WOMEN’s MENTAL HEALTH AND GENDER DIFFERENCES RESEARCH Release Date: March 6, 2000 PA NUMBER: PA-00-074 (see replacement PA-03-143) National Institute of Mental Health 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) invites grant applications from investigators for research on women's mental health and gender-related differences in mental disorders. This program announcement is a revision of PA 95-061 Women’s Mental Health Research , issued in 1995. The NIH Office of Research on Women’s Health, in its 1999 publication Agenda for Research on Women’s Health for the 21st Century, highlighted multiple factors that impact on women’s health across the life span. The field of women’s health was defined in that report as encompassing biomedical, behavioral, and psychosocial research on girls and women. It extends in scope beyond a traditional focus on women’s reproductive health to include disorders and conditions more prevalent in females than in males, or different in clinical features and risk factors. Of all demographic variables in epidemiological research, gender is the single strongest correlate of risk for different types of mental disorders. Despite the robustness of this correlation, gender itself is a proxy term for a complex of biological, behavioral, and psychosocial variables and processes, which remain as yet incompletely understood. Depressive disorders and most anxiety disorders are, on average, two to three times more common in females than males. Eating disorders are eight to ten times more common in females. Males are more likely to be affected by developmental disorders such as autism and attention deficit disorder and by substance and alcohol abuse and conduct disorders. For all disorders, including those more common in males than females and those in which gender prevalence is equal (e.g. schizophrenia; bipolar disorder), gender-related differences may occur in etiological risk factors or in clinical aspects. Gender differences in such features as neuropsychological profiles, risk for onset or recurrence, symptom severity, or disability have important practical significance for treatment and services needs. Mental disorders are major sources of disease-related disability. The Global Burden of Disease report (Murray and Lopez, 1996) identified major depression, bipolar disorder, schizophrenia and obsessive-compulsive disorder as among the ten leading sources of disease-related disability in women worldwide. In general, women are the primary consumers of treatments and services for mental disorders, but there is little consideration of epidemiological and clinical findings of gender differences applied to public mental health policy and services delivery systems. The majority of serious mental disorders have an onset in early adulthood or adolescence and a recurrent or chronic course. Thus the social impact of mental disorders falls disproportionately on women during the childbearing and childrearing years suggesting the need for more intervention research for women during pregnancy and lactation. 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), Women’s Mental Health Research, is related to the priority areas of mental health and mental disorders. 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. Foreign institutions are not eligible for R03 and P01 grants. 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) the R01, R21, R03 and P01 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 three years of funding with an average of $125,000 direct costs for each year; it is intended for pilot testing of 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 many grant mechanisms have special eligibility requirements, application formats, and review criteria, applicants are strongly encouraged to consult with program staff (listed under INQUIRIES) and to obtain the appropriate additional announcements for those grant mechanisms. Special instructions and information for the small grant program is found via the Internet at: http://grants.nih.gov/grants/guide/pa-files/PAR-99-140.html. R03s are not renewable. Because the R21 grants have a special application format and review criteria, applicants are strongly encouraged to consult with program staff (listed under INQUIRIES) and to obtain the appropriate additional announcements for those grant mechanisms. Special instructions and information for the Exploratory/Development Grants for MH Intervention Research, can be found at http://grants.nih.gov/grants/guide/pa-files/PA-99-134.html. The program project (P01) grant mechanism supports broadly based, multidisciplinary, multi-project, often long-term research programs that have a specific major objective or basic theme. To qualify for support, a program project must consist of at least three research subprojects as recommended by peer review. Applications may request support for up to five years. Annual awards will be made subject to continued availability of funds and progress achieved. All applicants for program project grants are strongly encouraged to discuss their proposals prior to submission with program staff. RESEARCH OBJECTIVES This program announcement identifies five areas for research emphasis. Because of the complexity of factors influencing women’s mental health, multidisciplinary, multi-method research is encouraged. Despite clear gender differences in prevalence of different mental disorders, there is relatively little linkage between epidemiological, etiological and intervention research. In this announcement, therefore, translational research is strongly encouraged. There is as yet an imprecise lexicon to describe differences in health status, etiology, progress, and treatment of disease between