NAMHC Minutes of the 231st Meeting
National Advisory Mental Health Council Minutes of the 231st Meeting
May 17, 2012
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 231st meeting in open policy session at 8:30 a.m. on May 17, 2012 in the Neuroscience Center in Rockville, Maryland, and adjourned at approximately 12:30 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 1:15 p.m. on May 17, 2012, at the Neuroscience Center in Rockville, Maryland, until adjournment at approximately 5 p.m. (see Appendix A: Review of Applications). Thomas R. Insel, M.D., Director, National Institute of Mental Health (NIMH) chaired the meeting.
Council Members Present at the Grant Review and/or Open Policy Sessions
(See Appendix B: Council Roster)
Chairperson: Thomas R. Insel, M.D.
Executive Secretary: Jane A. Steinberg, Ph.D.
- Virginia Trotter Betts, M.S.N., J.D.
- Randall L. Carpenter, M.D.
- Ralph J. DiClemente, Ph.D.
- Howard B. Eichenbaum, Ph.D.
- Lisa Greenman, J.D.
- Steven E. Hyman, M.D.
- Portia E. Iversen
- Roberto Lewis-Fernández, M.D.
- Thomas H. McGlashan, M.D.
- Steven M. Paul, M.D.
- Rhonda Robinson Beale, M.D.
- Gregory E. Simon, M.P.H., M.D.
- Carol A. Tamminga, M.D.
Ex Officio Members:
- Ira Katz, M.D., Ph.D., Department of Veterans Affairs
Liaison Representative at the Open Policy Session:
- Paolo del Vecchio, M.S.W., Acting Director, Center for Mental Health Services
Others Present at the Open Policy Session:
- Michael Bowers, American Association for Marriage and Family Therapy
- Yoshie Davison, American Academy of Child and Adolescent Psychiatry
- Danielle Hunter, Dixon Group
- Alan Kraut, Association for Psychological Science
- E. James Morton, Treatment and Research Advancements Association for Personality Disorders
- Mathild Schneider, Treatment and Research Advancements Association for Personality Disorders
- Jerilyn Schweitzer, Science Writer
- T.J. Shoneck, Tunnell Government Services
- Andrea Silva, American Academy of Child and Adolescent Psychiatry
- Shannon Skowronski, Administration for Community Living, Department of Health and Human Services
- Andrew Sperling, National Alliance on Mental Illness
- Karen Studwell, American Psychological Association
- Trevor Summerfield, American Foundation for Suicide Prevention
- Nancy Moy Yuen, SRI International
Open Policy Session: Call to Order and Opening Remarks
NIMH Director Dr. Insel called the open policy session to order and welcomed everyone in attendance.
Approval of the Minutes of the Previous Council Meeting
Dr. Insel asked the Council members for comments on the minutes from the January 2012 Council Session. Receiving none, the motion to pass the minutes was unanimously approved.
NIMH Director’s Report
Dr. Insel reviewed several ongoing activities at the Department of Health and Human Services (HHS) and National Institutes of Health (NIH) since the January 2012 NAMHC meeting.
HHS and NIH-Wide Updates
Dr. Insel highlighted the reauthorization of the Interagency Autism Coordinating Committee (IACC) , a Federal advisory committee that coordinates all efforts within HHS concerning autism spectrum disorder (ASD). Through its inclusion of both Federal and public members, the IACC helps to ensure that a wide range of ideas and perspectives are represented and discussed in a public forum. The committee membership was announced at the beginning of April, and the first meeting will be in July 2012.
At the NIH-level, Dr. Insel highlighted activities of the Common Fund committed to developing tools that are transformative and cut across many different areas of science. The Common Fund’s Early Independence Awards, which aim to foster innovation by providing independent funding to new Ph.Ds. by enabling them to skip post-doctoral positions in favor of early research independence, will likely award 15 grants in fiscal year (FY) 2012, as in FY 2011.
Dr. Insel noted that the Common Fund is looking for ideas that are transformative and synergistic. While funding for FY 2013 has already been committed, about 25% of the funds for FY 2014 will be open for new areas of research, and the NIH Office of the Director is starting to solicit ideas for FY 2014. At this stage, the Common Fund is casting a wide net to solicit interesting and innovative ideas, which will be winnowed down by a group of Institute and Center directors before going to an ultimate review by the Council of Councils.
Turning to the issue of replicability of research findings, Dr. Insel discussed the contention that results published in the best journals from academic labs often cannot be reproduced. Although this does not indicate the research is fraudulent, it may highlight the extreme complexity of biological research; even slight changes in procedure may lead to different results. Recent articles in Nature Reviews Drug Discovery and Nature have underscored the extent of the problem in both medicine and psychology, suggesting that the scope of the problem is greater than the scientific community may realize.
Moreover, at NIH’s Senate Appropriations Committee hearings, Richard Shelby (R-Ala.), the ranking minority member, asked NIH Director Francis Collins, M.D., Ph.D. about research replication. Dr. Insel concluded by stressing the necessity of figuring out how much of the issue may be due to true biological variation, to non-robust findings, to less-than-rigorous laboratory work, or to researchers rushing to publish.
There will be a series of meetings during the next several months to address these issues, one led by the National Institute of Neurological Disorders and Stroke (NINDS), and another that NIMH and the National Cancer Institute (NCI) will lead together. Most of the literature on non-replication has been in the field of cancer research, though there have been articles concerning neurological diseases as well. Suggestions to address the issue include developing a process of much more open data access, data sharing, and parallel projects.
In other news, Dr. Insel continues to serve as the Acting Director of the National Center for Advancing Translational Sciences (NCATS). He thanked Jane Steinberg, Ph.D., NAMHC Executive Secretary and Director of the Division of Extramural Activities at NIMH, Marina Broitman, Ph.D., Acting Referral Officer for NCATS, and Linda Brady, Ph.D., Director of the Division of Neuroscience and Basic Behavioral Science (DNBBS) at NIMH, for all of their hard work getting NCATS up and running. He added that NCATS is beginning to provide useful insights to other ICs. The role of NCATS is to enable new ideas as well as new tools by accelerating a linear approach of pushing discoveries from bench to bedside, to practice, and on to policy. One of the first insights to come from NCATS has been to challenge the idea of linear progress and to suggest a more circular, holistic approach by recognizing that the most important insights often go from bedside back to bench or clinic back to bedside.
