Full Text MH-92-03


NIH GUIDE, Volume 21, Number 9, March 6, 1992

RFA:  MH-92-03

P.T. 34, AA

  Child Psychology/Development 
  Learning Disorders+ 
  Social Psychology 

National Institute of Mental Health

Application Receipt Date:  May 19, 1992


The National Institute of Mental Health (NIMH) announces a Request for
Applications (RFA) for "Multimodal Treatment Study of Attention-Deficit
Hyperactivity Disorder and Attention Deficit Disorder (ADHD/ADD)."
This program is a five-year multi-site collaborative study intended to
address a range of issues concerning ADHD as emphasized by the
Institute of Medicine study "Research on Children and Adolescents with
Mental, Behavioral, and Developmental Disorders," the NIMH "National
Plan for Research on Child and Adolescent Mental Disorders," the
"Healthy People 2000" objectives in the area of mental disorders in
children and adolescents (6.3), and the existing literature.  Foremost
among these are treatment issues subsumed by the question:  Under what
circumstances and patient characteristics (e.g., comorbid conditions,
family socioeconomic background, metabolic/nutritional status,
physical/neurological findings, neurophysiological/neuropsychological
status, gender, age) do which treatment combinations (specific
medication, behavior therapy, parent training, school-based
intervention), have what impacts (improvement, stasis, deterioration)
on what domains of child functioning (cognitive, academic, behavioral,
neurophysiological, neuropsychological, peer relations, family
relations), for how long (short vs. long term), to what extent (effect
sizes, normal vs. pathological range), and why (processes underlying
change)?  These questions form the scaffolding for a multi-site,
multimodal treatment study of ADHD/ADD and its comorbid conditions.
During the first year, the Principal Investigators (PIs) of the
collaborating sites will develop a common protocol from their pooled
applications.  This common protocol will be designed to (1) maximize
the potential of the cross-site data set to address the treatment
questions outlined above and (2) support major studies focusing on
related issues of the assessment, comorbidity, etiology, and natural
history of ADHD with its comorbid conditions.  In year five, data will
be analyzed, scientific reports will be prepared for publication as
warranted by initial study findings, and the scientific merit of
examining long-term outcomes will be evaluated.


The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority objectives.  Of the
300 such objectives, 170 concerning children and adolescents have been
collected into "Healthy Children 2000."  This RFA, Cooperative
Agreement for a Multi-site Treatment Study of ADHD/ADD, is related to
the priority area of research on appropriate biomedical and
psychosocial interventions.  A copy of "Healthy People: 2000" (Full
Report:  Stock Number 017-001-00474-0, or the Summary Report:  Stock
Number 017-001-00473-1) may be obtained from the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325;
telephone 202-783-3238.


Applications may be submitted by domestic and foreign, public and
private, non-profit and for-profit organizations such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal Government.
Applications are encouraged from women and minority investigators, who
are still underrepresented in mental health research.


The cooperative agreement (U01) mechanism used to support this program
differs from investigator-initiated research grants.

Although awardees will be primarily responsible for the conduct of the
study, there will be (1) collaboration among the participating sites
and (2) programmatic involvement of NIMH staff above and beyond the
levels required for the traditional program management of grants.
Applicants are expected to recommend a design with specific methods,
instruments, psychosocial treatments, and psychopharmacological
protocol and, during year 1, will negotiate a common design/protocol
through the steering committee mechanism explained below under "Study
Organization and Oversight."  Applicants should realize that the final
actual common protocol is likely to be different from any one submitted
protocol; even though a grant is awarded partly on the basis of a
proposed protocol, the protocol proposed by an awardee is not likely to
be the final one collegially decided upon by the steering committee.

Period of Support

Applications may request support for a period of up to five years.  It
is anticipated that NIMH will accept competing continuation
applications after the initial award period.

Application Receipt and Review Schedule

To qualify for funding in Fiscal Year 1992, applications must meet the
following one-time only special schedule.
                Initial          Advisory       Funding
Receipt Date    Review        Council Review    Date

May 19, 1992    July 1992     Sept 1992         Sept 1992

Applications received after the receipt date will be returned to the
applicant without review.


It is anticipated that up to $2.5 million per year will be available to
support up to six new cooperative agreement awards under this RFA
during fiscal year 1992, subject to the availability of funds.  Funding
in future years will depend upon annual appropriations.



Clinical Features of the Syndrome:  ADHD/ADD is among the most common
of childhood Axis I mental disorders.  It has been estimated to afflict
between two percent and nine percent of children nationwide, accounts
for one-third to one-half of all referrals for child mental health
services, and comprises a large proportion of economic cost and human
suffering caused by childhood mental disorders.  The core clinical
features of ADHD, many of which can be detected as early as three years
of age and persist through the school years, include inappropriate
activity levels, low frustration tolerance, impulsivity, poor
organization of behavior, distractibility, and especially inability to
sustain attention and concentration.  There has been considerable
debate over the years about the appropriate definitional boundaries of
hyperactivity and about the scientific legitimacy of its status as a
distinct clinical syndrome.  There has never been controversy, however,
about whether or not a significant number of children suffer from the
core clinical symptoms described above or about the social and academic
impairments and psychiatric comorbidities described below.

Associated Functioning Deficits:  Tragically, the core clinical
symptoms of ADHD reflect impairments in precisely the domains of
functioning that are central to mastery of virtually all of the major
developmental milestones of childhood.  It is, therefore, not
surprising that a majority of diagnosed children tend also to perform
poorly in school, despite normal intelligence, and suffer significant
social and emotional impairments in the formation and maintenance of
relationships with classmates, peers, parents, and teachers.

