Solved by a verified expert :Read the article “Cognitive Effects of Risperidone in Children with Autism and Irritable Behavior,” and identify the research questions and/or hypotheses as they are stated. Consider the following questions: What are the variables (sample sizes, population, treatments, etc.)? How was the analysis of variance used in this article (and what type of ANOVA was used)?Write a two- to three-page paper presenting the information listed below. In addition, provide a title page and reference page in APA style. Cite any references made to the article within the body of the paper in APA style. Your paper should begin with an introductory paragraph (including a thesis statement) and end with a concluding paragraph summarizing the major points made in the body of the paper and reaffirming the thesis.The body of your paper must:Determine what question(s) the authors are trying to answer by doing this research.Determine the hypothesis being tested and the concepts that were applied in this process.Evaluate the article and critique the statistical analysis employed in the study. Would you have included more and/or different variables? Explain your answer.Examine the assumptions and limitations of the statistical study. What would you have done differently in this case? Explain your answer.Identify how the authors applied statistical testing to the problem.Interpret the findings of the author(s) using statistical concepts.Access theThe Critical Thinking Community website for tips on how to formulate your thoughts and discussion of these questions in a logical and meaningful manner.Writing the Article CritiqueThe Assignment:Must be two to three double-spaced pages in length (excluding title and reference pages), and formatted according to APA style as outlined in the Ashford Writing Center.Must include a title page with the following:Title of paperStudent’s nameCourse name and numberInstructor’s nameDate submittedMust document all sources in APA style as outlined in the Ashford Writing Center.Must include a separate reference page formatted according to APA style as outlined in the Ashford Writing Center.Carefully review theGrading Rubric for the criteria that will be used to evaluate your assignment.Cognitive Effects of Risperidone in Children with
Autism and Irritable BehaviorAbstract
Objective: The objective of this
research was to explore the effects of risperidone on cognitive processes in
children 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 subjects who participated in the clinical trial; 63
were unable to perform the cognitive tasks. A double-blind placebocontrolled
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. Performance 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.IntroductionLITERATURE FOCUSING ON the cognitive
effects of atypical antipsychotics in children and adolescents is exceptionally
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
investigators and clinicians have wondered if cognitive blunting 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 atypical
antipsychotics, especially early in treatment. However, a detailed analysis of
adverse events from risperidone treatment in children with autism indicated that
reports of somnolence usually dissipated between 2 and 4 weeks after the last
dose adjustment of risperidone (Aman et al. 2005). Thus it seems that the time
of greatest “risk” of cognitive impairment would be in the earliest weeks of
treatment. Literature from adult trials in schizophrenia, have provided 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 improvements in attention, executive function, and visuospatial
processes. 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 suggested that the results of the studies be
interpreted with caution, 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) analyzed the effects of AAPs on cognitive-motor functioning
in adults with schizophrenia. This review concluded that a variety of AAPs
(risperidone, clozapine, quetiapine) improved 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 domains and some
studies included more than one relevant measure on the domain under discussion.
The authors reported one study of clozapine in which attention was negatively
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
functioning in four studies and no change in four others.The findings of these adult trials
suggest that the atypical antipsychotics 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 disorder (ADHD) and disruptive behavior
disorders (DBDs) and in normal controls matched for age and IQ. No effect of
medication 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
developmental disorder not otherwise specified (PDD—NOS), Asperger’s disorder]
and found 12 (50%) to be testable on focused 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 receiving placebo substitution in
comparison to those maintained 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 response 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
risperidone. 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 Learning
Test (Delis et al. 1994). The design was a 6-week, parallel-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 maintained on risperidone (mainly for DBDs) on
a computer-controlled 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 risperidoneplacebo, 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, static tremor). The present study was designed
to test whether risperidone has an effect on cognitive performance in children
with autism accompanied by serious behavior problems. 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 differences
between placebo and risperidone.MethodDesign
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 assessed at the screen
visit, participants who met inclusion criteria for the study were then
reassessed with clinical instruments 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 conducted at baseline, 4
weeks, and 8 weeks. For any participant who terminated either condition
prematurely, the last observation was carried forward to endpoint. Participants’
parents or legal guardians provided written informed consent as approved by
institutional review boards of the five participating universities.Study
participantsParticipant characteristics, study
design, and outcome measures have been described in detail in previous
publications (Arnold et al., 2000; RUPP Autism Network, 2002; Scahill 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
behavioral disturbance. To be enrolled in the study, participants 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 Manual of Mental Disorders, 4th Edition (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 diagnosis was corroborated by
structured interview with one or more parents acting as informants, using the
Autism Diagnostic Interview—Revised (Lord et al. 1994). Exclusion criteria
included positive Beta HCG test for girls; significant medical condition; past
history of neuroleptic malignant syndrome; and, because of dosing
considerations, 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 total number of subjects who had scorable cognitive measures
at baseline and at least 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 subjects were assigned to placebo and 20 to risperidone. The
remaining 63 (62.4%) subjects were not testable either due to the severity of
their cognitive impairment and/or disruptive behavior.ProceduresAny 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. Maximum
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.Outcome
measuresThe following cognitive measures were
obtained. California Verbal Learning Task–Children’s Version (VLTC) 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. Respondents 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 (measuring 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 learning 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 total 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
sensitive to pharmacological treatment in adults having schizophrenia 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
position 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 delayed condition,
participants were required to name pictures of common objects taken from the
Peabody Picture Vocabulary Test—Revised (Dunn et al. 1981) to prevent verbal
rehearsal. 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 average
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. Participants 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
commission) were recorded as dependent variables.Purdue Pegboard Task (Tiflin, 1968;
Tiflin and Asher, 1948). Our modified version of the original Purdue Pegboard
Test was a measure of hand-eye coordination. It required 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,
followed 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 examiner then
counted and recorded the number of pins inserted 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 ability
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 capability and the level at which to conduct testing. The Classroom
Analogue Task involved presenting participants with numerous
ability-appropriate math problems. These problems 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 addition and
subtraction. Seven-minute work samples were derived 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 consisted of the total number of math problems
that the participant attempted and total number correctly calculated. The
Analogue Classroom Task took 7 minutes to administer.Prior to data analysis, the cognitive
assessors from each site prepared operational criteria for judging ambiguous
responses and for determining whether subjects had mastered the tasks or were
simply responding randomly. For example, 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.)Statistical
analysesAnalyses were carried out for the
children who had valid task measures. Mastery was determined by a set of
operational principles applied by the tester at each site, in consultation with
all other testers, before the blind was broken. The first analyses were t-tests
and ChiSquare tests to determine 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 baseline. 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, P 2) were provided in addition to p values.
Partial eta squared is the proportion of the effect plus the error variance
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 measure of effect for within subject designs. In all
tests, p values .05 were used to indicate statistical significance.ResultsSubjects 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 risperidone
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 cognitive 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 disability
(n 8) also quite common. Ethnically, the
large majority 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 university degree or higher and only one parent
without a high school diploma (Table 1). When these participants were compared
with those who failed to achieve mastery, the following differences were found:
(a) IQ was higher for the Mastery 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 differences were found for ABC Irritability score,
CGI-Severity score, or gender, although Irritability scores and CGI-Severity
tended to be nonsignificantly higher (worse) for the non Mastery group.
