JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY
Volume 18, Number 3, 2008
© Mary Ann Liebert, Inc.
Cognitive Effects of Risperidone in Children with Autism
and Irritable Behavior
Michael G. Aman, Ph.D.,1Jill A. Hollway, M.A.,1Christopher J. McDougle, M.D.,2
Lawrence Scahill, M.S.N., Ph.D.,3Elaine Tierney, M.D.,4James T. McCracken, M.D.,5
L. Eugene Arnold, M.D., M.Ed.,1Benedetto Vitiello, M.D.6Louise Ritz, M.B.A.,6Allison Gavaletz, B.S.,3
Pegeen Cronin, Ph.D.,5Naomi Swiezy, Ph.D.,2Courtney Wheeler, B.S.,4Kathleen Koenig, M.S.N.,3
Jaswinder K. Ghuman, M.D.,4and David J. Posey, M.D.2
Objective: The objective of this research was to explore the effects of risperidone on cognitive processes in chil-
dren with autism and irritable behavior.
Method: Thirty-eight children, ages 5–17 years with autism and severe behavioral disturbance, were randomly
assigned to risperidone (0.5 to 3.5 mg/day) or placebo for 8 weeks. This sample of 38 was a subset of 101 sub-
jects who participated in the clinical trial; 63 were unable to perform the cognitive tasks. A double-blind placebo-
controlled parallel groups design was used. Dependent measures included tests of sustained attention, verbal
learning, hand-eye coordination, and spatial memory assessed before, during, and after the 8-week treatment.
Changes in performance were compared by repeated measures ANOVA.
Results: Twenty-nine boys and 9 girls with autism and severe behavioral disturbance and a mental age ?18
months completed the cognitive part of the study. No decline in performance occurred with risperidone. Per-
formance on a cancellation task (number of correct detections) and a verbal learning task (word recognition)
was better on risperidone than on placebo (without correction for multiplicity). Equivocal improvement also
occurred on a spatial memory task. There were no significant differences between treatment conditions on the
Purdue Pegboard (hand-eye coordination) task or the Analog Classroom Task (timed math test).
Conclusion: Risperidone given to children with autism at doses up to 3.5 mg for up to 8 weeks appears to have
no detrimental effect on cognitive performance.
ally sparse. The bulk of the literature currently comes from
studies of adults with schizophrenia; in addition there are a
few investigations with patients having Alzheimer’s disease.
Given that antipsychotics often cause sedation, many inves-
tigators and clinicians have wondered if cognitive blunting
ITERATURE FOCUSING ON the cognitive effects of atypical
antipsychotics in children and adolescents is exception-
and/or sedation accompanying early treatment may impair
cognition (Ernst et al. 1998; Aman 1984; Aman et al. 1991).
The possibility of cognitive impairment seems likely in the
short term, as somnolence is a frequent side effect of atypi-
cal antipsychotics, especially early in treatment. However, a
detailed analysis of adverse events from risperidone treat-
ment in children with autism indicated that reports of som-
nolence usually dissipated between 2 and 4 weeks after the
last dose adjustment of risperidone (Aman et al. 2005). Thus
1Nisonger Center, Ohio State University, Columbus.
2Riley Hospital for Children, Indiana University, Indianapolis.
3Yale Child Study Center, Yale University, New Haven, Conn.
4Kennedy Krieger Institute, Johns Hopkins University, Baltimore.
5Department of Psychiatry, Neuropsychiatric Institute, University of California, Los Angeles.
6National Institute of Mental Health, Bethesda, MD.
This work was funded by contracts from the National Institute of Mental Health (N01MH80011, to Dr. Aman; N01MH70009 to Dr.
Scahill; N01MH70010 to Dr. McCracken; N01MH70001, to Dr. McDougle; M01 RR00750, to Indiana University; M01 RR00052, to Johns
Hopkins University, M01 RR 00034, to Ohio State University; and M01 RR06022, to Yale University.
it seems that the time of greatest “risk” of cognitive impair-
ment would be in the earliest weeks of treatment.
Literature from adult trials in schizophrenia, have pro-
vided us with some insight into the cognitive effects of these
drugs. Keefe et al. (1999) conducted a review of 15 studies
in which adult patients with schizophrenia were assessed for
cognitive effects while taking atypical antipsychotics (AAPs).
Contrary to cognitive impairment, they reported improve-
ments in attention, executive function, and visuospatial pro-
cesses. Purdon (1999) found a handful of studies reporting
beneficial effects of AAPs in verbal fluency, verbal learning,
and visuomotor tracking. In both reviews, the authors sug-
gested that the results of the studies be interpreted with cau-
tion, as many studies lacked sufficient controls (e.g., placebo
control, double-blind status, and baseline scores). In a few
of the studies that did have baseline scores, there was some
uncertainty regarding medication status at baseline.
In a more recent review of 26 studies, Stip et al. (2005) an-
alyzed the effects of AAPs on cognitive-motor functioning
in adults with schizophrenia. This review concluded that a
variety of AAPs (risperidone, clozapine, quetiapine) im-
proved attention in six studies but showed no change in nine.
