Efficacy and Duration of Effect of Extended-Release Dexmethylphenidate Versus Placebo in Schoolchildren With Attention-Deficit/Hyperactivity Disorder

Abstract

The aim of this study was to assess changes in symptomatology of attention-deficit/ hyperactivity disorder (ADHD) with extended-release dexmethylphenidate (d-MPHER) versus placebo in a laboratory classroom setting.
This double-blind, placebo-controlled, crossover study randomized 54 children 6-12 years of age, stabilized on methylphenidate 20-40 mg/day. Patients participated in a practice day, then received 5 days of treatment with d-MPH-ER 20 mg/day or placebo. After a 1-day wash-out, they returned to the classroom and received 1 dose of their assigned treatment. Evaluations occurred predose and at postdose hours 1, 2, 4, 6, 8, 9, 10, 11, and 12. Children were then crossed over to the alternate treatment, using identical protocol. Primary efficacy variable was the Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale (SKAMP)-Combined scores, and primary analysis time point was 1 hour postdose; secondary efficacy variables over 12 hours included SKAMP-Attention and -Deportment scores and written math test results. Safety was assessed by adverse event (AE) recording following each period. Vital signs were recorded at each visit; laboratory tests were conducted at screening and final visit.
D-MPH-ER 20 mg/day showed a significant advantage over placebo as early as 1 hour postdose on SKAMP-Combined scores (p < 0.001). When analyzing the entire sample of 54 children, d-MPH-ER maintained significant superiority over placebo from hours 1 through 12 (p-values ranged from < 0.001 to 0.046). D-MPH-ER was well tolerated, with no severe AEs reported.
D-MPH-ER is safe and effective and improves classroom attention, deportment, and performance in children with ADHD.

Full text

239
Efficacy and Duration of Effect of Extended-Release
Dexmethylphenidate Versus Placebo
in Schoolchildren With
Attention-Deficit/Hyperactivity Disorder
Raul R. Silva, M.D.,
1
Rafael Muniz, M.D.,
2
Linda Pestreich, B.Sc.,
2
Ann Childress, M.D.,
3
Matthew Brams, M.D.,
4
Frank A. Lopez, M.D.,
5
and James Wang, Ph.D.
2
ABSTRACT
Objective: The aim of this study was to assess changes in symptomatology of attention-
deficit/hyperactivity disorder (ADHD) with extended-release dexmethylphenidate (d-MPH-
ER) versus placebo in a laboratory classroom setting.
Methods: This double-blind, placebo-controlled, crossover study randomized 54 children
6–12 years of age, stabilized on methylphenidate 20–40 mg/day. Patients participated in a
practice day, then received 5 days of treatment with d-MPH-ER 20 mg/day or placebo. After a
1-day wash-out, they returned to the classroom and received 1 dose of their assigned treat-
ment. Evaluations occurred predose and at postdose hours 1, 2, 4, 6, 8, 9, 10, 11, and 12. Chil-
dren were then crossed over to the alternate treatment, using identical protocol. Primary
efficacy variable was the Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale
(SKAMP)-Combined scores, and primary analysis time point was 1 hour postdose; secondary
efficacy variables over 12 hours included SKAMP-Attention and -Deportment scores and
written math test results. Safety was assessed by adverse event (AE) recording following each
period. Vital signs were recorded at each visit; laboratory tests were conducted at screening
and final visit.
Results: D-MPH-ER 20 mg/day showed a significant advantage over placebo as early as 1
hour postdose on SKAMP-Combined scores (p < 0.001). When analyzing the entire sample of
54 children, d-MPH-ER maintained significant superiority over placebo from hours 1
through 12 (p-values ranged from < 0.001 to 0.046). D-MPH-ER was well tolerated, with no se-
vere AEs reported.
Conclusions: D-MPH-ER is safe and effective and improves classroom attention, deport-
ment, and performance in children with ADHD.
JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY
Volume 16, Number 3, 2006
Mary Ann Liebert, Inc.
Pp. 239–251
1
New York University School of Medicine, New York, New York.
2
Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
3
Nevada Behavioral Health, Inc., Las Vegas, Nevada.
4
Bayou City Research, Houston, Texas.
5
Children’s Development Center, Maitland, Florida.
James Wang, Ph.D., Novartis Pharmaceutical Corporation (East Hanover, NJ) served as statistical consultant.
This study was funded by Novartis Pharmaceuticals Corporation (East Hanover, NJ).
Raul Silva, Ann Childress, and Frank Lopez have received research grants and are members of a speakers’ bureau for
Novartis Pharmaceuticals Corporation (East Hanover, NJ). Raul Silva is also a consultant for Novartis Pharmaceuti-
cals. Matthew Brams has received research grants from Novartis Pharmaceuticals, and Rafael Muniz, Linda Pestreich,
and James Wang are Novartis Pharmaceuticals employees.
14275C04.pgs 5/15/06 3:05 PM Page 239

240 SILVA ET AL.
INTRODUCTION
A
TTENTION-DEFICIT/HYPERACTIVITY DISORDER
(ADHD) is diagnosed in approximately
5% to 6% of school-age children (4–17 years of
age) in the United States (Guevara et al. 2002;
Lesesne et al. 2003). The presence of ADHD is
more frequently diagnosed in boys than in
girls, with ratios ranging from 4:1 to 9:1 (Diag-
nostic and Statistical Manual of Mental Disorders,
Fourth edition, text revision (DSM-IV-TR;
American Psychiatric Association 2000)). The
disorder is characterized by persistent, devel-
opmentally inappropriate inattention, hyper-
activity/impulsivity, and non–goal-directed
behavior. Some patients, however, predomi-
nantly exhibit inattention, whereas others
exhibit predominantly hyperactivity or impul-
sivity. These symptoms lead to difficulties in
cognitive and behavioral areas, family and so-
cial relationships, and self-esteem (DSM-IV-TR
2000; Biederman et al. 1996). Typically first
identified during the elementary school years
(Goldman et al. 1998), ADHD can persist into
adolescence and adulthood. If poorly treated
or left untreated, ADHD can increase the risk
for failure at school or work, delinquent be-
havior, drug abuse, and the development of
antisocial personality disorder (Barkley 2002;
Biederman et al. 1996; Dulcan 1997; Wilens et
al. 2004).
The etiology of ADHD remains unknown.
