PA-99-090: PREVENTION AND EARLY INTERVENTION IN PSYCHOTIC DISORDERS

Department of Health
and Human Services (HHS)

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PREVENTION AND EARLY INTERVENTION IN PSYCHOTIC DISORDERS Release Date: April 20, 1999 PA NUMBER: PA-99-090 P.T. 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 research grant applications to study the early symptomatic manifestations of psychoses in the prodromal phase. The prodromal phase is defined as that period preceding the onset of the first florid psychotic episode, when there is increasing symptomatic presentation and functional deterioration. Among the psychotic disorders, schizophrenia and schizoaffective disorders are highly disabling brain disorders characterized by episodes of florid psychosis, as well as more persistent negative symptoms. Typically there is a delay of a year or more between onset of full-blown disorder and initiation of antipsychotic treatment. Despite remarkable therapeutic advances, only a minority of people make a complete recovery from a first episode of schizophrenia. Since complete recovery from schizophrenia is rare following the onset of full-blown disorder, intervention in the prodromal phase may be a critical strategy to improve course and outcome. Currently, prospective studies of the prodromal phase are limited. Few interventions are available specifically for prodromal individuals, and the efficacy of existing pharmacological or behavioral interventions during the prodromal phase has not been systematically studied. Applications that include one or more of the following aims are encouraged: 1) diagnostic, clinical, neurocognitive and neurobiological characterization of the prodromal phase, including longitudinal studies as the prodromal phase evolves into full-blown psychosis, 2) development of methods for identifying prodromal individuals in clinical and community settings, and 3) development and early testing of new interventions in the prodromal phase. The results of funded applications are expected to lead to clinically useful screens for detection of individuals at high risk for evolution into psychosis, the development and piloting of interventions with prodromal individuals, and clinical trials to test the efficacy of prodromal interventions and feasibility of prevention in this population. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS led national activity for setting priority areas. This Program Announcement (PA), Prevention and Early Intervention in Psychotic Disorders, is related to the priority area of Mental Health and Mental Disorders. Potential applicants may obtain a copy of "Healthy People 2000" at http://www.crisny.org/health/us/health7.html 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. Foreign institutions and organizations may not use the small grant (R03) mechanism. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) small grant (R03) and research project grant (R01) award mechanisms, including the Collaborative R01s for Clinical Studies of Mental Disorders. For the NIMH Small Grant Program, see http://www.nih.gov/grants/guide/pa-files/PA-99-071.html, and the Collaborative R01 Program is described in PAR-98-017 (see http://www.nih.gov/grants/guide/pa-files/PAR-98-017.html). The Collaborative R01s for Clinical Studies of Mental Disorders (CSMD) requires more than one applicant organization. Applications for awards may be submitted as part of a CSMD group. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may not exceed five years for the R01 and two years for the R03. Because the small grants and collaborative R01s have special eligibility requirements, application formats, and review criteria, and because of special issues with human subjects in the proposed research, applicants are strongly encouraged to consult with program staff (listed under INQUIRIES) and to obtain the appropriate additional announcements for those grant mechanisms. Specific application instructions have been modified to reflect the "MODULAR GRANT APPLICATION AND AWARD" process which has been adopted by the NIH (see the NIH Guide, December 15, 1998). For this PA, funds must be requested in $25,000 direct cost modules up to $250,000. A feature of the modular grant is that no escalation is provided for future years, and all anticipated expenses for all years of the project must be included within the number of modules being requested. Only limited budget information is required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. 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://www.nih.gov/grants/funding/modular/modular.htm RESEARCH OBJECTIVES Background Schizophrenia and schizoaffective disorder typically are first manifested in late adolescence or young adulthood. Full-blown psychosis is often preceded by months or years of a gradual deterioration of functioning, including the appearance of negative symptoms, odd behaviors and beliefs, and non-specific symptoms such as depression, anger outbursts, and anxiety. Following a first acute episode of schizophrenia or schizoaffective disorder, residual psychotic symptoms, negative symptoms and a variety of cognitive deficits often persist and are associated with major psychosocial impairments. One of the best predictors of outcome in first episode patients is treatment adherence, and there are data to suggest that earlier, more intense interventions produce better outcomes. This makes it critical to test whether intervention in the prodromal state of early pre-florid psychosis might prevent or delay onset of full-blown psychotic disorder and/or improve the subsequent course of illness. There are now a number of investigations (mostly outside the U.S.) focused on