Report of the NIMH Board of Scientific

Counselors Workgroup on Schizophrenia 

Research in the DIRP

March 2013
i

Executive Summary

The arrival of a new Scientific Director (SD) of the NIMH Division of Intramural Research 

Programs (DIRP), Dr. Susan Amara, and the departure of two long-standing DIRP principal 

investigators (PIs) within the Clinical Brain Disorders Branch (CBDB), provide an opportunity for

strategic planning and consideration of schizophrenia research in the DIRP. The purpose of this

report is to provide guidance to the NIMH on future directions for schizophrenia research in the

DIRP, specifically related to important directions for the field and to important areas/strategies 

for insuring high quality programmatic development. This document is a product of a 

workgroup created by the NIMH Board of Scientific Counselors (BSC) to discuss and make

recommendations around this topic. The charge to the workgroup was:

Based on public health needs, current NIMH extramural investments and the changing ecology 

of the DIRP, are there compelling scientific opportunities in the area of schizophrenia research 

that can be uniquely and effectively conducted within the DIRP?

In the course of its deliberations, the workgroup explored the opportunities and needs within 

the field of schizophrenia research and, to the degree possible, within the DIRP environment. 

Notably, the workgroup recommended that the DIRP not design a future research program to 

investigate the Diagnostic and Statistical Manual (DSM)-defined disorder of schizophrenia, but

instead to focus a future research program on psychoses, leading the field forward in the new

conceptualization of mental health research that is consistent with the NIMH Research Domain 

Criteria (RDoC) initiative. The subsequent recommendations identify scientific strategies and 

organizational steps to ensure high impact research related to psychosis and its prevention,

suggestions related to the analysis and use of existing resources within the DIRP that could be

enlarged through a strategic planning effort led by the new Scientific Director (SD).
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Table of Contents

I. Introduction and Workgroup Process........................................................................... 1

II. Opportunities and Needs.............................................................................................. 1

III. Tactical Recommendations........................................................................................... 3

IV. Conclusions................................................................................................................... 5

V. Appendix A....................................................................................................................7

VI. Appendix B ....................................................................................................................9

VII. Appendix C ..................................................................................................................10
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Introduction and Workgroup Process

The NIMH Mission is “to transform the understanding and treatment of mental illnesses 

through basic and clinical research, paving the way for prevention, recovery, and cure. “ The

NIMH Division of Intramural Research Programs (DIRP) offers outstanding resources, unique

funding mechanisms, and an exceptional environment for research that will contribute to the

NIMH Mission.

The arrival of a new NIMH DIRP Scientific Director (SD), Dr. Susan Amara, and the departure of a 

number of long-standing DIRP Principal Investigators (PIs) in the Clinical Brain Disorders Branch 

(CBDB) provides an opportunity for strategic planning and consideration of the future of 

schizophrenia research in the DIRP. The NIMH Board of Scientific Counselors (BSC) established 

this Workgroup on Schizophrenia Research in the DIRP to gather extramural experts in the field 

of schizophrenia and other brain disorders to discuss the unique contributions that could be

made through schizophrenia research in the DIRP, and to make recommendations to the BSC 

and the SD regarding ways in which DIRP leadership might best proceed to ensure high impact

scientific progress now and in the future.

Charge to the Workgroup

Based on public health needs, current NIMH extramural investments and the changing ecology

of the DIRP, are there compelling scientific opportunities in the area of schizophrenia research 

that can be uniquely and effectively conducted within the DIRP?

Workgroup Process and Guiding Questions

This workgroup was created by the BSC to make recommendations on future research within 

the DIRP related to schizophrenia. The workgroup’s members are listed in Appendix B; their

areas of expertise include research in schizophrenia and other brain disorders, and span from

genetic and molecular studies to clinical therapeutic research; each member is a wellestablished investigator with extramural research funding from NIH. The workgroup met three

times via phone and one time in person in January and February 2013.

The workgroup was guided by the following three questions regarding research opportunities in 

schizophrenia research:

• Is schizophrenia an important and timely area of research?