Dr. Collins and the HHS Secretary, Kathleen Sebelius, announced two weeks ago that through the NCATS Drug Rescue Program led by Dr. Brady, NCATS has formed a partnership with three pharmaceutical companies: AstraZeneca, Eli Lilly, and Pfizer, which will make compounds available to academic labs where they may be developed for new targets. This program is just one example of the work of NCATS; it represents the hope that by starting with only a very small group of compounds from a few companies, this “virtual medicine cabinet” will quickly grow into a program with many companies and, hopefully, scores of compounds.
Dr. Insel remarked that although the budget for FY 2012 is flat in comparison to FY 2011, FY 2013 is completely uncertain. We may see another flat budget, which many people consider the best possible outcome. One metric often used to describe the budget is the number of new and competing grants NIMH can award in a year. In FY 2011, NIMH had 465 new awards, much lower than typical, but FY 2012 appears to be on par with where NIMH has been for the past decade, which is around 530-550 grants. In FY 2013, if the budget is flat or even at a 2% cut, NIMH will continue to have a robust portfolio that is on par with recent years. That said, if the budget is cut 8%, far fewer new and competing applications will be funded.
Dr. Insel said that NIMH is trying to prepare for various budget scenarios through careful management of FY 2012 commitments. One way NIMH is doing this is by being mindful of the out year commitments on current awards. Given the potential for a budget reduction in FY 2013, NIMH has invested some of its FY 2012 funds ($15-$20M) on shorter term one-year commitments through administrative supplements. NIMH issued a notice announcing the availability of supplemental funds for research in four areas of particular interest: neural connectivity in development and aging; data sharing, standardization, and integration; biomarkers, particularly those linked to clinical trials; and public health impact, by asking services researchers to build in cost analyses to existing studies. NIMH also funded several unsolicited administrative supplements, and continues to fund diversity supplements and other one-year commitments.
A new NIH-wide pilot policy generated by the FY 2011 Appropriations Bill calls for a special council review for applications from any applicants with greater than $1.5M in total research project grants in a given year. This new policy does not enforce a cap on funding, but does require a separate discussion at Council to ensure that this will be money well spent. The policy resembles the current internal NIMH policy, in which NIMH discusses grantees with more than four or five grants before awarding another grant. This NIH-wide policy is being piloted at the May Advisory Council meetings.
Dr. Insel reported on several current challenges for NIMH. The first includes the needs of service members and veterans. While a partnership continues with the U.S. Department of Veterans Affairs (VA) and the U.S. Department of Defense (DOD), NIMH has a new partner in the non-profit One Mind for Research coalition, led by retired U.S. Army General Peter Chiarelli, formerly the Vice Chief of Staff of the Army. General Chiarelli had previously collaborated with NIMH on the Army Study to Assess Risk and Resilience in Service-members (Army STARRS) project.
A second challenge is medical morbidity and mortality observed in people with serious mental illness (SMI), particularly given data showing that people with SMI have a shortened life expectancy. NIMH’s Division of Services and Intervention Research (DSIR), Program Officers Denise Juliano-Bult, M.S.W. and Susan Azrin, Ph.D., are co-organizing a meeting later this fall with various stakeholders to address what science to focus on, clarifying science versus service needs, and whether SMI should be considered a health disparity population. Council member Roberto Lewis-Fernández, M.D. has also been quite involved in this meeting.
Another challenge is the issue of diagnosis from a precision medicine approach, which has garnered considerable media attention, specifically in light of the upcoming publication of the fifth edition of the Diagnostic and Statistical Manual of Mental
Steven Hyman, M.D., praised NIMH’s approach to taking on the issue of non-replicability by first trying to define the problem. He suggested that the problem is complex, and agreed that making all data publically available is critically important. He added that another issue involves biological variability, with reference to how reagents are handled by labs. Although nobody wants to do this, he noted, it seems essential to figure out ways to verify reagents or even re-sequence plasmids to address the problem of experiments undercut by junk input materials. The third issue is that unlike clinical scientists, basic scientists do not learn study design, including blinding and statistics, and educating them in a basic understanding of even such simple issues might be helpful.
Dr. Insel replied that NINDS is going in that very direction and has developed a set of standards that require blinding, randomization and other similar methods for their preclinical studies. He agreed that the type of scientific rigor that comes with clinical trials is not always found in basic science laboratories and needs to be included.
Steven Paul, M.D., agreed that the issue of reproducibility is extremely important. He described a natural selection process by which important findings that do not get replicated within five years of publication are forgotten. He wondered whether the government could be more proactive in following up on important studies, perhaps by funding a lab to reproduce them in a timelier manner.
Rhonda Robinson Beale, M.D., voiced support for Dr. Paul’s point. She added that at the applied level, research must be replicated in order to ensure insurance reimbursements, and therefore it is important to have reproducibility as part of the protocol. She suggested meeting with those in the publishing industry to try and convince them of the importance of reproducibility to the actual application of a given technology.
Dr. Insel agreed that this was a great idea and mentioned that a new journal, called eLife, will be emerging this summer. It will be funded through the Howard Hughes Medical Institute, the Wellcome Trust, and the Max Planck Institute, with the purpose of providing the highest profile publication to papers that might be replications. It will require that all of the data from the papers be made public at the time of the publication of the results. He added that this might help address the problem, because someone could try to reproduce the results using the original data from the article.
Based on her past experience as an NIH grantee, Carol Tamminga, M.D. wondered whether NIMH might engage in creating basic databases and directing people to validated start points in experiments with the thought of addressing the problem with replicability.
Dr. Insel said that that this made a good future agenda item for the NAMHC. He cited the example of how NIMH Senior Advisor Roger Little, Ph.D. called a meeting to discuss brain banking to address the issue of efficiency. When Dr. Little found that there was no universal registry, standardization, or database, he instituted the federalization effort to create a central database with standardized collection procedures and broad access. A centralized database of this sort would ensure that tissue samples are standardized and widely available. Dr. Insel added that this method can be applied in a number of other areas, as well.
Dr. Lewis-Fernández commended NIMH for the planned meeting on individuals with SMI, an issue of both clinical and political importance. He emphasized the importance of collaboration between different institutes, and noted that one topic of great importance that has not received as much attention as research on the causes of SMI, is implementation. He added that there is still a lot of work that needs to be done in services research.
