NAMHC Minutes of the 233rd Meeting
January 24, 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 233rd meeting in open session at approximately 8:30 a.m. on January 24, 2013, in the Neuroscience Center in Rockville, Maryland. In accordance with Public Law 92-463, the policy session was open to the public. The open session was recessed at approximately 1:00 p.m. The NAMHC reconvened for a closed session to review the Division of Intramural Research Programs (DIRP) as well as extramural grant applications at approximately 2:00p.m. on January 24, 2013, at the Neuroscience Center in Rockville, Maryland, until adjournment at approximately 5:00p.m. (See Appendix A: Review of Applications). Philip Wang, M.D., Dr.P.H., Deputy Director, National Institute of Mental Health (NIMH) chaired the open portion of the meeting and Thomas Insel, M.D., Director NIMH chaired the closed portion of the meeting.
Council Members Present at the Grant Review and/or Open Sessions
(See Appendix B: Council Roster)
- Thomas R. Insel, M.D.
- Philip Wang, M.D., Dr.P.H
- Jane A. Steinberg, Ph.D.
- Patricia A. Areán, Ph.D.
- Deanna Barch, Ph.D.
- Virginia Trotter Betts, M.S.N., J.D.
- B.J. Casey, Ph.D.
- Randall Carpenter, M.D.
- Hakon Heimer, M.S.
- Steven E. Hyman, M.D.
- Kay Redfield Jamison, Ph.D.
- Roberto Lewis-Fernández, M.D.
- Gene 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.
- J. David Sweatt, Ph.D.
- Carol Tamminga, M.D.
Ex Officio Members
- Ira Katz, M.D., Ph.D., Department of Veterans Affairs
Liaison Representative at the Open Policy Session
- Anna Marsh, Ph.D., Substance Abuse and Mental Health Administration
Others Present at the Open Policy Session
- Helen Avner, Sign Language Interpreter
- Alison Bennett, International Neuroethics Society
- Stefano Bertuzzi, American Society for Cell Biology
- Kelly Carr, National Alliance on Mental Illness
- Erika Davies, Society for Women’s Health Research
- Mark Egan, Alderson Court Reporting
- Suzanne Fenzel, DC Department of Mental Health
- Chanté Frazier, Sign Language Interpreter
- Karen Graham, International Neuroethics Society
- Phyllis Greenberger, Society for Women’s Health Research
- Kathi Hanna, Science Writer
- Benjamin Kaufman, Organization for Autism Research
- Julia Keyser, Community Oriented Correctional Health Services
- Alan Kraut, Association for Psychological Science
- Kevin McNaught, Tourette Syndrome Association
- Sarah Hutcheon Mancoll, Society for Research in Child Development
- Ngoda Mavongl, Society for Women’s Health Research
- Daria Nashat, Nashat Consulting, LLC
- Wendy Naus, Lewis-Burke Associates, LLC
- Joy Ridley, Synergy Enterprises, Inc.
- Karen Studwell, American Psychological Association
- Robert Yates, Social and Scientific Systems
- TaRaena Yates, Synergy Enterprises, Inc.
Open Policy Session Call to Order and Opening Remarks
NIMH Deputy Director Philip Wang, M.D., Dr.P.H. called the session to order and welcomed everyone in attendance. He explained that NIMH Director Thomas Insel, M.D. had been called to testify at a congressional hearing but was expected to join the Council meeting later in the day.
Approval of Minutes of the Previous Council Meeting
Dr. Wang asked NAMHC members for comments on the minutes from the September 13, 2012 Council session. Receiving none, the motion to approve the minutes was unanimously passed.
NIMH Director’s Report
Dr. Wang provided an update on NIMH activities related to the White House, the Department of Health and Human Services (HHS), and the National Institutes of Health (NIH). He noted the tragic events that took place in December 2012 in Newtown, CT and the many national discussions on this topic, beginning 50 years ago when President John F. Kennedy asked Congress to create a mental health system. The events of December 2012 should propel efforts to fundamentally understand the basis of mental illness and turn this knowledge into cure.
White House Update
NIMH contributed to the research and policy agenda for Vice President Biden’s Task Force to address issues of mental illness and gun violence, which informed President Obama’s January 16, 2013 Sandy Hook Response Plan . The Response Plan directs Secretary of 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 to address the culture of silence and negative perceptions of mental illness that keep so many of our nation's young people from seeking or receiving care. Along with this national dialogue , HHS Secretary Sebelius announced a plan to add 5,000 mental health specialists focused on the needs of youth, and created Project AWARE (Advancing Wellness and Resilience in Education) to reach 750,000 children by training teachers and other adults who interact with youth to recognize and properly refer children who may be in need of mental health services.
As the President noted in his remarks on January 16, people with serious mental illness (SMI), such as schizophrenia and bipolar disorder, account for only a small fraction of violent crimes, and are in fact more likely to be victims of violent crime than perpetrators. Violence is associated with untreated psychosis, particularly when accompanied by symptoms of paranoia and substance abuse. The risk of violence is reduced substantially with appropriate treatment. The role of NIH in the Response Plan is evolving, and NIMH aims to continue supporting research on earlier diagnosis and quicker delivery of appropriate treatment not only to people with SMI, but to all individuals affected by mental illness.