Comorbidity:  It has been known for some time that ADHD is
characteristically comorbid with other childhood mental disorders,
especially conduct and oppositional defiant disorders.  More recently,
investigators have examined the comorbidity of ADHD with mood and
anxiety disorders and learning problems.  A review of clinical studies
suggests substantial comorbid prevalence for conduct/oppositional-
defiant disorders (30-50 percent), mood disorders (widely disparate
reports averaging about one-third), anxiety disorders (about 25
percent), and learning disorders (20-25 percent).  Although the
definitive community epidemiological research on child and adolescent
mental disorders has not yet been completed in the United States, a
large community-based New Zealand study reported that 47 percent of
children with ADHD diagnoses had a coexisting conduct or oppositional
disorder, while 26 percent had a coexisting anxiety/phobic disorder,
and 18 percent had two or more comorbid conditions.  Similar patterns
of comorbidity with ADHD have been reported from epidemiological
studies in Puerto Rico and Canada.  These comorbid conditions and
associated social and academic impairments provide evidence of the
heterogenous nature of the disorder, add to its clinical complexity,
and have significant implications for its etiology, course, and

Long-Term Prognosis:  Although ADHD is classified as a childhood
disorder and is typically identified in the early school years, it has
been estimated that 70 percent of afflicted children continue to
experience the full syndrome in adolescence.  Children diagnosed in
childhood have been found as adolescents to suffer continuing
overactivity, poor school performance, and significant home, school,
and community behavior problems, such as temper tantrums, defiance,
police contacts, and peer rejection.  Moreover, it has been estimated
that as many as two-thirds of hyperactive adolescents suffer serious
discipline problems at school, with high rates of suspension and
expulsion and chronically low levels of self-esteem.

Although few long-term follow-up studies into adulthood have been
reported, those available converge on a portrait of continuing deficits
in many domains of functioning.  Compared to matched normal controls,
young hyperactive adults have been shown to suffer significantly higher
levels of impulsivity and restlessness, nonmedical drug use, court
referrals, incarceration, and personality disorders.  At the diagnostic
level, follow-up studies of hyperactive children into young adulthood
suggest that approximately half continue to have mental disorders,
including ADD, antisocial disorder, and drug use disorder.


Stimulant Treatment:  It has been estimated that between two and three
percent of all elementary school children in North America receive some
form of pharmacological intervention for hyperactivity.  Although
controlled studies support the efficacy of a variety of medications
(including antidepressants, clonidine, and neuroleptics) for
hyperactivity, by far the most widely prescribed and thoroughly studied
have been the psychostimulants, especially dextroamphetamine and
methylphenidate.  Since these are generally agreed to constitute the
"first-line" psychopharmacology for ADHD, it is anticipated that the
multi-site study will focus on them.  Antidepressants are generally
acknowledged as an established second-choice category, and have even
been advocated by a few authors as first-choice drugs.  Unfortunately,
serious safety concerns have been reported for some antidepressants.
Further, the antidepressants appear less predictable and specific and
in the estimation of many psychopharmacologists probably less
efficacious than the stimulants for the majority of ADHD children.

The popularity of stimulant drugs stems from their demonstrated
short-term efficacy, compared to placebo conditions, in dramatically
reducing a range of core hyperactivity symptoms such as task-irrelevant
activity and classroom disturbance, with associated increases in
compliance and sustained attention.  Positive effects of stimulants
have also been shown on parent-child interactions, problem-solving
activities with peers, aggressive behavior, and performance in a
variety of controlled laboratory tasks, including paired-associate
learning, cued and free recall, auditory and reading comprehension, and
arithmetic computation.

But these stimulant effects have been less reliable in bringing about
associated improvements, at least of an enduring nature, in
social-emotional and academic problems, such as antisocial behavior,
poor peer and teacher relationships, and school failure.  Several
factors may contribute to limitations in documented stimulant efficacy,
all of which have implications for subsequent treatment studies:

o  First, many tests of the effects of stimulant medication have been
short-term studies lasting only a few weeks or months.  Many of the
social and academic impairments associated with hyperactivity, however,
may require significantly longer periods for gradual improvements to
materialize.  The long-term effects of stimulants remain in doubt.

o  Second, some hyperactive children may not respond favorably to
stimulants even in the short run.  Earlier reports estimated the
prevalence of non-response to range from 10 to 40 percent, depending on
populations studied, criteria for clinical improvement, and whether
more than one stimulant was tried.  A recent controlled study concluded
that well over 90 percent of hyperactive children respond favorably to
either methylphenidate or dextroamphetamine if both are tried and if
dosages are carefully titrated; the most common type of "nonresponse"
was intolerable side effects.

o  Third, some evidence has suggested a possible dose-response
interaction with domain of functioning.  An example is the claim that
the higher dosages necessary for maximal effects on teacher-rated
classroom comportment may impair rather than improve learning abilities
in certain hyperactive children and that lower stimulant doses may be
necessary for learning improvements in these children.  Though the
hypothesis of differing drug-response thresholds for learning and
behavior is controversial, in more general terms the unexamined
dose-response relationships may obscure important individual
differences across children that have implications for stimulant
treatment effectiveness and interactions with psychosocial treatments.

o  Fourth, the possibility of state-dependent learning remains a
nagging question. Could some children's performance gains resulting
from stimulants fail to carry over effectively to the unmedicated
state?  Though the preponderance of evidence suggests that
state-dependent learning is not a problem for low doses of stimulants,
this is a complex question related to the dose-response issue.

o  Fifth, the magnitude of stimulant benefit may not be consistent
across age groups or mental age/IQ groups.

o  Sixth, the high levels of comorbidity characteristically associated
with ADHD may have important implications for differential stimulant
effectiveness in subgroups of hyperactive children.  For example, one
study found a significant interaction of methylphenidate effect with
comorbid anxiety and a trend of greater placebo response in the anxious
hyperactive subjects than in the nonanxious.