men and women. This difficulty reflects persistent conceptual lack of clarity related to the roles of biological, social and cultural factors in differences. In what follows, the term gender is used to refer to multiple processes and factors. However, investigators are encouraged to discuss their conceptual models of gender differences in their applications. The specific research topics and questions given below are illustrative only and are not intended to limit research in this area. Brain and behavior research There is increased recognition that biologically mediated gender differences influence behavioral outcomes and may modify vulnerability to different mental disorders, severity of course, or response to different treatments. Included here are basic studies in animals and humans as well as human clinical studies in subjects with mental disorders. Examples of research areas include studies of: o Gender differences in brain and behavior including structural and functional brain imaging of normative and clinical samples o Gender differences in the molecular and cellular bases of behavior, e.g. neurotransmitter levels and transporters, receptor subpopulations and enzyme levels o Gender differences in genetic factors, including differences in gene expression or gene-environment interaction in relation to mental disorders o Gender differences in the developmental-organizing and activating influences of sex steroids on brain and behavior and interactions with thyroid- and hypothalamic-pituitary adrenal axes, the immune system and neurotransmitters o Gender differences in the pharmacokinetics, pharmacodynamics and pharmacogenetics of psychotropic medications in relation to hormonal status and developmental phase Bio-behavioral dysregulation and adaptation to stress Evidence is accruing that response to stress may be mediated both by sex steroids as well as by experiential differences between men and women. Animal and human studies indicate that gender differences in hormonal factors may modulate physiological and behavioral response to stress. Epidemiological studies show that women are more likely to have experienced certain kinds of stress (e.g. childhood and adult sexual abuse), which are risk factors for mental disorders. Research also indicates that women are twice as likely as men to develop stress-related disorders and depression following exposure to traumatic events. To understand this complex area, multiple approaches are required, ranging from basic developmental and plasticity research to human clinical studies. Examples of research areas include studies of: Appetite, aggression, exploration, sleep, energy, mood and their biological rhythms as they are differentially regulated and dysregulated in males and females and in relation to mental disorders Developmental differences in males and females in risk for, exposure to, and response to, social and physical environmental variables, including stressors and trauma o The impact of stress at different developmental stages on gender- differentiated physiological and behavioral responses and risk for mental disorders o Biological, psychosocial and psychopathological correlates and consequences of violence and abuse of women and girls Epidemiological and clinical studies of disorders During the past two decades, advances in diagnosis and survey methodologies have enabled researchers to establish general estimates of the impact and service needs of adult women with mental disorders. This work remains to be done for younger females. The need for such research is particularly pressing, since in many disorders, gender differences emerge first in adolescence when early intervention strategies may be most effective in preventing full-blown mental disorders. Later in the lifespan, there is relatively little information on gender related factors in such important clinical aspects of disorders as risk for recurrence, chronicity, comorbidity and disability. Studies encouraged here include those of epidemiology, diagnosis, lifespan development and course of mental disorders in females. Studies are also encouraged for gender differences in social, behavioral, and biological risk factors for mental disorders. Examples of research areas include studies of: o Health disparities so as to identify, understand and target the burden of mental illness and related disability, and to improve treatment and services utilization among women and girls of different ethnic and socioeconomic, backgrounds o Reliability, validity and predictive value of diagnostic classifications and instruments for female populations o Taxonomies of functional outcomes and disabilities in women and girls with mental disorders and instruments to measure functional changes following interventions o Screening and identification of high-risk women and girls in primary care settings (e.g., general medical settings and obstetric-gynecology settings)for mental illness o Demographic variables and cultural and social factors (e.g. work and family roles, marriage, gender discrimination; propensity to use substances) in relation to gender differences in mental disorders o Childhood risk and protective factors related to the emergence of gender differences in mental disorders (particular mood, anxiety and eating disorders)at adolescence Reproductive transitions Menarche coincides with onset of gender disparities in incidence of depression and eating disorders. Menstruation is associated with severe mood variations in a small percentage of women. Since variance in hormonal levels per se has been found to have little correlation with mood or mood change in human research, there is need for studies of the interaction of multiple