NAMHC Minutes of the 234th Meeting
National Advisory Mental Health Council Minutes of the 234th Meeting
May 30, 2013
Department of Health and Human Services
Public Health Service
National Institutes of Health
National Institute of Mental Health
The National Advisory Mental Health Council (NAMHC) convened its 234th meeting in open policy session at approximately 8:30 a.m. on May 30, 2013, in the Neuroscience Center in Rockville, Maryland, and adjourned at approximately 1:55 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 May 30, 2013, at the Neuroscience Center in Rockville, Maryland, until adjournment at approximately 5 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)
- Thomas R. Insel, M.D.
- Jane A. Steinberg, Ph.D.
- Patricia A. Areán, Ph.D.
- Deanna Barch, 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.
- Kay Redfield Jamison, Ph.D.
- Roberto Lewis-Fernández, M.D.
- Gene Robinson, Ph.D.
- Rhonda Robinson Beale, M.D.
- Mary Jane Rotheram, Ph.D.
- Gregory E. Simon, M.P.H., M.D.
- J. David Sweatt, Ph.D.
- Carol Tamminga, 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
- Paolo Del Vecchio, M.S.W., Substance Abuse and Mental Health Services Administration (SAMHSA)
Others Present at the Open Policy Session:
- Linda Beth Berman, Adventist Healthcare, Inc.
- Erica Froyd, Lewis-Burke Associates, LLC
- Kathi Hanna, Science Writer
- Sara Jura, Alderson Court Reporting
- Teresa King, National Federal for Families for Children’s Mental Health
- Alan Kraut, Association for Psychological Science
- William Lawson, Howard University
- Wayne Lindstrom, Mental Health America
- Stacia Matthews, American Occupational Therapy Associates
- Ann Michaels, National Foundation for Mental Health
- Martha Nolan, Society for Women’s Health Research
- Heather Parsons, American Occupational Therapy Association
- Svetra Peoples, Teaching Every American Health Awareness
- Amanda Reeves, American Association for Marriage and Family Therapy
- Darrel Regier, American Psychiatric Association
- Joy Ridley, Synergy
- Michelle Rodrigues, SRI International
- Kelsi Shough, American Occupational Therapy Associates
- Jamie Siegel
- Paula Skedsvold, Federation of Associations for Brain and Behavioral Sciences
- Emily Smith, Response to Intervention
- Andrew Sperling, National Alliance on Mental Illness
- Karen Studwell, American Psychological Association
- Miranda Sweet, American Occupational Therapy Associates
- TaRaena Yates, Synergy
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 January 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. He began by noting a renewed focus on mental health and gun violence at multiple levels of government following the tragic events that took place in December 2012, in Newtown, CT. The conversation has evolved, recognizing that violence most often associated with mental illness is suicide, and that most violence is unrelated to mental illness.
White House Update
On January 16, 2013, the White House issued an Executive Order on gun violence reduction, the Sandy Hook Response Plan. The Response Plan directs Secretary of Health and Human Services (HHS) Kathleen Sebelius, through the Centers for Disease Control and Prevention and other scientific agencies within HHS, to conduct or sponsor research into the causes of gun violence and the ways to prevent it. One part of the Response Plan is to begin a National Dialogue on Mental Health, to be launched at the White House in June 2013. The Substance Abuse and Mental Health Administration is coordinating this effort, which will entail a yearlong effort to address negative attitudes and discrimination that keep those struggling with a mental disorder from seeking treatment. Along with this national dialogue, Secretary Sebelius has announced a plan to add 5,000 mental health specialists focused on the needs of youth to the health care workforce, and has announced Project AWARE (Advancing Wellness and Resilience in Education) to reach 750,000 children by training teachers and other adults to recognize and properly refer youths who may be in need of mental health services.
The White House and Executive Branch continue to focus on suicide in the military, which has been increasing since 2004, particularly in the Army and Marine Corps, where the military suicide rate has exceeded the civilian suicide rate. In response, President Obama issued an Executive Order in 2012, “Improving Access to Mental Health Services for Veterans, Service Members, and Military Families.” This order calls for a National Research Action Plan to provide a pathway to improve diagnostics and therapeutics for post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI). The order also mandates the creation of a Military and Veterans Mental Health Task Force to issue recommendations for improving treatment, recognizing that treatment can be provided within the military health system, at the Department of Veterans Affairs (VA) facilities, or in the civilian sector. The directive also required a longitudinal study of 100,000 soldiers. Because the Army Study to Assess Risk and Resilience in Service members (Army STARRS ) was already underway, this platform is being used as the longitudinal study for understanding the longer-term consequences of going into battle. These efforts have required extensive discussions with the Department of Defense (DoD), HHS, and the VA to understand and improve treatments.
On April 2, 2013, President Obama announced the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) initiative. A central focus of the BRAIN initiative is to revolutionize our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers aim to produce a dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interact in both time and space. Long desired by researchers seeking new ways to treat, cure, and even prevent brain disorders, such images will fill major gaps in our current knowledge and provide unprecedented opportunities for exploring exactly how the brain enables the human body to record, process, utilize, store, and retrieve vast quantities of information, all at the speed of thought. The NIH BRAIN Working Group , an advisory group to the NIH Director, has been formed to identify and catalyze interdisciplinary efforts.
To illustrate the advances that have been made in understanding the brain, Dr. Insel described work funded by NIMH and conducted by Karl Deisseroth, M.D., Ph.D., and colleagues at Stanford University. In the Clear Lipid-exchanged Anatomically Rigid Imaging/Immunostaining-compatible Tissue hYdrogel (CLARITY) project, the brain’s lipids are replaced with a clear hydrogel that turns the opaque and impenetrable brain into a transparent and permeable structure. The hydrogel holds the brain’s anatomy intact, and because it is permeable, the brain can be stained to localize proteins, neurotransmitters, and genes at a high resolution. The ability to apply this technology to post-mortem human brain tissue will greatly facilitate neuroanatomical studies of connectivity.
