May 22–23, 2008
Department of Health and Human Services
Public Health Service
National Institutes of Health
National Institute of Mental Health
- People Present
- Open Policy Session: Call to Order and Opening Remarks
- Concept Clearances
- Call to Order and Opening Remarks
- Approval of the Minutes for the Previous Council Meeting
- Director’s Report
- DSM-V Research Conferences and Task Force Development Report
- NAMHC Workgroup on Research Training: Update on Activities
- Council Workgroup on Neurodevelopment: Recommendations
- NIMH New Investigators
- Public Comments
- Appendix A: Review of Applications
- Appendix B: Council Roster
The National Advisory Mental Health Council (NAMHC) convened its 218th meeting in closed session to review grant applications at 11:00 a.m. on May 22, 2008, at the Neuroscience Center in Rockville, Maryland, and adjourned at approximately 3:15 p.m. (see Appendix A: Review of Applications). The NAMHC reconvened for an open session at the same location from approximately 3:35 p.m. until 5:10 p.m. The open session continued on the following day, May 23, 2008, in Building 31C, National Institutes of Health, Bethesda, Maryland, from 8:30 a.m. until adjournment at approximately 12:30 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)
Carl C. Bell, M.D.
Glorisa J. Canino, Ph.D.
Elizabeth Childs, M.D., P.C.
Robert Desimone, Ph.D.
Daniel H. Geschwind, M.D., Ph.D.
Raquel E. Gur, M.D., Ph.D.
Peter J. Hollenbeck, Ph.D.
Dilip V. Jeste, M.D.
Jeffrey A. Kelly, Ph.D.
Norwood Knight-Richardson, M.D., M.B.A.
Helena C. Kraemer, Ph.D.
Pat R. Levitt, Ph.D.
David A. Lewis, M.D.
John S. March, M.D., M.P.H.
Suzanne E. Vogel-Scibilia, M.D.
Thomas R. Insel, M.D.
Jane A. Steinberg, Ph.D.
Virginia Anthony, American Academy of Child and Adolescent Psychiatry
Thomas Blanpied, University of Maryland, Baltimore
Andrea Browning, Society for Research in Child Development
Dara Blachman, Office of Behavioral Social Sciences Research
Leah Engel, American Psychiatric Association
Renata Henry, National Association of State Mental Health Program Directors
Ann Hiller, American Psychiatric Association
Seung-Hu Hong, American Psychiatric Association
Emily Kuhl, American Psychiatric Association
David Kupfer, University of Pittsburgh School of Medicine
Amanda Law, University of Oxford
Beatriz Luna, University of Pittsburgh Medical Center
Meghan McGowan, Federation of Behavioral, Psychological and Cognitive Sciences
David Mandell, University of Pennsylvania School of Medicine
Anne Michaels, National Foundation on Mental Health
William Narrow, American Psychiatric Association
Darrel Regier, American Psychiatric Association
Stephanie Reed, American Association for Geriatric Psychiatry
Bette Runck, Science Writer
Rocio Salvador, American Psychiatric Association
Andrew Sperling, National Alliance on Mental Health
Joan Levy Zlotnik, Institute for the Advancement of Social Work Research
Open Policy Session: Call to Order and Opening Remarks
NIMH Director, Thomas R. Insel, M.D., called the open policy meeting to order. He welcomed all in attendance and commented that the afternoon session is devoted to the presentation of several concept clearances.
Promoting Outstanding Mental Health Innovators in Scientific Excellence (PrOMISE) Awards
Dr. David Armstrong, Chief of the NIMH Extramural Review Branch within the Division of Extramural Activities, described an initiative that seeks to identify outstanding scientists and clinicians who are at the early stage of their career and who intend to make a long-term career commitment to research in the mission areas of the NIMH. This program hopes to launch junior investigators in innovative research programs aimed at transforming the understanding of the diagnosis, treatment, and prevention of mental illness.
As this initiative is in its early conceptual stages, Dr. Armstrong said the Institute welcomes input regarding how to encourage imaginative applications and what the most appropriate eligibility criteria might be. Dr. Insel added that NIMH is modeling this initiative after the Outstanding New Environmental Scientist Award (ONES) program sponsored by the National Institute of Environmental Health Sciences. The ONES program uses the Howard Hughes Research Institute’s model, where only one application per school or college within a university will be accepted for review; therefore each institution essentially would perform triage before peer review begins.
Dr. Lewis asked how the new award would differ from simply funding more new investigators applying for R01 grants. Dr. Insel said that this type of award might target a field of science and possibly attract outstanding investigators from other fields to focus on this area of science. The new program could be framed in a way that might attract researchers working far outside of mental health fields.
Dr. Levitt thought this program might aim to support innovative, high-quality clinician scientists, who historically appear to have difficulty obtaining grants. Disadvantages are particularly noticeable in the field of child psychiatry and translational developmental neuroscience. Dr. Insel welcomed the suggestion and asked Council members to forward other ideas to Dr. Armstrong or to himself.
Suicide Prevention Efforts in Emergency Medicine Departments
Dr. Jane Pearson, from the NIMH Division of Services and Interventions Research, described an initiative that aims to improve identification, evaluation, and appropriate referral by emergency department providers of individuals at risk for suicide. The initiative calls for more research on practical interventions that can assist community providers who care for suicidal patients. The 2006 Institute of Medicine report, “The Breaking Point,” documented that there are fewer emergency departments handling more and more people. Data from Washington State show that suicide attempters released from emergency rooms sometimes return with injuries that might not be suicide attempts; conversely, those who come in with a motor vehicle accident sometimes return because of a suicide attempt. European data show that 2 percent of suicide attempters are dead after 2 years. Only a third of the youth who get referred to outpatient care after they have been seen in emergency rooms show up for the treatment.
An evidence base is needed to shed light on several issues surrounding the care of suicide attempters who are seen in emergency rooms. Are screening instruments being used to determine the intent of a suicide attempt, and if so, what is their validity? How are patients evaluated further after they are screened? How are referrals handled? What are some practical interventions? Is there a collaborative care model that could be adapted to help in the transition from the emergency room to further treatment?
In answer to a question from Dr. Bell, Dr. Pearson explained that the object of this program is not to reduce the overall suicide rate, a goal of other NIMH suicide prevention efforts, but rather to reduce the burden of suicide attempters who are seen in the emergency room.
Dr. Childs noted the connection between this initiative and the NIMH strategic plan priority of moving from population risk to individual risk. She recommended that the prevention effort be counterbalanced with protecting human rights and reducing the use of restraints. Dr. Vogel-Scibilia echoed Dr. Childs’s concerns and emphasized the need for attention to these matters.
Dr. March recommended that the program be extended to children and adolescents, who collectively make between one and two million suicide attempts a year. Dr. Pearson said that a pilot program with children may be needed, because parental involvement makes the intervention more complex.
Dr. Jeste pointed out that suicide is very common in the elderly. In addition, the Department of Veterans Affairs (VA) is devoting increasing resources to preventing suicides among veterans returning from war. He suggested that NIMH explore a possible partnership with the VA in these efforts. Dr. Geschwind suggested that partnerships may also be possible with other health care agencies, such as health maintenance organizations.
