Open-label study comparing the efficacy and tolerability of aripiprazole and haloperidol in the treatment of pediatric tic disorders.

Abstract

Due to its unique pharmacodynamic properties of dopamine partial agonist activity, and its association with few and mild side effects, aripiprazole is a candidate atypical antipsychotic for patients with tic disorders. This open-label study compared the efficacy and tolerability of aripiprazole with haloperidol, a typical antipsychotic widely used to treat patients with tic disorders. Forty-eight children and adolescents with tic disorders were recruited from the outpatient clinic at South Korea and treated with aripiprazole (initial dose, 5.0 mg/d; maximum dose 20 mg/d) or haloperidol (initial dose, 0.75 mg/d; maximum dose, 4.5 mg/d) for 8 weeks. Treatment efficacy was measured using the yale global tic severity scale (YGTSS), and tolerability was measured using the extrapyramidal symptom rating scale (ESRS) and an adverse effects checklist. Total tic scores as measured by the YGTSS decreased over time in both groups (p < 0.001) without any significant differences between groups. ESRS scores were significantly higher in the haloperidol group during the 4 weeks after commencement of medication (p < 0.05). These results indicate that aripiprazole may be a promising drug in the treatment of children and adolescents with tic disorders. Further controlled studies are needed to determine the efficacy and tolerability of aripiprazole in these patients.

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ORIGINAL CONTRIBUTION
Open-label study comparing the efficacy and tolerability
of aripiprazole and haloperidol in the treatment
of pediatric tic disorders
Hanik K. Yoo•Joong-Sun Lee•Kyoung-Won Paik•
Soon-Ho Choi•Sujung J. Yoon•Jieun E. Kim•
Jin Pyo Hong
Received: 29 March 2010/Accepted: 15 December 2010/Published online: 28 December 2010
? The Author(s) 2010. This article is published with open access at Springerlink.com
Abstract
of dopamine partial agonist activity, and its association
with few and mild side effects, aripiprazole is a candidate
atypical antipsychotic for patients with tic disorders. This
open-label study compared the efficacy and tolerability of
aripiprazole with haloperidol, a typical antipsychotic
widely used to treat patients with tic disorders. Forty-eight
children and adolescents with tic disorders were recruited
from the outpatient clinic at South Korea and treated
with aripiprazole (initial dose, 5.0 mg/d; maximum dose
20 mg/d) or haloperidol (initial dose, 0.75 mg/d; maximum
dose, 4.5 mg/d) for 8 weeks. Treatment efficacy was
measured using the yale global tic severity scale (YGTSS),
and tolerability was measured using the extrapyramidal
symptom rating scale (ESRS) and an adverse effects
checklist. Total tic scores as measured by the YGTSS
decreased over time in both groups (p\0.001) with-
out any significant differences between groups. ESRS
scores were significantly higher in the haloperidol group
Due to its unique pharmacodynamic properties
during the 4 weeks after commencement of medication
(p\0.05). These results indicate that aripiprazole may be
a promising drug in the treatment of children and adoles-
cents with tic disorders. Further controlled studies are
needed to determine the efficacy and tolerability of ari-
piprazole in these patients.
Keywords
disorder ? Children ? Adolescents ? Haloperidol
Aripiprazole ? Tic disorders ? Tourette
Introduction
Typical antipsychotics such as haloperidol and pimozide
have been prescribed to control tic symptoms as first-line
agent [1]. More recently, clinical experience with atypical
neuroleptics have increased owing to the efficacy and the
more tolerable adverse effects relative to some classical
antipsychotics [1–11]. Some drugs such as risperidone
[7, 12], quetiapine [13], and olanzapine [4, 10, 11], how-
ever, may cause unwanted metabolic side effects, which
may worsen patient quality of life as well as general
medical health status.
Aripiprazole is another candidate atypical antipsychotic
agent for patients with tic disorders. This drug has a lower
risk of metabolic side effects than other atypical neuro-
leptics. In addition, aripiprazole has a unique pharmaco-
dynamic property, namely dopamine partial agonist
activity [14]. Because abnormalities in the brain dopamine
system may be closely related to the pathology of tic dis-
orders [15], we hypothesized that aripiprazole may have
therapeutic effects on tic manifestations. Several clinical
trials, including our previous studies, have revealed that
aripiprazole may be successful in treating patients with tic
disorders, due to its high efficacy and tolerability [16–24].
