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

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

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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

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1652 Haddad & Anderson

been withdrawn in the UK include prenylamine, strongly implicate the antipsychotic as either the
terodiline, astemizole and cisapride, while the an- main factor, or at least a contributory factor, in
tihistamine terfenadine was restricted to prescrip- causing death.
tion only status.[7] This paper examines the possi- Only a few studies have specifically addressed
ble relationship between antipsychotic drugs, QTc the issue of sudden unexplained death and antipsy-
prolongation, TdP and sudden death. chotic medication. In a series of autopsy negative
deaths in Finland, Mehtonen et al.[23] found that
1. Sudden Unexplained Death phenothiazines, particularly thioridazine, were
over-represented compared to their population use.
Schizophrenia is associated with increased mor-
The main limitation of the study is that it was de-
tality. This results not only from an increased sui-
scriptive and did not control for potential con-
cide rate but also from increased mortality due to
‘natural causes’ including cardiovascular dis- founding factors such as age and cardiovascular
ease.[20] There are many possible explanations for disease. Two recent studies overcome this weak-
this association which should be regarded as being ness.
multifactorial. Central to this paper is the possibil- Reilly et al.[24] conducted a retrospective case-
ity that antipsychotic drugs may contribute to the control study of UK psychiatric in-patients dying
excess mortality by causing sudden, unexpected, suddenly and surviving controls matched for age,
unexplained death, defined by Jusic and Lader[21] gender and psychiatric diagnosis. Logistic regres-
as ‘death within the hour of symptoms (excluding sion analysis showed that probable sudden unex-
suicide, homicide and accident) which is both un- plained death was significantly associated with
expected in relation to the degree of disability be- current use of thioridazine (adjusted odds ratio =
fore death and unexplained because clinical inves- 5.3; 95% confidence interval [CI] 1.7 to 16.2; p =
tigation and autopsy failed to identify any plausible 0.004) as well as hypertension and ischaemic heart
cause’. Of course, the accuracy of the finding of disease. There was no significant association with
‘autopsy negative’ death depends on the extent of other individual antipsychotic drugs, although this
the examination and the skill and experience of the may reflect the small study size.
pathologist. Ray et al.[25] conducted a retrospective cohort
Case reports from the 1960s to the present day study of approximately half a million Tennessee
have documented sudden death in patients receiv- Medicaid enrolees, many of whom were prescribed
ing antipsychotics.[1-4,21,22] An association is also antipsychotics. The data related to the period 1988
evident in data collected by regulatory bodies. For
to 1993, prior to the introduction of atypical anti-
example, from the date of first marketing to May
psychotics other than clozapine. The cohort had
1996 the UK database of spontaneous adverse drug
1487 confirmed sudden cardiac deaths and multi-
reaction reports, maintained by the Medicines Con-
variate rate ratios were calculated controlling for
trol Agency (MCA), received 31 reports of unex-
plained sudden death and 63 reports of fatal cardiac potential confounding factors including age, sex,
arrest or arrhythmia in association with 11 antipsy- race, non-cardiac and cardiac illness. The risk of
chotic agents.[6] sudden cardiac death in those currently receiving a
Sudden unexplained death occurs in the general moderate-dose antipsychotic drug (>100mg thio-
population and so, even if antipsychotics exerted ridazine equivalents per day) was 2.39 times
no harmful effect, such deaths would occur among greater than for non-users (95% CI 1.77 to 3.22; p
patients receiving medication by coincidence. < 0.001). This was greater than the risk for current
However, the details of some case reports (such as low-dose antipsychotic use (p = 0.003). The risk
a close temporal link between starting an antipsy- among former antipsychotic-users was not signifi-
chotic and death or lack of other risk factors) cantly different to that of non-users.

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Antipsychotic-Related Arrhythmias 1653

Among current moderate-dose antipsychotic disease. In summary, although each study has its
users, an increased risk of sudden cardiac death weaknesses, a review of the whole evidence base
existed for both sexes and for both of two age provides a strong case that certain antipsychotic
groups, but was greater in females and in those drugs can increase the risk of sudden unexplained
aged 65 years or older.[25] Among cohort members death.
with severe cardiovascular disease, current moder- Arrhythmias have long been regarded as the
ate-dose antipsychotic users had a 3.53-fold in- most plausible mechanism by which antipsychot-
creased risk of sudden cardiac death compared ics could cause sudden unexplained death, al-
with non-users (the risk ratio in the absence of car- though other mechanisms have been proposed.
diac disease was 1.60). An increased risk existed These include peripheral vasodilation leading to
for subgroups defined by current use of haloperi- hypotension and cardiovascular collapse,[26] respi-
dol, thioridazine, chlorpromazine and thiothixene. ratory dyskinesias that impair co-ordination of re-
Absolute rates of sudden cardiac death per 10 000 spiratory muscles leading to asphyxia[27] and oral-
person-years of follow-up were calculated (stand- laryngeal-pharyngeal dystonia leading to acute
ardised to the age and sex distribution of the co- airway obstruction.[28]
hort).[25] Within the entire cohort the rate per 10 000- Acute myocarditis[29] and cardiomyopathy[30]
person years was 26.9 for users of moderate-dose have been implicated in sudden deaths associated
antipsychotics compared with 11.3 for non-users with clozapine but these should be recognised at
i.e. for every 10 000 person-years of follow-up the postmortem examination. Prolongation of the
antipsychotic use was associated with 15 addi- QTc interval is a surrogate marker or signal for the
tional deaths. In those with no cardiovascular dis- risk of arrhythmias associated with prolongation of
ease and severe cardiovascular disease, respec- cardiac repolarisation.[31] However, arrhythmias
may develop though other pathways, for example
tively, use of moderate-dose antipsychotics was
suppression or acceleration of atrioventricular
associated with 4 and 367 additional sudden car-
nodal conduction. Clearly, the cardiac safety of a
diac deaths.
drug can not be assessed solely on the basis of its
All three studies[23-25] indicate an association
effects on the QTc interval.
between antipsychotic use and sudden death but
none prove causality. Several factors could ex-
2. Mechanisms for QTc Prolongation
plain, or contribute to, the association. For exam-
and Proarrhythmia
ple, the higher rate of sudden death in antipsy-
chotic users may reflect under-diagnosis and
2.1 QTc Interval
under-treatment of cardiovascular disease or higher
rates of smoking within this group, factors that The normal QT interval runs from the beginning
were not assessed in any of the studies. However, of the QRS complex to the end of the T wave (fig-
these explanations are weakened by the fact that ure 1). It represents the time between the onset of
thioridazine was the only antipsychotic associated electrical depolarisation of the ventricles and the
with increased risk of death in the study by Reilly end of repolarisation, that is, it reflects the duration
et al.[24] and in the study by Ray et al.[25] the in- of individual action potentials in the cardiac myo-
creased risk associated with antipsychotics was cytes. The QT interval shortens with increasing
dose related and specific to current antipsychotic heart rate and correcting for this variation gives the
use, rather than former use. In addition, Ray et QTc or rate-corrected value. Various formulae ex-
al.[25] completed a secondary analysis that sug- ist for making this correction with some contro-
gested that the additional risk of sudden death con- versy regarding which is the most appropriate. One
ferred by smoking was already largely accounted of the most widely used, and that recommended by
for by controlling for diagnosed cardiovascular the European Medicines Evaluation Agency,[31] is