o  Seventh is the possibility of a differential effect by comorbidity
and/or domain of function between the two major stimulants.  Since
there is little overlap in the reported nonresponse rate, it appears
that different patient characteristics determine nonresponse for
methylphenidate than for d-amphetamine.  There is reason to suspect
that one such characteristic is comorbidity.  Furthermore, the
differential general efficacy (regardless of comorbidity) of the two
major stimulants remains in question.  The characterization of
methylphenidate as the "drug of choice" may not be warranted since the
available published studies that directly compared it to
dextroamphetamine in the same subjects failed to show an advantage for
methylphenidate, although individual children often responded better to
one stimulant than the other.

o  Eighth is the concern that for some children stimulant benefit may
possibly be offset by maladaptive psychological attributions of failure
and success.  The limited controlled data available suggest that while
most preadolescent medicated children attribute success to their own
efforts and failure to the pill (a normal, adaptive, self-enhancing
attributional style), a subgroup seems to attribute success to the pill
and failure to lack of ability, leading to a cessation of

o  Ninth, the possibility of a linkage between differential drug
response and minor physical anomalies, neurological "soft signs,"
neurophysiological aberrations, or metabolic/ nutritional status has
not been adequately explored.

o  Finally, a study of stimulant effects needs to consider the issue of
prior medication.  At any given age, a history of earlier medication
suggests more serious symptomatology, earlier manifestation, and/or
socioeconomic and familial variables such as parental concern/attitudes
and access to health care.  Therefore, merely excluding subjects with
a prior medication history would bias the sample.  If a withdrawal
period from prior medication is too short, carryover effects could
confound the baseline measures.  If too long, sample attrition may bias
the sample against the more serious or more drug-responsive cases.  The
nature of dependent variables is an important consideration:  While
behavior and cognition usually revert to baseline within a week after
stimulant withdrawal, some stimulant-induced biochemical changes have
been reported not to wash out for over two weeks.  Should only
drug-naive subjects have the affected biochemical tests, or should the
tests be confined to those tests presumed unaffected by drug carryover,
or should the washout period be prolonged enough to collect all desired
data on every subject?  Further, while most ADHD patients are medicated
at some point, the majority do not continue medication after several
years.  Previous studies have generally not addressed these issues.

There is an emerging consensus concerning an important yet limited role
for stimulant medication in the treatment of hyperactivity.  It may be
the necessary and sufficient treatment for a subset of ADHD children.
For others, it may be contraindicated.  For still others, stimulant
medication in isolation should not be expected to yield gains beyond
its immediate effects on attention, impulsivity, and activity levels.
It may be most effective in normalizing and stabilizing the primary
functioning characteristics of these ADHD children, whose behavior and
learning problems must then be addressed through a range of
psychosocial treatments.

Psychosocial Treatments:  Many of the research results and
considerations raised above have given rise to a newer phase of
research focused on the use of psychosocial treatment modalities, alone
and in combination with stimulants. Psychosocial interventions that
have been systematically explored include classroom-based behavior
modification, social skills and cognitive training, and parent
training/home-based interventions.  Controlled studies of stimulant
medication, psychosocial treatments, and their combination have
suggested that combined approaches may yield more favorable results
than single treatment modalities.  Some studies have demonstrated that
token reinforcement systems may "normalize" aggressive and other
off-task behaviors in the classroom.  A number of cognitive-behavioral
interventions have been shown to produce both increased self-control
and the use of specific coping strategies in hyperactive children; in
some cases, these effects were neither enhanced by the addition of, nor
produced independently by, stimulant medication.  Other child-focused
interventions, such as self-control procedures, have produced desired
treatment effects in experimental classrooms, but a critical problem
has been the lack of evidence that such interventions generalize to
other settings (e.g., regular school classrooms) or across behavioral
domains.  And still other interventions, such as interpersonal
problem-solving skills therapy, have failed to facilitate interpersonal
competence in either medicated or unmedicated children.  Similarly,
cognitive therapy and social skills training have produced only weak
and variable effects, with little evidence to date that they have a
significant impact on the academic performance or social behavior of
hyperactive children.  Parent training in child behavior modification
has been shown to improve both the school and home behavior of
hyperactive children; however, only with medication were there also
reductions of impulsivity and inattention.  Home-based treatments with
parental involvement, coordinated with school interventions, are
thought by many workers in this field to be an essential component of
treatment effectiveness; they may increase the salience of school
interventions for many children and facilitate the generalization of
treatment effects across settings and behavioral domains.  While there
is promising evidence for the clinical utility of a variety of
psychosocial interventions in the treatment of hyperactive children,
most psychosocial treatment studies have not attended to important
individual differences in the comorbidities and functioning impairments
of hyperactive children.

Multimodal Treatments:  It is clear from both the well-developed
literature on stimulant medication and the developing literature on
psychosocial treatments that no single treatment in isolation is likely
to yield clinically significant, long-term, cross-domain therapeutic
gains in an unselected, and, therefore, heterogeneous group of
hyperactive children.  Within any such group, there are likely to be
subgroups with significantly different patterns of comorbidity, family
backgrounds, and functioning deficits -- all of which have important
implications for children's treatment needs.

These considerations have given rise to an interest in multimodal
treatment strategies.  More closely approximating the ideal of sound
clinical practice, one multimodal strategy differs from traditional
research approaches by tailoring stimulant medication and/or
psychosocial interventions to the particular needs of individual ADHD
children and their families.  A prototypical multimodal approach begins
with an intensive evaluation of each child's impairments and strengths
in each domain of functioning, as well as those of his/her family.  On
the basis of these evaluations, specific treatment plans are developed
for each child's needs and are administered through an intensive,
coordinated team approach.

Multimodal treatment strategies may hold considerable promise for
matching combined treatments to the needs of ADHD children and their
families.  Although impressive early findings have been reported from
studies of multimodal treatments, enthusiasm has been tempered by
concerns over possible recruitment bias, the absence of no-treatment
control groups, failure to use blinded assessment procedures, and the
uncontrolled assignment of subjects to treatment conditions.  Studies
to date have experienced significant limitations of sample size and
methodology, precluding meaningful comparisons of treatment
combinations and interactions among treatment combinations, comorbidity
patterns, and child/family characteristics.