The broad spectrum of cognitive, behavioral,
and emotional symptoms seen with the disor-
der, however, suggests the involvement of
multiple genetic and psychosocial factors
(Faraone 2004). Structural and functional neu-
roimaging research indicate that disruption of
the frontal neostriatal dopaminergic system, as
well as cerebellar dysfunction, are central to
the executive function deficits and motor ab-
normalities that characterize ADHD (Roth and
Saykin 2004; Seidman et al. 2004).
Psychostimulants are the pharmacologic
treatment of choice for ADHD. The American
Academy of Child and Adolescent Psychiatry
(AACAP) has drafted practice parameters for
the use of stimulant medication (Greenhill et
al. 2002). Currently, the most widely pre-
scribed choices are immediate-release and
extended-release formulations of racemic
methylphenidate (MPH; a 50/50 mixture of
the d-threo- and l-threo-enantiomers) (NIH
1998). Developed in 1955, this agent has been
shown to be both efficacious and safe (Barkley
1977; Goldman et al. 1998; Kavale 1982;
Spencer et al. 1996; Wilens and Biederman
1992). Some studies indicate that the clinical
efficacy of d,l-MPH may be mediated by the d-
enantiomer (Patrick et al. 1987; Srinivas et al.
1992). In one study, improvement in sustained
attention was seen with equimolar doses of
dexmethylphenidate (d-MPH) and d,l-MPH,
but not with l-MPH (Srinivas et al. 1992).
Dexmethylphenidate hydrochloride (d-
MPH; Focalin™; Novartis Pharmaceuticals,
East Hanover, NJ) is the chirally pure d-isomer
of d,l-MPH. Like d,l-MPH, this agent is ap-
proved for twice-daily administration for the
treatment of ADHD. Because it does not
racemize after oral administration (Srinivas et
al. 1992), doses of d-MPH at one half those for
the racemic mixture can produce comparable
levels of efficacy and tolerability (Swanson et
al. 2004; Wigal et al. 2004). In a phase III trial
(Wigal et al. 2004), d-MPH was significantly
more effective than placebo in relieving
ADHD symptoms, yielding a level of efficacy
for ADHD symptoms comparable to that seen
with d,l-MPH doses containing the same
amount of d-MPH. The same study suggests
longer duration of therapeutic effects with d-
MPH than with racemic d,l-MPH; at 6 hours
postdose, parent-rated ADHD symptoms im-
proved significantly with d-MPH, but not with
d,l-MPH, when compared with placebo (Wigal
et al. 2004). In a prospective, open-label study
of d-MPH administered once-daily, parents
observed improvements that lasted 7.5 hours
and teachers observed improvements that
lasted 6.2 hours postdose (Silva et al. 2004).
Whereas sound clinical findings substanti-
ate the efficacy of d-MPH and other MPH-
containing compounds, the need for 2 doses
daily, with 1 dose typically given at mid-day,
presents certain challenges. Long-term compli-
ance with such a regimen can be problematic,
and concern about potential noncompliance
in the school setting has been raised. Moreover,
the daily need to receive a mid-day dose from
the school nurse may further erode the already
compromised social functioning and self-
14275C04.pgs 5/15/06 3:05 PM Page 240

esteem of children with ADHD. In response to
these issues, a once-daily extended-release for-
mulation of d-MPH (d-MPH-ER) has been de-
veloped using proprietary spheroidal oral
drug absorption system (SODAS) technology.
This formulation, which provides an initial re-
lease of medication immediately after dos-
ing—with a second release approximately 4
hours later—is intended to mimic the pharma-
cokinetic profile of immediate-release d-MPH
given twice-daily. If proven safe and effective,
once-daily d-MPH-ER may offer substantial
advantages over some currently available
ADHD preparations by improving long-term
patient compliance and by minimizing the risk
for drug diversion and for the social stigma as-
sociated with mid-day drug administration
during the school day.
The aim of this study was to evaluate effi-
cacy, in terms of the onset and duration of ef-
fect, as well as the safety and tolerability of
d-MPH-ER 20 mg/day versus placebo in pedi-
atric patients with ADHD over 12 hours in a
laboratory classroom setting. Used in previous
studies of various MPH formulations for
ADHD in school-age children (Lawrence et al.
2004; Swanson et al. 2004), the laboratory
classroom setting allows trained observers to
assess children’s attention, deportment, and
cognitive performance and to define the time
course of treatment effects based on repeated
assessments throughout the day. Assessments
in this trial were based on change from pre-
dose on the Swanson, Kotkin, Agler, M-Flynn,
and Pelham (SKAMP) rating scale (Swanson et
al. 1998) and on performance on a pencil-and-
paper math test.
METHODS
Study design
This study employed a double-blind,
placebo-controlled, within-subjects, crossover
design; this allowed each child to be exposed
to both treatments (6 days each of d-MPH-ER
20 mg/day and placebo) and act as his or her
own control. Patients were randomly assigned
to receive d-MPH-ER–placebo (sequence A) or
placebo–d-MPH-ER (sequence B) (Fig. 1). Fol-
DEXMETHYLPHENIDATE-ER IN CHILDREN WITH ADHD 241
lowing a practice day, efficacy of each treat-
ment was assessed during 12 hours in a labo-
ratory classroom on 2 consecutive Saturdays
(Table 1).
Study population
Boys and girls 6–12 years of age who had
been diagnosed with ADHD were eligible for
enrollment at 1 of 3 centers in the United States
participating in this study. Patients were re-
cruited from the investigators’ private prac-
tices, child neurology clinics, school referrals,
pediatricians’ offices, and general psychiatry
offices. Patients eligible for inclusion were re-
quired to fulfill the Diagnostic and Statistical
Manual of Mental Disorders, fourth edition
(DSM-IV; American Psychiatric Association
1994) criteria for ADHD of any type, as estab-
lished by the Computerized Diagnostic Inter-
view Schedule for Children (C-DISC-4).
Patients must also have been stabilized on
20–40 mg/day of MPH for at least 1 month
prior to screening. Only those patients whose
parents and/or guardians provided written,
informed consent were enrolled. Assent was
also obtained from all children (documented
by signature of those older than 9 years). Girls
were required to be premenarchal, sexually ab-
stinent, or using a reliable contraceptive
method. Sexually active girls were required to
show negative results on a urine pregnancy
test.