When violence is associated with mental illness, it is much more often related to suicide rather than homicide. Consistent with the HHS priority on suicide prevention, NIMH has increased its focus on suicide prevention research. For example, the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a Framingham-like study of military personnel. The goal of this five-year project is to identify, as rapidly as possible, risk and protective factors that will help the Army develop effective strategies to reduce suicide rates in the military, and to address associated mental health problems among soldiers. In fiscal year (FY) 2012, Army STARRS reached a number of milestones, including establishing survey sites at more than 70 locations around the world, surveying more than 100,000 soldiers, and collecting more than 56,000 blood samples. This research will also help to increase our understanding of suicide in the overall population, leading to more effective prevention and treatment for service members and civilians alike.
In addition to Army STARRS, programs such as the North American Prodrome Longitudinal Study (NAPLS 2.0), which is focused on finding biomarkers to identify those at risk for psychosis, and the Recovery After an Initial Schizophrenia Episode (RAISE) initiative, which is testing wraparound services for patients with schizophrenia, will be instrumental for not only targeting preventive interventions but also in designing interventions that are critical in the future.
Two years ago, NIH’s Scientific Management Review Board recommended that the NIH Director consider merging two NIH Institutes focused on addiction, the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. After a detailed review of the institutes as well as obtaining feedback from the scientific community, Francis Collins, M.D., Ph.D., NIH Director, has opted to proceed with a functional rather than structural merger in light of the costs and hurdles of eliminating two institutes and creating a new one.
Several NIH Institutes, including NIMH, participated in an Institute of Medicine (IOM) Neuroscience Forum on establishing psychotherapy efficacy and safety standards. Legislation calling for parity for mental health services, combined with the new health care reform legislation, which expands mental health services to be on par with general medical treatments, has brought this issue to the forefront. These statutes require that covered treatments meet standards for efficacy and safety; yet those standards do not exist for psychotherapy. The IOM Neuroscience Forum will proceed with a more comprehensive study.
Dr. Wang reported on Dr. Insel’s blog on the Top Ten Research Advances of 2012. These include understanding the genetic architecture of neurodevelopmental disorders, producing atlases of the transcriptional changes that occur in the brain during development and disease, progress in understanding the epigenetic marks that may be responsible for controlling gene transcription, advances in systems neuroscience, knowledge emerging from the 1000 Genomes Project and the ENCODE Project , the potential role of somatic mutations in brain cells of neurodevelopmental disorders, and early successes in combining behavioral prevention with biomedical prevention to control the spread of HIV infection.
NIMH is aiming to transform clinical research and trials through experimental medicine, which starts with targets and then leads to efforts to rapidly validate or reject them. Compounds are used as probes. If they functionally and structurally engage the target, the next step is to determine if there are functional effects on important phenotypes. Ketamine and its use as a rapid antidepressant is an example of such an approach. The ketamine work was initiated in the NIMH Division of Intramural Research Programs (DIRP), and now drug companies are using the data generated from that work to develop their own NMDA receptors. Early trials show promise in terms of both efficacy and tolerability.
NIMH is also pursuing the use of learning healthcare systems to transform clinical research. The Mental Health Research Network is an example of this approach, which involves study of the actual health care being delivered in large healthcare systems to quickly and economically answer research questions.
Although FY 2013 began on October 1, 2012, there is considerable uncertainty about the NIH and NIMH budgets. In order to continue in the absence of a formal FY 2013 budget appropriation, President Obama signed a continuing resolution (CR) on September 27, 2012. The CR continues government operations through March 27, 2013 at the FY 2012 level, plus 0.6 percent.
While operating under a CR, NIMH is issuing non-competing research grant awards at a level below that indicated on the most recent Notices of Award (generally up to 90 percent of the previously committed level). As in previous CRs, NIMH looks forward to upward adjustments after the final appropriation is enacted later in the fiscal year.
Dr. Wang concluded his report by noting that the Institute is seeking interested candidates for the NIMH Associate Director for Clinical Research position. In addition, he announced that Susan Amara, Ph.D. has assumed the reigns as the Scientific Director for the NIMH DIRP, and Kevin Quinn, Ph.D., who had been co-leading the Army STARRS program for NIMH, is now the Acting Director of the Office of Science Policy, Planning, and Communications.
Gregory E. Simon, M.P.H., M.D. noted that the discussion surrounding the Newtown, CT shootings appears to have focused on reducing duration of untreated psychosis or on early intervention for persons with severe mental illness, but perhaps it should also focus on suicidal violence and suicide prevention. He asked how the concept of violence fits into the Research Domain Criteria (RDoC) initiative in terms of basic markers or endophenotypes. Bruce Cuthbert, Ph.D., Director of the NIMH Division of Adult Translation Research and Treatment Development (DATR), responded that there are several constructs that bear elaboration within the context of endophenotypes, such as frustrative non-reward, social cognition, and social behavior. RDoC intends to provide the framework for many types of research looking at various constructs.
Carol Tamminga, M.D. asked whether RDoC, which focuses on normal behaviors and studying them in animal models, is useful in suicide, for which there may be no animal model. Dr. Cuthbert responded that RDoC aims to also look at the normal functions of the brain and how normal functions become perturbed. Steven Hyman, M.D. added that animal models may be appropriate for examining some behaviors, but not others. He cautioned against pushing extrapolation from animal models too far.