Please note that summaries often do not total to 26, because
not all studies addressed all possible cognitive-motor do-
mains and some studies included more than one relevant
measure on the domain under discussion. The authors re-
ported one study of clozapine in which attention was nega-
tively affected. In the area of verbal and working memory,
the authors reported that clozapine, olanzapine, quetiapine,
and risperidone improved functioning in 12 comparisons
while showing no change in 17. Finally, when the authors
reviewed the research on motor performance, they found
that treatment with the atypicals risperidone, clozapine, and
olanzapine was associated with improved motor function-
ing in four studies and no change in four others. The find-
ings of these adult trials suggest that the atypical antipsy-
chotics do not have an adverse effect on cognitive-motor
functioning. Indeed, there is some evidence that AAPs may
even enhance function.
Recently a few studies have assessed cognitive effects of
risperidone in children with severe behavioral disturbance.
Günther et al. (2006) assessed open-label risperidone in 23
children with attention-deficit/hyperactivity
(ADHD) and disruptive behavior disorders (DBDs) and in
normal controls matched for age and IQ. No effect of med-
ication was found on three tests of sustained and selective
attention (continuous performance, divided attention, and
Go/No-Go tasks). Troost et al. (2006) tested 24 children with
autism spectrum disorders [autism, pervasive developmen-
tal disorder not otherwise specified (PDD—NOS), As-
perger’s disorder] and found 12 (50%) to be testable on fo-
cused attention and divided attention tasks. All participants
were shown to be responders to risperidone in a previous
clinical trial, and risperidone was withdrawn and gradually
replaced with placebo for half of the participants after 24
weeks of treatment. Troost et al. found that performance on
the divided attention task (considered to be an index of
working memory) deteriorated significantly for subjects re-
ceiving placebo substitution in comparison to those main-
tained on risperidone.
Although, rarely considered in clinical trials, it has been
established that environmental variables can influence the
effects of pharmacotherapy (Yoo et al., 2003). In their study
of two doses of risperidone and tangible reinforcement, Yoo
et al. (2003), found that risperidone caused a decrease in re-
sponse rate and an increase in response time when compared
with placebo on a timed visual matching discrimination task.
However, these changes were much smaller when tangible
reinforcement was added to the risperidone alone condition.
The investigators suggested that the added reinforcement
had a protective effect on the rate decreasing effects of
Pandina et al. (2007) reported on the 6-week acute effects
of risperidone and placebo in 228 children with DBDs and
subaverage IQ (?84). The cognitive tasks were a continuous
performance task (CPT) and a Children’s Verbal Learning
Task modified from the California Children’s Verbal Learn-
ing Test (Delis et al. 1994). The design was a 6-week, paral-
lel-group, comparison of placebo and risperidone (0.02 to
0.06 mg/kg/d). There were no drug-group differences in
cognitive functioning in the acute trials.
Finally Aman et al. (in press) assessed 16 children main-
tained on risperidone (mainly for DBDs) on a computer-con-
trolled cognitive-motor test battery. Subjects were assessed
on their regular dose of risperidone and then assigned to one
of two drug orders: placebo-risperidone or risperidone-
placebo, each of which lasted 2 weeks. Assessments included
a Match-To-Sample Memory task, a Short-Term Recognition
Memory (STM) test, a Continuous Performance Task (CPT),
performance on the Graduated Holes Task (index of static
tremor), and seat activity electronically recorded during the
memory and CPT tasks. Response time was significantly
shorter with risperidone on the STM task, seat activity was
significantly lower with risperidone during the STM task,
and static tremor was significantly lower with risperidone
than placebo on the Graduated Holes Task.
Thus, on balance, most variables failed to show significant
changes due to drug condition in these studies with children.
However, when they did occur, changes favored risperidone
in the Troost et al. (2006) study (working memory) and in
the Aman et al. (2007) study (response time, seat activity, sta-
tic tremor). The present study was designed to test whether
risperidone has an effect on cognitive performance in chil-
dren with autism accompanied by serious behavior prob-
lems. This was an exploratory comparison, as no data were
available with AAPs in children with autism at the time of
the trial. The null hypothesis is that there would be no dif-
ferences between placebo and risperidone.
This was a multi-site investigation that was conducted at
five medical centers. This study used an acute, double blind,
placebo controlled, parallel groups design. After being as-
sessed at the screen visit, participants who met inclusion cri-
teria for the study were then reassessed with clinical instru-
ments at baseline and weekly for the next 8 weeks. Matched
placebo and risperidone were provided by the manufacturer
(Janssen Pharmaceutica) in tablet form. A flexible dosing
schedule was based on the participant’s weight, time in the
study, clinical response, and emergence of adverse events
(see Research Units on Pediatric Psychopharmacology
[RUPP] Autism Network, 2002). Cognitive assessments were
AMAN ET AL.228
conducted at baseline, 4 weeks, and 8 weeks. For any par-
ticipant who terminated either condition prematurely, the
last observation was carried forward to endpoint. Partici-
pants’ parents or legal guardians provided written informed
consent as approved by institutional review boards of the
five participating universities.
