NAMHC Minutes of the 225th Meeting
Friday, May 14, 2010
Department of Health and Human Services
Public Health Service
National Institutes of Health
National Institute of Mental Health
The National Advisory Mental Health Council (NAMHC) convened its 225th meeting in closed session to review grant applications at 10:00 a.m. on May 13, 2010, at the Neuroscience Center in Rockville, Maryland, and adjourned at approximately 5 p.m. (see Appendix A: Review of Applications). The NAMHC reconvened for an open policy session on the following day, May 14, 2010, in Building 31C, National Institutes of Health, from 8:30 a.m. until adjournment at 1:00 p.m. In accordance with Public Law 92-463, the open policy session was open to the public. Thomas R. Insel, M.D., Director, National Institute of Mental Health (NIMH) chaired the meeting.
Council Members Present at the Grant Review and/or Open Policy Sessions
(see Appendix B: Council Roster)
Chairperson: Thomas R. Insel, M.D.
Executive Secretary: Jane Steinberg, Ph.D.
David G. Amaral, Ph.D.
Carl C. Bell, M.D.
Elizabeth Childs, M.D., M.P.A
Robert Desimone, Ph.D.
Howard B. Eichenbaum, Ph.D.
Daniel H. Geschwind, M.D., Ph.D.
Portia E. Iversen
Dilip V. Jeste, M.D.
David A. Lewis, M.D.
Roberto Lewis-Fernandez, M.D.
John S. March, M.D., M.P.H.
Thomas H. McGlashan, M.D.
Steven M. Paul, M.D.
Enola K. Proctor, Ph.D.
Rhonda Robinson Beale, M.D.
Ex Officio Member: John A. Ralph, Ph.D., Department of Defense
Liaison Representative Present at the Open Session: Anna Marsh, Ph.D., Center for Mental Health Services (CMHS), Substance Abuse and Mental Health Services Administration (SAMHSA)
Virginia Anthony, American Academy of Child and Adolescent Psychiatry
Kirsten Beronio, Mental Health America
Bethany Brand, Towson University
Rebecca Daniel-Burke, American Counseling Association
Reuven Ferziger, Ortho-McNeil Janssen Scientific Affairs
John Gilmore, University of North Carolina
Bryan Goodman, Children & Adults with Attention Deficit/Hyperactivity Disorder
Wendy Greene, Executive Court Reporters
Hakon Heimer, Schizophrenia Research Forum (Press)
Ronald Honberg, National Alliance on Mental Illness
Christine Jamieson, American Psychological Association
Alan Kraut, Association for Psychological Science
Emily McCloskey, The AIDS Institute
Anna Marsh, Substance Abuse and Mental Health Services Administration
Ann Michaels, National Foundation on Mental Health
David Moore, Association of American Medical Colleges
Nancy Moy Yven, SRI International
Wendy Naus, Council on Social Work Education
Raquel Ogletree, The AIDS Institute
Amy Pollick, Association for Psychological Science
Donald Rheem, Rheem Media
Anita Sostek, Autism Speaks
Stuart Spielman, Autism Speaks
J. David Sweatt, University of Alabama School of Medicine
Tracy Todd, American Association for Marriage and Family Therapy
Jill Wetzel, Infinity Conference Group
Joan Zlotnik, Social Work Policy Institute of the National Association of Social Workers Foundation
Open Policy Session: Call to Order and Opening Remarks
NIMH Director Thomas R. Insel, M.D., called the open policy session to order and welcomed all in attendance.
Approval of the Minutes of the Previous Council Meeting
Turning to the minutes of the February 2010 Council meeting, Dr. Insel asked if Council members had any revisions or comments on the minutes. Hearing none, the minutes were unanimously approved.
NIMH Director’s Report
Dr. Insel took a moment to discuss recent scientific publications, noting that the field of mental health research is at a point of real transformation in terms of the science and social and political forces that are making a difference. These forces include the implementation of mental health parity, the American Recovery and Reinvestment Act (Recovery Act), and the Patient Protection and Affordable Care Act (PPACA) (P.L. 111-148), known as healthcare reform. An editorial in Nature discussed the many ways in which the understanding and treatment of conditions such as schizophrenia are ripe for a revolution. A commentary in Science discussed the direction psychiatric research is going in terms of genetics and neural circuits, noting that the neuroscience field is at an inflection point. Dr. Insel also discussed a special issue of the Journal of the American Medical Association (JAMA) on rethinking mental illness.
Health Care Reform: The Cures Acceleration Network (CAN) is a provision of the PPACA, which calls for dramatic advancement in the development of new treatments and cures by reducing barriers between laboratory discoveries and clinical trials. CAN will be overseen by the NIH Director in collaboration with a Review Board, which will be established to advise and provide recommendations to the NIH Director on policies, programs, and procedures for overcoming barriers to the successful translation of basic science into clinical application. The NIH Director is authorized to spend $500 million each year to promote innovation in technologies supporting the advanced research and development and production of high-need cures, including through the development of medical products and behavioral therapies. At this point, no funds have been appropriated specifically for CAN.
Another area of healthcare reform that will affect NIMH is the Patient-Centered Outcomes Research Initiative, a nonprofit effort that will help guide comparative effectiveness research and advise both the Agency for Healthcare Research and Quality (AHRQ) and NIH. In addition, the Melanie Stokes Postpartum Depression Research and Care Act instructs NIMH to consider additional research on the relative mental health consequences for women who are resolving a pregnancy—intended or unintended—in various ways, including carrying the pregnancy to term and parenting the child, caring the pregnancy to term and placing the child for adoption, miscarriage, and having an abortion. In addition, a new Centers of Excellence program under the Substance Abuse and Mental Health Services Administration (SAMHSA) has been authorized for depression centers that could represent an interesting opportunity for partnership. Another piece of legislation to watch is the Community Living Assistance Services and Support Act, or CLASS Act, which addresses disability insurance and may have significant implications for developmental disabilities.
American Recovery and Reinvestment Act of 2009 (Recovery Act): Under the Recovery Act, NIMH was provided $366 million of the $10 billion awarded to NIH. All Recovery Act funds must be obligated by September 30, 2010. NIH-wide, approximately $5 billion was spent in FY09 and another $5 billion to be spent in FY10. Recovery Act funding has involved approximately 13,000 grants and 2,000 new investigators, creating about 50,000 jobs over the course of two years. New facilities are being opened, with $1 billion invested in extramural construction for “shovel-ready” projects. Phase 2 of the John Porter Neuroscience Research Center will be constructed on the NIH campus and will be completed with Recovery Act funds, adding new space for the NIMH intramural program.
With Recovery Act funds, NIH more than doubled the 2007 funding for autism spectrum disorder (ASD) research. The Interagency Autism Coordinating Committee (IACC) involves five NIH Institutes, as well as several other Federal agencies involved with ASD research and services, advocacy groups, physicians, individuals with ASD, family members, and researchers. The IACC is charged with developing and annually updating a strategic plan for ASD research to serve as a guide to federal agencies that support ASD biomedical and services research; the committee is also charged with providing advice to the Secretary of Health and Human Services on matters pertaining to ASD. Secretary Sebelius has made ASD a high priority, and there have been a number of efforts to promote Federal investment and responsibility around services for ASD. Moreover, President Obama has highlighted ASD research as being among his highest priorities for health research funding, on par with cancer and heart disease.