identifying and intervening in psychotic disorders before the illnesses are fully expressed. An Australian study of individuals with symptoms of the prodromal phase found that 40 percent had converted to full-blown psychosis within a year, although other research indicates that the constellation of symptoms that make up the prodromal phase are not specific to schizophrenia. Strategies for case identification have included community outreach, education and screening in clinical, primary care and school settings. To date, however, relatively little research has been undertaken to validate and further refine definitions of psychosis prodromal phase by prospective study. The feasibility of different screening and case identification strategies has not been assessed in the context of U.S. health care, educational or legal systems. There is anecdotal data on psychosocial and pharmacological interventions in prodromal samples, but these intervention strategies need to be tested in larger, well-characterized samples, followed prospectively to assess the impact of an intervention on the evolution of disorder. In addition to strategies to control clinical symptoms, new strategies targeted to neurocognitive and functional deficits need to be developed. A number of studies have examined high-risk individuals (e.g., children of people with schizophrenia). While an estimated 10 percent of offspring of a parent with schizophrenia will become ill with a psychotic disorder, the period of risk stretches over two to three decades, and the great majority will not develop schizophrenia. Additionally, a minority of high-risk individuals may manifest neurocognitive and clinical symptoms that do not meet criteria for a major psychosis but which nonetheless disable. However, for this announcement, genetic high-risk individuals are not of themselves proposed for preventive intervention trials unless they are characterized by additional risk factors. Such individuals, however, might be an enriched population for screening for prodromal symptoms. There have also been a number of studies looking at patients with schizophrenia in their first- episode of illness. However, by definition, these patients already have a psychotic disorder, and many have endured the course of illness for at least a year. The subjects to be studied under this PA would typically fall between these extremes and would include typically adolescents or young adults who are manifesting symptomatic and/or functional changes but do not yet meet syndromal criteria for psychosis. The prodromal phase is a unique window of opportunity where primary and secondary prevention meet. The prodromal phase may also be a critical time in the pathophysiological processes leading to schizophrenia. It is increasingly clear that schizophrenia is a disorder of brain development. Its moderate heritability and association with second trimester stress, along with reports of premorbid behavioral abnormalities in pre-schizophrenic children suggest that schizophrenia is a delayed expression of earlier developmental events. Nonetheless, while early abnormal brain development may set the stage for disorder, later neural, neuroendocrine, and environmental processes may also play a role in actual expression of psychosis and onset of negative symptoms. There are some data to suggest that neuroanatomical abnormalities worsen over time in first episode patients. Understanding these later processes and related behavioral changes during the prodromal phase may provide new targets for intervention development. Examples of research topics and approaches that may be addressed under this PA are suggested. Examples are illustrative, but not restrictive. Characterization of the prodromal phase o What are the neurocognitive, clinical, behavioral and functional characteristics of the prodromal phase? How are they distinctive from high- risk, chronic schizotypal or psychotic samples? o Can the prodromal phase of psychosis be distinguished from the prodromal phase or early manifestations of other disorders (e.g. psychotic mood disorders)? o How are different domains of functioning impaired in the prodromal phase? How does the presence of a prodromal family member affect family functioning? o What relationship exists between prodromal impairment and neurocognitive factors? To what degree are these features predictive of subsequent clinical course? o What is the range of outcomes in individuals who exhibit prodromal symptoms but do not progress to psychosis? How are they distinguished prodromally from those who evolve psychosis? Methods for screening and identifying prodromal symptoms of psychotic disorders o What are the most distinguishing features of the psychotic disorder prodromal phase? Although family history is the strongest risk factor known for psychosis, first-degree relatives typically have only a 10 percent chance of developing schizophrenia. What are alternative or additional indices of risk? o What definitions of prodromal phase should be used in studies? What level of sensitivity and specificity should be required for prospective non- intervention studies, and for interventions? o What are feasible approaches to screening and/or recruitment for low base- rate disorders such as psychosis? What are the best strategies to identify high-risk persons in the context of U.S. health care and educational systems? Developing approaches to intervention in the prodromal phase o Which pharmacological and behavioral interventions are effective for ameliorating cognitive, behavioral, and functional deficits? o Does the appropriateness and efficacy of an intervention vary with phase (early versus late) of the prodromal phase? o Which interventions