Another advance is The Human Connectome Project (HCP) , an ambitious effort to map the neural pathways that underlie human brain function. The overarching purpose of the HCP is to acquire and share data about the structural and functional connectivity of the human brain. The project is expected to involve 1,200 subjects, including 300 twin pairs, by June 2014. This initiative may have the greatest value for those disorders for which a major lesion cannot be found but for which looking at a dynamic image may be most instructive (e.g., schizophrenia, autism spectrum disorder, bipolar disorder, and depression).
Dr. Insel acknowledged the recent media spotlight on the Research Domain Criteria (RDoC) Program and the Diagnostic and Statistical Manual (DSM). He emphasized that the two efforts serve different purposes; RDoC embraces precision medicine by focusing on assessing disorders in terms of fundamental neural systems and the behavioral functions that they implement. RDoC is not intended to replace the DSM, which focuses on clinical symptoms and signs. The goal of RDoC is to facilitate the study of disorders in terms of fundamental mechanisms, from neuroscience and behavioral science perspectives, to better understand pathophysiology and psychopathology. Increasingly, science is discovering that the biological findings do not match the diagnostic clinical criteria. DSM and International Classification of Disease (ICD) codes will remain the diagnostic classification systems relied on for clinical care and reimbursement. In contrast, RDoC will be the framework that NIMH will use for funding research applications (as stated in the 2008 NIMH Strategic Plan).
The President’s budget request for fiscal year (FY) 2014 includes $1.466 billion for NIMH, a $70 million increase over FY 2013 C.R. (Post Sequestration), but less than the FY 2012 allocation. In FY 2013, NIMH is implementing a 4 percent across-the-board cut in spending for all non-competing grants. In FY 2013 NIMH expects to fund up to 500 new competing research projects.
Gregory Simon, M.P.H., M.D. noted that it will be important to emphasize that the focus of RDoC is not diagnoses, but rather understanding the biological underpinnings of mental illness.
Roberto Lewis-Fernández, M.D. urged NIMH to engage in a dialogue with review committee members regarding the funding priorities within the overall NIMH portfolio, particularly the funding priorities related to RDoC.
Carol Tamminga, M.D. noted that not only has the scientific community failed to move the field away from a focus on symptoms toward function, but also it is worth asking why drug development has failed, remaining focused on postsynaptic receptors at the expense of other areas of emphasis.
Rhonda Robinson Beale, M.D. expressed concern about setting priorities during constrained budget times. Although RDoC is important, there are many unmet social needs, despite some progress in treatment of some mental illnesses. Dr. Insel responded that funded research can reveal what does not work, which points to the need for better and more precise diagnostics to individualize the interventions available. Precision approaches have advanced the fields of lymphoma, asthma, and hypertension—it is time for researchers to understand the targets in mental illness in order to discover interventions at the molecular, cellular, systems, behavioral, or cognitive levels. The field cannot continue to do what it has been doing. Dr. Robinson Beale urged a continued focus on practice-based evidence as a way of informing RDoC.
David Sweatt, Ph.D. expressed concern about the disconnection between the RDoC goals and the perspectives of traditional study sections. Dr. Insel agreed that one strategy for addressing this is through the formation of special study sections.
Patricia Areán, Ph.D. added that it will be important to ensure there is adequate expertise on standing study sections, and that grant applications go to sections that are familiar with RDoC.
Ira Katz, M.D., Ph.D. said that RDoC could have an impact sooner than expected. He cited the use of endophenotypes and RDoC-based approaches in the area of suicide.
Dr. Insel closed the discussion by urging patience and emphasizing that RDoC has to be rigorous and critically assessed because it is a novel approach. He also noted that the BRAIN initiative could be a critical game changer by providing better tools for diagnostics.
Innovative Technologies for Research and Health
Adam Haim, Ph.D., Acting Chief, Service Research and Clinical Epidemiology Branch, Division of Services and Intervention Research (DSIR), highlighted the need for a more efficient and effective mental health care delivery system. An estimated 60 million Americans currently have a mental health condition. Roughly 60 percent of those individuals do not receive any services; of the 40 percent that do, only about a third receive minimally acceptable care. Thus, only about 15 percent of the population with a mental illness receives minimally acceptable care. Researchers suggest that one way to improve this situation is to integrate newer technologies (for example, text messaging) into traditional care delivery system.
In an effort to evaluate this and other research questions, NIMH has been integrating technology use into its research portfolio. In 2009, the Institute analyzed its portfolio to identify technology-enhanced grants whose primary aim was to assess technology that was developed for or adapted to the delivery of mental health services. More than 200 grants are in the portfolio, of which 150 are active. Dr. Haim’s team found that applications associated with personal computers have declined, while those using mobile devices and smart phones have increased. A growing number of applications are device independent. Therapeutic technologies include telemedicine, use of computers and software to remotely access and monitor symptoms, use of electronic games, and use of instant messaging to administer and track outcomes. These technologies can be mapped according to whether they are addressing prevention, treatment, or relapse prevention. The current portfolio covers a broad range of devices, platforms, and technologies across a wide range of disorders. There is significant overlap in terms of interventions and the types of platforms being used. In addition, there is an ongoing evolution in the platforms being used with some becoming obsolete very quickly.
