NAMHC Minutes of the 235th Meeting

September 19, 2013

Department of Health and Human Services
Public Health Service
National Institutes of Health
National Institute of Mental Health

Introduction

The National Advisory Mental Health Council (NAMHC) convened its 235th meeting in open policy session at approximately 8:30 a.m. on September 19, 2013, in the Neuroscience Center in Rockville, Maryland, and adjourned at approximately 2:00 p.m. In accordance with Public Law 92-463, the policy session was open to the public. The NAMHC reconvened for a closed session to review grant applications at approximately 2:30 p.m. on September 19, 2013, at the Neuroscience Center in Rockville, Maryland, until adjournment at approximately 5:00 p.m. (See Appendix A: Review of Applications). Thomas Insel, M.D. Director, National Institute of Mental Health (NIMH) presided.

Council Members Present at the Grant Review and/or Open Sessions

(See Appendix B: Council Roster)

Chairperson

• Thomas R. Insel, M.D.

Executive Secretary

• Jane A. Steinberg, Ph.D.

Council Members

• Patricia A. Areán, Ph.D.
• Virginia Trotter Betts, M.S.N., J.D.
• Randall Carpenter, M.D.
• B.J. Casey, Ph.D.
• Lisa Greenman, J.D.
• Hakon Heimer, M.S.
• Steven E. Hyman, M.D.
• Roberto Lewis-Fernández, M.D.
• Gene E. Robinson, Ph.D.
• Rhonda Robinson Beale, M.D.
• Mary Jane Rotheram, Ph.D.
• Carla Shatz, Ph.D.
• Gregory E. Simon, M.P.H., M.D.

Ex Officio Members

• John W. Davison, M.B.A., Ph.D. Department of Defense (DoD)
• Ira Katz, M.D., Ph.D., Department of Veterans Affairs

Liaison Representative

• Paolo Del Vecchio, M.S.W., Substance Abuse and Mental Health Services Administration (SAMHSA)

Others Present at the Open Policy Session

• Michael Beyer, M3 Information
• Stefano Bertuzzi, American Society for Cell Biology
• Yoshie Davison, American Academy of Child and Adolescent Psychiatry
• Steven Davis, M3 Information
• Tanya Devonish, Synergy
• Craig Fisher, American Psychological Association
• Sharon Issurdatt, National Association of Social Workers
• Sara Jura, Alderson Court Reporting
• Alan Kraut, Association for Psychological Science
• Julianna Lovik, NIH Interpreter
• Lori Pellnitz, SRI International
• Emily Smith, Response To Intervention
• Andrew Sperling, National Alliance on Mental Illness
• Gary Thomas, NIH Interpreter
• Lori Whitten, Science Writer
• TaRaena Yates, Synergy Enterprises, Inc.

Open Policy Session Call to Order and Opening Remarks

NIMH Director Thomas Insel, M.D. called the open policy session to order and welcomed all in attendance.

Approval of Minutes of the Previous Council Meeting

Turning to the minutes of the May 2013 Council meeting, Dr. Insel asked if Council members had any comments, revisions, or questions about the minutes. Receiving none, the motion to approve the minutes was unanimously passed.

NIMH Director’s Report

Dr. Insel provided an update on activities related to NIMH at the White House and the National Institutes of Health (NIH) levels.

White House Update

The White House and Executive Branch continue to focus on suicide in the military, which has been increasing since 2004. Military suicides have increased steadily and surpassed the number of combat deaths in 2012. The National Research Action Plan (NRAP) , released in August 2013, responds to the 2012 Executive Order, “Improving Access to Mental Health Services for Veterans, Service Members, and Military Families” through the coordinated efforts of the Departments of Defense (DoD), Veterans Affairs (VA), Health and Human Services, and Education. Dr. Insel acknowledged the role of Council member Ira Katz, M.D., Ph.D., in this effort. NRAP addresses the need for research on post-traumatic stress disorder, traumatic brain injury, suicide risk, and other mental health issues among veterans, active military, and their families. Moreover, registries and data sharing will play prominent roles in accelerating and enhancing the process and results. NIMH staff members Farris Tuma, Ph.D., Susan Borja, Ph.D., and Jay Churchill, Ph.D. are working with collaborators at DoD and VA to identify common data elements and ways to integrate data for implementing NRAP.

Suicide prevention efforts for civilians are also coming to the forefront. Despite reductions in mortality based on other causes (e.g., chronic medical conditions, homicides, and traffic accidents), deaths from suicide have not decreased appreciably in 50 years. To address this problem, the National Action Alliance for Suicide Prevention , a public-private partnership, was formed in 2010 by HHS Secretary Sibelius and Defense Secretary Gates. The Action Alliance’s Research Prioritization Task Force (RPTF)  guides priority-setting research efforts in this area. The goal is to develop an agenda for research that, if implemented successfully, has the potential to reduce suicide attempts and deaths by at least 20 percent in 5 years and 40 percent or greater in 10 years. Dr. Insel commented that the RPTF’s analysis of suicide deaths points to opportunities for saving lives.

NIH Update

Council had previously heard a report on the Brain Research through Advancing Innovative Neurotechnologies  (BRAIN) Initiative in May 2013, and Dr. Insel highlighted several updates. The NIH BRAIN Working Group, an advisory group to the NIH Director, formed to identify and catalyze interdisciplinary efforts. The Working Group recommended, and the NIH Director accepted, nine themes for the BRAIN Initiative’s first year. Dr. Insel noted that Gregory Farber, Ph.D., was scheduled to speak about these themes and the implementation process (see below).

Dr. Insel next discussed a series of papers addressing problems replicating preclinical data from NIH-funded studies. A 2011 paper  from Bayer HealthCare reported that approximately two-thirds of 67 in-house, target-validation projects could not replicate preclinical data published by others. Most of these projects were in the field of oncology, but concerns about replication are not unique to cancer research. He noted that Story Landis, Ph.D., Director of the National Institute of Neurological Disorders and Stroke (NINDS) would be presenting later in the day on NIH efforts to improve the quality of preclinical research through more rigorous study design and transparent reporting (see below).

