NAMHC Minutes of the 249th Meeting

May 25, 2017

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

Introduction

The National Advisory Mental Health Council (NAMHC) convened its 249th meeting in open session at 9:00 a.m. on May 25, 2017, at the Neuroscience Center in Rockville, Maryland, and adjourned at approximately 12:45 p.m. In accordance with Public Law 92-463, the policy session was open to the public. The NAMHC then reconvened for a closed session to review grant applications at 2:00 p.m. until adjournment at approximately 5:00 p.m. (See Appendix A: Review of Applications). Joshua Gordon, M.D., Ph.D., Director, National Institute of Mental Health (NIMH) presided.

Council Members Present

(Appendix B, Council Roster)

Chairperson

Joshua Gordon, M.D., Ph.D.

Executive Secretary

Jean Noronha, Ph.D.

Council Members

• Patricia A. Areán, Ph.D.
• David A. Brent, M.D.
• Benjamin G. Druss, M.D., M.P.H.
• Michael F. Hogan, Ph.D.
• John H. Krystal, M.D.
• Marsha M. Linehan, Ph.D.
• Maria A. Oquendo, M.D., Ph.D.
• Hyong Un, M.D. (phone)

Ad Hoc Members

• Tami D. Benton, M.D.
• Randy D. Blakely, Ph.D.
• Ian H. Gotlib, Ph.D.
• Alan E. Greenberg, M.D., M.P.H.
• David C. Henderson, M.D.
• Lisa H. Jaycox, Ph.D.
• Gregory A. Miller, Ph.D.

Ex Officio Members

Liaison Representative

• Paolo del Vecchio, M.S.W.

Department of Veterans Affairs

• Amy Kilbourne, Ph.D., M.P.H.

NIMH Board of Scientific Counselors Present at the Open Policy Session

• Edwin (Ted) Abel, Ph.D., Iowa Neuroscience Institute, University of Iowa Carver College of Medicine

National lnstitute of Mental Health Staff

• Shelli Avenevoli, Ph.D.

Open Policy Session Call to Order and Opening Remarks

Dr. Gordon called the open policy session to order, and welcomed Dr. Amy Kilbourne as the new Council representative for the U.S. Department of Veterans Affairs (VA). Dr. Kilbourne is the Acting Director of the VA Health Services Research and Development Service Quality Enhancement Research Initiative (QUERI). She is a national expert in implementation science, partner-oriented research, and translation of clinical quality improvement intervention findings into actionable policy and practice. Dr. Kilbourne is the recipient of several awards, including the prestigious Presidential Early Career Award for Scientists and Engineers (PECASE). Dr. Kilbourne was recently promoted to full Professor with tenure at the University of Michigan Medical School Department of Psychiatry.

Dr. Gordon welcomed the ad hoc Council members and encouraged them to participate throughout the session. He anticipates that their member status will be made official in the near future.

Approval of Minutes of the Previous Council Meeting

The Council unanimously passed a motion to approve the Minutes of the 248th NAMHC meeting held on February 9, 2017.

NIMH Director’s Report

Joshua Gordon, M.D., Ph.D. Director, NIMH

Dr. Gordon began his report with some legislative highlights. NIH Director Dr. Francis Collins and five Institute directors, including Dr. Gordon, appeared on May 17, 2017 before the House Appropriations Subcommittee Oversight Hearing on Advances on Biomedical Research in which Dr. Gordon indicated that he responded to questions on the Brain Research through Advancing Innovative Neurotechnologies (BRAIN)  Initiative, suicide prevention in youth, and postpartum depression. The Subcommittee expressed unanimous support for NIH during the hearing.

The American Health Care Act of 2017 (H.R. 1628) was passed in the U.S. House of Representatives on May 4, 2017. The U.S. Senate plans to develop their own version. The Act should not affect NIMH research, except for certain provisions related to prevention.

Dr. Gordon attended a district meeting in Los Angeles with Congresswoman Grace Napolitano (D-CA) and the Mental Health Consortium. County health departments in California have utilized a tax program to fund mental health care and prevention efforts. Dr. Gordon spoke with the Los Angeles County Mental Health Commissioner regarding partnering opportunities with NIMH. Many universities in California are also working with their local mental health authorities though infusion of funding for their research with community health care centers.

United States Senator Shelley Moore Capito (R-WV) visited NIH and heard a compelling story from a patient of Dr. Carlos Zarate who had a remarkable response to ketamine. Senator Capito seemed interested and asked many questions. Dr. Gordon also met with Congressman Tim Murphy (R-PA), an advocate of NIMH’s work with the Substance Abuse and Mental Health Services Administration (SAMHSA) to advance an evidence-based care agenda in community mental health centers.

The NIMH Professional Coalition for Research Progress met on March 30, 2017 for the first time in several years. It was attended by over 30 leaders from national professional organizations with an interest in NIMH research. Topics covered included how to balance the portfolio, Research Domain Criteria (RDoC), the experimental therapeutics initiative, and the distribution of grant funding.

The hiring freeze instituted by the Trump Administration was officially lifted by the Office of Management and Budget (OMB) on April 12. However, each federal agency is required to develop a plan for workforce reorganization and efficiency. Plans will be developed in two stages, due June 30 and September 30, respectively. Once those plans are approved by OMB, the hiring freeze can be lifted at the discretion of each federal agency. The Department of Health and Human Services (HHS) anticipates that the lifting will be on the condition of meeting specific targets for workforce reduction. The National Institutes of Health will need to continue to manage its workforce carefully, even though the NIH budget is steady at this time. Secretary Tom Price’s discussion of the White House request to optimize HHS operations is archived on the HHS website.

There are some exemptions to the current hiring freeze. The initial exemptions were direct patient care, critical infrastructure, and national security. The NIH Clinical Center was able to hire patient care nurses and other direct patient care providers. Hiring within the intramural program was also frozen, with exemptions for post baccalaureate students, postdoctoral researchers, and fellows. In addition, NIH requested many exceptions that are under review. Important positions have been approved for the All of Us  Research Program precision medicine initiative as well as some director level positions that were vacant. White House approval is still required for new Council members and other special government employees, and they are therefore subject to the government-wide hiring freeze.

The final NIH budget for 2017 was passed by Congress. The budget for NIMH has doubled since the year 2000 to approximately $1.4 billion. However, since that time, it has stagnated. When real dollars are adjusted for inflation, the result is that the real purchasing dollars have decreased over time. This has led to the challenging funding issues NIMH has been experiencing over the last few years.

In the past two years, Congress allocated an additional $2 billion to the NIH budget. The NIMH budget increased by approximately $80 million in 2017. Of the 80 million, about $36 million was designated for the BRAIN  Initiative and the rest went into the general budget. This has enabled the funding of grants approved by previous Councils. Dr. Gordon expressed that the additional funding will help advance the mission of NIMH, and that the Council will do everything they can to ensure that the money is spent wisely and distributed to investigators as soon as possible. Virtually all the new funding is being apportioned to fully funding Request for Applications (RFAs) and new investigator-initiated Research Project Grants (RPGs). Since 2010, success rates for RPGs have been approaching the low 20th percentiles. In 2017, NIMH will be funding more grants than ever before.