Participant characteristics, study design, and outcome
measures have been described in detail in previous publica-
tions (Arnold et al., 2000; RUPP Autism Network, 2002; Sc-
ahill et al., 2001). Study participants were male and female
children or adolescents, ages 5 to 17 years 2 months, with
mental ages ?18 months who had autism and severe be-
havioral disturbance. To be enrolled in the study, partici-
pants received a score of ?18 on the Irritability subscale of
the Aberrant Behavior Checklist (ABC) (Aman and Singh
1994). In addition, participants must have been rated with a
Clinical Global Impressions-Severity (CGI-S) score of ?4 by
an experienced clinician (CGI-S; NIMH 1985, Arnold et al.
2000), and according to the Diagnostic and Statistical Man-
ual of Mental Disorders, 4thEdition (DSM-IV) (American
Psychiatric Association, 1994) a lifetime diagnosis of autistic
disorder. The diagnosis of autism was based on a clinical
evaluation that included a DSM-IV interview with a parent
and direct observation of the participants. The clinical diag-
nosis was corroborated by structured interview with one or
more parents acting as informants, using the Autism Diag-
nostic Interview—Revised (Lord et al. 1994).
Exclusion criteria included positive Beta HCG test for
girls; significant medical condition; past history of neu-
roleptic malignant syndrome; and, because of dosing con-
siderations, weight less than 15 kg. Originally, 52 children
and adolescents were randomly assigned to placebo and 49
to risperidone, for a total of 101 study participants. The to-
tal number of subjects who had scorable cognitive measures
at baseline and at lease one subsequent visit was 38 (37.6%)
and, depending on which test was administered, the sample
sizes ranged from 8 subjects to 30. Eighteen of the 38 sub-
jects were assigned to placebo and 20 to risperidone. The re-
maining 63 (62.4%) subjects were not testable either due to
the severity of their cognitive impairment and/or disruptive
Any participants receiving psychotropic medicines before
the study went through a washout for at least 2 weeks prior
to randomization (4 weeks for antipsychotics or fluoxetine).
Cognitive assessments were done at Baseline, Week 4 and
Week 8. Participants were started at either 0.25 or 0.50 mg
with gradual adjustments over the first four weeks. Maxi-
mum dose for smaller subjects (15—45 kg) was 2.5 mg/day,
whereas the maximum dose for larger participants (?45 kg.)
could be as high as 3.5 mg/day.
The following cognitive measures were obtained.
California Verbal Learning Task–Children’s Version (VLT-
C) and Modified VLT-C (MVLT-C) (Delis, Kramer, Kaplan, &
Ober, 1994). The VLT-C and the MVLT-C measure verbal
memory over brief and intermediate periods of time. Re-
spondents were presented with a 10- (MVLT-C) or 15-item
(VLT-C) list of nouns on five separate learning trials; most
participants were tested with the MVLT-C. The subjects were
asked to recall the words in any order after each trial (mea-
suring Immediate Free Recall). Once the Trial 5 responses
were recorded, the examiner administered the Cancellation
Task (see below). This took approximately 10 minutes and
prevented subjects from rehearsing the original verbal learn-
ing list. Following the Cancellation Task, subjects were asked
to recall as many of the words as possible (Long Delay Free
Recall). Finally, we administered one Recognition Trial to the
respondents, in which previously-presented and new words
were used. Subjects then had to determine whether they had
heard the word prior to the recognition trial by indicating
“yes” or “no” to the examiner.
The dependent measures for the MVLT-C included the to-
tal number of words correctly recalled on learning Trials 1-
5 (reflecting verbal memory with exposure and practice), the
total number of words correctly recalled after the 10-minute
delay (i.e., Long Delay Free Recall), and Recognition Score
(by taking the sum of the number of correctly-recognized
words and the number of non-list words correctly rejected
divided by the total number of words).
The Visuospatial Memory Test (“Dot Test”) (Keefe et al.
1997). The spatial memory test has been shown to be sensi-
tive to pharmacological treatment in adults having schizo-
phrenia or Alzheimer’s disease. It tests the ability to recall
the location of a black dot on a blank sheet of 8.5 by 11 inch
paper immediately or following a 10-second delay. The test
has 20 trials. Participants were asked to reproduce the posi-
tion of the dot on a blank page. Participants sat at a desk in
front of a stack of paper that had the numbers 1 to 20 on the
back. Trials 1-8 consisted of the no-delay trials and trials 9-
20 were the delayed trials (i.e., 10 seconds). During the de-
layed condition, participants were required to name pictures
of common objects taken from the Peabody Picture Vocabu-
lary Test—Revised (Dunn et al. 1981) to prevent verbal re-
Using a metric ruler and a transparent scoring template,
and a scoring sheet the examiner measured in millimeters
the difference between the stimulus dot and the respondent’s
dot on each of the 20 trials. The dependent measures for this
protocol included the average no-delay distance, the aver-
age 10-second delay distance, and the difference between the
two conditions (i.e., averaged delayed recall distance minus
the no-delay distance).
Cancellation Task (Barkley, 1991). In this commonly-used
test of attention span, the participant was required to scan
rows of geometric figures (circles, triangles, stars, diamonds,
and squares) and to cancel the target figure, which was a
square. All other figures were to be left un-cancelled. Par-
ticipants were given 5 minutes in which to cancel 6 pages of
stimuli. Correct detections, failures to mark squares (errors
of omission), and cancellation of non-targets (errors of com-
mission) were recorded as dependent variables.