• Are components of schizophrenia research insufficiently represented in NIMH 

extramural investments?

• Can this type of research be uniquely and effectively conducted within the DIRP?

Opportunities and Needs

• The workgroup identified the need to understand and define the neurobiology of 

schizophrenia, but the DSM-defined disorder “schizophrenia” is likely a collection of 

different illnesses; therefore a focus on psychoses and the cognitive deficits often
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observed in schizophrenia and related disorders will allow for more traction and will 

be consistent with the extramural NIMH Research Domain Criteria (RDoC) initiative

that emphasizes a dimensional approach to different domains of brain function 

instead of DSM-defined diagnoses. The current situation provides an opportunity for

the DIRP to lead the way forward in the conceptualization of mental illness research,

not bound by DSM-defined diagnoses.

• The workgroup identified the need to explore recruitment of a new leader for a DIRP

psychosis program. This individual must be at the forefront of the science, have a 

clear vision for the future of the field, be collaborative and facile with translational 

thinking, and be able to integrate across areas ofscience toward a unifying goal.

• The workgroup identified the need to consider a collaborative, center-like program

organization dedicated to the study of psychosis, either by de novo creation or

through strategic integration with existing units, and to increase communication 

among PIs and laboratories within the DIRP.

• The DIRP environment offers the unique resources for research with rare but

informative patient populations that can be studied intensively in a manner that is 

interactive with extramural community. For example, extramural investigators 

and/or clinicians could serve as the referral base for individuals who have certain 

rare genetic lesions of interest, associated with high risk for psychosis.

o This broad recruitment and focused research strategy is exemplified by Dr.

Karen Berman’s work with Williams syndrome individuals and Dr. Judith

Rapoport’s work with childhood onset schizophrenia.

o Genetically identified populations at high risk for psychosis offer an 

opportunity for the identification and study of individuals at all stages of 

illness (including before the onset of psychosis, during the first episode of 

psychosis, and across treatment).

o In depth knowledge from these populations could inform the development 

of model systems and a translational research program to gain a better

understanding of the mechanisms responsible for psychosis.

• The development of unique model systems, that are difficult to develop in the

extramural community (e.g. multiple allelic series analysis, noncoding variation 

transgenics), can drive discovery and fuel both forward and backward translational 

research, playing to the intrinsic strengths of the DIRP. In particular, the

workgroup recommends the development of clinically relevant, construct-valid

animal model systems and the integration of existing model system approaches

into a programmatic vision, moving to non-human primates where significant

investments are needed to catalyze the field (for example, transgenic marmosets).

• The DIRP environment offers the opportunity for longitudinal studies, as has been 

successfully demonstrated by many investigators including Dr. Jay Giedd. The

workgroup identified the need for longitudinal brain imaging studies (structural and 

functional magnetic resonance imaging (MRI) as well as positron emission 

tomography (PET)) at the time of the first episode of psychosis and across the

subsequent 5 - 10 years.
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• The DIRP environment offers the opportunity for off-medication studies requiring an 

outstanding inpatient psychiatric setting. This capacity could be used for various 

types of patient research related to psychosis, including deep phenotyping during

first episode psychosis and early stage treatment testing.

• The workgroup identified the need to define biomarkers of psychosis, especially 

those that index the pathophysiology of affected neural circuits. The DIRP has 

capacity for multiple neuroimaging modalities including PET and fMRI, and as the

DIRP has done in the past, the collaborative development of new measures of brain 

function that offer promise as informative biomarkers.

• While technology development is essential to provide the tools needed to test

compelling hypotheses in psychosis research, many of these goals may be most 

effectively achieved through an extramural request for applications (RFA) where

many research groups can respond. However, the NIMH DIRP does have a history of 

successful PET ligand development. The workgroup identified the need to develop

new PET ligands that target synaptic proteins involved in plasticity. The

development of such ligands would be very valuable to researchers investigating

psychosis and relevant treatments, and to the larger neuroscience community.

• The workgroup identified the need to more effectively utilize and share the existing 

resources within the DIRP, such as the NIMH Brain Bank and the research subject

registry and data collected through the longstanding schizophrenia sibling study.