Other Treatments:  Numerous other treatments (e.g., elimination diets,
nutritional supplementation, perceptual stimulation/training,
sensorimotor integration, biofeedback, progressive relaxation,
hypnosis, detoxification, antifungal therapy) have been
advocated/tried.  It is not anticipated that the multi-site study will
focus on these because they either have insufficient controlled
research evidence of efficacy or seem to benefit only a small
proportion of ADHD children.  However, baseline measures relevant to
such treatments could be considered for inclusion in the common

The Need for a Multi-Site Study under a Cooperative Agreement

Considerable research into treatment strategies will be needed to
establish answers to the manifold question posed earlier:  Under what
circumstances (e.g., comorbid conditions, family socioeconomic
background, age, gender, metabolic/nutritional status, physical
findings, neurophysiological/neuropsychological status) do which
treatment combinations (specific medication, behavior therapy, parent
training, school-based intervention) have what impacts (improvement,
stasis, deterioration) on what domains of child functioning (cognitive,
academic, behavioral, physical, peer relations, family relations), for
how long (short vs. long term), to what extent (effect sizes, normal
vs. pathological range), and why (processes underlying change)?  The
very nature of a multimodal treatment approach is such that answers to
these questions will require adequate numbers of ADHD subjects with
varying comorbid profiles, functioning deficits, physical/physiological
status, and family characteristics.  This will require coordination of
multiple sites in a unified investigation.  Such coordination is best
done through a cooperative agreement, which invokes substantial
involvement of NIMH collaborators.  Accordingly, NIMH staff will have
substantial involvement in the collegial negotiation of a common
protocol, the assuring of uniform cross-site training, the development
of monitoring systems to ensure cross-site fidelity to the protocol,
the development of centralized data management and analysis, and the
enhancing/facilitating of communication and cooperation among the

Program Description

Goals/Objectives and Research Questions.  The goal of this program is
to implement a five-year multi-site collaborative treatment study of
ADHD/ADD and its associated comorbidities and social/emotional and
academic impairments.  Examples of appropriate hypotheses that might be
tested are stated below in question form.  The main questions are
expected to concern synergism of stimulant and psychosocial treatment,
interaction of treatment type with comorbidity pattern and
socioeconomic status (SES), differential stimulant efficacy, and
differential efficacy of psychosocial treatment prescriptions:

o  Differential Effects of Stimulant Treatment and Interactions with
Comorbidity and SES:  How do comorbidity and socioeconomic status
affect drug response including placebo response?  Is there a difference
in efficacy between stimulants?  Do they have a differential affect by
comorbidity (i.e., interaction of stimulant type with comorbidity)?  Do
the stimulants differentially affect different domains of functioning
(i.e., interaction of stimulant type and domain of function)?

o  Differential Effects of Psychosocial Treatments and Interactions
with Comorbidity and SES:  Is tailored multicomponent psychosocial
treatment better than packaged (fixed battery) psychosocial treatment
of the same intensity?  Are multicomponent psychosocial treatments
better than single-modality?  Do comorbidity and SES affect treatment
response?  Do comorbidity and SES interact with the type of treatment?

o  Additive/Synergistic Effects:  How much do psychosocial treatments
add to stimulant benefit?  Does continuing stimulant medication add to
the efficacy of ongoing long-term psychosocial treatments?  Does
psychosocial treatment allow more successful weaning from successful
stimulant treatment?  If so, is this additive/synergistic effect
affected by comorbidity and socioeconomic status?

o  Is there a differential treatment response by gender? Does gender
interact with SES or comorbidity in treatment response?

o  How does a comorbid learning disorder affect treatment response?
Does learning disorder interact with Axis I comorbidity and/or SES?

o  Is the distinction "with" or "without" hyperactivity associated with
different comorbid patterns and/or differential treatment response?

o  Are baseline metabolic/nutritional status (e.g., minerals, heavy
metals, dietary habits), physical/neurological examination findings
(e.g., "soft signs" and minor anomalies), or neuropsychological
findings associated with differential treatment response?

o  Is each treatment, systematically closely monitored, truly better
than no contact?  Is the superiority of treatment over no contact
affected by comorbidity and SES?

o  Does parental restriction of treatment options (by refusal of drugs
or psychosocial treatment) affect treatment outcome?  Does parental
choice/restriction of treatment interact with comorbidity and SES?  Is
it only the less seriously disordered children who afford their parents
the luxury of refusing treatment options? How does the parental
decision to obtain treatment (presumably motivated by severity of the
child's symptoms) bias sample composition (e.g., comorbidity) and

Program Schedule.  Following the selection of participating sites, the
PIs participating in the cooperative agreement will meet with
participating NIMH staff to establish appropriate levels of
coordination and refine the governing structure (see "Study
Organization and Oversight" below).  The first year of the
collaborative effort will be devoted mainly to developing a common
protocol from the selected applications, developing the necessary
training and implementation procedures, finalizing manuals to ensure
cross-site consistency in study execution, and hiring and training
assistants/therapists.  The common protocol will be designed to (1)
maximize the potential of the cross-site data set to address the
manifold treatment questions, and (2) support major studies focusing on
related issues of the assessment, comorbidity, etiology, validity, and
natural history of ADHD with its comorbid conditions.  Domains of
assessment should include formal psychiatric assessments of probands
and parents, and assessments of all probands in the domains of
neurological, intellectual, cognitive, academic, behavioral/
psychosocial, and metabolic/nutritional/physiologic functioning.
Project years two through four will be devoted to the implementation of
the protocol developed during the first project year.  Most of the
subjects should be entered into the study during year two to allow at
least two years of treatment and follow up.  Year five of the project
will be used mainly to analyze the results, prepare scientific reports
for publication, and prepare data tapes for the public domain.

