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DOI: 10.1542/peds.2003-0264-F
; originally published online October 18, 2004; 2004;114;e634Pediatrics
and Fiona Dunbar
Sarah Shea, Atilla Turgay, Alan Carroll, Miklos Schulz, Herbert Orlik, Isabel Smith
With Autistic and Other Pervasive Developmental Disorders
Risperidone in the Treatment of Disruptive Behavioral Symptoms in Children
http://pediatrics.aappublications.org/content/114/5/e634.full.html
located on the World Wide Web at:
The online version of this article, along with updated information and services, is
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2004 by the American Academy
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
publication, it has been published continuously since 1948. PEDIATRICS is owned,
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Risperidone in the Treatment of Disruptive Behavioral Symptoms in
Children With Autistic and Other Pervasive Developmental Disorders
Sarah Shea, MD*; Atilla Turgay, MD‡; Alan Carroll, MD§; Miklos Schulz, PhD㛳; Herbert Orlik, MD*;
Isabel Smith, PhD*; and Fiona Dunbar, MBBCh¶
ABSTRACT. Objective. To investigate the efficacy
and safety of risperidone for the treatment of disruptive
behavioral symptoms in children with autism and other
pervasive developmental disorders (PDD).
Methods. In this 8-week, randomized, double-blind,
placebo-controlled trial, risperidone/placebo solution
(0.01–0.06 mg/kg/day) was administered to 79 children
who were aged 5 to 12 years and had PDD. Behavioral
symptoms were assessed using the Aberrant Behavior
Checklist (ABC), Nisonger Child Behavior Rating Form,
and Clinical Global Impression-Change. Safety assess-
ments included vital signs, electrocardiogram, extrapyra-
midal symptoms, adverse events, and laboratory tests.
Results. Subjects who were taking risperidone (mean
dosage: 0.04 mg/kg/day; 1.17 mg/day) experienced a sig-
nificantly greater mean decrease on the irritability sub-
scale of the ABC (primary endpoint) compared with
those who were taking placebo. By study endpoint, ris-
peridone-treated subjects exhibited a 64% improvement
over baseline in the irritability score almost double that
of placebo-treated subjects (31%). Risperidone-treated
subjects also exhibited significantly greater decreases on
the other 4 subscales of the ABC; on the conduct prob-
lem, insecure/anxious, hyperactive, and overly sensitive
subscales of the Nisonger Child Behavior Rating Form
(parent version); and on the Visual Analog Scale of the
most troublesome symptom. More risperidone-treated
subjects (87%) showed global improvement in their con-
dition compared with the placebo group (40%). Somno-
lence, the most frequently reported adverse event, was
noted in 72.5% versus 7.7% of subjects (risperidone vs
placebo) and seemed manageable with dose/dose-sched-
ule modification. Risperidone-treated subjects experi-
enced statistically significantly greater increases in
weight (2.7 vs 1.0 kg), pulse rate, and systolic blood
pressure. Extrapyramidal symptoms scores were compa-
rable between groups.
Conclusions. Risperidone was well tolerated and ef-
ficacious in treating behavioral symptoms associated
with PDD in children. Pediatrics 2004;114:e634–e641. URL:
www.pediatrics.org/cgi/doi/10.1542/peds.2003-0264-F; autis-
tic disorder, pervasive developmental disorders, risperidone.
ABBREVIATIONS. PDD, pervasive developmental disorders;
EPS, extrapyramidal symptom; CARS, Childhood Autism Rating
Scale; ESRS, Extrapyramidal Symptom Rating Scale; ABC, Aber-
rant Behavior Checklist; N-CBRF, Nisonger Child Behavior Rating
Form; VAS, Visual Analog Scale; CGI-C, Clinical Global Impres-
sion-Change; ITT, intention-to-treat; RUPP, Research Units on
Pediatric Psychopharmacology.
T
he pervasive developmental disorders (PDD)
are a group of neuropsychiatric disorders that
include autistic disorder, Asperger’s disorder,
childhood disintegrative disorder, Rett’s disorder,
and PDD not otherwise specified.
1
These disorders
are characterized by atypical development in social,
communicative, and behavior areas. Onset typically
occurs within the first years of life. Prevalence rates
as high as 63 per 10 000 children have recently been
reported.
2
Although commonly associated with men-
tal retardation, the developmental and behavioral
features of PDD are distinct and do not simply reflect
developmental level.
3,4
PDD are characterized by severe and pervasive
deficits in several areas of development.
1
These in-
clude reciprocal social interaction skills; communica-
tion skills; or the presence of stereotyped behavior,
interests, and activities. Children with PDD may
present with difficult behaviors including aggres-
sion, hyperactivity, inattention, impulsivity, stereo-
typies, screaming, and self-injurious behavior. These
behaviors may be disruptive in both school and fam-
ily environments; in addition, they can interfere with
the progress of the child and the well-being of the
child and the caregivers.
As yet, there are no pharmacologic interventions
that specifically target the core deficits of the PDD
profile. However, some progress has been made in
ameliorating the behavioral symptoms associated
with PDD. A number of studies, published since the
1960s, have shown that improved control of behav-
ioral symptoms can be achieved through the use of
conventional neuroleptics such as the dopamine re-
ceptor antagonist haloperidol.
