Full Text MH-97-002 TREATMENT OF PRIMARY MOOD DISORDERS IN THE COMORBIDLY ILL NIH GUIDE, Volume 26, Number 13, April 25, 1997 RFA: MH-97-002 P.T. 34 Keywords: Mental Disorders Alcohol/Alcoholism Drugs/Drug Abuse National Institute of Mental Health Letter of Intent Receipt Date: June 5, 1997 Application Receipt Date: July 10, 1997 PURPOSE The National Institute of Mental Health (NIMH) announces the availability of competitive supplementary support for existing clinical therapeutic research grants to study the efficacy and effectiveness of treatment of primary mood disorders in individuals with co-occurring mental, alcohol or substance abuse disorders, with or without associated physical disorders. The purpose is to optimize mental health treatments for primary mood disorders in the presence of comorbid disorders which occur frequently in clinical settings, complicating usual treatment efforts, but which generally preclude participation in controlled clinical treatment trials. 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 Request for Applications (RFA), Treatment of Primary Mood Disorders in the Comorbidly Ill, is related to the priority areas of reduction of tobacco use (objectives 3.4, 3.14, 3.16), increased evaluation and treatment of alcohol and substance use disorders (4.12, 4.19), reduction of rate of suicide (6.1), and enhanced recognition, diagnosis, and treatment of mood disorders (6.7, 6.8, 6.13). Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications for supplementary support may be submitted by Principal Investigators of National Institute of Mental Health (NIMH) grants focused on the treatment of mood disorders. 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. To be eligible for consideration for this competitive supplement, current treatment grants must be active and funded at the time of application, with a minimum of two years' funding remaining at the time of expected award. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use competitive supplements to the following NIH research project grant mechanisms: R01, R10, R18, R21, R37, P01, P30, P50, or U01. (Foreign institutions are not elibible to apply for P01, P30, or P50 supplements.) Questions about these grant mechanisms should be directed to Institute program staff (listed under INQUIRIES). This RFA is one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 1997. The total project period for an application submitted in response to this RFA may not exceed the tenure remaining on the parent grant to be supplemented. FUNDS AVAILABLE It is anticipated that at least $500,000 in direct costs will be made available. Direct costs for the first year of supplemental funding under this RFA may not exceed that of the previous year of the parent grant, up to a maximum of $200,000. Funding for subsequent years is dependent on demonstrated progress in meeting the goals of the project and on the continued availability of funds. TERMS AND CONDITIONS OF SUPPORT Supplemental funds may be used for expenses clearly related and necessary to conduct the proposed supplemental treatment research, including both direct and allowable indirect costs. Supplemental funds may not be used to conduct research that is an integral part of the parent grant, and may not be used to operate a treatment, rehabilitation, or other service program. RESEARCH OBJECTIVES Background The considerable advances made in the treatment of mood disorders over the past generation have largely been accomplished through the application of carefully controlled clinical trials. Rigorous attention to research methodology, including sharply focused inclusion and exclusion criteria designed to achieve homogenous study samples, has been necessary to assure the scientific validity of treatment trials in mood disorders. However, increasingly it is being recognized that an inadvertent limitation of this narrowly based research design has been difficulty in generalizing the resulting findings to nonprotocol clinical populations. In clinical settings, many patients with mood or other mental disorders presenting for treatment prove to suffer from coexisting mental health or substance use problems, which confound or interfere with treatment of a primary mood disorder and often constitute a focus for treatment in their own right. Such individuals as a rule are not represented in controlled clinical trials of mood disorder treatments, as comorbidity is a common exclusion criterion in such studies. Thus, frequently even a large research data base cannot be applied to nonprotocol patients in the clinic. Moreover, usual treatments for mood disorders may demonstrate an altered benefit:risk ratio in the presence of certain comorbidities, or may fail to work as expected under such circumstances. Examples of comorbid conditions affecting mood disorder patients, of interest for the present request for applications, include the following: o Other mental disorders. Depression in particular is often accompanied by other DSM-IV Axis I disorders. For example, speakers at a recent NIMH workshop identified comorbid panic disorder as a common cause of treatment-resistant depression. Of note, depression secondary to other mental disorders is not the focus of this RFA dealing with the treatment of primary mood disorders. As the multiaxial system of DSM-IV permits the diagnosis of personality disorders concurrently with Axis I mood disorders, these