NIMH Update

Dr. Insel briefed Council members on a topic that is emerging as a major focus at NIMH: Early Prediction and Prevention of Psychosis (EP3). Although research in this area is not new at NIMH, the Institute is now aiming to capture it all under one banner. With brain disorders, changes in behavior and cognition are very late events, while the underlying neurodevelopmental processes begin much earlier in development. Therefore, it is important to focus on identifying the earliest indications of disorders, including biomarkers for prediction, detection, and intervention, as preemption and prevention are critical for promoting the best outcomes long-term. Several existing NIMH projects address these topics—including the Recovery After an Initial Schizophrenic Episode (RAISE) Initiative. New York State is deploying RAISE, a project designed to reduce the likelihood of the long-term disability that people with this disorder often experience. Adoption of interventions developed under RAISE is a good example of moving NIMH research into public health efforts. Another existing project, and the North American Prodrome Longitudinal Study (NAPLS), is just finishing its 10th year. Dr. Insel added that the EP3 focus will be part of NIMH’s funding strategy over the next 2 to 4 years, which includes the two recently released funding opportunity announcements calling for projects to reduce the duration of untreated psychosis in the United States (PAR-13-187 ; PAR-13-188 ) and research to improve the care of persons at clinical high risk for psychosis (RFA-MH-210 ; RFA-MH-14-211 ; RFA-MH-14-212 ).

Score Percentiles and NIMH Grant Awards

In response to questions from Council members during past meetings, Dr. Insel presented data on NIMH funding in fiscal year (FY) 2012. During the two-tier review process, peer review determines each application’s scientific merit within the pool of grant applications submitted, and both NIMH Program staff and Council review the alignment with NIMH’s Strategic Plan and mission. Dr. Insel showed a chart with score and percentile rank and the number of applications and awards. There is a close, but not perfect, match between score/percentile and funding award. Some better-scoring applications do not receive awards; some applications thought to be outside the typical funding range are funded.

Why is it not a one-to-one relationship? Dr. Insel commented that this reflects the two-tier process. Across NIH, Institutes select applications outside the typical funding range from junior investigators call early stage investigators (link here). Some top scoring applications may not be funded because they examine topics that are deemed as of lower priority for the Institute’s mission or cover an already heavily funded area. The Institutes strive for a balance in its research portfolio. Dr. Insel encouraged ongoing discussion from Council on the review and funding process.

NIMH is also examining how it solicits and reviews clinical trials. This examination is in response to earlier recommendations from a Council workgroup (pdf) and aims to facilitate development of the next generation of treatments for mental disorders. NIMH aims to support clinical trials that posit an intervention’s mechanism of action by which the intervention might ultimately modify the functional domain or symptom(s) of interest. Objective, quantifiable, and reproducible measures of both target engagement and the intervention’s clinical effects are included in the refocused clinical trial effort at the NIMH. In addition, NIMH is particularly interested in the development of novel interventions that focus on operationally defined, empirically-supported functional domains or symptom(s) of mental disorders as opposed to broad diagnostic categories in which not all subjects may share the same underlying disease process. For example, NIMH Research Domain Criteria (RDoC) constructs may inform mechanism-based hypotheses and the selection of interventions, outcome measures and clinical subjects (see the RDoC webpage for more details). Overall, this shift underscores NIMH’s efforts to support clinical trials research with an emphasis on strengthening target identification and validation aims to improve treatments. NIMH is also emphasizing the need for increased efficiency, transparency, and data sharing.

Recent Research Developments

The news has featured many NIMH-funded projects recently. The Institute has seen explosive growth in scientific findings in many areas—including molecular biology, genetics, cell phone applications, and cognitive training tools to improve functioning. The results mentioned only scratch the surface of recent and highly impressive scientific findings. These findings are evidence that investments in science really make a difference. Recent meetings have focused on BrainSpan  (an online atlas of the molecular biology of the human brain across development), using genetics to guide interventions, access to mental health care, and other topics.

Dr. Insel noted the opening of the NIH Porter Neuroscience Research Center (Phase II) in a month. He acknowledged the visionary contributions of Steven Hyman, M.D. and Gerald Fischbach, M.D. in advancing this research center. The Porter Neuroscience Research Center will bring together 85 investigators from 10 Institutes and is organized according to scientific area of study (e.g., plasticity). Funding from the American Recovery and Reinvestment Act of 2009 supported completion of the center.

Dr. Insel reported that two NIMH grantees—Thomas C. Südhof, M.D., and Richard H. Scheller, Ph.D.—have received the Albert Lasker Basic Medical Research Award. Their discoveries concerned the molecular machinery and regulatory mechanisms that underlie the rapid release of neurotransmitters. Both investigators have a long history of research support and service with NIMH. This basic research, most of which was conducted in the 1990s, has interesting implications for mental health disorders. For example, the genes involved in these regulatory mechanisms are altered in those with autism spectrum disorder (ASD) and schizophrenia.

Budget Update

Dr. Insel commented on the concern that the NIMH budget has not grown in inflation-adjusted dollars since 2003. Financial constraints and the budget sequester continue to have a broad negative effect on scientists. A survey of 3,700 scientists (conducted in August 2013 by the American Society for Biochemistry and Molecular Biology  and others) is one indicator of the negative impacts of the budget sequester. The survey found that 5.8 percent of scientists have decided to leave research, and 18 percent are considering doing research in another country. Dr. Insel reiterated the remarks of Francis Collins, M.D., Ph.D., that 2013 could be the darkest year for biomedical research because of NIH budget challenges. This year’s NIMH budget is below last year’s and below the mean of the past several years.

Currently, the language from Congress on the NIH FY 2014 funding is encouraging. There is broad support for biomedical research on both sides of the aisle. Whether that will have an impact on the appropriation process is unclear. The Office of Management and Budget has taken a more precautionary stance by advising agencies to prepare for a possible government shutdown.

Discussion

Roberto Lewis-Fernández, M.D., thanked Dr. Insel for providing data on the gap between percentile/score and funding and agreed that the two-tier review process is appropriate. He suggested that Council have greater time to discuss applications where the institute and the review committee see things differently. Whether there is too much research in an area is a judgment call that requires discussion. During a time of resource constraint, it is easy to centralize decisions—but that is when transparency is most important.

