NIH GUIDE, Volume 22, Number 24, July 2, 1993

PA NUMBER:  PA-93-099

P.T. 34


  Mental Disorders 


  Treatment, Medical+ 

  Rehabilitation/Therapy, Emotional 

  Health Services Delivery 

National Institute of Mental Health


The purpose of this announcement is to encourage research grant

applications for studies on etiology, clinical course, biology,

treatment, and delivery of services for bipolar disorder.  The

collaborative development of common or complementary protocols or

methods to increase the knowledge yield from clinical resources is



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, Bipolar Disorder:  Clinical, Biological, and Treatment

Research, is related to the priority area of mental health and mental

disorders.  Potential applicants may obtain a copy of "Healthy People

2000" (Full Report:  Stock No. 017-001-00474-0) or "Healthy People

2000" (Summary Report:  Stock No. 017-001-004731) through the

Superintendent of Documents, Government Printing Office, Washington,

DC 20401-9325 (telephone 202-783-3238.)

This announcement also addresses recommendations set forth in "Caring

for People with Severe Mental Disorders: A National Plan of Research

to Improve Services".  This publication (Department of Health and

Human Services Pub. No. (ADM 91-1762) can be obtained through the

U.S. Government Printing Office, Washington, DC 20402-9325 (telephone



Applications may be submitted by domestic and foreign public and

private, non-profit and for-profit organizations, including

universities, colleges, hospitals, laboratories, units of State and

local governments, and eligible agencies of the Federal government.

Women and minority investigators are encouraged to apply.  Foreign

institutions are not eligible for the First Independent Research

Support and Transition (FIRST) (R29) awards.


Research support may be requested through applications for a regular

research grant (R01), a small grant (R03), and the First Independent

Research Support and Transition (FIRST) award (R29).  Applications

for collaborative and/or multipurpose research may be requested

through the Multi-Institutional Collaborative Research Project (R10)

mechanism as well as the new Interactive Research Project Grant

mechanism (IRPG).  Because some of these grant mechanisms have

specific program announcements with distinct application procedures

and deadlines, applicants should consult with NIMH staff concerning

choice of mechanism.



Bipolar disorder constitutes a major public health problem affecting

nearly 1.5 percent of the adult population.  Bipolar disorder can

have serious long-term effects and is often associated with

significant psychosocial impairment, lost work productivity, and high

morbidity and services utilization.  A recent analysis, funded by the

National Institute of Mental Health (NIMH) and the Agency of Health

Care Policy and Research, of outpatient and inpatient medical records

for 1.3 million patients with mood disorder found that the economic

cost of bipolar disorder is 3.5 times that of major depression.

Bipolar illness is also a significant risk factor for suicide.

Deaths by suicide are at least 35 times that found in the general

population.  There is evidence from epidemiologic and family studies

of trends toward earlier onset of bipolar illness and, possibly, of

increased prevalence in younger birth cohorts.  The factors

underlying these effects are unclear, but early onset is generally

associated with increased familial risk.

The presentation of bipolar disorder in clinical settings is

increasingly complicated by comorbid substance abuse, especially in

younger age groups.  Despite the high prevalence of comorbid bipolar

disorder and substance or alcohol abuse, there is relatively little

research with this population.  Other complications include dysphoric

mania (also known as a mixed state) and rapid cycling between mania

or hypomania and depression.  These clinical presentations are less

likely than standard bipolar disorder to respond to lithium.

Overall, they have received relatively little study in relation to

differential family patterns, gender, etiology, comorbidity,

treatment responsiveness, course, and outcome.  Increased attention

is reflected by plans to include subtypes in the DSM-IV criteria.

Childhood bipolar disorder is receiving new research attention.

Differential diagnostic issues remain a problem (e.g., with conduct

disorder, attention deficit disorder and schizophrenia), and

relatively little is known about the onset, presentation, and outcome

of childhood bipolar disorder.

Aside from lithium therapy, long-term treatment and rehabilitation of

bipolar disorder have been relatively neglected compared to

treatments for unipolar mood disorders and schizophrenia.  There is

need for greater focus on the development and application of

innovative, long-term therapeutic interventions involving both

biological and psychosocial treatments.

The following are examples of research topics focusing on bipolar

disorder research.  The list is illustrative, not exhaustive, and it

is expected that additional important research topics will be

identified by researchers who respond to this announcement.

Clinical Features, Course, and Risk Factors.  Research is encouraged

to identify factors associated with subtypes of bipolar disorder, as

well as factors associated with onset, course, and outcome of the

disorder.  Examples include studies of the following:

o  The influence of factors such as birth cohort membership, family

history, social supports, life events, comorbidity, personality, and

gender on the onset, clinical presentation, and course of bipolar


o  Risk factors in the onset of first episode and recurrence (course)

of bipolar disorder

o  Prevalence and risk factors associated with various clinical

presentations in general health care and specialty mental health


o  The time course of recovery from index episodes and relapse into

new episodes; and the predictive significance of episode-related

clinical features for recovery and relapse

o  Clinical and cognitive features that are characteristic of the

manic phases and depressed phases of bipolar disorder (e.g., thought

disorder and psychotic features) and their influence on course and


o  Course and outcome in childhood onset bipolar disorder and its

possible temperamental antecedents

o  Suicide risk in bipolar illness, including research on the

influence of comorbid substance abuse and personality disorders

Biological/Neuroscience/Psychological Functioning. Research is

encouraged to clarify the etiology, genetic susceptibility factors,

and pathophysiological and psychological characteristics of bipolar

illness. Examples include studies of the following:

o  The specific genetic bases for or contributions to the etiology of

bipolar disorder, including approaches using DNA markers of candidate

genes as well as research to identify biological measures that

co-segregate with clinical disorder in families or are present in

individuals at high risk by virtue of family history

o  Functional and structural neuroimaging techniques applied to the

study of bipolar disorder during episodes, as well as remission

o  Sleep, neuroendocrine, and circadian changes from manic to

depressed to euthymic states

o  Neurobiological, pathophysiological, cognitive, and other

psychological mechanisms or changes related to course of illness or

treatment efficacy

Treatment and Services.  Treatment of bipolar disorder is

increasingly marked by the recognition that traditional therapies

often fail to control effectively a variety of clinical presentations

such as mixed states and rapid cycling and the prevention or

treatment of breakthrough depression in the course of maintenance

therapy.  There is a special need for new therapies for women of

child-bearing age, because of concerns about teratogenic side effects

from available medications.  Studies are also needed to find the

optimum treatment for the depressive phase of the illness.  Examples

of study topics include the following:

o  Pharmacologic alternatives to lithium for both acute and long-term


o  Nonpharmacologic somatic approaches, e.g., electroconvulsive

therapy, phototherapy, sleep deprivation

o  New psychosocial treatment and rehabilitation approaches,

especially those that assess the long-term efficacy and effectiveness

of integrated biological- psychosocial and cognitive therapies

o  New treatments that take into account the high comorbidity of

substance abuse in bipolar illness

o  Management of compliance problems during long-term treatment

o  Reanalysis of treatment data sets to look for gender-specific or

ethnic factors in treatment and outcome

o  Cost-benefit and cost-effectiveness analyses of standard and

alternative treatment and rehabilitation modalities

o  Service needs and systems of care for patients with bipolar

illness and their families, including studies of service models which

coordinate care across different service systems (e.g., social,

judicial, mental health, general health service systems)





NIH policy is that applicants for NIH clinical research grants and

cooperative agreements will be required to include minorities and

women in study populations so that research findings can be of

benefit to all persons at risk of the disease, disorder or condition

under study; special emphasis should be placed on the need for

inclusion of minorities and women in studies of diseases, disorders

and conditions which disproportionately affect them.  This policy is

intended to apply to males and females of all ages.  If women or

minorities are excluded or inadequately represented in clinical

research, particularly in proposed population-based studies, a clear

compelling rationale should be provided.  The composition of the

proposed study population must be described in terms of gender and

racial/ethnic group.  In addition, gender and racial/ethnic issues

should be addressed in developing a research design and sample size

appropriate for the scientific objectives of the study.  This

information should be included in the form PHS 398 in Sections 1-4 of

the Research Plan AND summarized in Section 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including

the broadest possible representation of minority groups.  However,

NIH recognizes that it may not be feasible or appropriate in all

research projects to include representation of the full array of

United States racial/ethnic minority populations (i.e., Native

Americans (including American Indians or Alaskan Natives),

Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should

be provided.

For the purpose of this policy, clinical research includes human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions, including but not limited to

clinical trials.

The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including


If the required information is not contained within the application,

the application will be returned.

Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the

selected study population is inadequate, it will be considered a

scientific weakness or deficiency in the study design and will be

reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required

to address these policies.  NIH funding components will not award

grants or cooperative agreements that do not comply with these



Applications are to be submitted on the grant application form PHS

398 (rev. 9/91), available from most institutional offices of

sponsored research and from the Grants Management Branch, National

Institute of Mental Health, 5600 Fishers Lane, Room 7C-05, Rockville,

MD 20857, telephone 301/443-4414.  On item 2a of the application face

page, applicants must enter the number and title of this program

announcement (PA-93-099:  Bipolar Disorder:  Clinical, Biological,

and Treatment Research).

Applicants from institutions that have a General Clinical Research

Center (GCRC) funded by the NIH National Center for Research

Resources may wish to identify the GCRC as a resource for conducting

the proposed research.  If so, a letter of agreement from either the

GCRC program director or Principal Investigator could be included

with the application.


Applications in response to this announcement will be reviewed for

scientific and technical merit by an initial review group (IRG)

composed primarily of non-Federal scientific experts, and by the

appropriate National Advisory Council.  Review by the Council may be

based on policy considerations as well as scientific and technical

merit.  By law, only applications recommended for approval by Council

may be considered for funding.  Summaries of IRG recommendations are

sent to applicants as soon as possible following completion of the

IRG review.

Review Criteria

Applications will be judged on the criteria listed below:

o  Scientific significance and originality of proposed research

o  Appropriateness and adequacy of the design and methodology

proposed to carry out the research

o  Qualifications and research experience of the Principal

Investigator and staff, particularly in the area of the proposed


o  Availability of resources necessary to perform the research

o  Appropriateness of budget estimates for the proposed research

o  Adequacy of procedures for the protection of human subjects of


o  Conformance of the application to NIH policy on inclusion of women

and minorities in study populations


In making awards, the following criteria are considered: quality of

application as determined by IRG and Council recommendations, program

relevance, availability of funds.


Written and telephone 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.

Division of Clinical and Treatment Research

National Institute of Mental Health

5600 Fishers Lane, Room 10C-24

Rockville, MD  20857

Telephone:  (301) 443-1636

Direct inquiries regarding fiscal matters to:

Diana S. Trunnell

Grants Management Branch

National Institute of Mental Health

5600 Fishers Lane, Room 7C-15

Rockville, MD  20857

Telephone:  (301) 443-3065


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 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



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