At screening (days 14 to 7), all prospec-
tive patients underwent a physical examina-
tion, an electrocardiogram (ECG), blood and
urine sampling for routine laboratory tests,
urine drug screening, and, for girls, a urine
pregnancy test. Informed consent was also
documented. A complete medical and psychi-
atric history was obtained, and the C-DISC-4
was conducted to confirm ADHD diagnosis.
Children were excluded if the investigator
deemed the child’s IQ was below average or if
there was evidence of an IQ below 80, or if
they were home schooled, were diagnosed
with Tourette syndrome or a tic disorder, had a
concurrent or history of a significant medical
or psychiatric illness (schizophrenia, bipolar
disorder, or autism) or substance abuse disor-
der, or if they or their parents or guardians
14275C04.pgs 5/15/06 3:05 PM Page 241

were unable to understand or follow instruc-
tions necessary to participate in the study. Pa-
tients taking antidepressants, those who had
initiated psychotherapy within 3 months pre-
ceding screening, and those with a positive
urine drug screen, were also ineligible. Chil-
dren with poor response or intolerance to
MPH, currently taking other medications for
ADHD, taking or planning to take another in-
vestigational drug within 30 days of study
start, or who had previously participated in
d-MPH-ER studies were also excluded.
Treatment schedule
All eligible patients completed four visits: A
screening day (7–14 days before study initia-
tion), a practice day (day 0), a Period 1 class-
room day (day 7), and a Period 2 classroom
day (day 14). The latter three visits occurred
on three consecutive Saturdays at a participat-
ing center. Patients were randomized by com-
puterized random number assignment to a
treatment sequence and, 1–2 weeks following
screening, participated in a practice visit to be-
come familiar with the laboratory classroom
and study evaluations (Table 1). Children were
given a placement math test and assigned a
difficulty level, based on the number of prob-
lems answered correctly. Patients were in-
structed to take their last dose of regularly
prescribed medication on the Thursday prior
to the practice day.
Upon completion of the practice visit, the
first assigned treatment was dispensed to par-
ents; study medication comprised either 1 bot-
tle of 5 capsules of blinded study medication
or 1 bottle of 5 matching placebo capsules, ac-
cording to randomization sequence. Parents
were instructed to dispense the first dose (1
capsule) in the morning on the following day
(Sunday, day 1). Once-daily morning dosing
242 SILVA ET AL.
Screened
(
N
= 54)
Randomized
(
N
= 54)
Practice Day
(
N
= 54)
Sequence 1:
d
-MPH-ER Placebo
(
n
= 27)
Sequence 2:
Placebo
d
-MPH-ER
(
n
= 27)
Completed
(
n
= 27)
Completed
(
n
= 26)
Efficacy Population
(
n
= 53)
Safety Population
(
N
= 54)
Discontinued
(
n
= 1)
Adverse event
(nausea)
during
placebo
phase
FIG. 1. Flow chart. This diagram illustrates this study’s
progression and the number of children included in each
sequence.
14275C04.pgs 5/15/06 3:05 PM Page 242

was to continue for the next 4 days, with no
capsules administered on Friday to prevent
any behavioral carryover effect associated
with the active treatment arm. On the morning
of their Period 1 visit (day 7), the same blinded
study treatment from days 1 through 5 was
dispensed to the children by study personnel.
Upon completion of testing on day 7, treat-
ment was switched and dispensed to parents.
The same dosing schedule was repeated for
the second treatment period, with the Period 2
classroom visit occurring on day 14.
SKAMP and math test assessments
The SKAMP rating scale comprises 13 items
intended to measure target classroom manifes-
tations of ADHD (Swanson et al. 1998; Swen-
son et al. 2003). The ratings are based on the
frequency and quality of behaviors, as ob-
served by raters. Three independent, blinded
raters were trained on SKAMP rating instru-
ments by an instructor not involved in the
study. These trained raters completed SKAMP
ratings for all participants at specified inter-
vals throughout the 12-hour testing period.
The primary efficacy variable was the
SKAMP—Combined score, with a primary
analysis time point of 1-hour postdose. The
SKAMP Deportment and Attention subscales
were among the secondary efficacy measures
obtained over 12 hours postdose.
Secondary measures of academic productiv-
ity were derived from a paper-and-pencil
math test, the Permanent Product Measure of
Performance (PERMP), conducted at specified
intervals during the day (Swanson et al. 1998).
PERMP measures a child’s ability to pay atten-
DEXMETHYLPHENIDATE-ER IN CHILDREN WITH ADHD 243
TABLE 1. CLASSROOM SCHEDULE
6:15 a.m. Arrival to site 11:25 a.m. Transition lead-in game
6:45 a.m. Vital signs obtained 11:30 a.m. Math test; SKAMP begins
7:00 a.m. Transition lead-in game 11:40 a.m. Group game
7:05 a.m. 0 H Math test; SKAMP begins 11:50 a.m. Transition-out game; SKAMP ends
7:15 a.m. Group game (rated) 11:55 a.m. Lunch
7:25 a.m. Transition-out game; SKAMP ends 1:10 p.m. Vital signs obtained
7:30 a.m. Dose patients 1:25 p.m. Transition lead-in game
7:35 a.m. Snack 1:30 p.m. Math test; SKAMP begins
7:55 a.m. Transition lead-in game 1:40 p.m. Group game
8:00 a.m. Math test; SKAMP begins 1:50 p.m. Transition-out game; SKAMP ends
8:10 a.m. Group game 1:55 p.m. Free time/Snack
8:20 a.m. Transition-out game; SKAMP ends 3:10 p.m. Vital signs obtained
8:25 a.m. Transition lead-in game 3:25 p.m. Transition lead-in game
8:30 a.m. Math test; SKAMP begins 3:30 p.m. Math test; SKAMP begins
8:40 a.m. Group game 3:40 p.m. Group game
8:50 a.m. Transition-out game; SKAMP ends 3:50 p.m. Transition-out game; SKAMP ends
8:55 a.m. Free time/Snack 3:55 p.m. Free time/Snack
9:10 a.m. Vital signs obtained 5:10 p.m. Vital signs obtained
9:25 a.m. Transition lead-in game 5:25 p.m. Transition-out game
9:30 a.m. Math test; SKAMP begins 5:30 p.m. Math test; SKAMP begins
9:40 a.m. Group game 5:40 p.m. Group game
9:50 a.m. Transition-out game; SKAMP ends 5:50 p.m. Transition-out game; SKAMP ends
9:55 a.m. Free time/Snack 5:55 p.m. Dinner
10:25 a.m. Transition lead-in game 7:10 p.m. Vital signs obtained
10:30 a.m. Math test; SKAMP begins 7:25 p.m. Transition lead-in game
10:40 a.m. Group game 7:30 p.m. Math test; SKAMP begins
10:50 a.m. Transition-out game; SKAMP ends 7:40 p.m. Group game
10:55 a.m. Free time 7:50 p.m. Transition-out game; SKAMP ends
11:10 a.m. Vital signs 7:55 p.m. Dismissal
Note: This table reflects the trial schedule followed by all participants, indicating classroom activities and testing
times.