Dr. Hyman commented that the two-tier review process is good, and that we need scientists to review the scientific and technical merit of an application, and others to review the area of science as a whole. One area of concern is that scientists sometimes submit applications that score very well in peer review, but the boarder review of the area of research as a whole suggests that this area is not paying off with results. Reviewers may come from the same scientific community and do not acknowledge the lack of results from their approach. Dr. Hyman opined that NIMH needs to fund new investigators and to take risks.

Gregory Simon, M.P.H., M.D., noted that NIMH’s strategic recommendations are very impressive. However, investigators need a “map” indicating the high-priority areas and which areas are “too crowded” with funded research. Such a map would provide tangible advice for investigators. Dr. Insel commented that NIMH provides explicit advice and guidance to investigators on its Web site, but researchers do not always consider it.

Mary Jane Rotheram, Ph.D., asked Dr. Lewis-Fernández to specify the process he advocates. Dr. Lewis-Fernández clarified that the overall process is fine. He would like to see, however, more transparency in its implementation and a greater discussion in determining future NIMH’s direction.

Dr. Rotheram remarked that it would be useful to know the criteria for eliminating projects from further review ahead of time. What are the strategic aims behind those decisions? Dr. Hyman noted the danger in an agency restricting investigators’ thinking and imagination; however, NIMH has to distinguish areas that reflect its policy decisions and be transparent about it.

Dr. Insel explained that when NIMH considers significant changes—for example, in the area of clinical trials and other components of its Strategic Plan—it has sought and received outside advice. NIMH has only made such changes after careful consideration with Council. NIMH turns to Council for this advice because members have broad perspectives and experiences. He remarked that the Institute must ensure that it does not miss spectacular, potentially transformative science when reviewing grant applications.

Toward Early Prediction and Preemption

Molly Oliveri, Ph.D., Director, Division of Developmental Translational Research (DDTR), provided a brief overview and update. DDTR’s mission is to translate knowledge from basic science to discover the developmental origins of mental disorders, and influence their prevention and cure. DDTR’s awarded grants represent about 13 percent of NIMH’s extramural funding, and early stage investigators were 39 percent of new R01 grants funded in FY 2012. Research on the neurobehavioral mechanisms and on developmental trajectories of mental disorders both contribute to targeted, timely interventions. DDTR focuses on understanding various aspects of the neurobehavioral mechanisms underlying mental disorders: neurobiological, genetic, and experiential influences; biologically based markers that are relevant to risk, diagnosis, and treatment; dimensional phenotypic measurement; and sex differences. The DDTR’s work on developmental trajectories includes an emphasis on integrative longitudinal models of risk and protection, sensitive periods in development, and early identification and prediction. In the area of novel intervention, priorities include developing targeted treatments and preemptive strategies and determining mechanisms of action.

Dr. Oliveri introduced Shelli Avenevoli, Ph.D., Chief of the Developmental Trajectories of Mental Disorders Branch within DDTR. Dr. Oliveri commented that early prediction and prevention is a priority across NIMH. The goal is to determine how the Institute can predict who will become ill before any symptoms emerge. Such knowledge provides an opportunity to intervene early in the neurodevelopmental course, but it is a challenging area of research.

Dr. Avenevoli remarked that the challenge of early prediction and preemption is to identify and delineate disease processes early in neurodevelopment, before the onset of symptoms. The period prior to symptom onset offers the best opportunity to identify those at highest risk, intervene early, and alter the trajectory of mental illness. When examining developmental trajectories, one looks across time at development as it unfolds at all levels and attempts to understand what accounts for deviations from the normative healthy trajectory. This work forms the basis of early interventions that, ideally, alter these trajectories of development and growth and minimize the lifetime burden of mental illness.

Dr. Avenevoli presented the framework for early prediction and preemption, which guides NIMH’s efforts in this area. The framework is organized by stages of disease trajectory—disease origins (risks and exposures), pre-symptomatic period, early symptoms to prodrome, and disease. Research priorities include delineating risk and enhancing prediction; identifying biomarkers and mechanisms of risk/illness; charting trajectories of illness across development; determining sensitive periods (which informs the intervention timeline); and developing innovative, personalized interventions. Development is an essential part of the framework and cuts across priorities and stages of the disease trajectory.

Dr. Avenevoli presented an analysis of the state of the science in the different priority areas and stages of the disease trajectory—showing underrepresented, developing, and active research topics. DDTR is working with other NIMH divisions to fill these gaps. Initiatives to advance the science include Autism Centers of Excellence, work on cognitive training interventions, the functional brain networks workshop, the child trauma workshop, and research on epigenetics, neurodevelopment, sensitive periods, sex differences, novel interventions, and developmental neuroimmunology. Although research has emphasized the prodrome, a future focus will be the pre-symptomatic stage (early prediction before the onset of symptoms). Dr. Avenevoli commented that NIMH appreciates and follows the recommendations of Council’s Neurodevelopment Workgroup in efforts to fill research gaps.

Dr. Avenevoli summarized two examples that reflect NIMH’s research priorities in the area of early pre-symptomatic phases of development. Results from the Bucharest Early Intervention Project highlight research in the areas of early risk trajectories and sensitive periods. This project, which focuses on early social deprivation among children who were in Romanian orphanages, shows that early institutional rearing is associated with a prolonged period of greater activation in the right versus left hemisphere. This altered trajectory predicts internalizing symptoms in early childhood (age 4.5 years). However, brain activity is more amenable to recovery from social deprivation if children received foster care before 24 months of age (showing the importance of sensitive periods in intervention). As a second example, research findings on the neurobehavioral mechanisms of social engagement highlight work on early prediction, biomarkers, and early intervention. Two-year-old children with ASD show a distinctive pattern of gaze preference: they demonstrate no preferential attention to biological motion. This pattern contrasts with typically developing children and those with developmental delays. Gaze-preference patterns are detectable at two days of age in most infants. Researchers funded through an Autism Center of Excellence are testing young infants prior to symptom onset for the atypical gaze pattern and will conduct an intervention trial targeting these abnormalities.

Although this challenging area of research is time and staff intensive, it is critical to identify those most at risk for mental disorders early to intervene more effectively.