The total NIH spending for the BRAIN  Initiative in 2017 will be approximately $250 million, close to the original funding request. This is up over $100 million from last year's expenditures. There has been a dramatic increase in the number of funding opportunity announcements (FOAs) and applications to be addressed in the Closed Session of this NAMHC meeting. The NIH BRAIN Initiative Team decided to fund a portion of the FOAs now and others in August, as has been done in prior years.

The midpoint of the BRAIN  Initiative is approaching, requiring evaluation and assessment in several domains using the guidelines in the BRAIN 2025 Report . The Report outlines the goals of the BRAIN Initiative to understand the relationship between circuits and behavior, and the development of high-throughput tools and training. New grants are aimed at the dissemination of these tools and data sharing. There are also plans for the next couple of years to consider whether the BRAIN 2025 Report should be revisited based on the accomplishments of the past years and goals for the next five years.

Dr. Gordon stated that his first priority for the NIMH portfolio is to ensure that excellent science is funded. He plans to work with the NIMH leadership team to define good science, considering strong study design, high standards of rigor, and potential impact. The greatest limitation to obtaining high standards of rigor is sample size. NIMH now has a statistician integrated with the Division of Translational Research to assist in power calculations. The result may be that we need to provide additional funding per grant to ensure that they are adequately powered. 

Dr. Gordon’s second priority is to address issues of diversity. Diversity of time scales is very important in terms of NIMH’s short-, medium-, and long-term investments. Diversity of the workforce and research participants have been improving, and Dr. Gordon encouraged Council members to consider these issues when reviewing grants.

Dr. Gordon outlined the Institute’s research priorities that include suicide prevention (short-term goal), neural circuits (medium-term goal), and computational psychiatry (long-term goal). A suicide prevention workgroup led by Dr. Jay Churchill of the Office of the Director aimed to identify implementable evidence-based interventions that are ready to be disseminated to partners like SAMHSA as well as gaps in the research science.  At the workgroup meeting last week, the group confirmed that the joint commission has released a special alert encouraging universal screening for suicide ideation. A funding announcement (RFA-MH-18-400 ) was posted on May 15, 2017 to address suicide research gaps.

Dr. Gordon indicated that a workshop organized by both intramural and extramural scientists will be held on September 11-12, 2017 to identify how NIMH can support the development of technologies to interrogate neural circuits in primates and humans. A workshop to address opportunities and challenges of computational psychiatry will be held on June 26-27, 2017. A computational supplements program has also been initiated to permit existing NIMH grantees to increase the impact of computational components in their research. Dr. Gordon stated that many of the over 30 applications that were likely to receive funding.

Dr. Gordon highlighted two research studies. The first, “Thalamic Amplification of Cortical Connectivity Sustains Attentional Control” by Schmitt, et al., was published in Nature (PMID: 2846727 ). One of the authors, Dr. Michael Halassa, of New York University is a BRAIN Initiative award recipient. These awards are designated for high impact research by young investigators. It is Dr. Halassa’s third Nature paper from the BRAIN award and demonstrates the progress that he’s made. A separate companion paper was developed by Dr. Gordon on thalamo-cortical interactions.

Dr. Gordon explained that the thalamus provides input to the prefrontal cortex, but its particular function during working memory has been understudied. Dr. Halassa’s team devised a task to evaluate what was happening when the prefrontal cortex needed to attend to a specific rule and hold it in short-term memory. He taught mice to pay attention to either an auditory or visual cue to obtain a reward. The prefrontal cortex was recorded during the task, with a particular focus on the delay period where the mouse has to “hold-in-mind” experience-based rules on what to pay attention to. The investigators noted rule-specific and time-specific prefrontal neuronal firing rates related to amplification of the thalamus. Without stimulation from the thalamus, the decision-making ability of the mice was blocked. The investigators concluded that the thalamus is required to sustain the neuronal activity in the prefrontal cortex which holds the rule memory.  Dr. Gordon stated that the study provides an understanding of the circuits responsible for holding rules in mind and possibly for other executive functions. These circuits are disrupted in patients suffering from schizophrenia and working memory deficits.

The second study highlighted by Dr. Gordon, “Assembly of Functionally Integrated Human Forebrain Spheroids” by Birey et al., was published in Nature (PMID: 28445465 ). The senior author, Sergiu Pasca, is a Stanford University NIMH awardee who studies cultured neurons grown out of induced pluripotent stem cells. Pluripotent stem cells are derived from human blood cells and differentiated into cells that are capable of generating all kind of tissues, including neurons. Dr. Pasca generated both excitatory and inhibitory neurons and placed them together in a culture dish. The inhibitory neurons grew into the structure of excitatory neurons and migrated over time. The result was an ingrowth of the inhibitory neurons into the excitatory neurons. This was the first study in which cortex development was studied in a laboratory dish using patient derived human neurons. This study demonstrates the progress that has been made in the study of specific circuits and developmental processes with increasing power.

Dr. Gordon provided an update on the RDoC framework which is a template for psychopathology research. The purpose of RDoC is to foster an integrated understanding of the diverse biological and psychological contributors to mental disorder by identifying well supported constructs of behavioral and physiological function that have a well-established neuroscience implementation. These uniform measures will be developed and applied to large-scale studies. It is currently a top-down expert driven approach. Dr. Gordon recommended the consideration of bottom-up data driven approaches as well. The All of Us  Research Program will be building a cohort of one million Americans that will be continuously engaged through a web portal in which behavioral tests and assays can be completed on a very large scale. This will enable the use of bottom-up driven approaches to determine whether RDoC categories reflect natural divisions in behavior.

Patient electronic health records (EHRs) will also be accessible to evaluate the RDoC categories and help inform diagnosis, prognosis, and other clinical variables. Dr. Bruce Cuthbert, director of the RDoC unit, is assembling a list of currently available tests that span the RDoC domains and are either already built for the web or which could be developed for web use. Test panel development is building on previous efforts such as the NIH Toolbox ® and PhenX. The interest is on behavioral tests that assay behaviors as opposed to simple surveys.

The bottom-up driven approaches of RDoC is being timed with the enrollment of half a million registrants to the All of Us  Research Program. Dr. Gordon anticipates this will occur in about three years from now. The RDoC unit is cataloging the measures and gaps identified by the NAMHC workgroup on Tasks and Measures for RDoC chaired by Dr. Deanna Barch.

Dr. Gordon stated that NIMH is currently supporting research utilizing both the RDoC framework and DSM diagnoses to understand the relationship between behavior and neurobiology. Both rely on observations of behavior that result from hidden underlying latent psychological constructs. To understand latent constructs, the physiological states of the brain are studied using a variety of methods, including electrical recordings and neuroimaging. The physiological states themselves are produced from underlying causes, such as genetics or environmental exposures. Interpretations are made from observations of what the latent constructs are, what the hidden physiological states might be, and the potential underlying causes. Causation is thereby inferred from observations. The observations could include epidemiologic studies, electrophysiological studies, or expert diagnoses.