Deanna Barch, Ph.D. asked for clarification on Project AWARE. She noted that there are data suggesting that duration of untreated psychosis predicts some aspects of violence. However, there appears to be a lack of knowledge about symptomology particularly at the level of school and parent, who may be in the best position to identify those at risk, in terms of when kids should be referred for services and where they should be referred.
Dr. Wang replied that NIMH and the Substance Abuse and Mental Health Services Administration (SAMHSA) are in beginning phases of conceptualizing the program in terms of surveillance, recognition, triage, referral, and types of services needed. Dr. Barch added that one of the greatest concerns is youth who are not yet in the mental health system. There are limited data on early indicators of risk. Epidemiological research is needed to inform the development of structured education programs for personal counselors, school safety officers, and parents.
Dr. Wang commented that biological markers and biosignatures are critically needed to predict who is at risk, possibly even before the prodrome. Roberto Lewis-Fernández, M.D. cautioned that very early identification raises the potential for misuse and stigmatization. Identifying people by their biological susceptibilities could be very useful for prevention but only if handled very carefully. Stigma might be a significant factor in families not bringing children at risk into mental health services sooner.
Virginia Trotter Betts, M.S.N., J.D. noted that service gaps exist between the time a family becomes worried about the symptoms observed in the patient and the time when families seek intervention by law enforcement. Ms. Betts called for graduated interventions during this period of need and echoed Dr. Lewis-Fernandez’s comments concerning the issue of stigma.
Anna Marsh, Ph.D. said that Project AWARE, which is an unfunded initiative at this time, would involve expansion of the Safe Schools Healthy Students , co-funded by HHS, the Department of Education, and the Department of Justice following the Columbine shootings. One component is to raise the mental health literacy of the population in general, for example, through mental health first aid training in schools. She said that organizers of the project do not feel they have the knowledge base for predictive interventions but the idea of raising general understanding and awareness of mental health issues is a good step forward.
Hakon Heimer, M.S. said there seems to be a lack of services for young people who recognize their own fears or violent feelings. He mentioned an internet-based program called “headspace,” sponsored by the Australian National Youth Mental Health Foundation, which involves a series of venues in which young people can feel comfortable talking with others about mental health concerns in a nonjudgmental way.
Robert Heinssen, Ph.D., Director of the NIMH Division of Services and Intervention Research (DSIR) described the RAISE initiative as a comparable model to “headspace,” in that it focuses on developing a program that could be sustained in the healthcare system, providing a number of therapeutic approaches for individuals who have just had an initial schizophrenia episode. The goal is to offer combined treatment in a coordinated and sustained manner. Like “headspace,” it is based on the concept of creating a youth-friendly environment that would be more likely to engage people. Currently RAISE has 35 community sites involved in the trial of which 18 are intervention sites. These sites have shown that in fact they can achieve a level of coordinated care with therapists who are brought to competency. The RAISE sites are integrated into existing healthcare systems and aim to optimize the pathway to care as well as educate people about the particular psychology of the early episode. Treatment is offered within a shared decision-making framework. HHS leadership has been involved in discussions about how to ensure that the program results in a reimbursable service and that fidelity is maintained.
Dr. Hyman asked whether the Affordable Care Act might offer some possibilities for creating integrated and sustainable services that are also standards-based. Rhonda Robinson Beale, M.D. agreed that this is an important opportunity to incorporate mental health care into the health and educational systems; however, efforts must be knowledge-based.
Patricia Areán, Ph.D. added that the more complicated the intervention, the greater the drift. Even if standards are developed for evaluating psychotherapies and reimbursement is available, there is no guarantee that the person delivering the intervention is doing it correctly. It might be that simpler interventions will be needed.
Mary Jane Rotheram, Ph.D. stressed the need to look across evidence-based interventions for common factors and then focus training on those as competencies. In addition, one reason for lack of fidelity is that the intervention is not a replicable model for many clinicians. Interventions should be validated based on clinical input and not just based on a drug discovery model. More innovation is needed in interventions as well of sources of funding for prevention.
Carla Shatz, Ph.D. emphasized that despite the important emphasis on interventions and training, early identification is crucial.
Dr. Hyman opined that the risk that young people with severe mental illness will commit suicide is greater than the risk they pose to others. Therefore, early intervention should be the focus.
Dr. Wang concluded the discussion by noting the complexity of the problem, including the inadequate nosology of violence, our lack of understanding of the critical periods, the need to identify risk factors and trajectories for illness, the importance of identifying interventions at different points of time, including their toxicities, and the need to address stigma. All of these factors must be considered in applying preventive measures and in developing screening and intervention programs. These challenges have implications for the research agenda.
Biennial Report on the Inclusion of Women and Minorities in NIMH Research
Pamela Collins, M.D., M.P.H., Director of the Office for Research on Disparities and Global Mental Health (ORDGMH), presented the FY 2011 and FY 2012 data regarding the inclusion of women and minorities in NIMH-funded clinical research. The NIH Revitalization Act of 1993 mandated a biennial report describing the manner in which NIH Institutes have complied with its requirements. NIH guidelines ensure that women and minorities are included in NIH-funded clinical research and that NIH-defined Phase III clinical trials are carried out in a manner sufficient to examine differential effects of both females and males, as well as individuals of diverse racial and ethnic groups.