Comparative Studies of Cortical Development to Link Developmental Neuroscience and Behavior
Dr. Susan Koester, Deputy Director of the Division of Neuroscience and Basic Behavioral Science, discussed an initiative aimed at examining neural development across time, discipline or level of analysis, and species. She explained that there is a substantial and steadily growing understanding of cellular and molecular events during embryonic development. However, few research groups are looking at postnatal neural development, and even fewer are making connections between cellular and molecular events and behavioral changes across development. Mechanistic explanations for the events that are discovered are also missing. This initiative draws on the recommendations of the Council Workgroup on Neurodevelopment to support fundamental studies on the development of cells, circuits, and functions; to develop a toolbox of validated and change‑sensitive behavioral measures and biomarkers that are time‑sensitive; to establish creative behaviorally validated tasks for use across developmental time points and species; to create opportunities for effective cross‑disciplinary communication among grantees and, parenthetically, across divisions within NIMH; and also to model dimensional components of mental illnesses in animals, rather than symptoms or diagnoses.
This initiative is proposed to support studies directed to time points between birth and puberty and that connect the neuroscience of cortical development to cognitive, social, emotional, or other behavioral changes. The studies would include comparative integrative neuroscience studies in humans and other mammals. The ideal studies would provide links across species from specific developmental neurobiological events to behaviors and would show how comparable behaviors develop in different species. Especially welcome would be studies linking humans to other species as well as studies that make a functional connection between developmental events in monkeys and rodents.
Ideally, studies supported under this initiative might start from a well‑characterized behavioral task in one species and extend it to another, while looking for the developmental point when the child or the animal can do the task, and work toward an understanding of what developmental events may allow the emergence of that behavior. Potential topics might include development of cortico‑amygdala circuitry and fear‑related behaviors; relating development of circuits in prefrontal cortex to the development of attention; development of cortical circuits and behavioral response inhibition; brain mechanisms underlying development of working memory or reversal learning; or developmental mechanisms underlying cortical modulation of goal‑directed behavior. The goal would be that findings from these studies might be expected to elucidate the relevant developmental stages, circuits, and behavioral readouts for future development of effective treatments or prevention of mental disorders.
The Gene-Environment Initiative (GEI) Systems Biology Initiative
Dr. Thomas Lehner, Chief of the Genomics Research Branch within the Division of Neuroscience and Basic Behavioral Science, described an initiative that would provide support for studies in systems biology. The goal of this initiative is to expand on previous findings from genome-wide association studies to identify and characterize the molecular elements of large dynamic networks and their perturbations underlying complex human disease states. The GEI is a trans‑NIH undertaking proposed in the President's budget in fiscal year 2006 for 5 years for $50 million that aims to accelerate the understanding of genetic and environmental contributions to health and disease. The President’s budget includes these funds in the Department of Health and Human Services budget not the NIMH budget.
The GEI is intended to increase our understanding of the elements in the larger networks that may lead to a phenotype. The supported research projects will use approaches and tools from the emergent discipline of systems biology to investigate molecular pathways, cellular circuits, and regulatory networks that together determine the phenotype.
Dr. Geschwind endorsed the idea and emphasized the importance of systems thinking for biology. Many of these methods come from physics and graph theory and mathematics, and these are areas in which mental health and neurobiology investigators are not well trained. He thinks that quantitative thinking in biology should be emphasized, to bring investigators from physics and engineering into cross-disciplinary training. NIMH has a history of bridging people from quantitative backgrounds, such as computer science or economics, into biomedical research via the K-25 award mechanism.
Clinical Pharmacotherapy for Posttraumatic Stress Disorder (PTSD)
Dr. Farris Tuma, Chief of the Traumatic Stress Disorders Research Program within the Division of Adult Translational Research and Treatment Development, described an initiative to advance research on the efficacy of available and exploratory medications for treating PTSD, obtaining relief from troubling symptoms, and improving functioning in areas of concern for patients.
Dr. Tuma said that over the past 20 years progress has been made in developing effective treatments for PTSD. Well‑controlled studies with a variety of trauma patients have shown that various types of psychotherapy are effective and research is underway to determine what components of these are most important and how to make them practical, accessible, and available to patients and clinicians in very diverse contexts. In terms of medications, Dr. Tuma noted that two medications (both SSRIs) have been approved by the Food and Drug Administration for treatment of PTSD in adults, although clearly not everyone treated with these drugs improves. Surveys and some data on prescribing patterns suggest that other medications are used. Clinicians are struggling to deal with complex clinical presentations and patients that present with prior unsuccessful treatment histories. Clinicians lack guidance about the use of these other medications. Small-scale controlled studies, open trials, and case reports give some indication about a variety of classes of medications that are promising. He said that the proposed initiative might support the testing of existing compounds and medications but also would encourage exploration of novel medications targeting new molecular targets or putative brain pathways implicated in PTSD.
Dr. Jeste recommended that the focus should not be on efficacy but rather on the risk‑benefit ratio, because the side effects of many medications are somewhat higher in PTSD patients. For example, the metabolic syndrome associated with atypical antipsychotics is more common in patients with PTSD than in patients with schizophrenia.
Dr. March also welcomed the initiative and noted that it may be that the majority of patients, at least chronic patients, are on multi‑drug regimens already. He suggested that rather than doing sequential randomized trials, one might consider a combination allowing for several questions within single experiments. He suggested smart trial methodology as an option.
Dr. Kelly said it is both interesting and troubling that some individuals exposed to a traumatic event are receiving medications prophylactically. That possibility raises ethical issues. Dr. Tuma said several trials are underway using alpha‑adrenergic blockers, beta‑adrenergic blockers, and corticosteroids prophylactically with people who are at very high risk. NIMH and investigators doing these studies are also concerned with the issue.
Dr. Kraemer encouraged NIMH to consider collaboration with the VA. Dr. Tuma reported that NIMH and the VA have had a close relationship in recent years. Discussions about continued cooperation are ongoing. Dr. Insel pointed out that about 70 percent of those returning veterans who require services will seek treatment in the civilian sector.
Dr. Levitt suggested that it might be useful to collect biomarkers as a part of this initiative. Dr. Childs asked if the initiative would cover the psychopharmacology of trauma in children and its developmental implications. Dr. Tuma said that although the knowledge base on treatment of PTSD in children is limited, new studies in this area will be encouraged as well.
Viral and Host Genetic Factors Regulating HIV-Associated CNS Disease
Dr. Jeymohan Joseph, Chief of the Viral and Host Genetics program within the Center for Mental Health Research on AIDS, described an initiative aimed at stimulating research in understanding the role of viral and host genetic factors in regulating the pathophysiology of HIV‑associated central nervous system (CNS) disease. Despite the widespread introduction of highly active antiretroviral therapy, HIV‑associated neurologic and neuropsychiatric complications are increasing in prevalence as people are living longer. Considerable gaps exist in the understanding of the role of viral and host genetic factors in regulating the pathogenesis of the disease in the current treatment environment. The NIH Office of AIDS Research is also seeking to leverage genetics and genomics resources to study HIV/AIDS and has identified CNS disease as an important priority area. NIMH‑funded studies have supplied specimens to do these types of genetic studies.