Purdue Pegboard Task (Tiflin, 1968; Tiflin and Asher,
1948). Our modified version of the original Purdue Peg-
board Test was a measure of hand-eye coordination. It re-
RISPERIDONE IN CHILDREN WITH AUTISM AND IRRITABLE BEHAVIOR229
quired the participant to insert as many pins as possible into
a column of holes on a wooden pegboard. Each trial lasted
40 seconds. The assessment entailed one practice trial, fol-
lowed by three test trials with each hand. The total number
of pins correctly inserted was recorded. Study participants
alternated between their dominant and non-dominant
hands, and the examiner left all pins in place until both the
dominant and non-dominant hands had been tested. The ex-
aminer then counted and recorded the number of pins in-
serted by each hand. Dependent measures for this protocol
consisted of the total number of pegs inserted for each hand
and the total number of “drops” for each hand.
Classroom Analogue Task (Handen et al., 1990). Prior to
giving the Analogue Classroom Task, the child’s math abil-
ity was determined by the Wide Range Achievement Test
(WRAT) (Wilkinson, 1993). The WRAT was given only once
and was used solely to determine the participant’s math ca-
pability and the level at which to conduct testing. The Class-
room Analogue Task involved presenting participants with
numerous ability-appropriate math problems. These prob-
lems ranged from very basic [matching numbers to the size
of sets (e.g., finding the correct numeral from 2, 3, 4, 5 when
a set of 3 ducks was presented)] to more conventional addi-
tion and subtraction. Seven-minute work samples were de-
rived from each participant. The task has been extensively
used in ADHD research and in work with developmentally
disabled patients (Handen et al. 1990), and it has been found
to be sensitive to the use of psychostimulant medication
(Aman and Pearson, 1999). The dependent measures con-
sisted of the total number of math problems that the partic-
ipant attempted and total number correctly calculated. The
Analogue Classroom Task took 7 minutes to administer.
Consensus rulings on mastery and valid data
Prior to data analysis, the cognitive assessors from each
site prepared operational criteria for judging ambiguous re-
sponses and for determining whether subjects had mastered
the tasks or were simply responding randomly. For exam-
ple, on the Cancellation Task we determined that the pencil
mark had to actually touch the geometric form in order to
be counted (rather than to merely be in its proximity). We
also determined that direction of cancellations (left to right
and vice versa) did not invalidate performance on this task,
although it might influence the count of omission errors
(Written consensus operational rules available on request
from MGA or JAH.)
Analyses were carried out for the children who had valid
task measures. Mastery was determined by a set of opera-
tional principles applied by the tester at each site, in con-
sultation with all other testers, before the blind was broken.
The first analyses were t-tests and ChiSquare tests to deter-
mine if children with mastery differed from those who did
not on the following variables: Age, IQ, Irritability subscale
score on the ABC, gender, and CGI-Severity score at base-
line. Cognitive data were analyzed as a function of Drug (2
levels; placebo vs. risperidone) and by Time (3 levels, within
participants). The General Linear Models package in SPSS
was used to analyze the results with repeated measures
ANOVA tests (SPSS, 2003). Effect sizes (partial eta squared,
?P2) were provided in addition to p values. Partial eta
squared is the proportion of the effect plus the error vari-
ance that is attributable to the effect in the sample. It is not
additive as is the squared correlation ratio and according to
Keppel and Wickens (2004), it is often the most useful mea-
sure of effect for within subject designs. In all tests, p val-
ues ?.05 were used to indicate statistical significance.
Of the 101 participants in the clinical trial of risperidone
vs. placebo, 38 (37.6%) were able to provide valid cognitive
measures. Of these 38 participants, 12 (31.6%) were risperi-
done responders, 8 (21%) were risperidone nonresponders
and 18 (47.4%) were randomized to placebo. Of the 63
(62.4%) participants who were unable to complete valid cog-
nitive measures, 22 (34.9%) were risperidone responders, 7
(11.1%) were risperidone non-responders and 34 (54%) were
randomized to placebo. Characteristics of the 38 participants
including functional level, ethnicity, class placement, and
parent educational level are presented in Table 1. The modal
functional level was mild intellectual disability (n ? 18), with
average/borderline (n ? 8) and moderate intellectual dis-
ability (n ? 8) also quite common. Ethnically, the large ma-
jority was white, and educationally most participants were
assigned to special classes. Educational levels of the primary
caregivers were quite high, with 19 parents having a uni-
versity degree or higher and only one parent without a high
school diploma (Table 1). When these participants were com-
pared with those who failed to achieve mastery, the follow-
ing differences were found: (a) IQ was higher for the Mas-
tery group [t (86) ? 5.11, p ? .001 (M ? 62.6 and 39.6,
respectively)]; (b) age was higher for the Mastery group [t
(99) ? 2.05, p ? .04 (M ? 9.0 and 7.9, respectively)]. No dif-
ferences were found for ABC Irritability score, CGI-Severity
score, or gender, although Irritability scores and CGI-Sever-
ity tended to be nonsignificantly higher (worse) for the non-
Table 2 shows the outcome means (and SDs) for Drug by
Time on the Cancellation Task, Analogue Classroom Task,
and the Verbal Memory Test. The table shows the outcome
means (and SDs) and partial eta values (?p2) for Baseline,
Week 4 and Week 8, for Time and the Drug by Time inter-
action. Analysis of variance indicated two significant effects
attributable to Drug (i.e., the interaction of Time and Drug).