In the extramural program from Fiscal Year 2011 to Fiscal Year 2012 there was a slight decrease in the overall number of female participants in clinical research. This is largely due to the increasing recruitment into the Army STARRS program, which has 80 percent male participation. The race of participants has remained steady over the past two years, with Blacks constituting the largest racial minority group (22 to 23 percent), followed by Asians (9 percent). With respect to ethnicity, Hispanic participants represent roughly 10 percent of the pool.
In the DIRP, slightly half of participants are women with little change from FY 2011 to 2012. In both years, about 53 percent of participants identified as female and 47 percent as male. Seventy percent of participants are White, with Blacks comprising the largest racial minority group at 18 percent, followed by Asians at 5 percent. Hispanic enrollment was 4 percent in FY 2011 and 5 percent in FY 2012.
Dr. Collins also presented data on success rates by gender and type of application in NIH and NIMH applicant pools. Success rates are equivalent for men and women for R01s. However, there are large differences in terms of the total numbers of people funded. Women constitute only 27 percent of R01 principal investigators (PIs).
In contrast, in the DIRP, although there are fewer women PIs, on average, they fare better than men in terms of salary and budgets. This might be related to time since degree and/or longer tenure at NIMH.
Dr. Lewis-Fernández noted that these data help identify where there are gaps, for example, representation of women and racial/ethnic minorities in the DIRP. He also noted that it is important to study intra-ethnic and intra-racial distinctions as well as cultural influences.
Dr. Collins noted that ORDGMH does focus on ensuring diversity of ethnic and racial groups being studied as well as understanding the significance of the differences. Dr. Simon added that some minorities make an autonomous decision not to participate in research for historical reasons and such decisions should be respected. Dr. Collins responded that it is important to convey to people that there can be benefits to research participation, and therefore it is important to make sure that all people who want to participate can. Dr. Areán said that great strides have been made in recruiting minority populations in Alzheimer’s research by clearly communicating with that population, ensuring they understand the research, and demystifying some of the issues that have concerned minorities over time.
Dr. Hyman urged the Institute to consider requiring applicants to explain the logic of their sampling frame as well as who did not agree to participate and why.
Dr. Wang said that there is broader interest at NIH in workforce issues. The Advisory Committee to the NIH Director has endorsed an effort to enhance the scientific workforce through greater diversity. There is also an initiative to examine whether there is bias in the peer review process.
Following the discussion, NAMHC members voted their concurrence that the data are in compliance with the requirement to include women and minorities in clinical research.
Division of Adult Translational Research and Treatment Development: Portfolio and Priorities
In response to Council’s call for periodic updates on the division priorities and progress towards those priorities, Dr. Cuthbert was asked to give Council an overview of his division, DATR. Dr. Cuthbert summarized the programs in his division and how they relate to other NIMH divisions focused on basic science and services research. DATR receives 18 percent of the NIMH budget (approximately $263 million in FY2012).
The Adult Psychopathology and Psychosocial Research Branch focuses on psychosocial aspects of mental disorders, psychosocial mechanisms, new psychosocial treatments, and measurement and psychometrics of behavioral functions. The Clinical Neuroscience Branch includes programs in neuroimaging, molecular and cellular processes, new experimental therapeutics, and new device development. The Geriatrics Research Branch focuses on late life aspects of disorders that tend to occur across the lifespan, but also on those newly arising later in life. The Traumatic Stress Research Program funds a portfolio of grants and works on inter-agency efforts such as Army STARRS, the response to Sandy Hook, and the response to Hurricane Katrina. The Training Branch comprises a large portion of the division and handles many training components: 55 percent of the training funds go to mentored-K awards to junior investigators. These are significant awards in that they propel investigators toward a first R01 grant—50 percent of first-time R01 awardees have received mentored K-awards. Training grants to institutions (T32) constitute one-third of the budget and the remainder goes to R25 educational programs and individual fellowship programs to undergraduates and to pre-doctoral and postdoctoral investigators.
The goal of DATR is to move away from the paradigm in which disorders are diagnosed by symptoms only and episodes are treated rather cured, toward one in which the fundamental mechanisms of illness are understood and treatments are developed based on science and the unique features of the individual. RDoC is a centerpiece of this mission in that it aims to assess disorders more in terms of fundamental neural systems and the behavioral functions that they implement rather than on diagnostic criteria based on symptoms. This approach can parse the current categories of disorders into subcategories or into new dimensions of function, since it is recognized that current disorders are very heterogeneous and involve many different mechanisms. This will allow the study of disorders in terms of fundamental mechanisms, from neuroscience and behavioral science perspectives, to better understand pathophysiology and psychopathology. With that in hand, one can proceed to develop biomarkers and “psychomarkers” to measure fundamental mechanisms. Ultimately, clinical trials will be focused on specific dimensions with the goal to find precise indications for treatment.
The next step is to use an experimental medicine framework to move more quickly into humans to assess efficacy with respect to these sub-categories or functional dimensions. This approach has been called “precision medicine” by the Institute of Medicine, in which a large number of measures such as exposure to the environment, signs and symptoms, genomes, epigenomes, microbiomes, and other data are combined to develop precisely targeted therapies for a given individual.