3,5
The frequent occur-
rence of dyskinesias and other extrapyramidal side
effects limited their use. Not surprising, as the early
safety and efficacy data with the newer atypical an-
tipsychotics became available in the late 1980s and
early 1990s, interest in their use in PDD began to
grow.
Risperidone is an antagonist of both dopamine
(D
2
) and serotonin (5HT
2A
and others) receptors.
6,7
Particularly when used at lower doses, risperidone
From the *IWK Health Centre and Dalhousie University, Halifax, Nova
Scotia, Canada; ‡University of Toronto, Toronto, Ontario, Canada; §Glen-
rose Rehabilitation Hospital, Edmonton, Alberta, Canada; 㛳SciAn Clinical,
Etobicoke, Ontario, Canada; and ¶Janssen-Ortho Inc, Toronto, Ontario,
Canada.
Accepted for publication Apr 29, 2004.
doi:10.1542/peds.2003-0264-F
Reprint requests to (S.S.) IWK Health Centre, 5850 University Ave, Devel-
opmental Clinic, 8th Fl, Halifax, Nova Scotia, Canada B3J 3G9. E-mail:
sarah.shea@iwk.nshealth.ca
PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad-
emy of Pediatrics.
e634 PEDIATRICS Vol. 114 No. 5 November 2004 www.pediatrics.org/cgi/doi/10.1542/peds.2003-0264-F
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proved to be relatively free of the extrapyramidal
symptoms (EPSs) that had limited the use of conven-
tional agents.
8
A number of open-label trials were
undertaken to investigate the use of risperidone in
children with PDD.
9–18
Preliminary evidence from
these studies suggested that risperidone was both
safe and effective in reducing behavioral symptoms
in this population. However, more rigorously de-
signed studies were needed to confirm these find-
ings. At the time that this study was conducted, no
controlled studies had been reported. As a result, this
study was undertaken to evaluate critically the effi-
cacy and safety of risperidone for the treatment of
behavioral symptoms in children with PDD.
METHODS
Study Design and Conduct
This was an 8-week, randomized, double-blind, parallel-group,
Canadian, multicenter study designed to evaluate the efficacy and
safety of risperidone versus placebo in the treatment of disruptive
behavioral symptoms in children with PDD. Subjects attended the
clinic on 7 occasions: at the baseline/screening visit and at the end
of treatment weeks 1, 2, 3, 5, 7, and 8. The study was conducted in
accordance with the Declaration of Helsinki as revised in 1996 and
was approved by the institutional review board at each partici-
pating center. The child’s parent/guardian/legal representative
provided written informed consent. Supportive approaches were
used to obtain the child’s assent when possible. A responsible
person was required to accompany the subject at clinic visits,
provide reliable assessments, and administer medications.
Subjects
Physically healthy male and female outpatients who were aged
5 to 12 years inclusive were eligible to participate in this study
provided that they had a Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition Axis I diagnosis of PDD
1
and a total score
of 30 or more on the Childhood Autism Rating Scale (CARS),
19,20
with or without mental retardation. Subjects who had schizophre-
nia, other psychotic disorders, clinically relevant nonneurologic
disease, clinically significant laboratory abnormalities, or a seizure
disorder for which they were receiving ⬎1 anticonvulsant or if
they had had a seizure in the last 3 months were excluded. In
addition, subjects who had a history of hypersensitivity to neuro-
leptics, tardive dyskinesia, neuroleptic malignant syndrome, drug
or alcohol abuse, or human immunodeficiency virus infection
were excluded. Subjects were also excluded when they had used
risperidone in the last 3 months, had been previously unrespon-
sive or intolerant to risperidone, or were using a prohibited med-
ication.
Study and Other Medications
After screening at the baseline visit, eligible subjects were ran-
domized (1:1) to receive either risperidone or placebo in a double-
blind manner. Risperidone or placebo oral solution 1.0 mg/mL
was administered once daily in the morning at 0.01 mg/kg/day
on treatment days 1 and 2 and increased to 0.02 mg/kg/day on
day 3. Depending on the therapeutic response at day 8, the dose
could be increased by a maximal increment of 0.02 mg/kg/day.
Thereafter, the dose could be adjusted at the investigator’s discre-
tion at weekly intervals by increments/decrements not to exceed
0.02 mg/kg/day. The maximal allowable dosage was 0.06 mg/
kg/day. In case of drowsiness, the study medication could be
administered once daily in the evening, or the total daily dose
could be divided and administered on a morning and evening
schedule.
Medications that are used to treat EPSs were to be discontinued
at the time of entry into the trial. However, during the trial,
anticholinergics could be initiated to treat emergent EPSs after the
Extrapyramidal Symptom Rating Scale (ESRS) had been com-
pleted. Prohibited medications included antipsychotics other than
the study medication, antidepressants, lithium,
␣
2
-antagonists,
clonidine, guanfacine, cholinesterase inhibitors, psychostimulants,
and naltrexone. A single anticonvulsant and/or medications for
sleep or anxiety were permitted only in the case in which the
subject was already taking them at a stable dose for the 30 days
before enrollment. Similar restrictions were placed on the use of
behavior intervention therapy. Medications for preexisting or-
ganic disorders were allowed provided that the dose and schedule
of administration were kept as constant as possible.