SKAMP = the Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale.
14275C04.pgs 5/15/06 3:05 PM Page 243

tion and stay on task, correlated with an in-
crease in the number of correctly completed
problems. The test consisted of 400 math prob-
lems at the difficulty level assessed for each
child on the practice day. The children were in-
structed to work through as many problems as
possible in 10 minutes. Measures obtained
from these tests include the number of prob-
lems attempted (Math—Attempted) and the
number of problems answered correctly
(Math—Correct). The responses are reviewed
by comparing them to an answer template,
and they are triple-checked for accuracy.
Safety assessment and adverse events
Safety assessments included the monitoring
of vital signs at each visit and the recording of
adverse events (AEs) at the end of each treat-
ment period, which were obtained through
observation of the subject on the assessment
day, spontaneous reporting by the subject,
and reports from parents during the preced-
ing week. Laboratory parameters (including
hematology, blood chemistry, and urinalysis)
were also assessed for any abnormalities at
the screening and final visits. ECGs were con-
ducted at the screening visit and reviewed by
a physician and a pediatric cardiologist at
each site.
Statistical methods
The safety population consisted of all pa-
tients who received at least 1 dose of study
medication. The efficacy population com-
prised all randomized patients who provided
valid efficacy measurements for both treat-
ment periods. Descriptive statistics for all pa-
tients were obtained for background and
demographic variables at screening (Table 2).
The primary efficacy outcome measure was
defined as the change from predose in the
SKAMP—Combined score at 1 hour postdose.
This change was calculated by subtracting the
predose value from the postdose value; there-
fore, negative values indicate improvement in
ADHD symptoms. This variable was com-
pared between treatments, using an analysis of
covariance (ANCOVA) model that included
the fixed effects of center, sequence, treatment,
period, and baseline (hour 0 predose value)
and the random effects of patients within se-
quences and within-patient errors. The effects
of center and sequence were tested, using the
patients within sequences as the error term.
Overall treatment and period effects were
tested at the 0.05 level of significance, using
the mean square error from the ANCOVA
model. A t test with a two-sided alternative
was performed at the 0.05 level of significance
to establish superiority.
Secondary efficacy variables included
change from predose in SKAMP—Combined,
SKAMP—Attention, SKAMP—Deportment,
Math—Attempted, and Math—Correct scores
at postdose hours 1, 2, 4, 6, 8, 9, 10, 11, and 12.
The same methods used to calculate and ana-
lyze the primary efficacy variable were used to
analyze the secondary efficacy variables. Un-
like the SKAMP scores, however, positive
change from predose values for math test per-
formance indicates improvement. To control
for Type I error for multiple comparisons over
time for each secondary efficacy variable, the
null hypotheses of equal treatment effect were
tested at the 0.05 level at each time point, start-
ing at 1 hour postdose for each efficacy vari-
able. Testing proceeded to the next time point
only if the treatment difference at the previous
time point was significant (p  0.05).
244 SILVA ET AL.
TABLE 2. DEMOGRAPHIC AND BASELINE VARIABLES
All
Variable (N = 54)
Gender, n (%)
Male 38 (70.4)
Female 16 (29.6)
Mean age, years (SD) 9.4 (1.6)
Mean height, cm (SD) 138.6 (10.3)
Mean weight, kg (SD) 36.0 (11.5)
DSM-IV ADHD Type, n (%)
Inattentive 5 (9.3)
Hyperactive/impulsive 0
Combined 49 (90.7)
ADHD mean duration, years (SD) 4.6 (1.6)
Note: Information shown in this table reflects baseline
data from all randomized patients.
SD = standard deviation; DSM-IV = Diagnostic and Sta-
tistical Manual of Mental Disorders, 4th edition; ADHD =
attention-deficit/hyperactivity disorder.
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Duration of therapeutic effect was estimated
using change from predose values for the
SKAMP—Combined score observed across
postdose hours 1, 2, 4, 6, 8, 9, 10, 11, and 12.
Duration of effect was defined as the differ-
ence between offset and onset in hours (off-
set–onset). Treatment onset was defined as the
time point halfway between the last time at
which no effect was observed and the first
time point at which an effect was observed;
treatment offset was defined as the time point
halfway between the last time an effect was
observed and the first time that no effect was
observed.
Equality of paired predose values were ex-
amined, using paired differences formed by
subtracting Period 1 predose values from Pe-
riod 2 predose values. These paired differences
were analyzed, using an analysis of variance
(ANOVA) model, including sequence effect, to
test for unequal carryover effects (i.e., whether
the paired differences in predose values were
different between treatment sequences) (Hwang
1993). If the results were statistically signifi-
cant, a post hoc analysis was performed, based
on Period 1 data.
It was estimated that 54 patients were
required to detect a 0.05-level treatment differ-
ence at 90% power. The sample-size calcula-
tion was performed using PASS 2000 (NCSS,
Kaysville, Utah), with the assumptions that
the treatment difference and standard devia-
tion were 0.5 and 0.8 (on a per-item basis),
respectively.
RESULTS
Patient population and disposition
Randomized patients (N = 54) in both treat-
ment sequences had similar DSM-IV ADHD
subtype, demographic, and background char-
acteristics. Patients were predominantly Cau-
casian boys with a 4-year history of the
combined inattentive/hyperactive form of
ADHD (Table 2). Of the 54 randomized pa-
tients, 53 completed the study (sequence A [d-
MPH-ER–placebo], n = 27; sequence B
[placebo–d-MPH-ER], n = 26). One patient re-
ceiving sequence B discontinued because of
nausea during the first study period while re-
ceiving placebo. Exposure to study medication
in both treatment sequences was approxi-
mately 6.0 days.
