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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