Dr. Insel highlighted three signature projects that the NIMH funded with Recovery Act funds. The Study to Assess Risk and Resilience in Soldiers (Army STARRS) is the largest study of suicide and mental health among military personnel ever undertaken. Army STARRS will identify as rapidly as possible modifiable risk and protective factors related to mental illness and suicide. It also will support the Army's ongoing efforts to prevent suicide and improve soldiers' overall well-being. This $50 million project, funded by the U.S. Army, is an interdisciplinary Framingham-like study being conducted by a team of researchers across four institutions. NIMH has committed an additional $10 million in Recovery Act funds to jumpstart this important and timely project.
The second signature project is Recovery After an Initial Schizophrenia Episode (RAISE) and it seeks to fundamentally change the trajectory and prognosis of schizophrenia through coordinated and aggressive treatment in the earliest stages of illness. It aims to reduce the likelihood of long-term disability that people with schizophrenia often experience and aims to help people lead productive, independent lives. The results of this project could have a tremendous impact on public policy.
The third project highlighted by Dr. Insel is the Transcriptional Atlas of Brain Development. This project addresses the lack of information on human brain development and examines the geography of gene expression in the developing human brain. The effort will create the first transcriptional atlas of the human brain, an historic effort that will enable molecular-level examination of how the human brain develops. This two-year effort to map how the human brain develops is a joint effort, with participation from the University of Southern California, Yale University, and the Allen Brain Institute.
NIMH Budget: Dr. Insel noted that the President's proposed budget for FY11 calls for a 3.2 percent increase for NIH and 3.4 percent for NIMH. How and when Congress will act on the FY11 Labor, Health, and Human Services Appropriation is unknown. Dr. Insel remarked that much was accomplished in FY10 outside of the Recovery Act funds, stating that NIMH awarded approximately 550 new and competing research project grants.
Financial Conflict of Interest: Dr. Insel remarked that a commentary was published in JAMA on the subject of financial conflict of interest. The NIH working group will soon post a new set of regulations for public comment that represents a revision of the 1995 PHS regulations involving conflict of interest. NIH staff members are currently working to create a new training program around conflict of interest that will be distributed to residents in psychiatry programs.
Research Domain Criteria (RDoC): The Research Domain Criteria project (RDoC) has been launched by NIMH to develop, for research purposes, new way of classifying psychopathology based on dimensions of observable behavior and neurobiological measures. Many papers are expected to be published over the next few months exemplifying this new NIMH-led effort that seeks to link what is being learned from genetics and from neuroimaging and circuit studies to cognitive and behavioral states that may form the basis for this new nosology.
Thomas McGlashan, M.D. asked if CAN will involve funding investigators to conduct clinical trials of new compounds. Dr. Insel responded that it is not clear yet how CAN will function. Daniel Geschwind, M.D., Ph.D. noted that neuroscience in general has been behind the cancer field in many ways in terms of adopting new technologies over the past 10 to 20 years. Dr. Insel agreed but added that this is less true than it might have been a decade ago; more translation is occurring, as well as more reverse translation. Although the fundamental cell biology of cancer is somewhat easier to translate, it is also happening in neuroscience, albeit more slowly. The job of the Institute is to try to build that bridge to the extent that it can.
Imaging Early Brain Development in High-Risk and Normal Children
John Gilmore, M.D., Professor of Psychiatry and Vice Chair for Research and Scientific Affairs, University of North Carolina School of Medicine, noted that schizophrenia is considered a neurodevelopmental disorder that involves birth complications and subtle childhood developmental abnormalities. The genes of risk for schizophrenia play a role in brain development, and the actual pathology of schizophrenia is very subtle. MRI studies reveal large mediolateral ventricles and subtle changes in the volume of gray matter in the hippocampus; more recent studies show that there are abnormalities of the white matter as well. Investigating the minute structure, composition, and function of the brains of people who have schizophrenia reveals very subtle abnormalities. He reviewed some studies that were done in David Lewis, M.D.’s laboratory: slides presented images showing reduced amounts an integral neuronal membrane protein in the brains of people with schizophrenia, as well as other structural abnormalities relevant to brain cell connectivity.
In viewing schizophrenia broadly as a subtle disorder of how the brain is wired or connected, one developmental period of considerable interest is adolescence, during which synaptic elimination normally occurs. Researchers are interested in discovering what might be happening to disrupt this process, leading to problems in brain connectivity. Alternatively, something may occur very early in brain development, during a period of enormous, robust growth of synapses. Furthermore, different combinations of developmental events may be affecting the trajectory of the disorder.
Dr. Gilmore’s NIMH-funded Conte Center at the University of North Carolina is exploring the genetic vulnerability for schizophrenia within multiple developmental mechanisms, each ultimately contributing to a common endpoint of aberrant connectivity. Defining these development trajectories in high-risk children will allow the identification of these neurodevelopmental mechanisms in humans and ultimately, it is hoped, will provide early identification and preventive strategies in humans. The center has five projects—two preclinical projects on genetic high-risk children, a project led by Dr. Gilmore that examines the earliest phase of brain development, a project run by Dr. Aysenil Belger that looks at cortical maturation during adolescence, and three preclinical projects that focus on cortical development, mainly on inhibitory interneuron development and genes of risk.
Although many studies have explored what happens in gray matter and white matter during adolescence, little is known about these earliest stages of brain development. This study looks at the children of mothers with schizophrenia and a few other high-risk groups. It involves taking prenatal ultrasounds in the second and third trimester and using structural diffusion tensor and resting state fMRI in children at birth, at age one, and at age two. Recently, the project was funded to do follow-up on these children at age four and age six; developmental assessments and cognitive assessments are being conducted on these children as well. To date, approximately 40 babies of mothers who have schizophrenia and about 250 babies normal at birth have been scanned. An ongoing companion study is looking at twins. More than 150 twin pairs at birth have been scanned.
Initial studies found that in normal babies there is a large growth in gray matter in the first few of months of life. The occipital and parietal regions grow much faster than the prefrontal region, and there is a posterior-to-anterior gradient in how gray matter volume develops, which is consistent with studies in synapse development in the human brain, showing that in the visual cortex the numbers of synapses peak well before the prefrontal cortex. A follow-up study from birth to age two found that overall brain volume doubles in the first year of life and grows about 15 percent in the second year of life. Diffusion tensor imaging (DTI) is showing that there is some development of the more peripheral organization of white matter tracks, but the major white matter tracks are present at birth.
Another study of twin brain development, with 91 twin pairs, looked at genetic and environmental influences on neonatal brain volumes. The study found that white matter heritability in the neonate is very similar—about 85 percent genetic. But gray matter heritability is much lower in neonates than it is in older children and adults. Looking at the regional differences in heritability, at least in gray matter, the posterior regions of the brain have higher heritability of gray matter than the anterior regions of the brain, which seems to indicate that, perhaps, as the brain is developing the genetic programs are operating and higher heritability is seen as the gray matter is developing. There is high correlation of gray matter density in neonates in dizygotic twins versus monozygotic twins. It appears that the correlations actually decrease within the first year of life, when there is enormous growth of gray matter.
