DEVELOPMENTAL PSYCHOPHARMACOLOGY
Release Date: June 27, 2000 (see replacement PA-03-113)
PA NUMBER: PA-00-114
National Institute of Mental Health
National Institute of Child Health and Human Development
National Institute on Drug Abuse
THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS PA INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS PA.
PURPOSE
The National Institute of Mental Health (NIMH), the National Institute of
Child Health and Human Development (NICHD), and the National Institute on
Drug Abuse (NIDA) request research grant applications to study the possible
clinically significant effects that various psychotropic medications may have
on the brain when administered during the developing phase that spans from
birth to early adulthood. The purpose of this announcement is to spur new
clinical and basic research on the possible impact of psychotropic
pharmacotherapy on the developing brain. The main goal is to generate data
that are relevant to the clinical use of psychotherapeutic medications in
children and adolescents with respect to safety and/or efficacy within dose
ranges, schedules, and routes of administration that are usually employed
therapeutically. The ultimate purpose is to increase our knowledge of the
safety and effectiveness of psychopharmacological treatments administered to
children and adolescents.
HEALTHY PEOPLE 2010
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2010," a PHS-
led national activity for setting priority areas. This Program Announcement
(PA), Developmental Psychopharmacology, is related to the priority areas of
Mental Health and Mental Disorders and Biology of Brain Disorders Objectives.
Potential applicants may obtain a copy of "Healthy People 2010" at:
http://www.health.gov/healthypeople/
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal government. Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as principal
investigators.
MECHANISM OF SUPPORT
This PA will use the National Institutes of Health (NIH) R03, R21, and R01
award mechanisms. The Small Grant (R03) provides two years of funding with a
maximum of $50,000 direct costs for each year. The Exploratory/Developmental
Grant (R21) provides up to three years of funding with a maximum of $125,000
direct costs for each year; it is intended for development and pilot testing
of novel models, sensitive neurochemical measurements, interventions and
other aspects of intervention development. The total project period for an
application submitted in response to this PA may not exceed five years for an
R01 award. Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.
For all R03 and R21 applications, as well as all competing R01 applications
requesting up to $250,000 direct costs per year, specific application
instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME
streamlining efforts being undertaken at NIH. More detailed information
about modular grant applications, including a sample budget narrative
justification pages and a sample biographical sketch, is available via the
Internet at: http://grants.nih.gov/grants/funding/modular/modular.htm.
Applications that request more than $250,000 in any year must use the
standard PHS 398 (rev. 4/98) application instructions.
Because the R21 grants have a special application format and review criteria,
applicants are strongly encouraged to consult with program staff (listed
under INQUIRIES. Special instructions and information for the
Exploratory/Development Grants for MH research may be found at:
http://grants.nih.gov/grants/guide/pa-files/PA-00-073.html for neuroscience
research and at http://grants.nih.gov/grants/guide/pa-files/PA-99-134.html
for MH intervention research.
Special instructions and information for the small grant program is found at:
http://grants.nih.gov/grants/guide/pa-files/PAR-99-140.html. Neither the R03
nor R21 are renewable.
RESEARCH OBJECTIVES
Background
Psychotropic medications are prescribed with increased frequency to children
and adolescents, often for extended periods of time. Millions of
prescriptions of stimulants, antidepressants, and other psychotropic
medications are written every year for patients under 18 years of age. These
pharmacological compounds act on and through neurotransmitter systems that
undergo major developmental changes in humans during the first two decades of
life. Interactions between drugs and the developing brain are important
considerations in assessing the efficacy and safety of these agents in
children and adolescents. As psychopharmacological treatments become more
accepted in clinical practice, there is increasing concern over the
possibility that long-term exposure of developing children to psychoactive
agents might result in subtle but significant long-lasting adverse effects.
Thus, experimental data are needed to clarify the nature, extent, and impact
of these interactions. In addition, identification of brain regions and
physiological mechanisms responsible for both the therapeutic and negative
effects of drugs will be useful for the development of more selective
psychotherapeutic mechanisms with fewer side effects. For ethical,
methodological, and practical reasons, it is often difficult or impossible to
conduct this type of experiment in humans. In these cases, research in
animals is appropriate.
Currently, very limited experimental data indicate that exposure of animals
to psychotropic medications such as antidopaminergic or serotonergic agents
in early life can result in specific biochemical and molecular changes in the
CNS. In some cases, these changes can persist upon drug discontinuation and
into adulthood. Interpretation of results of these experiments is limited by
the compounds, doses, administration regimens and routes employed, and the
lack of studies of chronic neurochemical or behavioral drug effects. These
and other methodological limitations of previous studies have severely
restricted generalizations of the results of these small numbers of animal
studies to humans.
