clinical reviews Antipsychotic and antidepressant drugs

Association of antipsychotic and antidepressant

drugs with Q-T interval prolongation
Wesley R. Zemrak and George A. Kenna

C
ardiovascular disease is the
leading cause of death in the
United States. Of the 79.4 mil-
lion Americans who received medical
care for cardiovascular disease in
2004, approximately 871,000 died as
a result of the disease.1 In addition,
approximately 325,000 Americans
die each year without receiving
medical attention, with most of these
deaths attributed to sudden cardiac
death (SCD).2 The direct and indirect
health care costs of cardiovascular
disease were expected to total $431.8
billion in 2007.
As the population ages, a greater
number of patients receive addi-
tional drug therapies for a growing
number of diseases and conditions.
For example, a total of 3.38 billion
prescriptions were filled in 2005,
up from 3.27 billion in 2004.3 With
more patients taking a greater num-
ber of potent drugs, the frequency
and severity of adverse events may
increase.
An important risk factor caused by
both cardiac and noncardiac drugs is
Q-T interval prolongation. Prolon-
gation of the Q-T interval, a risk with
both cardiac and noncardiac drugs,
increases the risk for ventricular
fibrillation and torsades de pointes
leading to SCD.4,5 While torsades
Purpose. The association of antipsychotic
and antidepressant drugs with Q-T interval
prolongation is reviewed.
Summary. Prolongation of the Q-T interval
can be of particular concern to practi-
tioners when prescribing antidepressants
and antipsychotics. Patients may be at a
greater risk for developing fatal arrhyth-
mias when taking many of these drugs. In
general, antipsychotics cause Q-T interval
prolongation at a higher rate than do an-
tidepressants. The typical antipsychotics
thioridazine, pimozide, and intravenous
haloperidol all have the highest potential
for Q-T interval prolongation. The tricyclic
antidepressants have a higher rate of Q-T
interval prolongation than do selective
serotonin-reuptake inhibitors (SSRIs), par-
ticularly at higher concentrations and in
cases of overdose. In addition, nonphar-
macologic risk factors such as existing
heart disease, female sex, electrolyte
abnormalities, hepatic insufficiency, and
stimulant drug abuse contribute to the risk
for developing these arrhythmias, as do
de pointes can result in death, the
number of fatalities directly attribut-
able to Q-T interval prolongation is
unknown.
Many drugs used to treat psychi-
atric disorders, specifically antide-
pressants and antipsychotics, have
been implicated in Q-T interval pro-
pharmacologic factors such as multidrug
therapy and high dosages of drugs known
to prolong the Q-T interval. Risk factors
may be identified in the patients history
and demographic information. However, all
pharmacists may not have this information
readily available to them.
Conclusion. Antipsychotics cause Q-Tc
interval prolongation at a higher rate than
do antidepressants, and the typical anti-
psychotics thioridazine, pimozide, and i.v.
haloperidol all have the highest potential
for Q-Tc interval prolongation. Tricyclic
antidepressants have a higher rate of Q-Tc
interval prolongation than do the SSRIs,
particularly at higher concentrations and in
overdose situations. The frequency of ad-
verse events associated with drug-induced
Q-T interval prolongation is unknown.
Index terms: Antidepressants; Antipsy-
chotic agents; Dosage; Haloperidol; Long
QT syndrome; Pimozide; Thioridazine;
Toxicity
Am J Health-Syst Pharm. 2008; 65:1029-38
longation and torsades de pointes.6-9
Patients with psychiatric disorders
often have a greater risk of develop-
ing Q-T interval prolongation for
several reasons.10 For example, not
only do many such patients take
licit and illicit drugs, they may also be
prescribed multiple drugs or receive

Wesley R. Zemrak, Pharm.D., is Pharmacy Practice Resident, Maine
Medical Center, Portland. George A. Kenna, Ph.D., B.S.Pharm., is
Assistant Professor of Psychiatry and Human Behavior (Research),
Brown Medical School, Brown University, Providence, RI, and Clini-
cal Pharmacist, The Westerly Hospital, Westerly, RI.
Address correspondence to Dr. Kenna at the Center for Alco-
hol and Addiction Studies, Box G-S121-5, Providence, RI 02903
(george_kenna@brown.edu).
Copyright 2008, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/08/0601-1029$06.00.