Dr. Gilmore discussed early data from their high-risk study—a study of 26 children of mothers who have schizophrenia and 26 matched controls. It is important to recognize that most of the mothers did take antipsychotics during their pregnancy, which will confound or complicate study interpretation. This study looked at the prenatal ultrasound by which one can measure the width of the lateral ventricle. It is a standard obstetrical measure in prenatal ultrasounds, mainly to screen for hydrocephalus. No significant differences were found in overall head circumference or lateral ventricle width in the high-risk children compared to the controls. Nevertheless, the study did show that males at high risk for schizophrenia do have enlarged heads compared to the controls, and have a 20 percent increase in lateral ventricle volume. The females in the group had no differences compared to the control group. Looking at DTI tractography of different cortical spinal tracks, the genu and splenium of the corpus callosum, no differences were found in the white matter maturation or white matter organization in these children. In the high-risk group, males at high risk have larger brains, especially more gray matter, more cerebrospinal fluid, and larger lateral ventricle volumes. Follow-up studies are needed to assess whether these differences persist through early life. It may be that children at risk for schizophrenia, or at least male children at risk for schizophrenia, are evidencing abnormal development of the cortex by having more gray matter early in life.
In the future, Dr. Gilmore plans to conduct developmental assessments on the structural and functional underpinnings of language development and executive function in these children. They have been collecting DNA and are starting to look at candidate gene relationships to brain structure. They hope to add EEG assessments of cortical neuronal oscillatory activity, and they are working on this multimodal synthesis of the structural DTI and functional data in this cohort. Dr. Gilmore acknowledged his collaborators, especially Drs. Guido Gerig and Martin Steiner, who do the image analysis, Drs. Dinggang Shen, and Weili Lin, who is in charge of all the data acquisition.
Dr. Geschwind asked for Dr. Gilmore’s thoughts on the increase in heritability that occurs throughout aging. He noted that although researchers think of the brain as being controlled by genetic elements, it is an interaction of the genes and environment. Prenatally, there is not much sensory input, but there is more after the child is born, suggesting that genetic factors may be controlling the brain's response to the environment. The heritability becomes more evident as there is more environmental exposure. This concept of gene-environment becomes remarkable, because what researchers think of as a hardwired, developed number of neurons is actually much less genetic and is actually the brain's response to the environment and learning.
Dr. Gilmore agreed and said he believes there are many environmental influences prenatally as well. He noted that there is much discussion about the endpoint ultimately being genetically determined, but that one can get to that endpoint in a variety of ways based on the environment. There may be differences in the course of the trajectory, but the endpoint of the trajectory will be the same—high heritability in the cortex—given that the environment is reasonable enough for most people.
Dilip Jeste, M.D. was particularly interested in the gender difference and wondered whether that may be related to age of onset or prognosis given that men with schizophrenia tend to have an earlier age of onset and a worse prognosis than females with schizophrenia. It may be related not to schizophrenia itself but rather to the cause and outcome. Dr. Gilmore agreed.
Steven Paul, M.D. asked if there were any participants with bipolar disorder in this initial study. Dr. Gilmore said that with the renewal of the Conte Center, a high-risk group of people with bipolar disorder was added mainly as a comparison group to the people with schizophrenia. There is a third high-risk group of babies with ventriculomegaly—babies who are identified prenatally with large lateral ventricles, while the rest of the brain looks reasonably normal. Interestingly, large lateral ventricles are associated with increased gray matter at birth in these ventriculomegaly babies, which is reminiscent of what was seen in the male high-risk children. They have been hypothesizing that if there is a large lateral ventricle prenatally, there may be more subventricular zone area and more neurogenesis occurring, which may allow more early cortical development.
Evaluating NIMH Communication: Listen and Learn
Diane Buckley, M.A., Deputy Director, Office of Science Policy, Planning, and Communications, NIMH, provided an update on a project involving how NIMH communicates internally and with external stakeholders. Strategic Objective 4 of the NIMH Strategic Plan urges NIMH to strengthen its impact on public health. An important step toward meeting that challenge is to evaluate and adjust NIMH’s dissemination strategies. An extensive effort was undertaken over the last six months to gather information directly from stakeholders to identify their needs as well as learn effective ways to better meet those needs. A formal usability test of a redesigned version of the NIMH Website also was conducted.
Thirty stakeholder focus groups were convened, and interviews were conducted with a wide range of audiences. Representatives from mental health advocacy and professional organizations, state-based outreach partners, researchers, and representatives from diverse populations were heard from, as were a number of mental health practitioners and administrators. Individuals from various settings, including schools and universities, hospitals and private practice, courts and prisons, law enforcement in general, and community centers and churches were involved. Also included were members of the trade press, print, and broadcast media. To identify some best practices, staff also conducted interviews with representatives of 16 comparable organizations, including organizations within NIH, other federal agencies, and the private sector. Each conversation was guided by a unique set of questions tailored to the specific stakeholders involved. The information obtained is still under review.
Ms. Buckley highlighted important questions that many of these discussions addressed, such as: Where do stakeholders seek mental health information, and what material is most useful? Also, how do they prefer to receive that information, in what format, and through what channels?
The stakeholders were eager to participate in this conversation and share their experiences. Ms. Buckley heard that NIMH is seen as a highly credible and trusted source of information for those who are aware of the agency, particularly those in advocacy and professional organizations, and the media, but it is one source among many. Awareness and understanding of NIMH decrease as one gets closer and closer to affected individuals and families. Even practitioners tended to look primarily to their professional organizations and journals for information. In general, the most trusted source of information is not any type of organization, but rather the people whom they know and trust, such as community leaders and pastors. Among some populations, particularly among people of color, there is distrust of the information that comes from government-sponsored research.
For many people, the search for mental health-related information is no more sophisticated or reliable than a basic Google search. Many interviewees said such a search is the first thing they do and, in many cases, that is where they stop. There was a call for content and materials to be relevant and tailored to different populations and culturally appropriate for the target audience. Content also needs to be accessible and generally brief and straightforward. While information should be available via e-mail and the internet, print materials are still important. NIMH was encouraged to extend its reach, especially into underserved or hard-to-reach communities, by making better use of alternative formats, such as videos and podcasts. Several requests were made for PowerPoint presentations tailored to the audience and ready to use in various settings. Formal usability testing of the redesigned NIMH website showed that test users liked the redesigned look and feel. Based on the feedback, the design is being improved to ensure that stakeholders find it easy to use.
Regarding the information gathered from comparable organizations, Ms. Buckley highlighted three key lessons learned (1) it is very important to define the message and target particular audiences; (2) partners can be critical in helping raise visibility, reaching larger audiences, and disseminating information; and (3) many NIMH stakeholders rely on technology to gather information.
Ms. Buckley emphasized that NIMH’s current communications efforts are on the right track. More than 50 NIMH lay publications are being used by outreach partners, professional organizations, parents and caregivers across all the 50 states and Puerto Rico. Nineteen of those publications are available in Spanish. More than 20 videos and podcasts are available. So far during this fiscal year, more than 15,000 public inquiries have been received and more than 1.8 million publications have been distributed. NIMH’s social media presence is growing. On Facebook, as of the previous week, NIMH had more than 2,800 fans, more than 28,000 views of various videos on YouTube, and more than 30,000 followers on Twitter. NIMH also works closely with traditional media outlets to accelerate the translation of research findings into widespread understanding and use. NIMH has many partners in research and outreach efforts. Through the NIMH Alliance for Research Progress, Professional Coalition for Research Progress, and Outreach Partnership Program, stakeholders can hear from NIMH and provide critical feedback. The interviews with comparable organizations conducted as part of the evaluation provided another opportunity to establish and/or strengthen partnerships. For example, the interview with SAMHSA facilitated a partnership to promote May 6 as Children's Mental Health Awareness Day.