Discussion

B.J. Casey, Ph.D., thanked Drs. Oliveri and Avenevoli for presenting preliminary but exciting work in this area. The field is seeing the initial phases of breakthroughs, but there is much more work to do. Dr. Casey highlighted three recommendations made by the Council’s Neurodevelopment Workgroup. First, scientists should examine typical and atypical developmental trajectories to determine the basic principles of development. Such information will help differentiate deviation from regression or delays, and will require both animal and human research. Moreover, translating that research to special populations will help identify sensitive periods—not only for risk, but also for intervention. Second, this research requires a multidisciplinary approach to examine different levels of analysis. There will be a lag between initiatives in this area and education of those involved in the review process, so it will be necessary to work to close that gap. Third, the field needs a workforce prepared to conduct research in this area. Some initiatives could involve junior investigators who are trying to survive while conducting research in this challenging area.

Carla Shatz, Ph.D., remarked that Council must consider these issues carefully. The field should consider how it defines symptoms in the context of neurodevelopment, in order to facilitate early detection. For example, atypical eye movement in two-year-old children with ASD could be a symptom. Defining symptoms that occur early in development would help basic scientists study phenomena that are relevant to human conditions and identify phenotypes for mental disorders.

Dr. Simon noted the importance of conceptual and terminological clarity (e.g., preempt as compared with prevent) and remarked that we may need new words other than “symptoms.” It is important to avoid confusion about interventions and their goals. Dr. Insel commented that conceptual and terminology changes have played out in other diseases (e.g., diabetes), with interventions stemming from these shifts.

Kay Redfield Jamison, Ph.D., noted the tremendous importance of this work and remarked on the need to anticipate and deal with significant ethical and psychological implications of early diagnosis and preemptive interventions. Dr. Insel acknowledged that labeling and the potential for stigma are of great concern in mental illness, and Council and the Institute must consider a message that is helpful to early diagnosis and preemption.

Dr. Insel asked Council members to consider public health systems and how professionals will implement early prediction and preemption in the absence of symptoms. Rhonda Robinson Beale, M.D., noted a similar discussion around early screening for breast cancer and the disease-discovery rate compared with dollars invested. Paolo del Vecchio, M.S.W., commented that it is important to emphasize and reinforce protective factors in the prevention efforts of our health and social service systems. A great deal of exciting work focuses on positive childhood development efforts.

Gene Robinson, Ph.D., stressed the importance of discussing the environment. Program development efforts expect metadata on the environment. In heart disease, stress tests reveal important information when people are asymptomatic. Is there an equivalent measure in the mental health area? Dr. Insel noted that for ASD, early second trimester maternal and fetal stress is an important environmental factor. However, this is not what many think of when recording environment in studies. Some researchers are trying to measure environmental exposures through sensors.

Dr. Lewis-Fernández remarked that in early detection, it is important to offer something to improve the situation or families may experience harm and anxiety. The field could balance general interventions based on known risk factors with targeted interventions for specific problems.

Lisa Greenman, J.D., also asked about the ethical concerns of early prediction and preemption and underscored the importance of language—particularly when talking about very young children—because this can be an emotionally charged topic. For example, some research identifies “callous and unemotional” traits in children, which is highly charged language to apply to young people. Dr. Casey commented that the field should think differently and creatively when working with pre-symptomatic people, just as we do with physical health. We need to talk about mental health in a way that avoids stigma.

Dr. Insel commented that the researchers moving into the field of early prediction and preemption are young, dynamic, and smart. They have training in many disciplines and want to understand how development plays out in the genome, neural circuitry, cognition, and behavior. These researchers ask fundamental questions about how biological changes influence the emergence of mental life. This area of research is of great interest to the millennial generation. The field needs precision in its language and faces many scientific challenges, and the next 5 years will be very interesting.

Brain Initiative Update

Greg Farber, Ph.D., Director, Office of Technology Development and Coordination at NIMH, discussed the BRAIN Initiative. Activities for the initiative have moved quickly since President Obama announced “the next great American project” in April. The BRAIN Initiative aims to give scientists the tools they need to see the brain in action. Our understanding of the brain has improved greatly during the past 10 years. Advances in neuroscience are yielding new insights into brain structure and function. Progress in optics, genetics, nanotechnology, informatics, and other fields are rapidly advancing new tools and technologies (e.g., Brainbow, the human connectome, and Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue hYdrogel [CLARITY]) that will further our understanding of the brain.

The goals of the BRAIN Initiative are to:

1. 1. Accelerate the development and application of innovative technologies to construct a dynamic picture of brain function that integrates neuronal and circuit activity over time and space; and
   2. Build on a growing scientific foundation—neuroscience, genetics, physics, engineering, informatics, nanoscience, chemistry, mathematics, materials science, and other fields—to catalyze an interdisciplinary effort of unprecedented scope.

The BRAIN Initiative represents a partnership among government agencies (NIH, the Defense Advanced Research Projects Agency, and the National Science Foundation) and private organizations (Allen Institute for Brain Science, Howard Hughes Medical Institute, Salk Institute for Biological Studies, and the Kavli Foundation). Each partner has invested funds for FY 2014; NIH plans to invest $40 million in funds.

Dr. Farber explained that a Working Group of the NIH Advisory Council to the Director developed an interim plan that articulates the BRAIN Initiative’s scientific goals. The Working Group comprises visionary leaders and experts in the field and has held open meetings and workshops to receive broad input. The Working Group delivered an interim report  on high-priority areas for FY 2014 funding, which Dr. Collins accepted on September 16. This group will submit its final report in June 2014. Experts across sectors and disciplines informed the report, with assistance from the NIH Blueprint for Neurosciences Research. Dr. Farber encouraged all to read the interim report, which he described as “inspired.”

The Presidential Commission for the Study of Bioethical Issues  received a separate charge related to the BRAIN Initiative. The Presidential Commission will: (1) identify proactively a set of core ethical standards to guide neuroscience research and address ethical dilemmas that are raised by the application of the findings; and (2) engage a wide range of constituencies—including scientists, ethicists, legal scholars, and members of the public—to ensure findings reflect and strengthen our values as a nation.