Primary efficacy results
Analyses of the data revealed no sequence or
order effects at any of the measured time points
for each of the SKAMP ratings. The analysis for
site by treatment interaction was also not sig-
nificant. The predose value for SKAMP—Com-
bined score in the d-MPH-ER group was 25.7
± 11.14; in the placebo group, 21.6 ± 11.97 (see
Fig. 2A). The adjusted mean change in
SKAMP—Combined score from predose to
1-hour postdose was significantly greater with
d-MPH-ER 20 mg (10.014) than with placebo
(0.878; p < 0.001); effect size was 1.33. Mean
percent changes from predose were 42.7 with
d-MPH-ER versus 8.8 with placebo.
Duration of effect
SKAMP—Combined scores at all time
points showed significantly superior out-
comes with d-MPH-ER than with placebo (p <
0.001); effect size at 12 hours was 0.67. Based
on these results, the estimated duration of ef-
fect of d-MPH-ER is 1.0–12 hours postdose.
Mean change from predose in SKAMP—Com-
bined scores is shown in Figure 2B.
Predose values for SKAMP—Attention and
SKAMP—Deportment scores were 12.3 ± 4.8
and 13.4 ± 7.88, respectively, with d-MPH-ER
and 9.4 ± 4.7 and 12.2 ± 8.63 with placebo.
Changes from predose in SKAMP—Attention
and SKAMP—Deportment scores (largest p =
0.046, effect size at 12 hour = 0.40; largest p =
0.001, effect size at 12 hour = 0.69, respectively)
were significantly better at all time points with
d-MPH-ER than with placebo. Figures 2C and
2D show mean changes from predose in these
variables.
Predose values for Math—Attempted and
Math—Correct scores were 65.83 ± 35.97 and
62.53 ± 36.87, respectively, with d-MPH-ER
and 86.38 ± 41.6 and 79.89 ± 41.94 with placebo.
Changes from predose indicate that d-MPH-ER
DEXMETHYLPHENIDATE-ER IN CHILDREN WITH ADHD 245
14275C04.pgs 5/15/06 3:05 PM Page 245

was significantly more effective than placebo
at all time points (Math—Attempted, largest
p < 0.001, effect size at 12 hour = 0.88; Math—
Correct, largest p < 0.001, effect size at 12
hour = 0.84). Mean changes from baseline in
Math—Attempted and Math—Correct scores
are shown in Figure 3A and 3B.
At 2 hours postdose with d-MPH-ER, a time
point that corresponds approximately with
peak improvements in SKAMP scores, chil-
dren attempted an average of 123 math prob-
lems and correctly answered an average of 117
problems. This contrasts sharply with scores
from the same patients during the placebo
phase, when an average of 83 problems were
attempted and 79 were answered correctly.
Tests for imbalanced predose values were
statistically significant for SKAMP—Com-
bined (p = 0.001), SKAMP—Attention (p <
0.001), Math—Attempted (p < 0.001), and
Math—Correct scores (p < 0.001), meaning that
significant differences in predose values
emerged between treatment sequences for
these variables. For the SKAMP—Combined,
this finding was largely attributable to higher
predose values in patients given d-MPH-ER
during Period 1. Mean predose SKAMP—
Combined scores for patients in the d-MPH-
ER group were 27.7 in Period 1 and 21.6 in
Period 2. Supportive analyses on Period 1 data
showed that treatment-by-predose interac-
tions were not statistically significant, indicat-
ing greater effects with d-MPH-ER than with
placebo across the range of predose values.
Post hoc analysis of SKAMP—Combined
scores in Period 1 (n = 27) showed significant
246 SILVA ET AL.
10
15
20
25
30
0123456789101112
Hours Postdose
Mea n SKAMP- Combined Score
d-MPH-ER
Placebo
0 1 2 4 6 8 9 10 11 12
Hours Postdose
Mean Change, SKAMP-Combined Scores
d-MPH-ER
Placebo
10
5
0
5
10
15
*
*
*
*
*
*
*
*
Improvement
All
P
- values, d-MPH-ER versus placebo .
*
P
< 0.001
P
= 0.001
A
B
d-MPH-ER
Placebo
4
3
2
1
0
1
2
3
4
5
6
7
*
Improvement
Hours Postdose
All
P
- values, d-MPH-ER versus placebo .
*P < 0.001
P = 0.001
Mean Change, SKAMP-Attention Scores
0 1 2 4 6 8 9 10 11 12
P
= 0.046
*
*
*
*
*
*
0 1 2 4 6 8 9 10 11 12
Hours Postdose
d-MPH-ER
Placebo
*
Improvement
All
P
- values, d-MPH-ER versus placebo .
*P < 0.001
P = 0.001
6
4
2
0
2
4
6
8
10
Mean Change, SKAMP-Deportment Scores
*
*
*
*
*
*
C D
FIG. 2. (A) SKAMP-Combined raw scores. Mean SKAMP-Combined raw scores from predose (hour 0) through
hour 12. (B) SKAMP-Combined scores. Mean change from predose (N = 54) in SKAMP-Combined scores at postdose
hours 1 through 12. (C) SKAMP-Attention scores. Mean change from predose (N = 54) in SKAMP-Attention scores at
postdose hours 1 through 12. (D) SKAMP-Deportment scores. Mean change from predose (N = 54) in SKAMP-
Deportment scores at postdose hours 1 through 12. SKAMP = the Swanson, Kotkin, Agler, M-Flynn, and Pelham rat-
ing scales.
14275C04.pgs 5/15/06 3:05 PM Page 246

differences between d-MPH-ER and placebo
from hours 1 through 10 (p  0.015), but not at
hours 11 (p = 0.062) and 12 (p = 0.199) (Fig. 4).
SKAMP—Attention scores in Period 1 showed
significant differences between treatments at
hours 1, 2, 4, 6 and 9 (p  0.015) but not at
hours 8 (p = 0.099), 10 (p = 0.303), 11 (p = 0.086),
and 12 (p = 0.486). Because SKAMP—Deport-
ment scores did not show differences in pre-
dose values, post hoc analysis of Period 1 data
was unnecessary.
Post hoc analysis of Math—Attempted
scores in Period 1 showed significant differ-
ences between treatments at hours 1, 2, 4, 6,
and 8 (p  0.015) but not at hours 9 (p = 0.313),
10 (p = 0.191), 11 (p = 0.127) or 12 (p = 0.523).