Research Objectives
The ultimate goal of this research is to determine the short and long-term
consequences of chronic or acute psychotherapeutic drug administration. As
such, relevant studies in developing animals will examine behavioral,
neurochemical, physiological, and molecular effects of early drug
administration in both young and adult animals. Studies should focus on
specific behaviors and their relationship to biochemical endpoints within
defined brain regions. Research approaches to address these questions could
include, but are not limited to the following:
a) Develop models of psychotherapeutic medication delivery in normal
developing animals - Studies are needed to examine the long-term effects of
chronic and acute administration of therapeutic doses of psychotherapeutic
medications prescribed in children. Examples of relevant medications
include, but are not limited to, stimulants (as used in the treatment of
ADHD) and antidepressants. Examples of relevant research include:
o Examine effects of oral and other routes of administration to emulate as
closely as possible human dosing regimens and plasma drug concentrations
across a range of therapeutic doses. Comparisons should assess species,
gender, and age differences in the kinetics and metabolism of drugs over the
range of therapeutic doses.
o Examine effects of age and duration of psychotherapeutic drug
administration in animals within and across identified brain regions.
o Determine specificity of chronic psychotherapeutic drug effects to
developmental periods.
Endpoint measures for these studies might include, but are not limited to,
neurotransmitters (levels, metabolism, synthesis, release), expression and
activity of receptors, transporters, and other signaling molecules, gene
regulation, neuroendocrine measures in brain, electrophysiological activity,
plasticity, and brain development and growth including neuroanatomical and
neurochemical markers of brain development, tropic factor expression and
action, circadian rhythms, and hormonal effects on these processes.
b) Develop and apply behavioral models in animals to assess long-term effects
of psychotherapeutic drug administration during development on cognitive and
emotional measures. Examples of relevant research include:
o Develop objective and reliable measures to mirror specific clinical
behavioral attributes associated with psychiatric disorders occurring in
children and that serve as specific markers of psychotherapeutic drug
efficacy.
o Develop behavioral measures that are applicable over the lifespan
including juvenile, adolescent, and aged animals.
o Identify specific behavioral measures in young animals that are predictive
of adult behavioral responses including, for example, cognitive ability, drug
response, attention, and response to environmental challenges.
o Develop and apply behavioral measures to genetic models employing
regionally and temporally selective manipulations of gene expression in brain
to study anatomical, neurochemical, and signaling pathways mediating drug-
induced behavioral changes.
o Examine the effects of chronic drug administration in developing animals
on adult behavioral responses to pharmacological or environmental challenges
(i.e., stressors) or reinforcing stimuli.
The behavioral models should be amenable to studies of the neural pathways,
transmitters, and signaling molecules responsible for therapeutic and
negative effects of drugs.
Examples of some relevant behavioral measures for examining long-term effects
of therapeutic doses of psychotherapeutic medications might include, but are
not limited to, cognition, learning and memory, attention, impulsivity,
exercise, play, anxiety, fear, response to novelty, and social behavior.
Studies of the behavioral effects of stimulant medications used to treat
ADHD, for example, might identify mechanisms responsible for drug effects on
attention, eating, or sleep.
c) Apply pharmacological and behavioral animal models to assess drug
mechanisms and brain sites responsible for therapeutic and adverse drug
effects in developing animals. Relevant questions include but are not
limited to the following:
o Examine long-term effects of chronic psychotherapeutic medication
administration in developing animals (i.e., stimulants, antidepressants, and
antidopaminergic agents)on brain and behavior. Identify developmental stages
that may be uniquely sensitive to drug effects.
o Identify brain regions responsible for the therapeutic and negative
effects of therapeutic doses of psychotherapeutic medications on behavior.
o Determine neurochemicals responsible for the beneficial and adverse
effects of psychotherapeutic medications in developing animals. Identify
cellular mechanisms. Develop strategies for identifying novel
psychotherapeutic medications with fewer adverse effects.
o Examine the combined consequences of early environmental experience and
psychotherapeutic drug administration on brain and behavioral measures in
adult animals.
Integrative studies in both non-human primates and preliminary studies in
other species are encouraged. Brain imaging and gene targeting approaches to
identify molecules and brain regions responsible for behavioral effects of
drugs are also appropriate.
d) Develop and expand clinical studies to examine possible effects of
psychotherapeutic administration on the development of children as assessed
by behavioral and brain measures obtained during childhood and/or in adults.