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1654 Haddad & Anderson

R interval is subject to variation within the myocar-


dium and differs between ECG leads, a phenome-
non referred to as QT dispersion.[33] The QTc inter-
P T
val seen in a 12 lead ECG is the averaged measure
of repolarisation across most of the ventricles. The
Q S
QT interval is also subject to diurnal and prandial
variation, and increases during sleep[34] and after
PQ QRS
food consumption. Increases of 16 to 23 msec have
QT
been reported during the 60 minutes following a
Fig. 1. Schematic electrocardiographic trace showing the QT meal.[35] Obesity is often associated with QTc pro-
interval.
longation and a 10kg increase in fat mass has been
linked to a >5 msec increase in QTc.[36,37] Further-
Bazett’s formula (QTc = QT/RR1/2). Others include more, the mean QTc interval is longer in females
the Fridericia and Framingham formulae. than in males.[38] Difficulty in identifying the end
A disadvantage of all universal correction for- of the T-wave can introduce further variability in
mulae is that they can over or under correct the QT the measurement of the QTc interval, and manual
interval when the heart rate extends beyond a nar- and automatic measurements may not correlate
row physiological range. The Bazett formula in
well.[39] These factors have the potential to intro-
particular tends to overestimate the QTc interval at
duce inconsistencies within and across studies
higher heart rates. Consequently when applied to a
The marked intraindividual variability in the QT
drug that accelerates the heart rate it can result in
interval makes a strict divide between normal and
artificial QTc (Bazett) prolongation. The Fridericia
abnormal QTc values problematic. In 1997 the
formula (QTc = QT/RR1/3) is less sensitive to this
Committee for Proprietary Medicinal Products
effect. Conversely, the Bazett formula underesti-
mates the QTc when applied to drugs, such as β- (CPMP) published a report on the assessment of
blockers, that slow the heart rate. QT-interval prolongation by noncardiovascular
These correction problems reflect the assump- drugs.[31] This suggested normal, borderline and
tion that a single mathematical formula will de- prolonged values for the QTc after Bazett’s correc-
scribe the QT to RR relationship satisfactorily in tion (table II).
all individuals and this is not the case. In clinical The problems of measuring the QTc interval and
pharmacology studies improved heart rate correc- the lack of a direct relationship between the QTc
tion can be achieved by employing a data-specific interval and the potential for developing arrhyth-
correction formula but even this is liable to distor- mias has led to ongoing research into alternative
tions. The most reliable method of heart rate cor- measures of cardiac repolarisation including T-
rection is to devise a correction formula for each wave changes.[32] At present such work is at an ex-
study participant. This approach requires large perimental level.
numbers of ECGs for each individual, is expensive
and is largely restricted to academic research work.
Table II. Standard values for the QTc interval (Bazett correction)
These issues, and others related to the assessment suggested by the Committee For Proprietary Medicinal Products[31]a
of drug-induced QT prolongation, are comprehen- Women (msec) Men (msec)
sively dealt with in a recent review by Malik and Normal <450 <430
Camm.[32] Borderline 451-470 431-450
Multiple sources of variability in the measure- Prolonged >470 >450
ment of the QTc interval exist. For example, the QT a These values assume the absence of any drug or disease.

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Antipsychotic-Related Arrhythmias 1655

2.2 QTc Prolongation depolarisations in combination with increased het-


erogeneity of cardiac repolarisation.
The cardiac action potential is generated by the Although TdP may be asymptomatic or cause
transmembranal movement of various ion currents self-limiting palpitations, dizziness or syncope, in
in cardiac cells. These include sodium, calcium and rare cases it may progress to ventricular fibrillation
potassium, and a variety of ion channel subtypes and sudden death. The risk of TdP increases with
exist. Depolarisation is primarily the result of the increasing length of the QTc interval but the rela-
inward movement of sodium ions. The repolarisa- tionship is not linear.
tion phase is primarily the result of the outward The 1997 CPMP document provided guidance
movement of potassium ions. One of the most stud- on ‘signal’ values for QT measurements.[31] The
ied potassium currents is the delayed rectifier po- values refer to individual QTc changes (after
tassium current (Ik), which is the sum of two kin- Bazett’s correction) and not to mean values for
etically and pharmacologically distinct potassium study populations. Individual changes of less than
currents, a rapidly-activating (Ikr) and a slowly-ac- 30 msec were regarded as unlikely to raise signif-
tivating (Iks) component. icant concerns about the proarrhythmic potential
Virtually all drugs known to cause TdP have of a drug. In contrast, two changes were high-
been shown to block Ikr; the relevant ion channel lighted as raising ‘clear concerns’ about the poten-
is encoded by the human ether-a-go-go-related tial risk of a drug to induce arrhythmias including
gene (HERG).[40] TdP that is attributable solely to TdP:
the disruption of other ion channels has not been • an individual change in the QTc of greater than
reported.[32] However, such a possibility cannot be 60 msec relative to drug-free baseline measure-
ruled out. In particular, inhibition of potassium ments;
currents other than Ikr may be proarrhythmic, while • an absolute QTc value, or at lower heart rates an
effects on other ion channels may counteract this uncorrected QT value, greater than 500 msec.
tendency. For example, it has been postulated that Of these two indicators, the absolute QTc value
combined calcium and potassium channel block- was regarded as having greater prognostic signifi-
ade may reduce the proarrhythmic risk associated cance. Two other parameters relating to QTc dis-
with QTc prolongation.[41] This may explain why persion across a 12 lead ECG were regarded as
verapamil, a combined potassium and calcium raising ‘concern’ about the potential for arrhyth-
channel antagonist, has not been reported to cause mias:
TdP despite causing QTc prolongation in a dose- • dispersion greater than 100 msec;
dependent manner.[42] • a change in dispersion of more than 100%.[31]
The different propensity of antipsychotic agents It is important to emphasise that QTc prolon-
to cause QTc prolongation and TdP reflects their gation is only a surrogate marker or signal of ar-
differential effects on cardiac ion channels at ther- rhythmic risk and not the risk itself. Some drugs,
apeutic dosages. Haloperidol,[43] droperidol,[44] thio- including amiodarone, cause significant QTc pro-
ridazine,[45] pimozide[46] and sertindole[47] have all longation but rarely cause TdP.[13]
been shown to be high affinity antagonists of Ikr.
3. QTc Prolongation and Specific
Antipsychotic Drugs
2.3 Torsade de Pointes
3.1 Overview
TdP is a ventricular arrhythmia characterised by
QRS complexes of changing amplitude that appear QTc prolongation with antipsychotic agents, as
to ‘twist’ around the isoelectric line. It is believed with other drugs, is dose related.[48,49] Warner et
to be triggered by the occurrence of early after- al.[48] showed that QTc prolongation was signifi-

