Efficacy and Safety of Immediate-Release Methylphenidate Treatment for Preschoolers With ADHD

Article (PDF Available)inJournal of the American Academy of Child & Adolescent Psychiatry 45(11):1284-93 · November 2006with101 Reads
DOI: 10.1097/01.chi.0000235077.32661.61 · Source: PubMed
Abstract
The Preschool ADHD Treatment Study (PATS) was a NIMH-funded, six-center, randomized, controlled trial to determine the efficacy and safety of immediate-release methylphenidate (MPH-IR), given t.i.d. to children ages 3 to 5.5 years with attention-deficit/hyperactivity disorder (ADHD). The 8-phase, 70-week PATS protocol included two double-blind, controlled phases, a crossover-titration trial followed by a placebo-controlled parallel trial. The crossover-titration phase's primary efficacy measure was a combined score from the Swanson, Kotkin, Atkins, M-Flynn, and Pelham (SKAMP) plus the Conners, Loney, and Milich (CLAM) rating scales; the parallel phase's primary outcome measure was excellent response, based on composite scores on the Swanson, Nolan, and Pelham (SNAP) rating scale. Of 303 preschoolers enrolled, 165 were randomized into the titration trial. Compared with placebo, significant decreases in ADHD symptoms were found on MPH at 2.5 mg (p<.01), 5 mg (p<.001), and 7.5 mg (p<.001) t.i.d. doses, but not for 1.25 mg (p<.06). The mean optimal MPH total daily dose for the entire group was 14.2 +/- 8.1 mg/day (0.7+/-0.4 mg/kg/day). For the preschoolers (n=114) later randomized into the parallel phase, only 21% on best-dose MPH and 13% on placebo achieved MTA-defined categorical criterion for remission set for school-age children with ADHD. MPH-IR, delivered in 2.5-, 5-, and 7.5-mg doses t.i.d., produced significant reductions on ADHD symptom scales in preschoolers compared to placebo, although effect sizes (0.4-0.8) were smaller than those cited for school-age children on the same medication.

Figures

Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
Efficacy and Safety of Immediate-Release
Methylphenidate Treatment for Preschoolers
With ADHD
LAURENCE GREENHILL, M.D., SCOTT KOLLINS, PH.D., HOWARD ABIKOFF, PH.D.,
JAMES M
CCRACKEN, M.D., MARK RIDDLE, M.D., JAMES SWANSON, PH.D.,
JAMES M
CGOUGH, M.D., SHARON WIGAL, PH.D., TIM WIGAL, PH.D.,
BENEDETTO VITIELLO, M.D., ANNE SKROBALA, M.A., KELLY POSNER, P
H.D.,
JASWINDER GHUMAN, M.D., CHARLES CUNNINGHAM, P
H.D., MARK DAVIES, M.P.H.,
SHIRLEY CHUANG, M.S.,
AND TOM COOPER, M.A.
ABSTRACT
Objective: The Preschool ADHD Treatment Study (PATS) was a NIMH-funded, six-center, randomized, controlled trial to
determine the efficacy and safety of immediate-release methylphenidate (MPH-IR), given t.i.d. to children ages 3 to 5.5
years with attention-deficit/hyperactivity disorder (ADHD). Method: The 8-phase, 70-week PATS protocol included two
double-blind, controlled phases, a crossover-titration trial followed by a placebo-controlled parallel trial. The crossover-
titration phase`s primary efficacy measure was a combined score from the Swanson, Kotkin, Atkins, M-Flynn, and Pelham
(SKAMP) plus the Conners, Loney, and Milich (CLAM) rating scales; the parallel phase`s primary outcome measure was
excellent response, based on composite scores on the Swanson, Nolan, and Pelham (SNAP) rating scale. Results: Of
303 preschoolers enrolled, 165 were randomized into the titration trial. Compared with placebo, significant decreases in
ADHD symptoms were found on MPH at 2.5 mg (p G .01), 5 mg (p G .001), and 7.5 mg (p G .001) t.i.d. doses, but not for
1.25 mg (p G .06). The mean optimal MPH total daily dose for the entire group was 14.2 T 8.1 mg/day (0.7 T 0.4 mg/kg/day).
For the preschoolers (n = 114) later randomized into the parallel phase, only 21% on best-dose MPH and 13% on placebo
achieved MTA-defined categorical criterion for remission set for school-age children with ADHD. Conclusions: MPH-IR,
delivered in 2.5-, 5-, and 7.5-mg doses t.i.d., produced significant reductions on ADHD symptom scales in preschoolers
compared to placebo, although effect sizes (0.4Y0.8) were smaller than those cited for school-age children on the same
medication. J. Am. Acad. Child Adolesc. Psychiatry, 2006;45(11):1284Y1293. Key Words: preschool, attention-deficit/
hyperactivity disorder, psychopharmacology, treatment, adverse events.
Accepted October 25, 2005.
Dr. Greenhill and Posner, Mr. Davies (retired), Mr. Cooper, Ms. Skrobala,
and Ms. Chuang are with the New York State Psychiatric Institute, Columbia
University; Dr. Kollins is with Duke University, Durham, NC; Dr. Abikoff is
with the New York University Child Study Center, New York; Dr. Riddle is
with Johns Hopkins University, Baltimore; Dr. Ghuman is with the University
of Arizona, Tucson; Dr. Cunningham is with McMaster University, Hamilton,
Ontario, Canada; Drs. McCracken and McGough are with the University of
California, Los Angeles; Drs. Swanson, T. Wigal, and S. Wigal are with the
University of California, Irvine; and Mr. Cooper is also with the Nathan Kline
Institute, Orangeburg, NY; Dr. Vitiello is with the National Institute of Mental
Health, Bethesda, MD.
This research was supported by a cooperative agreement between the National
Institute of Mental Healt h and the following institutions: University of
California, Irvine (U01 MH60833), Duke University Medical Center (U01
MH60848), NYSPI/Col umbia University (U01 MH60903), New York
University Child Study Center (U01 MH60943), University of California,
Los Angeles (U01 MH60900), and Johns Hopkins University (U01 MH60642).