Dr. Insel said that an economic perspective on the issue is needed, and that mental illness can be considered a gateway disease based on its link to a number of physical disorders, including chronic pulmonary disease, metabolic diseases and diabetes and its complications. It appears that nobody truly understands the economic consequences of mental illness. Even the World Economic Forum report that came out September 2011 demonstrating the global burden of mental illness did not include a link between all of the other illnesses for which mental illness is a contributing factor.
Introducing himself as a representative of the VA, Ira Katz, M.D. Ph.D. pointed out that the VA can and should be a resource. He explained that Amy Kilbourne, Ph.D., a health services investigator shared between NIMH and the VA, found no mortality gap in the VA system as a whole, although she did find tremendous facility-by-facility and region-by-region variations. The VA is wrestling now with whether this is a matter of physiology or quality of care. Dr. Katz concluded that the VA may be able to contribute to the upcoming NIMH meeting, and that the VA can be a resource for moving forward.
Dr. Insel introduced Bruce Cuthbert, Ph.D., Director of the Division of Adult Translational Research and Treatment Development (DATR), to present a summary of the NIMH RDoC project. Dr. Cuthbert began with a summary of DATR’s mission: to gain a better understanding of the pathophysiology and psychopathology of mental disorders, to develop and refine biomarkers and behavioral assessments for these disorders, and to develop more effective interventions in the areas of pharmaceutical development, behavioral therapies and medical device interventions.
The immediate obstacle to achieving DATR’s mission is that mental disorders are currently defined on the basis of presenting signs and phenomenology, rather than on knowledge about brain and behavior generated by recent decades of research. The diagnostic system was developed to improve reliability across labs and clinics for diagnoses, but the categories have proven progressively invalid as disease entities. Each disorder has been shown to have numerous mechanisms, while any given mechanism, like fear circuit activity or working memory, cuts across many different disorders. This situation leads to the paradox inherent in our current research approach: we will never have circuit-based approaches to our disorders until we have a database that can inform such an approach, but we will never have that kind of database as long as we continue funding research based on our current diagnostic system.
This paradox is what led to NIMH Strategic Plan Strategy 1.4: to develop for research purposes new ways of classifying mental disorders based on dimensions of observable behavior and neurobiological measures. There are four components to this strategy:
- To identify those dimensions that cut across all disorders;
- To determine the full range of variation from normal to abnormal;
- To integrate genetic, neurobiological, behavioral, environmental, and experiential components; and,
- To develop reliable and valid measures of these fundamental components for use in basic and clinical studies.
Dr. Cuthbert cited the research matrix developed by RDoC, and described the five domains of brain functioning that the NIMH workgroup established: Negative Valence Systems; Positive Valence Systems; Cognitive Systems; Systems for Social Processes; and Arousal, Regulatory, or Modulatory systems. Each of these domains, which reflect the hierarchical nature of the nervous system, has some specific dimensional constructs to be associate with a particular sort of function and circuit, such as attention, fear, or working memory. Dr. Cuthbert discussed ways in which RDoC relates to traditional diagnoses. He noted that the problems associated with these disorders will still be studied, but in the context of these circuits; for example, post-traumatic stress disorder is a disorder within the Negative Valence Systems domain, relevant to the circuits of acute threat, potential threat, and sustained threat. Differences in the balance of activity in these circuits may account for some of the differences seen across patients.
Dr. Cuthbert completed the presentation with a discussion of the ways in which NIMH can move forward to encourage researchers to submit RDoC-themed applications. These methods included issuing requests for application and requests for proposals (contract mechanism) with set-aside funds and placing priority for funding on applications that explore RDoC constructs. Dr. Cuthbert concluded by asking for input from the NAMHC on how the Institute might increase the number of RDoC grants in the portfolio in order to advance translational research goals.
Gregory Simon, M.D., M.P.H. noted that he is very enthusiastic about this effort and advised that diagnostic categories have both walls and floors. Walls are what distinguish disorders from each other, and floors are that which distinguish individuals with disorders from so-called normal individuals. Wall questions are scientific questions, while floor questions are primarily cultural or political questions that tend to change over time and place.
Dr. Tamminga remarked that she is both a believer in these new concepts and a practitioner in the field, prompting the concern that one day she will have to submit a grant or a paper that justifies both RDoC and DSM criteria—indicating a need for some practical outcome to this potential issue. Dr. Tamminga also pointed out that although Dr. Cuthbert presents data as though everybody calls disorders such as schizophrenia the same thing, she has noticed that in the clinic, one tends to find the disorder that one is seeking. And now that researchers are recruiting for psychosis as a spectrum, they are getting everything in between. Researchers are really seeing a new spectrum of pathology as they recruit for spectrum instead of diagnosis.
Dr. Hyman agreed with Dr. Simon and added that you cannot set rational thresholds for treatment based on policy without an effective category. In other words, one needs a dimension of risk. He suggested that in order to go forward, researchers should be encouraged to describe all of their work across all the related disorders that might be in a cluster. He suggested that future medicine might bring together two different pathophysiological aspects, for instance insulin resistance and pancreatic function. Dr. Hyman concluded by noting that researchers will ultimately be constructing human disorders in terms of the interaction of different heterogeneous dimensions that are going to be different in people, which will seem strange to those fixed on traditional DSM diagnoses. Dr. Cuthbert replied that the terms for disorders like schizophrenia or depression can retain their usefulness, if they are understood to be syndromes; the problem is that researchers see the pathophysiology of schizophrenia as though it were solitary.
Thomas McGlashan, M.D. asked about the minimum data set needed for doing both forms of diagnosis, adding that it would help to address both how useful one system is versus the other, and to test the different categories that emerge against independent validators. Dr. Cuthbert replied that, as advocated by Dr. Hyman, the RDoC project should move forward within a chapter-wise structure, as the first phase of the experimental part of RDoC calls for: to validate the constructs and get a better idea of how the mechanisms work as they cut across disorders, with the goal being to build the kind of database that would allow us to ask Dr. McGlashan’s question.
Dr. Paul remarked that this is an incredibly important initiative, but cautioned against creating another pseudoscience with a new lexicon and new categories. He also cautioned that until the boxes in the matrix are filled, one would be making a huge leap of faith.