Methodological Considerations

Applicants are expected to propose resolutions of the complex design,
recruitment, sampling, assessment, and treatment issues involved,

o  Design.  Applicants should consider the relative advantages and
disadvantages of parallel group vs. within-subject crossover designs
and combinations/hybrids (e.g., one imbedded in the other or one
preceding the other) for the various hypotheses under study.  Which
design best suits any intended pharmacological comparison?  Which best
suit the psychosocial treatment comparison?  What is an optimal
compromise?  If a crossover is proposed, how will the issue of
carryover effects be resolved?  Should some aspects of the study be
"unbundled" into one or more preliminary brief studies before longer-
term treatment?  If so, what is an appropriate duration for such
preliminary treatment trials? What design will facilitate the optimal
individualized drug treatment being compared with various psychosocial
treatments, alone and in combination?  Multimodal treatment studies
typically suffer from severe sampling bias, partly because of the large
proportion of subjects who decline one treatment but would be willing
to participate in the other.  Nonetheless, it is important to study how
these children differ from full consenters in treatment response and
perhaps in other ways.  Should consent be a sequential process with
options for partial consent, or should consent be global and obtained
on an "all-or-none" basis?  What design will ensure maximal sample
retention of no-contact controls and/or those who consent to one
treatment modality (drug or psychosocial) but not the other, as well as
those who give full consent for random treatment assignment?  If an age
range wider than two to three years is sampled, how will the design
control for age in treatment response and participation/compliance?  If
mentally retarded subjects are included, how will the design control
for mental age?  How many variables can be managed with adequate
stratification at the site level without compromising cell size?

o  Subject Recruitment and Selection.  Applicants must describe the
anticipated demographics of the proposed sample and discuss its
population representativeness.  One consideration in the selection of
applicant sites will be overall cultural, socioeconomic, and
racial/ethnic representativeness of the total sample.  Although it
would not be possible for each site to recruit a nationally
representative sample, each site's sample should at least represent a
broad cross-section of the ADHD/ADD population in its metropolitan area
or region.  Centers in geographic proximity (within 1-2 hours travel)
are encouraged to form a consortium and apply as one site for the
purpose of broadening sample representativeness and accessing adequate
subject numbers.  If such a consortium is formed, arrangements should
be documented and a single principal investigator must be agreed on.

Issues of volunteer bias, referral bias (e.g., clinical samples versus
school-identified samples, whose condition may not be as significant or
severe as those who seek treatment), and subject attrition must be
addressed.  Subjects should be recruited with careful attention to the
range of comorbidity, especially such Axis I comorbidity as other
disruptive behavior disorders (conduct and oppositional-defiant
disorders), depression, and anxiety. Applicants must demonstrate access
to an adequate pool of eligible subjects from multiple sources.  In
view of the anticipated program schedule, the need for over 700 total
subjects (suggested by preliminary power analyses), and the expectation
of funding four to six sites, approximately 120-180 subjects will need
to begin the study at each site within a 15-month period (in order to
allow at least two years of treatment follow-up); applicants must state
how many subjects they can reasonably access in what time frame.
Estimates must be included for the proportion of subjects who are
expected to consent to each proposed treatment condition.  Estimates
must also be included for the proportions of subjects expected to have
each comorbid condition/combination.  Exclusion/inclusion criteria for
subjects must be well articulated.  It is anticipated that all subjects
will be in elementary school.

o  Sample Retention.  Applicants must propose and justify strategies
and procedures (e.g., sequential consent process for assessment,
stimulant treatment, and psychosocial treatments) to facilitate
retention of subjects who decline one or more treatment modalities and
to study their response to any treatment for which they do consent.

o  Diagnosis and Assessment Across Multiple Domains Using Multiple
Information Sources.  Significant concerns have been raised among
hyperactivity researchers about the validity of the DSM-III-R criteria
for ADHD and many workers in this area have noted that the empirical
evidence most closely fits the original DSM-III criteria.  The advent
of DSM-IV will bring a number of changes to the ADHD diagnostic
criteria that will more closely approximate original DSM-III criteria.
Each application must discuss and justify the proposed choice of
diagnostic criteria (DSM-III, DSM-III-R, DSM-IV, or combinations or
alternatives).  Applicants must specify validated diagnostic interviews
and other procedures and instruments for collecting symptom information
from parents, children, and their teachers.  Criteria for combining
information from multiple sources must be specified.  The method for
psychiatric assessment of parent as well as child must be specified.

o  Withdrawal Period from Previous Medication.  An appropriate
preliminary withdrawal period from any previous psychopharmacotherapy
must be proposed and justified in view of washout times of various
drugs in common use.  Applicants must specify how the history of prior
treatment will be handled in the overall design.

o  Treatments.  Given the emphasis of this study on the differential
effectiveness of various treatments by comorbidity, SES, and sex,
applicants should consider inclusion of at least two drugs and three
psychosocial treatments.  These are not required to be compared
simultaneously:  for example, the drugs could be compared in a
preliminary within-subjects crossover before assignment to psychosocial
treatment conditions with the best-response maintenance drug.  It is
anticipated that medication alternatives will include methylphenidate
and dextroamphetamine because the vast majority of hyperactive children
will respond to at least one of these when properly titrated.
Applicants will be expected to recommend specific drugs, dosages,
procedures for administration, management, and verification of
medication dose and compliance.  The choice of multiple fixed doses vs.
clinical titration and the choice of sustained-release vs. regular
tablets must be discussed and justified.  Applicants must specify
criteria for determining inadequate or negative drug response based on
standardized assessment instruments and clinical procedures/techniques.
Side effects in both responders and nonresponders should receive
special attention.  The types and formats of psychosocial treatments
must be specified, including a child-directed treatment, a
parent-directed treatment, and a school-oriented intervention.  The
issue of relative efficacy of tailored vs. packaged/fixed battery of
the same intensity must be addressed.  The procedure/algorithm for
individually prescribing tailored psychosocial treatment must be
specified.  Procedures for insuring uniform administration of
psychosocial and drug treatments across and within sites must be

o  Randomization/Stratification and Blinding Procedures.  Strategies,
techniques, and procedures for randomization and/or stratification of
subjects should be proposed and justified.  Since not all variables can
be stratified, applicants should justify their choices and priorities.
Which variables are best managed by inclusionary/exclusionary criteria?
Which ones are best left to chance without stratification?  Applicants
must propose, justify, and discuss alternatives for enhancing the
blindness of evaluations/ratings, considering such issues as parents'
detailed knowledge of treatments, teachers' knowledge of school-
oriented intervention, the possibility of keeping the medication-
managing psychiatrist blind, and the videotaping of child behaviors for
blind rater assessments.  For psychopharmacologic components/phases,
standard psychopharmacologic blinding procedures should be specified.