The opinions and assertions contained in this report are the private view of
the authors and are not to be construed as official or as reflecting the views of the
National Institute of Mental Health, the National Institutes of Health, or the
Department of Health and Human Services.
Correspondence to Dr. Laurence Greenhill, Division of Child and Adolescent
Psychiatry, New York State Psychiatric Institute, 1051 Riverside Drive, New
York, NY 10032; e-mail: larrylgreenhill@cs.com.
0890-8567/06/4511-1284Ó2006 by the American Academy of Child
and Adolescent Psychiatry.
DOI: 10.1097/01.chi.0000235077.32661.61
SPECIAL SECTION
1284
J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:11, NOVEMBER 2006
Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
Attention-deficit/hyperactivity disorder (ADHD) in
preschool children has been treated with the same
psychostimulants that have become the first-line
treatment for the disorder in school-age children. Yet
the safety and efficacy of methylphenidate (MPH) in
preschoolers with ADHD is unproven. This is because
only 10 single-site, small, randomized studies of MPH
involving a total of 240 preschoolers with ADHD have
been conducted (Greenhill, 1998; Kollins et al., 2006).
Results from these 10 preschool treatment studies are
mixed, with 6 reporting good efficacy and safety with
MPH treatment, 2 failing to demonstrate significant
differences between MPH and placebo (Barkley et al.,
1984; Cohen, 1981), and 2 reporting higher rates of
adverse events compared with older children (Firestone
et al., 1998; Handen et al., 1999), especially MPH-
associated social withdrawal.
These early preschool MPH trials were single-site,
short-duration, small-sample studies that used diverse
diagnostic methods. Teacher data were not included, and
there was no follow-up. Study doses were not based on
dose-ranging trials or pharmacokinetic studies in chil-
dren of comparable ages. Such methodological problems
preclude pooling of data for a meta analyses of the safety
and efficacy of MPH in this age range (Greenhill, 1998).
Even so, MPH has become the most commonly used
pharmacological agent for ADHD presenting before
age 6, and its use increased during the 1991Y1995 era
(Zito et al., 2000). This trend has occurred in spite of
the labeling by the U.S. Food and Drug Administration
that indicates that the medication should not be used
in children younger than 6 years of age.
There are no published pharmacokinetic studies of
MPH in preschool children with ADHD by the date of
this publication that could help estimate safe and
effective dose ranges for this vulnerable population. The
need for efficacy, safety, and dose-ranging data led to
the Preschool ADHD Treatment Study (PATS).
The PATS trial was designed as a randomized,
multicenter clinical trial that included a double-blind,
placebo-controlled titration phase followed by a double-
blind, placebo-controlled parallel-design phase. These
two phases were designed to evaluate the efficacy and
safety of MPH for preschoolers with ADHD. The
specific aims of the study, design, rationale for choices
made, and research methods are detailed by Kollins et al.
(2006). This report focuses on the two efficacy phases of
the PATS: the 5-week titration phase that determined
the effective dose range of MPH and the double-blind,
parallel-group controlled efficacy trial that compared
best dose MPH to placebo.
METHOD
Subjects
Participants were recruited without regard to sex, race, or
ethnicity at six academic sites (Columbia University, Duke
University, Johns Hopkins University, New York University,
University of California, Irvine, and University of California, Los
Angeles) from clinics, paid and public service advertisements in
newspapers and on the radio, primary care physicians, nursery
schools, day care centers, and kindergartens. Telephone screening of
1,915 referrals determined that 1,272 families (66%) were eligible;
of those, 553 (43% of eligible) signed consent, and 303 (24% of
eligible) met inclusion criteria during the period between February
2001 and April 2003.
Details on inclusion and exclusion criteria are presented by
Kollins et al. in this issue. Briefly, to be included, the children had to
meet the following criteria: stimulant naBve, children of both sexes,
ages 3 to 5.5 years with a DSM-IV consensus diagnosis of ADHD
(American Psychiatric Association, 1994) based on the Diagnostic
Interview Schedule for Children IV-Parent Version (Schaffer et al.,
1996) and semistructured interview; combined or predominantly
hyperactive subtype; an impairment scale score G55 on the
Children`s Global Assessment Scale (Shaffer et al., 1983);
hyperactive-impulsive subscale T score of 65 (1.5 SDs above the
age- and sex-adjusted means) on both the Revised Conners Parent
(Conners et al., 1998a) and Teacher (Conners et al., 1998b) Rating
Scales; Full Scale IQ equivalent of 970 on the Differential Ability
Scales (Elliott, 1990); participation in a preschool, day care group
setting, or other school program at least 2 half-days per week with at
least eight same-age peers; and the same primary caretaker for at
least 6 months before screening.
Children were excluded if there was current evidence of
adjustment disorder, pervasive developmental disorders, psychosis,
significant suicidality, or other psychiatric disorder in addition to
ADHD that required treatment with additional medication; current
stimulant or cocaine abuse in a relative living in the home; a
confounding medical condition; inability of the parent to under-
stand or follow study instructions, or history of bipolar disorder in
both biological parents.
Diagnostic and Assessment Baseline Measures
Baseline diagnoses of ADHD and associated comorbidities were
established using the Diagnostic Interview Schedule for Children
IV-Parent Version and a semistructured clinical interview con-
ducted by a child psychiatrist or psychologist, as described by
Kollins et al. in this issue. Data from parent and teacher rating
scales, Autism Screener, Differential Ability Scales score, Diagnostic
Interview Schedule for Children IV-Parent Version, and clinical
interview were summarized in an anonymized narrative and
subsequently circulated for review in a weekly consensus diagnosis
teleconference involving all of the clinicians from each site.
Unanimous agreement was required for diagnosis.
After a preliminary telephone review of inclusion and exclusion
criteria, parents were invited to visit the clinic to obtain consent. All
parents/guardians viewed a slide show presentation of the study and
METHYLPHENIDATE EFFICACY IN PATS
1285J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:11, NOVEMBER 2006
Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
then were asked to read and sign written informed consent forms.
They also were reconsented before entering each of the other seven
phases of the 70-week study. The institutional review board at each
of the six sites approved the study protocol and all consent
procedures. Central monitoring was performed by the Data and
Safety Monitoring Board of the National Institute of Mental Health.