DOI 10.2146/ajhp070279

Am J Health-Syst PharmVol 65 Jun 1, 2008 1029

 clinical reviews Antipsychotic and antidepressant drugs
high dosages to achieve a therapeutic
response. The use of illicit drugs and
acute alcohol consumption are also
confounding factors. For example,
acute alcohol ingestion can inhibit
the metabolism of tricyclic antide-
pressants, resulting in increased drug
bioavailability and possible over-
dose.11 Because psychiatric drugs are
commonly used, it is important to
understand the cardiac risks associ-
ated with their use. The aim of this
review is to highlight the evidence
linking these drugs to Q-T interval
prolongation, torsades de pointes,
and SCD. In addition to clinical
pharmacists working closely with
practitioners in areas such as inten-
sive care or the emergency depart-
ment, many other pharmacists work
closely with computerized drugdrug
interaction screening software that is
used to identify potentially harmful
drug combinations in the inpatient
and outpatient settings.12 Unfortu-
nately, except for tricyclic antidepres-
sants, there are no clear guidelines
for assessing and evaluating thera-
peutic serum concentrations for
antidepressants and antipsychotics.
Therefore, practitioners must be fa-
miliar with the current literature to
assess which specific antidepressant
and antipsychotic agents are reported
to increase the risk of Q-T interval
prolongation.
Risk factors for drug-induced Q-T
interval prolongation
As with other drug-induced ad-
verse events, there are several easily
identifiable risk factors for develop-
ing Q-T interval prolongation and
subsequent torsades de pointes.
Some nonpharmacologic risk fac-
tors can be identified solely from
the medical and personal history of
the patient. These include congeni-
tal long Q-T syndrome, underlying
heart disease, bradycardia, heart fail-
ure, and ischemic disease.13-16 Other
risk factors include sex (female),16,17
age (elderly),17 liver disease,16 elec-
trolyte abnormalities (hypokalemia
1030 Am J Health-Syst PharmVol 65 Jun 1, 2008
and hypomagnesemia),18 illicit drug
use (principally stimulants), 19,20
high dosages of the drug contribut-
ing to the lengthened Q-T interval,
and rapid infusion of torsadogenic
drugs.13
Pharmacologic risk factors in-
clude both pharmacokinetic and
pharmacodynamic drug interactions.
Because of the volume of individuals
prescribed medications in general,
these interactions have the potential
to occur most frequently with antide-
pressants and antipsychotics, which
undergo metabolism utilizing simi-
lar pathways. Adverse events due to
polypharmacy increase the potential
for life-threatening consequences.
Review of the Q-T interval
The Q-T interval describes the
hearts electric activity correspond-
ing to membrane repolarization as
reflected by the surface electrocar-
diogram (ECG). The normal beat is
carried through the cardiac conduc-
tion system, resulting in atrial and
ventricular depolarization. This elec-
tric current is achieved by the flow of
sodium, potassium, and calcium ions
through their respective channels in
the cardiomyocytes, resulting in con-
traction of the heart muscle.
There are five phases in the cardiac
action potential. Phase 0 initiates
the action potential with a rapid
depolarization of the cell caused by
high inward flow of sodium ions that
actually overshoots the necessary
depolarization point. Calcium begins
slowly flowing into the cell at the end
of phase 0. Phase 1 begins repolariza-
tion of the cell by a rapid outward
flow of potassium ions through hu-
man ether-a-go-go (hERG) potas-
sium ion channels, and repolariza-
tion continues during phases 24.
Simultaneously, sodium ion channels
slowly begin to close. The combined
effect of calcium and sodium ions
flowing into the cell, along with po-
tassium ions flowing out of the cell,
results in a delayed return to the rest-
ing membrane potential, also called
the plateau phase. Phase 4 of the ac-
tion potential refers to the complete
closure of calcium and sodium ion
channels, along with the full opening
of potassium ion channels in prepa-
ration for generation of the next ac-
tion potential.17
Atrial depolarization manifests
on the ECG as a slight upward bump
called the P wave. The QRS complex
reflects the ventricular depolariza-
tion. Phase 3 ventricular repolariza-
tion is characterized on the ECG as
the T wave. The time between the be-
ginning of ventricular depolarization
(Q wave) and the end of the T wave is
the Q-T interval. This interval repre-
sents the amount of time it takes for
the ventricle to complete ventricular
depolarization and repolarization.
The risk of torsades de pointes in-
creases if the Q-Tc interval and the
T peak-to-end interval both increase
after drug consumption, instead of
the T peak-to-end interval decreas-
ing as the Q-T interval increases.20
If an impulse arrives at the ventricle
prematurely, it can provoke an early
after-depolarization (EAD), which
may trigger a tachyarrhythmia.