biological, clinical and environmental factors. Pregnancy and recent childbearing may be associated with higher rates of depressive disorders. This association, as well as the fact that psychotropic drugs are commonly prescribed for women of childbearing age, raises special gender-related clinical and treatment considerations. Bioethical issues in the conduct of clinical research take on added importance since psychotropic agents have the potential to affect the fetus or nursing child. Examples of research include studies of: o The role of hormonal, biological and social factors in: - emergence of gender differences in mental disorders during adolescence - etiology and course of mental disorders and premenstrual, pregnancy, postpartum and perimenopausal mood changes - age-related health and cognitive changes in pre-menopausal, post-menopausal and elderly women with a history of mental disorders o The impact of maternal disorders on outcome of offspring, especially in relation to clinical and treatment history of mothers during pregnancy o Interventions to prevent or ameliorate the onset or recurrence of mental disorders during reproductive transitions. For example, studies of the effectiveness and safety of interventions in women during pregnancy and postpartum o Interventions for women with serious mental disorders including those requiring chronic treatment, during pregnancy, postpartum or other reproductive transitions that may heighten risk for recurrence or exacerbation of disorder Other interventions and services research In addition to interventions targeted specifically for women during reproductive transitions, Federally funded phase III clinical trials and Phase III submissions to the Food and Drug Administration (FDA) for approval of new treatments for use in both males and females are required to include sufficient numbers of females to permit analysis of outcome data for gender differences. This general focus also underscores the need to examine interventions for their impact separately in males and females, to identify multiple factors in relation to outcome and to address issues affecting recruitment and retention of female subjects in trials. Interventions are defined here to include preventive, treatment, services-system and rehabilitative interventions. Specific examples of research include studies of: o Gender differences in long-term and short-term treatment outcomes for mental disorders, including suicide and suicidal behaviors o Gender-related differences in compliance and side effects of treatments; and in treatment preferences, expectancies and services use o Gender differences in health-related behaviors (e.g. diet, exercise, nutritional, vitamin or herbal supplement use) and their impact on intervention response in women and girls o Drug-drug interactions, (e.g. supplements, replacement hormones and psychotropic medications) in females across the life span o Interventions incorporating attention to risk factors for mental disorders more common or different in females than in males (e.g. history of sexual abuse and violence; caregiver roles; ruminative thinking) o Interventions targeting the early manifestations or behavioral precursors of depression, anxiety and eating disorders, other behavioral disorders and suicidality in girls and adolescent females o Interventions aimed at multiple comorbid outcomes in women and girls at risk for mental disorders or diagnosed with mental disorders (e.g. comorbid anxiety disorders in depression; substance abuse in women with bipolar disorder and schizophrenia) 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 contacts 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. (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) 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. 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. 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. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types 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 Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group in accordance with standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Applications will compete for available funds with all other recommended applications assigned to the Institute. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Mary C. Blehar, Ph.D. Chief, Women’s Mental Health Program National Institute of Mental Health 6001 Executive Boulevard, Room 8125, MSC 9659 Bethesda, MD 20892-9650 Telephone: (301) 443-2847 FAX: (301) 443-8552 Email: mblehar@mail.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 The National Institute on Drug Abuse is not participating in this program announcement, but continues to fund a broad range of Institute-wide human and animal research focusing on women and gender differences, including studies on the co-occurrence of drug abuse/addiction and mental disorders. For more information call or write: Cora Lee Wetherington, Ph.D. Women and Gender Research Coordinator, National Institute on Drug Abuse 6001 Executive Boulevard, Room 4282, MSC 9555 Bethesda MD 20893-9555 Telephone: (301) 443-1263 FAX: (301) 594-6043 Email: wetherington@nih.gov The National Cancer Institute is not participating in this program announcement but continues to fund research in the area of women’s health related to cancer survivors and their family members. For more information, call or write: Julia H. Rowland, Ph.D. Director, Office of Cancer Survivorship National Cancer Institute 6130 Executive Boulevard, Suite 539 Bethesda, MD 20892 Telephone: (301) 402-2746 FAX: (301) 496-8675 Email: rowlandj@mail.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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