Dr. Farber noted that NIH plans to release a Notice in the Guide, which will detail the timeline for BRAIN Initiative program announcements. The 2013 Society for Neuroscience meeting will feature an open forum on the BRAIN Initiative with the Working Group co-chairs and key NIH Institute Directors. The BRAIN Initiative will release, review, and fund program announcements in FY 2014. NIMH staff will contribute to many stages of this process, and Council should expect to see a number of these applications late next year.

Discussion

Dr. Insel commented that NIMH would involve Council in the BRAIN Initiative process soon. Institutes involved in the NIH Blueprint for Neurosciences Research will construct funding announcements soon, and Council will have an opportunity to review applications. Dr. Hyman said he has heard concerns that institutes might divert money from R01s for the initiative, but the numbers shown suggest the opposite to him. He remarked that it is critical for the BRAIN Initiative to establish and refine its priorities. The Human Genome Project set a simple, well-defined goal. The further involvement of private funders is essential to advancing the initiative’s goals.

Dr. Shatz commented that the initiative represents an exciting opportunity to build tools, but there is a danger that scientists will focus on tools to the detriment of other areas of research. The field needs questions as well as tools. The initiative should fund risky, high-potential work. She noted that psychology was missing from the list of topic areas highlighted in the Work Group’s report. Psychology is a fundamental science, particularly if the initiative focuses on human conditions. Dr. Insel remarked that the report does include behavior, but it sometimes refers to psychology as cognitive science.

Dr. Insel suggested that Council discuss the process for identifying risky, high-potential research. Does NIMH have a process in place for determining and funding this kind of science? Is a different kind of review process or solicitation needed to obtain the interdisciplinary mix needed for this kind of science? Dr. Shatz suggested that dedicated review groups with a broad range of expertise (including engineers) might help identify such projects. Dr. Robinson noted the need to reach out to experts in various disciplines who are not already involved in neuroscience research. Dr. Insel commented that this issue is worth deeper thought, and those working on the BRAIN Initiative should be aware of the different cultures in neuroscience and engineering. Randall Carpenter, M.D., stressed that study sections need to comprehend the complexities of this research and ensure the inclusion of the most innovative applications.

Dr. Hyman remarked that because of its scope and scale, the Human Genome Project brought in industry—and was effective in doing so. Everyone benefited as a result, because the cost of DNA sequencing dropped dramatically. Dr. Farber commented that companies were at the open meetings for the BRAIN Initiative, and the team managing this project is aware that industry is important. Dr. Insel added that those involved with managing the initiative plan to meet with representatives from industry, which will include information technology and computing companies. Those industries may learn a great deal from the BRAIN Initiative.

Hakon Heimer, M.S., asked how the BRAIN Initiative relates to the European Union’s Human Brain Project . Drs. Insel and Farber explained that the European project involves computer simulation and has a computational focus; it is very different from the BRAIN Initiative. The two projects are complementary rather than competitive.

Improving the Quality of Preclinical Research through More Rigorous Study Design and Transparent Reporting

Story Landis, Ph.D., Director, NINDS, thanked Council for the opportunity to discuss this issue and acknowledged her colleagues, particularly Shai Silberberg, Ph.D., for leading efforts in this area at NINDS. The National Cancer Institute has made a parallel effort to enhance transparent reporting to improve preclinical research on tumor biomarkers.

Dr. Landis explained that NINDS’s interest in this issue originated with research on an animal model of amyotrophic lateral sclerosis (ALS). A rodent model (over-expression of mSOD1) recapitulates ALS symptoms (e.g., shortened lifespan and motor neuron death). Using this model, investigators looked at potential compounds that would influence survival. They found that minocycline enhanced the survival of SOD1 transgenic mice—a finding that led to a Phase III clinical trial for ALS patients. However, a randomized controlled trial completed in 2007 showed that patients treated for 9 months with minocycline failed more rapidly than those on placebo did. The preclinical work involved 10 animals per group, did not randomize treatments, and researchers were not blinded as to the conditions. These factors might have contributed to the enhanced survival seen in the preclinical study. A rigorous screening study using this animal model and appropriate statistical methods found that none of the 70 compounds tested, including several previously reported as efficacious, had any effects (PMID: 18273714 ).

In preclinical research on neurological diseases, there is evidence of insufficient reporting of methodological approaches—including randomization, blinded assessment of outcome, and sample-size calculation. Studies with fewer reported methods found greater apparent compound efficacy. This phenomenon is evident across biomedical research, not only in work on neurological diseases. Inadequate reporting of methodology is widespread.

NINDS has taken action to improve the quality of the preclinical and clinical research it supports. The Institute released a Notice in the NIH Guide (NOT-NS-11-023 ) encouraging researchers conducting preclinical studies to address elements of rigorous study design and transparent reporting of methods in grant applications. NINDS altered its in-house review process to emphasize the scientific rationale/premise of the study and the appropriateness of the experimental design as presented in the application. Dr. Landis commented that NINDS sees more description of methodological information in grant applications. Changes to the in-house review have had an impact on the kinds of applications received and the types of projects the Institute funds.

NINDS also held the Optimizing the Predictive Value of Preclinical Research Workshop. This workshop and an associated paper (PMC3511845 ) called for grant applications and scientific publications with in vivo animal experiments, at a minimum, to report on randomization, blinding, sample size estimation, and handling of all data. Transparent reporting of all animal projects will permit more accurate assessments of their results. However, it is important to distinguish between hypothesis-generating and hypothesis-testing experiments; it is appropriate that hypothesis-generating (exploratory) studies often have small sample sizes and un-blinded assessment. However, exploratory studies should have transparent reporting of methods.

Others are joining in the effort to improve the reliability of published results. The journal Nature has agreed to report all methods in its online versions and has added statistical experts to guide reviewers if needed. Science Translational Medicine has taken similar steps. Program announcements for various organizations also reflect efforts to improve the reproducibility and transparency of research findings. NIH Institute and Center Directors have agreed upon a set of principles for addressing the underlying issues: raise community awareness, enhance formal training, improve the evaluation of applications, protect the integrity of science by adopting more systematic review processes, and increase stability for investigators.