The risk for EAD can be increased
by electrolyte abnormalities (e.g.,
hypokalemia, hypomagnesemia)
or blockade of ion channels, result-
ing in multiple EADs (which is the
proposed mechanism for torsades de
pointes) or SCD.20
The Q-T interval is often cor-
rected (Q-Tc) for heart rate. For
men, a Q-Tc interval of <430 msec is
considered normal, between 431 and
450 msec suggests an increased risk,
and >450 msec is considered pro-
longed.22 For women, Q-Tc values of
<450 msec are normal, between 451
and 470 msec suggests an increased
risk, and >470 msec is considered
prolonged. The 20-msec difference
between men and women appears to
be driven by androgen.23 At puberty,
the male Q-T interval shortens and
remains shorter than the female
interval until age 5055 years, when
testosterone levels decline. There is
 clinical reviews Antipsychotic and antidepressant drugs
no consensus concerning the degree
of Q-T interval prolongation that in-
dicates a meaningful change from the
baseline Q-T interval. In clinical tri-
als, a Q-Tc interval prolongation to
>500 msec during therapy has been
a threshold of particular concern24,25;
however, individual changes in Q-Tc
intervals of 3060 msec from base-
line heighten suspicion of increased
risk of arrhythmias.22
Mechanisms of Q-Tc
interval prolongation
with antidepressants and
antipsychotics
Antidepressants. Tricyclic an-
tidepressants are more commonly
associated with prolongation of
the Q-Tc interval than are selec-
tive serotonin-reuptake inhibitors
(SSRIs).26,27 One mechanism by which
tricyclic antidepressants are thought
to lead to Q-Tc interval prolongation
is by delaying the inward sodium
current into cardiomyocytes.28 This
action slows cardiac depolarization
and lengthens the Q-Tc interval. Im-
ipramine and amitriptyline have also
demonstrated disruption in the de-
layed rectifier potassium current and
the inward slow calcium currents,
both leading to delayed repolariza-
tion and possible prolongation of the
Q-Tc interval.28,29
In contrast to tricyclic antidepres-
sants, SSRIs appear to prolong the
Q-Tc interval via two mechanisms:
direct blockade of the hERG potas-
sium ion channels30,31 and disruption
of hERG protein expression on the
cell membrane; the latter phenom-
enon reduces potassium ion flow
by decreasing the number of hERG
potassium ion channels.32 Research-
ers have found that the inhibition of
electric currents by fluoxetine and
its active metabolite, norfluoxetine,
quickly resolves once blood drug
concentrations are no longer mea-
surable.32 Witchel and colleagues28
found that citalopram also inhibits
the hERG potassium ion channels,
but this in vitro assessment of ci-
taloprams potential to cause Q-Tc
interval prolongation is contradicted
by the lack of clinical evidence of
this effect. One theory suggests that
citalopram also blocks the l-type
calcium current that offsets hERG-
mediated inhibition, leading to pro-
longed depolarization.29
Trazodone, a serotonin type 2-
receptor antagonist and reuptake
inhibitor, has also been associated
with Q-Tc interval prolongation.
Zitron et al.32 found that therapeutic
concentrations of trazodone inhib-
ited hERG potassium ion channels in
patients being treated for depression.
Several case reports of Q-Tc interval
prolongation involving antidepres-
sants have also been published,
most of which pertain to bupropion
overdose (Table 1).42 However, we are
not aware of any reports describing
bupropions mechanism for Q-Tc
interval prolongation.
Antipsychotics. Antipsychotic
drugs are more frequently associated
with prolongation of the Q-Tc inter-
val than are antidepressants. Similar
to antidepressants, most antipsy-
chotics prolong the Q-Tc interval by
blocking the hERG potassium ion
channels in cardiomyocytes.43-50 This
mechanism was initially demonstrat-
ed with pimozide47 and sertindole.49
Kongsamut and colleagues50 assessed
the affinities of sertindole, pimozide,
thioridazine, ziprasidone, quetiapine,
risperidone, and olanzapine for po-
tassium ion channels (toxicity) and
dopamine and serotonin receptors
(efficacy). Sertindole, pimozide, and
thioridazine had very little, if any, se-
lectivity for dopamine and serotonin
receptors but had a strong affinity for
hERG potassium channels, which is
linked to their ability to cause Q-Tc
interval prolongation. Risperidone
and olanzapine exhibited a greater se-
lectivity for dopamine and serotonin
receptors than for hERG potassium
ion channels, thereby having a rela-
tively low potential for prolonging
the Q-Tc interval. Ziprasidone and
quetiapine exhibited a relatively low
Am J Health-Syst PharmVol 65 Jun 1, 2008
selectivity for dopamine and sero-
tonin receptors and a higher affinity
for hERG channels. It is important to
understand that this trial was an in
vitro assessment, and the results may
not extend to clinical practice. For
example, in this study olanzapine did
not correlate to a lengthened Q-Tc
interval, though in vivo evidence has
demonstrated that olanzapine may
be related to Q-Tc interval prolonga-
tion (Table 2).