Once consented, families flowed through study phases as
summarized in the CONSORT chart (Fig. 1). Of the 303 families
eligible, 165 were randomized into the crossover-titration trial. As
shown in Table 1, the randomized group met the main study criteria
for preschool age, severe ADHD, had comorbidities, and a normal
IQ, with a mean age (SD) of 4.4 (0.68), and a mean (SD)
Differential Ability Scales General Ability Score of 97 (16). They
were predominantly male (73%). Symptom scores were severe, with
a mean (SD) parent CPRS ADHD symptom rating of 22.27 (3.5),
at a T score of 77, and a Child Global Assessment Scale (Shaffer
et al., 1983) score of 46.79 (4.3). Oppositional defiant disorder
(52%) was the most common comorbidity, followed by commu-
nication disorder (22%), anxiety disorder (including specific
phobia, 16%), and elimination disorder (8%).
Study Design
Those preschoolers who were eligible to enter the controlled
medication phases were those who continued to meet ADHD
severity criteria after 10 weeks of parent training. They entered a
sequential, open-label, safety lead-in phase in which the daily intake
of MPH was increased over 1 week through the dose range from
1.25 mg b.i.d. to 7.5 mg t.i.d.
Generic MPH was purchased by grant funds for the double-blind
phases of the study and was milled by a U.S. Food and Drug
Administration manufacturing pharmacy into similar-appearing
capsules of different dose strengths. Before receiving the study drug,
the eligible preschoolers were randomly assigned to one of a series of
dose sequences that included weekly doses of 1.25, 2.5, 5.0, or
7.5 mg MPH-IR or placebo on a t.i.d. schedule. Randomization was
done centrally at the coordinating site using a computerized
stratified randomization, 1:1:1:1 starting dose allocation ratio, using
a randomized, balanced, crossover protocol designed to avoid order
effects. A second randomization to active MPH or to placebo was
performed before entering the parallel-design, placebo-controlled
phase. Except in emergencies, clinicians remained blind to the dose
sequences. Blinding was maintained for the primary dependent
measures until after the best dose was determined or as needed.
Children who had tolerated all open MPH doses in the lead-in
phase then entered the 5-week, double-blind, crossover-titration on
algorithms used to find best dose in the MTA study (Greenhill et al.,
1996). Subjects were randomized to one of five sequences of four
different MPH doses (1.25, 2.5, 5, 7.5 mg) and placebo
administered t.i.d. in identical capsules for 1 week each. Parent
and teacher dose-response rating scale graphs were prepared and
blindly evaluated by two study clinicians who determined the
child`s best dose by identifying the week with the optimally
minimized ADHD symptoms and medication side effects.
The primary outcome measure for the titration phase chosen a
priori was a composite formed by standardizing and then
combining parent and teacher Conners, Loney, and Milich
(CLAM) and Swanson, Kotkin, Atkins, M-Flynn, and Pelham
(SKAMP) rating scales (Swanson et al., 1998) to reflect overall
medication response for each dose across settings. This data
reduction approach was used previously to measure effects in the
MTA titration trial (Greenhill et al., 2001) and at the end of the 14-
month MTA study (MTA Cooperative Group, 1999). The primary
efficacy measure for the parallel phase was borrowed from the
Bexcellent responder^ criterion using a combination of parent and
teacher Swanson, Nolan, and Pelham (SNAP) ratings scales
(Swanson et al., 2001).
Afterward, following a 1-day washout, subjects were randomly
assigned to their best dose or to placebo for a 4 week, double-blind,
placebo-controlled, parallel-design efficacy trial. Parent and teacher
SNAP questionnaires (Swanson, 1992) were collected to monitor
ADHD symptoms and determine responder status.
Medication Monitoring
MPH administration followed a manual-based procedure to
maintain fidelity to the protocol across the six performance sites.
Families had one pharmacotherapist throughout the study. In
addition to assessing the preschooler`s clinical status, response to
medication, and adverse events during 20- to 40-minute medication
visits, pharmacotherapists followed the general guidelines for best-
practice parameters for the MPH treatment of ADHD, collecting
blood pressures and pulses twice at each visit, collecting spontaneous
responses of parents to a nonsystematic general inquiry about the
child`s health, and a parent-scored drug-specific checklist of adverse
events first developed in the MTA study.
Data Analyses
The Nathan Kline Institute served as the data management
center. Data entry and verification, data transfer, confidentiality and
security, backup and storage, and initial data analyses were
conducted at this site. All analyses were run using the intent-to-
treat principle (i.e., each observation obtained for the child was used
in the analysis including those from children who entered each of
the two phases under consideration and did not complete the
phase). The statistical analytic plan and power analysis were
prepared during the planning phase of the study. Specific scientific
hypotheses with the corresponding statistical hypotheses were
included in the analytic plan. The null hypothesis tested was that
there were no significant differences in outcome measures between
the randomly assigned treatment groups. The primary outcome
measure for the crossover phase was the combined parent-teacher
scalar report using the CLAM/SKAMP; the primary outcome
measure for the parallel group phase of the study was excellent
responder status, a binary response variable, defined using the
SNAP. A mixed-effects linear random regression model was used to
estimate parameters and test hypotheses for the crossover phase.
Parameters were estimated and tested using SAS Proc Mixed (SAS
Institute, Cary, NC). A fixed effect for site was included; random
effects were the slope of the regression of the CLAM/SKAMP on
dose and child-specific random error. The average slope of the
regression of the CLAM/SKAMP on the dose of MPH was tested
against the value 0 to test the null hypothesis of no relationship
between dose and clinical improvement. The difference in the rates
of excellent response between children on placebo or best dose
during the 4-week parallel group phase was tested using a logistic
regression model. The model was tested using SAS Proc Logistic
with fixed effects included for site. For hypotheses regarding the
primary outcomes, all power analyses assumed that statistical
significance (type I error rate) is set at 5%; all tests are two-tailed; by
convention, adequate power is achieved at 80% or better.
Simplifying assumptions were made for the calculation of power
for analysis of the crossover-titration trial, including the assumption
GREENHILL ET AL.
1286 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:11, NOVEMBER 2006
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Fig. 1 PATS CONSORT chart depicting numbers of patients participating at each phase.