H. K. Yoo (&) ? J.-S. Lee ? S.-H. Choi ? J. P. Hong
Department of Psychiatry, University of Ulsan College
of Medicine, Asan Medical Center, 388-1 Pungnap-2 dong,
Songpa-gu, Seoul 138-736, South Korea
e-mail: hiyoo@amc.seoul.kr
K.-W. Paik
Department of Psychiatry, Hanyang University Medical Center,
Seoul, South Korea
S. J. Yoon
Department of Psychiatry, Catholic University Medical College,
St. Paul Hospital, Seoul, South Korea
J. E. Kim
Department of Psychiatry, Seoul National University College
of Medicine, Seoul National University Hospital,
Seoul, South Korea
123
Eur Child Adolesc Psychiatry (2011) 20:127–135
DOI 10.1007/s00787-010-0154-0

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No study to date, however, has compared the efficacy and
tolerability of aripiprazole and typical antipsychotics in
these patients. We therefore compared the efficacy and
tolerability of aripprazole with haloperidol, a typical anti-
psychotic agent widely used to treat children and adoles-
cents with tic disorders.
Methods
Participant characteristics
Forty-eight children and adolescents with tic disorders (33
males, 15 females; mean ± SD age = 10.3 ± 3.5 years;
range, 6–15 years) were recruited at an outpatient clinic at
a general hospital in Seoul, South Korea, from August
2005 to March 2007. Before determining eligibility, we
obtained informed consent and assent from both the study
subject and the child’s primary caregiver. The study pro-
tocol was approved by our local Institutional Review
Board.
Patients were deemed eligible if they had DSM-IV
diagnosis of tic disorders, as described in the Korean ver-
sion of the Kiddie-Schedule for Affective Disorders and
Schizophrenia-Present and Lifetime Version (KSADS-PL
[25]) and Total Tic scores C22 on the Korean version of
the yale global tic severity scale (YGTSS [26, 27]), cor-
responding to at least moderate tic severity. Each patient
was subsequently examined by a board-certified child
psychiatrist.
Exclusion criteria included current mood disorders,
psychotic symptoms, and anxiety disorders, except for
obsessive–compulsive disorder, the most common comor-
bid anxiety disorder in tic patients. Subjects with an
IQ B 70 on the Korean version of the Wechsler Intelli-
gence Scale for Children-Revised (WISC-R [28]) were also
excluded, as were patients with previous or current seizure
episodes, electroencephalogram (EEG) abnormalities, and
those who had used aripiprazole previously. Subjects who
had taken psychotropic medications must have been drug-
free for at least 2 weeks before study entry and had to be
devoid of any significant medical problems.
Study design
This was an open, non-randomized, parallel-group clinical
trial. All subjects were evaluated at baseline by routine
laboratory tests, electrocardiogram (ECG), resting pulse
rate and blood pressure while sitting, height and weight
measurement, medical history, and physical and neuro-
logical examinations. Choice of treatment was based on
patient’s preference. Patients in the aripiprazole group
started at a dose of 5.0 mg/d, which was increased in
5.0–10.0 mg/d increments every 2 weeks as tolerated
[23, 24]. Doses were reduced in 2.5–5.0 mg/d steps when
intolerable side effects emerged. The maximum allowable
dose was 20 mg/d and patients were treated for 8 weeks.
Patients in the haloperidol group were started at a dose of
0.75 mg/d and increased in 1.5–3.0 mg/day increments
every 2 weeks to a maximum tolerated dose of 4.5 mg/d
[29]. Psychotropic drugs to control comorbid psychiatric
symptoms were not prescribed during the study period.
Patients were assessed every other week, with the final
assessment 8 weeks after the start of study medications.
Measurements
The YGTSS is a semi-structured clinical interview
designed to assess current tic severity; this scale yields
three summary scores; total motor (0–25), total phonic
(0–25), and total tic (sum of motor and phonic) scores. The
YGTTS also contains an impairment scale (0–50), which
evaluates the global level of functional impairment arising
from tics [27]. Because this study was designed to compare
efficacy in reducing tic symptoms, the primary outcome
measure was total tic score. The YGTSS was administered
to each subject at each visit.