o  Data Management and Analysis.  Although management and analysis of
the pooled data will be centralized at NIMH, applicants must propose an
optimal plan for this, and describe plans and resources for site-level
data management.  Key issues to be addressed include: statistical
handling of dropouts during treatment; differences among drugs;
differences among psychosocial treatment conditions; synergism or
additive effect of drug and psychosocial treatments; effect of patient
characteristics (e.g., comorbidity); interactions.


Study Organization and Oversight

Although awardees will be primarily responsible for the conduct of the
study, there will be (1) collaboration among the participating sites
and (2) substantial programmatic involvement and participation of NIMH
staff above and beyond the levels required for the traditional program
administration of individual research grants (R01).  Applicants are
expected to recommend a design and specific methods, instruments, and
psychosocial treatments while recognizing that during year one,
awardees, in conjunction with NIMH collaborators, will negotiate a
common protocol.

Collaborating Site Research Teams.  Each research site funded under
this program will be a collaborative research team.  A consortium
formed to ensure sufficient subjects and sample representation will be
considered one site and must have one designated PI.  It is anticipated
that the staff needs at each site will include, but not be limited to,
the following personnel:

o  Principal Investigator (PI).  The PI will have overall
responsibility for the research program at his/her site.  Also, the PI
will be responsible for integrating the site's program goals and
procedures with those recommended for use by the collaborative program.
The PI represents the site in collaborative decision-making on the
overall scientific steering committee and is responsible for
maintaining communication with NIMH staff.  The PI must be able and
prepared to devote a substantial, significant percentage of time and
effort to this project, including extensive travel, especially the
first year, for steering committee meetings and cross-site training and
fidelity monitoring.

o  Co-Investigator(s) (Co-I).  At each site the Co-I takes a lead role
second only to that of the PI.  The Co-I shares all responsibilities
(outlined above) with the PI for the research program at his/her site.
In a consortium arrangement, it might be desirable for the Co-I to be
at a center/institution other than the PI's, or even to have multiple
Co-Is, one taking the lead at each center.

Multidisciplinary expertise is essential for the conduct of this
complex study, including strong clinical expertise, extensive knowledge
of diagnostic and nosologic issues, child development,
psychopharmacology, psychosocial treatments, assessment and
neuropsychology, statistics, epidemiology, and data management.
Expertise in evaluating psychosocial treatments is important,
preferably with experience in ensuring fidelity of treatment across
settings.  Therapists must be trained and receive sufficient monitoring
and supervision to ensure fidelity to the treatment protocol.  The
research team at each participating site should show evidence of
appropriate depth and breadth to accomplish the objectives of the
collaborative program.  To facilitate the multidisciplinary breadth of
the team, it might be helpful in some instances to have the PI and Co-I
(as defined above) from different disciplines.

Role of NIMH Staff.  The participation of NIMH staff in this
cooperative agreement will ensure the broader scientific and public
health goals of the collaborative agreement and bring a stabilizing
influence to the collaborative process.  In addition, the participating
NIMH staff members, associated with the Child and Adolescent Disorders
Research Branch and other branches of the Division of Clinical
Research, will bring to the collaboration a wide range of scientific
and clinical expertise in the areas of assessment, taxonomy, and
diagnosis, and in the treatment of hyperactivity and related childhood
conditions.  At least one NIMH staff member will participate in all
project meetings and committees.  Specifically, NIMH collaborators will
participate in development of the study plan, facilitation of
cross-site training, quality control, coordination of the project
across sites, data analysis and interpretation, and preparation of
publications, but will not participate in activities directly involving
human subjects.  NIMH staff who have significant involvement in
design/protocol development and/or data analysis/interpretation may
cooperate with awardees as coauthors of resulting publications.  In
this regard they will be subject to the publication/authorship policies
governing all participants.  In addition, publications involving NIMH
staff require internal NIMH clearance.

Steering Committee.  The steering committee will be the primary
decision-making body of this collaborative multi- site study.  Several
NIMH staff will be members of the steering committee but cannot hold
the position of chair. Membership will be composed of:

1.  Chief, Child & Adolescent Disorders Research Branch, Division of
Clinical Research, NIMH
2.  Other NIMH collaborators to be designated by the Division of
Clinical Research, NIMH
3.  Principal Investigator (PI) from each site
4.  One Co-Investigator from each site
5.  A statistical consultant designated by NIMH
6.  Other consultants as determined by the committee

Voting and Governance:  NIMH will have one vote on the steering
committee regardless of the number of representatives present.  Each
site will have one vote regardless of whether one or both
representatives are present.

A quorum will require at least one NIMH representative and at least one
representative from at least three-fourths of participating sites.
Membership on the steering committee becomes effective for sites upon
receipt of notice of award.

All decisions will be made by majority vote of a quorum, with an
attempt for consensus when possible.  Since the use of a common
standardized protocol is essential, all participating sites must agree
to carry out the study design, procedures, and policies developed by
this committee.  Any committee member who considers a committee
decision unacceptable may appeal to the arbitration procedure described
below.  The committee is expected to meet very frequently during the
first year to develop, standardize, and coordinate the common protocol.
In subsequent years the meeting frequency will probably decrease.  The
meetings will usually be held in the Washington, DC metropolitan area.
The steering committee may establish additional by-laws and/or
subcommittees for specific tasks, such as a data management committee
to coordinate data coding, entry, and analysis, and an implementation
committee to ensure uniformity of procedures across sites.  Each such
subcommittee will include at least one representative from each site
and NIMH.  No committee/subcommittee may be chaired by NIMH staff.