Crumb and colleagues62 conduct-
ed an in vitro study of several anti-
psychotics to determine whether
Q-Tc interval prolongation was due
to direct inhibition of cardiac ion
channels or disruption of hERG
potassium channels. Though these
drugs had little direct effect on cardi-
ac ion channels, the effects that were
seen were due to blockade of hERG
potassium channels. Thioridazine
and sertindole had the highest affin-
ity for hERG channels, olanzapine
and clozapine had the least, and halo-
peridol, pimozide, risperidone, and
ziprasidone had moderate affinities.
Evidence of Q-T interval
prolongation
Antidepressants. Relative to Q-Tc
interval prolongation, the primary
difference between tricyclic antide-
pressants and SSRIs is due to effects
of the drugs on hERG potassium
ion channels in cardiomyocytes. The
SSRIs are more likely to cause bra-
dycardia than tachycardia; the latter
often leads to arrhythmias with tricy-
clic antidepressants.63,64 Overall, the
SSRIs are not typically linked to an
increased risk of Q-Tc interval pro-
longation. Though tricyclic antide-
pressants have been associated with
Class I antiarrhythmic properties,
one study showed that imipramine
(whose antiarrhythmic properties are
similar to quinidines) was only mar-
ginally effective in preventing prema-
ture ventricular contractions.65
Vieweg and Wood66 highlighted
several case reports of Q-Tc interval
prolongation associated with the use
1031
1032
Table 1.
Case Reports of Antidepressant-Induced Q-Tc Interval Prolongationa
Maximum
Q-Tc Interval
Patient Age Change from
Ref. (yr), Sex Drug Q-Tc Interval Baseline Remarks
33 57, female Amitriptyline 3 mo before admission, normal; at ED, NR Patient had 2 episodes of TdP, possibly due to interaction
482 msec between fluconazole and amitriptyline
34 30, male Bupropion hydrochloride 4 hr after ingestion, 470 msec; maximum, 23 msec Q-Tc interval returned to safe level 71 hr after bupropion
overdose 493 msec ingestion
34 51, female Extended-release bupropion 2.7 hr after ingestion, 404 msec; 144 msec Q-Tc interval returned to safe level 78 hr after bupropion
hydrochloride overdose (30 g) maximum, 548 msec ingestion
35 50, female Doxepin overdose (6 g)b On admission, 490 msec; 30 min later, 90 msec TdP responded to physostigmine within 30 min; no

Am J Health-Syst PharmVol 65 Jun 1, 2008

580 msec subsequent arrhythmia
36 74, female Fluoxetine 20 mg dailyb On admission, NR; postcardioversion, NR Q-Tc interval remained stable after cardioversion and
600 msec discontinuation of fluoxetine
37 52, male Fluoxetine 40 mg dailyb Before fluoxetine, 380 msec; 3 mo 120 msec Complete resolution of Q-Tc interval prolongation after
later, 560 msec; 10 days after fluoxetine discontinuation
discontinuation, 380 msec
38 83, female Fluoxetine 20 mg dailyb On admission, 478 msec; 2 mo after 70 msec Multiple episodes of TdP during evening of admission;
discontinuation, 421 msec; 8 mo after resolution of all ECG abnormalities after fluoxetine
discontinuation, 408 msec discontinuation
39 44, female Nefazodone overdose Baseline, 405 msec; 85 min after 85 msec Q-Tc interval returned to safe level 125 min after
ingestion, 490 msec; 125 min after nefazodone ingestion
clinical reviews Antipsychotic and antidepressant drugs

ingestion, 435 msec

40 58, female Nefazodone hydrochloride 100 9 hr postadmission, 508 msec NR TdP spontaneously resolved; Q-Tc interval remained
mg b.i.d. normal
41 29, female Trazodone hydrochloride 12 hr after ingestion, 607 msec; 26 hr 178 msec Patient treated with activated charcoal and gastric lavage;
overdose (3 g) after ingestion, 486 msec; 3 days after complete resolution of Q-Tc interval prolongation
ingestion, 429 msec
a
ED = emergency department, NR = not reported, TdP = torsades de pointes, ECG = electrocardiogram.
b
As the hydrochloride.