Dr. Gordon said that a computational approach to the RDoC framework has been developed, based on the concept that any given observation occurs with some probability given a set of underlying latent constructs. Latent variables quantify these constructs and in return could provide a probability of a future diagnosis and prognosis. Dr. Gordon provided an example in which the prognoses for chronic or episodic pathological states (e.g., schizophrenia or depression) could be determined by periodic assessments of particular latent variables and constructs. The latent constructs themselves are probabilistic outcomes associated with some hidden neurophysiological and behavioral states. For example, too little activity in the prefrontal cortex results in a certain probability of a dysfunctional working memory system, which then provides some probability of a diagnosis of schizophrenia. It also provides some probability of observable measurable impairment in working memory on an RDoC behavioral test. Conversely, a given set of clinical outcomes (e.g., prognoses, diagnoses, measurements, and symptoms) can provide probabilistic predictions regarding a particular set of latent constructs. The set of measurements, diagnoses, symptoms, or prognoses considered can be optimized to provide a better estimate of what the underlying constructs might be. Alternatively, the set of potential constructs can be optimized to provide a better estimate of clinical outcomes.

Dr. Gordon emphasized that this approach will permit model testing as well as the evaluation of the addition of RDoC domains to DSM diagnoses on patient prognoses, whether the set of causes explains the hidden physiologic states, and to what extent RDoC and DSM explain the hidden latent constructs and variables. Conclusions could be made about whether it makes sense to add more measurements to diagnoses or remove them. Clinical care and the understanding of the underlying neurobiology could be improved.

Discussion

John Krystal, M.D. applauded the development of a Bayesian framework to avoid the possibility that RDoC become prematurely ossified and potentially destructive to the field. He also applauded the focus on replicability. The purpose of research is to utilize the science and information obtained to change behavior, improve clinical practices, and influence public policy. Unreliable data can result in mistakes and bad investments that will harm people, waste money, and damage the credibility of science. In his role as a scientific journal editor, Dr. Krystal noted that the most common problem he encountered was inadequate statistical power from use of overly liberal statistics that undermine replicability.

Dr. Krystal asked whether more universities are receiving research funding with the increase in the funding rate. Dr. Gordon replied that he did not yet have the 2017 data; however, there is a renewed focus on the funding of early stage investigators and mid-career researchers who are applying for their second research project grant (R01) or first renewal of an R01. The latter group of mid-career investigators is struggling across NIH.

Marsha Linehan, Ph.D. discussed the value of the insight she gains from attendance at NAMHC meetings and the benefit of that insight to her graduate students. She stated that she has learned that funding can be obtained to replicate a previous study. She suggested improving upon the dissemination of such insights to universities to avoid grant failure. Dr. Gordon agreed and suggested the use of newsletters or postings on NAMHC grant discussions.

David Brent, M.D. noted that power calculations are often based on the assumption that no related data are available. He asked whether recommendations could be made towards the utilization of public databases to estimate potential study success. Dr. Gordon noted that – as an example - sample size is a factor in studies demonstrating the effectiveness of selective serotonin reuptake inhibitors: however, he has yet to see a treatment study with an adequately powered sample size in the low thousands. This is a problem with imaging studies as well.

Final Report: Council Workgroup on Opportunities and Challenges of Developing Information Technologies on Behavioral and Social Science Clinical Research

Patricia Areán, Ph.D., Professor, Department of Psychiatry and Behavioral Sciences, University of Washington

Dr. Gordon welcomed Dr. Areán who served as the Co-chair of the Council Workgroup on Opportunities and Challenges of using Emerging Technologies on Behavioral and Social Science Clinical Research. Dr. Areán stated that the scope of the Workgroup was to discuss the opportunities and directions for technology to facilitate innovative and efficient clinical studies and to improve the reach, accuracy, efficiency, and effectiveness of assessment, intervention, and service delivery. On March 7 and June 13, 2016, the Workgroup addressed five key questions related to their mission: (1) What technologies need to be developed to understand the life course/etiology of mental disorders? (2) How can new technologies be used to predict/prevent mental illness? (3) How can new technologies be used to achieve more efficient and effective diagnosis and treatment? (4) How can these new technologies be used to improve quality in mental health practice? (5) How can new technologies enable more rapid and nimble research? The overarching recommendation from the Workgroup was to fund science that tests principles, not products or applications. A mobile application cannot simply be developed to market to an agency or organization, for instance, it must be clear that it was developed to test a scientific principle.

The Workgroup recommended that investigators be encouraged to compile data from multiple sources to better understand how mental illness progresses. The All of Us  Research Program is an example of platform that charges investigators to compile information from EHRs and surveys and combine it with biological information such as biomarkers. Crowdsourcing could be used to identify predictive algorithms for the prevention and early identification of mental illnesses. All of this information should be open-sourced.

Dr. Areán stated that the Workgroup concluded that multi-modal real-time data collection could be used to develop and guide personalized approaches for changing behavior over time. An individual’s data, particularly deviation from the usual pattern, may be a better predictor than averaged group data. For example, data from one individual from a set with generalized anxiety disorder can be compared to the crowd or used to identify other individuals that have similar behavioral patterns. This information could then be used to make decisions about how to treat the individual by identifying patters in their behavior over time. Researchers should also be challenged to consider novel analytic approaches such as machine learning technologies to combine data to improve assessment and prediction capabilities.

New technologies can be used to achieve efficient and effective diagnosis and treatment of mental illness through new paradigms for developing intervention content/formats. In the past three years, the number of mental health and wellness mobile applications developed has exploded from about 100 to tens of thousands. The role of these mobile applications in mental health treatment needs to be considered and how they may extend care delivery, particularly for those in rural areas or those who avoid obtaining mental health services.

New technologies can also be used to improve the quality of mental health services by encouraging the field to consider strategies for coupling patient data from personal devices with EHRs. Predictive analytics can be coupled with EHR data to identify individuals at risk for illness or relapse. The information collected from a patient’s devices could be fed back into the healthcare system. The technologies also need to work closely with healthcare systems and the end-users of EHRs (clinicians) to avoid “alert fatigue.” The information should be consumable and actionable to assist clinicians in treatment decisions and demonstrate the technological value.

The pace of technological development is much faster than that of scientific research. It takes an average of five years to collect data on 100 or more people in a standard randomized clinical trial. The use of technology can reduce the amount of time spent in recruitment and the costs of clinical trials by engaging more remote research methods. However, the use of technology could also result in lower quality data and the need for creative approaches to keep individuals engaged in longitudinal studies.

There are ethical restrictions on the use of data obtained from personal devices. The mental health field is embracing the concept that the patient is the one who owns the data, not the investigator. The patient community needs to be educated in regard to what information they are sharing, why they are sharing it, and how they might be able to tailor their degree of research participation.

Dr. Areán stressed that another consideration is the leveraging of ongoing projects and existing infrastructure. She added that the NIMH could supplement existing studies to embed mobile technology. For some tools, it might be best to direct investigators to small business grants and partnering with startups interested in healthcare technology to obtain a better proliferation of evidence-based technology assessment and treatment tools. Mechanisms to ethically test ideas can then be identified and exploratory research conducted.

Dr. Areán added that another Workgroup recommendation was to develop and identify training mechanisms for clinicians and researchers to incorporate the use of new technologies. She provided an example where the development of study designs allow technology to evolve during the research life cycle. The Workgroup recommended that the NIMH be flexible in this regard so that research involving quickly developing technology is funded expeditiously and investigators are encouraged to propose research in cutting-edge technological development. The Workgroup also suggested partnerships with large provider organizations.