Post hoc analysis of Math—Correct scores in
Period 1 showed significant differences be-
DEXMETHYLPHENIDATE-ER IN CHILDREN WITH ADHD 247
0 1 2 4 6 8 9 10 11 12
Hours Postdose
d-MPH-ER
Placebo
*
Improvement
All
P
- values, d-MPH-ER versus placebo .
*P < 0.001
Mean Change, Math–Attempted
60
50
40
30
20
10
0
10
20
*
*
*
*
*
*
*
*
0 1 2 4 6 8 9 10 11 12
Hours Postdose
d-MPH-ER
Placebo
Improvement
All
P
- values, d-MPH-ER versus placebo .
*P < 0.001
Mean Change, Math–Correct
60
50
40
30
20
10
0
10
20
*
*
*
*
*
*
*
*
*
A B
FIG. 3. (A) Math-Attempted scores. Mean change from predose (N = 54) in the number of problems attempted on
math tests at postdose hours 1 through 12. (B) Math-Correct scores. Mean change from predose (N = 54) in math ques-
tions answered correctly at postdose hours 1 through 12.
0 1 2 4 6 8 9 10 11 12
Hours Postdose
d-MPH-ER
Placebo
5
0
5
10
15
20
*
Improvement
All
P
- values, d-MPH-ER versus placebo .
*P < 0.001
P = 0.015
Mean Change, SKAMP-Combined Scores
*
*
*
*
*
FIG. 4. Period 1 SKAMP-Combined scores. Mean change from predose (N = 27) in SKAMP-Combined scores at
postdose hours 1 through 12, Period 1 only.
14275C04.pgs 5/15/06 3:05 PM Page 247

tween treatments at hours 1, 2, 4, 6, and 8 (p 
0.022) but not at hours 9 (p = 0.418), 10 (p =
0.146), 11 (p = 0.109) or 12 (p = 0.419).
Safety
AEs were attributed to the treatment re-
ceived at the time of AE onset. Reported AEs
were mild or moderate in intensity, with no
unexpected, serious, or severe AEs occurring;
there was also no evidence of toxicity to any
organ. The percentage of patients experienc-
ing AEs was comparable between d-MPH-ER
(28.3%) and placebo (22.2%). In line with AEs
typically associated with psychostimulant medi-
cations, AEs that occurred more frequently
with d-MPH-ER than with placebo and were
considered possibly related to study drug in-
cluded decreased appetite (9.4% vs. 0%),
anorexia (7.5% vs. 0%), upper abdominal pain
(5.7% vs. 1.9%), fatigue (3.8% vs. 0%), and in-
somnia (3.8% vs. 0%). Other AEs reported in
2% or more of patients included headache
(1.9% vs. 5.6%) and irritability (0% vs. 5.6%).
Few clinically notable laboratory or vital sign
abnormalities occurred. Specifically, 2 patients
each had a pulse rate of 68 while on d-MPH-ER,
as compared to 1 patient on placebo, with the
same pulse rate. There were no clinically no-
table systolic or diastolic blood pressure changes
associated with either d-MPH-ER or placebo
during this trial. During placebo treatment,
1 patient discontinued the study because of
nausea. There were no discontinuations attribut-
able to laboratory abnormalities.
DISCUSSION
The aim of this study was to assess the effi-
cacy, safety, tolerability, and duration of ef-
fect of d-MPH-ER 20 mg/day versus placebo
observed in children over 12 hours in a labo-
ratory classroom setting. D-MPH-ER effec-
tively improved a broad range of ADHD
symptoms. Improvements in attention, de-
portment, and math test performance oc-
curred rapidly (within 1 hour postdose) and
were maintained for periods up to 12 hours
postdose. D-MPH-ER was safe and well toler-
ated, with no severe AEs reported; only 1 pa-
tient, who was receiving placebo, withdrew
because of an AE.
The behavioral improvements observed
with d-MPH-ER emerged rapidly, showing
significant advantages over placebo as early as
1 hour postdose in all efficacy variables. When
examining the entire sample of 54 subjects, the
improvements were maintained throughout
the 12-hour evaluation period (Figs. 2 and 3).
The primary efficacy end point, change in pre-
dose SKAMP—Combined score at 1 hour post-
dose, was significantly better with d-MPH-ER
than with placebo. Similar changes were ob-
served in SKAMP—Attention, SKAMP—
Deportment, Math—Attempted, and Math—
Correct scores. Effect onset was first detected
at hour 1.0 postdose but may have occurred
earlier. Future studies should investigate dif-
ferences earlier than 1.0 hour following
medication administration. D-MPH-ER also
demonstrated a significantly superior effect on
the primary and secondary end points, com-
pared with placebo at all other times assessed;
duration of effect of d-MPH-ER was estimated
to be 12 hours when the data for the entire
sample were analyzed. This duration of action
is in line with two previous reports of longer-
lasting therapeutic effects observed with
twice-daily dosing of immediate-release d-
MPH than with traditional, racemic, immedi-
ate-release d,l-MPH (Quinn et al. 2004; Wigal
et al. 2004). In each study, the authors found
significantly greater improvements with d-
MPH than with placebo at 6 hours postdose
(Quinn et al. 2004; Wigal et al. 2004) and, in
one of these studies, no significant effect of d,l-
MPH persisted at 6 hours postdose (Wigal et
al. 2004). A recent open-label study of d-MPH
in school-age children yielded similar findings
(Silva et al. 2004). The difference in duration of
effect between racemic d,l-MPH and d-MPH
does not appear to be attributable to the phar-
macokinetic profile of d-MPH; Quinn et al.
found that, at 6 hours after oral administra-
tion, serum levels of d-MPH were similar for
both agents. Our findings in this study pro-
vide further evidence of the extended duration
of action of d-MPH-ER.
D-MPH-ER was well tolerated by the patient
population in this study; reported AEs were
consistent with those seen for other psycho-
248 SILVA ET AL.
14275C04.pgs 5/15/06 3:05 PM Page 248

stimulants. The most frequently reported AEs
were decreased appetite and anorexia, both of
which were considered at least possibly re-
lated to study drug by raters and were antici-
pated side effects of d-MPH-ER. No serious or
severe AEs were observed during this study,
and the few clinically notable findings re-
ported for vital sign measures and clinical lab-
oratory values were considered to be not
related to study drug. However, in a study
such as ours, the inclusion of individuals that
are currently stabilized on a similar stimulant
medication tends to impact by decreasing the
number and severity of AEs reported by sub-
jects. Larger-scale, placebo-controlled studies
of patients that include treatment naïve sub-
jects are better suited for identifying the array
of AEs associated with an active agent.
