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Piracetam Therapy Does Not Enhance Cognitive Functioning in Children With Down Syndrome
Nancy J. Lobaugh, PhD;
Vladimir Karaskov, MD;
Vicki Rombough, MA;
Joanne Rovet, PhD;
Susan Bryson, PhD;
Rachel Greenbaum, MA;
Robert H. Haslam, MD;
Gideon Koren, MD
Arch Pediatr Adolesc Med. 2001;155:442-448.
ABSTRACT
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Background Piracetam is widely used as a purported means of improving cognitive
function in children with Down syndrome. Its efficacy, however, has not been
rigorously assessed.
Objective To determine whether 4 months of piracetam therapy (80-100 mg/kg per
day) enhances cognitive function in children with Down syndrome.
Design A randomized, double-blind, placebo-controlled crossover study.
Participants and Methods Twenty-five children with Down syndrome (aged 6.5-13 years) and their
caregivers participated. After undergoing a baseline cognitive assessment,
children were randomly assigned to 1 of 2 treatment groups: piracetam-placebo
or placebo-piracetam.
Main Outcome Measure The difference in performance while taking piracetam vs while taking
placebo on tests assessing a wide range of cognitive functions, including
attention, learning, and memory.
Results Eighteen children completed the study, 4 withdrew, and 3 were excluded
at baseline. Piracetam therapy did not significantly improve cognitive performance
over placebo use but was associated with central nervous system stimulatory
effects in 7 children: aggressiveness (n = 4), agitation or irritability (n
= 2), sexual arousal (n = 2), poor sleep (n = 1), and decreased appetite (n
= 1).
Conclusion Piracetam therapy did not enhance cognition or behavior but was associated
with adverse effects.
INTRODUCTION
PIRACETAM is a member of the class of drugs known as nootropics, which
are generally thought to enhance cognitive function in instances of brain
dysfunction. Putative mechanisms of action differ depending on the disease
process being modeled and include enhanced membrane fluidity,1
increased neurotransmitter release (eg, dopamine),2
protective effects on specific receptors (eg, glutamate),3
increased blood flow,4 enhanced corticosteroid
function,5 and effects on calcium channel function.6 Piracetam has been administered to patients with diverse
clinical conditions such as stroke,7 Alzheimer
disease,8, 9, 10, 11, 12
and developmental dyslexia.13, 14, 15
However, research on the efficacy of piracetam and related compounds to ameliorate
cognitive deficiencies in these populations, and in animal studies, has frequently
produced small or inconsistent results.16
Down syndrome is associated with developmental delay, and affected children
generally attain mental and cognitive capacity in the range of mild to moderate
mental retardation. Interest in using piracetam to improve cognitive function
in children with Down syndrome surged in North America after the television
program Day One was nationally broadcast on January
19, 1995. In this program, claims were made that piracetam therapy improved
cognitive function in a child with Down syndrome. This was followed by television
reports on December 20, 1996 (Nightline), and on
August 21, 1997 (48 Hours), and widespread dissemination
of anecdotal evidence through Internet newsgroups. For example, parents of
a 6-year-old girl indicated that " . . . her concentration and awareness have
improved. Her speech has improved to the point that she is finally saying
phrases and sentences; improvement is slow but she is finally making some"
(May 1995). An 11-year-old boy became "healthier, happier, has more energy,
pays attention better, is growing like crazy . . . absolutely full of energy"
(January 1999). Partially in response to claims such as these, piracetam has
gained widespread use among children with Down syndrome. Although thousands
of children are believed to presently receive the drug, no well-designed studies
testing the efficacy or assessing the adverse effects of piracetam therapy
have been published in the peer-reviewed medical literature.
Unbiased assessment of the effects of piracetam therapy in Down syndrome,
beneficial or harmful, is of great importance. Most of the media reports have
indicated that cognitive functions such as learning, memory, and attention
improve rapidly with the use of piracetam. To test these claims, we designed
a randomized, double-blind, placebo-controlled crossover study.