Dr. Areán stated that the Workgroup Report is complete. It will be posted on the NIMH website and the recommendations published in Psychiatric Services. The Workgroup hopes to conduct outreach to the field via conferences and review groups. The Report should help guide applicants and future initiatives.

Discussion

Dr. Linehan commented that her research indicates that computerized treatments work as well as treatment conducted by humans. She asked Dr. Areán what she meant when she discussed discouraging the development of new technological products. Dr. Areán clarified that technologies should be developed for the purpose of fulfilling a gap in mental health treatment.  Ian Gotlib, Ph.D. remarked that he liked the idea of partnering with the Small Business Innovation Research (SBIR) program.

Jean Noronha, Ph.D. stated that the Workgroup Report will be approved by the Council and posted on the NAMHC webpage. From there, NIMH will move forward with the initiatives to address the recommendations. Some of them have already been addressed in grants for technological devices.

The Council unanimously passed the motion to approve the final report: Council Workgroup on Opportunities and Challenges of Developing Information Technologies on Behavioral and Social Science Clinical Research.

NIH Updates

Lawrence Tabak, D.D.S., Ph.D., Principal Deputy Director, NIH

Dr. Lawrence Tabak presented new efforts by NIH to promote a stronger and more stable biomedical research workforce and maximize the impact of NIH’s research dollars. He stated that the Office of Extramural Research (OER) has been carefully observing biomedical research trends over the last several years. Dr. Bruce Alberts and colleagues reported that “The long-held but erroneous assumption of never-ending rapid growth in biomedical science has created an unsustainable hypercompetitive system that is discouraging even the most outstanding students from entering our profession…this is a recipe for long-term decline…It is time to confront the dangers at hand and rethink some fundamental features of the US biomedical research system” in “Rescuing US Biomedical Research from its Systemic Flaws” published in Proceedings of the National Academy of Sciences (PMID: 24733905 ). Although the number of NIH research grant applicants has been increasing since 2003, the number of awardees has essentially remained the same.

Dr. Tabak explained that the OER divided investigators into three age cohorts. The percentage of those in the first cohort (over the age of sixty) has continued to increase since the mid-2000s. The second cohort includes early stage investigators that are under the age of 45. They experienced a decrease in funding awards until the mid-2000s when NIH instituted an early stage investigator program. The final cohort includes mid-career investigators aged 46 to 60. They reached a peak in the mid-2000s, but have since declined in percentage funded. Multiple analyses indicate that established principal investigators (PIs) outcompete the other groups. Even if their grant applications fail, they benefit from the ability to draw upon institutional resources and other grant support until they regain funding.

Dr. Tabak showed data where one percent of PIs receive 11 percent of NIH dollars. Ten percent of PIs receive 40 percent. Twenty percent of PIs receive 56 percent. Dr. Tabak recognized that though this phenomenon is skewed by large clinical trials, it nevertheless represents an enormous concentration of resources in the hands of relatively few NIH scientists.

Bibliometrics were employed to evaluate the influence of awards on publication productivity. The most commonly used measures to determine the value of funded awards include publication counts, impact factor, citation rates, h-index, and relative citation ratio (RCR). The relative citation ratio is a method devised by NIH scientists that was published and validated by Hutchins et al., 2016 in PLOS Biology. The advantage of this measure is that it works at the article level and allows comparisons within the same scientific fields. In three independent experiments, the scientific value of publications was scored by a panel of scientists relative to publication RCR value regressed on a linear line. This validated measure, iCite, is available in the public domain to calculate RCRs.

The OER team used iCite to evaluate the sum RCR of every publication of 71,943 scientists funded between 1996 and 2014. They discovered that substantial incremental returns occur when an investigator receives their first grant as well as when they receive their second R01-equivalent. However, output levels off once investigators reach their third and fourth R01-equivalent. Study sections have also noticed the compression of scores resulting from hyper-competition. Dr. Tabak indicated that when funding resources are limited, it would therefore be more cost-effective to distribute awards to first or second R01-equivalent award investigators than those on their third or fourth award. However, he stressed that he was not suggesting the substitution of outstanding science for mediocre science.

Dr. Tabak showed similar results obtained by evaluating the median RCR across all publications. He stated that the use of log-log transformation is appropriate because the data are not normally distributed but rather most scientists publish very few papers. Some papers are never cited and others are cited many times.

Dr. Taybak highlighted a paper entitled “Concentration of Research Funding Leads to Decreasing Marginal Returns ,” published in Research Evaluation by Mongeon, et al. The authors conclude, “The main determinant of scientific production is not so much the money invested, but rather the number of researchers at work, and that by funding a greater number of researchers, we increase the overall research productivity. Furthermore, there is a certain degree of serendipity associated with scientific discoveries and funding the work of as many researchers as possible increases the likelihood that some of them make major discoveries.”, Dr. Tayback described another manuscript, “Big Science vs, Little Science: How Scientific Impact Scales with Funding,” published in PLOS ONE (PMID: 23840323 ). The authors, Jean-Michel Fortin and David Currie, stated “Impact was generally a decelerating function of funding. Impact per dollar was therefore lower for large grant-holders. Further, the impact of researchers who received increases in funding did not predictably increase.” Isabelle Cook and colleagues wrote, “We show that three measures of productivity, the number of publications, the impact factor of the journals in which papers are published and the number of citations, are all positively correlated to group size, although they all show a pattern of diminishing returns - doubling group size leads to less than a doubling in productivity." Economists call this the law of diminishing returns.

One theory is that the most prominent and important work is conducted by the best supported scientists. To evaluate this hypothesis, the OER plotted the RCRs of extraordinary investigators against a modified grant count, the grant support index (GSI). They discovered that the majority of exceptional investigators have fewer than the three R01-equivalents.

Dr. Tabak then discussed the belief that the best early stage investigators come from well-funded laboratories, and it is therefore important to continue funding these laboratories. The OER team plotted early stage investigator awardees per mentor versus the FY16 direct costs of their RPG-funded mentors and obtained a straight line. They concluded that early stage investigators who are successful at obtaining an NIH RPG are no more likely to come from well-funded laboratories than modestly-funded laboratories. The 21st Century Cures Act also includes the Next Generation of Researchers Initiative which encourages the NIH Director to promote policies that will stimulate earlier independence and increased funding for new investigators.

The Federation of American Societies for Experimental Biology (FASEB) produced a report entitled, Sustaining Discovery in Biological and Medical Sciences: A Framework for Discussion . They noted that, “Research sponsors should monitor…limiting the amount of funding awarded to any individual scientist would enable more people to be actively engaged in research…might enhance productivity overall.” Judith Kimble and colleagues identified two core problems confronting the biomedical research community from workshops at the University of Wisconsin at Madison in “Strategies from UW-Madison for Rescuing Biomedical Research in the United States,” published in eLife (PMID: 26122792 ). The first was that too many researchers are vying for too few research dollars. The second was that too many postdoctoral researchers are competing for too few faculty positions. Their recommendations were to redistribute funds to support both junior investigators and pioneering projects. They noted that such redistribution will be painful, especially for established senior investigators, but necessary to support the next generation and cutting-edge research. In 2015, NIH released a Request for Information (RFI) for optimizing funding policies and other strategies to improve the impact and sustainability of biomedical research. Among the most common suggestions by both individuals and institutional respondents was to cap the number of NIH grants or funds a PI can have. 