chronic Axis II conditions, affecting perhaps half of primary mood disorder patients and long associated with impaired response to conventional treatments of mood disorders, are appropriate candidates for study. o Alcohol and substance abuse and dependence disorders. The importance of substance use disorders as comorbid conditions accompanying mood disorders was highlighted by the NIMH Epidemiologic Catchment Area (ECA) study, a community-based survey that identified an increased risk for alcohol or substance abuse or dependence in individuals with diagnosed mood disorders that was even greater than the average enhanced risk evidenced by subjects with any mental disorder. For example, more than 60% of individuals with bipolar I disorder have an active substance abuse problem, with nonalcohol drug abuse or dependence 11-times greater than in people without bipolar disorder. While less common than in bipolar patients, alcohol and substance use diagnoses in unipolar depressed patients still exceed those found in the general population. These concurrent problems contribute to the morbidity of mood disorders, including frequency of hospitalizations, to difficulties with adherence to treatment regimens, and to refractoriness to conventional therapies of comorbid mood disorders. Certainly, mood disorders often occur secondary to alcohol or substance abuse or dependence. Applications regarding the treatment of such secondary mood disorders are not the province of this request for applications, and should be directed, as appropriate, to program staff at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) or the National Institute on Drug Abuse (NIDA). o Physical health disorders. As with all individuals, people with mental disorders may also suffer from impairment of their physical health. Some evidence suggests that certain types of physical illness, such as cardiovascular disease, may be more prevalent in patients with mood disorders than in the general population. Expansion of current study inclusion criteria under this RFA to encompass mood disordered patients with comorbid conditions can be expected to increase the likelihood of co-existing physical illness, such as gastrointestinal and liver dysfunction in patients with active alcohol abuse or dependence. Investigators are encouraged to include such physically impaired subjects when scientifically justified and feasible. However, medical illness should not be the sole comorbid condition under study. Although depression in the medically ill is sometimes felt to be an "understandable" reaction to disease or disability, the DSM-IV multiaxial diagnostic system recognizes the independence of assessment of mood disorders (Axis I) and physical health impairments (Axis III). Consequently, for purposes of this request for applications, mood disorders need not be considered "secondary" to physical health problems and thus not appropriate for research under this RFA except when clearly organic in etiology, e.g. the direct result of injury to brain tissue, or medication (such as reserpine or steroids)-induced. Research Issues The aim of this announcement is to encourage research focusing on optimizing the efficacy and effectiveness of treatment of primary mood disorders in the context of comorbid mental disorders, including concurrent alcohol or substance abuse or dependence. For purposes of this announcement, the group of mood disorders are those recognized by the Diagnostic and Statistical Manual, 4th Edition (DSM-IV, 1994), including bipolar disorder, unipolar depression, dysthymia, and their defined subtypes. Except as specified below, the descriptor "primary" refers to temporal sequence of diagnostic entities, such that patients studied under the terms of this announcement would be expected to have been diagnosed with a mood disorder at a time prior to the diagnosis of any other Axis I disorder. This restriction is not absolute in terms of comorbid Axis II or III disorders (see above). Many of the issues involved are confronted regularly in clinical settings in the absence of an adequate well-researched data base. Studies that will advance the field by addressing the following or similar outstanding questions are encouraged: o Does the presence of a comorbid disorder alter the adverse effects of mood disorder treatments, either qualitatively or quantitatively? o How can adherence to treatment plans be maximized in the comorbidly ill mood disorder patient? o In the presence of comorbid mental or substance use disorders, is the pathophysiology of primary mood disorders altered in ways that have implications for treatment? o What is the optimal relationship and sequencing of treatment of the presenting mood disorder and comorbid disorders? How is this affected by the nature and severity of the comorbid condition? o Are there relevant pharmacokinetic and pharmacodynamic considerations in using antidepressant, antimanic, and mood-stabilizing medications in the face of additional concurrent psychopathology or alcohol/substance abuse, with or without physical illness? How should medication choice or dosing be adjusted in comorbidly ill patients? What are the gaps in knowledge regarding interactions between drugs used in the treatment of mood disorders and those prescribed for the most common comorbid physical illnesses? o For which patients is psychotherapy or psychosocial rehabilitation likely to be helpful? When