David Chambers, D.Phil., Chief, Services Research and Clinical Epidemiology Branch, DSIR, continued by addressing efforts to overcome challenges. Ongoing collaborations with other agencies as well as a series of papers that appeared in General Hospital Psychiatry led to the development of some key principles for priority research in this area: the need to demonstrate improvement in the use of technologies, not just equivalence; the need to harness the full capabilities of technology; and, the need to connect mental health research with technology expertise.
One ongoing challenge in research is determining how to evaluate technologies that outpace the usual research timeline: for example, a project developed in 2005 could not anticipate the emergence of YouTube, the Wii, or the smart phone, platforms that have significantly impacted how people connect through technology. Another challenge is to avoid investigators reinventing the wheel; each project developing user interfaces or data capture in its own unique way. Finding innovative ways to recruit participants into studies outside the clinic is another challenge. A final challenge is balancing the tendency to “freeze” an intervention so that it can be tested for its integrity while industry products are constantly advancing and being refined.
These challenges have motivated NIMH to collaborate with health information technology (IT) experts who are not working in the area of mental health, and to infuse mental health research within health IT products to ensure those products are as evidence-based as possible. These efforts have led to a focus on funding grants to improve mental health care through technology. One strategy is to pursue approaches that are device-independent; they do not require someone to use something that they are not already using. Another strategy is to use existing tools rather than reinvent the wheel. Another approach uses different test beds of users of mobile technologies to assess efficiencies in recruitment to research. Finally, more emphasis is being placed on demonstrating improvements rather than just equivalence.
Long-term strategies seek to identify incentives for incorporating mental health science in technology, aggregating and sharing health IT tools, and matchmaking between researchers and technology firms.
Moderator Mary Jane Rotheram, Ph.D. asked if there is a way in which NIMH should or could invest in infrastructure for its grantees that could reduce the cost and increase the robustness of technology platforms used by investigators. This effort could reduce the barriers and costs to new investigators. The challenges lie in synthesizing information at the back end of the existing portfolio so that researchers are not reinventing the wheel and information can be best leveraged across studies.
Dr. Areán said that her institution’s Center for Translational Science Award has developed a program called Catalyst in which investigators are paired with technology companies to develop projects focused on health. Many companies are interested in obtaining data to support their interventions or at the very least working with investigators to collect the data. Dr. Areán suggested that NIMH consider such an approach.
Deanna Barch, Ph.D. asked whether NIMH could sponsor workshops or conferences for mental health researchers to become informed about available information technologies and what has worked. She also mentioned VA and the DoD Defense Advanced Research Projects Agency (DARPA) initiatives that use gaming technology for treating PTSD. Dr. Simon added that it is important to assess what you are using the technology for, for example, to assess brain functioning, to modify it, or to compensate for it. Investigators must be able to identify the target of the intervention.
Dr. Robinson Beale noted that as more provider systems become focused on costs they will be looking for interventions that are more efficient and more cost effective. In behavioral health, one of the most expensive forms of practice is the individual psychotherapy session. New technologies can build efficiencies into that approach by tapping into certain brain functions that are affected by psychotherapy approaches.
Gene Robinson, Ph.D. asked whether any research focuses on how people with different diagnoses use the technologies. Dr. Chambers responded that it is important to study the feasibility and acceptability of using technologies among different populations, and to not make assumptions about the ability of people with particularly disorders to use technology. Dr. Tamminga added that clinicians will also need to be trained in how to incorporate modern IT techniques.
Dr. Rotheram closed by advocating for investment in infrastructure in open-source platforms that are based on an analysis of NIMH investments to date. Robust platforms have the potential to reduce the cost for researchers to study cognitive processes across multiple disorders. The NIMH Division of Intramural Research Programs may be a means to jumpstart this effort by building a robust infrastructure for mobile technologies.
Enabling Informative NIMH Clinical Trials
Dr. Insel began by referencing an Institute of Medicine report evaluating the National Cancer Institute (NCI) clinical trials system. The report called for improvements in the speed and efficiency of the design, launch, and conduct of clinical trials; in the translation of scientific innovations; in the selection, prioritization, support, and completion of clinical trials; and in the participation of patients and physicians in clinical trials. In response, NCI has engaged in an evaluation of its clinical trials program, and other NIH institutes, including NIMH, are following suit. In 2008, NIMH funded approximately 530 non-AIDS trials at an annual cost of approximately $200 million. In 2012, NIMH funded approximately 264 non-AIDS trials at an annual cost of approximately $111 million. Behavioral therapy trials comprise the largest fraction overall. Most of the current investment is in exploratory trials supported by the research planning grant (R34) and exploratory/developmental research (R21) mechanisms.
NIMH is evaluating the efficiency of its currently funded trials, as industry-sponsored trials are much shorter in duration. The Institute is focusing on transparency (e.g., registration on clinical trials.gov, the use of common data elements, data sharing), clinical impact, improved understanding of pathophysiology, the development of personalized and preemptive interventions, and public health impact. The NAMHC Workgroup report, From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses, underscored the importance of validating and defining targets or mediators to inform our understanding of the disorder(s) itself. Emphasizing target validation/definition is more likely to attract the drug companies who have recently left this field because of a lack of targets. Efforts are also needed to better understand dose, duration, and intervention effectiveness. Dr. Insel cited work by Sofia Vinogradov, M.D., as an example, in which cognitive training targeted executive functions, such as working and verbal memory, can be used to demonstrate differences between healthy controls and people with schizophrenia.
NIMH aims to publish new funding announcements to explain precisely what the Institute is looking for in the field of experimental medicine. Guidelines will clarify expected public health and clinical practice significance, as well as review criteria, including issues of feasibility and readiness. Jean Noronha, Ph.D., Division of Extramural Activities added that once these new funding announcements are posted to the NIH Guide, the intention is that NIMH will no longer accept clinical trials under the general R01 announcement.