Dr. Cuthbert provided some examples of research being supported to better ascertain individual differences. One involves measurements of overall reactivity, which can be identified in neural imaging as well as through assessments on various types of behavioral tasks. These assessments could be applied, for example, to understanding heterogeneity in post-traumatic stress disorder (PTSD), that is, why some individuals are more severely affected than others.
Another example is the EMBARC study (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care), which is evaluating differences in the response to treatment for depression. Investigators are collecting a large number of candidate markers at baseline and one week later to see if examining the change from baseline to one week will predict who will respond to a particular drug. The goal is to develop a biosignature for use as a differential treatment response index that can then be deployed to guide treatment and shorten the time it takes to know who will respond.
Another study maps out the spectrum observed in serious mental illness across a variety of factors, from DNA structural variants to lower-level biological systems, molecular and cellular factors, synaptic processes, influence of the environment, and major normal systems. All of these variables normally function to promote effective adaptive behavior, but when things go awry a variety of these factors and symptoms overlap with each other and result in the type of spectra seen in neurodevelopmental pathology. Mapping the spectrum helps point the way to understanding heterogeneity and developing targeted treatments. As another example, the Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) consortium uses continuous performance task measurements to study context processing and working memory in schizophrenia. This tool is now available for use internationally.
Dr. Cuthbert then summarized some recent findings from funded research. First, results from the North American Prodromal Longitudinal Study (NAPLS) show that the strongest predictor for conversion to psychosis in high-risk groups is loss of gray matter in dorsal and ventral aspects of the frontal cortex. This loss of gray matter creates an overall biosignature that could be combined with other biomarkers to potentially assist in early interventions.
Second, the Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP) is a large study tracking measures to assess executive control, intelligence, ability to direct operations, and sensory motor reactivity. Performance along these three measures is related to gray matter loss. Variability in performance across the measures demonstrates the heterogeneity among patients. These data can then be combined with other data, for example, functional gene groups or aspects of synaptic functioning, to better inform what had previously been viewed as broad, opaque disorders.
Dr. Cuthbert concluded that these types of studies provide opportunities for looking from prodrome and “pre-prodome” all the way into the services sector. He added that synaptic biology is critical to understanding everything across their portfolio, for example what happens with different genetic polymorphisms, to epigenetic mechanisms, to reactions to stress. Other programs include Fast-Fail Trials, to be presented by Dr. Hyman, and the Rapidly-Acting Treatments for Treatment-Resistant Depression (RAPID) study, involving the efficient evaluation of treatments for rapidly-acting treatments for severe treatment-resistant depression. This type of study involves a continuous intervention selection process seeking robust proof-of-concept data.
In summary, Dr. Cuthbert said that DATR is focused on new concepts and ways of thinking about disorders through an integrative neural and behavioral systems framework, in order to recast the search for biomarkers and psychological measurements to inform new approaches to treatment.
Dr. Hyman said that the RDoC program offers a new opportunity to look at resilience and recovery. Dr. Cuthbert responded that because the framework starts from a normal functioning perspective that includes resilience, disease is being defined as when resilience-protective factors breakdown into dysfunction.
Kay Redfield Jamison, Ph.D. asked how suicide and temperament impulsivity are addressed within the division’s portfolio. Dr. Cuthbert responded that the division has a strong program in the synaptic biology of suicide including postmortem studies. Investigators study various aspects of under-controlled behavior and in the neural imaging of impulsivity in the Clinical Neuroscience Branch. Other projects focus on actual aggression and the psychological aspects of impulse control and failures of impulse control.
Update from the National Advisory Mental Health Council FAST Working Group
Dr. Wang opened the session by explaining that at the September 2012 Council meeting members encouraged NIMH to quicken its pace in terms of target engagement and developing new interventions. In response, three new contracts for clinical trials have been issued to support a search for targets and compounds in three areas: autism spectrum disorders, psychosis spectrum, and mood and anxiety disorders. Dr. Hyman, Co-Chair, Director, Stanley Center for Psychiatric Research, Broad Institute, was asked to chair the FAST Working Group. He provided an update on the activities of the group.
Dr. Hyman said that it will take at least a decade to turn fundamental knowledge, whether it is molecular mechanisms or phenotyping, into treatments. Despite advances in some psychotherapy, deep brain stimulation, and other forms of modulation, drug treatments have only improved in terms of safety and tolerability since the 1950s. In other words, the best antidepressants available today are no more efficacious than the prototype antidepressant discovered in 1957. Clozapine was discovered in the early 1960s and nothing has equaled it since. Lithium, still in use, was first identified as potentially therapeutic in 1949. What is needed is more rational treatment design, but the pharmaceutical industry is not investing in this field. Of all drugs that make it into phase I trials in the central nervous system only 8 percent receive regulatory approval; many of those are “me-too” drugs. Many companies have exited this area of drug development. Many drugs fail in phase II or III because the indications are based on the artificial categories found in the Diagnostic and Statistical Manual (DSM).