Outcome Measures
Efficacy assessments that were scored at each clinic visit in-
cluded the Aberrant Behavior Checklist (ABC),
21
the parent ver
-
sion of the Nisonger Child Behavior Rating Form (N-CBRF),
22
a
Visual Analog Scale (VAS) for the most troublesome symptom,
and the Clinical Global Impression-Change (CGI-C). The ABC
consisted of 58 items subdivided among 5 scales: irritability, leth-
argy and social withdrawal, stereotypic behavior, hyperactivity/
noncompliance, and inappropriate speech. The parent version of
the N-CBRF consisted of 60 items subdivided among 6 scales:
conduct problem, insecure/anxious, hyperactive, self-injury/ste-
reotypic, self-isolated/ritualistic, and overly sensitive. The ABC
and N-CBRF subscales were completed by the parent or caregiver
under the guidance of the investigator; scores for both scales
ranged from 0 to 3, with 0 ⫽ no problem and 3 ⫽ severe problem.
At the baseline visit, the parent/guardian reported which symp-
tom was the most troublesome. The severity of that symptom was
recorded on a VAS completed by the parent/guardian with a
vertical mark on a 100-mm line, with lower scores indicating a
better condition. At baseline, the CGI-Severity of the subject’s
PDD was scored by the investigator on a 7-item scale ranging from
absent to extremely severe. At subsequent visits, changes in the
subject’s global condition were rated by the investigator on a
7-point item scale (CGI-C) ranging from very much improved to
very much worse.
Safety assessment measures, which included adverse event
data, vital signs, and body weight, were collected at each visit. In
addition, the presence and the severity of EPSs were assessed at
each visit by the investigator using the ESRS.
23
A 12-lead electro
-
cardiogram and routine biochemistry, hematology, and urinalysis
were performed at baseline and at the end of treatment.
Statistical Analyses
The primary population for safety assessments was the inten-
tion-to-treat (ITT) population, defined as all randomized subjects
who received at least 1 dose of study medication. The primary
population for efficacy assessments was the ITT-efficacy popula-
tion, defined as all randomized subjects who received at least 1
dose of study medication and for whom there was at least 1
postbaseline efficacy assessment. The primary efficacy parameter
was the change in irritability from baseline to study endpoint (ie,
the last observation) as measured on the irritability subscale of the
ABC. This was a 15-item subscale that included items such as
“injures self,” “aggressive to other patients and staff,” “temper
tantrums,” “irritable,” “depressed mood,” and “cries and screams
inappropriately.”
24
Secondary efficacy parameters included the
changes from baseline to endpoint in the other 4 subscales of the
ABC, the 6 subscales of the N-CBRF (parent version), the VAS for
the most troublesome symptom, and the CGI-C. All changes from
baseline in the ABC and N-CBRF subscales and in the VAS were
analyzed by analysis of covariance using model terms of treat-
ment, center, and baseline score. A “responder” analysis was also
performed, whereby a “responder” was defined as having a 50%
or greater decrease from baseline in at least 2 of the 5 ABC
subscales with none of the other subscales presenting a 10% or
larger increase. The Cochran-Mantel-Haenszel test, controlling for
investigational site, was used to compare response rates between
risperidone and placebo groups; it was also used to compare
CGI-C scores. Adverse events were tabulated by type and inci-
dence. Heart rate, systolic and diastolic blood pressures, and
weight were analyzed using analysis of variance. Change in ESRS
scores was analyzed using a Cochran-Mantel-Haenszel test with
modified ridit scores (Van Elteren’s test). Descriptive statistics
were used to report other safety outcomes. All tests were inter-
preted at the 5% significance level (2-tailed) with no adjustment
for multiple testing.
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RESULTS
Subjects
A total of 80 subjects at 7 investigational sites met
the eligibility criteria and were enrolled into this
study. Of these, 41 were randomized to receive ris-
peridone and 39 were randomized to receive pla-
cebo. One subject who was randomized to the ris-
peridone group did not receive any study drug and
had no baseline assessments. Therefore, 79 subjects
(40 in the risperidone group, 39 in the placebo group)
were included in the ITT population, the primary
safety assessment population. In addition, because 1
subject in each group had no postbaseline efficacy
data recorded, 77 subjects (39 in the risperidone
group, 38 in the placebo group) were included in the
ITT-efficacy population, the primary efficacy assess-
ment population.
In the ITT population, risperidone- and placebo-
treated subjects were similar in terms of their demo-
graphic and baseline data (Table 1). The mean age of
participants was 7.5 years, and more than three quar-
ters were male. Most (88.6%) lived with their parents.
All subjects had a CARS score of 30 or greater, in-
dicative of autism. More than half (55.7%) of all
participants were within the “severe autism” cate-
gory, as assessed by the CARS. According to the
Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, which postdates the CARS and is a
less inclusive diagnostic system, 69% of subjects had
a diagnosis of autistic disorder. Twenty-three of the
40 risperidone-treated subjects and 25 of the 39 pla-
cebo-treated subjects had standard IQ testing per-
formed; 15 (65.2%) in the former group and 12
(48.0%) in the latter group were had either mild or
moderate mental retardation. Seventeen subjects (8
in the risperidone group, 9 in the placebo group),
whose intellectual abilities precluded the administra-
tion of standard IQ testing, completed other cogni-
tive testing using either the Leiter International Per-
formance Scales or Raven’s Progressive Matrices.