Dr. Insel added that we are not trying to create a nosology so much as to create a framework for research. NIMH is concerned about the gap between what we are trying to create for the future and the traditional DSM model, and the Institute is not certain of how best to make this transition. Everyone is eager for this change, based to some degree on frustration with the DSM model, and although this new system of categorization is still in its infancy, it will never come to pass unless NIMH begins funding research in this realm.
Dr. Lewis-Fernández remarked that the difficulty is that this system is meant to be both a set of research priorities and a new classification system to replace the DSM system in the future. He added that we cannot have two systems at the same time without destabilizing the field, but that at some point we need to address the “floor” by giving NIMH’s position on what is a treatable disorder and what is reimbursable by insurance. The speed with which the RDoC system takes over the classification approach depends on the success of the RDoC approach for research. He concluded that he would keep RDoC as a portion of the portfolio, while leaving in the other elements in the existing system, as well.
Dr. Robinson Beale asked whether Dr. Cuthbert could focus grant money on those entities for which he already has a great deal of information with respect to response to treatment. She added that if he did so, he would set up some powerful data that would stimulate the interest of many people, not just researchers but also the general public and funders, as well. Dr. Cuthbert responded that he hopes to find some of these “early wins” in the fear circuit disorders.
Portia Iverson said that the discussion made her think about individualized medicine, and she wondered about the difference between that and precision medicine. She also asked whether the ultimate purpose of precision medicine is to provide individuals with individualized treatment. She added that precision medicine sounds like we are just trying to make more categories under which to fit individuals, as opposed to identifying domains within which to characterize and treat individuals.
Dr. Insel said that NIMH needs to work on its language to avoid confusion on the subject. He added that enthusiasm in the field has been remarkable and the transition to accepting RDoC very rapid.
Dr. Paul added that drugs do not treat disease categories, they treat symptoms; for instance, antipsychotic drugs are not anti-schizophrenia drugs. He said that while this is very important work, we should not set up unrealistic expectations that this biology is going to advance far enough to make these categorical types of studies feasible. Dr. Insel responded that RDoC implies a different set of therapeutic targets; for example, rather than antipsychotic drugs, we will be looking for therapeutics for working memory and therapeutics for anhedonia. We will be actually changing the targets in the hope of finding more effective treatments and even rejuvenating the field of translational and clinical science.
Dr. Insel concluded that over the next couple of years, while NIMH defines what the different clusters or constructs are, the Institute is really talking about a way to organize research, not a nosology, which will probably come in five to ten years, or possibly inform DSM-VI. It will become a set of organizing principles that begin to build a different way of approaching what we now think of as symptom clusters.
A Peek into the NIMH Interventions Portfolio: The Research and Development Pipeline
Dr. Insel introduced Stefano Bertuzzi, Ph.D., M.P.H. Director of the NIMH Office of Science Policy, Planning, and Communications (OSPPC). Dr. Bertuzzi provided a broad overview of the NIMH intervention portfolio, mapping it over a canonical discovery pipeline, to understand the strengths of and gaps along the NIMH discovery pipeline, to serve as the baseline for informed discussion, and to inform strategic planning activities. Dr. Bertuzzi pointed out that he had included the areas of effectiveness research, dissemination, services research, and population epidemiology in his illustration of the discovery pipeline, which make up a significant portion of the portfolio. A portfolio analysis working group has been established, comprising members of each NIMH Division, OSPPC, and the Office of the Director (OD).
Dr. Bertuzzi picked schizophrenia to illustrate that although the disease has four phases (population at risk, prodromal, progressive, and residual), typically, intervention does not occur until well into the prodromal phase. He stated that one of NIMH’s short term goals should be to identify the risk factors, as early detection might well yield substantial improvements in future outcomes. Subsequently, patients could be engaged in treatment earlier. In the long run, NIMH needs to address the medical disorders that co-occur with many severe mental illnesses, and which may be robbing the mentally ill 8-25 years of life.
Therefore, a short term goal should be to change the trajectory of the disease to decrease the most manifest episodes of psychosis and improve overall functioning in the individual. A longer term goal might be to create diagnostic tests to identify those at risk in the population, a goal which would require a combination of approaches, including measures that look at genetic risk and possibly high-resolution imaging or cognitive tests, as well. And finally, our goal should be to eliminate co-occurring conditions that have a significant impact on the lifelong management of the disease. A possible aspirational goal might be the complete preemption of the onset of the disease.
Dr. Bertuzzi introduced Yancy Bodenstein, Chief of the Reports and Analysis Branch (RAB) of OSPPC, to provide graphical illustrations of the NIMH intervention portfolio, a product of the new portfolio analysis working group. Mr. Bodenstein presented graphs of the entire FY 2011 intervention development portfolio, using a three-dimensional ‘heat map’ with axes for the developmental stage along the discovery pipeline, the type of intervention, and the number of funded projects. The graphs included a ‘human squared quadrant’ containing behavioral-based interventions with late-stage developmental processes. The overall portfolio graph showed a robust line along the small molecule pipeline with a good activity level in preclinical, phase 1, and phase 2 areas, into the dissemination and implementation area, illustrating a nice s-shaped curve where the basic science is feeding into the clinical setting and out into services dissemination.
Mr. Bodenstein showed graphs for specific condition portfolios (schizophrenia, ADHD, anxiety disorders, and eating disorders) as well as for methods (e.g., neuroimaging). Mr. Bodenstein concluded that there is a sizeable investment in the small molecule and along the entire pathway illustrated by the slides, and a sizable investment within the human squared quadrant. In contrast, there is minimal investment in the cell-based and genetic therapies. Finally, there is a small investment with the earlier development stages of the pipeline.
Next, Dr. Insel introduced William Potter, M.D., Ph.D., from the NIMH OD. Dr. Insel noted that with his background in the pharmaceutical industry, Dr. Potter was uniquely situated to bring an industry set of standards to the interventions portfolio. Dr. Potter began by comparing treatment development in industry versus what is currently being funded in the NIMH portfolio, in terms of speed, risk, and coordination. He further explained the challenges of validating or rejecting potential drug targets, the flaws in relying on preclinical data such as exposure in animals, and the need to begin to include a consideration of RDoC criteria.