John March, M.D., M.P.H. said he thought it is very important for NIMH to try to disseminate correct information early. He commented that it would be productive for NIMH to use the extramural community and the variety of stakeholders who are available to weigh in on some of these questions. Carl Bell, M.D. emphasized the importance of this subject given the amount of misinformation and anti-psychiatry bias on the internet.
Roberto Lewis-Fernandez, M.D. wondered how much attention has been paid so far on what messages to disseminate. Certain communities hear the message that disorders have a biological basis which can lead to distrust, because they have heard similar, erroneous messages in the past that were associated with race, origin, or class. He wondered if some of the effort using qualitative data on how to reach people could encompass what it is that people would trust in a message.
Enola Proctor, Ph.D. said she wanted to encourage thinking about the role of communication in an evidence-based manner. Colleagues at the National Cancer Institute and Washington University are doing research on effective ways to disseminate various messages to various audiences. Some of the most innovative work involves testing kiosks in laundromats with messages about what cancer is, what the signs are, and what the evidence-based treatments are. There is an enormous need to know what messages are appropriate, about what, and for what targets, because the disparities in information about mental disorders and in particular about the availability of effective treatments are troubling. There is much to learn about how consumer demand and provider demand for evidence-based care could help us achieve Strategic Objective 4.
Rhonda Robinson Beale, M.D. said that in working with the Institute of Medicine on Crossing the Quality Chasm and To Err Is Human, they learned that the media will pick up a story as long as it has shock value. Strategizing a media and dissemination plans could help deliver the desired message. Health plans also need this information because they have to look at new technology regularly and make coverage decisions. Perhaps there could be a role for NIMH as the pipeline for new evidence and for some collaboration in building an evidence hierarchy that health plans could easily and uniformly interpret.
Dr. McGlashan noted that he and some of his colleagues in Scandinavia have been using public information campaigns about the early signs of psychosis and have been successful in getting people with first-episode psychosis into treatment on average about 3-5 months earlier than usual. The five-year follow-up is showing that this confers a long-lasting advantage. The campaign includes general public information as well as targeted information for schools, teachers, and primary care providers. The power of the message can have direct clinical impact.
NIMH Council Workgroup on Interventions Development: Update on Activities
Dr. Lewis, co-chair of the Council Workgroup on Interventions Development, took a moment to thank his co-chair, Dr. March as well as the workgroup members and NIMH staff members who worked on this workgroup and were instrumental in the drafting of the workgroup recommendations. Dr. Lewis reminded Council of the charge to this workgroup, to lay the foundation for developing the next generation of interventions for mental disorders, especially those that are preemptive and personalized.
Over the course of two two-day meetings, the workgroup was briefed on the NIMH portfolio and NIH activities and held a number of discussions about how to assess critically the goals and the barriers to developing new interventions and ultimately, cures. The focus was on NIMH Strategic Objective 3, to develop new and better interventions that incorporate the diverse needs and circumstances of people with mental illnesses. Dr. Lewis reviewed the four questions that the workgroup considered: How can NIMH best identify novel treatment targets; foster strategies that enhance all steps of small molecule and biological development from target validation to lead optimization; determine the steps that must be taken to advance behavioral and device approaches; and develop viable candidates for preclinical studies through Phase 1, 2, and 3 trials in humans?
The Workgroup Report identifies four goals, each of which was followed with a set of recommendations. The goals are:
- Discover and develop novel, effective interventions that prevent and cure mental illnesses.
- Optimize current treatments and NIMH’s treatment research.
- Use existing resources effectively.
- Create partnerships.
Under the first goal, it is recognized that the signs and symptoms of mental illness are the emergent properties of aberrant activity of brain circuits, and thus methods are needed that will identify and interrogate these circuits. This knowledge must then be used to guide the development of novel interventions, whether pharmacological, behavioral, or devices that are based upon a pathophysiological basis. That is, understanding the underlying disease process will provide new ideas about how to intervene. Identification of newly validated targets must be accelerated, whether the targets are biological, behavioral, or clinical, as biomarkers and as new therapeutic interventions. Finally, it is important to ensure that there are ways to accelerate the transition into early phase clinical trials.
The second goal involves finding predictors or moderators of the safety, benefits, and harms from existing treatments that will be useful in tailoring how they are applied. Trials need to be designed in such a way to maximize the ability to see whether the intervention is effective—and ensure that the experimental design will test the hypothesis that underlies the intervention. It is important in this regard to facilitate and advance research that will lead to personalized treatments. Toward this end, in looking at existing treatments, any adaptation or extension of proven interventions should be based on a compelling rationale supported by empirical evidence.
The third goal involves leveraging existing resources effectively to maximize the achievement of the first two goals. There was a great deal of discussion around how NIMH should use existing NIH guidance to establish data sharing expectations in the terms and conditions of grants and contracts to ensure that data sharing occurs. The workgroup recommends that NIMH create standards or models that will facilitate data sharing and enhance data mining and research. This may involve standardizing approaches to enhance the capacity, for example, to develop model experimental designs for conducting preclinical toxicology and safety in juvenile animals so that the data that are available for studies in humans are not based purely upon information obtained from adults.
The fourth goal focused on establishing partnerships, such as engaging biotechnology and pharmaceutical companies in public-private partnerships that will enhance the identification of targets and markers; collaborating more broadly with industry partners and academic centers in a blended fashion; and exploring new partnerships for constructively dealing with intellectual property issues and financial conflict of interest rules. Patient and clinician groups also need to be thoughtfully and deliberately integrated into these efforts to be sure that the infrastructure involves the key players. The workgroup is optimistic that new approaches and existing tools will provide NIMH with a historic opportunity to change the lives of those with mental illness dramatically.
Dr. March added to Dr. Lewis’ presentation by noting that the workgroup brought together diverse individuals from across NIH, industry, academic health centers, and advocacy organizations to facilitate an understanding of how to develop new interventions more efficiently and optimize available treatments. While Strategic Objective 3 outlines the vision for new and better treatments that initially will be stratified by patient subgroups and ultimately personalized by individuals, it does not describe how to get there. The recommendations discussed in this workgroup aim to set a pathway to meet the vision presented in the objective.
Dr. Proctor commented that the workgroup report is a very forward-looking report with challenges to the field because some of the architecture called for in the conduct of clinical trials is not yet in place. It is extremely important to understand and use the capacity of electronic medical records not only to help learn whether care is improving but also to build that into the conduct of trials. One cautionary note is that not all treatment research settings have this architecture. A few members of the workgroup emphasized the importance of looking at behavioral treatments, and given the continuing evidence of the environment's influence on the trajectory of mental disorder, that will remain important.
Portia Iversen said that her interest and focus in the workgroup was to emphasize the need for policies, including data sharing and biologic material sharing, which will have important downstream effects and help enable interventions to be developed and resources to be used more efficiently. This sentiment was echoed by Dr. Geschwind who noted the success the NIMH has seen with the National Database for Autism Research (NDAR).