Secondary outcome measures included the Clinical
Global Impressions-Improvement scale (CGI-I [30]), and
the CGI-Severity of Illness scale (CGI-S [31]). Scores of 1
(very much improved) or 2 (much improved) in the CGI-I
were regarded as positive responses. Both of these tests
were administered at every visit.
Adverseeffectsassociatedwiththesedrugswereassessed
using an in-house adverse effect checklist, which included
the most commonly encountered side effects of aripiprazole
and haloperidol, as well as general questions on health
issues,currentillnessesorinjuries,andconcomitantmedical
treatments. The Extrapyramidal Symptom (EPS) Rating
Scale (ESRS) was also used to rate the severity of Parkin-
sonism, akathisia, dystonia, and dyskinesia [32]. We mea-
suredheightandweightateveryvisit.Atthestudyendpoint,
physical and neurological examinations, laboratory tests,
and ECG assessments were repeated.
All tests were admitted by a single psychiatrist, who was
blinded to dose changes but not to the drug of choice.
Statistical analyses
We used intent-to-treat analyses, based on patients assessed
at least once after baseline. Multiple linear regression and
generalized estimation equation (GEE) regression model-
ing were used to identify medication efficacy and the sig-
nificance of changes in ESRS scores. Age, gender, duration
of illness, and baseline scores of each outcome were
covariates for each analysis. Fisher’s exact test and the
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Mann–Whitney U test were used as appropriate for
between-group comparisons. All analyses were two-sided,
with statistical significance defined at an a level of 0.05.
Results
Participant characteristics
Of the 48 children and adolescents with tic disorders, 31
were prescribed aripiprazole and 17 were prescribed halo-
peridol.Twenty-sixpatients(54.1%)hadTourette’sdisorder
and 11 (21.9%) had chronic motor and vocal tic disorders.
Eighteen participants (37.5%) had other comorbid psychi-
atric disorders, the most common being attention-deficit
hyperactivitydisorder(31.3%).Themeandurationofillness
was3.0 ± 2.7 yearsand18subjects(37.5%)hadahistoryof
previous medication to control tic symptoms.
Although gender ratio, total IQ, type of tic disorders,
comorbid conditions, duration of illness, and study medi-
cations did not differ between the two groups, the mean age
was significantly higher in the aripiprazole than in the
haloperidol group (11.2 ± 3.5 years vs. 8.6 ± 2.9 years;
Z = 2.68, p\0.01). The mean dose and duration of ari-
piprazole were 10.6 ± 5.2 mg/d and 51.7 ± 12.6 d,
respectively, whereas the mean dose and duration of hal-
operidol were 1.9 ± 1.1 mg/d and 46.3 ± 15.8 d, respec-
tively (Table 1).
Efficacy of aripiprazole and haloperidol: yale global tic
severity scale
At baseline and at each follow-up visit, there were no
significant between-group differences in tic scores, indi-
cating that these two drugs were similarly efficacious in
reducing tic symptoms (Table 2). After 8 weeks of
treatment, 54.3% of the aripiprazole and 63.4% of the
haloperidol group showed reductions in total tic scores.
Total tic score decreased over time in both groups (Z =
-9.60, p\0.001) (Table 2). This reduction was particu-
larly marked at the first follow-up visit (week 2) in both
groups (p\0.001) and was sustained throughout the study
period (Fig. 1a). There were no significant between-group
effects or interactions.
At baseline, the mean motor tic score was higher in the
haloperidol than in the aripiprazole group (20.5 ± 3.1 vs.
17.5 ± 5.3; Z = -1.87, p = 0.06), but the difference did
not reach statistical significance. Aripiprazole reduced
motor tic scores 54.3% and phonic tic scores 50.0%,
whereas haloperidol reduced these scores by 58.5 and
66.2%, respectively. Motor (Z = -8.29, p\0.001) and
phonic (Z = -5.59, p\0.001) tic scores decreased over
time in both groups (Table 2; Fig. 1b, c), but there were no
significant between-group effects or interaction terms.