The target validation stage along the drug development pipeline provides a specific opportunity to improve consistency across labs in terms of the results, sharing of data, understanding what we are testing, and testing this up through biomarkers and drug action. By addressing these issues at this early stage will enable researchers to prove they are hitting the target in the human brain, then testing whether or not this relates to a clinical outcome or an RDoC-defined domain outcome in that space. To do that, Dr. Potter suggested that NIMH should avoid funding clinical studies without strong evidence that treatment affects the target or function in the human brain. He added that NIMH might want to require occupancy versus efficacy measures in animal models that can be analogized to humans.
Additional opportunities to improve include studying more specific and parametrically quantifiable clinical “targets” in more homogenous populations, and the timely execution and reporting of proof-of-concept studies. Dr. Potter added that NIMH should expect studies to be executed within a couple of years. For early phase studies, researchers want to fail quickly and often, and they want the tools in place to confirm their hypotheses. Biomarkers and precompetitive partnerships are essential to making this process work, because neither government nor industry can do this alone. The process is expensive and complicated, and it requires much more efficient ways of sharing data early on.
Dr. Potter discussed how to align the therapeutic goal with the target selection, and to align biomarkers with molecule progression. Ultimately, NIMH wants to align preclinical and clinical neuroscientists on common definitions and criteria for testing hypotheses and target validation, and insisting on replication of the preclinical data.
Dr. Insel noted that Dr. Potter’s presentation focused on small molecule medications and asked if Dr. Potter was suggesting the same kind of rigor for psychosocial interventions. Dr. Potter responded that he was; he was using the example of drug development, an area which has been industrialized, to think about how it could be related to the interventions portfolio. He added that the high-level concept of articulating the core idea and ensuring one has the tools and coordination necessary to test the idea and replicate the results should apply to any sort of intervention.
Dr. Hyman asked whether we know how to validate a target for polygenic neuropsychiatric disorder in humans when we lack a convincing animal model. He wondered what we would use for validation criteria. He noted that even if there is an animal model, it might be a false negative that stops you from bringing forward compounds that might work and giving you false hope for those that should not come forward. Finally, he asked if, with respect to induced pluripotent stem cells (iPSC) cells, Dr. Potter could imagine a day when one could get conviction about a target from a cellular model rather than an animal model.
Dr. Potter responded that this is a core question where the theme of setting criteria becomes the first step in being able to compare what we learn from certain animal models, what we do not learn, and what it would take to rule them in or out. He noted that at present we go around in circles because we do not have a common body of data we could use to get agreement on whether or not models are or are predictive. With iPSCs, the same question is going to arise. He added that we need to put in place a fundamental agreement of what we will mean by target validation and what the components are, so we can start ruling things in or out.
Dr. Paul remarked that it would be great to have animal models and iPSCs we could use to screen drugs. He noted the importance of getting these things into humans, and wondered whether NIMH could create a list of targets that have been quasi-validated in humans. He listed as an example of findings with strong animal data a recent paper showing that M1/M4-preferring muscarinic agonists were as effective as any of the atypical antipsychotics in schizophrenia as monotherapy. He concluded that having animal data doesn’t always correlate with effective treatments in humans.
Dr. Tamminga asked Dr. Potter for his thoughts about combining treatments and wondered if drugs alone were enough. She added that there are some dimensions she looks at as being function symptoms, like psychosis, where you can take a drug and wipe the symptom out without intending to build anything or create new function. Then there are other types of dimensions, like cognitive dysfunction in schizophrenia, where you really want to build the brain systems that subserve those functions. She asked if we need to be careful to add on the cognitive or psychosocial component along with the drug.
Dr. Potter said that Dr. Tamminga’s basic question is what one needs to have in place to test a hypothesis, and what variables need to be controlled and tracked. He continued that the high-level theme is that it gets complicated to test the hypotheses, which means additional measures, resources, and time. He described the beta amyloid hypothesis of Alzheimer’s disease, adding that this is a very expensive proposition with a $100 million investment just to develop the tools to ask the question. The real question would be whether there are some big hypotheses that require more coordinated work to move forward to testing, or whether it is preferable to see lots of peaks of involvement that somehow coalesce into an answer. It becomes a strategic question of how one manages a portfolio to ask big questions.
Dr. Insel followed up on Dr. Tamminga’s question. He noted that over the last five decades, NIMH has taken an infectious-disease model to treatment development, with the implicit notion of a magic bullet cure—and this may not be appropriate for mental illness. He asked if that is a different model, and if so, how one builds that into what we do, whether or not one calls it combined therapy.
Dr. Hyman added that a way of rephrasing the question is, ‘Do you think about adding two more arms, making the trial more expensive but more comprehensive?’
Randall Carpenter, M.D., noted that he works in a single gene disorder that is highly penetrant, in which single gene mutation does not make a single protein, and which can be modeled in animals. The protein may have a highly conserved function in the signaling pathway in animal and human models, but the effect on the circuit function is not conserved. To go forward, NIMH needs to ask if there is a drug that normalized the signaling pathway; then, as long as it is safe, test what it does in humans. He commented that this is a culture change because many people in the pharmaceutical industry and at the U.S. Food and Drug Administration (FDA) want to see a behavioral effect in an animal model before testing in humans.
Dr. Insel commented that Dr. Hyman made the incredibly important point that we may be eliminating things just as much by not allowing them to proceed because they are not predictive for toxicity or efficacy. We are making mistakes on both sides. Dr. Paul agreed and added that one result from repurposing may be to stumble on a novel mechanism that is inelegant.
Paolo del Vecchio, M.S.W. remarked that with respect to combined approaches and recovery, the Substance Abuse and Mental Health Services Administration’s approach to recovery is holistic. In the real world, people use a variety of strategies and approaches to achieve wellness. He remarked on a recent study that suggested that taking a walk in the woods is beneficial for individuals with depression, and mused about the day when we can prescribe a walk in the woods along with an antidepressant.
Dr. Simon asked whether there is any role for the equivalent of clinical trial registries in this area. He noted that today even failures should become public, which is progress, especially with respect to failure to replicate findings. He concluded that instituting some kind of registry requirement would take a great deal of work but would accelerate progress, too.
Dr. Insel said that this is a topic for a much longer discussion about data sharing, but a big issue is that even for NIH-funded research, people do not share their failures, which leads to continued funding of dead ends.
Dr. Simon remarked that the sharing of failures is even more important than the sharing of successes.