Dr. Paul said that the workgroup has presented a comprehensive set of recommendations that could be transformational if thoughtfully implemented and might be best approached by determining which actions will be most catalytic and synergistic and then leveraging the resources of NIMH. Also, it would be important to identify what is rate-limiting. This could help turn the current malaise about psychiatric drug discovery and development into a real opportunity four or five years from now and, hopefully, would accelerate that process by enriching the scientific substrate for drug discovery and development. This could be accomplished by determining whether there are mechanisms that seem ripe for pursuing at this time and then making the necessary investments in either the public or private sector.
Dr. Jeste said that, especially in developing new treatments, it is important to keep in mind from the beginning he right population for testing the treatments. Studies have shown, for example, that ethnic minorities are under-represented in clinical trials. Also, because people with any kind of medical illness are often excluded from psychiatric studies, when the treatments are used in the real-world population, unanticipated side effects occur.
Several members of Council noted some changes to the text of the workgroup report. Jane Steinberg, Ph.D. noted the changes and agreed to follow-up with several Council members after the meeting to finalize the language of the draft report. Dr. Insel recommended taking a vote on the report with the provision that some revisions would be made. This report would be designated as an interim final report, which would be up for a vote before the final version is developed that will integrate these comments.
The Council voted unanimously to approve the interim final version. Dr. Insel thanked everyone who served on the workgroup and reminded Council that the final version of the report will be posted to the NIMH Website before the September Council meeting.
Update from the NIH Basic Behavioral and Social Science Opportunity Network
Kevin Quinn, Ph.D., Branch Chief within the Division of Neuroscience and Basic Behavioral Science (DNBBS) provided an update on a new NIH initiative within the Office of Behavioral and Social Science Research (OBSSR). The Basic Behavioral and Social Sciences Opportunity Network (OppNet) is a new initiative with the mission of pursuing opportunities for strengthening basic behavioral and social science research at the NIH while innovating beyond existing investments. The definition of behavioral and social science research being used for OppNet includes three categories. The first refers to basic behavioral and social processes, which run the gamut from very basic mechanisms such as perception all the way through more complex examinations of social networks or population dynamics. The second involves looking at how these processes interact with biology, which ranges from behavioral neuroscience, to behavioral genetics, to behavioral cardiology, and other areas. The third category involves developing new and enhanced tools to develop better methodologies to collect, analyze, and model data.
Similar to other NIH-wide efforts, all NIH Institutes and Centers share the mission of supporting OppNet. In FY10, $12 million will be available to support OppNet funding opportunity announcements (FOAs), $10 million of which comes from Recovery Act funding. For FY11, $20 million will be provided to support OppNet FOAs, and then OppNet will be fully funded at $30 million per year from FY12 through FY14. In FY10, five FOAs were issued, and NIH anticipates the review of these applications in the next few months; they will be considered by the NAMHC later this summer.
Care has been taken to be sensitive to the need to try to engage the external scientific community in planning OppNet’s direction. This began with a Request for Information that was released in late January asking the extramural community to identify opportunities and challenges related to areas of possible investment. A report was posted on the OppNet website describing the input that was received. In addition, a large meeting is planned in the fall of 2010 to continue this dialog with the extramural community about areas of research that can best fit NIH’s needs and interests.
Dr. March asked whether the initiative dovetails with the Roadmap's emphasis on community engagement, particularly as related to population-based mapping of health behaviors using technologies. Dr. Quinn said that the charge is to synergize with but not duplicate existing NIH investments. A ‘Science of Behavior Change’ initiative will address health behaviors from a perspective that is perhaps slightly more applied. However, this issue has been a subject of discussion at many levels within OppNet. Dr. Insel said that Science of Behavior Change is a new Roadmap initiative that will have significant funding behind it for the next four years and represents another place to look for support in the trans-NIH arena.
National Database for Autism Research: An Example of Science in the 21st Century
Michael Huerta, Ph.D., Associate Director, NIMH and Director, National Database for Autism Research, NIH, presented a progress report on the National Database for Autism Research (NDAR). He described NDAR as a platform for community science, which has been developed with a great deal of interaction with NIH program staff, ASD investigators, other Federal research funding organizations, and private funders of ASD research.
Modern biomedical research is increasingly depending on three interrelated paradigms: high-volume data collection and aggregation; computation and informatics; and team science. Once many members of the research community have access to many of the tools and much of the data of that community, a fourth paradigm emerges, called community science.
In terms of collection and aggregation of data, the types of data available in NDAR include genetic and genomic, phenotypic, and imaging, but any data type can be accommodated. Information about the studies, including the methodology used to obtain the data and the tools used to analyze the data, are also available. Currently, data from some 45,000 subjects are destined to reside within NDAR, and its federation capabilities are deeply linking it with other data resources containing data from an additional 40,000 subjects. This federation of major informatics platforms forms a network of data and allows investigators to use a single search to retrieve data from any and all platforms in the network. NDAR's many other capabilities include the use of unique study participant identifiers (called global unique identifiers, or GUIDs), a data dictionary, and a community use tool.
Collaboration across informatics frameworks is being promoted; a consortium with Autism Speaks, the Simons Foundation, and others has been formed, and they are working with other agencies and organizations to harmonize informatics. Because NDAR resides in a rich programmatic environment, initiatives both in ASD and informatics research programs can be leveraged. Doing all of this together in a robust way helps move the field from collaboration toward this notion of community science.
In addition, the Nonhuman Primate Gene Expression Atlas and the Human Connectome Project, both funded by the NIH Blueprint for Neuroscience Research, were designed to be compatible with NDAR. NDAR is progressing towards achieving community science, with this robust platform run by a respected team, and fueled by a strong regime for data sharing.
Ms. Iversen told Council about a workshop she attended in April, focusing on nonverbal ASD hosted by the Communications Institute and co-sponsored by NIMH. She noted that as awareness and interest in autism have grown over the last 15 years, funding and research have increased. However, it seems that people with ASD who are nonverbal are often excluded from research participation. In the past, it was erroneously assumed that because of an inability to communicate, nonverbal individuals with ASD have impaired cognitive ability. Dr. Insel followed up on Ms. Iverson’s discussion noting that this issue has not received enough attention. The mistake may have been dividing children into high functioning and low functioning and assuming that nonverbal children had severe intellectual deficits. In fact, sometimes they do not, but they have a problem with communication. Ms. Iverson advocates for more research with nonverbal individuals with ASD and the development of new and effective interventions for this subpopulation of individuals with ASD.
David Amaral, Ph.D. said he is incredibly encouraged by the progress NDAR has made, but he wants to encourage even more be done in terms of guaranteeing the quality control of the data. He emphasized that comparability of data must be ensured. Dr. Amaral suggested that NIMH consider setting some additional standards for quality control in the various data domains that are going into NDAR.
Dr. Geschwind said that having the database is important, but only if it is used. He suggested that the database be monitored regarding its use, and that investigators should be encouraged to use it as their primary resource. He also commented that perhaps there should be another mechanism or initiative through which data mining can be conducted.