Risperidone resulted in more correct detections than placebo
on the Cancellation Task [F (1, 17) ? 3.18, p ? .05, ?p2? .16]
and more correct recognitions than placebo on the Verbal
Learning Task, [F (1, 13) ? 4.42, p ? .05, ?p2? .20]. Immedi-
ate recall on the Verbal Learning Task in both drug condi-
tions showed a significant effect of Time (suggesting a sig-
nificant practice effect).
Table 3 shows the outcome means (and SDs) for Drug by
Time on the Purdue Pegboard Test and the Visuospatial
Memory Test. On the Purdue Pegboard, dominant hand in-
sertions showed a significant effect over time for both treat-
ments (i.e., a practice effect). Results indicated no significant
AMAN ET AL.230
effect attributed to drug (i.e., the Time by Drug interaction).
The Visuospatial Task (Dot Test) showed a significant effect
of Drug by Time favoring risperidone on the difference score
between immediate recall of the dot’s placement (average
distance) and the delayed recall of the dot’s placement (av-
erage distance–delay), [F (1,6) ? 5.22, p ? .05, ?p2? .46]. We
noted a significant baseline difference (p ? .05) by t-test, so
we reanalyzed this variable by analysis of covariance (AN-
COVA). With this comparison, the interaction term was no
longer significant [F (2,5) ? 3.29, p ? .12].
As noted earlier we were able to evaluate the cognitive
performance of 38 children with autism. These 38 partici-
pants were similar to the remaining 63 (those unable to per-
form the cognitive tests) on CGI-Severity score, ABC Irri-
tability score, and gender. Not surprisingly, the participants
who could be tested had higher IQs (about 23 points, on av-
erage), and they were older (9.0 vs. 7.9 years). Thus, there
were important differences in presumed cognitive ability
and maturity, but they were similar in terms of symptom
severity and gender. However, of those assigned to risperi-
done, similar proportions of responders and nonresponders
could perform the cognitive tests. These findings have im-
plications for generalizability of the findings, a point that we
return to later.
No declines, significant or otherwise, were indicated in the
measures of attention (i.e., Cancellation Task, timed math
test), hand-eye coordination (Purdue Pegboard), or short
term verbal memory (verbal learning task). Conversely, sig-
nificant improvement occurred with risperidone in two ar-
eas of cognitive processing, namely on the Cancellation Task
(correct detections) and on the Verbal Learning Task (correct
recognitions); improvement occurred equivocally on the
Spatial Memory Task (Dot Test, difference score). Whereas
this stability of cognitive performance may appear to be at
odds with reported tiredness with risperidone (Aman et al.,
2005), the two are not necessarily inconsistent. For example
risperidone caused a large reduction in irritable/disruptive
behavior (E.S. ? 1.20) and hyperactivity (E.S. ? 1.00), which
may have enabled the participants to perform as well or bet-
ter, even if somnolence were present.
Purdon’s (1999) review of atypical antipsychotic studies
in adults with schizophrenia suggested enhancement in the
areas of verbal fluency and attention, although he cautioned
that some investigations used open-label designs. In our
study, subjects taking risperidone showed significant im-
provement compared with controls on verbal learning recog-
nition performance but not on short-term or delayed recall.
RISPERIDONE IN CHILDREN WITH AUTISM AND IRRITABLE BEHAVIOR231
TABLE 1.SAMPLE CHARACTERISTICS (N ? 38)*
Age, yr, mean ? SD (range) 9.42 ? 2.96 (5–17 yrs)
Sex, no. (%)
Race, no. (%)
Functional level, no. (%)**
Average/low average ability
Mild intellectual disability
Moderate intellectual disability
Severe intellectual disability
Profound intellectual disability
Daily dose risperidone (mg), mean ? SD*** 1.12 ? 0.44
Class placement, no. (%)
Regular school class
Primary caregiver education level, no. (%)
*There were 63 children who could not be successfully assessed. Testable participants had a signifi-
cantly higher IQ (23 points higher) and higher mean age (9.0 vs. 7.9 years) than the untestable subjects.
**IQ score unavailable for one subject.
***Range = 0.5–2.0 mg/day.
FINDINGS FOR CANCELLATION, ANALOGUE CLASSROOM, AND VERBAL LEARNING TASKS
Analogue Classroom Task
Verbal Learning Task
Sample sizes differ because many of the participants could not do all cognitive tasks and, in some cases, subjects could not perform all parts of the given task. an ? 7. bn ? 12. cn ? 8. dn ? 8. en ? 8.
fn ? 12. gn ? 6. hn ? 10. in ? 5. jn ? 10.
* p ? 0.05, ** p ? 0.01.