Dr. Simon endorsed this approach and emphasized the need for study sections to move from an advocacy mode—supporting the trial because they think it will work—to a discovery mode in which failure is expected and acceptable.
Dr. Robinson Beale added that this change in culture has to be extended to publications. Dr. Insel noted that new regulations require clinical trial results to be posted on clinical trials.gov; however, psychosocial interventions do not have to be included. The Institute could require that as part of its funding announcement. Dr. Tamminga added that not every failed trial is important; only those that were designed for discovery can yield negative information that is just as important as positive information.
Dr. Lewis-Fernández expressed concern about eliminating research the does not meet this new standard, stating that some areas might still warrant a traditional clinical trials approach. He urged to not entirely subsume clinical trials within this new strategy, moving them from efficacy to target validation only. Dr. Insel said that clinical trials going forward need not be solely mechanistically based. However, they must be constructed so that if the trial fails, the field will still learn something from them.
Dr. Areán said that this approach will enhance research on psychosocial interventions because current strategies are far too complicated to implement. Having a better understanding of what makes some people more are less responsive to treatment will help inform the selection of existing treatments or the creation of new ones. She added that this approach as well as RDoC must also assess the impact of environmental stress on neural networks because they can lead to simple environmental interventions that are effective.
Dr. Rotheram asked whether this approach would eliminate clinical trials focused on access. Dr. Insel said that such studies would not be eliminated as a focus but will be subject to a different set of standards. However, emphasis will be placed on innovation, not just expanding what is known in one population to application in another. Research must demonstrate something that makes a difference. Institute leadership will be mindful of possible unintended consequences of these changes, but feels this approach is necessitated by lack of innovation in the grant applications being received.
Executive Order on Improving Access to Mental Health Services for Veterans, Service Members, and Military Families
Farris Tuma, Sc.D., Chief, Traumatic Stress Disorders Research Program, Division of Adult Translational Research (DATR), summarized the Executive Order directing the DoD, VA, and HHS to: 1) substantially improve suicide prevention efforts, including outreach and evaluation; 2) increase the number of mental health providers and form new partnerships between VA and community-based organizations; and most relevant to NIMH; and, 3) develop a National Research Action Plan (NRAP) for coordinated research priority-setting process across the agencies. The Executive Order recognized that approximately 20 percent of the 2.2 million service members deployed since 2001 are affected by PTSD, TBI, or both, and that suicide rates and attempted suicide rates have been increasing.
NIMH has been contributing to the NRAP effort to coordinate strategies for: biomarkers for diagnosis and treatment; improved diagnostic criteria for TBI; mechanisms underlying PTSD, injuries, and disorders following TBI; new treatments based on mechanisms; improved data sharing and use of electronic health records; collaborative research on suicide prevention; and, continuation of Army STARRS . The Executive Order makes clear that the work funded by NIH is important to both Active Duty and veteran populations, as well as to the civilian community. Research findings in the civilian community with regard to mechanisms or treatments can translate across populations. In developing NRAP, NIH organized a series of workgroups on PTSD, brain injury, and suicide prevention. NIH also conducted a joint portfolio review across the agencies involved to identify knowledge gaps along the continuum from basic research through to delivery of healthcare.
The draft NRAP is under review and is expected to focus on key priorities spanning all of the conditions in the Executive Order: coordination across agencies through scientific tracking and management systems; improved data and specimen sharing; leveraging large biomarker efforts, infrastructure, and electronic health records; identification of more precise phenotypes; and directing treatment specifically to patients of particular targeted dysfunctions and deficits (precision medicine). NIMH is actively involved in the NRAP as it relates to PTSD and suicide prevention, and a related effort involving the National Institute of Neurological Disorders and Stroke (NINDS) in underway on TBI.
Dr. Tuma introduced two Concepts focused on PTSD heterogeneity and translation. He noted that the heterogeneity within PTSD has complicated the ability to separate signal from noise regarding the mechanisms and course of dysfunction. There has been an invalid assumption that each patient in a diagnostic category reflects the same disease entity. This thinking has stymied efforts to predict the course and trajectory of distress and dysfunction phenotypes. Although PTSD has a clear precipitating event, the field lacks an understanding of the different pathophysiological changes that characterize subtypes of the PTSD syndrome.
Dr. Tuma also reported that substantial research has been conducted aimed at understanding the circuitry of fear and the role of learning and memory in both normal functioning and in response to stress. But there has been limited translation of this knowledge in identifying biomarkers or markers of different clinical phenotypes. New efforts are needed to determine whether basic science models of fear, learning, and memory dysfunctions can help identify markers of heterogeneous human phenotypes and serve as targets for intervention.
NIMH is proposing two potential initiatives in this area. The first, “Mechanisms of Fear, Learning, and Memory,” would encourage translational research through collaboration between basic and clinical researchers targeting fear, learning, and memory processes. The goal would be to apply/interrogate putative mechanisms that underlie changes seen in response to stress to humans, particularly clinical populations. Multi-stage research grants are envisioned, involving collaboration between basic and clinical researchers, to develop proof-of-principle studies (from model animals to humans with well characterized paradigms of specific fear, learning, and memory dysfunctions) prior to progression to pilot clinical studies.
The second initiative, “Probing Early Pathophysiology in Post-Traumatic Stress Conditions,” would aim to identify specific phenotypes of distress and dysfunction and understand the course and trajectory to optimize “treatments as prevention” based on the related pathophysiological changes observed/expected. The initiative may involve new projects and longitudinal designs to identify and probe early pathophysiological changes and adjustment post exposure in trauma patients seen in emergency rooms and other acute trauma settings. Additionally, this effort may involve secondary analyses of existing biological, experiential, demographic, and cognitive data to supplement new data collection. The overall goal would be reliable, multi-method risk prediction algorithms based on biomarkers and cognitive tests that yield phenotypes of post-traumatic stress conditions for further research, as well as an actionable understanding of the course and trajectory of these conditions to optimize prevention based on markers of pathophysiological changes.