Discussion

Dr. Simon mentioned a clinical trials registry, standard checklists for publishing, and Consolidated Standards of Reporting Trials (CONSORT) diagrams as tools to guide researchers on this issue. Dr. Landis agreed that those are good standards. With approximately 30,000 preclinical animal studies, it is difficult to have a registry. Dr. Landis highlighted another issue: few publish negative findings. It is likely that researchers have tried and failed to replicate some preclinical results but never submitted them for publication. Dr. Insel added that researchers have not developed CONSORT or other similar guidelines for preclinical work, despite the importance of these findings for subsequent clinical studies. Dr. Carpenter emphasized that preclinical work must provide pharmacological understanding and ensure that the drug gets into the brain and is selective for the target.

Dr. Landis remarked that some investigators perceive that NIH only funds projects relevant to a disease. Basic scientists may feel pressure to work in an animal model of disease and assume that the drugs they test hit their brain targets. NIH should consider how it might convey that it is not always necessary to examine a disease, and the importance of using an appropriate animal model to young researchers.

Dr. Hyman thanked Dr. Landis and her colleagues for addressing this issue with the seriousness that it deserves. He said that it is important to socialize new researchers and influence training programs in the biomedical and behavioral sciences. It is good to hear that journals and the larger research community are starting to get involved in this critical issue. Dr. Insel remarked that these efforts must be positive and proactive and noted that professional societies have a significant role to play. Dr. Landis agreed and commented that an emphasis on accurate and transparent reporting facilitates such an approach.

Dr. Robinson Beale applauded efforts to improve transparent reporting of preclinical research. When scientific papers do not report critical information about clinical research, providers may fill in the gaps—making the translation of science into practice poor. Dr. Landis noted that in the area of neurological diseases, there are examples of interventions moving far too quickly to the clinic. Dr. Robinson Beale remarked that clinics interpret results differently; problems can arise when clinics make decisions based on faulty science.

A Prioritized Suicide Research Agenda: Update on the National Action Alliance for Suicide Prevention Research Prioritization Task Force

Jane Pearson, Ph.D., Chief, Preventive Interventions Program, Division of Services and Intervention Research at NIMH, thanked Dr. Insel for his leadership and her colleagues, particularly Chelsea Booth, Ph.D., and Maureen Iselin, for their work on this effort.

Overall, rates of suicide death in the United States have not decreased appreciably in 50 years. Each year, more than 670,000 individuals report that they received medical attention for a suicide attempt, and each year, more than 36,000 individuals die by suicide. The goal of the Research Prioritization Task Force  (RPTF) is to develop an agenda for research that has the potential to reduce morbidity (attempts) and mortality (deaths) each, by at least 20 percent in 5 years, and 40 percent or greater in 10 years, if implemented successfully. Suicide is the 10th leading cause of death in the United States, but it is difficult to study. Dr. Pearson commented that the RPTF wants to focus the field’s research and map a way forward. To implement the goal successfully, research must inform interventions.

The RPTF published a paper explaining its strategic public health approach to prioritizing suicide prevention research. The approach, which is organized along three dimensions—accessibility of high-risk subgroup, timeline of opportunity, and level of support for prevention and intervention—will guide funding decisions. The approach helps identify current research and gaps in knowledge. The RPTF has also discussed the approach with the research community through multiple conference presentations and a NIH Request for Information.

Dr. Pearson explained that the RPTF deconstructed suicide death statistics in the United States to find out more about who dies by suicide and where they were most recently to point out opportunities for intervention. Many (51 percent) suicides are due to firearms; more firearm deaths are suicides rather than homicides—a fact that may surprise most people. There are also more suicides in jails/prisons than among active duty military. With suicides among military veterans, it is important to distinguish between individuals seen in treatment and those not seeking care. About 45 percent of people who die by suicide accessed health care within 30 days of death. Emergency departments (ED settings) see a significant number of people who attempt suicide and then die by suicide within the year.

The group modeled the impact of several diverse approaches and interventions to reduce suicides. For example, effective psychotherapeutic interventions in ED settings could reduce re-attempts for those individuals by at least one-third annually with 100 percent uptake of the treatments. While 100 percent uptake is unlikely, modeling allows for the examination different degrees of uptake, intervention effectiveness and decay. Modeling the potential impact of these interventions should stimulate researchers to consider approaches that they could apply on a large scale. For the Prioritized Research Agenda report, the RPTF examined a combination of interventions implemented in optimal ways psychotherapy in ED settings, separating suicidal individuals from firearm access, and separating suicidal individuals from carbon monoxide motor vehicles—and found that these efforts could reduce suicide deaths by nearly 20 percent. Firearm deaths and the number of households that own these weapons have decreased over the past 20 years, although those that do own firearms may possess more of them. What interventions might further influence these trends? In the area of suicide by carbon monoxide, the Centers for Disease Control and Prevention estimate that new vehicles could feature a sensor for this deadly gas for less than the $48-per-car tire pressure gages now required (there are far fewer deaths caused by underinflated tires than suicide deaths).

An expert panel helped the RPTF organize the Research Agenda around six key questions:

1. Why do people become suicidal?
2. How can we more optimally detect/predict suicide risk?
3. What interventions can prevent suicidal behavior?
4. What services are most effective for treating the suicidal person and preventing suicidal risk?
5. What preventive interventions (outside health care settings) reduce suicide risk?
6. What existing infrastructure can be better utilized, and what new infrastructure needs must be met in order to reduce further suicidal behavior in the United States?

Dr. Pearson remarked that there are already some research solicitations for Key Question 2 (e.g., NIMH’s Emergency Department Safety Assessment and Follow-up Evaluation trial; efforts by the Defense Advanced Research Projects Agency; and ongoing analyses by the VA, NRAP, and Army Study to Assess Risk and Resilience in Service members [Army STARRS ]). The RPTF is working with a diverse group of stakeholders to develop relevant messages for the Research Agenda such as suicide research funders, scientists/researchers, leaders of organizations and sectors that can reach individuals at risk, survivors of suicide loss, suicide attempt providers, those at risk for suicide, and concerned family members.