• The workgroup identified the need to develop a stronger computational, analytic,

and informatics resource for use by DIRP investigators.

• The DIRP should consider whether opportunities exist to integrate existing programs 

with efforts of the BRAIN initiative to evaluate molecular, cellular and systems 

networks not practical in the extramural community.

Tactical Recommendations

• The workgroup recommends the DIRP build on existing strengths and consider

establishing a psychosis research program, identifying and recruiting a new leader

for this effort. As noted above, this individual must be at the forefront of the

science, have a clear vision for the future of the field, be collaborative and facile with 

translational thinking, and be able to integrate across areas of science toward a 

unifying goal. This leader must also be able to foster a center-like environment in 

which investigators collaborate within a horizontal organizational structure. Given 

her experience and tenure in the DIRP, Dr. Karen Berman will be very valuable in 

discussions related to the qualities of the optimal leader. Such a leader should be

considered in the goals and strategies articulated by a Strategic Planning Group 

charged to review existing programmatic structures, laboratories and sections and 

to make recommendations on best practices for aligning structures for the future

with likely resource commitments and high impact science. This group could include

senior members of the Board of Scientific Counselors, but also scientists with 

experience in administrative coordination of multi-scale programs and initiatives.
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• The workgroup recommends the Scientific Director consider pursuing the intensive

investigation of defined populations at high risk for psychosis toward the goal of

identifying prevention strategies in these vulnerable populations as one of the DIRP

strategic priorities. The DIRP offers the unique ability to recruit subjects across the

country (via a distributed referral network) and bring them to one location for indepth study, ensuring quality controls and consistency across all subjects. It is likely 

that an informative population or populations could be defined by specific genetic

lesion(s), but the specific selection of populations should be determined by the lead 

investigator(s). Factors other than genetic liability might also be informative in 

selecting populations for study (e.g., psychosis associated with anti-NMDA receptor

paraneoplastic syndromes or ketamine abuse). Within the study of rare, informative

populations, the workgroup recommends pursuing the development of informative

biomarkers that index some aspect of pathophysiology or therapeutic response. 

Such biomarkers could include neuroimaging or electroencephalogram (EEG) 

patterns of brain activity, cerebrospinal fluid (CSF) proteins, or induced pluripotent 

stem (iPS) cell characteristics. Examination of multiple high-risk populations could 

identify convergence and generalizability of the neurobiological basis of psychosis.

• The workgroup recommends that the DIRP consider pursuing scientifically 

justifiable, longitudinal studies, paced as resources and other priorities permit. 

Careful consideration should be given to which longitudinal studies would most

benefit the field; a longitudinal study may be most beneficial when used in the

investigation of individuals with rare genetic lesions that convey high risk for

psychosis.

• The workgroup recommends that the DIRP make an effort to maintain the capacity

for long term in-patient psychiatric studies as resources and other priorities permit.

Careful consideration should be given to possible off-medication studies requiring an

inpatient setting, potentially including deep phenotyping of subjects experiencing

first-episode psychosis or early stage treatment testing.

• The workgroup recommends that any psychosis-focused program in the DIRP

include the development of model systems (based on the biological knowledge

gained through the study of the identified high risk populations) to further

investigate the neurobiological mechanisms of psychosis. Examination of multiple

model systems could detect convergence and increase evidence to support the

identified pathophysiology. These models could also serve as important translational 

research tools, helping to identify potential therapeutic targets and interventions.

• The workgroup recommends that emphasis be placed on integrating clinical and 

basic research to ensure effective translation of research findings (forward and 

backward) within the proposed psychosis program.

• The workgroup recommends that the NIMH DIRP consider developing a core to 

provide computational, analytic, and informatics resources for use by the proposed 

psychosis program and across the NIMH DIRP.

• The extramural community has a number of programs investigating the prodrome

and conversion to psychosis. The DIRP is not well-suited to examine the prodrome,
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which benefits from distributed research sites where subjects do not have to travel 

long distances to participate in the studies. Therefore, the workgroup recommends 

that prodromal studies related to idiopathic psychoses not be pursued within the

DIRP.