FINDINGS FOR PURDUE PEGBOARD AND SPATIAL MEMORY TASKS
Dominant hand insert
Nondominant hand insert
Dominant hand drops
Nondominant hand drops
Both hands inserts
Both hands drops
Average Distance - Delay
Sample sizes differ because many of the participants could not do all cognitive tasks. an ? 13. bn ? 17. cn ? 4. dn ? 4.
* p ? 0.05.
Current literature is mixed regarding the effect of risperi-
done on spatial memory. Results from Reilly, Harris, Ke-
shaven and Sweeney (2006), in subjects with schizophrenia,
showed worsening of deficits in the maintenance of spatial
working memory. In contrast, a comparison of clozapine and
risperidone in patients with schizophrenia conducted by
McGurk et al. (2005) found improvements in spatial mem-
ory with risperidone and worsening with clozapine. Our
study suggests an equivocal improvement in delayed spa-
tial memory for the risperidone group compared to placebo
controls. (Loss of significance with the ANCOVA may have
been due merely to reduced degrees of freedom, given the
smallness of the sample.)The “significant” finding was based
on a difference score between no-delay and delay conditions,
and only 8 participants could conduct the task. As the find-
ing of improvement with risperidone can result from wors-
ening in the no-delay or improvement in the delay condition
with risperidone (or the opposite with placebo), this “sig-
nificant” outcome needs replication.
The choice of cognitive-motor tasks in children with de-
velopmental disabilities has varied greatly, and results have
also differed across cognitive constructs. Results of the can-
cellation task used in this study suggest that the risperidone-
treated participants were more task oriented than placebo-
treated subjects. This is not consistent with the Günther et
al. (2006) study, which found no risperidone effects on at-
tention in adolescents with ADHD. However, in Troost et al.
(2006) and in the present study, aspects of memory and at-
tention did improve (Troost et al., characterized their divided
attention task as an index of working memory.) Findings for
the Verbal Learning test differed from the Pandina (2007)
study in that we observed enhanced word recognition with
risperidone, but Pandina et al. did not. (However, Pandina
et al. did report improvements in uncontrolled one year
open-label extension studies.) We are not aware of any other
study with children having pervasive developmental disor-
ders in which the Visuospatial Memory Task has been used.
This is not surprising in that it proved to be very difficult to
convey instructions to these children on how to perform the
Children with autism and accompanying irritable behav-
ior are exceptionally difficult to assess for cognitive change.
Troost et al. (2006) commented that a testable rate of 50% of
children with PDDs was “very favorable” and “would have
been lower if a larger proportion of the children . . . had an
autistic disorder.” (pg. 571) Indeed, only 2 of 14 participants
(14.3%) in the Troost et al. study had a diagnosis of autism,
whereas the remainder had PDD—NOS or Asperger’s dis-
order. Our study was conducted exclusively with children
having autistic disorder accompanied by serious behavior
problems. Furthermore, the large majority of the original
sample (83%) had intellectual disability. Collectively, these
features made this group of children very challenging to test.
As such, our data may provide important information on the
selection of cognitive-motor tasks in this population. The
Purdue Peg Board task was clearly the easiest for these
youngsters to understand. By contrast, the “Dot Test” was
remarkably difficult for them to grasp. The MVLT-C, Can-
cellation Task, and Analogue Classroom Task were of inter-
mediate difficulty. It is easy to see how all of these latter tests
may reflect important skills that are relevant to learning in
traditional classroom settings. The advantages of being able
to sustain attention better over time (as in the Cancellation
task) and to be more capable of recognizing previously-heard
words would seem apparent both in academic settings and
in real life. Likewise, enhanced memory for location (Visu-
ospatial Task) would seem to carry advantages in real-life
settings as well. As partial eta squared ranged from .16 to
.46, this indicates that the drug condition actually accounted
for substantial amounts of variance in these outcome vari-
ables. Nevertheless, it is also somewhat reassuring that there
were no indications of risperidone-associated deterioration
on any of the other variables.
This study has several limitations that caution against
over-embracing the statistically-significant (and one equivo-
cal) findings. First, given the exploratory nature of this work
(there is only one other study of atypical antipsychotics in
children with PDDs), we adopted the .05 level for alpha. Had
we corrected for multiple comparisons, none of the compar-
isons would have exceeded alpha. Second, only a minority
of our participants were able to perform these tasks. This re-
sulted in (a) small sample sizes and (b) the observation that
the testable group had a higher IQ and was older than the
untestable group. This indicates that the findings may not
be fully representative of what would be observed if all the
101 clinical trial participants were testable. However, as re-
ported by others (Troost et al. 2006), children with autism
and irritable behavior are very challenging to assess with
such cognitive tests, and the proportion of participants as-
sessed was probably quite respectable under the circum-
stances. Third, we have already stated our reservations about
the “significant” drug finding for the Dot test in that only a
small number of participants could perform it.
Despite these obvious limitations, the findings are note-
worthy for several reasons. First, autistic disorder is often
coupled with substantial cognitive disability. Therefore, it is
important that pharmacotherapy not increase any functional
handicap that is already present. We did not see evidence of
risperidone-induced deficits in performance, and there was
some indication of enhancement on some variables. Second,
the magnitude of change, assessed by partial eta squared,
suggests sizable gains in adaptive skills if upheld by future
studies. Third, it is worth noting that the data were gathered
across multiple sites under double-blind conditions, which
may help to discount any individual examiner effects (i.e.,
unintended bias). Finally, the mechanism of any improve-
ment is unknown. These were performance tests which
tapped what the participant was able to achieve on test days.