Dr. Hyman noted that it is critical to not only fail fast but also fail smart; that is, having tested a hypothesis. We should learn from the results regardless of the outcome. The strategy is to focus on early-phase trials, demonstrate target engagement, link target engagement in measures of brain activity, and where possible, align with RDoC principles. Dr. Hyman reiterated that the FAST Working Group was charged to advise Council on the process to select the most promising molecular targets and compounds. The Working Group has formed sub workgroups for each disorder spectrum and is in the early stages of investigators bringing forth candidate targets and candidate compounds.
Dr. Barch asked whether there was to be any emphasis on the development of PET ligands. William Potter, M.D., Ph.D., Advisor to the NIMH Director, clarified that if a ligand is close to becoming an available tool, there will be a means for matching ligands with compounds.
It was clarified in response to a question from J. David Sweatt, Ph.D., that the investigators will put forward a list of compounds for consideration by the FAST Working Group and NIMH officials. Dr. Sweatt also asked whether endophenotypes would be a focus of successful outcomes. Dr. Hyman replied that the goal is to work within the RDoC framework. Dr. Cuthbert further clarified those clinical outcomes measures, such as working memory, can be used to assess efficacy.
With regard to repurposing existing compounds, Dr. Lewis-Fernández asked how proprietary concerns were being addressed for those compounds held by industry. Jill Heemskerk, Ph.D., Deputy Director of DATR, replied that NIMH is negotiating with companies, and groundwork already laid by the National Center for Advancing Translational Sciences has paved the way for working with compounds that hit particular targets. The goal is to develop enough new information about these compounds that industry will be interested in picking them up for trials and development. Dr. Heemskerk said that the FAST Working Group will be monitoring progress on the contracts and will report to Council.
Dr. Tamminga asked how NIMH would ensure the best molecular targets are incorporated into FAST trials. Dr. Potter responded that the entire NIH portfolio, not just NIMH, is considered when identifying molecular targets in the brain that might be relevant to brain functioning.
Dr. Simon asked how the trials would recruit subjects who will be the most informative while waiting for RDoC to be completed. Dr. Hyman suggested that investigators be asked to consider this question. Dr. Cuthbert added that it is important to clarify and be able to measure the actual impairment you are trying to treat and then only include those who have measurable deficits on that particular construct. The aim is to have a more specific mechanism-based orientation than just relying on a broad DSM classification.
Randall Carpenter, M.D. noted that in testing a whole new class of compounds, animal models should not be used when there is no human correlate for testing efficacy. Drug companies are unlikely to invest in compounds that are based on irrelevant effects in, for example, the mouse.
Dr. Hyman concluded by saying that although currently available drugs are effective, they are not ideal and do not help clinicians who are dealing with vast heterogeneity and comorbidities. In mental illness, the human model is essential when it is both pragmatic and ethical. Animal models, if used wisely, as well as cellular models, will continue to be essential.
Progress Report from the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS)
Dr. Wang opened the session by noting that the Army STARRS program is not the first time that NIMH been asked to attend to the urgent mental health needs in the military. During World War II, the military sought a way to screen for those who are not fit to serve, and also to identify those who were suffering from ‘shell shock,’ which we now refer to as PTSD. Several years ago, the Army approached NIMH asking for help in developing a speedy response to the growing rates of military suicides. The Army did not want a long-term study; rather, the military needed a rapid approach to unraveling the disease mechanism, finding modifiable determinants, testing interventions rapidly, and then pushing them out to field.
James Churchill, Ph.D., Office of the Director, NIMH serves as the program official for this large project and Michael Schoenbaum, Ph.D., Office of Science Policy, Planning and Communications, serves as the science official for this larger project and are invited here today to summarize the Army STARRS program to date.
Dr. Churchill said that in 2012, there were 349 confirmed suicides across the military. As of 2004, the suicide rate in the Army was significantly lower than in the general population for the relevant age/sex groups, but that changed in 2008 when the rate climbed above the rate for demographically matched civilians. The Army STARRS program is a partnership between Army and NIMH and is the largest study of mental health risk and resilience ever conducted among military personnel.
Army STARRS investigators are looking for factors that help protect a Soldier’s mental health and factors that put a Soldier’s mental health at risk. Army STARRS is a five-year study that will run through 2014; however, research findings are reported as they become available, so that they may be applied to ongoing health promotion, risk reduction, and suicide prevention efforts. Because promoting mental health and reducing suicide risk are important for all Americans, the findings from Army STARRS will benefit not only Servicemembers, but also the nation as a whole.
Dr. Churchill described the many components of this large set of studies. Army STARRS investigators are using five separate study components—Historical Data Study, New Soldier Study, All Army Study, Soldier Health Outcomes Study, and Special Studies—to identify factors that help protect a Soldier’s mental health, and factors that put a Soldier’s mental health at risk.
Historical Data Study
In the early stages of Army STARRS, investigators launched the Historical Data Study. This component involves examining more than a billion lines of data from the de-identified historical health and administrative records of more than 1.6 million Soldiers who were on active duty between 2004 and 2009. Researchers hope to detect risk and protective factors related to psychological resilience, mental health, risky behaviors, and suicide.
All Army Study
In January 2011, the research team began using surveys to gather information directly from active duty Soldiers (including mobilized Army Reserve and Army National Guard) who volunteer to participate in the All Army Study. This component of Army STARRS assesses Soldiers' psychological and physical health; events encountered during training, combat, and non-combat operations; and life and work experiences across all phases of Army service. Researchers are using this information to determine how these various factors affect Soldiers’ psychological resilience, mental health, and risk for self-harm.