Dr. Lewis-Fernández commended that the intent is to focus on heterogeneity as well as the different phenotypes of presentation. He said that although fear conditioning is an important element of trauma response, other types of emotions or phenotypes of PTSD, such as anger and shame, and the dissociative subtype, are also worth noting. He questioned whether non-fear related studies would also be considered. He also asked whether there would be an effort to differentiate between acute and chronic trauma as well as other types of trauma response beyond PTSD and TBI, for example, acute stress disorder or adjustment disorders. An additional consideration is to collect data on how development affects patterns of trauma response as well as environmental factors, for example, presence of social support. Finally, Dr. Lewis-Fernández asked where within the overall effort research on implementation, services, access, and quality would occur.
B.J. Casey, Ph.D. said there is a gap in knowledge regarding the development of the circuitry in PTSD and urged interdisciplinary efforts among clinical and animal researchers.
Dr. Robinson encouraged also looking at the relationship between extinction and forgetting in mechanistic terms.
Dr. Davison said that the plan is very comprehensive. He noted that despite having evidence-based treatments for PTSD, the DoD and VA still face challenges delivering the treatments because not all PTSD cases looks the same. He welcomes efforts to understand heterogeneity in terms of mechanisms and early pathophysiology in order to optimize psychotherapeutic approaches.
Dr. Katz asked whether neurodegeneration related to persistent and profound stress will be investigated.
Dr. Tuma closed the session by saying that the two Concepts presented encompass areas in which NIMH is particularly well suited to play a role. He added that the focus will not be restricted to fear and may also include emotion regulation and dysregulation more broadly.
Prediction of Psychosis
Robert Heinssen, Ph.D., Director, DSIR, opened the Concept discussion by noting a shift in psychiatry over the past 10 years from focusing on the earliest stages of psychosis to emphasizing early detection and intervention, which became more urgent in the wake of the December shooting tragedy that occurred in December 2012 in Newtown, CT.
Twenty years ago, NIMH efforts focused on the first episode of psychosis because it represented a unique opportunity to understand some of the fundamental characteristics of schizophrenia, without the complications of prolonged medication exposure or the accumulation of disability over time. NIMH learned from that research that much of the damage actually occurs prior to the first episode of psychosis, and recognized the need to explore the high-risk states that precede the emergence of psychotic symptoms. Several projects are focused in this area, such as the Recovery After an Initial Schizophrenia Episode (RAISE) Project, which is testing evidence-based, multicomponent specialty care programs in the public health system. The North American Prodrome Longitudinal Study (NAPLS) study has focused on the at-risk states that precede psychosis onset, helping to map some of the pathways by which risk converts into active illness. The Philadelphia Neurodevelopmental Cohort Study is a population-based study that has enrolled thousands of young individuals to characterize them in terms of genomics and cognitive phenotypes, with the goal to identify cohorts of individuals at risk who could be followed longitudinally. Combined, these projects provide ways of looking at early psychosis through population risk studies, clinical at risk studies, and intervention studies in the earliest episode of illness.
Review of these studies, as well as others, led to the formulation of a plan grounded in public health deliverables with the goal of implementing high-quality programs throughout the United States with the capacity of identifying people at risk with great precision and offering them effective care prior to the onset of psychosis. To do this, NIMH needs practical risk prediction tools, preemptive interventions, a platform for early detection and intervention, and the means for disseminating stage-specific specialty care programs.
The current NIMH portfolio includes many studies on risk prediction, promising interventions to preempt illness, and approaches to addressing the first episode of psychosis. In February 2013, a concept clearance presentation was followed by a funding announcement for research in settings with specialty care programs for persons experiencing first-episode psychosis. Applicants were asked to map referral pathways, identify gaps and bottlenecks, and then develop and test strategies to remove barriers in order to reduce the duration of untreated psychosis to the international standard of three months or less.
In April 2013, another concept clearance presentation discussed a research initiative to improve the care of persons at clinical high risk. The initiative would support research on the treatment of early psychosis which segments the at-risk population into subgroups and offers targeted interventions designed to interrupt the progression from risk states into active illness. The potential initiative aims to conduct research using an RDoC conceptualization for deconstructing psychotic symptoms, finding more tractable targets for intervention, subjecting those to experimental medicine, developing promising signals through mechanism-based efficacy studies, and conducting a second generation of clinical high-risk effectiveness studies.
Stacia Friedman-Hill, Ph.D., Chief, Mechanisms of Cognitive Dysfunction Program and Trajectories of Neurocognitive Functioning Program, Division of Developmental Translational Research, presented the concept, “Toward Early Prediction of Psychosis: Collaborative Research on Developmental Risk in 22q11.2 Deletion Syndrome.” The primary goal of this concept is to track neurodevelopmental trajectories and to collect biomarkers in children and adolescents at high risk for psychosis by virtue of having 22q11.2 Deletion Syndrome. Because there is already a significant loss of function in individuals by the early stages of the prodrome, biomarkers are needed even earlier where there is a chance to head off the progression of the disorder or even reverse it. Understanding the interplay of genetic and environmental risk and characterizing early neurodevelopmental trajectories of psychosis has been challenging.