PARTICIPANTS AND METHODS
STUDY DESIGN
This study used a double-blind, placebo-controlled design consisting
of a baseline assessment and two 4-month treatment arms (Figure 1). To control for maturation effects, 2 treatment orders
were used. Children were randomly assigned to receive piracetam in phase 1
and placebo in phase 2 (piracetam-placebo) or placebo in phase 1 and piracetam
in phase 2 (placebo-piracetam). Cognitive evaluations were conducted at the
end of each phase while the children were in school. Baseline assessments
were conducted at the end of the 1996-1997 school year, phase 1 testing occurred
at the end of the fall 1997 term, and phase 2 testing occurred near the end
of the spring 1998 term. This study was approved by the research ethics board
at The Hospital for Sick Children in Toronto, Ontario.
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Figure 1. Flow chart of study design.
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PARTICIPANTS
The target sample size (N = 25) was chosen to allow detection of large
performance differences (0.8 SD) between the piracetam and placebo phases
with power of 80% and  = .05. A large effect size was chosen because
most reports in the popular press have indicated immediate and substantive
effects of piracetam treatment in children with Down syndrome.
Moderate- to high-functioning children with Down syndrome (aged 6.5-13
years) were recruited through pediatricians and Down syndrome support groups
throughout southern Ontario. Initial interviews with the child's parent(s)
and teacher determined the child's general health and cognitive abilities.
Exclusion criteria were hearing, vision, language, or other physical or cognitive
limitations that would interfere with their ability to complete the test battery;
known problems in swallowing capsules; use of piracetam during the previous
6 months; and concurrent use of megavitamins.
BASELINE SCREENING ASSESSMENT
Twenty-five children passed the initial telephone screening and were
invited to The Hospital for Sick Children for baseline physical and cognitive
assessment. All children were assessed with the Stanford-Binet Intelligence
Scale, 4th Edition,17 to establish mental age
equivalents, and the cognitive test battery was also administered. Children
were examined by a physician, and a medical history was obtained from the
parents. Testing was divided into two 3- to 4-hour sessions, with a break
for lunch and additional breaks as needed.
PRIMARY OUTCOME MEASURES: COGNITIVE TEST BATTERY
The 14 tests selected for this study were culled from a variety of standardized
tests and experimental paradigms and broadly covered the following functional
domains: attention, learning and memory, perceptual abilities, executive function,
and fine motor and visuomotor skills. Additional criteria were that the tests
be suitable for children with Down syndrome and show minimal or no learning
or practice effects with repeated administration. Brief descriptions of the
tasks are listed in Table 1, and
full descriptions can be obtained from the authors. The standardized tests
in the battery are typically used to assess children in the 3- to 5 year-old
age range, and the remaining tests have been used in 3- to 5-year-old children
(eg, see Johnson18) or patients with Down syndrome
(eg, see Dalton19). The child's effort on each
task was monitored by the tester using a 5-point rating scale (5 = fully compliant
and 1 = noncompliant).
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Table 1. Primary Outcome Measures: Description of Cognitive Test Battery*
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SECONDARY OUTCOME MEASURES: PARENT AND TEACHER QUESTIONNAIRES
Parents and teachers completed standardized questionnaires at each test
phase (Table 2). Parent questionnaires
provided 80 items that assessed activity levels, social behavior and well-being,
stress, parenting and family issues, and the child's temperament. Teacher
questionnaires provided 24 items that assessed activity levels, learning,
and social behaviors in the school environment.
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Table 2. Secondary Outcome Measures: Parent and Teacher Questionnaires
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TEST ADMINISTRATION
The cognitive battery was administered by the same tester (V.R.) at
all visits to ensure the best possible rapport with the children. The 14 tests
were divided into three 25-minute blocks. No more than one 15-minute task
was in each block. To control for the order of test administration, 3 block
orders were created and children were randomly assigned to 1 of the 6 possible
combinations. Children received breaks between each block and as otherwise
necessary. Parents sat in a nearby room and were brought into the test room
only when poor compliance interfered with testing or the child's verbal responses
were not readily understood.