These children would likely have fallen within the
moderate to severe range of mental retardation. A
total of 59 (75%) subjects presented with a currently
active medical condition, most commonly ear/nose
or throat, eyes, gastrointestinal, dermatologic, geni-
tourinary, respiratory, or allergic/immunologic ab-
normalities.
Seventy-two (91.1%) subjects completed the
8-week study. Seven (8.9%) subjects withdrew before
completion; of these, 2 had been randomized to treat-
ment with risperidone and 5 had been randomized to
placebo. Among risperidone-treated subjects, 1 with-
drew because of an adverse event (the result of an
accidental overdose on day 2) and 1 withdrew be-
cause of insufficient response. Among placebo-
treated subjects, 1 withdrew because of an adverse
event (an accidental medication overdose on day 16),
2 withdrew because of insufficient response, and 2
withdrew consent.
Study and Other Medications
Subjects received double-blind treatment with pla-
cebo for a mean of 49.6 days (range: 7– 63 days) or
with risperidone for a mean of 52.7 days (range: 2–62
days). The mean daily dose of risperidone adminis-
tered during the treatment period, which included at
TABLE 1. Baseline Demographic and Disease Characteristics for the ITT Population
Characteristic Risperidone
(n ⫽ 40)
Placebo
(n ⫽ 39)
Age, y
Mean ⫾ SE 7.6 ⫾ 2.3 7.3 ⫾ 2.3
Median (range) 7.0 (5–12) 7.0 (5–12)
Gender, n (%)
Male 29 (72.5) 32 (82.1)
Female 11 (27.5) 7 (17.9)
Race, n (%)
Black 6 (15.0) 6 (15.4)
White 27 (67.5) 28 (71.8)
Other 7 (17.5) 5 (12.8)
Weight, kg, mean ⫾ SE 31.2 ⫾ 14.5 27.6 ⫾ 8.6
VAB score, mean ⫾ SE 46.6 ⫾ 13.1 52.2 ⫾ 19.8
DSM-IV Axis I diagnosis of PDD, n (%)
Autistic disorder 27 (67.5) 28 (71.8)
Asperger’s disorder 5 (12.5) 7 (17.9)
Childhood disintegrative disorder 1 (2.5) 0 (0)
Rett’s disorder 0 (0) 0 (0)
PDD not otherwise specified 7 (17.5) 4 (10.3)
CARS, mean ⫾ SE 38.9 ⫾ 5.3 39.1 ⫾ 6.7
Nonautistic, score ⬍30, n (%) 0 (0) 0 (0)
Mild/moderate, score 31–36, n (%) 17 (42.5) 18 (46.2)
Severe, score 37–60, n (%) 23 (57.5) 21 (53.8)
IQ test performed, n (%) 31 (77.5) 35 (89.7)
IQ of those tested
Normal, score ⱖ85, n (%) 3 (9.7) 11 (31.4)
Borderline, score 71–84, n (%) 6 (19.4) 4 (11.4)
Mild, score 50–70, n (%) 12 (38.7) 8 (22.9)
Moderate, score 35–49, n (%) 10 (32.3) 12 (34.3)
VAB indicates Vineland adaptive behavior; DSM-IV, Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition.
e636 RISPERIDONE USE IN CHILDREN WITH PDD
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minimum a 1-week titration period, was 1.17 mg; the
mean dosage was 0.04 mg/kg/day. At study end-
point, the mean daily dose of risperidone was 1.48
mg, and the mean dosage was 0.05 mg/kg/day. In
the risperidone group, the majority of subjects (n ⫽
37) started on a once-daily morning administration
schedule; 8 of these subjects remained on that sched-
ule for the duration of the trial. The dosing schedule
was modified for the remaining 29 subjects (14 sub-
jects changed to pm and 15 to twice-daily dosing)
mainly because of somnolence.
A total of 62 (78.5%) subjects received at least 1
concomitant medication during the trial. More sub-
jects in the risperidone group received concomitant
medications for other medical conditions than did
those in the placebo group: 36 (90%) versus 26
(66.7%), respectively. The most commonly used
medications were analgesics (37.5% and 17.9%, re-
spectively), cough and cold preparations (25% and
10.3%, respectively), antibiotics (12.5% and 12.8%,
respectively), and anti-asthmatics (15% and 10%, re-
spectively). Sedatives/hypnotics were administered
to 11 (27.5%) risperidone-treated subjects and 9
(23.1%) placebo-treated subjects on an as-needed ba-
sis to relieve anxiety during laboratory testing. An-
ticholinergics were administered to 3 (7.5%) subjects
in the risperidone group and 1 (2.6%) subject in the
placebo group to treat emergent EPSs.