22q11.2 Deletion Syndrome is a rare disorder with an incidence of 1 in 4,000 births; it can be detected in infants with fluorescence in situ hybridization. Approximately 30 percent of these individuals will experience psychosis. NIMH has invested in several longitudinal imaging studies of brain and behavioral development in these individuals that are showing significant differences in cortical structure and function between such individuals and age-matched, normally developing adolescents. Changes in neuroimaging measures over time have been correlated with changes in neurocognition in these patients. Researchers have found that in presymptomatic individuals, gray matter reduction correlates with an increase in positive symptoms.
A coordinated multisite study with pre-adolescent youth could focus on how neurocognitive and neurodevelopmental trajectories are shaped by potential moderators and mediators such as stress, puberty, social and emotional support, and genomic factors of risk and resilience. The strategy of this concept is to identify early biomarkers or biosignatures for risk and disease progression in this population of individuals. It will involve deep phenotyping using multi-modal neuroimaging, and neurocognitive and behavioral measures. A prospective, longitudinal design will measure markers of disease progression. An accelerated cohort design will cover trajectories from age 6 through 25, providing a unique opportunity to capture longitudinal neurodevelopmental change from an early age in order to enhance predictive power.
The multisite approach enhances the power and requires maximal use of common data elements, harmonization of methods, and data sharing to enable comparisons of different risk groups. The ultimate goal is to identify presymptomatic biomarkers and biosignatures, leading to early intervention to prevent progression, and novel interventions to reverse the course.
Dr. Barch said that while this approach is very promising, the mechanisms for psychosis in this patient population are very different from those involved in psychosis in the rest of the population. The general population is unlikely to seek treatment prior to the onset of symptoms, so the question is how such biomarkers can be used in a community setting.
Kay Redfield Jamison, Ph.D. asked for clarification on the definition of psychosis, given the broad range of symptoms from transient hallucinations to fixed delusions. Dr. Simon added that although study of this subgroup provides efficiencies, questions remain about whether it is a valid group in which to study psychosis. He urged an interim assessment of the course of progression and the markers of progression in the subpopulation as they relate to the general population.
Dr. Barch asked whether the study would harmonize with other NIMH-funded studies on this syndrome. She also urged consideration of what it is that we are trying to predict, that is, it cannot be limited to conversion to psychosis. Dr. Friedman-Hill responded that there is coordination among related studies and efforts to develop common measures.
Dr. Sweatt urged including other aspects of this population in the research beyond psychosis, consistent with the RDoC approach. Dr. Friedman-Hill responded that 22Q11.2 Deletion Syndrome is well suited to RDoC because in addition to high rates of psychosis in this population, there are high rates of comorbid anxiety disorder and autism spectrum disorders. Thus, this concept includes neurocognitive and as well as social processes. Currently the emphasis is on finding biomarkers that can be used in staged interventions. For example, if there is a drop in test scores in the school setting, the child might be identified as someone who should be followed, with the possibility of cognitive remediation.
Dr. Jamison asked whether attention was being paid to the ethical concerns surrounding pretreatment and pre-intervention. Dr. Insel responded that such concerns must be addressed before predictive measures are identified.
Research Doman Criteria (RDoC) Project
Bruce Cuthbert, Ph.D., Director, DATR, introduced the first of two RDoC Concepts, “First Generation RDoC Standard Data Elements.” Currently, RDoC contains 23 constructs involving hundreds of paradigms. The matrix involves multiple dimensions including developmental trajectories from before birth throughout the lifespan, and environmental effects. Building a more unified dimensional structure and looking at its effects on various neural and behavioral systems makes it more tractable to study disorders. Going forward, NIMH has to facilitate interoperability of data and enable the capacity for investigators to share data in a meaningful way. This Concept is focused on facilitating common data elements. It aims to develop and implement an operational template for standard data elements in RDoC-themed research and produce an initial set of recommended provisional standard data elements.
There are seven objectives: 1) establish a working group to advise on tasks and measures in all domains; 2) survey the current status of paradigms and measurement development to determine recommended elements for all domains and constructs; 3) determine standards for databases following current standards; 4) evaluate the development of a platform for developing and distributing laboratory paradigms using a standard experimental system; 5) where available, implement well-validated tasks and measures into a common system; 6) where no or insufficient measures are available, generate a project to develop new paradigms; and, 7) devise a procedure for revising the data elements on a periodic basis, revising or replacing tasks and measures as appropriate.
Dr. Cuthbert emphasized the need to achieve a balance between obtaining standard data while allowing flexibility to enhance the matrix and move on to develop better tools. As an example, the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia project just completed a process of converting relatively long laboratory tasks in cognitive neuroscience into relatively brief but reliable and valid tasks that could be used in clinical trials or actual clinical use. A primary metric will be the development of standards for data formatting that will allow investigators to share data more easily. The number of paradigms and measures that can be evaluated and actually implemented for inclusion in the standard data elements is another metric. Yet another means of assessment would be to look at the number of RDoC-themed grants that incorporate various components of the standard data elements. Finally, the goal is to develop a process for revising the standard data elements to reflect new findings at least every 3 to 4 years.
Sarah Morris, Ph.D., Chief, Schizophrenia Spectrum Disorders Research Program, DATR, presented the second RDoC Concept, “Secondary Data Analyses to Explore RDoC Domains.” This initiative is designed to maximize investigators’ exposure to RDoC and increase opportunities for investigators. NIMH would encourage investigators to mine existing data for RDoC purposes, by leveraging existing clinical research datasets by supporting secondary analyses to investigate RDoC domains or test novel RDoC hypotheses. Such secondary analyses would provide a rapid, low-cost opportunity to jumpstart RDoC research and would expedite efforts to validate RDoC constructs. Further, it would encourage investigators to develop new collaborations that would be optimal for conducting RDoC work. The intent is to generate novel hypotheses and pilot data for new, larger-scale projects.