Dr. Tabak stressed that the NIH is committed to supporting investigators and tracking funding patterns across all career stages. To promote a more stable workforce, NIH must consider how to increase the number of early career funded scientists, stabilize career trajectories, and maximize the impact of funding. Approaches to “bend the curve” include adherence to the Early Stage Investigator Policy. Some Institutes could expand R01 investigator initiated research. Others use R56 Bridge Awards to fund early stage investigators with R01 application priority scores or percentiles that fall just outside the funding limits of participating NIH Institutes and Centers (IC). They should also continue targeting R35 awards for mid-career emerging investigators. 

Unfortunately, none of these approaches directly addresses the issue of diminishing returns from the laboratories of highly funded investigators. As these investigators are supported by two or more ICs, a trans-NIH solution is required. Dr. Tabak introduced the GSI, a modified grant count to estimate the research project support of PI's. It is not simply a measure of dollars. Dr. Tabak recognizes that some science is understandably more expensive. For example, clinical trials cost more than genetics research on drosophila. The initial focus should be RPGs used to support research efforts, not infrastructure or training. The GSI would be benchmarked to the R01 or U01 as seven points. That means that if an R01 is seven points, Small Grant Program (R03) and Exploratory/Developmental Research Grant (R21) mechanisms need to be less than seven points. Likewise, Outstanding Investigator (R35) and Transformative Research (TR01) Awards need to be more than seven points. All sub-projects on Program Project Grants (P01) will be treated separately, as if the grantees were co-principal investigators.

Dr. Tabak outlined how the GSI would be used to institute a new trans-NIH policy that resets expectations for the support provided to any single investigator. The GSI for every PI would be estimated and the research project support of any single PI would be limited to a GSI of 21 (roughly equivalent to 3 R01s). Applications with investigators above a GSI of 21 would submit a plan for any new or competing application to mitigate any increase to their GSI.

Dr. Tabak indicated that the proposed policy will be introduced in the fall of 2017. The Council would therefore begin reviewing the affected applications one year from now. Application of the policy would be “rolling” upon submission of a new application or a competitive renewal. A rigorous “exceptions” process will be initiated by IC directors to take into account the unique research requirements of an IC, the commitment to support investigators at all career stages, and the need to maximize productivity of grant resources. The final decisions would be made centrally by the NIH Office of the Director. No IC director would make the final decision to grant an exception. If the maximum GSI across all of NIH was 21 and only RPGs were included, it is estimated that about 3.1 percent of investigators would be affected. The result will be the redirection of resources to create about 900 new awards over the next several years. An analogous program would be put into place for the NIH Intramural Program.

Dr. Tabak explained that stakeholders and Council members have expressed concerns regarding the GSI plan. To eliminate concerns about complex clinical trial networks, training grants, and other infrastructure programs, the initial plan would focus on RPGs. To address team science related concerns, the OER team proposes to set a multi-PI R01 GSI at five points. The rationale being that if a single PI can handle three R01 equivalents, mitigating the burden with a colleague as co-principal investigator would make it possible to handle more than three. Hence, with five, PIs would get to conduct four multi-PI R01 equivalents. In the case of a funded multi-PI with three sub-projects with separate PIs, the multi-PI and two of the co-PIs would get a five. However, the third entity is a core and would not count toward the GSI score.

The OER also acknowledges that in order to attract highly talented investigators into a new field of science, special considerations are needed. In addition, all GSI decisions are post-hoc and do not affect peer review. The I/C directors, and advisory councils will make decisions about applications that fall into this category. Ultimately, final exceptions decisions would be made by the NIH Office of the Director.

Dr. Tabak concluded by stating that a variety of approaches will be utilized to “bend the curves,” for example, resetting expectations on research project support provided to any one investigator. All resources used for this purpose would be monitored and tracked to identify and mitigate unintended consequences. In addition, the proposed plan will continue to be shaped by stakeholder feedback.

Discussion

Amy Kilbourne, Ph.D., M.P.H. questioned whether the OER had considered how the RCR might have differed between physicians, clinician scientists, and Ph.D. or non-clinician scientists. Dr. Tabak responded that the general pattern of diminishing returns is observed regardless. Dr. Brent asked whether the metric of productivity was per article or a measure of total output. Dr. Tabak replied that the first set of data was an aggregate and the second set of data was a measure of best score. These findings will be posted on bioRxiv and will contain both a synopsis as well as the raw data and any annotated code.

Dr. Brent wondered if the conclusions of the OER Team suggest that the output per article of highly funded investigators is dropping. Dr. Tabak confirmed that these data demonstrate that output drops as investigators become highly funded. This occurs both at the article level and when based on the aggregate in terms of the influence of the research of an individual investigator.

Benjamin Druss, M.D., M.P.H. applauded Dr. Tabak and the OER for investigating the impact of resource allocation, but questioned whether RCR could capture broader areas of impact on science and public health. Dr. Tabak replied that in time, they will have the benefit of evaluating some of these other measures to determine if they reinforce or contradict RCR predictions.  Lisa Jaycox, Ph.D. noted that collaborative team science approaches may not fit the standard research model that the proposed policy changes are based on. It is possible that research teams could list less experienced members that lack R01s as PIs on grant applications to gain advantage under the new policy. Dr. Tabak stated that NIH will continue to carefully evaluate PI credentials in funding decisions. A potential positive outcome is that junior members of research teams with independent funding could be propelled to team lead in five or 10 years via extant awards.

Dr. Krystal noted that costs per grant are reduced when PIs distribute their salary across more than one grant. Dr. Tabak noted that there is a $190,000 cap on salary recovery, and not many PIs need five grants to distribute that amount. Most senior PIs have salaries in excess of the cap and do not get all of their salary from grants. Dr. Tabak stated that if only RPGs are under consideration, it may not be quite as large a number.

Dr. Linehan questioned whether senior researchers such as herself should refrain from applying for NIH grants going forward. Dr. Tabak replied that the new policies would only apply to current grants held by researchers, not the aggregate over their entire careers. Dr. Linehan asked how the policy would apply to PIs that have already received funding for a particular grant, but want to apply for another grant that is better than the one that is already funded. Dr. Tabak stated that such decisions would be in the hands of the ICs, but this example does not reflect typical study section scoring.

Dr. Linehan praised NIMH for its role in developing her research career. She remarked that young investigators would benefit from grant writing assistance from NIH. Dr. Tabak agreed that the Council should consider mentoring strategies.

It was noted that researchers should not be discouraged from submitting applications based on their actual or estimated scores. Dr. Gordon concurred that the decision about whether to fund additional grants with a grant support index (GSI) greater than 21 is made at the time of funding, not at the time of the application. The NIH Office of the Director may consider exceptions depending on grant expiration dates and productivity.