The viral genetics questions might include: What is the role of viral sequences in viral trafficking into the brain? What are the determinants of neurotropism? How does virus compartmentalize in the brain versus the periphery? What is the evolution of the virus in the CNS and the evolution of drug‑resistant mutations? What is the role of viral sequences in the establishment of viral reservoirs in the brain? What is the impact of viral diversity in regulating HIV neuropathogenesis from a global perspective?
The host genetics studies would focus on identifying unique host genes linked with susceptibility and disease progression. This work would take advantage of the genome‑wide association studies and resources such as the International HapMap Project. Dr. Joseph said that the HIV field has yet to exploit some of these areas, particularly CNS pathogenesis, gene-environment interactions, and epigenetics in the development of CNS disease caused by HIV.
Dr. Geschwind asked if there is evidence that the individual variation in disease‑host response and treatment response is heritable. One would need to know this information before embarking on a large-scale genetic‑association study. Dr. Joseph said that an MCP1 polymorphism has been identified in HIV dementia, and it has been suggested that it could be heritable. Dr. Insel added that the problem is confounded by different clades, which drive neurotropism.
Dr. Hollenbeck asked what fraction of the neuropathology is due to the viral life cycle and what fraction is due to treatment. Dr. Joseph said there is increasing evidence of toxicity in the CNS caused by treatment.
Home-Based Lithium Level Testing for Bipolar Patients
Dr. William Riley, Deputy Director of the Division of AIDS and Health and Behavior Research, described a potential initiative that may be in the form of a phase-I small business innovation research (SBIR) contract solicitation aimed at testing the feasibility of a home-based lithium level test. He noted that the narrow therapeutic window for lithium treatment requires testing at least twice a week during the acute treatment phase and at least every 2 months during the maintenance phase. Easier access to regular monitoring of lithium levels could improve adherence in clinical management and potentially increase the use of lithium in the treatment of mental illness. A reliable office‑based measure for obtaining lithium levels was developed recently and is now FDA approved.
This initiative would attempt to develop a prototype of a home-based test, assess its usability in a very small sample of bipolar patients, and establish some initial data on adequate concordance with lab‑based measures currently used. If the phase-I trials are successful, they would be followed with one phase-II award that would further develop and refine the home‑based test, evaluate its accuracy, and potentially develop ancillary systems (e.g., patient feedback and real-time feedback to health professionals).
Dr. March said that the need for testing is a large barrier to more widespread use of lithium in children, who are probably more vulnerable to shifting lithium levels than adults. The phase-I procedure should be done in a way that is mindful of its application in children.
Dr. Vogel-Scibilia suggested that the necessary testing of thyroid and creatinine levels is also essential and expressed concern that this might not be adequately monitored if the lithium level monitoring is done at home. Dr. Bell added that the different tolerance levels in various individuals should also be considered.
Addressing the Mental Health Needs of Returning Combat Veterans in the Community
Dr. Robert Heinssen, Deputy Director of the Division of Services and Interventions Research, described an initiative that would support research on existing national, State, and community programs that address the mental health and behavioral adjustment needs of returning veterans. Partnerships between mental health services researchers and program providers will be encouraged. This initiative was developed from the recommendation in the Council Workgroup Report “The Road Ahead” that NIMH seek opportunities to add research components to ongoing efforts and demonstration projects funded by other agencies and departments.
As background, Dr. Heinssen said that studies conducted by researchers from the Walter Reed Army Research Institute have shown that 3-6 months after leaving the theater of war, veterans of Operation Iraqi Freedom and Operation Enduring Freedom had high rates of depression, PTSD, and alcohol misuse. Those rates were, in general, higher among the reserve component troops than their active duty counterparts. Overall, both groups are at considerable mental health risk, as determined by these assessment instruments. The need for mental health care by large numbers of returning veterans has been confirmed by other studies, but many veterans do not have access to care. Difficulties in accessing services are particularly acute among members of the Reserve and National Guard components. Despite tremendous efforts from the Department of Defense (DoD) and the VA to reach out and address the needs of these individuals, some veterans have fallen through the cracks.
A group of NIMH staff have identified several State programs that specifically focus on the reintegration of returning Reserve troops. In addition, nonprofit, mostly volunteer, initiatives have been developed to meet the mental health needs of the soldiers or their family members. These programs vary considerably in scope, professional involvement, and targeted group, and they tend to lack a systematic evaluation of the impact the program has on the adjustment of the soldier and the family member.
This proposed initiative would emphasize the importance of partnerships between the program providers, those who developed these programs, and mental health services researchers who would take responsibility for developing the evaluation component. The assessment would consider a broad range of outcomes of interest to the stakeholders and also capture dimensions indicating the success of reintegration (e.g., psychiatric status and interpersonal and occupational functioning). The ultimate goal of the project is to use results to improve the mental health care of service members and their families. By evaluating the natural experiments in different types of services, the project aims to help identify the services that work best.
Dr. Desimone encouraged the NIMH to partner with the DoD. Dr. Heinssen said that he and his colleagues have been reaching out to DoD and other agencies to try to ensure that these efforts are not duplicative.
Dr. March encouraged Dr. Heinssen to be particularly mindful of programs that are designed to assess and prevent suicide attempts and completed suicide in both active duty and returning soldiers. He also emphasized the importance of assessing the impact that a parent returning with PTSD or traumatic brain injury has on the children. Dr. March also emphasized the need for programs to be rapidly disseminated, and therefore variables designed to measure translation should be built into the models.
Dr. Childs noted that many returning reservists actually have health insurance through employers and are receiving services outside of the programs designed explicitly for veterans. Claims data might shed light on the treatment received in mainstream mental health facilities. She said she was heartened to hear that NIMH has the opportunity to work with DoD and the VA system, because the Institute might help shape how those departments assess their mental health treatments.
Following the discussion, the Council voted unanimously to approve all the concept clearances that were described.
Dr. Insel adjourned the initial session of the Council meeting at approximately 5:10pm.
Call to Order and Opening Remarks
The Council reconvened the following morning on the main campus of the NIH in Bethesda, Maryland. Dr. Insel opened the meeting by introducing the two Council members attending their first Council meeting: Dr. Carl Bell is the President and Chief Executive Officer of the Community Mental Health Council in Chicago, Director of Public and Community Psychiatry and a Clinical Professor of Psychiatry and Public Health at the University of Illinois at Chicago. Dr. Daniel H. Geschwind occupies the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and is Professor in Residence with the Departments of Neurology and Psychiatry and Biobehavioral Sciences at the University of California at Los Angeles.
Approval of the Minutes of the Previous Council Meeting
Turning to the minutes of the January 2008 Council session, Dr. Insel asked if Council members had revisions or comments on the minutes. Hearing none, the minutes were unanimously approved.
NIMH Director’s Report
Dr. Insel said that two of the NIH Roadmap initiatives that began last year are continuing: the epigenome represents an effort to develop the tools for epigenetic tags in the genome; and the microbiome project is an exploration of the universe of microbes that live within the human body. Several new Roadmap initiatives are being discussed. The most likely to begin in the next year is a project called the Science of Behavior Change, that will focus on the general area of behavioral economics. There is also discussion of an effort to understand mitochondria more systematically and in more detail. Another program, the GTEx, would examine the connection between genomic sequence and transcriptional expression.