 Table 2.
Case Reports of Antipsychotic-Induced Q-Tc Interval Prolongationa
Maximum
Q-Tc Interval
Patient Age Change from
Ref. (yr), Sex Drug(s) Q-Tc Interval(s) Baseline Remarks
51 66, female Chlorpromazine, quetiapine Baseline, 450 msec 34 msec Q-Tc interval reduced to 416 msec following
discontinuation of chlorpromazine and quetiapine
51 66, female Olanzapine 60 mg daily Baseline, 416 msec; 2nd ECG, 436 msec; 20 msec Q-Tc interval returned to safer value (415 msec) after
3rd ECG, 415 msec decrease to 40 mg daily of olanzapine
52 45, male Clozapine 150 mg Admission, 428 msec; day 14, 472 msec; 44 msec Q-Tc interval normalized and patient remained stable after
day 17, 428 msec clozapine discontinuation
53 75, male Haloperidol i.v. 2 mg/hrb Baseline, 435 msec; maximum, 615 msec 180 msec Q-Tc interval returned to baseline after haloperidol
discontinuation
53 68, male Haloperidol i.v. 2 mg/hrb Baseline, 407 msec; maximum, 648 msec 231 msec Q-Tc interval stabilized at 470 msec 48 hr after haloperidol
discontinuation
53 77, male Haloperidol i.v. 2 mg/hrb Baseline, 393 msec; maximum, 554 msec 161 msec Q-Tc interval returned to normal within 36 hr of
haloperidol discontinuation
54 41, female Haloperidol i.v. Baseline, 426 msec; day 7, 610 msec; day 184 msec Received total of 910 mg of haloperidol over 7 days and
12, 435 msec developed TdP on day 7; haloperidol discontinued
55 36, male Haloperidol 20 mg daily p.o. Baseline, 720 msec; 24 hr later, 520 msec; 340 msec Q-Tc interval prolongation resolved after haloperidol
48 hr later, 380 msec discontinuation and isoproterenol infusion
56 28, female Olanzapine 20 mg b.i.d. Baseline, 412 msec; 2nd ECG, 485 msec; 73 msec Q-Tc interval prolongation resolved after olanzapine
3rd ECG, 424 msec discontinuation
57 19, male Quetiapine overdose (10 g)c 2, 14, and 27 hr after ingestion: 581, 710, 270 msec Admitted to inpatient psychiatric unit and discharged 5
and 440 msec, respectively days later; Q-Tc interval remained <440 msec
58 46, male Risperidone 2 mg daily, Day 2, 2 hr after ingestion, 504 msec; day 104 msec 4 subsequent ECGs showed Q-Tc intervals of <407 msec
haloperidol 5 mg 3, 451 msec; day 4, 400 msec after discontinuation
59 50, male Ziprasidone overdose Admission, 490 msec NR Q-Tc interval returned to normal within 24 hr
60 38, female Ziprasidone overdose 6 hr after ingestion, 445 msec NR Only minimal Q-Tc interval prolongation after activated
charcoal and gastric lavage
61 17, male Ziprasidone and bupropion ED ECG, 440 msec; 2.5 hr after ingestion, 40 msec Q-Tc intervals remained <440 msec 40 hr after ingestion
overdose 480 msec; 336 hr, varied from 420 to
480 msec; 40 hr, 440 msec
a
TdP = torsades de pointes, ECG = electrocardiogram, NR = not reported, ED = emergency department.
b

Am J Health-Syst PharmVol 65 Jun 1, 2008

As the lactate.
c
As the fumarate.
clinical reviews Antipsychotic and antidepressant drugs

1033
 clinical reviews Antipsychotic and antidepressant drugs
of tricyclic antidepressants. Ami-
triptyline and maprotiline were the
drugs most commonly implicated in
these cases.
Ray et al.26 conducted a retrospec-
tive cohort study to establish the
risk of SCD in Tennessee Medicaid
recipients receiving therapy with a
tricyclic antidepressant or an SSRI.
Approximately 480,000 patient
records were screened. Deaths were
attributed to the antidepressant if
the patient did not have a coexisting
cardiac condition. The patient group
not taking any antidepressant served
as the control. The use of SSRIs did
not increase the risk of SCD (inci-
dence rate ratio [IRR], 0.95; 95%
confidence interval [CI], 0.422.15).