Examples of the types of projects anticipated include efforts to reorient focus from the categorical to the dimensional within a patient group, among patient groups, and across developmental stages. Existing data could be reoriented and reanalyzed, taking a dimensional approach, with the dependent and independent variables mapped onto the RDoC matrix, either cutting across constructs or looking within a construct. Such work could focus on exploiting variability within a heterogeneous group, combining data from different patient groups, or taking a developmental perspective combining data collected from different age groups to look at developmental changes within or between a construct.
As another example, an investigator might be able to reprocess and reanalyze EEG data or functional or structural magnetic resonance imaging data with the goal of filling in empty cells on the RDoC matrix, validating the RDoC construct, or testing a novel hypothesis about one or more RDoC constructs. Investigators could take a fresh look at data that previously were thought to be uninformative. Data from clinical studies could be combined and analyzed dimensionally, defining meaningful relationships with genetic factors or behavior within a given construct, or looking at relationships with other units of analysis in other constructs. The success of the initiative would be evaluated by the extent to which these secondary analyses of existing data lead to new understanding of mental disorders, help to validate defined constructs, fill gaps in the RDoC matrix, or lead to new hypotheses that can be tested with new data collection efforts. Another test would be to see how many investigators who have not previously focused on RDoC activities propose projects and also how many applications for new funding use these secondary analyses as preliminary data.
Dr. Casey stressed the importance of this dimensional approach for linking symptoms to biology and for identifying new targets. However, she cautioned against over standardization that could impede discovery or weaken efforts to optimize existing paradigms. The peer review process could be used to diffuse some of these potential problems. In addition, although the focus has been on researching humans, it will be important to include opportunities for human and animal researchers to work together.
Dr. Areán said that this activity provides many opportunities for exploiting big data such BrainNet, in which investigators can upload data and allow others to combine data to explore paradigms and concepts around brain illnesses, including mental health. It will also be important to collect data through health systems on a regular basis. If collected in a time-efficient manner, such data could provide greater understanding of the differences in treatment response, especially if data include measures of working memory, attention, and affect regulation. Some of these data could be collected through mobile technology.
Dr. Robinson agreed with the importance of including animal models to gather phenotypic data that could be used to test some of the hypotheses in the current RDoC constructs.
Dr. Simon suggested using the supplement mechanism to support secondary analyses on existing studies. Dr. Sweatt said that the supplement approach might be more effective than traditional funding mechanisms in which study sections might not be likely to score secondary analyses of data very highly. Dr. Morris replied that NIMH is considering such an approach, but that smaller funding mechanisms such as small research grants (R03) may allow greater flexibility than supplements for investigators to examine data from studies that are already completed.
Dr. Sweatt emphasized the importance of collecting epigenetic data in a consistent format.
Dr. Barch reiterated the point that it is important to make clear that both innovation and standardization are desired.
Approval of the Concept
Dr. Steinberg asked NAMHC members for a vote on approval of the two RDoC-related concept presentations. The motion to approve the concepts was unanimously passed.
Imaging the Brain
Gregory Farber, Ph.D., Director, Office of Technology Development and Coordination, introduced the Concept, “Development of a BrainSpan RNA-seq Browser.” In 2009, NIMH made a significant investment to create the BrainSpan Atlas of the Developing Brian. BrainSpan was designed to map gene expression patterns in the brain across time and space throughout the lifespan, using next-generation sequencing techniques. The range of ages represented in BrainSpan begins at 4 weeks post-conception and extends through approximately 40 years, encompassing 11 periods of development. The atlas comprises multiple data types, including high-resolution anatomical reference atlases based on both prenatal stages as well as from one adult stage. These atlases were created using high resolution imaging technology, as well as canonical brain cell staining methods. The BrainSpan team focused analysis on genes and brain regions matched to the genes and structures used in the NIH Blueprint-funded non-human primate atlas. Whole genome sequencing data are now available as well.
Although more than 50 papers have been published using the data in the BrainSpan Atlas, its use has nevertheless been limited to a small cadre of involved researchers. A straightforward web-browser is needed to enable the broader research community to mine the dataset. This initiative will create such a browser at modest cost. This web-based browser will allow a greater number of interested neuroscientists to query the valuable multi-modal data set and likely generate many hypothesis driven research proposals to study the neural underpinnings of mental health disorders, especially those with a developmental component.
Dr. Farber next discussed a second Concept, “Imaging Data and Biomarkers.” NIMH and other Institutes support numerous studies each year to acquire magnetic resonance brain images of various types, via large awards to single laboratories, as well as smaller awards for studies that will collect far fewer images. Unlike other areas of biomedical science such as oncology or musculoskeletal diseases, brain images in mental disorders have not resulted in any widely used imaging biomarkers. It remains unclear whether the root cause of this lack of biomarkers is our limited understanding of how the brain works, the heterogeneity of patient groups, the current resolution in the imaging experiments, or the inability of the research community to access information from a large collection of images that have diverse phenotypic information. The goal of this initiative is to try to understand where the barriers truly are in finding imaging biomarkers, to enable more strategic investment decisions.
As noted earlier, the HCP database includes structural, functional, and diffusion images as well as significant phenotype information, using imaging protocols that can be conducted in most reasonably modern imaging machines. HCP imaging protocols and data analysis platform produce very high resolution data—especially related to brain connectivity. Adding data generated from individuals with a broad spectrum of atypical behavior (along with appropriate phenotype information) could help identify biomarkers associated with psychopathology. Such a project would also speed progress toward common imaging data collection protocols, and such standardization could enable comparisons of data from different laboratories and the development of robust image processing tools.