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1656 Haddad & Anderson

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

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Antipsychotic-Related Arrhythmias 1657

Specific antipsychotics, particularly those where icantly associated with current use of thiorida-
QTc prolongation has been highlighted as a poten- zine (adjusted odds ratio = 5.3; 95% CI 1.7 to
tial problem, are discussed in more detail in sec- 16.2; p = 0.004).[24]
tions 3.2 and 3.3. • Since 1964 the Committee on the Safety of
Medicines (CSM)/MCA has received 42 reports
3.2 Conventional Antipsychotics of suspected arrhythmias associated with thio-
ridazine in the UK.[18] Of the cases where the
3.2.1 Thioridazine outcome was known 21 of 39 were fatal. These
QTc prolongation appears a particular problem reports included patients receiving low dosages
with thioridazine with evidence accumulating of thioridazine or with a history of dementia.
from several sources. • Multiple case reports have documented TdP and
• Reilly et al.[49] showed an increased risk of QTc sudden death in patients prescribed thioridazine
prolongation with thioridazine compared with at therapeutic dosages and following over-
other antipsychotic drugs (adjusted odds ratio dose.[1,2,52-56] This includes a case published in
5.4; 95% CI 2.0 to 13.7; p < 0.001). In this study 1963 that was the first report of sudden death in
15 of 64 patients treated with thioridazine had a patient prescribed an antipsychotic agent.[2]
a prolonged QTc interval. • Thioridazine causes significant blockade of
• In a large series of consecutive patients present- Ikr.[45]
ing to hospital with antipsychotic drug over- Despite these data, thioridazine has often been
doses, compared with other drugs thioridazine used as an anxiolytic or hypnotic in the UK, even
was more likely to cause tachycardia (odds ratio though there is little evidence for such use.[57] In
1.7; 95% CI 1.1 to 2.9; p = 0.03), a prolonged QTc the year 2000, following a review by the CSM, the
interval (>450 msec) [odds ratio 4.7; 95% CI 2.7 MCA in the UK restricted the indications for thio-
to 7.9; p = 0.001] and arrhythmias (odds ratio ridazine.[58] The CSM concluded that the risk to
infinity; 95% CI 2.4 to infinity; p = 0.004).[51] benefit ratio would be favourable only when thio-
• A study of medico-legal autopsies conducted by ridazine was used as a second-line treatment in
Mehtonen et al.[23] in Finland over a 3-year pe- schizophrenia in adults under the supervision of a
riod (1985 to 1988) identified 49 cases of sud- consultant psychiatrist.[18] Previous indications
den death associated with the therapeutic use of which included anxiety, mania, impulsive behavi-
antipsychotic or antidepressant drugs. Pheno- our and agitation in the elderly were deemed inap-
thiazines, especially thioridazine, were over propriate. In addition, new contraindications and
represented when compared with estimates of precautions for safely using thioridazine were de-
antipsychotic use in the population (based on tailed. These are summarised in table IV. In the
defined daily dosages per 1000 population per year 2000 the FDA took similar action with regard
day). Phenothiazines were associated with 46 of to thioridazine[59] and mesoridazine.[60]
the 49 cases (94%) of sudden death and were
estimated to account for 60% of total antipsy- 3.2.2 Pimozide
chotic use in the population. Thioridazine was In a randomised, controlled trial the QTc inter-
involved in over half of the total deaths (28 of val was significantly prolonged by pimozide but
49) and 75% of deaths that involved the use of not haloperidol or placebo.[62] In the UK, between
a single antipsychotic (15 of 20). However, it 1971 and 1995, 16 deaths and 24 other cases of
was estimated that thioridazine accounted for serious cardiac events (predominantly arrhyth-
only 18% of antipsychotic use in the population. mias) in patients prescribed pimozide were re-
• In a retrospective matched case-control study of ported to the CSM.[19] This led to recommenda-
UK psychiatric in-patients dying suddenly, tions in the UK and the US that patients prescribed
probable sudden unexplained death was signif- pimozide periodically undergo ECGs. If the QTc

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1658 Haddad & Anderson

Table IV. Principal changes to the UK Summary of Product Char- 3.2.4 Haloperidol
acteristics for thioridazine as introduced in the year 2000[61] Haloperidol has been associated with QTc pro-
Indications longation, TdP and sudden death in single case re-
Only as second-line treatment of schizophrenia in adults ports and small series. This occurred at normal
Precautions for use therapeutic dosages with both oral[65,66] and intra-
Baseline ECG <450 msec in men and <470 msec in women
venous administration,[67] and also in overdose.[68]
Baseline serum potassium, magnesium and calcium levels
should be within normal limits When sudden death occurs in psychiatric patients
Regular ECG and electrolyte monitoring there is often no ECG evidence, thus making it dif-
Discontinue treatment if QTc >500 msec
ficult to determine whether the cause was an ar-
Contraindications rhythmia. In this respect haloperidol is interesting,
Clinically significant cardiac disorders (e.g. cardiac failure,
angina, cardiomyopathy) as it has been widely used on medical wards, in-
QTc prolongation cluding intensive care units (ICU), to control agi-
History of ventricular arrhythmias or Torsade de Pointes tation. Patients in ICUs usually have frequent, if
Bradycardia or 2nd or 3rd degree heart block
Family history of QTc prolongation
not continuous, ECG monitoring and this provides
Uncorrected hypokalaemia or hypomagnesaemia a valuable source of information. Over 24 cases of
Decreased CYP 2D6 activity haloperidol-induced TdP have been reported from
Administration of a substrate or inhibitor of CYP 2D6 ICUs, and in one study, 8 of 223 consecutive ICU
Administration of another QTc prolonging drug
CYP = cytochrome P450.
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
interval is prolonged, doctors are advised to con-
death, the risk of these outcomes appears far less
tinue treatment under close supervision or to con-
than with thioridazine. In the Finish autopsy study
sider withdrawing the drug.[63]
conducted by Mehtonen et al.[23] there were 46 sud-
3.2.3 Droperidol den deaths associated with antipsychotics of which
Outside of psychiatry, droperidol has been used only 6 (13%) involved haloperidol compared with
as a pre-anaesthetic agent. Dose-dependent in- 28 (61%) that involved thioridazine. In none of the
creases in the QTc interval have been observed in 6 haloperidol-related deaths was haloperidol the
surgical patients treated with droperidol[64] and
sole drug used. In contrast, thioridazine was the
also in in vitro heart perfusion models.[44] Among
only drug prescribed in 15 of the 28 thioridazine-
psychiatric patients, Reilly et al.[49] showed an in-
related deaths. At the time of the study both halo-
creased risk of QTc prolongation with droperidol
compared with other antipsychotic drugs (adjusted peridol and thioridazine accounted for a similar
odds ratio 6.7; 95% CI 1.8 to 24.8; p = 0.004). In proportion of total antipsychotic use in Finland
this study, six of the 37 droperidol-treated patients (approximately 18% for each drug). In the UK the
had a prolonged QTc interval. Between 1993 and recommended maximum dosage of haloperidol has
1999 the manufacturers received reports of 72 recently been substantially lowered.[63]
cases worldwide of QT prolongation, serious ven-
tricular arrhythmia or sudden death in association 3.2.5 Chlorpromazine and Sulpiride
with droperidol.[18] In the UK the manufacturer TdP has been reported in association with chlor-
voluntarily discontinued distribution of droperidol promazine[70] and sulpiride[71] but the degree of
from 31 March 2001.[18] risk is uncertain.