MEDICATION PREPARATION, ADMINISTRATION, AND MONITORING
Piracetam was donated in powder form by Medisca Pharmaceuticals (St-Laurent,
Quebec) and was encapsulated in gelatin capsules at The Hospital for Sick
Children. Children received piracetam, 80 to 100 mg/kg per day, in 3 doses
8 hours apart. Placebo was starch and was encapsulated and administered in
the same manner. To monitor adverse effects and establish compliance, parents
were interviewed on a weekly to biweekly basis during both treatment arms
by a physician. Parents also were asked to note any substantial behavioral
or cognitive changes (positive or negative) during each treatment arm in a
diary provided to them. Psychologists involved in testing the children were
masked to drug status; to ensure safety, a team of physicians who did not
participate in the measurement of outcome was unmasked.
PRIMARY DATA ANALYSIS
Across the 14 tests, 87 dependent variables were identified, including
measures such as the number of correct responses and errors (eg, perseverations,
omissions, and false alarms), reaction times, and the number of trials to
the first correct response. The effectiveness of the randomization to treatment
order was confirmed on the baseline data using between-group analysis of variance
(SPSS version 10.0; SPSS Inc, Chicago, Ill; piracetam-placebo vs placebo-piracetam).
The primary analyses were repeated-measures analyses of variance, with treatment
phase (piracetam vs placebo) as the repeated measure. Cases with missing data
were excluded on a test-by-test basis, which was necessary for only 5 tests
(Go/No-Go, n = 15; Stroop Color/Shape, n = 16; Stroop Color/Word, n = 10;
Delayed Match-to-Sample, n = 17; and Animal Pegs, n = 17). Huynh-Feldt–adjusted
probabilities30 were used to evaluate the significance
of the repeated-measures factors. The strength of all statistical results
is indicated by  2, which indicates the proportion of total
variability attributable to the factor.
ADDITIONAL ANALYSES OF PRIMARY OUTCOME MEASURES
The children's ages fell naturally into 2 nonoverlapping age groups:
younger (n = 8; mean [SE] age, 8.0 [0.3] years; range, 7.0-8.9 years) and
older (n = 10; mean [SE] age, 11.4 [0.3] years; range, 10.0-13.0 years). To
ensure that no treatment effects were being masked by differences in age at
baseline, additional analyses were conducted separately for younger and older
children.
Based on telephone interviews with parents, we identified a subset of
children (n = 11) for whom the parents indicated some cognitive improvement
during piracetam treatment (eg, "sharper," "attentive," "brighter," or "more
focused"). (Two parents indicated cognitive improvement during placebo treatment,
one of whom indicated adverse cognitive effects during piracetam treatment.
No parent indicated decreased cognitive performance with placebo use.) The
"improvement" group was analyzed separately to determine whether parents'
anecdotal comments corresponded to any measurable improvement due to piracetam
use. (The diaries provided to the parents were not completed consistently
and were not analyzed.) Finally, performance of individual children was examined
to determine whether any child demonstrated beneficial effects while taking
piracetam.
RESULTS
PARTICIPANTS
Twenty-five children were invited to participate based on telephone
screening, and 18 were included in the final sample. Three children could
not complete the baseline assessment and were not enrolled; their verbal reasoning
age equivalents (2.5-3.0 years) were significantly lower than those of the
study children. Four enrolled children withdrew during the course of the study:
3 had difficulty swallowing the capsules and withdrew during phase 1 and the
fourth required heart surgery in phase 2 (placebo condition). Baseline demographics
and performance on the Stanford-Binet Intelligence Scale for the 22 enrolled
children are shown in Table 3.