Efficacy Outcomes
Mean baseline scores on the irritability subscale of
the ABC, the primary efficacy parameter, were com-
parable between the 2 groups: 18.9 and 21.2 for ris-
peridone- and placebo-treated subjects, respectively
(Table 2). At each subsequent visit, the mean scores
decreased from baseline in both groups; however,
the mean decrease in the risperidone group was
consistently greater than that in the placebo group
(Fig 1). Furthermore, the differences in these mean
decreases were statistically significant at each visit
from treatment week 2 (P ⱕ .05) through week 8 (P ⱕ
0. 001). By study endpoint, the mean decrease from
baseline in the irritability score experienced by ris-
peridone-treated subjects was almost twice that of
placebo-treated subjects: ⫺12.1 compared with ⫺6.5,
respectively (P ⬍ .001; Table 2). At study endpoint,
risperidone-treated subjects exhibited a 64% im-
provement over baseline irritability compared with a
30.7% improvement in placebo-treated subjects.
A similar pattern of response was observed when
a subset analysis of the irritability subscale scores
was performed among the 54 subjects (26 in the
risperidone group, 28 in the placebo group) who had
a diagnosis of autistic disorder. Mean baseline scores
were 20.6 ⫾ 8.1 and 21.6 ⫾ 10.2 for risperidone- and
placebo-treated autistic subjects, respectively. Again,
differences in the mean decreases were statistically
significantly in favor of risperidone from treatment
week2on(P ⱕ .05). By study endpoint, the mean
decreases from baseline in the irritability scores were
⫺13.5 ⫾ 5.2 and ⫺7.5 ⫾ 7.6 for risperidone- and
placebo-treated autistic subjects, respectively (P ⱕ
.01), representing improvements over baseline of
65.5% and 34.7%, respectively.
By study endpoint, risperidone-treated subjects
also experienced statistically significantly greater
changes from baseline for each of the other 4 sub-
scales of the ABC (P ⱕ .05; Table 2). The largest
difference was observed for the hyperactivity/non-
compliance subscale for which risperidone-treated
subjects experienced a decrease of 14.9 in mean
score and placebo-treated subjects experienced a de-
crease of 7.4 (P ⬍ .001). Compared with 15 (39.5%)
subjects in the placebo group, 27 (69.2%) risperidone-
treated subjects met the definition of a responder
(P ⫽ .01).
Similarly, risperidone-treated subjects experienced
greater improvement from baseline on the conduct
problem subscale of the parent version of the N-
CBRF: mean decreases at study endpoint of 10.4
versus 6.6 for placebo-treated subjects (P ⱕ .01; Table
2). Risperidone-treated subjects also showed statisti-
TABLE 2. Change From Baseline in the ABC, N-CBRF (Parent Version), and VAS at Study
Endpoint
Efficacy Measure Risperidone (n ⫽ 39) Placebo (n ⫽ 38)
Baseline* Endpoint† Baseline* Endpoint†
ABC subscale
Irritability 18.9 ⫾ 8.8 ⫺12.1 ⫾ 5.8‡ 21.2 ⫾ 9.7 ⫺6.5 ⫾ 8.4
Hyperactivity/noncompliance 27.3 ⫾ 9.7 ⫺14.9 ⫾ 6.7‡ 30.9 ⫾ 8.8 ⫺7.4 ⫾ 9.7
Inappropriate speech 4.6 ⫾ 3.4 ⫺2.6 ⫾ 2.6§ 4.8 ⫾ 3.7 ⫺1.6 ⫾ 3.0
Lethargy/social withdrawal 13.7 ⫾ 7.0 ⫺8.6 ⫾ 5.9¶ 14.3 ⫾ 8.2 ⫺5.7 ⫾ 6.9
Stereotypic behavior 7.9 ⫾ 5.0 ⫺4.3 ⫾ 3.8§ 8.1 ⫾ 5.6 ⫺2.4 ⫾ 4.0
N-CBRF (parent version) subscale
Conduct problem 16.8 ⫾ 9.4 ⫺10.4 ⫾ 7.4‡ 23.3 ⫾ 12.0 ⫺6.6 ⫾ 9.5
Hyperactive 17.2 ⫾ 5.8 ⫺8.1 ⫾ 4.6§ 18.9 ⫾ 5.3 ⫺5.6 ⫾ 6.6
Self-isolated/ritualistic 7.5 ⫾ 4.1 ⫺4.8 ⫾ 3.9 8.2 ⫾ 4.5 ⫺3.6 ⫾ 4.6
Insecure/anxious 8.7 ⫾ 8.1 ⫺4.6 ⫾ 6.5§ 10.6 ⫾ 7.6 ⫺3.5 ⫾ 5.5
Overly sensitive 6.9 ⫾ 3.4 ⫺3.8 ⫾ 2.8§ 7.4 ⫾ 3.5 ⫺2.7 ⫾ 3.2
Self-injurious/stereotypic 4.2 ⫾ 4.2 ⫺2.6 ⫾ 3.3 3.5 ⫾ 4.2 ⫺1.3 ⫾ 2.8
VAS (most troublesome symptom) 81.0 ⫾ 13.3 ⫺38.4 ⫾ 28.9§ 84.8 ⫾ 14.1 ⫺26.2 ⫾ 29.2
* Mean ⫾ SD.
† Mean change from baseline ⫾ SD.
‡ P ⱕ .001 versus placebo.
§ P ⱕ .05 versus placebo.