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Antipsychotic-Related Arrhythmias 1659

3.3 Atypical Antipsychotics incidence of QTc ≥500 msec in the ziprasidone


clinical programme was two of 3095 patients
3.3.1 Sertindole
(0.06%) compared with 1 of 440 patients (0.23%)
Sertindole was introduced on the market in
receiving placebo.[8] In comparison, the incidence
1997, being launched in several European coun-
tries. It was associated with dose-dependent QTc of QTc ≥500 msec with sertindole was 3.1[73] to
prolongation with an average increase of 21 msec 8%,[74] which is approximately 50 or 100 times
at the maximum recommended dosage of 24 mg/ higher than that of ziprasidone.
day.[72] The proportion of patients with QTc values To date no cases of TdP have been reported
≥500 msec has been reported as 3.1 to 4.0%[73] and with ziprasidone. However, the manufacturer’s
7.8%[8] in different documents. In a randomised prescribing information in the US states that when
trial of sertindole versus haloperidol, 8% of the selecting an antipsychotic drug the prescriber
sertindole-treated patients had QTc intervals ≥500 should consider the greater capacity of ziprasidone
msec compared with none in the haloperidol group to prolong the QT/QTc interval compared with sev-
(p < 0.05).[74] During the clinical trials programme eral other antipsychotic drugs.[76] It also specifies
there were two documented cases of TdP; both that ziprasidone is contraindicated in patients with
were associated with overdose and neither was fa- a known history of QT prolongation, recent acute
tal.[75] By the end of November 1998, the MCA/ myocardial infarction or uncompensated heart fail-
CSM had been notified that sertindole had been ure, and should not be co-prescribed with other
associated with 36 fatalities, nine of which had oc- QT-prolonging drugs.
curred in the UK.[17] In addition, there were 13 A variety of data suggest that TdP may not be a
reports of serious but nonfatal arrhythmias in the serious problem with ziprasidone. These include
UK over the same time period. The manufacturers the following:
of the drug voluntarily suspended its European • ziprasidone has not been associated with an in-
marketing in December 1998, pending a full eval- creased rate of syncope, sudden death or TdP in
uation of its risks and benefits. clinical trials;[8]
• the effects on QTc prolongation with zipra-
3.3.2 Ziprasidone
Ziprasidone recently entered clinical use in the sidone are less than those observed with thiorid-
US. Its approval was initially delayed because of azine[8] (figure 2, table III) and sertindole;[72]
concerns over effects on the QTc interval. Study • QTc prolongation of ≥500 msec is relatively
054, discussed previously in section 3.1, indicated rare with ziprasidone;[8]
that ziprasidone had a greater effect on the QTc • ten cases of overdose with ziprasidone have
interval than did risperidone, olanzapine, quetiap- been reported.[8] None were associated with se-
ine or the conventional antipsychotic haloperidol, rious cardiac events or death. This includes one
but a lesser effect than did thioridazine (table III, patient who ingested 4.6g of ziprasidone which
figure 2).[8,50] is nearly 29 times the daily maximum dosage;
Comparisons with sertindole are complicated • in study 054, QTc prolongation with zipra-
by the need to compare across studies but suggest sidone was not significantly increased in the
that ziprasidone has a less marked effect on presence of a metabolic inhibitor suggesting
repolarisation. In ECGs obtained at random inter- that pharmacokinetic interactions are unlikely
vals during short-term trials of ziprasidone, the to be a major problem.[8]
mean increase in the QTc (Bazett) was 9.7 msec at However, a repeated message in the literature
the maximum licensed dosage of 160 mg/day.[8] regarding QTc prolongation and noncardiac drugs
ECG data gathered in a similar way for sertindole is that the risk of TdP and sudden death often only
showed a mean QTc increase of 21 msec at the became apparent several years after licensing.
maximum licensed dosage of 24 mg/day.[72] The There are two key reasons for this. Firstly, TdP and

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1660 Haddad & Anderson

sudden death are often rare complications. For ex- 3.3.4 Clozapine
ample, based on adverse drug reaction data for Clozapine has been shown to increase QTc in a
cisapride, it has been estimated that there was one dose-dependent manner but it is rare for this to be
report of a serious disorder of cardiac rhythm for pathological.[80] In a study of 61 patients treated
approximately every 110 000 prescriptions and one with clozapine, a QTc >500 msec was seen in two
reported fatality for approximately every 430 000 patients. Of these, one had a baseline ECG abnor-
prescriptions (on average each patient was pre- mality and in the second the QTc normalised de-
scribed the drug on three occasions).[32] A far spite the dosage of clozapine being increased.[80]
higher incidence was reported with QTc-prolong- Thus, it is questionable as to what extent, if any,
clozapine was involved in the effects on QTc.
ing antiarrhythmic agents, such as sotalol,[13-15]
partly because these drugs were targeted at a highly A preliminary study reported that the sudden
death rate during treatment with clozapine (4/561,
vulnerable group, that is, those with cardiac dis-
0.71%) was 2.5 times higher than for other psychi-
ease. The second reason why sudden death often
atric agents.[81] However, the small number of
becomes apparent several years after licensing is
cases of sudden death and the failure of the re-
that clinical trials have highly selective entry cri-
searchers to control for potential confounding fac-
teria and will exclude patients who are susceptible
tors severely limit the study. An autopsy was avail-
to the induction of TdP, such as the elderly, those able for only one of the four clozapine recipients
with comorbid substance misuse or comorbid who died suddenly and this revealed death due to
physical disorders (e.g. heart disease) and those pulmonary emboli. It cannot be assumed that any
prescribed multiple medications. In this respect it of the other three sudden deaths were arrhythmic
should be noted that most of the safety data on in origin. This is particularly relevant as clozapine-
ziprasidone originates from clinical trials. induced myocarditis can cause sudden death.[29]
In summary, the effect of ziprasidone in pro- Clozapine has also been associated with fatal
longing the QTc interval is an indication that it cardiomyopathy and, in a recent case report, it was
could cause TdP and sudden death - whether or not suggested that this might have been a factor con-
it does will only become clear after greater clinical tributing to sudden death.[30] In theory, cardiomy-
use and postmarketing surveillance. opathy could increase the proarrhythmic effect of
clozapine. However, to date there are no unequiv-
3.3.3 Risperidone
In contrast to sertindole and ziprasidone, other ocal reports of a fatal cardiac arrhythmia in a pa-
tient prescribed clozapine.
atypical antipsychotics have far less of an effect on
the QTc interval. Risperidone has been shown to
3.3.5 Zotepine
cause minor QTc prolongation at therapeutic dos- In an analysis of six clinical trials, involving a
ages,[8,77] and this effect has also been noted in total of 537 patients, zotepine caused a small but
overdose.[78] There are no reported cases of TdP in statistically significant prolongation of the QTc in-
patients prescribed risperidone. A recent report de- terval (mean increase 8.3 msec).[82] Of the zotep-
scribed a 34-year-old woman, with no history of ine-treated patients, 106 (20%) experienced a QTc
cardiac disease, who had a fatal cardiac arrest sev- prolongation greater than 30 msec and 21 (4%) ex-
eral days after commencing risperidone.[79] Her perienced a QTc prolongation greater than 60 msec.
ECG showed mechanical and electrical dissocia- In contrast 13 (9%) placebo recipients had a QTc
tion (pulseless electrical activity) and a prolonged prolongation greater than 30 msec and none had a
QTc interval (480 msec). However, there was no QTc prolongation greater than 60 msec. The prod-
evidence of either TdP or ventricular fibrillation. uct monograph concludes that zotepine has a mod-
Although it is possible that risperidone was a ca- est effect on QTc interval which probably does not
sual factor in this death, it was not the result of TdP. represent an important pro-arrhythmic effect.