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Table 3. Baseline Demographics and Stanford-Binet Intelligence
Scale Results*
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PRIMARY OUTCOME MEASURES: COGNITIVE TEST BATTERY
Of the 87 items selected for analysis, 22 reflected easier components
of the tasks. These items had no variability because all children had perfect
performance, and they were not analyzed further. Raw scores while taking piracetam
and placebo for the 65 remaining variables were analyzed. To aid visualization
of the magnitude of the differences between the piracetam and placebo arms
across tests, all raw scores were converted to z-score
differences from the grand average. All data are reported as mean ±
SE.
Baseline Performance
Children were generally compliant during testing, as seen in a mean
effort rating of 4.2 ± 0.2 across all tasks (range, 3.4-4.6). Performance
on the standardized tests concurred with mental age equivalents determined
from the Stanford-Binet Intelligence Scale. For example, on the McCarthy tests,
the mean raw scores for Verbal Fluency (9.9 ± 1.3), Verbal Memory (10.6
± 1.1), and Tapping (2.4 ± 0.2) are typical for children aged
4.5, 3.5, and 4.0 years, respectively. There were no differences at baseline
attributable to the randomization to treatment order (P>.09 for all).
Treatment Effects
The children also worked well at the tasks in the 2 test arms of the
study. The mean effort ratings were identical on the piracetam and placebo
arms (4.6 ± 0.2; range, 4.2-4.9).
The differences between the piracetam and placebo arms on the primary
outcome battery are shown in Figure 2,
with reaction times and test scores shown in panel A and errors shown in panel
B. Only one measure, an error measure on the Stroop attention task, reached
statistical significance (F1,16 = 5.66, P<.03, 2 = 0.26). On average, children made 2.1 ± 0.8 errors while taking
piracetam and 3.3 ± 1.2 errors while taking placebo. As shown in Figure 2, the differences between the piracetam
and placebo arms were small, with a maximal difference of 0.55 SD.
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Figure 2. Mean ± SEM differences
(and 95% confidence intervals of the differences [horizontal lines]) between
the piracetam and placebo arms for all primary outcome measures (A and B)
and significant differences from secondary outcome measures (C). A, Measures
such as reaction times, total scores, and number correct. B, Measures that
reflect task errors such as false alarms, omissions, naming color instead
of shape, and perseverations. C, The 6 measures from the parent and teacher
questionnaires that approached or reached significance. Positive numbers indicate
better performance while taking piracetam and negative numbers indicate better
performance while taking placebo. Scores are expressed as z-score deviations from the grand average of piracetam and placebo
scores. The letter in parentheses after each measure name indicates whether
the measure came from a test designated as primarily reflecting attention
(A), memory (M), perceptual abilities (P), executive function (E), or fine
motor skills (FM) and are listed as in Table 1. Strp indicates Stroop; RT, reaction time; Diff, difference;
AudCPT, auditory continuous performance task; VisCPT, visual CPT; FA, false
alarms; VLearn, Verbal Learning; Max, maximum recalled; E, error; B1, B2,
blocks 1 and 2; T1-T4, trials 1-4; DMTS, Delayed Match-to-Sample; CBCL, Child
Behavior Check List; CBQ, Children's Behavior Questionnaire; TRF, Teacher's
Report Form; and asterisk, significant differences.
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SECONDARY OUTCOME MEASURES: PARENT AND TEACHER QUESTIONNAIRES
At baseline, only one of the questionnaire items differed as a function
of assignment to treatment order. Parents of children in the placebo-piracetam
group reported greater feelings of isolation (14.1 ± 0.9) than did
parents in the piracetam-placebo group (9.8 ± 0.9; F1,16
= 11.61, P<.01, 2 = 0.42). In
the comparison of piracetam and placebo scores, 6 items from the parent and
teacher questionnaires reached or approached significance (Figure 2C). For parents, these indicated improvements in leadership
(FACES III: F1,13 = 4.45, P<.055, 2 = 0.26), fewer thought problems (Child Behavior Check List: F1,15 = 4.93, P<.04, 2 =
0.25), and poorer attention while taking piracetam (Children's Behavior Questionnaire:
F1,15 = 5.43, P<.03, 2
= 0.27). Teachers indicated that the children seemed happier (Teacher's Report
Form: F1,11 = 8.04, P<.02, 2 = 0.42), had fewer internalizing problems (Teacher's Report Form:
F1,13 = 8.65, P<.01, 2
= 0.40), and had fewer total problems while taking piracetam (F1,13
= 5.01, P<.04, 2 = 0.28). We note,
however, that all of these differences, although statistically significant,
were small from a clinical perspective. For example, on the parent questionnaire,
thought problem scores below 67 are not considered clinically significant.
