Release Date:  April 20, 1999

PA NUMBER:  PA-99-090


National Institute of Mental Health



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.


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


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.


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, and the
Collaborative R01 Program is described in PAR-98-017 (see  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:



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 þenrichedþ
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

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

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

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

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?


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

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.


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:


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

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.


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:  Applications are also available on the World
Wide Web at:


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.

of the PHS 398.  It is not required and will not be accepted with 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 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:

- 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 þ99 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

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:

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)


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

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.


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 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

Direct inquiries regarding studies of randomized intervention efficacy trials

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

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


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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