Dr. Insel replied that we have a publishing industry that is based on the latter and avoids the former. Then he concluded the discussion in the interest of time, summarizing that the take-home lesson from the discussion is that the ability to look at the portfolio quantitatively will help us as we begin the discussion of the future of the NIMH Strategic Plan.
A Look at the NIMH Strategic Plan: Future Directions
Dr. Insel reminded Council that NIMH’s current Strategic Plan was implemented in August 2008 and was intended to be a five-year plan. It had four over-arching strategic objectives:
- Promote Discovery in the Brain and Behavioral Sciences to Fuel Research on the Causes of Mental Disorders
- Chart Mental Illness Trajectories to Determine When, Where and How to Intervene
- Develop New and Better Interventions that Incorporate the Diverse Needs and Circumstances of People with Mental Illnesses
- Strengthen the Public Health Impact of NIMH-Supported Research
Much of what has been done over the past four years has been directed by the Plan. There were Council workgroups for each of the four objectives, and at least 25 Requests for Applications (RFAs) were generated in response to one or more of the Plan’s Strategies. The Plan has been used as an organizing principle for the Institute. Dr. Insel wanted to engage Council on what they thought should come next: keep the plan as is, revise it, create a new related effort, or develop an entirely different plan? NCI just went through the Provocative Questions Initiative, a public outreach effort to bring in the most interesting questions that had not already been addressed. This could be a model approach for NIMH to use.
Dr. Hyman agreed with Dr. Insel and said that the current Strategic Plan is a good one, but needs to be expanded, noting that this is both critical and particularly difficult during times of constrained budgets. Dr. Hyman argued the importance of supporting high throughput methods, given the many variants likely to be found and shared across different diagnoses. He concluded that the wisest use of public monies will be to find some balance between new and traditional experimental methods; that this is a great beginning, but we will need a revision that brings us in line with research on cancer or metabolism.
Dr. Paul remarked that he would be surprised if there would be any huge changes in the plan, but that Dr. Insel might want to ask each NIMH Division to ask some hard questions about what has and has not worked. He added that rather than spending money on areas that have already been exhausted, NIMH should put that money into new areas to see if it can advance the field. He suggested asking for all relevant categories the following objective questions: What have we learned? What will we likely learn if we continue down this path? Are there other ways to get a better return on our investments in each bucket?
Dr. Robinson Beale complimented the breadth of topics in the Strategic Plan. Her suggestion was to fine tune it. She added that from a corporate perspective, when there are budget crunches one must show outcomes in order to continue to get funding. She suggested prioritizing those areas or issues that are close to showing results, so they can be brought before Congress. In addition, Dr. Robinson Beale suggested that it would be helpful if NIMH could synthesize some of the huge amounts of available information into a white paper that explains what is and is not known at this point. She said that people in the field are confused by all the information, and want NIMH to tell them when something is a fact, adding that the replication of research is exceptionally important for that.
Dr. Insel commented that the first Plan was about what to do. Perhaps the second plan should be about a clearer strategy of how to do it.
Dr. Tamminga also complimented the Strategic Plan, though it needs tweaking to become more practical and for investigators take it more seriously when they submit their applications; Perhaps NIMH could introduce into the grant process the requirement of including a few lines about how the grant would fit into the Strategic Plan.
Dr. Simon suggested that we need to address what has changed in the outside world in the last five years, and what that means about the tools we have been using. He added that the real revolution has been in the area of tools used for cognitive assessment; we now can reach the world by creating a phone application which can be scaled to millions of people by next week. He suggested NIMH might need to rethink at what stage of problems researchers use which tools and how the information revolution may change mental health research.
Dr. Insel mused that today we could take a problem from biology, such as protein folding, turn it into a video game, get 50,000 people to play, and have the problem solved by an 11-year-old boy from upstate New York. He concluded that the world has changed a great deal from the way it was in 2008 when the Strategic Plan was created, and that it is time to think about innovative opportunities.
Cognitive Training in Mental Disorders: Advancing the Science
Dr. Insel introduced Ann Wagner, Ph.D., from the Division of Developmental Translational Research at NIMH, to discuss a workshop held by NIMH in April 2012. The workshop facilitated discussion between representatives from academia, NIH, local human services agencies and private industry interested in the translation of advances in cognitive neuroscience research into effective cognitive training (CT) interventions for individuals with psychiatric disorders. Drawing on the diverse expertise and experience of workshop attendees, presentations and discussions focused on current studies of CT efficacy, emerging approaches and applications, integration of CT with other interventions, and implementation of CT in health care systems.
Workshop participants were enthusiastic about the potential utility of CT, but noted that several questions remain. First is the question of the value of combined approaches and how one decides how to combine them. There is a need for larger sample sizes to better explain the variability in treatment outcomes, mediators, and moderators. Several presentations noted the need for more in-depth understanding of relationships between circuits, cognition, and behavior, especially in the context of different symptom clusters and across development. Several discussions included the need to demonstrate that intervention effects on cognitive tasks generalize to real-world functioning.
Finally, Dr. Wagner discussed the role of NIMH in facilitating communication, standardization, and resource sharing. She noted a joint effort between Tel Aviv University and the NIMH Division of Intramural Research Programs to standardize protocols and pool data, in an effort to increase the size of trials of attention-bias modification training. On the extramural side, NIMH will be proactive in shaping the science that is being proposed and conducted through existing funding opportunity announcements; will encourage and facilitate standardization and data sharing; and, will continue discussions with other federal agencies to ensure that policy and regulation decisions are based on good science.
Dr. Paul noted that the inclusion of brain measures in treatment development, as noted in one example, is useful for both pharmacological and non-pharmacological interventions. He added that this is the kind of work that will advance the field.
Patient-Derived Reprogrammed Cell Research: Portfolio and Workshop Updates
Dr. Insel introduced David Panchision, Ph.D. from DNBBS. Dr. Panchision noted that NIMH had funded 23 grants related to iPSCs and instituted a new repository in anticipation of an influx of patient-derived lines. In addition, NIMH has convened meetings to foster the research community, including an April 2012 workshop to discuss progress and challenges for using iPSCs for biological discovery, target identification, screening, and drug development. The workshop revealed great progress in reprogramming methods and agreed-upon standards for validating the resulting iPSC lines. However, challenges remain in several areas, including efficiently generating and validating specific neural cell types with respect to regional identity, establishing assays with predictive validity to mental illness pathophysiology, and generating sufficient statistical power and replication of results across labs.