New Soldier Study
Army STARRS researchers also are inviting new Soldiers just entering the Army to volunteer for the New Soldier Study. Using a survey, neurocognitive tests and blood collection, researchers are assessing the health, personal characteristics, and prior experiences of new Soldiers as they begin their Army service. The New Soldier Study began in February 2011.
Soldier Health Outcomes Study (SHOS-A & B)
This component is actually two case-control studies. Each study compares participants who have exhibited suicidal behavior (cases) with those who have not (controls). SHOS-A focuses on Soldiers who have attempted suicide and are admitted to a medical treatment facility. SHOS-B focuses on Soldiers who have committed suicide and involves interviews with next of kin and Army supervisors. Both studies will attempt to identify characteristics, events, experiences and exposures that predict negative (or positive) health and behavior outcomes. SHOS-A began in November 2011, SHOS-B began in March 2012.
Dr. Schoenbaum described the Historical Data Study in greater detail. There are 1.6 million soldiers in the study population, including those who served on Active Duty between 2004 and 2009, to include Army and activated Guard and Reserve soldiers. The start date of 2004 was selected because the Army is comfortable that homogeneous reporting began at that time. Data are derived from roughly 39 Army/Department of Defense (DOD) databases and all data are de-identified before being delivered to the study. In all, there are more than 1.1 billion data records, containing rich information on Servicemembers' characteristics, exposures, experiences, tests, aptitude scores, deployments, promotions, disciplinary history, encounters with the criminal justice system, HIV status, drug test results, history of household violence, performance on training tests, and health records. However, detailed data are only available for time periods when personnel are on active duty Army service. Approximately 80 percent of the 100,000 members of the prospective cohorts for which there will be linkage to administrative data have consented to such linkage.
The team is developing risk models to can help lower Army suicide rates. One example focuses on non-deployed Army soldiers who have received a psychiatric diagnosis and/or received a psychotropic prescription in the previous 3 months. This amounts to 363,000 soldiers at any point in time, with a total of 411 suicides in this group over the six-year period 2004-2009. That amounts to a suicide rate of 19/100,000 person years. Applying the single filter of recorded psychopathology and/or receipt of a psychotropic medication reduces the population to 63,000 soldiers, with a total of 215 suicides during 2004-2009, for a suicide rate of 57/100,000 person-years. Thus, more than half of all the suicides in the group accrue in this smaller sub-population based on this one filter. This is an average suicide risk that is three times that of the overall population. If then one uses additional filtering information (e.g., demographic information, family composition, deployment history, more detailed medical information), suicide risk can be predicted based on the model; then we can rank soldiers from the highest predicted suicide risk, based on the algorithm, to the lowest. Each filter isolates a subgroup with a higher projected risk. The goal is to ultimately allow the Army to view its large population and based on a defined phenotype identify and target certain soldiers with more intensive and careful intervention in a way that could not be done for an undifferentiated group.
Dr. Simon said that in gathering data from large health systems as part of the Mental Health Research Network, they have found that the Patient Health Questionnaire (PHQ9) depression score, which includes a question about suicidal ideation, predicts people who have a suicide attempt at a rate 10 times higher than those who score low on that item. Thus, it is a useful discriminator. He also said that clinicians report that some patients consistently score high in that category, whereas others fluctuate, which could suggest some form of resilience or adaptation. These factors can only be studied when we move from between-person to within-person comparisons. However, some who score zero still attempt suicide shortly afterwards, suggesting there is a “surprise suicidal behavior” which must be studied. Thus, some people might need to be assessed more frequently.
Dr. Schoenbaum noted that if an individual has had one previous suicide attempt, the risk for a second and dying from it is very high. However, if one attempts 15 times without succeeding, the risks of succeeding are low. So even if PHQ9 is not a failsafe discriminator, it is better than none. He added that the risk model being developed identifies populations of people who then warrant individualized assessment.
Dr. Robinson Beale asked if there had been any increase or changes in the percent of the recruit population that entered service with a mental health or substance abuse diagnosis. Dr. Schoenbaum said that during the surge in 2005 through 2007, the Army granted accession waivers to some individuals who would not otherwise have met recruiting standards. However, the receipt of such waivers does not correlate with suicide death. In addition, there has been a rise in prevalence over time of psychiatric diagnoses and the use of psychotropic medications within the Army. This is in part because of an increased focus on identifying these issues and in trying to reduce stigma in seeking care. However, possible correlative associations will be examined.
Dr. Lewis-Fernández asked if there was a plan for the half of the suicides that are not captured by the model. Dr. Schoenbaum clarified that the model presented was a proof-of-concept and that further analysis will focus on less obvious indicators of risk, for example, soldiers who deploy within a year of entering the Army, which should not happen.
Dr. Tamminga noted the advances that have been made in knowledge about military mental health and asked whether suicide attempts are more successful than civilian suicides. Dr. Churchill noted that because 85 percent of the military is male and has access to guns, that might be true but there are no data to support it at this point.