Examples of relevant research include:
o Study the possible impact of psychopharmacological treatment on
developmentally relevant clinical parameters, such as, physical growth,
sexual maturation, and cognitive development.
o Study possible toxicities of psychotropic medications, which are specific
or more common in certain phases of development as compared with adulthood.
o Utilize non-invasive imaging techniques to study the effects on the brain
of psychotropic medication in children.
o Employ brain imaging techniques to assess the effects of childhood drug
administration on adult brain function.
o Identify brain regions responsible for the therapeutic and negative
effects of therapeutic doses of psychotherapeutic medications.
o Develop valid biochemical, imaging, or pharmacogenetic biomarkers or
objective behavioral outcome measures for assessing clinical efficacy and
safety of psychotherapeutic medications.
e) Study the possible effects of development on the pharmacokinetics,
metabolism, disposition, and pharmacodynamics of psychotropic medications
commonly used in children and adolescents. Examine gender and ethnic
differences in these measures. Examples of possible relevant research:
o Study the pharmacokinetics, pharmacodynamics, and/or
pharmacokinetic/pharmacodynamic correlations of medications commonly used in
the treatment of children with mental disorders.
o Study developmentally mediated changes in the ability to metabolize
psychotropic medications in children.
o Study the bioavailability of liquid formulations of psychotropic
medications used in young children.
o Study the effects of drug-drug interactions when combined therapies of
psychotropic medications are used.
o Study the effect of development on the bio-distribution of psychoactive
agents.
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of
the research. This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).
All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28,
1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol.
23, No. 11, March 18, 1994 available on the web at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by
the NIH, unless there are scientific and ethical reasons not to include them.
This policy applies to all initial (Type 1) applications submitted for
receipt dates after October 1, 1998.
All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects" that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
APPLICATION PROCEDURES
Applicants are strongly encouraged to contact the program staff listed under
INQUIRIES with any questions regarding their proposed project and the goals
of this PA.
Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated
in the application kit. Application kits are available at most institutional
offices of sponsored research and from the Division of Extramural Outreach
and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, Email:
GrantsInfo@nih.gov. Applications are also available on the World Wide Web
at: http://grants.nih.gov/grants/forms.htm.
SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS
The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The
just-in-time concept allows applicants to submit certain information only
when there is a possibility for an award. It is anticipated that these
changes will reduce the administrative burden for the applicants, reviewers
and Institute staff. The research grant application form PHS 398 (rev. 4/98)
is to be used in applying for these grants, with the modifications noted
below.
BUDGET INSTRUCTIONS
Modular Grant applications will request direct costs in $25,000 modules, up
to a total direct cost request of $250,000 per year ($125,000 for R21).
Applications that request more than $250,000 direct costs in any year must
follow the traditional PHS 398 application instructions. The total direct
costs must be requested in accordance with the program guidelines and the
modifications made to the standard PHS 398 application instructions described
below:
PHS 398
o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 increments up to a maximum of $250,000 or $125,000 for R21) and
Total Costs [Modular Total Direct plus Facilities and Administrative (F&A)
costs] for the initial budget period Items 8a and 8b should be completed
indicating the Direct and Total Costs for the entire proposed period of
support.
o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page
4 of the PHS 398. It is not required and will not be accepted with the
application.
o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required
and will not be accepted with the application.
o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for
sample pages.) At the top of the page, enter the total direct costs
requested for each year. This is not a Form page.
o Under Personnel, list key project personnel, including their names,
percent of effort, and roles on the project. No individual salary
information should be provided. However, the applicant should use the NIH
appropriation language salary cap and the NIH policy for graduate student
compensation in developing the budget request.
o For Consortium/Contractual costs, provide an estimate of total costs
(direct plus facilities and administrative) for each year, each rounded to
the nearest $1,000. List the individuals/organizations with whom consortium
or contractual arrangements have been made, the percent effort of key
personnel, and the role on the project. Indicate whether the collaborating
institution is foreign or domestic. The total cost for a
consortium/contractual arrangement is included in the overall requested
modular direct cost amount. Include the Letter of Intent to establish a
consortium.
o Provide an additional narrative budget justification for any variation in
the number of modules requested.
o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a
specific role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for
all key personnel, following the instructions below. No more than three
pages may be used for each person. A sample biographical sketch may be
viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm
- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;
o CHECKLIST - This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the
type of agreement and the date. All appropriate exclusions must be applied
in the calculation of the F&A costs for the initial budget period and all
future budget years.
o The applicant should provide the name and phone number of the individual
to contact concerning fiscal and administrative issues if additional
information is necessary following the initial review.
Applications not conforming to these guidelines will be considered
unresponsive to this PA and will be returned without further review.
Applicants planning to submit grant applications requesting $500,000 or more
in direct costs for any year are advised that he or she must contact the
Institute program staff before submitting the application, i.e., as plans for
the study are being developed. Furthermore, the application must obtain
agreement from the Institute staff that the Institute will accept the
application for consideration for award. Finally, the applicant must
identify, in a cover letter sent with the application, the staff member and
Institute who agreed to accept assignment of the application.