Maria Oquendo, M.D., Ph.D. asked for clarification regarding what would happen if a PI had a grant expiring within a year, if obtaining another grant would result in a score over 21. Dr. Gordon replied that NIH would not terminate an existing grant eligible for a non-competitive renewal in this case. However, if PIs with multiple grants submit a renewal, he imagines that NIH would develop a system for competitive renewals where applicants can apply early to receive awards after current grant expiration dates. The scoring system would be amended for fall applications and would include a hard cap as well as an exceptions process. Dr. Gordon encouraged the participants to contact Dr. Tabak or Dr. Michael Lauer of the OER for additional information on the GSI.

Concept Clearances

A Practice-Based Research Network to Transform Mental Health Care: Science, Service Delivery & Sustainability

Michael Freed, Ph.D., Division of Services and Intervention Research

Dr. Freed stated that although his concept was initiated in the Division of Services and Intervention Research (DSIR), it would be co-funded by colleagues in the NIMH Office for Research on Disparities and Global Mental Health (ORDGMH). Healthcare research has public health impact only when its findings influence practice. A practice-based research network to transform the development, delivery, and sustainability of evidence-based mental health practices and services across the United States would embody the research practice partnership that is central to a continuous learning healthcare system model. It would serve as a national laboratory for conducting research that improves mental health outcomes by generating the evidence base needed by healthcare system decision-makers. In turn, the healthcare system drives the research questions, based on its most urgent practice priorities. The ideal learning healthcare system values data from patients, clinicians, and communities. Evidence, science, and care delivery inform one another.

In 2007, the Institute of Medicine described a conceptual approach for integrating the disparate spheres of clinical research and clinical medicine. The NIMH and other ICs responded; NIMH invested in a Mental Health Research Network (MHRN), and the award went to Dr. Greg Simon. The goals of the MHRN are to prioritize population-based research on mental health, develop partnerships with numerous healthcare systems, and serve millions of beneficiaries across the United States. The Infrastructure allows high priority research to be conducted and leveraged with other agencies. An example is the COMPASS Initiative.

The Mental Health Research Network has produced over 30 publications to date with many more under review. The NIMH is excited about changes to healthcare systems as a result of the MHRN. Dr. Freed clarified that the MHRN is an example of a practice-based research network, not the example. Other organization and practice transformation networks have emerged in recent years.
The expected structure of the open competition research program cooperative agreement (U19) application would include cores and units, including operations, informatics, outreach and external collaboration, as well as methods in big data science. They would like the network to be able to identify and recruit large patient populations into effectiveness and pragmatic trials (including pharmacotherapy trials) that align with NIMH priorities. Other capabilities would include the harmonization of EMRs to include EMR phenotyping and the ability to collect, store, and analyze biologic material. The new network would ideally involve three pilot projects as well as one “signature” research project, in addition to leveraging of infrastructure.

Dr. Freed stressed that changing established practices requires more than just presenting the practice community with interventions determined to be effective in research contexts. The network must produce deployment-focused research for ready uptake; and implementation science to incentivize adoption and sustained practice change. Another feature of the network is comparative effectiveness research and pragmatic trials aligning to NIMH research priorities and formalized rapid response capabilities to address the urgent needs of NIMH and other key stakeholders. It would be a unique opportunity to study mental health disparities, underrepresented populations, and low base rate events like suicide and autism spectrum disorders with sufficient power, using cutting-edged analytic techniques. The enhanced care of today should become the usual care of tomorrow.

Discussion

Dr. Jaycox asked whether the Announcement will be for an expansion or replacement of the MHRN. Dr. Freed replied that the grant is for an open competition research program cooperative agreement (U19), separate from the MHRN. Dr. Kilbourne noted that there is no standard way of collecting status data on veterans via the Health Care Systems Research Network and was wondering if the proposed network would include opportunities to collect veteran information and link to the Department of Defense (DOD) and the VA. Dr. Freed remarked that servicing veteran and military populations is one of NIMH’s missions and agreed that the network should include linkages to the DOD and VA.

Paolo del Vecchio, M.S.W. questioned how the proposed network would be scalable on a national level. Dr. Freed mentioned the Recovery after an Initial Schizophrenia Episode (RAISE) model as an excellent example of how this could be accomplished. He hopes that new ideas will be brought to the table via the open competition grant.

NIMH Research Career Enhancement Award to Enhance Autism Services for Adults and Transition-Age Youth

Lauren Hill, Ph.D., Division of Services and Intervention Research

Dr. Hill stated that the NIMH Research Career Enhancement Award to Enhance Autism Services for Adults and Transition-Age Youth represents a collaborative effort between members of the NIMH training team and the scientific program staff in DSIR. She was joined by her colleague Dr. Denise Juliano-Bult, who manages the scientific portfolio addressing autism services for adults and transition-age youth. The overarching goal of the proposed concept is to rapidly increase the capacity of the research workforce to conduct NIMH-supported research project grants that test the effectiveness of a broad range of services for adults and transition-age youth with autism spectrum disorders (ASD).

The proposed concept would use the NIH Career Enhancement Award mechanism (K18) to support part-time, short-term mentored research training of experienced investigators at 50 to 75 percent effort for a period of no less than 12 and no more than 24 months. The purpose is to enable grantees to receive an intensive, individually-tailored period of mentoring and research training providing the opportunity to redirect or expand their research programs. Grantees would acquire new skills and knowledge that would provide the scientific competencies to conduct services research relevant to people with ASD across the life span.

Recent studies indicate that there are 5.3 million adults over the age of 20 diagnosed with ASD. In addition, half a million youth with ASD will enter adulthood over the next decade. Adults with ASD are less likely to receive various types of services and more likely to have more and different needs for services than ASD children. The vast majority of studies that develop and test the effectiveness of services for people with ASD focus on children, even though functional challenges associated with core deficits of ASD typically last into adulthood.

Recognizing this knowledge gap, the 2013 Interagency Autism Coordinating Committee (IACC) Strategic Plan  laid out life span research objectives for transition-age youth and adult services across a number of domains. In response, NIMH issued Request For Applications (RFAs) in 2014 and 2017 to support pilot projects addressing the identified gap areas. Among the grants funded in 2017, NIMH noticed that some important service domains called for by the IACC remain unaddressed, and the pool of new PIs to address those domains is not growing at a rate sufficient to meet the need. Dr. Hill stressed that this is the rationale for the concept.

The concept establishes research training goals and objectives to prepare established PIs to conduct independent research in gap areas. Based in part on experience with earlier RFAs, the anticipated applicant pool will be composed of individuals from related or complimentary fields. Dr. Hill provided an example of an established PI in autism services for young children in school settings. This PI has identified a need to train in a new setting with a new population. The PI proposes mentor training in that new setting from an expert mentor who conducts research on adults with serious mental illness in that setting. The PI proposes research with an expert mentor in vocational service needs for adults with developmental disabilities. The PI develops an 18-month program of mentored research training and submits a competitive research project grant in ASD services for adults. Dr. Hill concluded by stating that the overarching purpose of the concept is to develop an enriched pool of investigators well-positioned to apply for NIMH research project grants in order to increase both the number and the breadth of NIMH applications. This will in turn help to generate an evidence base for effective services that improves the health and functioning of individuals with ASD across the life span.