NIH has emphasized increased public access. The law now requires that all publications generated with the support of NIH grants be submitted to PubMed Central, an on-line database maintained by the National Library of Medicine. It is hoped that this mechanism will help ensure that research funded with taxpayer dollars is accessible to the public.
NIH continues the effort to analyze the peer review process. The review of peer review began because of concerns over tight budgets and the increasing complexity of science. The peer review system is charged with funding the best science, by the best scientists, with the least administrative burden. Much debate has centered on defining what is meant by the term "best," which depends on many factors, including scientific quality. The complex analysis of peer review began with a series of regional meetings to get input from academia, community groups, and national organizations. Based on those meetings, a draft recommendation report was submitted to the NIH Director’s Advisory Council at the end of February. During the subsequent design and implementation phase, more town hall meetings were held involving the public and NIH staff. The final set of recommendations will go the NIH Director on June 6, 2008, and will be described in a June 13, 2008, article in Science magazine. The draft report noted that the main issues that needed to be addressed are the following:
- Reducing administrative burden on applicants, reviewers, and NIH staff
- Enhancing the rating system
- Enhancing review and reviewer quality
- Optimizing support at different career stages
- Optimizing support for different types and approaches of science
- Reducing stress on the support system of science
- Meeting the need for continuous review of peer review
Dr. Insel said that the need for junior investigators is particularly acute for NIMH. Researchers at the beginning of their careers may be more likely to have the necessary training and the world view needed to undertake the research that is now required. NIH‑wide data show that the success rate for new investigators submitting an initial grant application is below 10 percent. Because most grants that are now eventually funded have gone through a second or third review, the burden of peer review has increased substantially since 1998, when most applications that were funded were approved after the initial submission. Reviewers are spending much more time for every grant that ultimately gets funded. Whether the science is actually better after repeated submissions is open to question.
Discussion of these issues has led to many possible recommendations. Among them are changes to ensure that the very best reviewers are chosen for study sections, which may involve providing incentives to those who serve or requiring service from grantees with merit awards, multiple grants, or center grants. Another possibility is making the task less burdensome by altering the review process or allowing more flexibility in the review and/or service schedule.
Ensuring the fairness and clarity of peer review led to suggestions that the description of the science be designated by more than just a single number. For example, should there be different ratings for innovation, experience, or the individual? Should the project be ranked for the likelihood of its impact? It is may be better to let applicants know when a proposed project should not be resubmitted–even if it is elegantly designed. If it has a low score for impact, that information might be very useful for the program and Council to know.
NIMH Strategic Plan
After being subjected to extensive internal and external discussions, the strategic plan now consists of four objectives that are being operationalized and are under review at the departmental level. The objectives are:
- Promote discovery in the brain and behavioral sciences to fuel research on the causes of mental disorders–genes to circuits to behavior and back, genomics and epigenomics, developmental neuroscience.
- Chart mental illness trajectories to determine when, where, and how to intervene–predictive biomarkers, longitudinal designs, individual risk.
- Develop new and better interventions for mental disorders that incorporate the diverse needs and circumstances of people with mental illness–rational therapeutics, preemptive and personalized interventions, moderator trials.
- Strengthen the public health impact of NIMH-supported research–participatory research, impact on practice, health disparities.
NIMH has initiated searches to fill the positions of the NIMH Scientific Director and the Clinical Director for the Intramural Research Program (IRP) as well as the Director for the Extramural Office of Special Populations. The current IRP Clinical Director, Dr. Donald L. Rosenstein, is moving to the University of North Carolina. Dr. Husseini Manji, Director of the Mood and Anxiety Program in the IRP was recently recruited to Johnson & Johnson to be Vice President for Global Neuroscience Efforts.
Dr. Insel recounted a few of the many recent breakthroughs in the science supported by NIMH. First, in the field of autism research, Dr. Insel noted that over the past 18 months three separate groups or scientists have identified the same gene to be associated with autism. The gene is contactin‑associated protein‑like 2 (CNTNAP2), which is in a family of genes found in the post‑synaptic density. This finding begins to clarify how this disorder, which is associated with profound behavioral and cognitive dysfunctions, is associated with no apparent gross brain anatomy disturbance. Despite suspicions to the contrary, macroscopic studies showed virtually no anatomic associations to the profound disability in autistic children. Almost all the findings now are leading to the conclusion that autism can be thought of as a synaptic disorder. In the future, the focus of studies in the pathophysiology of autism will be on synaptic dysfunction and what that means in terms of early brain development.
In the arena of schizophrenia research, it may soon be possible to shift the focus from the late stages of schizophrenia, when psychosis has emerged and the disorder is on its way to becoming chronic, to developing interventions for individuals before their psychosis becomes full blown. This possibility has been enhanced by recent research findings published by Cannon et al. Five variables were found in adolescents who had not yet had a psychotic episode, but those five variables predicted who would develop psychosis. In addition to these five clinical variables, there may soon be specific genetic variables that could help to increase the odds of correct predictions. Cortical differences in 15-year-olds with the early prodromal syndrome may make it possible to use imaging to add genetic information and clinical phenotyping to improve the predictive power further. The goal for the next 5 years is to find even earlier predictive variables, such as the genetic risk of individuals.
A third highlight is the recently published work by Kessler et al., which reported the cost to society of major mental illnesses was more than $193 billion in 2002 in lost earnings alone. The study showed that the annual cost reaches nearly $317 billion when the direct expenditures on health care and the cost of Federal disability payments for major mental illnesses are added. That figure does not include the costs of incarceration, homelessness, and other comorbid conditions that often accompany schizophrenia, bipolar illness, PTSD, and other disorders. These figures give us pause and encourage consideration about how much money should go towards research that could lead to a decrease in these costs.
DSM‑V Research Conferences and Task Force Development Report
Dr. Darrel A. Regier, Director of the Division of Research at the American Psychiatric Association (APA) and vice-chair of the DSM-V Task Force, began his presentation by acknowledging the support of NIMH, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism in supporting a cooperative agreement conference grant that has assisted in developing the research base for the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V). The deficiencies in the fourth edition of the manual have been apparent for more than a decade, and they include insufficient attention to the very high rates of comorbidity, difficulty in separating individual diagnostic areas, high use of the "not otherwise specified" category, lack of treatment specificity, and the lack of laboratory markers.
The field has exerted pressure to shift the emphasis in the DSM from diagnostic reliability to diagnostic validity, to move toward a more etiologically based classification, and to consider whether research findings in cognitive behavioral science, family studies, molecular genetics, neuroscience, and functional and structural imaging can be brought into diagnostic conceptualizations. What to call this new polygenetic-environmental paradigm is open to question.