Discussion

Dr. Insel thanked Dr. Pearson and commented that this is an ambitious and vital effort. The RPTF has not yet published the report, so this is a good time to discuss the issue. Dr. Simon commented that there are different predictors of the “who” and “when” of suicide. If these are mixed in analyses, then the ability to dissect the phenomenon is diminished. Similarly, there are stable and time-dependent predictors of suicide. Dr. Hyman added that Army STARRS has some early but interesting results on suicide risk factors beyond mental disorders (e.g., stress responsiveness and impulsiveness). He applauded the refinement of the demographic data and suggested that examining the individual risk factors beyond substance abuse and mental disorders would advance the field.

Dr. Katz thanked Dr. Pearson on behalf of the VA. He is looking forward to seeing the final version of the RPTF Research Agenda to develop a cross-walked, suicide prevention research agenda for the VA.

Virginia Trotter Betts, M.S.N., J.D., commented that although suicide ranks as the tenth leading cause of death, it has a very broad impact on families, schools, and communities. Communications on the public health impact of suicide should address its broader effects. She remarked that sometimes violence against others represents a suicide in progress. Ms. Trotter Betts thanked Dr. Pearson and the RPTF and commented that the field has progressed significantly. Dr. Insel noted that family members affected by a suicide often say that for every death there are at least ten people whose lives will never be the same. Science in this area faces a challenge: how to move from demographics to individual prediction.

Comments from Retiring Council Members

Dr. Insel commented that he thinks of Council members as “graduated” rather than “retired,” and he welcomed the remarks and observations of those who are attending their final meeting as Council members today.

Kay Redfield Jamison, Ph.D., praised Dr. Insel for deftly navigating difficult scientific, advocacy, and Congressional waters. She applauded Dr. Insel’s scientific vision. She expressed her enthusiasm for the research criteria discussed. The BRAIN Initiative and early prediction and preemption projects are particularly important, because they are qualitatively different from previous work.

The early prediction and prevention of psychosis has staggering potential but causes concern for different communities. It is important to get early prediction and preemption work right from the beginning. NIMH should emphasize transparency and articulating information on this area of research to non-scientists. Exuberance for this work is great but must be tempered by people who examine the possible limitations and liabilities. The prodrome for various psychiatric disorders may overlap with the diverse ways of going through life (e.g., high energy, rapid thinking, risk taking, and other characteristics of temperament or cognitive style). What does this mean for early diagnosis? For example, mania is a psychotic disorder, but is often not thought of in this way. Large population studies link mania and creativity. With creative people, premedication would change who they are—good and bad. We do not know the effect of premedication and what might be lost. NIMH must discuss this issue openly. Dr. Insel thanked Dr. Jamison for her comments and said that the issue requires much discussion and thought.

Dr. Lewis-Fernández commented that it has been a privilege to debate the direction of the most important Institute that funds mental health research. He shared his view on the future direction for NIMH to maximize its immediate public health impact and pay attention to research that influences patients today as well as tomorrow. The brain mechanisms of disease are critical in the long-term, but making an impact in the short- or medium-term requires funding research on how to implement existing interventions. Such research includes tailoring interventions for diverse clinical settings and populations and overcoming barriers that limit their use and effectiveness. Many disorders have good prevention strategies and treatments that practitioners do not use widely. Poor patient adherence to therapy is also a problem despite the availability of approaches to improve adherence. The Institute should support work to implement these approaches more widely and extend them to other patient populations.

Dr. Lewis-Fernández recommended that Council adopt a more robust process for discussing the Institute’s priorities and engage in a continuous, broad conversation on this issue. What percentage of the budget should go to particular areas? What is the priority of immediate public health problems? How should NIMH leverage collaborations with other agencies to attain rapid public health impact? Dr. Lewis-Fernández suggested that the Institute set an agenda that increases the immediate public health impact of NIMH-funded research and develop an effective process for planning and implementing this agenda, including creating more opportunities for discussion in Council. He expressed gratitude for the ability to share thoughts today and throughout his years of service. Dr. Insel commented that he appreciates Dr. Lewis-Fernández’s forthright comments and said that NIMH is a better Institute because of Dr. Lewis-Fernández’s contributions.

Dr. Robinson Beale thanked Dr. Insel, Jane Steinberg, Ph.D., and Philip Wang, M.D., Dr.P.H., and said that it was a career highlight to be part of such an important group. As a clinician in a managed care organization for 18 years, Dr. Robinson Beale focused on delivering quality care in a capitated system. She was honored to participate in the Institute of Medicine’s study on the quality chasm, which emphasized how the health system influences quality of care. As a member of Council, she felt fortunate to learn more about the complexity of the biomedical research and funding endeavor. Dr. Robinson Beale commented that she has seen positive changes during her tenure of service on Council. She echoed Dr. Lewis-Fernández’s suggestion to attend to the needs of today’s patients. Interventions must fit into a health care system, and it is important to identify touch points in the NIMH process that can influence mental health treatment.

In terms of gaps and priorities, Dr. Robinson Beale stressed improving implementation and refining interventions. New technologies offer opportunities. Payers want to use these technologies; however, developers test these tools themselves. Payers are somewhat skeptical of those results, and NIMH could bring credibility and trust by supporting studies that objectively test technologies. Dr. Robinson Beale recommended that the Institute continue funding practice-based research. She thanked NIMH for accepting different points of view and responding to these perspectives and noted that she will continue to communicate with the Institute. Dr. Insel thanked Dr. Robinson Beale for providing the system perspective, which is very important to consider.

Dr. Shatz thanked NIMH for the privilege to serve, work collaboratively, and learn. Addressing Institute priorities and patient needs presents a sobering challenge. She expressed appreciation of Dr. Insel’s leadership on deciding NIMH’s priorities during difficult budget conditions. Dr. Shatz encouraged support for an “endangered species”—neuroscientists working on fundamental studies that do not have an immediate connection to translation. This year’s Lasker Award is a great example of how investments in basic science can produce tremendous knowledge with an impact on disease. She remarked that the future of innovation in biomedical science and patient care depends on fundamental neuroscience research. Dr. Insel thanked Dr. Shatz for her comments and noted that a retrospective article in Neuron will try to communicate clearly that not all NIMH grant applicants need to address diseases. Basic knowledge in neuroscience is impoverished (e.g., the field lacks a basic taxonomy of cells in the human brain), and NIH must invest in this fundamental research. NIMH will continue to seek Council’s advice on how to balance long-term and short-term needs.