METHYLPHENIDATE EFFICACY IN PATS
1287J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:11, NOVEMBER 2006
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TABLE 1
Characteristics of the Sample
Variable
Passed Caseness
(n = 303)
Enrolled in Crossover
Titration (n = 165)
Enrolled in Parallel Trial
(n = 114)
Subject Variables
Age,
a
yr, mean (SD) 4.41 (0.70) 4.74 (0.69) 4.76 (0.70)
Male, no. (%) 229 (76) 122 (74) 85 (75)
Ethnicity, no. (%)
White 190 (63) 104 (63) 74 (65)
Black or African American 58 (19) 29 (18) 19 (17)
Hispanic or Latino 47 (16) 29 (18) 19 (17)
Asian 6 (2) 2 (1) 1 (0.9)
American Indian or Alaskan Native 2 (0.7) 1 (0.6) 1 (0.9)
Group educational activity, no. (%)
Public nursery 11 (4) 4 (2) 2 (2)
Public kindergarten 34 (11) 19 (12) 15 (13)
Private/parochial nursery 67 (22) 35 (21) 29 (25)
Private/parochial kindergarten 10 (3) 3 (2) 0 (0)
Special school for preschoolers with learning problems 27 (9) 15 (9) 9 (8)
Day care 48 (16) 23 (14) 12 (11)
Play group 1 (0.3) 0 (0) 0 (0)
Prenursery 6 (2) 3 (2) 1 (0.9)
Prekindergarten 91 (30) 60 (36) 45 (39)
Not in school, play group, or day care 8 (3) 3 (2) 1 (0.9)
Conners Teacher Rating Scale, mean (SD)
Inattention 16.78 (5.53) 17.85 (5.40) 17.6 (5.15)
Hyperactivity 21.71 (3.65) 22.27 (3.48) 22.29 (3.49)
Total 38.52 (8.03) 40.16 (7.67) 39.95 (7.49)
Conners Parent Rating Scale, mean (SD)
Inattention 15.20 (5.87) 15.39 (5.84) 14.84 (5.81)
Hyperactivity 20.17 (4.63) 20.43 (4.62) 20.55 (4.69)
Total 35.43 (9.08) 35.91 (8.92) 35.48 (8.85)
Differential Ability Scales IQ, mean (SD) 99.06 (18.30) 97.93 (17.67) 97.45 (16.11)
CGAS Impairment Scale, mean (SD) 47.33 (4.07) 46.79 (4.26) 47.35 (4.20)
ADHD subtype, no. (%)
Hyperactive-impulsive 75 (25) 39 (24) 29 (25)
Combined 228 (75) 126 (76) 85 (75)
Comorbidity (clinical evaluation), no. (%)
Oppositional-defiant disorder 158 (52) 90 (55) 60 (53)
Communication disorder 66 (22) 33 (20) 25 (22)
Elimination disorder (i.e., encopresis, enuresis) 24 (8) 14 (8) 8 (7)
Specific phobia (i.e., animals, needles, social phobia) 23 (8) 11 (7) 8 (7)
Anxiety disorder (i.e., separation, generalized,
posttraumatic stress disorder)
23 (8) 17 (10) 12 (11)
Developmental coordination disorder 10 (3) 7 (4) 6 (5)
Conduct disorder 7 (2) 5 (3) 3 (3)
Pica 6 (2) 3 (2) 1 (0.9)
Adjustment disorder 4 (1) 1 (0.6) 1 (0.9)
Reactive attachment disorder 3 (1) 3 (2) 2 (2)
Obsessive-compulsive disorder 2 (0.7) 1 (0.6) 1 (0.9)
Sleepwalking disorder 1 (0.3) 1 (0.6) 1 (0.9)
Parent/Family Variables
High school graduate, no. (%)
Mother 288/297 (97) 154/161 (96) 107/11 (96)
Father 242/250 (97) 130/133 (98) 91/93 (98)
GREENHILL ET AL.
1288 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:11, NOVEMBER 2006
Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
that the within-individual correlation among the repeated measures,
week 1 to week 5, is constant (r = 0.60).
To evaluate the clinical significance of the impact of treatment on
outcome, effect sizes (Cohen`s d, the standardized difference of the
means) are calculated as d = MC/SD pooled, where MC is the
difference between means in the active and placebo conditions, and
SD pooled is the pooled SD for the active and placebo conditions
(Rosenthal et al., 2000). The sample size was set to detect an effect
size of at least 0.45. We anticipated that the parent`s report of
outcome would show smaller differences than the teacher`s report.
For the crossover phase, the smallest slope detectable with
adequate power is 0.020 standardized units on the CLAM/SKAMP
per milligram of MPH. Over a 22.5-mg range from placebo to the
maximum dose of 22.5 mg, this slope translates to an effect size of
0.45 (0.020 slope * 22.5 mg) for comparison of placebo and the
highest dose. For the double-blind parallel phase, children were
randomized equally to best dose of MPH or placebo. Before the
study, we planned to recruit 120 children to be randomized, so that
differences in response rates in excess of 28% (e.g., 36% response for
children on placebo and 64% response for children on MPH) could
be detected with adequate power (83%). We anticipated that the
difference would be substantially larger than 28%.
RESULTS
Primary Outcomes
Crossover Phase. Mean (SD) composite SKAMP/
CLAM scores are presented by dose level for both the
crossover-titration and parallel phases in Table 2.
During the crossover-titration, random-coefficient
regression analyses of composite SKAMP/CLAM scores
identified a statistically significant linear trend with
dose (F
1,156
= 51.45, p G .0001). In addition, the
2.5-mg (F
1,148
= 4.26, p G .001), 5-mg (F
1,150
= 4.96,
p G .001), and 7.5-mg (F
1,126
= 6.36, p G .001) doses
given t.i.d. also were associated with significantly
reduced ADHD symptom scores compared to placebo
on the primary outcome measure. The 1.25-mg t.i.d.
dose differed from placebo at the trend level only
(F
1,146
= 1.8, p G .06).
By the end of titration, blind ratings classified 7 (4%)
preschoolers as nonresponders (4%); 14 (8%) as placebo
responders; 24 (15%) as best responding to 1.25 mg t.i.d.