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Antipsychotic-Related Arrhythmias 1661

However, caution is advised in the use of zotepine Table V. Risk factors for arrhythmias
in patients at risk of arrhythmias (e.g. those with Nonpharmacological risk factors
coronary heart disease or those prescribed other Congenital long QT syndromes
QTc prolonging drugs) and a pre-treatment ECG is Individual predisposition
recommended before initiating treatment in these Specific cardiac disorders (e.g. ventricular hypertrophy, heart
failure, bradycardia)
patient groups.[82]
Electrolyte imbalance (especially hypokalaemia)
3.3.6 Other Atypical Agents Overdose of antipsychotic drug
Analyses of ECGs obtained during four ran- Female sex
Restraint and psychological stress
domised, controlled trials (n = 2700) involving
Substance misuse
olanzapine showed that the incidence of maximum
Miscellaneous factors
QTc ≥450 msec during treatment was approxi- elderly
mately equal to the incidence of QTc ≥450 msec at renal and hepatic impairmenta
baseline.[83] In addition, no patients had a QTc slow metaboliser statusa
>500 msec during olanzapine treatment. In a study Pharmacological risk factors
of quetiapine, mean QTc increases of up to ≤8 msec Pharmacokinetic factors
were observed, but again there were no reported inhibition of specific cytochrome P450 enzymes
instances of QTc >500 msec.[84] In 12 patients competition for specific cytochrome P450 enzymes
treated with amisulpride 400 mg/day the mean QTc Pharmacodynamic factors
independent QTc prolongation
interval decreased by 5.9 msec compared with the
electrolyte disturbance
pretreatment value.[85] a Depending on metabolism and route of elimination of drug.

4. Risk Factors for Arrhythmias


Warner et al.[48] found QTc prolongation (>420 nonpharmacological risk factors are reviewed in
msec) in 23% of inpatients with chronic schizo- sections 4.1 and pharmacological risk factors in
phrenia compared with 2% of age-matched, drug- section 4.2. It should be noted that several of these
free controls. Reilly et al.[49] assessed 495 psychi- risk factors are listed in the ‘contra-indications’ or
atric patients, the majority of whom were prescribed ‘precautions’ section of the Summary of Product
antipsychotics, and reported an 8% prevalence for Characteristics (SPC) of pimozide, thioridazine
QTc prolongation (>456 msec, equivalent to a and ziprasidone.
value 2 standard deviations above the mean value
seen in a healthy reference group). The difference 4.1 Nonpharmacological Factors
in the incidence between the two studies may
partly reflect the variations in patient charac- 4.1.1 Congenital Long QT Syndromes
teristics between the studies and the higher cut-off Two inherited forms of QTc interval prolonga-
value adopted by Reilly et al. Irrespective of this, tion exist. The Romano-Ward syndrome shows
it is apparent that QT-interval prolongation occurs autosomal dominant inheritance. The Jervell and
in a significant minority of psychiatric patients Lange-Nielsen syndrome is associated with con-
with antipsychotic treatment being a major cause. genital deafness and is very rare. The most com-
However, arrhythmias are rare in patients pre- mon presentation is with episodes of syncope trig-
scribed antipsychotics, and sudden death rarer still, gered by emotional or physical stress, although
so it seems that the presence of one or more other cardiac arrest or sudden death may be the initial
risk factors are required to precipitate an arrhyth- presentation.[86] The syncopal episodes are some-
mia in an individual with QT prolongation. times misdiagnosed as epilepsy. Symptoms usually
These risk factors can be divided into pharma- begin in childhood or adolescence but presentation
cological and nonpharmacological (table V). Key may be at any age from a few days after birth to

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


1662 Haddad & Anderson

middle age. The prevalence is unknown but may be posed to a drug with a marked proarrhythmic po-
as high as 1 in 5000.[87] tential or if other predisposing factors are present
The genetic cause of congenital long QT syn- which reduce the repolarisation reserve (e.g. hypo-
dromes (LQTS) is heterogeneous with at least kalaemia, bradycardia). Within this model the dif-
seven genes being involved.[88] All the genes iden- ference in the proarrhythmic potential of drugs re-
tify to date encode ion channel proteins indicating lates to the degree of predisposing abnormality
that the congenital LQTS are an ion-channel- required for TdP to manifest.
opathies. The concept of an underlying genetic predispo-
sition is of potential clinical importance as it raises
4.1.2 Individual Predisposition the possibility of developing screening tests for
There is strong evidence that those individuals mutations of the involved genes and the early iden-
who develop TdP when prescribed a proarrhythmic tification of individuals who are at risk.
drug have an underlying predisposition to manifest
such a reaction. A study of patients prescribed class 4.1.3 Cardiac Disorders
III antiarrhythmics showed that those who devel- Patients with cardiac hypertrophy and cardiac
oped TdP had more marked drug-induced QT pro- failure are more susceptible to drug-induced TdP.
longation that those who did not develop TdP.[89] This is because both conditions reduce Ikr and pro-
Furthermore, the degree of QTc prolongation in the long the action potential.[95] Bradycardia is another
group with TdP was unrelated to drug dosage. In risk factor and the mechanism is straightforward;
other words, those patients who developed TdP the slower the heart rate the longer the repolarisa-
showed an abnormal response to the drug. Further tion phase. Ischaemic heart disease also increases
support is provided by the finding that some pa- the pro-arrhythmic risk.[32]
tients who experience drug-induced TdP are at high
4.1.4 Electrolyte Imbalance
risk of a further arrhythmic episode if exposed to a
Hypokalaemia, hypomagnesaemia and hypocal-
second QTc prolonging drug.[90]
caemia can cause QT prolongation and so increase
In some patients the susceptibility has a genetic
the risk of arrhythmias. Electrolyte disturbances
basis. Molecular analysis has shown that a propor-
may result from physical illness and reflect diar-
tion of patients who develop drug-induced QT pro-
rhoea, vomiting, malabsorption or limited fluid in-
longation and arrhythmia have mutations of genes
take. Drugs may also cause electrolyte imbalance,
that code for cardiac ion channels. In some patients
for example certain diuretics cause hypokalaemia.
the mutations involve genes associated with con-
genital LQTS[91,92] suggesting that, in these indi- 4.1.5 Overdose
viduals, drug-induced TdP represents a ‘forme Suicide and nonfatal overdose are common
fruste’ of the congenital LQTS. In others the ge- among patients with schizophrenia. An association
netic abnormality is unrelated to the genes associ- between antipsychotic dosage and QTc prolonga-
ated with congenital LQTS.[93] tion has been demonstrated in several studies.[48,49]
The ‘susceptibility’ model helps explain the It is possible that some deaths following antipsy-
apparent idiosyncratic nature of drug-induced chotic overdose reflect cardiac arrhythmias caused
TdP.[94] In individuals with a marked repolarisation by dose-related QTc prolongation. In support of
abnormality (low repolarisation reserve) TdP will this, ventricular arrhythmias have been reported
occur when they are exposed to a drug with a low with overdoses of thioridazine, haloperidol, sulpir-
proarrhythmic potential. In such persons TdP is ide, mesoridazine, pimozide, chlorpromazine,
less to do with the drug and more to do with the sertindole and remoxipride.[96] With pimozide, a
underlying susceptibility. In contrast, individuals drug known to cause QT prolongation, ten of 13
with a minor repolarisation abnormality (high deaths reported to the CSM by 1990 were associ-
repolarisation reserve) will only develop TdP if ex- ated with dosages greater than 20mg daily, the up-