Compared with patients not taking
antidepressants, patients receiving a
tricyclic antidepressant had a slightly
higher but dose-dependent risk of
SCD (IRR, 1.12; 95% CI, 0.891.40).
Though the risk of SCD was not in-
creased in patients who were taking
less than 100 mg of amitriptyline
equivalents (IRR, 0.97; 95% CI,
0.721.29), the risk was about 2.5
times greater in patients taking at
least 300 mg of amitriptyline equiva-
lents (IRR, 2.53; 95% CI, 1.046.12).
Table 1 highlights case reports of
antidepressant-induced Q-Tc inter-
val prolongation.
Antipsychotics. Typical antipsy-
chotics are recognized as having a
greater risk of Q-Tc interval prolon-
gation than are atypical antipsychot-
ics. As the years of experience with
atypical antipsychotics increase and
their use becomes more widespread,
case reports of Q-Tc interval pro-
longation in patients receiving these
drugs are surfacing. Table 2 high-
lights several case reports of Q-Tc
interval prolongation with typical
and atypical antipsychotics.
Thioridazine has been associ-
ated with Q-Tc interval prolongation
and SCD since it was introduced in
1959.24 Reilly et al.67 examined the
rates of Q-Tc interval prolongation
in patients taking antipsychotics and
1034 Am J Health-Syst PharmVol 65 Jun 1, 2008
found that thioridazine use was more
than five times more likely to prolong
the Q-Tc interval compared with the
use of other antipsychotics (odds ra-
tio, 5.4; 95% CI, 2.013.7; p = 0.03).
Pimozide, another typical anti-
psychotic, is indicated for the treat-
ment of Tourettes syndrome in the
United States. Pimozide has been
extensively linked to Q-Tc interval
prolongation.24
Haloperidol is used quite fre-
quently in a wide variety of clinical
situations, but many of the cases of
Q-Tc interval prolongation have
occurred with off-label i.v. adminis-
tration of haloperidol in the inten-
sive care setting. In a retrospective
casecontrol study, 8 (3.6%) of 223
patients treated with i.v. haloperidol
developed torsades de pointes.68 The
risk was significantly greater in pa-
tients receiving at least 35 mg within
24 hours, in patients with a Q-Tc
interval of >500 msec, or in patients
who had both risk factors compared
with controls. Most cases of Q-Tc in-
terval prolongation typically involve
higher doses of haloperidol used to
control agitation after intubation or
psychosis, though prolongation has
occurred with lower doses as well.53,54
While the majority of cases of
Q-Tc interval prolongation have
been associated with the use of typi-
cal antipsychotics, atypical agents
have also been found to cause some
degree of prolongation.69 Sertindole
was the first atypical antipsychotic
to be associated with prolongation
of the Q-Tc interval. The manu-
facturers of sertindole first applied
for labeling approval in the United
States in the late 1990s, only to see
the drug fail to progress through
initial marketing trials due to adverse
events.69 In these initial trials, sertin-
dole was associated with a marked
increase (approximately 22 msec)
in the Q-Tc interval and 12 cases of
SCD. For these reasons, the Food
and Drug Administration (FDA) did
not approve the drugs marketing,
but sertindole was approved for use
in Europe in 1997.69 After reports of
increased rates of SCD, sertindole
was voluntarily withdrawn from the
European market.
Among the atypical antipsychot-
ics currently marketed in the United
States, the agent most frequently
linked to Q-Tc interval prolongation
is ziprasidone, which received mar-
keting approval from FDA in 2001.
Preclinical research demonstrated
that the drug prolonged the Q-Tc
interval in a non-dose-dependent
manner.69 In small-sample premar-
keting trials, few cases of Q-Tc inter-
val prolongation, torsades de pointes,
and SCD were reported.
In 2004, Harrigan et al.70 con-
ducted a study of six antipsychotic
drugs to determine their effects on
the Q-Tc interval both in the absence
and presence of other drugs metabo-
lized by the cytochrome P-450 (CYP)
isoenzyme system. The investigators
randomized 183 patients (of which
164 completed the study) to receive
maximum daily doses of ziprasidone
hydrochloride 160 mg (n = 31),
quetiapine 750 mg (as the fumarate)
(n = 27), olanzapine 20 mg (n = 24),
or risperidone 68 mg or 16 mg (n =
25) or typical daily doses of haloperi-
dol 15 mg (n = 27) or thioridazine
hydrochloride 300 mg (n = 30).