Paving the Way for Assessing Novel Pediatric Interventions

Margaret Grabb, Ph.D., Division of Translational Research

Dr. Grabb introduced a model for safely testing investigational drug candidates in pediatric populations. The concept was co-developed with Dr. Ann Wagner of the Biomarker and Intervention Development for Childhood-Onset Mental Disorders Branch. Pediatric clinical psychopharmacology is a neglected area of research and development. The majority of psychopharmacologic trials listed on ClinicalTrials.gov  are focused on dopaminergic and serotoninergic agents. Many medications are used off-label without adequate understanding of appropriate dose, safety, or efficacy. Pediatric clinical pharmacologist expertise is critical in terms of pharmacokinetic modeling, dosing, and help designing early stage trials. Conversely, if drug candidates fail in adult trials due to efficacy, but not due to safety, rarely are they ever tested in pediatric populations. It is also important to consider that molecular targets most relevant to the developing central nervous system (CNS) may be very different from those appropriate for treating psychiatric disorders in adults.

Dr. Grabb stated that the proposed pediatric trial model would test drug candidates safely, even if the drug candidate has not received formal approval in any adult indication. A framework will be established that brings together the expertise of pediatric clinical pharmacologists, pediatric trial psychiatrists, and the regulatory infrastructure support of Contract Research Organizations (CROs) or the Clinical and Translational Science Awards (CTSA) Program  sites that have experience in pediatric studies. Built into the model is experimental medicine design which is in line with NIMH’s priorities to assess novel mechanism of action drug candidates by quantifying immediate brain effects in pediatric populations.

Dr. Grabb and Dr. Wagner have discussed in person and received formal guidance on the trial design from the U.S. Food and Drug Administration (FDA). It is proposed that the first pilot trial utilize a staged pharmacokinetic/pharmacodynamic (PK/PD) bridging design to determine if acute drug dosing in pediatric subjects can achieve drug plasma levels that are comparable to adults (PK measure), if adequate acute drug exposure correlates with a CNS functional response (PD measure), and if adequate dose exposure is safe and tolerable. If these three milestones are met in adolescent subjects aged 12 to 17 years, children aged 6 to 11 years will be tested, and a subchronic study will be performed that is to four to six weeks in length. It will incorporate CNS functional measures and behavioral readouts.

This is expected to establish a new model for supporting early stage drug trials in pediatric psychiatric populations that incorporates the experimental medicine strategy. Dr. Grabb also proposed that the pharmacologic data be provided to the research community to help inform evidence of target engagement and safety in pediatric populations for novel drugs. Finally, registration quality data would be provided for use in a regulatory approval package if a company was interested in further pursuing a pediatric indication.

Discussion

Dr. Benton asked what class of drugs aside from stimulants the proposed model would investigate considering that few medications are approved for younger pediatric populations. Dr. Grabb replied that she was not able to provide specific details but could confirm that it was not a stimulant.

Dysregulation and Proximal Risk for Suicide

Stacia Friedman-Hill, Ph.D., Division of Translational Research

Dr. Friedman-Hill commented that most papers and research applications on suicide usually begin with grim statistics. Suicide is the tenth leading cause of death in the United States. For children aged 10 to 14, it is the third leading cause of death, and for individuals aged 15 through 34, it is now the second leading cause of death. With the National Action Alliance for Suicide Prevention, NIMH has pledged to reduce the suicide rate by 20 percent by the year 2025.

In June of 2016, the Division of Translational Research (DTR) held a workshop to review their suicide portfolio and consider how the RDoC framework could be applied to suicide. Several gap areas were identified, particularly in regards to the mechanisms by which dysregulation dynamically interacts with cognitive, social, and affective processes to confer proximal risk for suicide. Dr. Friedman-Hill indicated that the goal of the concept is to identify modifiable targets for timely interventions during high-risk periods. The concept is focused not only on predicting who is at risk, but when and why.

The approach examines interactions between constructs in the RDoC domains of arousal and regulation and one or more constructs in the RDoC domains of cognition, negative and positive valence, and social processes in a transdiagnostic sample, utilizing multi-level methods that allow for dynamic measurements with fine-grained temporal resolution. They will focus on individuals with high “distal” or developmental risk for suicide in order to identify “proximal” risk states. There are both environmental and population level factors for risk, such as economic downturns, social upheaval, and access to mental health services. Individual-level risk factors can be divided into three broad categories: distal (predisposing) factors such as family history and genetics, or early-life adversity; developmental (mediating) factors such as increased levels of anxiety, impulsive aggression, or chronic substance use; and proximal (precipitating) factors such as acute substance use or life events. In summary, as there are multiple different interacting risk factors, there is unlikely to be a single biotype which confers risk for suicide.

Dr. Matthew Nock and colleagues published “Risk Factors for Suicidal Thoughts and Behaviors: A Meta-Analysis of 50 Years of Research” in Psychological Bulletin (PMID: 27841450 ). The authors concluded that the same suicide risk factors are being studied over and over again. No broad category can predict suicide risk above chance. They noted that studies on proximal risk are needed as most suicide risk studies evaluate longer-term distal factors. Studies also tend to focus on single versus multiple risk factors.

To reach a goal of reducing the suicide rate by 20 percent by 2025, NIMH should categorize funding strategies into those evaluating biomarkers or predicting risk, those which are improving screening, referral, and treatment with existing interventions, and those which are informing novel and personalized interventions. The Agency has been evaluating distal risk factors through the DoD Study to Assess Risk and Resilience in Servicemembers - Longitudinal Study (STARRS-LS) as well as the RFA, “Addressing Suicide Research Gaps: Aggregating and Mining Existing Data Sets for Secondary Analyses” (RFA-MH-18-400 ). In terms of improved screening, referral, and treatment, NIMH has instituted the MHRN. They have also had great success with the Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE), the Emergency Department Safety Assessment and Follow-up Evaluation 2 (ED-SAFE 2), and the Emergency Department Screen for Teens at Risk for Suicide (ED-STARS). Three awards have also been issued for the 2016 RFA, “Applied Research Toward Zero Suicide Healthcare Systems” (RFA-MH-16-800 ). All of the awards are aimed at identifying at-risk individuals and improving interventions using existing systems.

Agency investments in proximal risk are limited to individual grants investigating dynamic processes and how they interact with distal risks.  No large-scale RFAs have been issued to consider proximal risk. The Agency also has few funding opportunities for novel and personalized interventions.

Dr. Friedman-Hill stated that the concept proposes to focus on emotion regulation, particularly dynamic changes in behavior and physiology in a naturalistic setting. Potential topics include suicide risk conferred by sleep-related modulation of cognitive and/or emotional domains, disordered eating or substance and dynamic effects on cognition and mood, contextually inappropriate reactivity to external and internal stimuli, dysregulation following childbirth, and changes in arousal and regulation in response to behavioral, pharmacological, or neuromodulatory interventions. The aim is to understand risk not as a static factor, but to understand dynamic risk states in order to understand how to intervene to reduce risk in the moment.

Discussion

Dr. Oquendo praised the trans-diagnostic aspect of the concept. Dr. Gotlib also applauded the concept but noted that suicide is a very low base rate behavior in terms of successes and even attempts. He questioned whether there was a focus on collaborative, multi-site studies that also addressed suicide ideation. Dr. Friedman-Hill replied that the workshop addressed the need to build collaborative networks and that there is also consideration of the standardization of methodology across studies. The investigators who participated in the workshop plan to continue to meet and collaborate to share negative findings and avoid repeat studies.