(0.2 mg/kg/day); 26 (16%) as best responding to 2.5 mg
t.i.d. (0.4 mg/kg/day); 30 (18%) as best responding to
5 mg t.i.d. (0.8 mg/kg/day); 36 (22%) as best responding
to 7.5 mg t.i.d. (1.2 mg/kg/day); and 7 (4%) as best
responding to 10 mg t.i.d. (1.3 mg/kg/day). The mean of
optimal MPH total daily doses was 14.2 T 8.1 mg (0.7 T
0.4 mg/kg/day). There was no significant correlation
between age and MPH absolute dose or MPH dose by
weight.
The clinical significance of MPH treatment on
outcome during the titration trial was evaluated by
calculating effect sizes relative to placebo for the scalar
composite SKAMP/CLAM ratings. Effect sizes for
MPH during titration with doses of 1.25, 2.5, 5, and
7.5 mg t.i.d. were 0.16, 0.34, 0.43, and 0.72,
respectively. Effect sizes for MPH doses during the
parallel phase (1.25, 2.5, 5, and 7.5 mg versus placebo)
were 0.22, 0.48, 0.52, and 0.87, respectively.
Separate examination of the composite SKAMP/
CLAM ratings by informants indicated that teacher
TABLE 1
Continued
Variable
Passed Caseness
(n = 303)
Enrolled in Crossover
Titration (n = 165)
Enrolled in Parallel Trial
(n = 114)
Employed, no. (%)
Mother 213/295 (72) 120/160 (75) 80/110 (73)
Father 214/287 (75) 112/158 (71) 80/109 (73)
Welfare, no. (%) 22/275 (8) 13/148 (9) 7/98 (7)
Married, no. (%) 184/297 (62) 98/163 (60) 68/112 (61)
Hollingshead socioeconomic status, mean (SD) 47.20 (9.56) 47.01 (9.58) 47.61 (9.45)
Family composition, no. (%)
2 parents 246 (76) 130 (79) 91 (80)
1 parent 57 (18) 35 (21) 22 (19)
Note: Employed refers to the proportion of the sample whose parents held full- or part-time jobs, were unemployed and looking for work, or
were full- or part-time students; married refers to those with intact two-parent families (married or common law). CGAS = Clinical Global
Assessment Scale.
a
Age at screening for the passed caseness group and age at baseline at the beginning of the medication trial for the enrolled in crossover
titration and enrolled in parallel trial groups.
METHYLPHENIDATE EFFICACY IN PATS
1289J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:11, NOVEMBER 2006
Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
ratings (F
1,139
= 39.64, p G .0001) show a greater
sensitivity to the medication effects than parent ratings
(F
1,156
= 35.83, p G .0001). Teacher ratings also yielded
a significant dose effect when children were taking
1.25 mg (F
1,104
= 23.38, p G .0192), but parent ratings
did not, as shown in Figure 2.
Parallel Phase. Only 13/61 (22%) of subjects
randomized to best-dose MPH and 7/53 (13%) of
those randomized to placebo met criteria for excellent
response on the SNAP composite score, a difference that
did not reach statistical significance ( p G .3). This
outcome may have been related to attrition, with 36
(32%) patients leaving the parallel phase before comple-
tion (33 had behavioral deterioration, 2 declined study
participation, and 1 had medication-related side effects).
This included 24 of 53 (45%) randomized to placebo,
and 9 of 61 (15%) randomized to best-dose MPH.
In an additional post hoc, intent-to-treat, last
observation carried forward analysis, we used the
primary efficacy composite SNAP rating of the parallel
phase as a continuous measure to supplement the
categorical approach cited above. This revealed sig-
nificantly (p G .02) lower mean symptom scores for
those randomized to MPH (1.49, n = 61) versus
placebo (1.79, n = 52). The significant advantage for
best dose was maintained for completers` composite
scores between those assigned to MPH (1.39, n = 51)
versus placebo (1.76, n = 26, p G .049). Attrition from
TABLE 2
Outcome Scores in the Crossover Titration and Parallel Phases
Crossover Phase Summary Scores While Receiving Placebo, Mid-low, Mid-high, and High Doses of MPH
Informant/Scale
Placebo
(n = 165)
Low
MPH Dose
(1.25/1.25/1.25 mg)
(n = 165)
Mid-Low
MPH Dose
(2.5/2.5/2.5 mg)
(n = 165)
Mid-High
MPH Dose
(5/5/5 mg)
(n = 165)
High
MPH Dose
(7.5/7.5/7.5 mg)
(n = 142)
Effect
Size
on
Best
Dose F
dose
p
Parent
CLAM A/D 1.33 (0.86) 1.30 (0.86) 1.25 (0.82) 1.14 (0.84) 1.04 (0.78) 0.71 13.63 .0003
CLAM I/O 1.47 (0.70) 1.40 (0.73) 1.28 (0.73) 1.15 (0.76) 1.09 (0.69) 1.00 37.97 G.0001
CLAM Mixed 1.35 (0.69) 1.28 (0.70) 1.18 (0.67) 1.17 (0.75) 1.02 (0.63) 0.89 18.39 G.0001
SKAMP Attention 0.94 (0.63) 0.89 (0.58) 0.74 (0.56) 0.73 (0.60) 0.64 (0.50) 0.74 16.16 .0001
SKAMP Deportment 1.37 (0.68) 1.28 (0.74) 1.10 (0.68) 1.04 (0.71) 0.90 (0.63) 1.12 48.90 G.0001
Teacher
CLAM A/D 1.51 (0.79) 0.99 (0.89) 0.94 (0.84) 0.89 (0.92) 0.72 (0.80) 0.65 17.81 G.0001
CLAM I/O 1.31 (0.79) 1.34 (0.82) 1.25 (0.84) 1.13 (0.83) 1.00 (0.74) 0.95 41.90 G.0001
CLAM Mixed 1.08 (0.88) 1.20 (0.81) 1.13 (0.81) 1.02 (0.78) 0.99 (0.69) 0.75 24.27 G.0001
SKAMP Attention 0.95 (0.74) 0.81 (0.73) 0.79 (0.76) 0.70 (0.70) 0.63 (0.56) 0.68 24.83 G.0001
SKAMP Deportment 1.30 (0.78) 1.21 (0.86) 1.09 (0.80) 0.98 (0.81) 0.89 (0.69) 0.85 39.22 G.0001
Parent Composite 1.30 (0.60) 1.23 (0.62) 1.12 (0.60) 1.06 (0.65) 0.94 (0.55) 1.05 36.48 G.0001
Teacher Composite 1.23 (0.67) 1.12 (0.72) 1.04 (0.72) 0.95 (0.72) 0.85 (0.58) 0.90 40.05 G.0001
Parent-Teacher
Composite
1.28 (0.52) 1.19 (0.59) 1.09 (0.54) 1.03 (0.61) 0.91 (0.48) 1.20 51.61 G.0001
End of Parallel Phase Summary Scores
Scale Placebo (n = 53) Best Dose (n = 61) Effect Size Test Statistic p
Excellent Responder, N (%) 13 (21.7) 7 (13.2) V #
2
= 1.18 .2765
Parent-Teacher SNAP
Composite, mean (SD)
17.79 (0.61) 1.46 (0.57) 0.55 F
ran
= 6.63 .0114