All treatment groups in the study
had a mean increase in Q-Tc interval
from baseline; however, no intervals
were greater than 500 msec. Thio-
ridazine was associated with a mean
increase of 30.1 msec; ziprasidone,
15.9 msec; haloperidol, 7.1 msec;
quetiapine, 5.7 msec; risperidone, 3.6
msec; and olanzapine, 1.7 msec.
Case reports of Q-Tc interval
prolongation associated with risperi-
done have been published71; however,
a meta-analysis of trials with risperi-
done failed to establish a relation-
ship between its use and either Q-Tc
interval prolongation or torsades de
pointes.71
Quetiapine has been linked to
Q-Tc interval prolongation, par-
ticularly in overdose situations. In
 clinical reviews Antipsychotic and antidepressant drugs
one case report, the patients Q-Tc
interval peaked at 710 msec, 14 hours
after ingesting 9.6 g of quetiapine.57
Harrigan and colleagues70 found that
quetiapine was associated with a
modest increase of 5.7 msec in Q-Tc
interval, much less than that of thi-
oridazine and ziprasidone. Of all the
atypical antipsychotic drugs studied,
olanzapine was associated with the
shortest prolongation of the Q-Tc
interval70; however, several published
case reports have described greater
increases in the Q-Tc interval with
olanzapine, 56,61 including one de-
scribing a possible interaction be-
tween olanzapine and ciprofloxacin
that resulted in a Q-Tc interval of
610 msec.72
Clozapine may prolong the Q-Tc
interval, but clinical trials have failed
to consistently report this effect.73
Antipsychotics have also been
linked to SCD.74 For example, Ray
et al.75 evaluated the risk of SCD in
481,744 Tennessee Medicaid recipi-
ents who were taking antipsychotics.
SCD was confirmed in 1,487 of these
patients. These results demonstrated
that patients receiving moderate
doses of antipsychotics had an in-
creased risk of SCD, thought to be
associated with an increased risk of
serious ventricular arrhythmias. An-
tipsychotics should therefore be used
with caution, particularly in patients
with cardiovascular disease.
Pharmacokinetic and
pharmacodynamic considerations
Drugdrug interactions must be
considered when treating patients
with antidepressants or antipsychot-
ics. Pharmacodynamic interactions
are of concern in such patients, as
many antidepressants and antipsy-
chotics compete with each other
for receptor-binding sites. Further,
pharmacokinetic reactions are com-
mon in this patient population due
to polypharmacy and cometabolism
by the CYP isoenzyme system.
Many antidepressants and anti-
psychotics undergo metabolism by
CYP2D6 and CYP3A4 isoenzymes.
All tricyclic antidepressants un-
dergo some degree of metabolism by
CYP2D6.76 There is also considerable
evidence of antipsychotics inhibiting
this pathway, resulting in increased
blood concentrations of tricyclic
antidepressants77 and tricyclic antide-
pressants inhibiting the metabolism
of antipsychotics.78,79 In a study of
Q-T interval prolongation, women
diagnosed with schizophrenia and
bipolar and schizoaffective disorders
received either antipsychotic mono-
therapy (haloperidol, olanzapine,
risperidone, or quetiapine) (n = 19)
or an antipsychotic (haloperidol,
olanzapine, risperidone, or quetiap-
ine) combined with an antidepressant
(citalopram, escitalopram, sertraline,
paroxetine, fluvoxamine, mirtazapine,
venlafaxine, or clomipramine) or
lithium (n = 19).80 The mean S.D.
Q-Tc intervals increased significantly
in the group receiving combination
therapy (increase, 24 21 msec)
compared with the monotherapy
group (increase, 1 30 msec) (p <
0.01). Furthermore, 38% of the pa-
tients in group 2 compared with 7%
of patients in group 1 had a Q-Tc in-
terval of >450 msec (p < 0.05). These
results suggest that patients receiving
a combination of antidepressants
and antipsychotics must be carefully
monitored. A follow-up ECG should
be taken at steady-state plasma drug
concentrations to ensure that any in-
crease from baseline does not exceed
60 msec. These interactions are of
particular interest in clinical prac-
tice, as patients often receive these
concomitant drugs. Although many
practitioners prescribe newer agents
(SSRIs and atypical antipsychotics),
using higher dosages or a combina-
tion of drugs increases patients risk
of Q-Tc interval prolongation, tor-
sades de pointes, and possible SCD.