The strategy in designing the new classification system is to incorporate research, to build on empirical findings rather than rely on clinical consensus, and to seek multidisciplinary and international scientific participation in the task of planning DSM-V. The research agenda has been informed by a series of white papers, that have been published. In the second phase, a steering committee was created, made up of representatives from the three NIH Institutes most involved with mental disorders and substance abuse, along with the APA and the World Health Organization. Thirteen conferences were held to promote international collaboration in producing the new DSM and international classification system. The purpose was to foster international consensus on the scientific criteria for mental disorders and to stimulate empirical research to inform decision-making on crucial diagnostic areas. Four monographs based on the conferences have been published so far. Another four are in press; four are in preparation, and more than 83 journal articles have been published and are available on PubMed.
Dr. David Kupfer, chair of the Department of Psychiatry at the University of Pittsburgh School of Medicine and chair of the DSM‑V Task Force, acknowledged the five Council members and eight NIMH staff members who have served either on the task force or on work groups. Dr. Kupfer said the revision of the DSM will give the highest priority to clinical utility, with recommendations guided by research evidence. Although continuity with previous editions of the DSM is important, revisions are underway with no a priori constraints on the degree of change between DSM‑IV and DSM‑V. He underscored the intention to emphasize neurodevelopment across the life span; to consider the dimensionality of distress, disability, and severity; and to incorporate new knowledge about risk factors, prodromes, and prevention. The task force is planning to make DSM‑V, which will be published in early 2012, a living document.
The task force is composed of work group chairs and health professionals from different stakeholder groups. Work groups are made up of individuals working in specific diagnostic areas. Together, the task force and work groups include about 150 individuals as well as an additional 500 to 1,000 advisors to the work groups. The task force itself has oversight responsibility for final recommendations. It and the work groups are charged with assessing the readiness of individual disorders to incorporate biological measures and dimensional approaches to diagnosis.
In addition to the considerations mentioned by Dr. Regier, issues surrounding gender and cross-cultural expressions of mental disorders will be addressed. Dr. Kupfer emphasized that integration of psychiatry with general medicine will also be considered. Validators for diagnostic groups will be explored (e.g., temperamental antecedents, symptom similarity, cognitive and emotional processing, high rates of comorbidity, course of illness, and treatment response). After the analysis of the literature is completed, the task force will draft questions to test in field trials. The team is considering several formats for these field trials, from widespread experiments to trials at scientific meetings using video clips, to Web-based trials.
Dr. Levitt asked for elaboration on the need to be sensitive to cross‑cultural issues in validating diagnostic criteria. Dr. Kupfer said that datasets on U.S. populations that oversample minority groups will be helpful in developing criteria for major adult disorders and some childhood and adolescent disorders. Dr. Philip Wang, Director of the NIMH Division of Services and Interventions Research, noted that the work group he is involved with has been trying to approach the issue empirically by looking first at differences in rates of disorders and considering if the issue is diagnostic definition or reflects actual differences in incidence. If it is the former, the group will try to find equivalent ways of expressing the disorder (e.g., with somatic symptoms). Dr. Regier said that a major concern is that language and culture influence the syndromes’ nature and the way symptoms are expressed. He said that Dr. Wang has been encouraging the group to identify symptom characteristics that are immutable across different cultural groups. Then, the search for differences in expression can begin.
NAMHC Workgroup on Research Training: Update on Activities
Dr. Dilip Jeste, Chair of the NAMHC Workgroup on Research Training, said that an essential component of the NIMH mission is to promote the training of investigators who will conduct research into the causes and treatment of mental illness. The Council Workgroup on Research Training was charged with advising the NAMHC on NIMH’s investment in research training and to provide strategic recommendations about how NIMH could better achieve its goals in recruiting, training, and retaining a workforce capable of integrating novel technologies and approaches across multiple levels of analysis in its NIMH-relevant research.
To date, the workgroup has met for three 2-day face-to-face meetings, each preceded by a conference call. The workgroup analyzed the types of research training programs that have been supported by NIMH over the last decade including the type of support given, the type of programs funded, and outcomes. Programs outside of NIMH were also discussed. In addition, six M.D.‑Ph.D.s at various stages of training were invited to a workgroup meeting, offering insights into their experiences. Recommendations are now being generated and are expected to be finalized over the next few months. The workgroup plans to share its draft recommendations at the September Council meeting.
Council Workgroup on Neurodevelopment: Recommendations
Dr. John March, co-Chair of the NAMHC Workgroup on Neurodevelopment, outlined the workgroup’s research priorities, which are aimed at charting typical and atypical behavior across development to understand the origins of mental illness:
- Build the knowledge base of how the brain typically develops, on the molecular, neuroanatomical, and functional levels.
- Identify and improve the characterization of sensitive, malleable periods of neurodevelopment.
- Further understand how and why healthy brain development goes awry to result in mental illness.
- Understand gene-by-environment interactions in mental illnesses.
- Increase collaborations between developmental epidemiology and developmental neuroscience.
- Develop new intervention strategies targeting developmental trajectories.
- Build resources, develop new methodologies, and promote platforms to facilitate information/resource sharing.
To foster the development of the new field of translational developmental neuroscience, NIMH will need to encourage investigators to collaborate across disciplines and foster a culture of sharing among grantees. NIMH should also work to enhance collaboration with patient advocacy groups to recruit the patient samples required for large research networks. Another step to foster the new discipline is to support knowledge management and transfer to ensure rapid dissemination of the newest techniques, resources, and concepts; many NIH initiatives are designed exactly for this purpose. In addition, the workgroup recommends enhancing the cross‑talk between extramural and intramural NIMH programs, as well as across divisions and branches within the extramural program.
This Council workgroup recognized the need to foster an effective and well-trained workforce to build this new area of science, translational developmental neuroscience. The workgroup report recommends steps for attracting clinician‑scientists, allowing opportunities for individuals to get training outside their own area, and for established scientists to reinvent themselves. Other recommendations include a focus on integrating research and training initiatives, particularly on ways to capitalize the NIMH investment in translational developmental neuroscience, and creating opportunities to inject expertise and knowledge of new technologies at all levels of the workforce. The full workgroup’s report, “Transformative Neurodevelopmental Research in Mental Illness,” will soon be available on the Web.
Dr. Insel said that the group’s work has already resulted in a request for supplements to current grants related to the addition of a developmental component in ongoing research.
Dr. Geschwind asked if the workgroup discussed cross‑disciplinary biomedical or environmental training. Dr. Levitt, co-chair of the workgroup, said there was extensive discussion about introducing undergraduate clinical neuroscience training and noted that the report includes recommendations on new ways of accessing technologies and training.
Dr. Lewis said that he found the workgroup’s report inspiring and interesting. He wondered whether there was enough emphasis on the need for age‑specific pharmacological targets, even within the same spectrum of the disorder. Dr. March replied that the group understood that as new biomarkers are discovered, given the understanding of mental illnesses as neural developmental, investigators will have to rethink how clinical trials are conducted. New methodologies, such as designs that support adaptive treatment strategies, may be needed. An infrastructure will have to be built that will make it possible to study new chemical entities in children. One reason the issue is not emphasized is that the science has not yet matured sufficiently.
Drs. Levitt and March said that the report addresses the practical issues in providing the necessary training to transform the field to a more developmental perspective. Dr. March suggested that if psychiatrists are able to take a lifespan perspective, the field may no longer be divided into adult and child specialties. Dr. Insel reminded the Council of the initiative described by Dr. Armstrong earlier in the meeting that would invest in training at an early stage of a career; this field may be one target for such training. Council members agreed that it should be.