A brainstorming session yielded a number of suggestions, including a need to:
- Facilitate the replication of results by standardizing protocols and samples used across labs, and focus on gene variants of relatively large effect to yield robust cellular differences;
- Improve technology by generating cheaper/faster targeting methods, reporters and assays; and,
- Improve resource sharing and collaboration, with an emphasis on rapid sharing of new cell lines, technologies, and best practices.
It was suggested that many of these improvements could be incorporated into a precompetitive consortium involving NIH, academia, and private industry. While these suggestions are being considered, Dr. Panchision noted that immediate steps were being taken to leverage the existing NIMH iPSC projects to address some of these goals, along with continued coordination in areas of common interest with other NIH funding institutes, the Center for Regenerative Medicine and NCATS.
Dr. Paul asked if any lessons could be learned from ongoing European initiatives on iPSCs and psychiatric disease. Dr. Panchision replied that the Innovative Medicines Initiative (IMI) is devoting resources to a public-private partnership for iPSC research. As with other IMI initiatives, private industry and the European Union are each providing 50 percent of total funds. He added that a number of the workshop participants were involved in IMI projects and provided suggestions that could be useful in informing future NIMH efforts. Dr. Insel cautioned that the enthusiasm for large scale efforts must be tempered by the need to first control for genetic and environmental variables that may confound cellular analysis.
Dr. Hyman noted the effort by Steven Zorn, Ph.D., Executive Vice President of Lundbeck Research USA, to assess whether the U.S. needs its own precompetitive consortium like IMI. He added that this is a very exciting time in this area, but that there remain enormous challenges with standardization and data replication. It will be critical to develop a toolkit to reliably generate disease-relevant cell types. Dr. Insel concluded that, based on outcomes of the cognitive training meeting and the patient-derived reprogrammed cell workshop, NIMH’s most important role will be to provide shared resources and templates for researchers that will facilitate the generation of robust, replicable results.
Increasing the Use of the National database for Autism Research (NDAR)
Dr. Insel introduced Michelle Freund, Ph.D., of DNBBS, who is presenting on behalf of Greg Farber, Ph.D., Director of the Office of Technology Development and Coordination.
Dr. Freund described the purpose of this initiative as encouraging researchers to use the data in the National Database for Autism Research (NDAR) to: (1) reproduce and extend published data; (2) validate hypotheses generated during experiments performed on small samples; and, (3) generate new findings and hypotheses. To stimulate utilization and mining of the increasingly diverse data available in NDAR, NIMH is considering issuing a Challenge, in which a small monetary prize will be offered to a winning proposal that uses NDAR data to make progress towards discovering relationships among NDAR data that are novel or unexpected, or confirming hypothesized, but as yet unproven concepts in the field of autism spectrum disorder (ASD) research. Information about Challenges sponsored by the U.S. Government can be found at http://challenge.gov .
Dr. Freund remarked that NDAR serves as a secure repository for research data related to ASD. The goal of the data repository is to accelerate scientific discovery in ASD through data sharing, data harmonization, and the reporting of research results. NDAR contains ASD-related data from NIH funded researchers and facilitates access to three additional autism data repositories: the Interactive Autism Network, the Autism Tissue Program, and the Autism Genetic Resource Exchange.
Created in 2006, with the first data submissions occurring 2008, NDAR has since expanded to contain more than 170,000 data records from over 25,000 research participants, from over 100 different sources. The data can be classified into four main categories: demographics, clinical assessments, neuroimaging, and genomics. The ASD research community has embraced the use of NDAR global unique identifier (GUID) software, which allows data from individuals who participate in multiple studies at multiple sites to be aggregated without revealing personally identifiable information about that individual. The community has also helped NDAR create data dictionaries that define the lexicon for all of the reported experiments. These data definitions help the community standardize the way that data is collected and reported.
Now containing sufficiently diverse and large amounts of data, NDAR is poised to allow researchers to make significant progress in ASD research, leading to the definition of biologically meaningful sub-groups among individuals with ASD or yielding insights into gene-brain-behavior relationships.
Dr. Insel added that the critical job for NDAR at present is to get researchers to submit data into the database. The existence of the database is supposed to make it easier for researchers to mine the data. The goal of this initiative is to change how the research community thinks of NDAR; instead of thinking of it as a burden, we want them to think of it as a goldmine.
Dr. Simon praised the notion of using the Challenge mechanism. He asked whether researchers would compete for the best proposal or the best result, adding that the best result is probably what NDAR should aim for. Dr. Freund clarified that the Challenge Prize mechanism is a competition for the best result.
Dr. Tamminga remarked that the field needs to be trained in how to use these big databases. Dr. Freund replied that there are a number of ways to do that, and that NDAR staff are willing to help researchers whenever they can. In addition, the hope is that initiatives such as this one will stimulate people to examine this dataset and develop this pipeline of investigators.
Dr. Robinson Beale said that part of ASD research funding looks at the medical trajectory and wondered if those findings will go into NDAR. Dr. Insel replied that the administrative data will not go into NDAR. He said that NDAR is looking more at raw individual data, especially imaging, genetics, and phenotypic data.
Clinical and Translational Science Awards
Dr. Insel, Acting Director of NCATS, welcomed the staff from NCATS, including Josie Briggs, M.D., Director of the National Center for Complementary and Alternative Medicine, who joined the discussion by phone and has been the architect of the program.
Dr. Insel stated that the largest single project funded by NIH is the Clinical and Translational Science Awards (CTSAs), a project which was originally funded through the Common Fund. The CTSA program seeks to strengthen the entire spectrum of translational research by providing integrated academic homes for the clinical and translational sciences, and by supporting research resources and workforce training to improve all phases of clinical and translational research.
NCATS was formed with the mission to catalyze the next generation of innovative methods and technologies that will enhance the development, testing, and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions. The mission of NCATS includes strengthening the entire spectrum of translational research. NCATS defines translational research broadly to include the early steps necessary to develop new therapeutics, devices, and diagnostics from basic discoveries, the steps necessary to establish real world efficacy, and the research needed to improve the practical implementation and dissemination of improved approaches to care.