At this stage, it is unknown whether the participants were
simply more compliant (i.e., the changes were a secondary
consequence of suppressed irritable behavior) or whether
risperidone affected true cognitive ability at a more basic
The results reported here are reassuring to clinicians pre-
scribing risperidone for school children with autistic disor-
der. It does not appear to impair academic ability or cogni-
tive-motor performance. However, at the current state of
knowledge, clinicians should not conclude that risperidone
can be counted on to improve cognitive-motor performance
AMAN ET AL. 234
or even that it is innocuous. The main value of these find-
ings is to reduce one, and only one, of several safety con-
cerns, with the serious possibilities of metabolic and neuro-
logical risks remaining. Further research will be needed to
determine the robustness and extent of any favorable effects
on cognitive performance.
Dr. Aman has affiliations with Bristol-Myers Squibb Co.,
Forest Research Institute, Johnson and Johnson, Neu-
ropharm, and Supernus. Dr. Arnold has affiliations with
Shire, Neuropharm, Lilly, Novartis, Organon, Janssen, and
McNeil. Dr. Ghuman has affiliations with Bristol-Myers
Squibb Co. Dr. McDougle has affiliations with Bristol-Myers
Squibb Co., Eli Lilly and Co., Forest Research Institute,
Janssen Pharmaceutica, and McNeil Pediatrics. Dr. Scahill
has affiliations with Janssen Pharmceutica, Bristol-Myers
Squibb Co., Neuropharm and Supernus. Dr. Posey has affil-
iations with Bristol-Myers Squibb Co., Eli Lilly and Co., For-
est Research Institute, and Shire. Dr McCracken has afflia-
tions with Bristol Myers Squibb, Eli Lilly, McNeil Pediatrics,
Janssen Pharmaceutica, Pfizer, Shire, UCB, Wyeth, and No-
vartis. Dr. P. Cronin, Ms. A. Gavaletz, Ms. J. Hollway, Ms.
K. Koenig, Ms. L. Ritz, Dr. Swiezy, Dr. Tierney, Dr. Vitiello,
and Ms. Wheeler have no affiliations.
The opinion and assertions contained in this report are the
private views of the authors and are not to be construed as
official or as reflecting the views of the Department of Health
and Human Services, the National Institutes of Health or the
National Institutes of Mental Health.
Aman, MG: Drugs and learning in mentally retarded persons.
In G. D. Burrows & J. S. Werry (Eds.), Advances in Human
Psychopharmacology (Vol. 3, pp.121–163). Greenwich, Ct.: JAI
Aman MG, Arnold L, McDougle CJ, Vitiello B, Scahill L, Davies
M, McCracken JT, Tierney E, Nash PL, Posey DJ, Chuang S,
Martin A, Shah B, Gonzalez NM, Swiezy NB, Ritz L, Koenig
K, McGough J, Ghuman JK, Lindsay RL: Acute and long-term
safety and tolerability of risperidone in children with autism.
J Child Adolesc Psychopharmacol 15:869–884, 2005.
Aman MG, Hollway JA, Leone S, Masty J, Lindsay R Nash P,
Arnold LE: Effects of risperidone on cognitive-motor perfor-
mance and motor movements in chronically medicated chil-
dren. Res Dev Disabil. (in press).
Aman MG, Marks RE, Turbott SH, Wilsher CP, Werry SN:
Methylphenidate and thioridazine in the treatment of intel-
lectually subaverage children: Effects on cognitive-motor per-
formance. J Am Acad Child Adolesc Psychiatry 30:816–824,
Aman MG, Pearson DA: Monitoring and measuring drug ef-
fects. II. Behavioral, emotional, and cognitive effects. In JS
Werry, MG Aman (eds.) Practitioner’s Guide to Psychoactive
Drugs for Children and Adolescents (2nd ed). New York:
Plenum Press, 1999. pp. 99–164.
Aman MG, Singh NN: Aberrant Behavior Checklist Manual.
East Aurora, NY: Slosson Educational Publications, 1994.
Arnold LE, Aman MG, Martin A, Collier-Crespin A, Vitiello B,
Tierney E, Asarnow R, Bell-Bradshaw F, Freeman BJ, Gates-
Ulanet P, Klin A, McCracken JT, McDougle CJ, McGough JJ,
Posey DJ, Scahill L, Swiezy NB, Ritz L, Volkmar F: Assess-
ment in multisite randomized clinical trials of patients with
autistic disorder: The Autism RUPP Network. J Autism Dev
Disord 30:99–111, 2000.
American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, 4th Edition. Washington, D.C.:
American Psychiatric Association, 1994.
Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M,
Sheitman B, Lindenmayer J, Citrome L, McEnvoy J, Kunz M,
Chakos M, Cooper TB, Horowitz TL, Lieberman JA: Neu-
rocognitive effects of clozapine, olanzapine, risperidone, and
haloperidol in patients with chronic schizophrenia or schizoaf-
fective disorder. Am J Psychiatry. 159:1018–1028, 2002.