Dr. Huerta commented that ways to encourage that kind of activity are being considered. The data for the 45,000 subjects are still being received, but little of the data will be shared over the next few months. Developing processing pipelines to connect with NDAR and making those pipelines available to the broader community is costly and requires considerable investment in NDAR and internal staff.
NIMH'S Role in Global Mental Health
Pamela Collins, M.D., M.P.H., is the Director of the NIMH Office for Research on Disparities and Global Mental Health (ORDGMH), a newly formed office within NIMH. She commented that NIMH combined its Office for Special Populations and Office of Global Mental Health earlier this year in acknowledgment of the fact that mental disorders affect populations across borders and that a global lens can deepen the Institute’s understanding of processes that create disparities in the United States and beyond. The office seeks to evaluate research trends and to help guide science in its main areas of concentration—women’s mental health, mental health disparities, global mental health, and, in collaboration with NIMH’s Office of Rural Mental Health Research, rural mental health disparities—to determine how to invest the research money and how to work with the rest of the institute to set priorities.
Dr. Collins presented a depiction of the burden of neuropsychiatric disorders around the world, noting that mental health resources are inequitably distributed between countries, between regions, and within local communities. Dr. Collins noted that neuropsychiatric disorders account for about 30 percent of the burden of non-communicable diseases and are found in both rich and poor countries and across both genders. She presented information on the relationship between the burden of disease and budgets for mental health services around the world, noting that worldwide, the percentage of the health budget that is typically devoted to mental health care ranges from less than 1 percent in the poorer countries, to around 7 percent in high-income countries. Huge disparities exist in terms of mental health human resources, including psychiatric nurses and psychiatrists, and these disparities have implications for the implementation of interventions.
In the United States, there is some understanding of the disparities that exist between people with serious mental illness and the general population. People with serious mental illness live, on average, 25 years less than the general population. There is fairly limited data by racial and ethnic group on the leading causes of death within this population. Referring to a 2009 Cochrane review, she noted that much needs to be done for those with serious mental illness in the United States, and she remarked that even less is known about the health status of people with serious mental illness in other countries, particularly in low- and middle-income countries.
Disparities in the United States also occur by geographic region. In general, in rural communities, there are higher poverty rates than in non-rural communities. Many of the problems in rural communities involve the availability, accessibility, and acceptability of care. Suicide rates are higher, and many of the kinds of accessibility problems in rural areas are related to lack of health insurance, fewer mental health care providers, and high rates of co-morbidity.
Dr. Collins discussed a successful intervention conducted by Atif Rahman and colleagues in Pakistan that could have relevance for rural or other marginalized communities in the United States. Lay health workers were trained to deliver cognitive-behavioral therapy (CBT) to pregnant and postpartum women, and it was found that the health workers who were trained in CBT effectively delivered the intervention. The women in the experimental group had better outcomes, and their children had better outcomes on selected measures.
Francis Collins, M.D., Ph.D., NIH Director, has identified global health as one of his priorities, and NIMH has been working to develop a strategy for addressing global mental health by convening thought leaders and other stakeholders to address the broad research needs in these areas and the specific areas of research that focus on addressing inequities. In March, ORDGMH organized a meeting focused on global mental health, bringing together non-governmental organizations, policymakers, and researchers to consider some of the questions around research implementation in low- and middle-income countries. Discussions were held with implementation researchers and the policymakers from these settings to find out how research is influencing policy and whether research is relevant to the service providers. One of the main findings was that service providers and policymakers want research that they can actually use
ORDGMH is also focused on strengthening collaborations. In partnership with the Global Alliance for Chronic Diseases (which NIMH joined in November 2009), NIMH has launched an initiative, the Grand Challenges in Global Mental Health, to determine the broad research questions to target in global mental health. NIMH is also working with the World Health Organization to support its Mental Health Gap Action Programme, a program that will implement evidence-based packages of care in low- and middle-income countries.
In collaboration with the Fogarty International Center (FIC), NIMH is working to support a career path for those who are interested in global mental health research. NIMH helps to support two FIC programs: the Clinical Research Scholars Program, which trains pre-doctoral students; and the Fellows Program, which supports post-doctoral researchers from the US and from low- and middle-income countries. NIMH has also joined the Brain Disorders in the Developing World FOA, for which Fogarty is the central partner, and the Institute is part of the President's Emergency Plan for AIDS Relief(PEPFAR) Medical Education Partnership Initiative. Through participation in these initiatives, NIMH is working to lay the foundation for training and capacity building in global mental health research.
Competitive Supplements for Targeted Research on Mental Health Disparities
Dr. Collins discussed a potential NIMH initiative to stimulate research that uses existing data sources to increase knowledge in three areas of mental health disparity research: identification of differences in engagement, outcomes, or mediators for health disparity populations in clinical trials; epidemiology of cardiovascular disease (CVD) risk factors among health disparity populations with serious mental illness (SMI); and methodologies for measuring and tracking mental health disparities.
This initiative encourages the development of methods to characterize mental health disparities quantitatively; to analyze existing data sets to increase the understanding of the intersecting or additive relationships between SMI, race/ethnicity, and CVD morbidity and mortality; and, to examine factors that may deepen the evidence base for intervention effectiveness in diverse groups.
Regional Mental Health Networks in Low- and Middle-Income Countries
Dr. Collins discussed a second potential NIMH initiative to establish regional centers for coordinated mental health research and research capacity-building in low- and middle-income countries.
The goal of the initiative is to develop multidisciplinary regional research centers, with complementary areas of expertise, in low- and middle-income countries, that will conduct research of public health relevance in these settings, build research infrastructure, and develop research capacity. The centers will provide resources to (1) develop or strengthen regional collaborations, including partnerships among governmental and non-governmental organizations, research institutions, and mental health service user advocacy groups; (2) conduct translational, clinical, or policy research, taking advantage of health system and sociocultural diversity; (3) support research capacity building; and (4) educate local communities on research processes and study outcomes.
Dr. Bell suggested looking at what other countries do in terms of prevention, including Australia and New Zealand. In his view, prevention is needed to eliminate disparities. Also, in the area of disparities, it is important to deal with those who have mental disorders in correction facilities. Dr. Bell also recommended that ORDGMH connect with the Carter Center on potential future collaboration.
Dr. March said that National Heart Lung and Blood Institute (NHLBI) has a large global health program, with a NHLBI Center for Excellence funded in Peking University that is also linked to the George Institute in Australia and an FIC grant to train Chinese neurologists in research methods for stroke.
Update on NIMH HIV/AIDS Research and Discussion of AIDS-Related Concept Clearances
Philip Wang, M.D., Dr.P.H., Acting Director, Division of AIDS Research (DAR) and Dianne Rausch, Ph.D., Deputy Director of the Center for Mental Health Research on AIDS, provided an update and suggested some ways that the division is trying to meet the research needs of the changing and evolving HIV epidemic. Dr. Wang said that the division's main programmatic areas include decreasing the incidence and spread of HIV by developing effective, efficacious, preventive interventions; translating efficacious interventions into those that are cost-effective and can be widely used in communities; and understanding the pathogenesis of neuroAIDS and developing new therapeutics for this condition.