Note: Values in parentheses represent SD. All F
dose
values are significant. The error degrees of freedom ranged from 131 to 156. MPH =
methylphenidate; CLAM = Conners, Loney, and Milich scale; A/D = Aggressive/Defiant subscale; I/O = Inattentive/Overactive subscale;
Mixed = sum of I/O + A/D; SKAMP = Swanson, Kotkin, Atkins, M-Flynn, and Pelham scale; Parent or Teacher composites = statistical
summary of all parent or teacher ratings; CLAM and SKAMP Composites = statistical summary of all parent or teacher ratings. CLAM and
SKAMP scores shown are standard CLAM and SKAMP scores used to generate the composite scores. Effect size is calculated as the difference
between the rating on placebo and the rating on the child`s best dose, divided by the standard deviation of the rating on placebo. Excellent
response was defined by a cutoff of e1.0 on the parent-teacher SNAP composite score at the end of treatment.
GREENHILL ET AL.
1290 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:11, NOVEMBER 2006
Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
the parallel phase was significantly correlated with
elevated composite SNAP scores (p G .009), suggesting
that parents withdrew their children from the study
because of a lack of medication response.
Effect sizes for active MPH doses during the parallel
phase were 0.22 for 1.25 mg t.i.d., 0.48 for 2.5 mg t.i.d.,
0.52 for 5 mg t.i.d., and 0.87 for 7.5 mg t.i.d..
Safety and Tolerability
Ninety-two percent of preschoolers tolerated MPH
doses in the open safety lead-in phase (see Wigal et al.,
2006). Fourteen children left during the lead-in,
crossover-titration, and parallel phases because of
adverse events, with 9 of 14 leaving because of
emotionality or irritability. Five side effects occurred
more frequently on the high MPH doses than on
placebo or low MPH doses: appetite loss, trouble
sleeping, stomachaches, social withdrawal, and lethargy
(dull/tired/listless). During the crossover-titration
phase, high blood pressure was reported on eight
occasions and tachycardia was reported on at least one
measurement.
Although 36 participants dropped out of the parallel
phase, only one discontinued because of a drug-related
adverse event. Weight velocity decreases were evident
after the preschool children had completed both the
titration and parallel phases and are described in the
report by Swanson et al. (2006).
There were eight serious adverse events in the entire
study, but only one, a possible seizure, was thought to
be related to medication. There were no episodes of
mania, hypomania, depression, or suicidality.
DISCUSSION
The PATS trial determined the optimal MPH doses
for 147 children between 3 and 5.5 years with
symptoms of severe ADHD, the efficacy of MPH,
as well as their safety profile on MPH. The multisite
team enrolled 303 preschoolers with severe DSM-IV
ADHD over 3 years. One hundred sixty-five of these
preschoolers with ADHD entered the multisite,
randomized MPH clinical trial. The behavioral outcome
measure used in this study shows that preschoolers with
ADHD do benefit from treatment with MPH.
Preschoolers with severe ADHD responded to 7.5 to
30 mg of MPH (total daily dose). Treatment was
initiated at low doses, although higher doses were
required for maintenance. The children`s mean optimal
dose at the end of titration was 14.22 T 8.1 mg/day
(0.7 T 0.4 mg/kg/day). Randomized into a parallel
design comparing the optimized MPH dose in the form
of active drug or placebo, more children taking the
active drug showed a decrease of ADHD symptoms
than did those on placebo.
Despite the statistically significant and clinically
meaningful improvements in ADHD symptoms with
MPH, effect sizes for this medication in PATS are
smaller than those reported in the MTA study of
school-age children. Factor scores derived from CLAM
ratings showed an MPH effect size of 0.35 for parents
and 0.43 for teachers. The MTA reported effect sizes of
0.52 and 0.75, respectively, on the same measures
(Greenhill et al., 2001). For the CLAM attention (IO)
subscale, the PATS best-dose effect sizes for parents was
0.54 and for teachers was 0.66, whereas in the MTA
study, they were 0.63 and 1.31, respectively. However,
rating attention in preschoolers is more difficult than in
school-age children because the task set in most
preschool educational settings emphasizes socialization,
not attending to cognitive tasks.
Does the lower effect size for MPH treatment in
PATS suggest a different response in preschoolers?
Matching responses across the age range between these
two studies is difficult. The PATS trial was a more
complex study than the MTA study, with interlocking,
interdependent phases (eight versus two), multiple
reconsenting during the trial, an option to Bskip out of^
double-blind phases and go directly to maintenance,
and increased attrition from the controlled phases. This
attrition may have lowered the estimate of MPH
Fig. 2 Methylphenidate dose-response curve in preschool children with
attention-deficit/hyperactivity disorder (N = 165). CLAM = Conners,
Loney, and Milich scale; SKAMP = Swanson, Kotkin, Atkins, M-Flynn, and
Pelham scale.
METHYLPHENIDATE EFFICACY IN PATS
1291J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:11, NOVEMBER 2006
Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
efficacy in PATS. Another interpretation is that
preschoolers benefit less from MPH than do their
school-age counterparts. More research will be neces-
sary to settle this question.