should these interventions be attempted alone, as opposed to combined with pharmacotherapy? o What is the role of nonpharmacological somatic treatments, such as electroconvulsive therapy (ECT), bright light treatment, sleep deprivation, or repetitive transcranial magnetic stimulation (rTMS), in the treatment of primary mood disorders comorbid with other disorders? o Are there predictors of response or nonresponse to treatment for primary mood disorders with specific therapies in the presence of particular comorbid conditions? In addition, general issues confronting all treatment research are relevant for consideration in responses to the present announcement. These include: o Evaluation of any variation in efficacy, effectiveness, or toxicity of treatment of comorbid mood and other mental/physical disorders across ethnic, racial, or age groups o Need for development and utilization of valid and reliable measures of social and vocational skills, behavioral stability, functional capabilities, quality of life, and cost-effectiveness to complement the measures of psychopathology heavily emphasized in most treatment studies 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 new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. 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 reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are asked to submit by June 5, 1997 a letter of intent that includes the title, number, and source of the existing PHS treatment grant for which supplementary funding is sought. Additional requested information includes a descriptive title of the proposed research, the name, mailing and Email address, and telephone / FAX numbers of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of this request for applications. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows NIMH staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent should be sent to: Matthew V. Rudorfer, M.D. Assistant Chief, Clinical Treatment Research Branch Division of Clinical and Treatment Research National Institute of Mental Health Parklawn Building 5600 Fishers Lane, Room 18-105 Rockville, MD 20857 Telephone: (301)443-4527 FAX: (301)480-4417 Email: mrudorfe@nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research or from the Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910; telephone (301) 710-0267; fax (301) 480-0525; Email: ASKNIH@ODROCKM1.OD.NIH.GOV. The RFA label available in the PHS 398 (rev. 5/95) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number, Treatment of Primary Mood Disorders in the Comorbidly Ill, MH-97-002, must be typed in section 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 three signed, photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier/overnight mail service) At the time of submission, two additional copies of the application must be sent to: Mary Lou Prince Clinical Treatment Research Branch Division of Clinical and Treatment Research National Institute of Mental Health Parklawn Building 5600 Fishers Lane, Room 18-105 Rockville, MD 20857 Applications must be received by July 10, 1997. If an application is received after that date, it will be returned to the applicant without review. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The DRG will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants (DRG) and for responsiveness by NIMH staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the Request for Applications will be evaluated for scientific and technical merit by an appropriate peer review group convened in July / August 1997 in accordance with the review criteria stated below. 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 will be discussed, assigned a priority score, and receive a second level review by the National Mental Health Advisory Council in September 1997. Review criteria o suitability of the currently funded treatment research grant for adaptation to the presence of comorbid disorders; o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources necessary to perform the research, including adequete numbers of appropriately diagnosed subjects; o appropriateness of the proposed budget and duration in relation to the proposed research; o adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human subjects, the safety of the research environment, and conformance with the NIH Guidelines for the Inclusion of Women and Minorities as Subjects in Clinical Research. AWARD CRITERIA Competitive supplements under this RFA will be awarded based on scientific merit as determined by peer review, availability of funds, and programmatic priorities. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Matthew V. Rudorfer, M.D. Division of Clinical and Treatment Research National Institute of Mental Health Parklawn Building 5600 Fishers Lane, Room 18-105 Rockville, MD 20857 Telephone: (301)443-4527 FAX: (301)480-4417 Email: mrudorfe@nih.gov Direct inquiries regarding fiscal matters to: Diana S. Trunnell Assistant Chief, Grants Management Branch National Institute of Mental Health Parklawn Building, Room 7C-08 Rockville, MD 20857 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 Public Health Service Grants Policy Statement (April 1, 1994). PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the nonuse 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, any 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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