He reviewed how the epidemic has changed and noted that because an etiology for AIDS has been found and highly active antiretroviral therapies have been discovered, the life expectancy of those living with HIV has increased dramatically, which has contributed to the increase in opportunities for new infections. There are more than 50,000 new HIV infections occurring in the United States each year. Communities of color have been increasingly affected by increasing HIV transmission rates. The changing profile of the epidemic and its persistence has important implications for the preventive interventions that are targeted and developed and how they are disseminated.
The Division was challenged last summer to rethink its research portfolios critically and examine whether it was meeting the needs of this changing epidemic. It is important to learn how to optimize reach while avoiding redundancy in the development of interventions. After developing effective and cost-effective interventions, there is a need to learn how to ensure that they are used in communities and by stakeholders. Last fall, an AIDS summit was held that included a wide range of thought leaders who were challenged to develop goals for the division that would dramatically impact public health outcomes quickly. Dr. Wang presented the goals that were developed to increase investment in a number of areas and noted that these goals from the AIDS summit have been driving the strategic planning process of the division.
Dr. Rausch added that in response to the recommendations of the AIDS summit, staff analyzed all currently funded intervention research—150 active grants—based on target population, ethnicity, gender, age range, risk behaviors, intervention target setting, and more. An effort also has been made to increase collaboration and communication with partners, such as expanded discussions with the NIH Office of AIDS Research, Centers for Disease Control, Veterans Affairs, World Health Organization, and the Office of National AIDS Policy. The strategic planning process has been expanded to develop new initiatives and to develop more focused and targeted funding opportunities.
Reinvigorating HIV Prevention for Men Who Have Sex with Men
Andrew Forsyth, Ph.D., DAR, discussed a potential NIMH initiative to facilitate the development and testing of new, efficacious HIV prevention interventions, which, if scaled-up and implemented, would help to curb incidences of HIV infection, reduce HIV-associated morbidity and mortality, and reduce health disparities in HIV among men who have sex with men. He noted that this initiative is the kind of research that will be needed to meet the challenges posed by the evolving nature of the HIV epidemic.
He noted that some of the scientific areas of interest might include strategies to improve reach and uptake of prevention, to expand the research focus to stable dyads and social networks, to understand the interplay of social, biological, and behavioral determinants of risk, and to test novel strategies to intervene at community and structural levels. He noted too that 50 to 68 percent of new infections are occurring in same sex couples, and it is important to better understand some of the social and contextual determinants of risk.
Behavioral Mechanisms in Biomedical Strategies to Prevent HIV Infections
Dr. Forsyth discussed a second potential NIMH initiative focusing more on the behavioral mechanisms and biomedical strategies to avert HIV infection. New strategies are being developed, including those involving pre-exposure prophylaxis (giving antiretroviral drugs to targeted people who are at risk). Other interventions, such as male circumcision and prevention of mother-to-child transmission, have offered even more compelling evidence. The problem is that even with the promise of these interventions, it is critically important to understand that their true efficacy is likely to be diluted by changes in behavior that may occur as the interventions roll out. The goal of this potential initiative is to advance understanding of the complex behavioral and social factors that may partially determine the efficacy and, ultimately, the effectiveness of new biomedical strategies to curb HIV infection.
Work has been ongoing for many years with the other Institutes to integrate rigorous behavioral science into biomedical and clinical trials. This initiative aims to look at facilitators and barriers to the uptake and sustained use of products as well as at misperceptions about preventive products, and to focus on behavioral decision making, particularly under conditions of uncertainty.
Unbiased in vitro Analysis of Neurobiological Function
Andrea Beckel-Mitchener, Ph.D., DNBBS, presented a potential initiative to support the use of unbiased neurobiological assays in the development of robust analytical platforms that could be used to reveal changes in neuronal function, with the intent to move basic neuroscience discoveries into translational applications. The novel assay platforms would provide opportunities to measure neurobiological endpoints, and build a pipeline to be used in the context of target identification and drug discovery.
This initiative seeks to fill the existing gap in early assay development with measures relevant to neurobiological processes and pathways. Supported projects could incorporate phenotypes including, but not limited to, dendritic or axonal outgrowth, plasticity, synaptic maturation or synaptic function, receptor function, protein synthesis and turnover, cell fate specification, or chromatin remodeling. The use of novel technologies for manipulation, detection, and analysis would be encouraged. Since it is assumed that analytical platforms are under development, there is no pre-determined expectation with regard to throughput; however, assays with potential for future scale-up are of significant interest. Analytical approaches supported through this initiative would promote NIMH-relevant measures in related NIH-wide Common Fund programs, such as the Library of Integrated Network-based Cellular Signatures (LINCS), the Molecular Libraries, Therapeutics for Rare and Neglected Diseases (TRND), and CAN.
New, Rapidly-Acting Treatments for Treatment-Resistant Depression (RAPID)
Bruce Cuthbert, Ph.D., Director, Division of Adult Translational Research and Treatment Development (DATR), discussed a potential NIMH initiative to promote the development of rapid treatments (acting within less than 48 hours of administration) for severe, treatment-resistant depression. He noted that in recent years a number of approaches have shown the ability to act as rapidly acting treatments for depression. A major goal is to ameliorate the symptoms of treatment-resistant or severe depression; another goal is to decrease suicidal ideation.
The goal of this initiative is to develop new interventions that can provide rapid amelioration of symptoms in severe treatment-resistant depression as an initial target. This initiative aims to test new compounds similar to ketamine but without its side effects (e.g., other NMDA antagonists, allosteric modulators of AMPA receptors, 5-HT4 receptor drugs, thyrotropin-releasing hormone (TRH)) or non-pharmacologic interventions (e.g., sleep deprivation, TMS, ECT, MST) for treatment-resistant depression. The outcome of this initiative could be expected to lead to the further understanding of underlying mechanisms and development of innovative, rapid treatment approaches for treatment-resistant depression.
Epigenomic Modifications in Neurodevelopment
Michelle Freund, Ph.D., DNBBS, discussed a potential NIMH initiative to identify both the developmental and tissue-specific targets of epigenetic regulation resulting from environmental and social stimuli and the components of the signaling pathway(s) that link stimuli to gene regulation and subsequent phenotypic variability. The primary objective would be to gain insight into critical windows of plasticity in neural development and to develop a deeper understanding of the specificity of these marks across tissue and cell types and identify target gene regions or loci that have a specific function or significance to critical developmental milestones.
Research supported by this initiative will focus on epigenomic plasticity during development and how modifications translate into changes in neural architecture and function. Further, this initiative will focus on how early experiences and the environment impact the epigenome which, in turn, may influence the risk of developing mental disorders. Comparison of data from multiple species, with exposures to different environmental stimuli, throughout development will provide an understanding of the impact of epigenetic regulation on neuro-architecture, and the interaction of the epigenome with the genome’s primary sequence. The hope is to fund applications that integrate genomic and epigenomic paradigms to study brain function. These applications will use cross-species comparisons and combine genetic and epigenetic approaches to understand brain development and sex differences.
Improving Evidence-Based Mental Health Screening, Referral, and Treatment for Persons with Mental Disorders in the Justice System
Denise Juliano-Bult, M.S.W., Division of Services and Intervention Research (DSIR), discussed a potential NIMH initiative to investigate the effectiveness of new and existing strategies for the delivery of mental health treatments in criminal (adult) or juvenile justice settings, focusing on improving mental health outcomes for people with mental illness who come in contact with the justice system. The motivation for this effort is to test strategies to address the significant unmet need for mental health treatment among this population.