The Council then voted to approve the workgroup’s report.
NIMH New Investigators
Dr. Insel introduced the next series of presentations by noting that the Institute is committed to supporting new investigators and to facilitating the independence of emerging scientists. These investigators are a critical resource to the research enterprise both in terms of the new knowledge they are contributing to the field and as a resource to the Institute in terms of how we can best serve researchers.
Neural Plasticity and Postsynaptic Density
Dr. Insel introduced Dr. Thomas Blanpied who is an Assistant Professor at the University of Maryland School of Medicine. His laboratory, recently dedicated as the Katherine D. and Theodore J. Carski Memorial Laboratory, investigates the molecular and cellular mechanisms underlying the role of neurons in producing healthy behavior.
Dr. Blanpied said that he is primarily interested in learning the relation between synaptic strength and the dynamics of synaptic scaffold proteins within the postsynaptic density (PSD). He seeks to use new optical approaches in live neurons to study molecular dynamics at single synapses. These changes will be analyzed in relation to modifications of synaptic strength, and in relation to data derived from molecular biochemical, and crystallographic studies. The goals of his research are to measure morphology of individual living synapses; determine mobility of core proteins within the PSD; and examine kinetic and spatial events underlying synapse plasticity.
He then presented early results from his laboratory, including work begun during his postdoctoral position with Dr. Michael Ehlers at Duke University. He and his colleagues approached the problem by leveraging the enormous explosion in fluorescence imaging technology, live cell microscopy, and high-resolution imaging capabilities to examine living synapses. They typically grow neurons in dissociated cell culture, because they can get high resolution images of the synapses themselves, and then express various synapse-associated proteins tagged with the green fluorescent protein (GFP) to visualize the organization of that protein within the cell. By tagging the protein PSD‑95 with GFP, surprisingly good resolution of the morphology of synapses in living cells can be obtained.
The group’s live-cell techniques showed morphological transitions that individual PSDs undergo over time in established synapses–those that exist for very long periods of time, probably years. Moment to moment, however, the entire post-synaptic complex undergoes dramatic, coordinated morphological restructuring. Through a series of experiments, the researchers found that this process is driven by actin in the dendritic spines. Actin is a key determinant of the morphology of spines and synapses and the growth of synapses. The actin cytoskeleton within spines drives the moment-to-moment restructuring. Thus, it is a dynamic force, rather than simply a stability molecule.
The next problem Dr. Blanpied’s group pursued was the internal mobility of proteins in the PSD. Using an approach called photobleaching to monitor the movement of proteins, they found that PSD‑95 is bound into a matrix in the PSD. To assess the activity in a longer time scale, the investigators again used photobleaching and a photoactivation approach to optically define subdomains in the PSD.
The findings–PSD structure is continuously dynamic, but protein movement within the PSD is strictly limited–are at first glance contradictory. Dr. Blanpied and his colleagues thus propose a new model of PSD architecture, a flexible matrix model. In this model, proteins are bound into the matrix, but the structure of the overall PSD can be changed, not by rearranging the proteins but by changing their relative positions without changing relationships with their nearest neighbors. It is, in other words, a change in shape without a change in topology. The implication of the new model is that it may be possible to regulate the function of synapses by rearranging receptors underneath the sites of neurotransmitter release. Receptor density where vesicles are releasing neurotransmitter can be altered, thereby changing the strength of the synapse–with essentially no molecular alteration. The proposed matrix suggests very concrete ways to add or replace its elements, grow the synapse or prune it back, and very specific models for how that synapse would be taken apart. Dr. Blanpied said that he would like to know how the matrix is modified during synaptic growth and plasticity and pruning.
In summary, he said that he believes that the matrix model describes an information storage method whereby the synapse is able to keep track of its own history in the spatial relationship of its molecules. In the long term, he said, he hopes that these new insights into how the PSD is put together and how its proteins relate to one another can guide understanding of the dynamic moment-to-moment regulation of synaptic plasticity. It may also aid understanding of how these and other molecularly indistinguishable changes in the PSD can regulate the function of other proteins, such as signaling molecules and other proteins intimately involved in cognitive impairment
Neuregulin 1 and Schizophrenia: Molecular Mechanisms of Genetic Association
Dr. Insel introduced Dr. Amanda J. Law who is an Associate Professor at the University of Oxford and a Visiting Scholar in the NIMH Intramural program working with Dr. Daniel Weinberger in the Genes Cognition and Psychosis Program. Dr. Law described her work on the neurodevelopmental signaling pathway involving two primary genes, the neuregulin‑1 and more recently its receptor erb4.
In an effort to understand the molecular mechanisms behind the genetic association of the 5’ region of neuregulin-1 with schizophrenia, Dr. Law focused on a previously unstudied novel isoform of the gene, Type IV, which is characterized by the presence of the E187 lead exon. She began her work by asking whether the single nucleotide polymorphisms (SNPs) that associate with schizophrenia and lie upstream of the E187 exon affect expression or function of the Type IV isoform. In a study of the hippocampal formation in the post-mortem brain of patients with schizophrenia and normal controls, she and her colleagues found that individuals carrying the risk allele at a specific risk SNP in the DeCODE haplotype, SNPNRG18243177, exhibited elevated expression levels of Type IV, with individuals homozygous having the highest levels. SNPNRG18243177 has been associated with schizophrenia and bipolar disorder, as well as intermediate brain phenotypes and cognition in normal individuals, and individuals had high risk of mental illness. Next, the investigators conducted classical promoter experiments, which showed that the SNP is a functional promoter variant, with increased promoter activity associated with the risk allele in-vitro. Indepth cloning and characterization of Type IV neuregulin-1 revealed a family of brain‑specific developmentally regulated proteins.
Other experiments on the structure of Type IV in both adult and fetal brain revealed that full-length Type IV neuregulin-1 is the isoform related to genetic variation in the adult brain in schizophrenia. Dr. Law identified two splice isoforms that are expressed exclusively during fetal development and are absent in the adult brain. She showed that these isoforms are subject to differential biochemical processing compared to full-length Type IV. Very little change in levels of full-length Type IV expression was observed over the course of development; however, the novel splice variant seems to be “switched on” around 16 gestational weeks and stays active until about 12 months of life. In addition, Dr. Law and her colleagues found that the SNP associated with the clinical phenotype of schizophrenia and adult brain Type IV expression (SNPNRG18243177) also predicts expression of the novel Type IV variant during fetal development.
To explore how molecular mechanisms translate at the cell level, the groupis now investigating the effect of Type IV neuregulin-1 overexpression on hippocampal neuronal development in culture. The findings suggest that specific developmental isoforms of the neuregulin-1 Type IV family may act as transcription factors early in critical periods of neurodevelopment and that overexpression of full length type IV and novel fetal isoforms affects dendritic spine development. Understanding the involvement of Type IV in neurodevelopment may provide insight into the pathogenesis of schizophrenia.