• The NIMH, in collaboration with other Institutes, is constructing a new National 

Neurobiobank for the centralized acquisition, receipt, storage and dissemination of 

human brains, related biospecimens, and associated clinical data. Research efforts 

within the DIRP should utilize this national resource, and if appropriate, contribute

to it. Unfortunately, the data available to the workgroup regarding the existing

NIMH DIRP Brain Bank data was not sufficient to determine how, and whether,

integration with the National Neurobiobank might occur. The workgroup 

recommends that the DIRP arrange for a complete assessment of the NIMH Brain 

Bank to catalogue all of the material in the bank and all associated data (e.g.,

psychiatric autopsy, measures of agonal factors and tissue quality, etc). Until a 

complete and accurate inventory of this publically-funded resource is accomplished,

the workgroup recommends that no sample withdrawals be made and no additional 

accruals occur. The DIRP is encouraged to maintain relationships with medical 

examiners’ offices, if possible.

• The workgroup recommends that the DIRP arrange for an independent examination 

of the data collected as part of the clinical protocol “A Neurobiological Investigation 

of Patients with Schizophrenia Spectrum Disorders and Their Siblings” (95-M-0150). 

This examination should include subject information, as well as any data, deep 

phenotyping, and/or samples collected and stored. Until a complete inventory and 

assessment of this publically-funded resource is accomplished, the workgroup 

recommends that no future studies using these subjects be conducted and 

additional recruitment of subjects not occur. The DIRP is encouraged to maintain 

contact with subjects so they might be re-contacted for participation in future

studies.

• Typically, the departure of a DIRP PI results in the sun-setting of that PI’s research 

programs, however some research projects of departed CBDB PIs have continued 

under reassigned leadership, with non-DIRP researchers utilizing DIRP resources 

(such as space and imaging time), and without a clearly defined review structure. 

The workgroup recommends that these relationships be evaluated and structured to 

conform to DIRP standards for resource use by non-DIRP researchers and to ensure

appropriate review mechanisms are in place.

• The DIRP and its faculty should maintain the highest standards of data and resource

sharing, setting an example for the extramural research community.

Conclusions

The charge to this workgroup was both overarching and specific, asking the members to 

consider the current state of the science and the specific resources and environment of the

DIRP. As described in this report, a number of promising avenues for research in psychoses
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have been identified and specific recommendations regarding existing NIMH DIRP resources 

have been made. This workgroup was asked to make recommendations at a time of transition,

with a new SD and recently departed DIRP PIs. This time of transition is a unique opportunity

for the NIMH DIRP to move forward in developing a new and innovative program in psychosis 

research, with the mission of transforming the understanding of mental illness and paving the

way for prevention, recovery, and cure.
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Appendix A

National Institutes of Health

National Institute of Mental Health

Board of Scientific Counselors

Chairperson

Randy D. Blakely, Ph.D.

Professor of Pharmacology and Psychiatry

Vanderbilt University

Nashville, TN

Members

Roberta Brinton, Ph.D.

Professor of Molecular Pharmacology and 

Toxicology

University of Southern California 

Los Angeles, CA

Maja Bucan, Ph.D. 

Professor of Genetics 

University of Pennsylvania 

Philadelphia, PA

Joseph T. Coyle, M.D.

Eben S. Draper Professor of Psychiatry and 

Neuroscience

McLean Hospital/Harvard University

Boston, MA

Beatriz Luna, Ph.D. 

Professor of Psychiatry

University of Pittsburgh 

Pittsburgh, PA

Peter R. MacLeish, Ph.D. 

Professor of Neurobiology and 

Director, Neuroscience Institute

Morehouse University

Atlanta, GA

Matthew State, M.D., Ph.D.

Professor and Chair of Psychiatry

Director, Langley Porter Psychiatric Institute

University of California – San Francisco

San Francisco, CA

 

Kamil Ugurbil, Ph.D.

McKnight Presidential Endowed Chair 

Director, Center for Magnetic Resonance

Research

University of Minnesota

Minneapolis, MN

Matthew A. Wilson, Ph.D.