A second isoenzyme that has a sig-
nificant effect on the metabolism of
many drugs is CYP3A4. Interactions
involving CYP3A4 are of particular
interest for the antipsychotics halo-
Am J Health-Syst PharmVol 65 Jun 1, 2008
peridol, pimozide, and clozapine, as
all have been shown to cause Q-Tc
interval prolongation at higher blood
drug concentrations. 76 The anti-
depressants paroxetine, sertraline,
and trazodone are at least partially
metabolized by CYP3A476 and could
induce Q-Tc interval prolongation if
a drugdrug interaction occurred.
Hepatic function is another im-
portant consideration when prescrib-
ing antipsychotics or antidepressants.
Since drug metabolism occurs in the
liver, adequate functioning of liver
enzymes is required to properly proc-
ess these drugs. This is of particular
interest in psychiatric patients as
many of them also abuse alcohol and
other drugs that could cause liver
disease and Q-Tc interval prolon-
gation81 and torsades de pointes.82
Moreover, hepatitis C can also affect
drug metabolism, leading to a pro-
longed Q-Tc interval.83,84 The phar-
macokinetics and drug interactions
pertinent to antidepressants and
antipsychotics are far more complex
than the scenarios mentioned here
and are outside the scope of this
review. A more detailed presenta-
tion of this topic has been published
elsewhere.76
Recommendations
Prolongation of the Q-Tc inter-
val is a concern for clinicians when
prescribing antidepressants and an-
tipsychotics. The risk is minimal in a
patient with no apparent risk factors
receiving a drug at therapeutic dos-
ages; however, some patients have an
increased risk of fatal arrhythmias
when taking some of these drugs.
Risk factors such as existing heart
disease, liver disease, female sex, el-
derly age, electrolyte abnormalities,
and stimulant drug abuse contribute
to the possibility of developing these
arrhythmias, as does concomitant
drug use or high dosages of drugs
known to prolong the Q-Tc interval.
These risk factors are potentially
identifiable in the patients history
and demographic information.
1035
 clinical reviews Antipsychotic and antidepressant drugs
ECGs are essential in determin-
ing how a drug may be affecting
the Q-Tc interval. Before initiating
therapy with these causative agents,
ECGs should be performed. If the
baseline Q-Tc interval is over 450
msec in men or over 460 msec in
women, an explanation for such a
high interval should be sought (e.g.,
family history of congenital long Q-T
syndrome, bradycardia) and cor-
rected if possible (e.g., treatment for
hypomagnesemia or hypokalemia).
If the interval remains above 450
msec in men or above 460 msec
in women and the patient has one
or more risk factors, then the drug
should not be given or the use of
an alternative drug that causes less
Q-Tc interval prolongation should
be considered.27 Patients should have
an ECG when the drug or drugs
reach steady-state levels, when add-
ing drugs that increase the risk of
Q-Tc interval prolongation, or with
any dosage adjustment, particularly
when the maximum approved dos-
age has been reached or exceeded.
There is evidence that the Q-Tc
interval may lengthen until a ceiling
is reached, particularly with antipsy-
chotic drugs.85 Additional ECGs may
help ensure that drug therapy is not
adversely affecting the cardioelec-
tric potential, especially with drugs
known to prolong the Q-Tc interval.
After the steady-state plasma drug
concentration is reached, additional
ECG monitoring should occur when
other factors that can alter the QTc
interval occur (e.g., marked reduc-
tion in heart rate, diuresis, dialysis,
evidence of myocardial infarction or
ischemia, hypokalemia, hypomag-
nesemia). An increase of the Q-Tc
interval approaching 60 msec signals
the need for more aggressive moni-
toring and consideration of stopping,
reducing, or changing drug therapy
to a less arrhythmogenic drug.27
Although it is a significant risk
factor, Q-Tc interval prolongation
should not deter appropriate anti-
depressant or antipsychotic therapy.
1036 Am J Health-Syst PharmVol 65 Jun 1, 2008
However, the clinician must use the
available evidence and knowledge
to weigh the risks and benefits in
each situation. Once the evidence is
evaluated, the clinician can initiate
safeguards to make an informed,
evidence-based decision that de-
creases the patients risk as much as
possible.
Conclusion
Antipsychotics cause Q-Tc inter-
val prolongation at a higher rate than
do antidepressants, and the typical
antipsychotics thioridazine, pimo-
zide, and i.v. haloperidol all have the
highest potential for Q-Tc interval
prolongation. Tricyclic antidepres-
sants have a higher rate of Q-Tc
interval prolongation than do SSRIs,
particularly at higher concentrations
and in overdose situations. The fre-
quency of adverse events associated
with drug-induced Q-T interval pro-
longation is unknown.
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