In summary, Dr. Law said that she and hercolleagues have demonstrated that genetic association of the 5‑prime region of neuregulin-1 is associated with the regulation of a previously unstudied brain-specific, developmentally regulated neuregulin family. The regulation is mediated by a functional SNP–one of the first demonstrations of a noncoding functional SNP that affects the function of a gene associated with a disorder, in this case, schizophrenia. The investigators are currently working on validating observations in vitro using an in vivo mouse model of transgenicoverexpression of type-IV neuregulin.
Cognitive and Brain Systems Maturation Through Adolescence
Dr. Insel introduced Dr. Beatriz Luna who is an Associate Professor of Psychiatry and Psychology and Director of the Laboratory for Neurocognitive Development at the University of Pittsburgh Medical Center. Dr. Luna is the recipient of a Presidential Early Career Award for Scientists and Engineers and was selected to join the President and talk about the opportunities for science in the next generation.
Dr. Luna said that she and her colleagues are interested in adolescence because it is a vulnerable period, when there is a 200-300 percent increase in the mortality rate, which likely results from risk-taking behavior. In addition, mental disorders begin to emerge during the transition from adolescence to adulthood. During adolescent development, voluntary planned behavior through cognitive control reaches mature levels. This type of behavior, which is needed to override impulsive, automatic behavior, is consistently impaired in mental disorders.
Dr. Luna described experiments that provide a quick link to the neuroanatomy of inhibitory control, which is essential to executive behavior. Subjects are asked to look at a central fixation target and when another light appears to look in the opposite direction. The test shows that children younger than 10 have the ability to inhibit a response and to have voluntary control as a tool, but their ability to use the tool improves with age and reaches adult levels by the age of 14 to 15. Functional MRI (fMRI) scans however show continued improvements in the processing of inhibitory control as a widely distributed circuitry comes on line that supportthe ability to flexibly engage inhibitory control.
Dr. Luna said that the implication of these findings is that the ability to have response preparation and planning is crucial to cognition, and this ability is still immature in adolescents. The fMRI showed that adolescents had increased activity in the prefrontal cortex reflecting increased difficulty in inhibitory control. The implications are that just as adults are more prone to error when doing difficult tasks, adolescents are more prone to error when undertaking executive functions. When an error in inhibitory control occurs,activity in the very rostral aspect of the anterior cingulate is suppressed (indicating an error has occurred), followed by increased activity in the more dorsal aspect of anterior cingulate (using the information about the error to affect subsequent behavior). Adolescents are well able to recognize when they make an error in inhibitory control, but the part of the brain that allows them to use this information is still immature.
The next experiments explored the processes of motivation that might be influencing decision making. Again, adolescents show overactivity in reward detection but underactivity inthe executive processing of reward. On the fMRI, adolescents show delayed and overactivity in the ventral striatal region, including the nucleus accumbens, which is a part of the reward system that is structurally and physiologically immature in adolescence. They show little activity in the orbitofrontal cortex, which is involved in executive processing of reward information.
Further work using diffusion tensor imaging of the brain’s white matter, where myelination is a primary factor, found that the regions adjacent to the gray matter areas associated with executive control–orbital frontal cortex, striatum,and prefrontal cortex–also show progressive maturation during adolescence. These results indicate that structural immaturities may underlie age related differences in the ability to engage a widely distributed circuitry and engage executive control in a mature manner.
Summarizing her talk, Dr. Luna said that during the transition from adolescence to adulthood, flexibility in using mature cognitive abilities increases, even though the abilities were there long before. Neuroimaging studies that her group is undertaking are showing that there is a shift to a better‑specified, more widely distributed circuitry with enhanced functional integration. She suggested that this shift has implications for psychopathology because it may be vulnerable to impairment in two ways: The actual shift might trigger impairment; alternatively, the transition in the mode of operation that results from the shift may tap into systems that were already impaired.
Interstate Variation in Health Care Use Among Children with Autism
Dr. Insel introduced Dr. David Mandell who is an Assistant Professor of Psychiatry and Pediatrics at the University of Pennsylvania School of Medicine. In addition to his research, Dr. Mandell also participates in the strategic planning efforts on autism.
Dr. Mandell outlined the aims of his research:
- Examine State policies that may affect Medicaid-financed health care delivery to children with autism spectrum disorder.
- Provide accurate national and state-level estimates of the types, intensity, and patterns of service use.
- Estimate associations of state policies, and demographic, clinical, and system-of-care characteristics with health service use.
He and his colleagues pursue these aims by combining Medicaid data with policy data from all 50 States. Early findings on psychotropic medication use among children with autism, published recently in Pediatrics, show that use of these medications increases dramatically with age; almost three quarters of Medicaid-enrolled adolescents with autism use some psychotropic medication. Medication use is common among young children as well, with nearly one in five of those younger than two years of age taking psychotropic medications, most commonly sedatives.
In addition to individual demographic and socioeconomic characteristics of children/adolescents with autism, county- and State-level factors also appear to affect medication use. The more urban the county (i.e., the higher the population density), the more pediatricians per capita, and the greater the prevalence of Medicaid-enrolled children with autism, the less frequently medications are used. One possible explanation for this pattern is that State Medicaid programs have different eligibility criteria for children with autism; those States that have more generous eligibility criteria may be capturing children who are not as severely affected.
Dr. Mandell originally hypothesized that increased identification and services for children with autism in the education system would result in less commensurate use of Medicaid services. The opposite was observed; education and medication use appear to be complementary. It may be that in States with generous Medicaid policies for service use, the education system is more willing to identify those children. Adjusted analyses using random effects largely confirmed these findings.
Dr. Mandell and his colleagues now are trying to determine how State policies and local healthcare resources affect health and mental health service use in addition to medications. He pointed out that these studies are association studies and it is necessary to think creatively when using natural experimental designs to test hypotheses.
Dr. Vogel-Scibilia asked whether Dr. Mandell’s group had addressed the issue of wrap‑around services when children are in foster care and receiving medical assistance. He said that he is trying to gather data on this critical point and welcomed her input on how to think about the issue.
Dr. Jeste asked Dr. Luna if she has data on error detection and executive processing in the elderly population. She said that in studies she conducted as a postdoctoral fellow she found unique differences between adolescent and elderly subjects. In the elderly, the initial attempt to correct errors is not very good, but their subsequent ability to correct what they've done is actually still intact. Although superficially similar to adolescent attempts, the processes appear to be qualitatively different.
In answer to a question from Dr. Gur, Dr. Luna said that her group had not generally found gender differences. However, some differences were evident in early-maturing females, who appear to have limitations in cognitive control even though their IQs were normal or higher; this finding indicates that the prepubertal brain development of executive functioning may be different than the development of general mental intelligence.
Dr. Gur also asked whether the research could shed light on the transition to psychopathology during adolescence. Dr. Luna said that her work is longitudinal, with subjects first studied when they are 8 years old. Some of them have developed ADHD, and their presymptomatic development can be compared with those who have not developed the disorder. Her group is also studying some children with autism, who appear to exhibit dramatic improvement between childhood and adolescence.