The MTA study also differed from PATS in the
MPH dose range tested. The PATS protocol was
restricted by the Data and Safety Monitoring Board to
total daily doses of 3.75 to 30 mg, narrower than the
15- to 50-mg range used in the MTA study. This could
have artificially truncated the upper range of optimal
MPH treatment daily doses required to optimally treat
some of the preschoolers in our study.
Limitations
PATS had to overcome several limitations. First, the
study design did not support retention. Negative
expectancy of deterioration on placebo, repeated
reconsent procedures, and the always available option
to skip directly into open maintenance undermined
parental willingness to stick with the research protocol.
Parents in this study also may have been more nervous
about medication side effects. They may have been
more likely to withdraw the child for adverse events that
would have been tolerated in a school-age child. It is
difficult to determine whether PATS` attrition rate was
the result of more MPH side effects, more wary parents,
or a combination of the two.
Another problem arose in the controlled parallel
phase with the choice of an Ball-or-nothing^ categorical
outcome measure criterion for remission we used to
define our excellent responders. Although more chil-
dren on active drug met this strict responder criterion
than did those assigned to placebo, the difference did
not reach significance. Failure to meet this remission
criterion does not mean that MPH is ineffective in
preschoolers with ADHD. Rather, the failure to remit
may be caused by the severity of the ADHD symptoms
in this study. As a group, they were more severely
impaired than the school-age children recruited for the
MTA study. Furthermore, it is not known whether
remission of ADHD symptoms on the SNAP means
that the preschool children treated have any less
impairment. This caution is supported by our post
hoc analyses of SNAP scores at the end of the parallel
phase, which indicated improvement on MPH com-
pared with placebo.
Third, the dose-optimizing titration trial used a
crossover design could have been confounded by
carryover effects. We sought to reduce this problem
by collecting parent and teacher ratings after 7 days on
each treatment condition. This should have reduced the
impact of the any carryover effects from the previous
week`s dose.
Fourth, the PATS dose optimization algorithm was
complex and thus is not readily transportable into
clinical practice. PATS employed MPH-IR, not the
once-daily, long-duration, controlled-release formula-
tions ubiquitous in clinical practice. Long-duration
preparations may be more palatable to preschoolers
than MPH-IR because these new medications can be
sprinkled on food.
Clinical Implications
PATS data suggest that preschoolers with ADHD
need to start with low MPH doses. Treatment may best
begin using MPH-IR at 2.5 mg b.i.d. and then be
increased to 7.5 mg t.i.d. during the course of 1 week.
The mean optimal total daily MPH dose for
preschoolers was 14.2 T 8.1 mg/day, lower than the
mean found in school-age children in the MTA study
(Greenhill et al., 2001). Replication of this finding with
a study design that includes higher MPH doses is
needed because it goes against the commonly held
notion that smaller children actually require higher
doses than can be predicted by their weight.
PATS is the first controlled multisite trial to address
the question of the safety and efficacy of MPH in
preschool children with ADHD. Preschoolers with
ADHD in PATS tolerated MPH, although higher rates
of emotional lability on drug were noted. Treatment
effect sizes were smaller than those reported in school-
age children (Greenhill et al., 2001; MTA Study
Cooperative Group, 1999). Nonetheless, this is one of
the first controlled studies that shows an advantage of
low MPH doses (1.25 mg t.i.d.) over placebo in the
classroom setting. Additional reports from PATS in this
issue address patterns of MPH-related adverse events in
preschoolers (T. Wigal et al.), the long-term impact of
MPH on preschooler`s growth (Swanson et al.), and the
pharmacokinetics of MPH in preschool children
(McGough et al.).
The authors acknowledge the following members of the PATS
Group: University of California, Irvine: Annamarie Stehli, M.S.,
Marc Lerner, M.D., Ken Steinhoff, M.D., Robin Epstein, M.D.,
Steve Simpson, M.A., Ron Kotkin, Ed.D., Audrey Kapelinsky,
L.C.S.W., Joey Trampush, Ben Thorp; Duke University Medical
GREENHILL ET AL.
1292 J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:11, NOVEMBER 2006
Copyright @ 2006 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.
Disclosure: The authors` relationships with for-profit enterprises for the
period 2000Y2006 are as follows: Dr. Kollins: Cephalon, Pfizer,
Psychogenics, Shire, Eli Lilly, New River Pharmaceuticals, McNeil;
Dr. Greenhill: Eli Lilly, Shire Pharmaceuticals, Cephalon, McNeil,
Celltech, Novartis, Sanofi Aventis, Otsuka, Janssen; Dr. Swanson:
Cephalon, Eli Lilly, Janssen, McNeil, Novartis, Shire, UCB; Dr. S.
Wigal: McNeil, Cephalon, Shire, Eli Lilly; Dr. Abikoff: McNeil, Shire,
Eli Lilly, Pfizer, Celltech, Novartis; Dr. McCracken: Eli Lilly, Wyeth,
Shir e, Pfizer, McNeil, Novartis, Bristol-Myer s Squibb, Janss en;
Dr. Riddle: Pfizer; Dr. McGough: Eli Lilly, McNeil, Novartis,
Shire, Pfizer, New River Pharmaceuticals; Dr. Posner: GlaxoSmith-
Kline, Forest Laboratories, Eisai Inc., AstraZeneca Pharmaceuticals,
Johnson & Johnson, Abbott Laboratories, Wyeth Research, Organon
USA, Bristol-Myers Squibb, Sanofi-Aventis, Cepalon, Novartis, Shire
Pharmaceuticals, and UCB Pharma; Dr. T. Wigal: Cephalon, Eli
Lilly, McNeil, Shire; Mr. Davies: Pfizer, Amgen, Johnson & Johnson,
Wyeth, Merck, GlaxoSmithKline, Bard. Dr. Cunningham receives
compensation for talks and workshops regarding the COPE program.
The other authors have no financial relationships to disclose.