Two different approaches could be supported. The first would be to focus on a particular disorder to employ HCP protocols in the study of a clinically defined disorder—in alignment with the NIMH RDoC project. A second approach would be to strongly encourage current awardees doing imaging studies with NIMH support to add or substitute HCP imaging experiments to their protocols, potentially via supplemental support. Existing studies that might be appropriate include projects with cohorts that were narrowly selected for particular disorders, as well as projects with cohorts that were selected on the basis of involvement of a particular function domain or neural circuit.
For final consideration, Dr. Farber presented an initiative with the goal of making use of existing imaging data which were collected using a wide range of scanners and protocols and might have lacked robust data analysis or agreed-upon quality control measures. To date, it has been challenging to combine imaging data. However, the 1000 Functional Connectomes project and the International Neuroimaging Data Sharing Initiative have demonstrated that it is possible to aggregate images from multiple laboratories. Dr. Farber presented a Concept for a potential initiative to make use of the few existing data-rich resources, for example, the National Database for Autism Research . Activities could include adding data to an existing repository; developing persistent and robust image analysis pipelines for data that already exist; or analyzing data in existing collections and making the analysis available for further use.
With regard to the Concept to enhance the HCP, Dr. Tamminga commented that in addition to conducting deep phenotyping using imaging, consideration should be given to collecting and analyzing high-quality postmortem tissue for molecular and cellular analyses. Dr. Simon added that this effort should not be bogged down by requirements to use the traditional modes of characterizing diagnostic states.
Hakon Heimer, M.S. encouraged looking at expression data from adolescents.
With regard to the initiative to find ways to make use of existing data, Dr. Insel commented on big data, standardization, and integration. For example, NIMH was instrumental in creating the Psychiatric Genome-wide Association Study (GWAS) Consortium, involving 300 investigators in 80 institutions in 20 countries. Collectively, the Consortium has have obtained more than 200,000 DNA samples or other samples from 200,000 subjects. Analyses have shown that there is power in numbers in terms of eliminating noise. The nature of the genetic signals requires large numbers. This necessitates standardization, integration, and sharing of data, which has been done well in the area of genetics. In the NIMH context, the goal is to require everyone to share images and create a public resource that can be crowd sourced to allow thousands of people to study these images.
Dr. Rotheram asked whether images could also be collected through healthcare provider networks and whether there could be ways to incentivize those systems to collect data in a standardized way. Dr. Tamminga commented that some types of images are more easily combined than others.
Dr. Robinson encouraged emulating what happened in genomics to develop principles for data sharing in this arena.
Randall Carpenter, M.D. emphasized the need for consistent phenotypic data, because little will be learned from just viewing images from normal people.
Dr. Insel thanked both the presenters and Council members for their comments. Dr. Insel reminded Council members and members of the public that the cleared Concepts will be posted on the NIMH Web site and there will be opportunity for additional comment through those Web pages.
Dr. Insel invited members of the audience to make any comments to the Council.
Darrell Regier, M.D., M.P.H. from the American Psychiatric Association (APA) noted the complementary relationship of RDoC to the DSM. He presented the Institute with a copy of the DSM-V, inscribed with notes of appreciation for the contributions of NIMH staff and grantees to the development of DSM-V. He added that laboratory tests are not the only valid means for making a medical diagnosis. The challenge is in finding different validators for diagnoses and recognizing the impact of lay interpretation of what constitutes validity.
Dr. Insel responded that the reason he released a joint statement with Jeffrey Lieberman, M.D., President of the APA, was to emphasize that the two efforts were complementary and not competitive projects. He said it is critically important to communicate to the public and to journalists the science behind the study of mental disorders and the tools being developed to improve that science.
Dr. Insel thanked all who participated in the meeting. He recessed the open session meeting at approximately 1:55 p.m.
Thomas R. Insel, M.D., Chairperson
Summary of Primary MH Applications Reviewed
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)
- Thomas R. Insel, M.D.
National Institute of Mental Health
- Jane A. Steinberg, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
- Patricia A. Areán, Ph.D. (16)
Department of Psychiatry and Langley Porter
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
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
- Randall L. Carpenter, M.D. (15)
Co-Founder, President and Chief Executive Officer
- BJ Casey, Ph.D. (16)
Department of Psychiatry and Neuroscience
Sackler Institute for Developmental Psychobiology
Weill Medical College of Cornell University
New York, NY
- Lisa Greenman, J.D. (15)
Federal Public Defender Organization
District of Maryland
- Hakon Heimer, M.S. (16)
Schizophrenia Research Forum
Brain and Behavior Research Foundation
- Steven E. Hyman, M.D. (15)
Director, Stanley Center for Psychiatric Research
- 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
- 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
Center for Advanced Study Professor in Entomology
University of Illinois at Urbana-Champaign
- Rhonda Robinson Beale, M.D. (13)
Chief Medical Officer
OptumHealth Behavioral Solutions
- 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)
Professor of Biology and Neurology
James H. Clark Center
- Gregory E. Simon, M.P.H., M.D. (14)
Senior Scientific Investigator
Center for Health Studies/Behavioral
Group Health Cooperative
- J. David Sweatt, Ph.D. (16)
Evelyn F. McKnight Endowed Chair
Department of Neurobiology
Director, McKnight Brain Institute
University of Alabama at Birmingham
- Carol A. Tamminga, M.D. (15)
Professor and Chair
Department of Psychiatry
University of Texas
Southwestern Medical Center
Ex Officio Members:
Office of the Secretary, DHHS:
- Kathleen Sebelius
Department of Health and Human Services
National Institutes of Health:
- Francis Collins, M.D., Ph.D.
National Institutes of Health
- Ira Katz, M.D., Ph.D.
Department of Veterans Affairs
Office of Mental Health Services
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
- Paolo del Vecchio, M.S.W.
Center for Mental Health Services