Dr. Levitt noted that some review articles list only about 17 proteins in the synapse, whereas it appears that there are actually as many as 14,000. Some summary drawings do not even include neuregulin and other proteins. He asked how dynamic and different the composition is and how it can be determined. Dr. Blanpied observed that the explosion of genetic information and new methodologies are cause for optimism. Dr. Law added that many of the new genes, especially those now being related to schizophrenia, bipolar disorder, and other diseases, were discovered outside of the synapse. That fact has limited the understanding of the function of these molecules in the brain. The field is playing catch‑up with many of the newly discovered genes. The greater the understanding of the basic function of genes at the synapse, the greater will be the understanding of how dysregulation in the disease may affect brain development and physiology.
Dr. Insel asked the investigators to tell the Council about barriers they face as new investigators. The four investigators agreed that a difficult problem is the tension between the demand for immediate productivity and the need for innovation and the types of translational and discipline‑spanning approaches that are important in the future. Dr. Luna said that the K mechanism is important in allowing scientists to make the transition to an R01 grant. Dr. Mandell pointed out that there is often no laboratory for conducting innovative research. He suggested that a mechanism is needed to bring disciplines or training from multiple sites together and to educate review committee members about the process of moving innovative science forward.
Dr. Childs asked what NIMH and universities can do to support young investigators in understanding and fitting their work into translational research. What helps a scientist envision where cellular, molecular understanding fits into the disease process? Dr. Luna said that her institution supports collaborations, which facilitate insights that might not come out of work within a single discipline. Dr. Law said that one needs a translational mindset and then what one is doing at the level of the cell or the gene will translate into clinically useful information.
Dr. Geschwind asked whether disease‑related centers that are now supported should become centers for translational neuroscience. Dr. Mandell said that his own experience leads him to believe that both are needed in combination.
Dr. Hollenbeck noted that the requirements for tenure involve the production of papers. Institutions must find a way of evaluating a scientist’s career progress that rewards establishment of collaborations and interdisciplinary work. Dr. Blanpied enthusiastically agreed. A cultural change is needed, he said, one that allows young scientists to become independent, yet oriented towards a vertically integrated approach.
Dr. Lewis asked the investigators to identify the factors that had been most helpful in facilitating their career development. They agreed that a good mentor has been critical to their own careers, one who taught them to ask questions in a scientifically rigorous way and how to write a successful grant application.
Dr. Insel summarized the points made by the investigators: First is the tension between the need for recognition for individual contributions, on the one hand, and the need for large‑scale team science, on the other. Second, there is a tension between the need for innovation–shifting the science in new directions and thinking creatively about familiar problems–while at the same time there is the need for rapid funding and rapid, acceptable results that can be published. It boils down to the difference between what the Institute needs and what the academic world needs. Universities look to NIMH for funding to support their educational mission, whereas the Institute is interested in reducing the morbidity and mortality of mental disorders. Although the two priorities are sometimes compatible, they tend not to be aligned around issues of innovation and team science. Dr. Insel asked the Council to think about how to shift investments to get the greatest public health impact without making the best investigators suffer professionally in the process. He suggested that more thought is also needed about NIMH's role within global health and using resources outside the United States to accomplish the Institute’s goals.
Renata Henry, M.Ed., Director of the Delaware Division of Substance Abuse and Mental Health, said that she was speaking on behalf of her agency, as well as the National Association of State Mental Health Program Directors (NASMHPD). She said she was heartened to hear that the Council is giving priority to issues of diversity. She also endorsed the NIMH strategic plan, which she said encouraged NIMH to disseminate widely, beyond scientists and researchers. NASMHPD is particularly interested in goals 2 through 4, which emphasize early intervention and the development of more effective interventions. She said the organization welcomes the focus on the interaction of mental illnesses with substance abuse and other medical conditions. Another issue where State program directors are interested is working in diverse settings, including nontraditional and nonmedical settings, and involving community leaders and teachers.
Ms. Henry said she looks forward to the results of research that focus on State data and mental health policy. It is critical to understand how public systems of care actually work. She applauded the new investigators who presented their work and asked them and the Council to make sure that the research NIMH supports is translated so that it can be used by clinicians and teachers who serve the mentally ill.
Dr. Insel reminded Council members that the next meeting would be held September 18-19, 2008. With that, he adjourned the meeting.
Dr. Insel adjourned the 218th meeting of the NAMHC at 12:27 p.m. on May 23, 2008.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Thomas R. Insel, M.D., Chairperson
Appendix A: Review Of Applications
Summary of Primary MH Applications Reviewed
Council: May 2008
|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
|Carl C. Bell, M.D. (11)|
President and CEO
Community Mental Health Council and Foundation, Inc.
Glorisa J. Canino, Ph.D. (09)
Director, Behavioral Sciences Research Institute
University of Puerto Rico
Medical Sciences Campus
San Juan, PR
Elizabeth Childs, M.D., P.C. (10)
Jonathan D. Cohen, M.D., Ph.D. (08)
Eugene Higgins Professor of Psychology
Director, Princeton Neuroscience Institute
Robert Desimone, Ph.D. (11)
Director, McGovern Institute for Brain Research
Massachusetts Institute of Technology
Daniel H. Geschwind, M.D., Ph.D. (11)
Director and Professor
University of California, Los Angeles
Los Angeles, CA
Raquel E. Gur, M.D., Ph.D. (08)
Director, Neuropsychiatry Section
University of Pennsylvania Medical Center
Peter J. Hollenbeck, Ph.D. (08)
Professor of Biological Sciences
Department of Biological Sciences
West Lafayette, IN
Dilip V. Jeste, M.D. (10)
Ester and Estelle Levi Chair in Aging
Distinguished Professor of Psychiatry and Neurosciences
University of California, San Diego
VA San Diego Healthcare System (116A-1)
La Jolla, CA
|Jeffrey A. Kelly, Ph.D. (08)|
Professor of Psychiatry and Behavioral Medicine
Director, Center for AIDS Intervention Research (CAIR)
Medical College of Wisconsin
Norwood Knight-Richardson, M.D., M.B.A. (09)
Vice Chairman of Department of Psychiatry
Director of the Public Psychiatry Training Program
Director of Oregon Health and Science University Neuropsychiatric Institute
Oregon Health and Science University
Helena C. Kraemer, Ph.D. (08)
Department of Psychiatry and Behavioral Sciences
Pat R. Levitt, Ph.D. (09)
Professor, Department of Pharmacology and Director, Vanderbilt Kennedy Center for Research on Human Development
David A. Lewis, M.D. (11)
Director, Translational Neuroscience Program
University of Pittsburgh
John S. March, M.D., M.P.H. (10)
Professor and Chief
Department of Psychiatry
Child and Adolescent Psychiatry
Duke University Medical Center
Enola K. Proctor, Ph.D. (10)
Frank J. Bruno Professor of Social Work Research
Washington University in St. Louis
St. Louis, MO
Suzanne E. Vogel-Scibilia, M.D. (08)
Beaver County Psychiatric Services
|Ex Officio Members||Liaison Representative|
|Office of the Secretary, DHHS|
Michael O. Leavitt
Department of Health and Human Services
National Institutes of Health
Elias A. Zerhouni, M.D.
National Institutes of Health
Ira Katz, M.D., Ph.D.
Department of Veteran's Affairs
Office of Mental Health Services
|A. Kathryn Power, M.Ed.|
Director, Center for Mental Health Services