¶ P ⱕ .01 versus placebo.
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cally significantly greater mean decreases on the in-
secure/anxious (P ⫽ .039), hyperactive (P ⫽ .035),
and overly sensitive (P ⫽ .038) subscales of the N-
CBRF. Greater mean decreases were seen on the
self-injury/stereotypic and the self-isolated/ritualis-
tic subscales; however, the differences between treat-
ments were not statistically significant.
For all subjects, the most frequently reported trou-
blesome symptoms were aggression (23.4%), fol-
lowed by tantrums/negative mood (18.2%), as rated
on the VAS. At study endpoint, the mean VAS of the
most troublesome symptom had decreased (im-
proved) by a mean of 38.4 in the risperidone-treated
subjects and by a mean of 26.2 in the placebo-treated
subjects (Table 2). As with the 5 ABC subscales and
the conduct problem, insecure/anxious, hyperactive,
and overly sensitive subscales of the N-CBRF, the
improvement in the mean VAS rating (P ⱕ .05) was
significantly greater in the risperidone-treated sub-
jects. More than twice the number of risperidone-
treated subjects exhibited a clinical improvement in
their condition at endpoint, as assessed by the
CGI-C, compared with placebo-treated subjects: 34
(87.2%) versus 15 (39.5%), respectively. Three times
as many risperidone-treated as placebo-treated sub-
jects were rated as much improved or very much
improved: 21 (54%) versus 7 (18%), respectively (P ⬍
.001). Statistically significant differences in the CGI-C
between risperidone- and placebo-treated subjects
were evident at each visit (P ⱕ .05).
Safety Outcomes
Risperidone, at a mean dosage of 0.04 mg/kg/day,
was well tolerated by the children who participated
in this 8-week study. The most common adverse
events reported among risperidone-treated subjects
were somnolence (72.5%), upper respiratory tract in-
fection (37.5%), rhinitis (27.5%), and increased appe-
tite (22.5%; Table 3). The most common events
among placebo-treated subjects were aggressive re-
action (20.5%), fever (17.9%), upper respiratory tract
infection (15.4%), insomnia (15.4%), vomiting (15.4%),
diarrhea (15.4%), and emotional lability (15.4%).
Most adverse events were mild in severity. Only 5
(12.5%) risperidone-treated subjects experienced ad-
verse events that were categorized as severe and
related to study medication: 1 case of hyperkinesia
and somnolence and 1 case each of weight gain,
somnolence, aggressive reaction with impaired con-
centration, and extrapyramidal disorder as a result of
an accidental overdose. Two (5.1%) placebo-treated
subjects experienced severe events that were consid-
ered related to study medication: 1 case of insomnia
and sunken eyes and 1 case of accidental medication
overdose. Two subjects withdrew from the study
because of adverse events: the case of extrapyrami-
dal disorder as a result of accidental overdose in the
risperidone group and the case of accidental over-
dose in the placebo group. Both events subsequently
resolved without residual effects.
Twenty-nine (72.5%) risperidone-treated subjects
and 3 (7.7%) placebo-treated subjects experienced
somnolence during the study with an average time to
onset of first event of 8 and 15 days, respectively. Of
the 29 risperidone-treated subjects, somnolence re-
solved in 18 of the 20 subjects who had their dosing
schedule changed to either once daily in the evening
or twice daily. Somnolence also resolved in the 2
subjects who had their dose reduced and in 5 of the
7 subjects for whom no dose adjustments were made.
Fig 1. Irritability subscale of ABC (mean ⫾ SE) versus time profiles by treatment group. *P ⱕ .05 for between-group comparison of change
from baseline; †P ⱕ .01 for between-group comparison of change from baseline; ‡P ⬍ .001 for between-group comparison of change from
baseline.
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Thus, in total, somnolence resolved in 86.2% (25 of
29) of risperidone-treated subjects who experienced
this event. A subgroup analysis among risperidone-
treated subjects with and without somnolence
showed similar improvements on the irritability
score of the ABC, suggesting that the positive effect
of risperidone on the primary efficacy outcome was
independent of somnolence.
By study endpoint, pulse rate had increased from
baseline by a mean of 8.9 beats per minute (bpm)
among risperidone-treated subjects compared with a
mean decrease of 0.6 bpm among placebo-treated
subjects (Table 4). Five cases of mild to moderate
tachycardia in the risperidone group were reported
as adverse events (Table 3); 1 of these resolved by
study end.
Changes from baseline in the electrocardiogram
recordings were deemed to be clinically important
for 1 subject in the risperidone group; these changes
included tachycardia and a possible mild conduction
anomaly. In addition, by study endpoint, systolic
blood pressure had increased by a mean of 4.0 mm
Hg among risperidone-treated subjects compared
with a mean decrease of 0.7 mm Hg among placebo-
treated subjects. None of the cases of elevated sys-
tolic pressure was deemed by the investigator to be
clinically significant. Over the course of the study,
risperidone-treated subjects experienced a mean
weight gain of 2.7 kg compared with a gain of 1.0 kg
by placebo-treated subjects (P ⱕ .001).