Responsibilities of steering committee members include:

1.  Collaboratively finalizing the study plan, including design,
assessment instruments, component protocols, and detailed
implementation procedures

2.  Abiding by and directing the study design determined by the
steering committee

3.  Monitoring the study

4.  Facilitating the pooling of data for common analysis and for
eventual release to the larger scientific community (see "Public
Domain" below)

5.  Reporting study results

6.  Abiding by all scientific, practical, and policy decisions of the
steering committee and the provisions and intent of this RFA

Management and analysis of the pooled data will be centralized at NIMH
under procedures approved by the steering committee.  The steering
committee will develop policies on publication and authorship.
Publication policies will be written and authorship will be decided
using procedures developed by the steering committee.  PIs may publish
results from a single site but must obtain prior approval from the
steering committee.  The quality of publications will be the
responsibility of authors; no NIMH clearances will be required except
for NIMH staff who may serve as coauthors.

Arbitration Procedure.  If a steering committee decision is not
acceptable to an awardee, the awardee may, within 30 days of
notification of the decision, request a review by an arbitration panel
composed of one arbitrator nominated by the awardee, one nominated by
NIMH, and one chosen by the first two nominees.  This panel will make
a decision within 60 days of the request.  Failure to comply with the
decision of the panel may result in termination of support for the
awardee by NIMH.  This arbitration procedure in no way affects the
awardee's right to appeal an adverse action in accordance with PHS
regulations at 42 CFR Part 50, subpart D, and HHS Grant Administration
Regulations at 45 CFR Part 74, section 304 and HHS regulations at 45
Parts 16 and 75.

External Data Monitoring Board.  During the first year, as part of the
protocol development process, four external scientific advisors who
have no project involvement will join a senior NIMH scientist on a
monitoring board chaired by the Director, Division of Clinical
Research.  These external advisors will be selected from eminent
scientists knowledgeable of adult and child psychopathology and
treatment studies.  The monitoring board will periodically (at least
annually) review study progress and will provide input and
recommendations to NIMH.  While it will have no supervisory role, its
input and annual review of the project are expected to help maintain
the highest quality of research by facilitating transfer of new
knowledge from adult treatment studies to this project.

Public Domain of Data.  It is expected that the data from this study
will be collected and stored in a form suitable for alternative
analyses.  The data will first be used by the collaborators.  However,
since the data set will represent a potential national scientific
resource, NIMH intends that it be made available to the larger research
community as soon as feasible.  NIMH will determine when all or parts
of the collected data should be made available to the larger community.


Applications for Alcohol, Drug Abuse, and Mental Health Administration
(ADAMHA) grants and cooperative agreements are required to include both
females and minorities in study populations for clinical research,
unless compelling scientific or other justification for not including
them is provided.  This requirement is intended to ensure that research
findings will be of benefit to all persons at risk of the disease,
disorder, or condition under study.  For the purpose of these policies,
clinical research involves human studies of etiology, treatment,
diagnosis, prevention, or epidemiology of diseases, disorders or
conditions, including but not limited to clinical trials; and
minorities include U.S. racial/ethnic minority populations
(specifically:  American Indians or Alaskan Natives, Asian/Pacific
Islanders, Blacks, and Hispanics).

ADAMHA recognizes that it may not be feasible or appropriate in all
clinical research projects to include representation of the full array
of U.S. racial/ethnic minority populations.  However, applicants are
urged to assess carefully the feasibility of including the broadest
possible representation of minority groups.

Applications should include a description of the composition of the
proposed study population by gender and racial/ethnic group, and the
rationale for the numbers and kinds of people selected to participate.
This information should be included in the form PHS 398 in Section 2,
A-D of the Research Plan AND summarized in Section 2, E, Human

Applications should incorporate in their study design gender and/or
minority representation appropriate to the scientific objectives of the
work proposed.  If representation of females or minorities in
sufficient numbers to permit assessment of differential effects is not
feasible or is not appropriate, the reasons for this must be explained
and justified.  The rationale may relate to the purpose of the
research, the health of the subjects, or other compelling circumstances
(e.g., if in the only study population available there is a
disproportionate representation in terms of age distribution, risk
factors, incidence/ prevalence, etc., of one gender or
minority/majority group).

If the required information is not contained within the application,
the review will be deferred until it is complete.  Peer reviewers will
address specifically whether the research plan in the application
conforms to these policies.  If gender and/or minority
representation/justification are judged to be inadequate, reviewers
will consider this as a deficiency in assigning the priority score to
the application.

All applications/proposals for clinical research submitted to ADAMHA
are required to address these policies.  ADAMHA funding components will
not award grants that do not comply with these policies.


Applicants are to use the grant application form PHS 398 (rev. 9/91).
The number and title of this RFA,  Cooperative Agreement for a
Multi-site Treatment Study of ADHD, MH-92-03, must be typed in item
number 2 on the face page of the PHS 398 application form.  Application
kits containing the necessary forms and instructions may be obtained
from business offices or offices of sponsored research at most
universities, colleges, medical schools, and other major research
facilities.  If such a source is not available, the following office
may be contacted for the necessary application material:

Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-05
Rockville, MD  20857
Telephone:  (301) 443-4414

The signed original and four legible copies of the completed
application must be sent to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Additionally, it is requested that one copy be sent to:

Division of Extramural Affairs
National Institute of Mental Health
5600 Fishers Lane, Room 9-105
Rockville, MD  20857

Applications submitted for the special receipt date of May 19, 1992,
must be complete and contain all information needed for initial and
Advisory Council review.  No subsequent addenda will be accepted unless
specifically requested by the Scientific Review Administrator of the
review committee.  No site visits will be made.