Delis DC, Kramer JH, Kaplan E, Ober BA: California Verbal
Learning Test Manual—Children’s Version. San Antonio, TX:
The Psychological Corporation, 1994.
Dunn LM, Dunn LM, Robertson GJ, Eisenberg JL: Peabody Pic-
ture Vocabulary Test—-Revised (PPVT-R). Circle Pines, MN:
American Guidance Service, 1981.
Ernst M, Malone RP, Rowan AB, George R, Gonzalez NM, Silva
RR: Antipsychotics (neuroleptics). In JS Werry, MG Aman
(eds.). Practitioner’s Guide to Psychoactive Drugs for Children
and Adolescents. New York: Plenum, 1988. Pp. 297–327.
Günther T, Herpertz-Dahlmann B, Jolles J, Konrad K: The in-
fluence of risperidone on attentional functions in children and
adolescents with attention-deficit/hyperactivity disorder and
co-morbid disruptive behavior disorder. J Child Adolesc Psy-
chopharmacol. 16:725–735, 2006.
Handen BL, Broaux AM, Gosling A, Ploof DL, Feldman H: The
efficacy of methylphenidate among mentally retarded chil-
dren with attention-deficit/ hyperactivity disorder. Pediatrics.
86: 922–930, 1990.
Keefe RS, Silva SG, Perkins DO, Lieberman JA: The effects of
atypical antipsychotic drugs on neurocognitive impairment in
schizophrenia: A review and meta-analysis. Schizophr Bull.
Keefe RS, Lees-Roitman SE, Dupre RL: Performance of patients
with schizophrenia on a pen and paper visuospatial working
memory task with short delay. Schizophr Res. 26:9–14, 1997.
Keppel G, Wickens TD: Design and Analysis: A Researcher’s
Handbook (4th. ed.). New Jersey: Prentice Hall, 2004.
Lord C, Rutter M. LeCouteur A: Autism diagnostic interview-
revised: A revised version of a diagnostic interview for care-
givers of individuals with possible pervasive developmental
disorders. J Autism Dev Disord: 24:659–685, 2004.
McGurk SR, Carter CC, Goldman R, Green MF, Marder SR,
Haiyi X, Schooler NR, Kane JM: The effects of clozapine and
risperidone on spatial working memory in schizophrenia. Am
J Psychiatry. 162:1013–1016, 2005.
National Institute of Mental Health: CGI (Clinical Global Im-
pressions Scale). Psychopharmacol Bull. 21:839–844, 1985.
Pandina GJ, Bilder R, Harvey PD, Keefe RSE, Aman MG, Gharab-
awi G: Risperidone and cognitive function in children with dis-
ruptive behavior disorders. Biol Psychiatry, 62, 226–234, 2007.
Purdon SE. Cognitive improvement in schizophrenia with novel
antipsychotic medications. Schizophr Res. 35:S51–S60, 1999.
Reilly JL, Harris MS, Keshavan MS, Sweeney JA: Adverse effects
of risperidone on spatial working memory in first-episode
schizophrenia. Arch Gen Psychiatry. 63:1189–1197, 2006.
Research Units on Pediatric Psychopharmacology Autism Net-
work: Risperidone in children with autism and serious be-
havioral problems. N Engl J Med. 347:314–321, 2002.
Scahill L, McCracken J, McDougle CJ, Aman MG, Arnold LE,
Tierney E, Cronin P, Davies M, Ghuman J, Gonzalez N, Koenig
K, Lindsay R, Martin A, McGough J, Posey DJ, Swiezy N,
Volkmar F, Ritz L, Vitiello B: Methodological issues in de-
RISPERIDONE IN CHILDREN WITH AUTISM AND IRRITABLE BEHAVIOR235
signing a multisite trial of risperidone in children and ado- Download full-text
lescents with autism. J Child Adolesc Psychopharmacol. 11:
SPSS: SPSS 13.0 for Windows. Chicago: SPSS, 2003.
Stip E, Chouinard S, Boulay LJ: On the trail of a cognitive en-
hancer for the treatment of schizophrenia. Prog Neuropsy-
chopharmacol Biol Psychiatry. 29:219–232, 2005.
Tiflin J, Asher EJ: The Purdue Pegboard: Norms and studies of
reliability and validity. J Appl Psychology. 32:234–247, 1948.
Tiflin J: Purdue Pegboard Examiner Manual. Chicago: Science
Research Associates, 1968.
Troost PW, Althaus M, Lahius BE, Buitelaar JK, Minderaa RB,
Hoekstra PJ: Neuropsychological effects of risperidone in chil-
dren with pervasive developmental disorders: A blinded dis-
continuation study. J Child Adolesc Psychopharmacol.
Wilkinson GS: Wide Range Achievement Test—Third Edition.
Administration Manual. Wilmington DE: Wide Range, Inc,
Yoo HJ, Williams DC, Napolitano DA, Peyton RT, Baer DM,
Schroeder SR: Rate-decreasing effects of the atypical neu-
roleptic risperidone attenuated by conditions of reinforcement
in a woman with mental retardation. J Appl Behav Anal.
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AMAN ET AL.236