In response to a question from B.J. Casey, Ph.D. about availability of forensic data following suicide, Dr. Schoenbaum explained that although a toxicology screen is done as part of the autopsy, neuropathology is not assessed as a matter of course. The Armed Forces Medical Examiner System is attempting to build a brain bank for such studies.
Dr. Jamison asked if data are available on time of antidepressant prescription and suicide and whether family histories are obtained. Dr. Schoenbaum responded that family histories data are collected as well as claims data, so temporal relationships can be assessed. Those who receive a psychiatric medication and no psychiatric diagnosis have systematically lower suicide risk than people who received both a psychiatric diagnosis and no medication or people who receive both a psychiatric diagnosis and a medication.
Dr. Churchill clarified for Dr. Sweatt that efforts are made to minimize stigma, for example, information is never shared within the chain of command. Dr. Schoenbaum added that suicide is a rare event even in high-risk groups.
In response to a question from Gene Robinson, Ph.D., Drs. Churchill and Schoenbaum stated that there are plans to follow soldiers post-separation. Ira Katz, M.D., Ph.D., Department of Veterans Affairs (VA) added that the VA is addressing high risk for suicide among veterans, developing prevention programs, and integrating mental health services with primary care.
Mr. Heimer asked if there was a plan to anticipate the effect of drawdown of the Force as well as apply what is learned to the civilian sectors. Dr. Schoenbaum explained that the Army will carry the work forward into the years 2010-2012. Discussions are ongoing within NIMH on how to apply these methods to the more limited data available on civilian populations.
Dr. Wang noted that there could be lessons learned from Army STARRS for gun violence in terms of identifying risk factors and critical periods.
Beverly Pringle, Ph.D., Chief, Child and Adolescent Mental Health Services Research Program, Division of Services and Intervention Research, presented a concept for clearance, Services for Autism Spectrum Disorders Across the Lifespan (ServASD).
As the prevalence of autism spectrum disorder (ASD) diagnoses in the United States increases, so does the need for a science-base on which to build optimal, integrated service systems that provide early diagnosis and engage people with ASD in developmentally appropriate care to reduce symptoms; enhance functioning; and, improve health, safety, and quality of life across the lifespan. ASD begins in early childhood. It also affects growing numbers of youth and adults, as children with an ASD diagnosis age into subsequent stages of life. The ASD diagnosis is shared by people who vary widely in abilities and symptoms. This heterogeneity in presentation, coupled with development over time, has expanded understanding of ASD, including the wide variation in service needs and attendant service delivery challenges across individuals and over the lifespan. While there has been considerable progress in biological research on ASD, important knowledge gaps in the provision of effective services and supports for people with ASD persist. For example, available tools for identifying ASD early are not widely used; only a fraction of children with ASD are identified in the first years of life, which is of particular concern given evidence that early intervention can change the course of ASD by raising IQ levels and improving language skills and behavior. For youth with ASD, exiting high school is associated with a steep decline in receipt of services and with disparities in service use on the basis of race, socioeconomic status, and mental skills. Scientific evidence about effective services for adults with ASD is underdeveloped, and the extant research does not adequately reflect impairment heterogeneity, the range of service needs, and the necessity for coordination across service sectors.
Accordingly, the state of the science on care and service delivery for ASD differs at these three stages. For very young children, there is a critical need for effective strategies to consistently and comprehensively identify those with ASD and link them to treatment at the earliest age possible. For youth with ASD who are “aging out” of the services and supports delivered via K-12 education and other child/adolescent service systems, research is needed on how to help them realize capacity for independence, to the extent possible, and optimize normative functioning in the adult world of continuing education and training, meaningful work, independent living in the community, and social support services. New research should incorporate effective services strategies to reduce or eliminate documented racial, ethnic or gender disparities in the identification of ASD and the receipt of intervention services. It is time to yoke together education and social science, and mental, behavioral, and physical health sciences in a concentrated effort to achieve these goals by focusing research on the service needs and research gaps associated with specific age groups. The goal of this initiative is to support research to develop and test the effectiveness of services strategies to improve functional outcomes and quality of life for people with ASD at three key life stages: early childhood, transition from youth to adulthood, and adulthood.
Dr. Barch said that by focusing only on school-based children with ASD for transition planning, many youth with ASD would be missed. Dr. Pringle said that schools are a logical place to begin since transition planning is required, and that the team will consider how to resolve that issue.
Dr. Hyman cautioned against considering all ASD together and the need to recognize that the needs of those with intellectual disability will be different from those who are high functioning. Dr. Pringle agreed and added that the needs of racial and minority populations, as well those in low socioeconomic backgrounds, will be considered.
Drs. Casey, Hyman, and Lewis-Fernández asked staff to consider redundancy with other programs and to address which populations will not be captured based on the current plan. Dr. Casey also urged staff to look at what is being done in other psychiatric disorders.
Dr. Wang closed the session by noting that as this concept develops, staff may bring more information forward to Council and that all concepts are pending budget decisions. Council concurrence through the presentation can allow staff to start developing the concepts further to create some exciting opportunities.
Dr. Wang invited members of the audience to make any comments to the Council. Hearing none, Dr. Wang thanked all who participated in the meeting. He recessed the open session meeting at approximately 1:00 p.m.
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
- Paolo del Vecchio, M.S.W.
Center for Mental Health Services