Changes of the magnitude found here would not be interpreted by health care
professionals as indicative of either improvement or decrease on the factor.
Scores while taking piracetam and placebo were within the reference range,
at 56.3 ± 1.5 and 60.1 ± 1.6, respectively. Similarly, for teachers,
the total problem scores were in the clinically relevant range (>60) at 62.1
± 2.7 for the piracetam arm and 64.4 ± 2.6 for the placebo arm.
ADDITIONAL ANALYSES
Age at Baseline
To ensure that age-related beneficial effects of piracetam therapy were
not being masked in the primary analysis, we examined the data for the younger
and older children separately. Significant treatment x age group interactions
were found for only 3 measures. Older children had better performance while
taking placebo on 2 measures (Tapping and perseverations in Verbal Learning, P<.05), whereas younger children showed no differences
while taking piracetam vs placebo. On the first trial to correct reversal
in the Go/No-Go task, young children were better while taking placebo (4.3
trials) and older children were better while taking piracetam (3.9 trials; P<.05 for both).
Perceived Cognitive Improvement
Analysis of the remarks made during telephone interviews indicated that
11 parents made some comment of improved cognition or attention during the
piracetam arm. The data for these children were analyzed separately (mean
± SD age, 10.3 ± 0.6 years; range, 7.0-12.4 years). None of
the cognitive measures reached or approached significance in this subsample.
Individual Cases
Inspection of performance on a case-by-case basis indicated that occasionally
individual children showed meaningful changes in performance (improved or
worsened relative to baseline) on 1 or 2 measures while taking piracetam.
However, these effects were not consistent across children of similar ages
or across tasks within a child.
ADVERSE EFFECTS
Adverse effects during the piracetam phase reported by caregivers were
mostly associated with central nervous system stimulatory effects and were
seen in 7 children: aggressiveness or violent behavior (n = 4), agitation
or irritability (n = 2), sexual arousal (n = 2), poor sleep (n = 1), and decreased
appetite (n = 1). In 1 boy (aged 10.6 years at baseline), previously noted
inappropriate sexual and aggressive behaviors increased during piracetam use
and were especially disruptive at home and at school. No such effects were
reported in the placebo arm. To ensure that the adverse effects were not overshadowing
possible beneficial effects of piracetam treatment, performance was analyzed
separately for the 11 children not showing behavioral problems. No beneficial
effects of piracetam were identified, and the 2 groups did not differ from
each other on any measure.
COMMENT
Piracetam has received significant attention in the media for its purported
beneficial effects on cognition in children with Down syndrome. Because enhancement
has been reported on several cognitive functions, we explicitly designed the
present study to capture a wide range of cognitive functions and behaviors.
Thus, our primary outcome measure incorporated tests of sustained and short-term
attention and memory; tests that assess processing in the visual and auditory
domains; tests that examine verbal abilities, such as word fluency and learning
and remembering new words; and basic fine motor and perceptual motor skills.
The study is strengthened by the addition of a set of standardized parent
and teacher questionnaires to evaluate behavior, temperament, and social and
academic performance. The 2 test sessions of primary importance (piracetam
and placebo) were conducted within a single school year, and well within each
school term, providing a degree of stability to our measurements. It also
strengthens the teacher reports, as the same teacher conducted both assessments.
Because of the inherent difficulties in assessing changes in cognitive function
in cognitively impaired individuals, we were careful to include tasks that
children with Down syndrome could complete. In addition, our screening measures
ensured that the participating children would have sufficient capacity to
understand and perform all tasks. These goals were met for most measurements.