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


Antipsychotic-Related Arrhythmias 1663

per limit recommended in the British National For- widely publicised’. However, the risk needs to be
mulary.[97] kept in perspective and must be balanced against
the dangers of withholding pharmacological treat-
4.1.6 Female Sex
ment from highly disturbed psychotic individuals.
Several studies have shown that women are
These risks include patient distress, damage to
more prone to drug-induced TdP. For example,
property, and injury to self and others.
women accounted for 70% of the 323 cases of TdP
related to cardiovascular drugs which were identi- 4.1.8 Substance Misuse
fied in an extensive survey.[98] The increased inci- Alcohol and substance misuse are relatively
dence in women remained irrespective of the pre- common in patients with schizophrenia and may
sence of other risk factors. Female gender was a contribute to sudden death. Chronic alcohol mis-
major risk factor for increased mortality in patients use[105,106] and cocaine misuse[107,108] are both as-
treated with sotalol versus those receiving placebo sociated with QT prolongation. Sudden death is
in the SWORD study.[16] A female predominance well recognised in people using cocaine[109] and
is also apparent in the FDA reports of erythromy- has been reported in cocaine users who have been
cin-associated cardiac arrhythmias.[99] The in- restrained.[110] Some of these deaths appear to be
creased vulnerability of women to TdP may reflect due to arrhythmias but other mechanisms may con-
the fact that the QTc interval is longer in women tribute. For example, cocaine can cause coronary
than in men by about 20 msec.[38] artery vasospasm and so lead to myocardial infarc-
tion.[111]
4.1.7 Restraint and Psychological Stress
Strenuous exercise[100] and psychological 4.1.9 Miscellaneous Factors
stress[101,102] are associated with sudden death in Hepatic and renal impairment have the potential
the general population. Both factors may be rele- to increase the plasma concentrations of a QTc-
vant in situations where an agitated or excited pa- prolonging drug and so increase its cardiotoxic ef-
tient is restrained. The underlying mechanism may fect. The size of this effect will vary between drugs,
relate to increased plasma noradrenaline and and will reflect the individual metabolism and
adrenaline levels leading to increased myocardial elimination characteristics of the drug. Renal im-
instability and fatal arrhythmias.[6] Such a mecha- pairment was implicated as a contributory mech-
nism could account for sudden death during peri- anism in a case report that documented sudden
ods of restraint without implicating the antipsy- death in a psychiatric inpatient who was prescribed
chotic medication. If patients concurrently receive chlorpromazine.[112] The patient was identified as
antipsychotic medication, which causes QTc pro- having renal insufficiency several days before
longation, then such changes may act in an additive death. The only relevant autopsy finding was an
way to trigger sudden death.[103] Given the rela- elevated serum chlorpromazine concentration, pre-
tionship between QTc prolongation and antipsy- sumably reflecting accumulation secondary to re-
chotic dosage, the risk is likely to be at its greatest nal impairment. The authors concluded that the
if patients receive high dosages of parenteral med- most likely cause of death was an arrhythmia in-
ication. duced by the high serum chlorpromazine concen-
In a review of deaths in patients detained under tration.
the Mental Health Act 1983 in England and Wales The elderly are particularly vulnerable to the
over a 2-year period, Banerjee et al.[104] identified adverse effects of drugs because of their impaired
two patients who died while being restrained after renal excretion and hepatic metabolism, and the
receiving antipsychotic medication and concluded increased likelihood of physical illnesses and in-
that ‘the risk of sudden cardiotoxic collapse in re- teractions with co-prescribed medications.
sponse to neuroleptic medication given during a Genetic polymorphisms within the hepatic cy-
period of high physiological arousal should be tochrome P450 (CYP) enzyme system mean that