Although studies of different designs cannot
be directly compared, two trials of other
ADHD medications in similar patient popula-
tions—with similar duration of drug expo-
sure—suggest that d-MPH-ER may have a
different tolerability profile. In our study, for
example, the placebo-subtracted rates of de-
creased appetite or anorexia totaled 16.9%
with d-MPH-ER 20 mg, whereas in other stud-
ies the comparable rate of decreased appetite
was 29.7% to 45.4% with OROS-methyl-
phenidate 18–54 mg (Concerta®, ALZA Cor-
poration; Mountain View, CA) and that of
anorexia was 4.7% to 32.7% with extended-
release mixed amphetamine salts 10–30 mg
(Adderall XR®, Shire U.S., Inc.; Wayne, PA)
(McCracken et al. 2003; Stein et al. 2003).
Similarly, the placebo-subtracted frequency of
insomnia was considerably lower with d-
MPH-ER (3.8%) than with OROS-methyl-
phenidate (19.7% to 27.2%) (Stein et al. 2003).
The comparable rates of abdominal pain were
5.7% with d-MPH-ER, 15.9% to 25.1% with
OROS-methylphenidate, and 4.7% to 11.5%
with extended-release mixed amphetamine
salts (McCracken et al. 2003; Stein et al. 2003).
The somewhat higher AE rates reported with
OROS-methylphenidate may be partly a re-
flection of the subjects’ previous experience
with stimulant medications. In this study of d-
MPH-ER, all patients had been previously sta-
bilized on MPH; hence, they were likely to
tolerate this drug class well. Similarly, 92% of
patients in the extended-release mixed am-
phetamine salts study had a history of positive
response to stimulants. In contrast, only 30%
of children in the OROS-methylphenidate
study had prior experience with stimulants
(McCracken et al. 2003; Stein et al. 2003). From
this review of the literature, it seems that d-
MPH-ER did no worse and might have done
better. Ultimately, a head-to-head comparison
is needed to make any reasonable statement of
difference.
In this study, the issues of imbalanced pre-
dose values dictated a post hoc analysis, which
had diminished power owing to the reduced
number of subjects. This constraint may have
contributed to the lack of significant differ-
ences between placebo and d-MPH-ER at the
later hour ratings. It should be noted that the
power analysis done prior to study com-
mencement specified that the full sample size
(N = 54) would be required to demonstrate
significant differences between the treatment
arms. Although this difference may have been
the result of reduced power, it is also pos-
sible that they reflect the true situation. Future
studies should be undertaken to replicate our
findings. A larger sample, without issues of
imbalanced predose values, would help con-
firm the duration of action of this agent.
Limitations
As with any study, there are always limita-
tions. One of the inclusion criteria in this study
was patients who were known to be currently
stable on another methylphenidate prepara-
tion. As a result, information related to onset
of action and duration of effect were limited to
populations that responded to a methyl-
phenidate agent. In terms of AEs, we listed all
side effects irrespective of whether they were
identified by a parent or child. These were
gathered both during the week preceding the
laboratory observation days and during the
laboratory classroom day. This may have
posed certain limitations in assessing side ef-
fects and the type of side effects most com-
plained about by individuals taking the
medication. Another limitation was that we
did not systematically analyze compliance
data during the week preceding the laboratory
DEXMETHYLPHENIDATE-ER IN CHILDREN WITH ADHD 249
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classroom; it should be noted that there was
100% compliance with study medication on all
laboratory classroom sessions. Finally, cross-
over designs are subject to carryover effects
and order effects. There were no order effects
in this study. However, the predose effect seen
in this study may be considered a form of
carryover effect by some. The randomization
created two different groups that had signifi-
cantly different predose values. However,
even with this discrepancy, there were no
treatment-by-group interactions.
CONCLUSIONS
In this study, once-daily d-MPH-ER 20 mg
was a safe and effective treatment for ADHD
symptoms in pediatric patients. The onset of
effect was relatively rapid (1.0 hour), and the
duration of effect was relatively long (up to 12
hours), as demonstrated by improvements in
attention, deportment, and math test perfor-
mance over a 12-hour testing period. These
findings indicate that d-MPH-ER is a safe and
effective once-daily treatment for pediatric
ADHD. This agent adds to the current options
for long-acting stimulants for the treatment of
ADHD.
REFERENCES
American Psychiatric Association: Diagnostic and
Statistical Manual of Mental Disorders, 4th ed.
(DSM-IV). Washington (DC), American Psychi-
atric Association, 1994.
American Psychiatric Association: Diagnostic and
Statistical Manual of Mental Disorders, fourth
edition, text revision (DSM-IV-TR). Washington
(DC), American Psychiatric Association, 2000.
Barkley RA: A review of stimulant drug research
with hyperactive children. J Child Psychol Psy-
chiatry 18:137–165, 1977.
Barkley RA: Major life activity and health out-
comes associated with attention-deficit/hyperac-
tivity disorder. J Clin Psychiatry 63(Suppl 12):
10–15, 2002.
Biederman J, Faraone S, Milberger S, Guite J, Mick
E, Chen L, Mennin D, Marrs A, Ouellette C,
Moore P, Spencer T, Norman D, Wilens T, Kraus I,
Perrin J: A prospective 4-year follow-up study of
attention-deficit/hyperactivity and related disor-
ders. Arch Gen Psychiatry 53:437–446, 1996.
Dulcan M: Practice parameters for the assessment
and treatment of children, adolescents, and
adults with attention-deficit/hyperactivity disor-
der. American Academy of Child and Adolescent
Psychiatry. J Am Acad Child Adolesc Psychiatry
36(Suppl 10):85S–121S, 1997.
Faraone SV: Genetics of adult attention-deficit/hy-
peractivity disorder. Psychiatr Clin North Am
27:303–321, 2004.
Goldman LS, Genel M, Bezman RJ, Slanetz PJ: Di-
agnosis and treatment of attention-deficit/hyper-
activity disorder in children and adolescents.
Council on Scientific Affairs, American Medical
Association. JAMA 279:1100–1107, 1998.