Applicants are reminded that the combined number of pages for Sections
1 through 4 of the Research Plan must not exceed 30 pages.
Applications exceeding this limitation will be returned.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research Resources
may wish to identify the GCRC as a resource for conducting the proposed
research.  In such a case, a letter of agreement from either the GCRC
program director or the Principal Investigator must be included with
the application.

If the applicant has an approved assurance covering the research
(Multiple Project Assurance for human subjects), the applicant must
provide with the application the certification of ethical IRB approval.
The review and approval should occur prior to submission of the

Terms and Conditions of Award

Cooperative agreement funds may be used only for expenses clearly
related and necessary to conduct the research outlined under this
program including direct costs that can be specifically identified with
the project and allowable indirect costs of the institution.

Grants must be administered in accordance with the "PHS Grants Policy
Statement (revised October 1, 1990)," which is available from any
office of sponsored research and from the Superintendent of Documents,
U.S. Government Printing Office, Washington, DC.  Federal regulations
at 42 CFR Part 52, "Grants for Research Projects," and 45 CFR Parts 74
and 92, generic requirements concerning the administration of grants,
are applicable to these awards.

Application Characteristics

Applicants must follow the guidelines for a research grant in
completing the application (PHS 398 application kit, revised 9/91).
The application must include a design and protocol in the same detail
as an R01 application to be used as one of the starting points in the
year 1 development of the common protocol.  The protocol should
address, for example, the issues outlined under "Methodological
Considerations" and the objectives of this RFA.  Because of the
expected complexity of the design, applicants may use 5 additional
pages, up to 30 pages total, for sections 1 through 4.

Budget Considerations.  The first year, focused mainly on common
protocol development and hiring and training of therapists and
assessment staff, is expected to have a much lower budget than the
years of assessment, treatment, and data gathering.  The $2.5 million
per year mentioned under "AVAILABILITY OF FUNDS" is the average total
costs per year available for all sites, including indirect costs, over
the five years.  This estimate includes a reasonable allowance for
purchased baseline metabolic, nutritional, and medical tests on urine,
blood, and other tissue/fluid and compensation to subjects, parents,
and teachers for cooperating with data collection.

Collaborative Aspects.  Because collaboration is so essential to the
success of this study, it is important to include in the application
evidence of good working relations in the applicant team, including any
on-site consortium arrangement, and between the applicant team and
cooperating referral sources.  It is also useful to list any past
research experience involving collaboration between the applicant team
and other research teams or between the PI and investigator(s) at
another university/center/institution.

Protection of Human Subjects

Applicants must demonstrate adequate procedures for minimizing risks
and ensuring the safety and confidentiality of human subjects.  The
Department of Health and Human Services has developed additional
regulations for protection of children involved as research subjects,
including parental consent.  A copy of these regulations (45 CFR 46,
Protection of Human Subjects) is available from the NIMH staff listed
below.  During year one, the collaborators will need to develop common
elements for use in a consent form that can then be adapted to
individual sites-specific IRB requirements.  While it is not
anticipated that subjects would be compensated for participating in
treatment, applicants should consider fair compensation/reimbursement
for assessment time, inconvenience, lost time from work of the parents,
transportation and parking cost, and possible discomfort or stress of
tests.  The following questions must be addressed in the application:
What are appropriate but not coercive incentives for completing
assessments?  Should subject compensation/reimbursement vary by site in
view of differing local costs of living and differing IRB standards or
be uniform across sites?  What are the implications for cross-site
comparability in retention?


Applications received under this announcement will be reviewed for
scientific and technical merit by an initial review group (IRG)
consisting primarily of non-Federal experts.  Final review is by the
Mental Health Advisory Council.  Notification of the initial review
outcome will be sent to the applicant by the NIMH.  Only applications
recommended for approval by Council may be considered for funding.

Criteria for scientific/technical merit review of research applications
include the following:

o  potential contributions in areas covered by the objectives and scope
of this announcement and responsiveness to the issues outlined above

o  scientific merit of the research design, approaches, and methodology

o  qualifications and experience of the Principal Investigator and
proposed staff

o  adequacy of the conceptual and theoretical framework for the

o  evidence of familiarity with relevant research literature

o  feasibility of the research plan

o  adequacy of proposed procedures for protecting human subjects and
for ethical use of animal subjects

o  appropriateness of the budget, staffing plan, and timeframe to
complete the project

o  adequacy of the existing and proposed facilities and resources

o  evidence of appropriateness of collaborative arrangements

o  plans for dissemination of research findings

o  appropriate inclusion of women and minorities in the study


Factors considered in determining which research applications will be
funded include:  scientific and technical merit as determined in the
initial review, Council recommendations, responsiveness to the goals of
this announcement, significance of the topic under study to NIMH
priorities as announced in this or other special announcements or
guidelines, program balance, public health significance, and
availability of funds.


Potential applicants are encouraged to seek pre-application
consultation from:

L. Eugene Arnold, M.D.
Child and Adolescent Disorders Research Branch
Division of Clinical Research
National Institute of Mental Health
Parklawn Building, Room 10-104
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-5944
FAX:  (301) 443-4045

Inquiries about grants management issues may be directed to:

Stephen J. Hudak
Chief, Grants Management Section
National Institute of Mental Health
Parklawn Building, Room 7C-05
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-4456

Potential applicants may obtain a copy of the "NIMH National Plan for
Research on Child and Adolescent Mental Disorders" from:

Information Resources and Inquiries Branch
National Institute of Mental Health
Parklawn Building, Room 15C-05
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-4513


This program is described in the Catalog of Federal Domestic Assistance
Number 93.242.  Awards are made under the authorization of the Public
Health Service Act, Title IV, Part A (Public Law 78-410, as amended by
Public Law 99- 158, 42 USC 241 and 285) and administered under PHS
grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part
74.  This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency review.


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