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1664 Haddad & Anderson

some individuals, termed ‘slow metabolisers’, msec.[114] Cisapride in isolation is associated with
have a decreased ability to metabolise certain a QTc prolongation of 6 to 18 msec.[115,116] In one
drugs. Different antipsychotics are metabolised by study, monotherapy with cisapride led to a 6 msec
different cytochrome enzymes. Thioridazine is me- QTc elevation and clarithromycin alone (a CYP
tabolised by the CYP 2D6 pathway, which is defi- 3A4 inhibitor) caused a minimal QTc increase.[115]
cient in 7 to 10% of the Caucasian population.[113] However, the combination of cisapride and clar-
Such individuals may achieve particularly high ithromycin caused an average QTc increase of 25
plasma concentrations of the drug and be at greater msec above pretreatment values in parallel with a
risk of arrhythmias. 3-fold increase in the plasma cisapride concentra-
tion.
4.2 Pharmacological Factors
These interactions had serious clinical repercus-
If a patient is prescribed an antipsychotic drug sions. Between 1993 and 1999 the FDA received
that significantly prolongs the QTc interval, then 341 reports of QT prolongation and ventricular ar-
additional drugs can increase the risk of arrhythmia rhythmias (80 of which were fatal) in association
via pharmacokinetic or pharmacodynamic interac- with cisapride.[117] Concomitant prescriptions of
tions. The likelihood of interaction is high as many drugs known to inhibit CYP 3A4 accounted for 126
drugs, from a diverse range of classes, can be in- (37%) of these reports and was the largest single
volved. Furthermore, many patients will be treated risk factor. Most of the cardiac arrhythmias and
simultaneously by more than one doctor (e.g. psy- sudden deaths reported with terfenadine occurred
chiatrist, general practitioner and other specialist) following overdose or when it was co-prescribed
if there is a comorbid physical disorder. Preventing with a CYP 3A4 inhibitor.[118] The potential for
pharmacological interactions relies not only on
interactions with CYP 3A4 substrates is also in-
each doctor being familiar with many drugs but
creased with the concurrent intake of grapefruit
also knowing what colleagues are co-prescribing
juice as it is a potent inhibitor of the enzyme.[116]
for any given patient.
Some drugs that inhibit CYP 3A4, for example
4.2.1 Pharmacokinetic Interactions imidazole and macrolide antibiotics, also prolong
A co-prescribed drug may increase the plasma the QTc interval in their own right. However, when
concentration of a QTc prolonging drug by inhib- these drugs were co-prescribed with cisapride or
iting its metabolism by a specific CYP enzyme or terfenadine it was the pharmokinetic, rather than a
by competing as a substrate for that enzyme. The pharmacodynamic, interaction that appeared most
importance of this mechanism is highlighted by the relevant to the generation of TdP.[115]
experience with the motility stimulant cisapride
Pimozide is largely metabolised by CYP 3A4,
and the antihistamine terfenadine. The metabolism
although CYP 2D6 also plays a role. In vitro data
of both drugs is highly dependent on the CYP 3A4
indicate that potent CYP 3A4 inhibitors, such as
isoenzyme system. When prescribed alone cisapr-
ide and terfenadine cause only minor QTc eleva- macrolide antibiotics, will inhibit the metabolism
tion. However, if co-prescribed with a potent inhib- of pimozide resulting in a markedly elevated
itor of CYP 3A4, there is a marked rise in QTc plasma concentrations of pimozide.[22] A recent
values reflecting an increase in plasma cisapride or case report[22] detailed the sudden death of a 27-
terfenadine concentrations. year-old man 2 days after he was prescribed pimoz-
In most studies terfenadine causes a mean in- ide and clarithromycin, a macrolide antibiotic.
crease in the QTc interval of between 8 and 18 Prior to combining these drugs the patient had a
msec.[32] However, in a study in which terfenadine prolonged QT interval. The UK SPC for pimozide
was co-prescribed with ketoconazole, a CYP 3A4 contraindicates the concomitant prescription of
inhibitor, the QTc interval increased by 82 drugs known to inhibit CYP 3A4 or 2D6.[61]

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Antipsychotic-Related Arrhythmias 1665

The UK SPC for thioridazine, metabolised by cases of QTc prolongation with SSRI treatment
CYP 2D6, contraindicates concomitant use of CYP have been documented,[125,126] and TdP has been
2D6 inhibitors such as selective serotonin reuptake reported with citalopram.[127] In summary, al-
inhibitors (SSRIs), tricyclic antidepressants though safer than TCAs, it would be an oversim-
(TCAs) and β-blockers.[61] plification to regard SSRIs as having no cardio-
Ziprasidone is metabolised by an aldehyde ox- toxic or proarrhythmic potential.
idase pathway and CYP 3A4. In study 054, concur- Antipsychotic polypharmacy (the co-prescrib-
rent administration of ketoconazole, a CYP 3A4 ing of more than one antipsychotic) is common in
inhibitor, elevated plasma ziprasidone concentra-
clinical practice, although there is little, if any, ev-
tions but did not cause further prolongation of the
idence base to support it. In a 10-year prospective
mean QTc interval suggesting a flattening of the
dose-QTc response.[8] This finding, plus the exist- study of a cohort of 88 psychiatric patients with
ence of two metabolic pathways and the fact that schizophrenia (mean age of 63 years) there were
there are no known clinically relevant inhibitors of 39 deaths with no instances of suicide.[128] This
aldehyde oxidase, suggests that ziprasidone is less equated to a 1.33-fold higher relative risk of death
susceptible to pharmacokinetic interactions that in- compared to the general population. An inde-
crease the QTc to above values seen with mono- pendent risk factor for death was the concurrent
therapy. prescription of more than one antipsychotic drug
(relative risk 2.46; 95% CI 1.1 to 5.47; p = 0.03).
4.2.2 Pharmacodynamic Interactions A possible explanation is that there was a toxic
The effect of an antipsychotic on the QTc inter-
additive effect of the antipsychotics. However, it
val will be potentiated by the concurrent use of
cannot be assumed that the mechanism was pro-
other drugs that prolong the QTc interval (table I).
arrhythmia. Antipsychotic polypharmacy was re-
Examples of nonpsychotropics that can prolong
the QTc interval include certain antihistamines, an- garded as present if it had occurred at any point in
tiarrhythmics and antimicrobials. Psychotropic the study period, not just at the time of death,[128]
drugs that can cause QTc prolongation, and have and this is not consistent with a direct effect of
been associated with TdP, include lithium, chloral concurrent medications on cardiac repolarisation.
hydrate, certain TCAs (amitriptyline, desipramine, In summary, it is advisable to ensure that anti-
doxepin and imipramine)[7] and the tetracyclic an- psychotics that cause significant QTc prolongation
tidepressant maprotiline.[119] In a study of psychi- are not co-prescribed with other QTc-prolonging
atric patients, TCA use was an independent predic- drugs. Advice to this effect appears in the manu-
tor of QTc prolongation (adjusted odds ratio 4.4, facturers prescribing information for ziprasi-
95%; CI 1.6 to 12.1; p = 0.004).[49] Life-threaten- done[76] in the US, and in the UK SPCs[61] for
ing ventricular arrhythmias[120] and a case of sud- pimozide and thioridazine. For example, the SPC
den death[121] have been reported in patients co-
for thioridazine specifically contraindicates the
prescribed imipramine and thioridazine. Sudden
concomitant prescribing of TCAs, maprotiline,
death has also been reported with the combination
phenothiazines and pimozide, as well as a variety
of imipramine and chlorpromazine.[121]
of nonpsychotropic agents.
The SSRIs are generally regarded as less cardio-
toxic than the TCAs, both at therapeutic dosages A second way in which a co-prescribed drug can
and in overdose.[122] Studies with various SSRIs, increase the risk of arrhythmias is by causing elec-
including paroxetine[123] and fluoxetine,[124] have trolyte disturbance. For example, some diuretics
indicated absent or minimal effects on the QTc in- can cause hypokalaemia. Low extracellular potas-
terval, and the SSRIs are not generally regarded as sium concentrations increase the risk of TdP by
QTc-prolonging agents. However, occasional reducing Ikr.