Efficacy of aripiprazole and haloperidol: clinical global
impression
The CGI-S scores of both groups decreased over time
(Z = -8.83, p\0.001) without group or interaction
effects. Twenty-two children and adolescents (71.0%) in
the aripiprazole group and ten (58.8%) in the haloperidol
group were ‘‘much improved’’ or ‘‘very much improved’’
on the CGI-I measurement after 8 weeks of medication.
Dropout rate
Although 25 children and adolescents in the aripiprazole
group (80.6%) experienced one or more unwanted side
effects, only five (16.1%) patients inthis group discontinued
Table 1 Demographic and
clinical characteristics of the 48
children and adolescents with
tic disorders
ap\0.01 by the Mann–
Whitney U Test
IQ intelligence quotient
Aripiprazole group
(n = 31)
Haloperidol group
(n = 17)
Male, n (%)
Age meana(SD), years
22 (71.0)11 (64.7)
11.2 (3.5) (range: 6–18)8.6 (2.9) (range: 6–16)
Total IQ108.2 ± 12.4105.5 ± 9.1
Type of tic disorders
Tourette’s disorder, n (%)19 (61.3)7 (41.2)
Chronic motor and vocal tic disorder, n (%) 7 (22.6)4 (23.5)
Transient tic disorder, n (%)5 (16.1)6 (35.3)
Comorbidities
Attention deficit hyperactivity disorder, n (%) 9 (29.0)6 (35.3)
Oppositional defiant disorder, n (%)2 (6.5)0 (0)
Obsessive compulsive disorder, n (%)3 (9.7) 0 (0)
Duration of tic disorders mean (SD), years 3.4 (2.9)2.3 (2.3)
Dose/day mean (SD), mg 10.6 (5.2) (range: 2.5–20.0) 1.9 (1.1) (range: 0.75–4.5)
Duration of study medication mean (SD), days51.7 (12.6) (range: 14–60) 46.3 (15.8) (range: 15–61)
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medication prematurely owing to intolerability. In contrast,
all 17 subjects in the haloperidol group experienced unex-
pected side effects and 6 (35.3%) were not able to continue
medication owing to unbearable adverse events. Although
frequencies of side effects between two groups during study
period were not different (v2= 2.08, p = 0.15), rates of
drug discontinuation were lower in the aripiprazole group
relative to the haloperidol group (v2= 7.17, p = 0.007).
The major intolerable side effects included nausea (2
patients), headache (2 patients) and sedation (1 patient) in
the aripiprazole group, and sedation (4 patients) and head-
ache (2 patients) in the haloperidol group.
Extrapyramidal symptom rating scale
The total ESRS score at study endpoint was higher in the
haloperidol than in the aripiprazole group. There were
interaction effects between groups and a time effect of the
total ESRS score (Z = -2.17, p = 0.03). Total ESRS
scores did not change significantly in the aripiprazole
group between 2 and 4 weeks (1.1 ± 1.7 and 1.1 ± 1.8,
respectively), but increased significantly in the haloperidol
group between 2 and 4 weeks (1.4 ± 2.1 and 2.8 ± 2.6,
respectively); these interaction effects were statistically
significant (Z = -2.083, p = 0.037) (Fig. 2). In addition,
the subscale scores for Parkinsonism, akathisia and, dys-
tonia were higher in the haloperidol group at 8 weeks. The
Parkinsonism subscale of the ESRS showed an interaction
effect between group and time Z = -2.06, p = 0.04). No
subjects experienced dyskinesia in this study (Table 3).