No significant differences in the postbaseline mean
total ESRS scores were evident between groups. The
mean total scores on the postbaseline ESRS ranged
from 0.2 to 0.9 in the risperidone group and from 0.3
to 1.1 in the placebo group. EPSs were reported as
adverse events in 11 (27.5%) risperidone-treated sub-
jects and 5 (12.8%) placebo-treated subjects. Among
risperidone-treated subjects, tremor (4 cases) and ex-
trapyramidal disorder and hypokinesia (2 cases
each) were the most common EPSs. The 6 EPS events
reported in the 5 placebo-treated subjects included 1
occurrence each of tardive dyskinesia, abnormal gait,
ataxia, dyskinesia, hypertonia, and involuntary mus-
cle contractions. The majority of events were mild
and transient and did not require intervention. Two
subjects in the risperidone group and 1 in the placebo
group received anti-EPS medication; in all 3 cases,
the EPS resolved by study end. Finally, most patients
had hematologic, biochemical, and urinalysis param-
eters within normal ranges. There were no notewor-
thy differences in laboratory values between treat-
ment groups.
DISCUSSION
This 8-week, randomized, multicenter, double-
blind, placebo-controlled study confirmed findings
reported from a number of small, open-label stud-
ies
9–18
and from a recently completed double-blind
study conducted by the Research Units on Pediatric
Psychopharmacology (RUPP) Autism Network.
25,26
That is, risperidone proved to be a consistently effec-
tive agent for relieving many of the behavioral symp-
toms associated with PDD in children. As measured
by the ABC, the N-CBRF, and the VAS, risperidone
was significantly more effective than placebo at al-
leviating irritability, hyperactivity/noncompliance,
inappropriate speech, lethargy/social withdrawal,
stereotypic behavior, conduct problems, hyperactive,
insecure/anxious, and overly sensitive behaviors
and the symptom identified as most troublesome. In
addition, as measured by the CGI-C, significantly
more risperidone-treated subjects exhibited clinical
improvement. In addition, although mean differ-
ences in the change from baseline at study endpoint
were not statistically significant, risperidone-treated
subjects consistently achieved lower scores than pla-
cebo-treated subjects on each of the other subscales
examined in this study. These included the N-CBRF
TABLE 3. Incidence of Adverse Events Reported in ⱖ10% of
Risperidone-Treated Subjects
Event, n (%) Risperidone
(n ⫽ 40)
Placebo
(n ⫽ 39)
Any event 40 (100) 31 (79.5)
Somnolence 29 (72.5) 3 (7.7)
Upper respiratory tract infection 15 (37.5) 6 (15.4)
Rhinitis 11 (27.5) 4 (10.3)
Increased appetite 9 (22.5) 4 (10.3)
Abdominal pain 8 (20.0) 3 (7.7)
Fever 8 (20.0) 7 (17.9)
Insomnia 6 (15.0) 6 (15.4)
Vomiting 6 (15.0) 6 (15.4)
Coughing 6 (15.0) 4 (10.3)
Headache 5 (12.5) 2 (5.1)
Constipation 5 (12.5) 1 (2.6)
Apathy 5 (12.5) 0 (0.0)
Tachycardia 5 (12.5) 0 (0.0)
Influenza-like symptoms 4 (10.0) 2 (5.1)
Anorexia 4 (10.0) 1 (2.6)
Fatigue 4 (10.0) 1 (2.6)
Saliva increased 4 (10.0) 1 (2.6)
Weight increase 4 (10.0) 1 (2.6)
Tremor 4 (10.0) 0 (0.0)
TABLE 4. Change From Baseline in Vital Signs and Weight at Study Endpoint
Safety Variable Risperidone (n ⫽ 40) Placebo (n ⫽ 38)
Baseline* Endpoint† Baseline* Endpoint†
Pulse, bpm 90.2 ⫾ 12.0 8.9 ⫾ 13.9‡ 95.0 ⫾ 13.7 ⫺0.6 ⫾ 13.1
Diastolic BP, mm Hg 68.1 ⫾ 9.8 0.7 ⫾ 9.1 67.8 ⫾ 10.3 ⫺0.7 ⫾ 8.8
Systolic BP, mm Hg 99.8 ⫾ 9.6 4.0 ⫾ 10.4‡ 100.4 ⫾ 10.5 ⫺0.7 ⫾ 10.7
Weight, kg 31.2 ⫾ 14.5 2.7 ⫾ 2.0¶ 27.5 ⫾ 8.7 1.0 ⫾ 1.6
BP indicates blood pressure.
* Mean ⫾ SD.
† Mean change from baseline ⫾ SD.
‡ P ⱕ .01 versus placebo.
¶ P ⱕ .001 versus placebo.
www.pediatrics.org/cgi/doi/10.1542/peds.2003-0264-F e639
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subscales measuring self-isolated/ritualistic and self-
injurious/stereotypic behaviors.
On the basis of the primary efficacy outcome (the
mean change in the irritability score), risperidone
was significantly more effective than placebo at each
visit starting with the second postrandomization as-
sessment at treatment week 2. By study endpoint,
risperidone-treated subjects exhibited a 64% im-
provement over baseline in the irritability score—an
improvement almost twice that exhibited by place-
bo-treated subjects. Similar results were observed for
the subset of autistic subjects. Improvements over
baseline irritability at study endpoint for children
and adolescents who had autism and were random-
ized to risperidone treatment were 66%, whereas
those who were randomized to placebo exhibited a
35% improvement. A similar difference in response
was recently reported for 101 children, mean age 8.8
years, who had a diagnosis of autistic disorder ac-
companied by severe tantrums, aggression, or self-
injurious behavior and participated in the 8-week,
randomized, double-blind, placebo-controlled RUPP
study.