This policy requires an applicant to obtain agreement for acceptance of both
any such application and any such subsequent amendment. Refer to the NIH
Guide for Grants and Contracts, March 20, 1998 at:
http://grants.nih.gov/grants/guide/notice-files/not98-030.html
Any application subject to this policy that does not contain the required
information in a cover letter sent with the application will be returned to
the applicant without review.
The title and number of the program announcement must be typed on line 2 of
the face page of the application form and the YES box must be marked.
Submit a signed, typewritten original of the application, including the
Checklist, and five signed photocopies in one package to:
CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the NIH
Center for Scientific Review (CSR). Applications that are complete will be
evaluated for scientific and technical merit by an appropriate peer review
group convened in accordance with NIH peer review procedures. As part of the
initial merit review, all applications will receive a written critique, and
may undergo a process in which only those applications deemed to have the
highest scientific merit will be discussed, assigned a priority score, and
receive a second level review by a national advisory council or board.
Review Criteria
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. In
the written comments reviewers will be asked to discuss the following aspects
of the application in order to judge the likelihood that the proposed
research will have a substantial impact on the pursuit of these goals. Each
of these criteria will be addressed and considered in assigning the overall
score, weighting them as appropriate for each application. Note that the
application does not need to be strong in all categories to be judged likely
to have major scientific impact and thus deserve a high priority score. For
example, an investigator may propose to carry out important work that by its
nature is not innovative but is essential to move a field forward.
(1) Significance: Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced?
What will be the effect of these studies on the concepts or methods that
drive this field?
(2) Approach: Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics?
(3) Innovation: Does the project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does the project challenge
existing paradigms or develop new methodologies or technologies?
(4) Investigator: Is the investigator appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?
(5) Environment: Does the scientific environment in which the work will be
done contribute to the probability of success? Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements? Is there evidence of institutional
support?
The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders,
minorities and their subgroups, and children as appropriate for the
scientific goals of the research and plans for the recruitment and retention
of subjects; the provisions for the protection of human and animal subjects;
and the safety of the research environment.
AWARD CRITERIA
Applications will compete for available funds with all other recommended
applications. Funding decisions will be made based on the quality of the
proposed project as determined by peer review as well as program priorities
and availability of funds.
INQUIRIES
Inquiries are encouraged. The opportunity to clarify any issues or questions
from potential applicants is welcome.
Direct inquiries regarding programmatic issues about basic or clinical
neuroscience research including sites and mechanisms of drug action to:
Lois Winsky, Ph.D.
Division of Neuroscience and Basic Behavioral Research
National Institute of Mental Health
6001 Executive Boulevard, Room, 7184, MSC 9641
Bethesda, MD 20892-9641
Telephone: (301) 443-5288
FAX: (301) 402-4740
Email: lois@helix.nih.gov
Direct inquiries regarding programmatic issues about research focused on
clinical outcomes to:
Benedetto Vitiello, M.D.
Division of Services and Intervention Research
National Institute of Mental Health
6001 Executive Boulevard, Room 7147, MSC 9633
Bethesda, MD 20892-9633
Telephone: (301) 443-4283
FAX: (301) 443-4045
Email: bvitiell@nih.gov
Direct inquiries regarding psychotropic medication interactions with child
growth to:
George P. Giacoia, M.D.
Endocrinology, Nutrition and Growth Branch
Center for Research in Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B11B
Bethesda, MD 20982-5288
Telephone: (301) 496-5589
FAX: (301) 480-9791
Email: gg65m@NIH.GOV
Direct inquiries regarding applications relevant to drug abuse to:
Roger M. Brown, Ph.D.
Division of Neuroscience and Behavior Research
National Institute on Drug Abuse
6001 Executive Boulevard, Room 4282
Bethesda, MD 20892-9555
Telephone: (301) 435-1311
FAX: (301) 594-6043
Email: rb99w@NIH.GOV
Direct inquiries regarding fiscal matters to:
Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Boulevard, Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-2805
FAX: (301) 443-6885
Email: Diana_Trunnell@nih.gov
Mary E. Daley
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E03D, MSC 7510
Bethesda, MD 20892-7510
Telephone: 301-496-1305
FAX: (301) 402-0915
Email: md74u@nih.gov
Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
6001 Executive Boulevard, MSC 9541
Bethesda, MD 20892-9541
Telephone: (301) 443-6710
FAX: (301) 594-6849
Email: gfleming@nida.nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.242. Awards are made under 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 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.
The PHS strongly encourages all grant and contract recipients to provide a
smoke-free workplace and promote the non-use of all tobacco products. In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking
in certain facilities (or in some cases, and portion of a facility) in which
regular or routine education, library, day care, health care or early
childhood development services are provided to children. This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.
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