PA-00-114: DEVELOPMENTAL PSYCHOPHARMACOLOGY

Department of Health
and Human Services (HHS)

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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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