General adverse events
The most common side effects of aripiprazole were hyper-
somnia (58.1%), nausea/vomiting (29.0%), EPS (19.4%),
and headache (16.1%), whereas the most common side
effects of haloperidol included hypersomnia (82.4%),
headache (58.8%), EPS (41.2%), nausea/vomiting (23.5%),
gastrointestinal disturbances (11.8%), emotional hypersen-
sitivity (11.8%), dizziness (11.8%), and chest discomfort
(11.8%) (Table 4). Hypersomnia (v2= 4.17, p = 0.04),
EPS (v2= 7.84, p = 0.005), and headache (v2= 24.34,
Table 2 Efficacy of aripiprazole and haloperidol in the treatment of tic disorders
Outcome measuresAripiprazole group
(n = 31)
Haloperidol group
(n = 17)
Statistical valuea
Baseline8 weeksBaseline8 weeksGroup effect Time effectGroup 9 time
Interaction effect
zpzpzp
YGTSS mean (SD)
Motor tic scores17.5 (5.3)8.0 (4.4)20.5 (3.1)8.5 (6.7)-1.21 0.227-8.29
\0.001
\0.001
\0.001
0.61 0.540
Phonic tic scores 9.0 (6.7) 4.5 (4.6)7.1 (8.3) 2.4 (4.3)0.99 0.320-5.591.13 0.258
Total tic scores
CGI-I, n (%)b
26.5 (4.9) 12.1 (6.4)27.6 (7.3)10.1 (7.5)-0.610.543-9.601.280.201
Very much improved– 9 (34.6)– 5 (45.5)––––
Much improved–13 (50.0)–5 (45.5)
Minimally improved– 3 (16.7)–0 (0)
No change– 1 (3.8)– 1 (9.1)
Minimally aggravated–0–0
Much aggravated–0–0
CGI-S, n (%)
Normal, not Ill0 2 (7.7)0 1 (9.1)-0.94 0.35-8.83
\0.0010.690.490
Minimally ill08 (30.7)06 (54.5)
Mildly ill010 (38.5)0 3 (27.3)
Moderately ill 4 (12.9)3 (11.5)1 (20.0)0
Markedly ill12 (38.7)3 (11.5)7 (36.9)0
Severely ill15 (48.4)0 9 (37.5) 1 (9.1)
Extremely severely ill0000
aTo examine the group and time effects for each outcome variable, generalized estimation equation (GEE) modeling was adopted, with age,
gender, duration of illness, and baseline scores for each outcome variable included as covariates
bCalculating patients who dropped-out
YGTSS yale global tic severity scale, CGI-I clinical global impression-improvement, CGI-S clinical global impression-severity of illness
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p\0.001) were observed less frequently in the aripiprazole
group. All laboratory results before, during and after treat-
ment were within normal limits. Any abnormalities in the
results of the ECGs including QTc changes were observed
before and after treatment. Between baseline and 8 weeks,
the mean body weight of the subjects in the aripiprazole
and haloperidol groups increased 0.16 kg/week and
0.21 kg/week,respectively,buttheseincreasesdidnotdiffer
between the two groups (Mann–Whitney U test, Z = 0.291,
p = 0.771).
Discussion
To our knowledge, this study is the first to directly
compare the efficacy and tolerability of aripiprazole and
haloperidol in the treatment of children and adolescents
with tic disorders. We found that aripiprazole was as
effective as haloperidol in reducing tic symptoms, as well
as being better tolerated. The mean dose of aripiprazole
used in this study, 10.6 mg/d, was similar to that used in
our previous studies in which children and adolescents
with tic disorders were treated with aripiprazole [16, 23,
24], and to doses used in previous studies of youths with
developmental disabilities [33–35], delusional disorder
[36], and bipolar disorders [37]. In contrast, higher doses
of aripiprazole have been used to treat children and ado-
lescents with bipolar disorders [38, 39], catatonia [40],
and generalized anxiety disorder [41], as well as in psy-
chiatric inpatients [42]. The aripiprazole dose used in this
study was lower than that used in adults with Tourette
disorder [21, 43–45].
Although various atypical antipsychotics are widely used
to treat tic disorders, they had weaker efficacy than typical
neuroleptics such as haloperidol and pimozide, which can
decrease ticsymptomsbymorethan60%[29].Eventhefirst
atypicalantipsychotic,clozapine,wasnotabletosufficiently
Fig. 1 a Percentage changes in total tic scores over time in the
aripiprazole and haloperidol treatment groups. b Percentage changes
in motor tic scores over time in the aripiprazole and haloperidol
treatment groups. c Percentage changes in phonic tic scores over time
in the aripiprazole and haloperidol treatment groups The error bars
refer to standard deviation
Fig. 2 Changes in ESRS scores over time in the aripiprazole and
haloperidol treatment groups. Abbreviations ESRS extrapyramidal
symptom rating scale. The error bars refer to standard deviation
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