The results of this study indicate no consistent or pervasive beneficial
effects of piracetam therapy over placebo use in these children. Across 3
analyses of the formal test battery, 2 measures indicated better performance
while taking piracetam and 2 indicated better performance while taking placebo.
For the parent and teacher reports, all detected changes were either within
the reference range or remained in a clinically relevant range. Given the
small number of significant effects and the mixed nature of the findings,
we conclude that there is no strong evidence to indicate that piracetam use
improved cognition in these children, either in the formal test battery or
from parent and teacher reports.
As is typical in clinical trials, some children were lost to the study.
Because this reduced our sample size below that needed to detect large effects
of the drug, we were careful to examine multiple aspects of the data, including
relaxing the threshold for statistical significance, to ensure that positive
effects of piracetam treatment were not being masked. We did not identify
even a single case that would suggest the possibility that piracetam therapy
generally improved cognition. Most telling, perhaps, is that although 11 parents
noted that cognitive function seemed to be better when children were taking
piracetam, this did not translate into measurable beneficial effects of piracetam
over placebo.
The dose of piracetam used by us was within the range used in adults
and in children with dyslexia.13 Despite this,
potentially serious adverse effects were experienced by 7 of the 18 children
while taking piracetam. This finding excludes the option of dose escalation.
The results of this study are strikingly different from the anecdotal
testimonials presented in the popular press. One possibility that might partially
account for the perceived beneficial effects of piracetam therapy might lie
in the stimulatory effects of this medication. This type of behavioral stimulation
could easily be confused with actual cognitive improvement in the absence
of objective measures. Especially relevant to parent observations of alertness
and better focus, none of our attention tasks revealed enhanced performance
while taking piracetam over placebo on any measure. In conclusion, the results
of this study indicate that piracetam treatment is associated with adverse
effects and does not substantially enhance cognition or behavior.
AUTHOR INFORMATION
Accepted for publication December 1, 2000.
This research was supported by the Motherisk Research Fund and by a
grant from The Scottish Rite, Toronto, Ontario.
Presented in part at the Pediatric Academic Societies/Society for Pediatric
Research annual meeting, San Francisco, Calif, May 3, 1999.
The Down Syndrome Association of Toronto, provided valuable help in
recruiting participants for this study. Piracetam was donated by Medisca Pharmaceuticals.
Arthur J. Dalton, PhD, graciously allowed us to use the Dalton/McMurray Visual
Memory Test. We thank Zina Levichek, MD, and Dionne Laslo, MA, for their assistance
in data analysis; Orna Citrin, MD, for help with evaluating adverse effects
of medication use; and especially the parents and children who participated
in the study.
From the Rotman Research Institute of Baycrest Centre for Geriatric
Care and University of Toronto (Dr Lobaugh); the Division of Clinical Pharmacology
and Toxicology (Drs Karaskov and Koren and Ms Greenbaum), the Department of
Psychology (Dr Rovet and Ms Greenbaum), and the Division of Neurology (Drs
Bryson and Haslam), The Hospital for Sick Children; the Departments of Paediatrics
(Drs Rovet and Haslam), Pharmacology (Dr Koren), Pharmacy (Dr Koren), Medicine
(Drs Lobaugh, Haslam, and Koren), and Psychology (Dr Rovet), University of
Toronto; and the Department of Psychology, York University (Ms Rombough and
Dr Bryson), Toronto, Ontario.
Corresponding author: Nancy J. Lobaugh, PhD, Imaging Research and
Cognitive Neurology Unit, Sunnybrook and Women's College Health Sciences Centre,
2075 Bayview Ave, Room S604, Toronto, Ontario, Canada M4N 3M5 (e-mail: nlobaugh{at}sten.sunnybrook.utoronto.ca).
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Piracetam Does Not Help Cognition in Down's Syndrome
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Child Advocacy and Robust Community-Centered Research
Feudtner
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