26
In that study, risperidone-treated subjects
exhibited a 57% improvement over baseline in their
mean irritability score, whereas placebo-treated sub-
jects exhibited only a 14% improvement (P ⬍ .001).
The results of the present study are similar to those
of the RUPP study and together support the effec-
tiveness of risperidone in ameliorating some of the
disruptive behavioral symptoms in children with au-
tism and other PDD. The main limitation of this
study is the relatively short duration of treatment
Treatment with risperidone was generally well tol-
erated: only 1 risperidone-treated subject was with-
drawn from the study because of an adverse event;
that event was caused by an accidental study medi-
cation overdose from which the subject recovered
fully. Somnolence was reported in a majority of the
risperidone-treated subjects, yet it resolved in 86% of
subjects for whom it was reported. Somnolence ei-
ther resolved spontaneously or was managed effec-
tively by dose reductions or a change in dosing reg-
imen to twice daily or evening schedules. It is
interesting to note that somnolence when present did
not influence the improvement seen in irritability,
the primary efficacy parameter.
Over the course of 8 weeks of treatment, pulse rate
increased among risperidone-treated subjects with
mild to moderate tachycardia being reported as an
adverse event for 5 subjects. The tachycardia re-
solved in 1 subject. In addition, 1 subject in the
risperidone group was reported to have a possible
mild conduction anomaly (on the V1 lead), which
was considered clinically relevant. There was also a
small but statistically significant increase in the sys-
tolic blood pressure observed in the risperidone
group, although none of the cases was deemed clin-
ically significant. These slight increases in heart rate
and blood pressure in risperidone-treated over pla-
cebo-treated subjects were not seen in the recently
reported controlled trial in children with autistic dis-
order,
26
and their possible relevance is not known.
There were no significant differences in the weekly
total ESRS scores between the risperidone and pla-
cebo treatment groups either in this study or in the
8-week RUPP study that was conducted in children
with autistic disorder.
26
Although more risperidone-
treated subjects than placebo-treated subjects experi-
enced at least 1 EPS, the majority of symptoms were
assessed as mild and transient and did not require
intervention. In subjects who did receive treatment,
the events were managed effectively. No cases of
tardive dyskinesia were reported for the risperidone-
treated subjects. Longer-term studies to follow EPSs
and other safety outcomes are warranted.
Finally, risperidone-treated subjects experienced a
weight gain of 2.7 kg compared with a gain of 1.0 kg
experienced by placebo-treated subjects. A similar
degree of weight gain was observed in the RUPP
study.
26
Longer-term studies of risperidone use in
children up to 1 year in duration have demonstrated
that the degree of weight gain is more pronounced
during the first months of therapy.
27
Nonetheless, as
a preemptive measure to prevent or diminish possi-
ble weight gain, children who have PDD and are
prescribed a course of risperidone should be encour-
aged to institute a dietary regimen and physical ac-
tivity plan.
As is the case with some other antipsychotics, hy-
perglycemia and exacerbation of preexisting diabetes
have been reported in rare instances during risperi-
done use;
28
this was not observed in this study or the
RUPP study.
26
Diabetic ketacidosis has also been
reported.
28
Appropriate clinical monitoring is ad
-
vised in diabetic patients and those with risk factors
for the development of diabetes mellitus.
In conclusion, risperidone solution (mean dosage:
0.04 mg/kg/day; 1.17 mg/day) was efficacious and
well tolerated in the treatment of behavioral symp-
toms, including aggression, in children 5 to 12 years
of age with PDD, as assessed by the ABC subscales
(irritability, hyperactivity/noncompliance, inappro-
priate speech, lethargy/social withdrawal, stereo-
typic behavior) and the N-CBRF subscales of conduct
problem, hyperactive, insecure/anxious, and overly
sensitive behaviors. Most adverse events were self-
limiting or readily manageable with dosing modifi-
cations. The encouraging efficacy outcomes achieved
with this agent offer new hope for the management
of behavioral symptoms exhibited by children with
PDD.
ACKNOWLEDGMENTS
This trial was supported by Janssen-Ortho Inc, Canada, and
Johnson & Johnson Pharmaceutical Research and Development.
RIS-CAN-23 Study Group: A. Carroll, W. Fleisher, S. Shea, M.
Steele, K. Streilein, A. Turgay, and H. White.
We thank Margaret Light, PhD, and Colleen Duncan, MSc
(Janssen-Ortho Inc).
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DOI: 10.1542/peds.2003-0264-F
; originally published online October 18, 2004; 2004;114;e634Pediatrics
and Fiona Dunbar
Sarah Shea, Atilla Turgay, Alan Carroll, Miklos Schulz, Herbert Orlik, Isabel Smith
With Autistic and Other Pervasive Developmental Disorders
Risperidone in the Treatment of Disruptive Behavioral Symptoms in Children
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