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METHYLPHENIDATE EFFICACY IN PATS
1293J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 45:11, NOVEMBER 2006
    • "While some parents perceive psychosocial interventions as more acceptable and less stigmatizing than pharmacological treatments for ADHD (dosReis et al. 2003; Dreyer et al. 2010), it is possible that financial concerns (Bussing et al. 2003), lack of parent time (Krain et al. 2005 ), regional scarcities of qualified therapists, or other system factors (Epstein et al. 2014) such as an absence of referral or long wait times contribute to the observed treatment patterns. Because of uncertainty over the efficacy, tolerability, and longterm safety of stimulants in preschool children (Greenhill et al. 2006; Wigal et al. 2006 ) and evidence supporting the effectiveness of behavioral interventions (Barke et al. 2001; Webster-Stratton et al. 2011 ), several practice guidelines recommend parent-or teacher-administered behavior therapy as the first-line treatment for ADHD in preschool children (Gleason et al. 2007; National Collaborating Center 2009; Subcommittee ADHD 2011). Yet only around 1 in 10 stimulant-treated preschoolers received any psychosocial services. "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: To describe national stimulant treatment patterns among young people focusing on patient age and prescribing specialty. Methods: Stimulant prescriptions to patients aged 3-24 were analyzed from the 2008 IMS LifeLink LRx Longitudinal Prescription database (n = 3,147,352), which includes 60% of all U.S. retail pharmacies. A subset of young people from 2009 with service claims (n = 197,654) were also analyzed. Denominators were adjusted to generalize estimates to the U.S. Population: Population percentages filling ≥1 stimulant prescription during the study year by sex and age group (younger children, 3-5 years; older children, 6-12 years; adolescents, 13-18 years; and young adults, 19-24 years) were determined. Percentages prescribed stimulants by psychiatrists, child and adolescent psychiatrists, pediatricians, and other physicians were also determined along with percentages that were treated for a long or short duration; coprescribed other psychotropic medications; used psychosocial services; and received clinical psychiatric diagnoses. Results: Population percentages with any stimulant use varied across younger children (0.4%), older children (4.5%), adolescents (4.0%), and young adults (1.7%). Among children and adolescents, males were over twice as likely as females to receive stimulants. Percentages of stimulant-treated young people with ≥1 stimulant prescription from a child and adolescent psychiatrist varied from younger children (19.1%), older children (17.1%), and adolescents (18.2%) to young adults (10.1%), and these percentages increased among those who were also prescribed other psychotropic medications: young children (31.0%), older children (37.9%), adolescents (35.1%), and young adults (15.8%). Antipsychotics were the most commonly coprescribed class to stimulant-treated younger (15.0%) and older children (11.8%), while antidepressants were most commonly coprescribed to adolescents (17.5%) and young adults (23.9%). Conclusions: Stimulant treatment peaks during middle childhood, especially for boys. For young people treated with stimulants, including younger children, low rates of treatment by child and adolescent psychiatrists highlight difficulties with access to specialty mental health services.
    Full-text · Article · Mar 2016
    • "It is a common condition, with a community sample in the United Kingdom showing a prevalence of 2.2% in children aged 8–19 [2]. Among children with ADHD, about 38–52% also meet diagnostic thresholds for ODD [2, 17, 18], and of the remainder many will have symptoms of ODD but not of sufficient severity or consistency to meet the diagnostic criteria. People with ODD typically overreact with anger in response to minor frustrations [9]. "
    Full-text · Chapter · Jan 2015 · Journal of Child Psychology and Psychiatry
    • "Compared to both control groups, NFPP yielded clinically significant reductions in parent-reported ADHD symptoms and conduct problems (oppositional, defiant behaviors), increases in observed on-task behavior, and improved maternal sense of well-being. The improvements in ADHD symptoms were in the range found with stimulants in preschoolers (Greenhill et al., 2006) and persisted to 15 weeks follow-up. A second controlled study found no evidence of efficacy when NFPP was delivered by nonspecialist primary care nurses (Sonuga-Barke, Thompson, Daley, & Laver-Bradbury, 2004). "
    [Show abstract] [Hide abstract] ABSTRACT: Background The ‘New Forest Parenting Package’ (NFPP), an 8-week home-based intervention for parents of preschoolers with attention-deficit/hyperactivity disorder (ADHD), fosters constructive parenting to target ADHD-related dysfunctions in attention and impulse control. Although NFPP has improved parent and laboratory measures of ADHD in community samples of children with ADHD-like problems, its efficacy in a clinical sample, and relative to an active treatment comparator, is unknown. The aims are to evaluate the short- and long-term efficacy and generalization effects of NFPP compared to an established clinic-based parenting intervention for treating noncompliant behavior [‘Helping the Noncompliant Child’ (HNC)] in young children with ADHD.MethodsA randomized controlled trial with three parallel arms was the design for this study. A total of 164 3-4-year-olds, 73.8% male, meeting DSM-IV ADHD diagnostic criteria were randomized to NFPP (N = 67), HNC (N = 63), or wait-list control (WL, N = 34). All participants were assessed at post-treatment. NFPP and HNC participants were assessed at follow-up in the next school year. Primary outcomes were ADHD ratings by teachers blind to and uninvolved in treatment, and by parents. Secondary ADHD outcomes included clinician assessments, and laboratory measures of on-task behavior and delay of gratification. Other outcomes included parent and teacher ratings of oppositional behavior, and parenting measures. (Trial name: Home-Based Parent Training in ADHD Preschoolers; Registry: ClinicalTrials.gov Identifier: NCT01320098; URL: http://www/clinicaltrials.gov/ct2/show/NCT01320098).ResultsIn both treatment groups, children's ADHD and ODD behaviors, as well as aspects of parenting, were rated improved by parents at the end of treatment compared to controls. Most of these gains in the children's behavior and in some parenting practices were sustained at follow-up. However, these parent-reported improvements were not corroborated by teacher ratings or objective observations. NFPP was not significantly better, and on a few outcomes significantly less effective, than HNC.Conclusions The results do not support the claim that NFPP addresses putative dysfunctions underlying ADHD, bringing about generalized change in ADHD, and its underpinning self-regulatory processes. The findings support documented difficulties in achieving generalization across nontargeted settings, and the importance of using blinded measures to provide meaningful assessments of treatment effects.
    Full-text · Article · Oct 2014
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