with family members are most helpful in ameliorating prodromal symptoms in an affected relative? o Are there differential effects of intervention on different domains of outcome and functioning? o Which combination and staging of pharmacological and behavioral interventions are most efficacious? SPECIAL REQUIREMENTS This PA poses a number of issues related to human subjects that must be addressed. Despite the presence of multiple risk indices and functional impairment, some individuals may not develop a later psychotic disorder. Conversely, since there is no currently effective intervention for schizophrenia that constitutes a cure, prodromal intervention may provide the best means available for improving clinical course. Depending on application aim(s), applicants are asked to address issues concerning human subjects including the following: How will criteria be defined to maximize probability of correctly identifying a psychosis-prone individual? How will the aims of the study be explained both to the study participant, family members and other possible subject recruitment sources? At what phase in the prodromal phase should an individual be entered into a clinical trial using pharmacological interventions and/or psychosocial interventions? At what phase should an individual be dropped from the placebo arm of a clinical trial and entered into antipsychotic treatment? How will adverse side effects be monitored and addressed? All applications must address in detail how research subjects will be identified and how their families will be approached about involvement in proposed studies, and how confidentiality will be assured. Investigators may wish to consider obtaining certificates of confidentiality for the protection of study subjects. For reasons of confidentiality, reasonable medical screening and treatment costs may be included within application budgets to maintain privacy. 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 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) 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://www.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 the responsiveness of their proposed project to the goals of this PA. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. 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://www.nih.gov/grants/forms.htm. BUDGET INSTRUCTIONS o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments) 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 - Use a Modular Grant Budget Narrative page. (See http://www.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. 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 must be mindful of the salary cap limitation in the DHHS budget appropriation language and the NIH graduate student compensation policy. 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. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. 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://www.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page, - List current position(s) and then previous positions, - List selected peer-reviewed publications, with full citations, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. o OTHER SUPPORT - Form Page 7. This form must be completed for applications in response to this PA to allow awards to be negotiated and made on or before September 30, 1999. o CHECKLIST - This page must be completed and submitted with the application in response to the PA to allow awards to be considered for FY 99 funding. If the F&A rate agreement has been established, indicate the type of agreement and the date. It is important to identify all exclusions that were used in the calculation of the F&A costs for the initial budget period and all future budget years. 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 application types requesting $500,000 or more in direct costs for any year (includes CSMD direct costs combined) are advised that they must contact Institute program staff before submitting the application, i.e., as plans for the study are being developed (See INQUIRIES, below). Furthermore, the applicant must obtain agreement from 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 subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 (http://www.nih.gov/grants/guide/notice-files/not98-030.html 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 convened in accordance with the 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? Are human subjects issues adequately addressed? (3) Innovation: Does the project employ novel concepts, approaches or method? 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 approved applications. 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 general programmatic issues and research on early identification, clinical characterization and intervention studies to: Mary C. Blehar Ph.D. Division of Mental Disorders, Behavioral Research and AIDS National Institute of Mental Health 6001 Executive Boulevard, Room 6186, MSC 9625 Bethesda, MD 20892-9625 Telephone: (301) 443-1636 FAX: (301) 443-4611 Email: mblehar@nih.gov Direct inquiries regarding studies of randomized intervention efficacy trials to: Jane L. Pearson Ph.D. Division of Intervention and Services Research National Institute of Mental Health 6001 Executive Boulevard, Room 7160, MSC 9635 Bethesda, MD 20892-9635 Telephone: (301) 443-3598 FAX: (301) 594-6784 Email: jp36u@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 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. Awards will be administered under PHS grants policy as stated in the NIH Grants Policy Statement (October 1, 1998). 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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