Greenhill LL, Pliszka S, Dulcan MK, Bernet W,
Arnold V, Beitchman J, Benson RS, Bukstein O,
Kinlan J, McClellan J, Rue D, Shaw JA, Stock S:
Practice parameter for the use of stimulant med-
ications in the treatment of children, adolescents,
and adults. J Am Acad Child Adolesc Psychiatry.
41(Suppl 2):26S–49S, 2002
Guevara J, Lozano P, Wickizer T, Mell L, Gephart
H: Psychotropic medication use in a population
of children who have attention-deficit/hyperac-
tivity disorder. Pediatrics 109:733–739, 2002.
Hwang DS: Statistical examination of carryover ef-
fects in a 4  4 Latin square design (Williams de-
sign) using the baseline data (Internal report).
East Hanover (New Jersey), Sandoz Pharmaceu-
ticals Corporation, 1993.
Kavale K: The efficacy of stimulant drug treatment
for hyperactivity: A meta-analysis. J Learn Dis-
abil 15:280–289, 1982.
Lawrence V, Houghton S, Douglas G, Durkin K,
Whiting K, Tannock R: Executive function and
ADHD: A comparison of children’s perfor-
mance during neuropsychological testing and
real-world activities. J Atten Disord 7:137–149,
2004.
Lesesne CA, Visser SN, White CP: Attention-
deficit/hyperactivity disorder in school-aged
children: Association with maternal mental
health and use of health care resources. Pediatrics
111:1232–1237, 2003.
McCracken JT, Biederman J, Greenhill LL, Swanson
JM, McGough JJ, Spencer TJ, Posner K, Wigal S,
Pataki C, Zhang Y, Tulloch S: Analog classroom
assessment of a once-daily mixed amphetamine
formulation, SLI381 (Adderall XR), in children
with ADHD. J Am Acad Child Adolesc Psychia-
try 42:673–683, 2003.
National Institutes of Health: Diagnosis and treat-
ment of attention-deficit/hyperactivity disorder
(ADHD), NIH Consensus Statement, 16th ed.
Washington, (DC), National Institutes of Health,
1998.
Patrick KS, Caldwell RW, Ferris RM, Breese GR:
Pharmacology of the enantiomers of threo-
methylphenidate. J Pharmacol Exp Ther
241:152–158, 1987.
250 SILVA ET AL.
14275C04.pgs 5/15/06 3:05 PM Page 250

Quinn D, Wigal S, Swanson J, Hirsch S, Ottolini Y,
Dariani M, Roffman M, Zeldis J, Cooper T: Com-
parative pharmacodynamics and plasma concen-
trations of d-threo-methylphenidate hydrochloride
after single doses of d-threo- methylphenidate
hydrochloride and d,l-threo-methylphenidate hy-
drochloride in a double-blind, placebo-controlled,
crossover laboratory school study in children
with attention-deficit/hyperactivity disorder. J
Am Acad Child Adolesc Psychiatry 43:1422–
1429, 2004.
Roth RM, Saykin AJ: Executive dysfunction in at-
tention-deficit/hyperactivity disorder: Cognitive
and neuroimaging findings. Psychiatr Clin North
Am 27:83–96, 2004.
Seidman LJ, Valera EM, Bush G: Brain function and
structure in adults with attention-deficit/hyper-
activity disorder. Psychiatr Clin North Am
27:323–347, 2004.
Silva R, Tilker HA, Cecil JT, Kowalik S, Khetani V,
Faleck H, Patin J: Open-label study of dex-
methylphenidate hydrochloride in children and
adolescents with attention-deficit/hyperactivity
disorder. J Child Adolesc Psychopharmacol
14:555–563, 2004.
Spencer T, Biederman J, Wilens T, Harding M,
O’Donnell D, Griffin S: Pharmacotherapy of at-
tention-deficit/hyperactivity disorder across the
life cycle. J Am Acad Child Adolesc Psychiatry
35:409–432, 1996.
Srinivas NR, Hubbard JW, Quinn D, Midha KK:
Enantioselective pharmacokinetics and phar-
macodynamics of d,l-threo-methylphenidate in
children with attention-deficit/hyperactivity dis-
order. Clin Pharmacol Ther 52:561–568, 1992.
Stein MA, Sarampote CS, Waldman ID, Robb AS,
Conlon C, Pearl PL, Black DO, Seymour KE,
Newcorn JH: A dose-response study of OROS
methylphenidate in children with attention-
deficit/hyperactivity disorder. Pediatrics 112:e404–
e413, 2003.
Swanson JM, Wigal S, Greenhill LL, Browne R,
Waslik B, Lerner M, Williams L, Flynn D, Agler
D, Crowley K, Fineberg E, Baren M, Cantwell DP:
Analog classroom assessment of Adderall in chil-
dren with ADHD. J Am Acad Child Adolesc Psy-
chiatry 37:519–526, 1998.
Swanson J, Kinsbourne M, Roberts W, Zucker K:
Time-response analysis of the effect of stimulant
medication on the learning ability of children
referred for hyperactivity. Pediatrics 61:21–29,
2003.
Swanson JM, Wigal SB, Wigal T, Sonuga-Barke E,
Greenhill LL, Biederman J, Kollins S, Nguyen AS,
DeCory HH, Hirshe Dirksen SJ, Hatch SJ; CO-
MACS Study Group: A comparison of once-daily
extended-release methylphenidate formulations
in children with attention-deficit/hyperactivity
disorder in the laboratory school (the Comacs
Study). Pediatrics 113:e206–e216, 2004.
Wigal S, Swanson JM, Feifel D, Sangal RB, Elia J,
Casat CD, Zeldis JB, Conners CK: A double-blind,
placebo-controlled trial of dexmethylphenidate
hydrochloride and d,l-threo-methylphenidate
hydrochloride in children with attention-deficit/
hyperactivity disorder. J Am Acad Child Adolesc
Psychiatry 43:1406–1414, 2004.
Wilens TE, Biederman J: The stimulants. Psychiatr
Clin North Am 15:191–222, 1992.
Wilens TE, Faraone SV, Biederman J: Attention-
deficit/hyperactivity disorder in adults. JAMA
292:619–623, 2004.
Address reprint requests to:
Raul R. Silva, M.D.
New York University School of Medicine
550 First Avenue, NB 21S6
New York, NY 10016
E-mail: raul.silva@med.nyu.edu
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