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1666 Haddad & Anderson

5. Managing the QTc Risk risk. The prescribing information was changed and
all healthcare professional were informed by letter.
5.1 Antipsychotic Selection A survey of prescribing patterns the year prior to
and after this action showed that there had been no
QTc prolongation is one of many factors that
material effect on contraindicated use of cisapr-
need to be considered when selecting an antipsy-
ide.[132] Prior to the regulatory action cisapride use
chotic. Selection should be on an individual patient
was contraindicated in 16, 30 and 60% of patients
basis. However, given that antipsychotics show lit-
in the three study sites. In the year after the figures
tle difference in efficacy and that QTc prolongation
were 24, 28 and 58%, respectively. This finding
can have fatal consequences, it seems prudent to
indicates that more effective ways to communicate
avoid drugs that have a significant effect on the QT
and implement safety measures are needed.
interval where possible.
ECG monitoring of psychiatric patients raises
5.2 Patient Selection and Monitoring certain practical problems. Many psychiatric de-
partments do not have ECG facilities, and patients
Occasionally there will be good reasons to use may comply poorly with appointments to attend
an antipsychotic associated with significant QTc the ECG department of a neighbouring hospital or
prolongation, such as when a patient has failed to clinic. Even if the ECG is taken in the psychiatric
respond to other agents or has shown a good re- clinic, many psychiatrists lack the training or ex-
sponse to the QTc prolonging drug in the past. Yap perience to interpret an ECG. A survey of trainee
and Camm[129] listed four key principles for safer psychiatrists in three hospitals found that only 20%
prescribing of QTc prolonging drugs: could identify prolongation of the QT interval on
• not exceeding the upper recommended dose; an ECG.[133] Thus, improved facilities and training
• restricting the dosage in patients with pre- are necessary.
existing heart disease or other risk factors; Doctors need to be alert to symptoms that could
• avoiding concomitant prescribing of drugs that indicate cardiac arrhythmias in any patient pre-
inhibit drug metabolism or excretion, prolong scribed antipsychotic medication. These include
the QT interval or produce hypokalaemia; dizziness, palpitations and syncope. Such symp-
• ensuring that serum potassium levels are regu- toms should prompt examination and an ECG. If a
larly checked. patient develops TdP, the responsible drug should
It must be emphasised that these are general be stopped and appropriate treatment for the ar-
principals. Any specific advice regarding QTc pro- rhythmia instigated. Psychiatrists should also re-
longation in the SPC should be considered for each ceive regular training in cardiopulmonary resusci-
drug. With certain antipsychotics this is extensive tation.
and includes specific contraindications and precau-
tions designed to reduce the risk of cardiac compli- 5.3 Advice for Patients
cations. For example, with pimozide and thiorida-
zine an ECG is recommended prior to Patients prescribed an antipsychotic or other
commencement of treatment and at specified inter- drugs known to cause clinically significant QTc
vals thereafter. prolongation should be advised about which med-
The experience with terfenadine[130,131] and icines to avoid, and should be carefully monitored
cisapride[132] is that clinicians often failed to follow to ensure that they comply with these instructions.
prescribing restrictions and monitoring require- Some cardiologists recommend that patients be
ments. In 1998 concern about QTc prolongation led provided with a warning card that lists contraindi-
the FDA to determine that cisapride was contrain- cations for co-prescriptions.[129] If the patient is
dicated in those with medical conditions or pre- seeing more than one doctor (e.g. a general practi-
scribed medications that increased the arrhythmic tioner and a psychiatrist) both doctors need to be

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Antipsychotic-Related Arrhythmias 1667

aware of the possible dangers associated with co- several countries and it is likely that short acting
prescribing QTc-prolonging medications. intramuscular formulations of other atypical anti-
psychotics will become available in the near fu-
5.4 Use of High Dosages ture. The place of such agents is as yet unclear but
the favourable cardiac profile of olanzapine sug-
Clinical trials do not support the widespread use
gests that it should be a safer option for rapid
of high dosages of antipsychotic drugs, but many
tranquillisation.
clinicians believe that individual patients occa-
sionally respond to high dosages. Given that QTc
prolongation is dose dependent, particular caution 5.6 Adopting a Coherent Policy
is needed if exceeding licensed dosages. The Royal
College of Psychiatrists has provided guidance on A coherent policy on drug-induced QTc prolon-
using antipsychotic dosages that exceed the upper gation is needed to assist health professionals and
limits given in the British National Formulary.[134] patients manage the associated risks. This should
The recommendations include carrying out a base- include advice and education for clinicians and pa-
line ECG to exclude QT prolongation and other tients, assessment during drug development, post-
abnormalities, repeating the ECG periodically, in- marketing surveillance, adverse drug reaction
creasing the dosage slowly, being alert to the pos- monitoring and further research.
sibility of drug interactions and carrying out regu- It is 15 years and 5 years, respectively, since the
lar physical observations (pulse, blood pressure American Psychiatric Association[5] and the Royal
and temperature). College of Psychiatrists[6] published reports on the
association between antipsychotic drugs and sud-
5.5 Rapid Tranquillisation
den death. Since that time knowledge of QTc pro-
The use of antipsychotics in patients who are longation has increased, clinical practice has
struggling and require restraint is a complex and a changed and the range of antipsychotics available
poorly researched area. Attempts to ‘talk down’ the to clinicians has altered. Given these changes, up-
patient should be made, but in certain situations to-date guidance on good clinical practice in the
parenteral medication is a necessity. In such pa- management of QTc associated risk is required and
tients failure to medicate can lead to escalating dis- should be regularly updated.
turbance, damage to property and injury to self and A working party of the European Society of
others. Where possible it is advisable to use the Cardiology recommended that the pharmaceutical
intramuscular route rather than intravenous admin- industry introduce more thorough assessment of
istration. In several UK studies of prescribing prac- repolarisation effects during the development of
tice haloperidol has been the antipsychotic of new drugs.[7] They recommended that any conclu-
choice, often being administered in combination sion that a drug is ‘safe’ be reserved until the results
with a benzodiazepine.[135,136] Droperidol was also of postmarketing surveillance were available.
frequently used.[135,136] In the UK the maximum Clinical trials involve relatively small numbers of
recommended dosage for haloperidol has recently carefully selected patients and TdP may only man-
been reduced from 100mg to 30mg a day for oral ifest after a drug has been used by a large number
therapy and from 60mg to 18mg a day for intra- of patients who have one or more risk factors or
muscular administration.[63,137] Given this, plus the those prescribed medications for which there is a
recent withdrawal of droperidol by the manufac- potential for drug interactions. This explains why
turer,[18] it is likely that benzodiazepines will play with several drugs, including terfenadine, the link
a larger part in rapid tranquillisation than they have between QTc prolongation and arrhythmias only
in the past. A short-acting intramuscular formula- became apparent several years after initial market-
tion of olanzapine has recently been approved in ing and after widespread clinical use.

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1668 Haddad & Anderson

A recent editorial in the British Medical Jour- other factors including other aspects of safety as
nal[129] recommended that all drugs that signifi- well as efficacy, tolerability, contraindications,
cantly prolong the QT interval be listed and regu- price and patient preference. If an antipsychotic
larly updated in a national drug catalogue such as that increases the QT interval is prescribed, doctors
the British National Formulary, and any such ad- and patients need to take precautions to minimise
verse events be urgently reported to drug safety the proarrhythmic risk.
authorities and drug manufacturers.
Methodologically robust epidemiological re- Acknowledgements
search is needed to clarify the association between No external funding was used to assist in preparing this
antipsychotic agents and sudden unexplained manuscript. In 2001 Dr Haddad was a member of the Cardiac
death. A UK multicentre study is currently investi- Safety In Schizophrenia Group, an educational group sup-
gating sudden death in psychiatric inpatients.[138] ported by Eli Lilly.
Comorbid physical illness, physiological arousal
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