Professor of Neurobiology

Picower Institute for Learning and Memory

Massachusetts Institute of Technology

Boston, MA

Charles F. Zorumski, M.D.

Professor and Chair of Psychiatry and 

Professor of Neurobiology

Washington University

St. Louis, MO

Executive Secretary

Rebecca C. Steiner, Ph.D.

National Institute of Mental Health 

Bethesda, MD

Ex Officio Members

Susan Amara, Ph.D. 

Scientific Director

Division of Intramural Research Programs

National Institute of Mental Health 

Bethesda, MD
8

Michael Gottesman, M.D.

Deputy Director for Intramural Research 

National Institutes of Health

Bethesda, MD

Marlene Guzman

Senior Advisor to the Director

National Institute of Mental Health 

Bethesda, MD

Thomas R. Insel, M.D.

Director

National Institute of Mental Health 

Bethesda, MD

Barry Kaplan, Ph.D.

Associate Director for Fellowship Training

Division of Intramural Research Programs

National Institute of Mental Health 

Bethesda, MD

Sue Murrin

Executive Officer

National Institute of Mental Health 

Bethesda, MD

Maryland Pao, M.D.

Clinical Director and Acting Deputy

Scientific Director

Division of Intramural Research Programs

National Institute of Mental Health 

Bethesda, MD

Philip Wang, M.D., Dr.P.H.

Deputy Director

National Institute of Mental Health 

Bethesda, MD
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Appendix B

Board of Scientific Counselors’

Workgroup on Schizophrenia Research

in the DIRP Roster

Chairperson

David Lewis, M.D.

UPMC Endowed Professor in Translational 

Neuroscience

Chair, Department of Psychiatry

University of Pittsburgh 

Pittsburgh, PA

Members

Huda Akil, Ph.D.

Co-Director of the Molecular and Behavioral 

Neuroscience Institute and

Gardner C. Quarton Distinguished Professor

of Neurosciences

Department of Psychiatry

University of Michigan 

Ann Arbor, MI

Randy Blakely, Ph.D.*

Allan D. Bass Professor of Pharmacology

and Psychiatry

Vanderbilt University

Nashville, TN

Stephan H. W. Heckers, M.D.

William P. and Henry B. Test Professor of 

Psychiatry

Chair, Department of Psychiatry

Vanderbilt University

Nashville, TN

John Krystal, M.D.

Robert L. McNeil Jr. Professor of 

Translational Research

Chair, Department of Psychiatry

Yale University

New Haven, CT

Bita Moghaddam, Ph.D.

Professor of Neuroscience and Psychiatry

University of Pittsburgh

Pittsburgh, PA

Matthew State, M.D., Ph.D.*

Donald J. Cohen Professor in the Child Study 

Center

Department of Psychiatry

Yale University

New Haven, CT

J. David Sweatt, Ph.D.

Professor and Evelyn F. McKnight Endowed 

Chair, Department of Neurobiology

University of Alabama at Birmingham

Birmingham, AL

* Indicates a member of the Board of Scientific Counselors
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Appendix C

NIMH Staff Contributing to the Workgroup

on Schizophrenia Research in the DIRP

Staff Participants

Susan Amara, Ph.D.

Scientific Director, Division of Intramural 

Research Programs

Karen Berman, M.D.

Division of Intramural Research Programs

Marlene Guzman

Office of the Director

Thomas Insel, M.D.

Director, National Institute of Mental 

Health

Barry Kaplan, Ph.D.

Division of Intramural Research Programs

Barbara Lipska, Ph.D.

Division of Intramural Research Programs

Sarah Morris, Ph.D.

Division of Adult Translational Research

Maryland Pao, M.D.

Clinical Director and Acting Deputy

Scientific Director, Division of Intramural 

Research Programs

Darren Schneider

Office of Resource Management

Rebecca Steiner, Ph.D.

Division of Intramural Research Programs

and Division of Extramural Activities

Philip Wang, M.D., Dr.P.H.

Deputy Director, National Institute of 

Mental Health