The goal of this initiative is to support studies testing the effectiveness of strategies to improve mental health treatment for criminal and juvenile offenders with mental disorders, in community corrections, and during incarceration as well as the transition to release from the justice jurisdiction. A two-pronged approach will be used. Prospective studies will be encouraged to validate strategies to facilitate delivery, improve outcomes, and foster broad uptake of established, effective, evidence-based mental health interventions in justice settings. In addition, the initiative will explore the impact of existing programs using national-, state-, and county-level administrative databases. This would provide an opportunity to track broad trends in treatment provision.
A Repository to Support NIMH-Relevant Patient-Derived Stem Cell Research
David Panchision, Ph.D., DNBBS, discussed a potential initiative to establish a repository for human control and patient-derived cells and their reprogrammed derivatives, such as induced pluripotent stem cells (iPSCs), to support stem cell research relevant to mental disorders. New technologies now allow the reprogramming of patient-derived tissue to cell lines, such as iPSCs and induced neuronal cells (iNCs). Because these cells recapitulate many processes that occur during brain development, they provide unique tools to elucidate the basic molecular, cellular, and developmental defects underlying psychiatric illnesses.
Realization of the full potential of these tools requires the free and open sharing of cellular material with associated phenotypic and genotypic data among researchers. A cell repository will serve several purposes: (1) it will accumulate sample sizes that have adequate statistical power for detecting subtle phenotypic differences; (2) it will facilitate the rapid replication of new findings, and (3) it will provide well-characterized, standardized cellular reagents to a broader cross-section of the neuroscience community who might not otherwise have access to patient samples. A repository thus will maximize the value of NIMH investments in stem cell research and will accelerate biomarker identification as well as development of new therapeutics.
This initiative would establish a repository/bank for patient-derived cells and their reprogrammed derivatives to support research relevant to mental disorders, including but not limited to schizophrenia, bipolar disorder, and autism. The capabilities of the repository will range from derivation and banking of primary source cells from human subjects to more comprehensive banking and validation of iPSCs or similar reprogrammed/de-differentiated cells. Successful applications will demonstrate exceptional quality control and quality assurance procedures, clear standard operating procedures, as well as facilities and infrastructure for inventory and database management, storage, and distribution of viable biologicals, and procedures for adherence to all NIH rules and guidance regarding informed consent and tissue acquisition. It is expected that the repository will be staffed by a team of investigators with expertise in patient sample collection, cellular and molecular biology, with the ability to effectively interface with experts in information sciences and genetics.
Following some brief discussion among the presenters and Council members, the Council voted to unanimously approve all nine concept clearances that were presented. Dr. Insel reminded Council members and members of the public that the cleared concepts will be posted to the NIMH website and there will be opportunity for additional comment through those web pages.
Dr. Christine Courtois, a psychologist in private practice since 1981 and Co-founder and Clinical and Training Director of the Center for Post-Traumatic Disorders (PTSD) Program, addressed the Council. She commented on the ramifications of the treatment of complex PTSD stating that children are the most victimized segment of the general population in the United States, according to the recent review of the literature by Finkelhor. A broad array of initial and long-term problems develop in a number of life domains in the aftermath of abuse and other adverse childhood events, including dissociative responses, and problems with the development of a positive identity, as well as with the ability to identify and regulate emotional reactions in relationships with others. While under recognized or under treated, these and other common developmental aftereffects tend to compound over time. Two diagnostic conceptualizations have developed from research findings as aids to the parsimonious cataloguing and understanding of complex developmental and dissociative post-traumatic reactions. These are complex PTSD and Disorders of Extreme Stress Not-Otherwise-Specified for adults, and Developmental Trauma Disorder for children, both proposed for inclusion in the DSM-V and subject to upcoming field trials.
Epidemiological research has documented the ubiquity of traumatic stress in the background of a majority of mental health patients. Yet this history often goes unrecognized because of a lack of knowledge about trauma or because of the diversity of symptoms that come forward and the disconnection between the time of the original traumatizing experience and the emergence of symptoms years after the original traumatizing experience. Treatments are currently under development and need outcome testing. What has so far proven to be effective for the treatment of classic PTSD may not be effective for complex PTSD. She urged increased funding for research into all dimensions of trauma, which is so pernicious and costly in terms of how it affects the individual, the family, and society.
Dr. Bethany Brand, a Professor of Psychology at Towson University, said that for 17 years she has been treating the kind of patients that Dr. Courtois discussed in her comments. For the last 10 years, she has been attempting to conduct treatment outcome studies. She emphasized that her experience with these patients suggest that they are largely understudied and underserved; they are often suicidal or engage in self-injurious behavior and substance abuse; they have dissociative reactions; and they also frequently have their psychiatric medications adjusted, any or all of which would render them ineligible for many treatment studies for classic PTSD. This means that current empirically supported treatments for PTSD probably do not generalize to these patients. Dr. Brand called for more research on the prevalence of these problems as well as cost effectiveness studies. She referred to the Mansfield and associates study in the New England Journal of Medicine that showed that women who had been diagnosed with dissociative disorders were seen for, on average, 93 therapy sessions over four years, compared to an average of 73 sessions for people with substance abuse problems, 65 sessions for people with simple PTSD (DSM-recognized PTSD), and 45 sessions for people with depression.
Dr. Brand noted that she is the Principal Investigator of an on-going study of dissociative disorders, for which the initial cross-sectional results show some promise. Over the stages of treatment, the patients showed decreased suicide attempts, decreased hospitalizations, increased Global Assessment of Functioning score, decreased depression, decreased PTSD, and decreased dissociation. These disorders are so prevalent and so expensive that it is important to develop innovative treatments to help patients and bring down costs.
Dr. Insel adjourned the open policy session of the 225th meeting of the NAMHC at approximately 1:00 p.m. on May 14, 2010.
Summary of Primary MH Applications Reviewed
|Scored #||Scored Direct Cost $||Not Scored (NRFC)#||Not Scored (NRFC) Direct Cost $||Other #||Other Direct Cost $||Total #||Total Direct Cost $|
Appendix B: Council Roster
(Terms end 9/30 of designated year)
|Thomas R. Insel, M.D.
National Institute of Mental Health
|Jane A. Steinberg, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
David G. Amaral, Ph.D. (12)
Carl C. Bell, M.D. (11)
Elizabeth Childs, M.D., M.P.A. (10)
Robert Desimone, Ph.D. (11)
Ralph J. DiClemente, Ph.D. (12)
Howard B. Eichenbaum, Ph.D. (12)
Daniel H. Geschwind, M.D., Ph.D. (11)
Portia E. Iversen (12)
Kay Redfield Jamison, Ph.D. (13)
Dilip V. Jeste, M.D. (10)
David A. Lewis, M.D. (11)
Roberto Lewis-Fernandez, M.D. (13)
John S. March, M.D., M.P.H. (10)
Thomas H. McGlashan, M.D. (12)
Steven M. Paul, M.D. (12)
Enola K. Proctor, Ph.D. (10)
Rhonda Robinson Beale, M.D. (13)
Ex Officio Members
Office of the Secretary, DHHS
National Institutes of Health
Department of Defense
A. Kathryn Power, M.Ed.