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



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.


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: 


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 


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:  
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: for neuroscience 
research and at 
for MH intervention research. 

Special instructions and information for the small grant program is found at:  Neither the R03 
nor R21 are renewable.



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 
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 

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:


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 

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.


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:  Applications are also available on the World Wide Web 


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 


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 

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 

4 of the PHS 398. It is not required and will not be accepted with 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 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 

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:

- 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:

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:

BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)


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 

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.


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 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

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 

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

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

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


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.

Return to Volume Index

Return to NIH Guide Main Index

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS) - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.