
cocaine use. J Electrocardiol 1997; 30: 337-9
108. Gamouras GA, Monir G, Plunkitt K, et al. Cocaine abuse:
repolarisation abnormalities and ventricular arrhythmias. Am
J Med Sci 2000; 320: 9-12
109. Karch SB. Cardiac arrest in cocaine users. Am J Emerg Med
1996; 14: 79-81
110. Wetli CV, Fishbain DA. Cocaine-induced psychosis and sudden
death in recreational cocaine users. J Forensic Sci 1985; 30:
873-80
111. Lange R, Cigarroa R, Flores E, et al. Cocaine-induced coronary-
artery vasoconstriction. N Engl J Med 1989: 321; 1557-62
112. Dorson PG, Crismon ML. Chlorpromazine accumulation and
sudden death in a patient with renal insufficiency. Drug Intell
Clin Pharm 1988; 22: 776-8
113. Kroemer HK, Eichelbaum M. ‘It’s the genes, stupid’. Molecular
bases and clinical consequences of genetic cytochrome
P4502D6 polymorphism. Life Sci 1995; 56: 2285-98
114. Honig PK, Wortham DC, Zamani K, et al. Tefenadine-ketocon-
azole interaction: pharmacokinetic and electrocardiographic
consequences. JAMA 1993; 269: 1513-8
115. Van Haarst AD, van’t Klooster GAE, van Gerven JMA, et al.
The influence of cisapride and clarithromycin on QT intervals
in healthy volunteers. Clin Pharmacol Ther 1998; 66: 542-6
116. Kivisto KT, Lilja JJ, Backman JT, et al. Repeated consumption
of grapefruit juice considerably increases plasma concentra-
tion of cisapride. Clin Pharmacol Ther 1999; 66: 448-53
117. Wysowski DK, Corken A, Gallo-Torres H, et al. Postmarketing
reports of QT prolongation and ventricular arrhythmia in as-
sociation with cisapride and Food and Drug Administration
regulatory actions. Am J Gastroenterol 2001; 96: 1698-703
118. Woosley RL, Chen Y, Freiman JP, et al. Mechanism of the car-
diotoxic actions of terfenadine. JAMA 1993; 269: 1532-6
119. Herrmann HC, Kaplan LM, Bierer BE. Q-T prolongation and
torsade de pointes ventricular tachycardia produced by the
tetracyclic antidepressant agent maprotiline. Am J Cardiol
1983; 51: 904-6
120. Heiman EM. Cardiac toxicity with thioridazine-tricyclic anti-
depressant combination. J Nerv Ment Dis 1977; 165: 139-43
 Adis International Limited. All rights reserved.
1671
121. Swanson JR, Jones GR, Krasselt W, et al. Death of two subjects
due to imipramine and desipramine metabolite accumulation
during chronic therapy: a review of the literature and possible
mechanisms J Forensic Sci 1997; 42: 3335-339
122. Coupland N, Wilson S, Nutt D. Antidepressant drugs and the
cardiovascular system: a comparison of tricylics and selective
serotonin reuptake inhibitors and their relevance for the treat-
ment of psychiatric patients with cardiovascular problems. J
Psychopharmacol 1997; 11: 83-92
123. Edwards JG, Goldie A, Papayanni-Papasthatis S. Effects of
paroxetine on the electrocardiogram. Psychopharmacology
1989; 97: 96-8
124. Baker B, Dorian P, Sandor P, et al. Electrocardiographic effects
of fluoxetine and doxepin in patients with major depressive
disorder. J Clin Psychopharmacol 1997; 17: 15-21
125. Rodriguez de la Torre B, Dreher J, Malevany I, et al. Serum
levels and cardiovascular effects of tricyclic antidepressants
and selective serotonin reuptake inhibitors in depressed pa-
tients. Ther Drug Monit 2001; 23: 435-40
126. Eefurth A, Loew M, Dobmeier P, et al. ECG changes after
paroxetine. 3 case reports [in German]. Nervenarzt 1998; 69:
629-31
127. Meuleman C, Jourdain P, Bellorinin M, et al. Citalopram and
torsade de pointes. A case report [in French]. Arch Mal Coeur
Vaiss 2001; 94: 1021-4
128. Waddington JL, Youssef HA, Kinsella A. Mortality in Schizo-
phrenia. Antipsychotic polypharmacy and absence of adjunc-
tive anticholinergics over the course of a 10-year prospective
study. Br J Psychiatry 1998; 173: 325-9
129. Yap YG, Camm J. Risk of torsade de pointes with non-cardiac
drugs. BMJ 2000; 320: 1158-9
130. Cavuto NJ, Woosley RL, Sale M, et al. Pharmacies and preven-
tion of potentially fatal drug interactions. JAMA 1996; 275:
1086-7
131. Thompson D, Oster G. Use of terfenadine and contraindicated
drugs. JAMA 1996; 275: 1339-41
132. Smalley W, Shatin D, Wysowski DK, et al. Contraindicated use
of cisapride: impact of food and drug administration regula-
tory action. JAMA 2000; 284: 3036-9
133. Warner JP, Gledhill JA, Connell F, et al. How well do psychi-
atric trainees interpret electrocardiographs. A cross-sectional
survey. Psychiatr Bull R Coll Psychiatr 1996; 20: 651-2
134. Thompson C. Consensus statement: the use of high-dose anti-
psychotic medication. Br J Psychiatry 1994; 164: 448-58
135. Simpson D, Anderson I. Rapid tranquillisation: a questionnaire
survey of practice. Psychiatr Bull R Coll Psychiatr 1996; 20:
149-52
136. Pilowsky LS, Ring H, Shine PJ, et al. Rapid tranquillisation: a
survey of emergency prescribing in a general psychiatric hos-
pital. Br J Psychiatry 1992; 160: 831-5
137. Haw C, Stubbs J. New BNF maximum recommended dose for
haloperidol. Psychiatr Bull R Coll Psychiatr 2001; 25: 120-1
138. Appleby L, Thomas S, Ferrier N, et al. Sudden unexplained
death in psychiatric in-patients. Br J Psychiatry 2000; 176:
405-6
Correspondence and offprints: Dr Peter M. Haddad, Bolton,
Salford and Trafford Mental Health Partnership, Cromwell
House, Cromwell Road, Eccles, Salford, M30 0GT, UK.
Drugs 2002; 62 (11)