The NCATS CTSA program is central to NCATS’ mission to produce improvement in quality, validity, generalizability, and efficiency of translational research. The CTSA program was initiated by NIH in 2006 to transform the local, regional, and national environment for clinical and translational research. The program now supports 60 sites across the country, providing resources for the creation of academic homes, the provision of services and facilities, and direct support of career development and training for translational scientists. The broad goals of the CTSA program under NCATS are not changed from the original mission: to continue to support the development of integrated academic homes for the clinical and translational sciences, to strengthen all phases of the planning and implementation of clinical research, to support the training and career development of a strong scientific workforce for the translational sciences, and to engage local communities in the research process. In addition, the program will collaborate actively with other Institutes and Centers at NIH to provide effective support for major studies, particularly multi-site studies.
Dr. Hyman remarked that he is impressed by the success of the program in the educational aspect: teaching professional translational and clinical research. In addition, he felt that it made sense to let centers specialize. He noted the importance of training young translational and clinical investigators and wondered whether there might be a risk that issues of curricula, training, and standards might be lost if the sites do specialize.
Dr. Insel replied that this is an important point that has been taken to heart. He added that their discussions have raised the issue of numbers; namely that if you train 900 researchers will you have 900 spaces for them? Training is going to continue to be an important mission of the CTSA program, but the question of whether it should be made larger or smaller has not yet been addressed. There is a training workforce program underway through the Advisory Committee for the Director (ACD).
Dr. Paul asked what the CTSAs will do differently now relative to the mission of finding new treatments and to Dr. Insel’s stated mantra of twice the patients in half the time.
Dr. Insel responded that that they are talking about having one nationwide Institutional Review Board (IRB) and using ResearchMatch, which has been developed to bring people with rare diseases together into a single network where they can be matched up with researchers; there are already 20,000 entries in the system. In addition, Research Electronic Data Capture, or REDCap, has over 50,000 individual users; this resource will speed things up and harmonize them.
Dr. Paul remarked that given the problems with attrition, placebo response, and trying to find and enroll enough typical patients in the U.S., researchers who try to enroll participants too quickly, may get “professional” patients and then placebo effects go up dramatically. If there was some way to orchestrate a network that would allow the enrollment of good patients quickly, that would have a huge positive impact.
Dr. Briggs replied that the CTSAs have begun analyzing the road blocks. There is a great deal of variation in the time from initiation of an NIH-funded idea to first patient enrollment, but it takes a long time—at least a couple of years. She agreed that being able to quickly establish a large enough network would enable researchers to quickly find good patients. To that end, NIH is involved in another project to strengthen partnerships with healthcare systems.
Dr. Insel added that while the CTSAs are in academic settings, the patients are in health care systems in a sort of parallel universe. He and Dr. Briggs have discussed how to build bridges between these two worlds. He concluded that CTSA 2.0 provides an opportunity to have an even greater impact.
Small Business Concepts
Dr. Insel welcomed Marina Broitman, Ph.D., Acting Referral Officer for NCATS, and Christopher P. Austin, M.D., Director of the Division of Preclinical Innovation in NCATS.
Dr. Broitman began by explaining that the largest NCATS program aside from the CTSAs is the small business program, which includes the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs. She then discussed one initiative that pertains to new strategies for data visualization, particularly from large-scale efforts like the CTSAs. The goal of visualization technologies is to look at data in different ways, using networks, mapping, and data clustering, in order to find new ways to use the data to find the research gaps in translational research.
The second concept discusses innovative gaming approaches, such as the on-line protein folding game Foldit. The idea behind this initiative is to use games and other interactive technologies to engage consumers in crowd-sourcing to come up with innovative approaches to scientific research in the translational spectrum.
Dr. Austin discussed three additional potential initiatives. The first, the Biomarker Study for Creatine Transporter Deficiency, is an outgrowth of an ongoing project within the therapeutics for rare and neglected diseases program. This disorder is an intellectual disability disorder caused by the mutation of a transporter that prevents creatine from being transported across the blood-brain barrier, resulting in severe intellectual deficits. This potential initiative would aim to find biomarkers to diagnose and follow the progression of treatment of the disease.
The second initiative, the Automated Instrument to Clean Microtiter Plates, has the goal of developing the world’s most precise dishwasher. High throughput screening sites use a large number of very expensive plates on a weekly basis. The plates can be used only once. This initiative aims to develop a method to put these used plates in a “dishwasher,” to allow them to be reused, thereby cutting costs.
The third initiative, the Assay Development for High-Throughput Screening (HTS) of Chemicals of Toxicological Concern, has potential relevance to a different project in the Division of Preclinical Innovation called Tox21. It is a very ambitious, long-term effort to develop in vitro fingerprint surrogates for in vivo toxicity. The problem is that toxicity can be caused by the dysfunction of any pathway that is important to normal homeostasis in physiology. This has necessitated developing high throughput screenable assays of every pathway operative in human cells, which is an exciting, yet daunting project. The goal of this potential initiative is to develop HTS-ready assays that are able to report on the activity of particular cellular pathways and phenotypes relevant to toxicity, and in ways that are amenable to very high throughput screening.
Dr. Simon praised the gaming initiative, especially the notion that every consumer and provider would become a researcher, actively asking questions of data as a way of understanding more about themselves and their own treatment. One of the challenges will be that the people developing the tools will not have the data you would want to mine. He added that the development needs to focus more on engaging people, despite lacking data with which to engage them.
Dr. Katz said that with the same announcement, ecological momentary assessment or experience sampling has the potential to fundamentally restructure how one evaluates self-report symptoms. He added that it has been limited by being seen as a curiosity in certain labs, rather than something that can be used with high throughput.
Dr. Insel asked for public comment. Hearing none, Dr. Insel thanked everyone for their participation and recessed the open session of the meeting.
Dr. Insel recessed the meeting at approximately 12:40 p.m. As noted in the Introduction, the NAMHC reconvened for a closed session to review grant applications at 1:15 p.m. and adjourned at approximately 5 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Thomas R. Insel, M.D., Chairperson
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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 Steinberg, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
Ex Officio Members
- Office of the Secretary, DHHS
Department of Health and Human Services
- National Institutes of Health
Francis Collins, M.D., Ph.D.
National Institutes of Health
- Veterans Affairs
Ira Katz, M.D., Ph.D.
Department of Veterans Affairs
Office of Mental Health Services
Paolo del Vecchio, MSW
Acting Director, Center for Mental Health Services