Public Comment

Dr. Insel invited members of the audience to make any comments to Council. Hearing none, he thanked all who participated in the meeting. He recessed the open session meeting at approximately 2:00 p.m.

Thomas R. Insel, M.D., Chairperson

Appendix A

Summary of Primary MH Applications Reviewed

January 2013

Category	IRG Recommendation
	Scored #	Scored Direct Cost $	Not Scored (NRFC) #	Not Scored (NRFC) Direct Cost $	Other #	Other Direct Cost $	Total #	Total Direct Cost $
Research	547	$532,894,360.00	514	$420,412,483.00	9	$2,967,609.00	1070	$956,274,452.00
Research Training	2	$4,707,647.00	0	$0.00	1	$43,963.00	3	$4,751,610.00
Career	62	$41,383,706.00	20	$12,494,420.00	0	$0.00	82	$53,878,126.00
Other	0	$0.00	0	$0.00	0	$0.00	0	$0.00
Totals	611	$578,985,713.00	534	$432,906,903.00	10	$3,011,572.00	1155	$1,014,904,188.00

Appendix B

Department of Health and Human Services
National Institutes of Health
National Institute of Mental Health
National Advisory Mental Health Council

(Terms end 9/30 of designated year)

Chairperson

• Thomas R. Insel, M.D.
  Director
  National Institute of Mental Health
  Bethesda, MD

Executive Secretary

• Jane A. Steinberg, Ph.D.
  Director
  Division of Extramural Activities
  National Institute of Mental Health
  Bethesda, MD

Members

• Patricia A. Areán, Ph.D. (16)
  Professor
  Department of Psychiatry and Langley Porter
  Psychiatric Institute
  University of California, San Francisco
  San Francisco, CA
• Deanna M. Barch, Ph.D. (16)
  Gregory B. Couch Professor of Psychiatry
  Department of Psychology, Psychiatry and Radiology
  Washington University
  Editor-in-Chief
  Cognitive, Affective and Behavioral Neuroscience
  Director, Conte Center for the Neuroscience
  of Mental Health
  St. Louis, MO
• Virginia Trotter Betts, M.S.N, J.D. (14)
  Professor of Nursing and Public Policy
  University of Tennessee Health Science Center
  College of Nursing
  Memphis, TN
• Randall L. Carpenter, M.D. (15)
  Co-Founder, President and Chief Executive Officer
  Seaside Therapeutics
  Cambridge, MA
• BJ Casey, Ph.D. (16)
  Sackler Professor
  Department of Psychiatry and Neuroscience
  Sackler Institute for Developmental Psychobiology
  Weill Medical College of Cornell University
  New York, NY
• Lisa Greenman, J.D. (15)
  Staff Attorney
  Federal Public Defender Organization
  District of Maryland
  Washington, DC
• Hakon Heimer, M.S. (16)
  Founding Editor
  Schizophrenia Research Forum
  Brain and Behavior Research Foundation
  Providence, RI
• Steven E. Hyman, M.D. (15)
  Director, Stanley Center for Psychiatric Research
  Broad Institute
  Cambridge, MA
• Kay Redfield Jamison, Ph.D. (13)
  The Dalio Family Professor in Mood Disorders
  Professor of Psychiatry
  Department of Psychiatry and Behavioral Sciences
  The Johns Hopkins University School of Medicine
  Baltimore, MD
• Roberto Lewis-Fernández, M.D. (13)
  Professor of Clinical Psychiatry at Columbia University
  Director of NYS Center of Excellence for Cultural
  Competence and Hispanic Treatment Program
  NY State Psychiatric Institute NYSPI
  New York, NY
• Gene E. Robinson, Ph.D. (14)
  Director, Institute for Genomic Biology
  Swanlund Chair
  Center for Advanced Study Professor in Entomology
  And Neuroscience
  University of Illinois at Urbana-Champaign
  Urbana, IL
• Rhonda Robinson Beale, M.D. (13)
  Chief Medical Officer
  OptumHealth Behavioral Solutions
  Glendale, CA
• Mary Jane Rotheram, Ph.D. (16)
  Bat-Yaacov Professor of Child Psychiatry
  And Behavioral Sciences
  Director, Global Center for Children and Families
  Director, Center for HIV Identification Prevention
  And Treatment Services (CHIPTS)
  Semel Institute and the Department of Psychiatry, University of California, Los Angeles
  Los Angeles, CA
• Carla Shatz, Ph.D. (13)
  Director, Bio-X
  Professor of Biology and Neurology
  Stanford University
  James H. Clark Center
  Stanford, CA
• Gregory E. Simon, M.P.H., M.D. (14)
  Senior Scientific Investigator
  Center for Health Studies/Behavioral
  Health Service
  Group Health Cooperative
  Seattle, WA
• J. David Sweatt, Ph.D. (16)
  Professor
  Evelyn F. McKnight Endowed Chair
  Department of Neurobiology
  Director, McKnight Brain Institute
  University of Alabama at Birmingham
  Birmingham, AL
• Carol A. Tamminga, M.D. (15)
  Professor and Chair
  Department of Psychiatry
  University of Texas
  Southwestern Medical Center
  Dallas, TX

Ex Officio Members

Office of the Secretary, DHHS

• Kathleen Sebelius
  Secretary
  Department of Health and Human Services
  Washington, DC

National Institutes of Health

• Francis Collins, M.D., Ph.D.
  Director
  National Institutes of Health
  Bethesda, MD

Veterans Affairs

• Ira Katz, M.D., Ph.D.
  Department of Veterans Affairs
  Office of Mental Health Services
  Washington DC

Department of Defense

• John W. Davison, M.B.A., Ph.D.
  Director, Behavioral Medicine Division
  Office of the Chief Medical Officer (OCMO)
  TRICARE Management Activity, OASD (HA)
  Falls Church, VA

Liaison Representative

• Paolo del Vecchio, M.S.W.
  Director
  Center for Mental Health Services
  Rockville, MD