Novel Approaches to Understanding the Mechanisms of the Neuropsychiatric Symptoms in Alzheimer’s and Advancing Therapy Development

Jovier Evans, Ph.D., Division of Translational Research

Dr. Evans stated that the goals of the concept are to consider novel approaches to understanding the mechanisms of the neuropsychiatric symptoms (NPS) in Alzheimer’s and advancing therapy development are aligned with NIMH’s Strategic Research Plan, Objective 3.1., to develop novel treatments based on discoveries in genomics, neuroscience, and behavioral science. The intent is to promote mechanistically oriented studies that will address target validation and identification for intervention development, encourage novel approaches to identify and target mechanisms of NPS, and collaborate with other ICs to promote research on effective treatments. The burden of Alzheimer’s disease is compounded by NPS which occur in almost all patients, are persistent, and associated with accelerated cognitive and functional decline, decreased quality of life, earlier institutionalization, and accelerated mortality. Depression, apathy, anxiety, agitation, and irritability are the most commonly observed NPS symptoms. Higher rates of these symptoms are also reported along all courses of the disease and are a major predictor of decline. Depression has been associated with dementia incidence and most of the symptoms are treated primarily with psychoactive medications, most notably antipsychotics.

In 2005 the FDA issued black box warnings for the use of antipsychotic medications in the elderly. Despite these warnings, the use of these drugs has risen and most of the prescriptions are for off-label use. Problems associated with the use of antipsychotic medications include weight gain and dangerous side effects such as strokes, fractures, and increased mortality.

The proportion of seniors treated with these medications increases as a function of age. Among older adults aged 80 to 84, the rate is twice that of adults aged 65 to 69. This suggests a need to focus on new ways to treat the underlying causes of agitation and confusion in the elderly that avoids the use of medications and targets environmental and behavioral treatments.

The NIMH and the National Institute on Aging held a joint workshop to assess patient, caregiver, and environmental factors that may be potential targets for treatment development on NPS and behavioral symptoms in dementia. If successful, the research stimulated by the concept would clarify both behavioral and biological mechanisms associated with NPS and may provide clues to novel intervention targets for alleviating some of the burden associated with these symptoms. The concept may also suggest which intervention or prevention strategies might be optimal across the intervention spectrum. Dr. Evans expects the concept to strengthen the field of NPS and move it in a more mechanistic direction. Examples of studies that might be responsive to the concept include target identification and/or novel approaches to target identification, biomarker development in patients with NPS to understand circuitry disruptions, environmental approaches that might address aspects of circadian rhythm disruption, and other studies to understand mechanisms associated with behavioral treatments.

Rare Genetic Syndromes as a Window into the Genetic Architecture of Mental Disorders:  22qDS and Beyond

Geetha Senthil, Ph.D., Office of Genomics Research Coordination

Dr. Senthil stated that the goal of this concept is to delineate underlying genetic risk architecture of mental health disorders using rare genetic syndromes in a model. Towards this goal, NIMH would like to foster collaborative and coordinated efforts to comprehensively characterize the full spectrum of genetic variation underlying varying phenotypic expression in populations with rare genetic syndromes and identify the shared genetic risk with idiopathic neuropsychiatric disorders. Rare genetic syndromes encompass a clinically homogenous group of disorders that result from rare, single gene mutations or a reoccurring cog chromosomal number mutation such as deletions and duplications with an incidence of 1 per 2000 to 1 per 100,000 individuals in the general population. These genetic lesions have typically been associated with various psychiatric disorders such as anxiety, attention deficit hyperactivity disorder, schizophrenia, and autism.

These rare genetic lesions confer elevated risk of developing disease and have large effect. For example, individuals carrying the 22q deletion are at a 30-fold higher risk for developing psychosis or schizophrenia compared to general population. Phenotypes mirror those of idiopathic neuropsychiatric disorders. However, it is not yet understood how the same genetic lesion can lead to a variety of phenotypic outcomes and different genetic lesions can converge on similar phenotypic expressions. The rare genetic syndromes offer a unique opportunity to explore the genotype to phenotype relationships in neuropsychiatric disorders.

However, it is still unknown as to how a single genetic lesion can lead to a wide range of psychiatric phenotypes. There is a lack of understanding of the full genetic architecture (e.g., common and rare variation) and a limited understanding of the range of damage to all phenotypes that cross diagnostic boundaries in these populations. Limitations in research have included small sample sizes in any given study and methodological differences across sites. The overarching goals of the concept are deeper genetic analyses and dimensional phenotyping.

The concept would encourage coordinated, collaborative efforts to aggregate samples and data within and across syndromes, characterize the full spectrum of genetic variability, characterize variable expression of quantitative and dimensional phenotypes, and generate resources. The characterization of the full spectrum of genetic variability would include genome-wide risk contributions of common and rare variation, high resolution mapping of breakpoints, gene regulation, and analysis of haplo-insufficient genes. The characterization of variable expression of quantitative and dimensional phenotypes would include core phenotypic measures that may be applicable across multiple syndromes and the harmonization of phenotypic data within and across syndromes. The investigators will form a network to facilitate harmonization efforts across and within syndromes and generate a resource of bio-samples, phenotypic, and genetic data for broader dissemination to the scientific community.

Leveraging Electronic Medical Records for Psychiatric Genetic Research

Anjene Addington, Ph.D., Division of Neuroscience and Basic Behavioral Science

Dr. Addington presented a concept to encourage innovative molecular epidemiological research strategies that leverage existing electronic medical records (EMRs) from large, population-based cohorts and incorporate individual level genetic risk (both common and rare) to conduct analyses that advance the understanding of the complex etiology, phenomenology, treatment response, and life course of severe mental disorders. Hundreds of genetic loci associated with neuropsychiatric disorders provide critical insights to etiology. An individual’s background risk can be estimated using the output of genome-wide association studies. The availability of biobanks and linked health information resources provide an unprecedented opportunity.

Nordic countries have comprehensive records on 26 million people. Millions of citizens have provided genotyping data and many more millions have provided biosamples for research purposes. Comprehensive, life-long health (including prescription information) and demographic data are also available. The data are harmonized, consistent, and everyone has the same access to care.  In the United States, many academic centers have built critical infrastructure to enable research on individual health system data on millions of individuals. Many of these systems have linked biobanks with DNA samples and hundreds of thousands of genotyped individuals.

Discussion

Dr. Brent asked if data on family members could be linked. Dr. Addington replied that the Nordic countries have full family information and linkages available, but acknowledged that linking family information in the United States is more difficult.

Explainable Artificial Intelligence for Decoding and Modulating Behaviorally-Activated Brain Circuits

Michele Ferrante, Ph.D., Division of Neuroscience and Basic Behavioral Science

Dr. Ferrante presented the state of current machine learning focus on classifying and predicting brain and behavioral signals but that it generates uninterpretable solutions. Explainable Artificial Intelligence (XAI) can retain classification and prediction accuracy while endowing these models with explanatory features.

The concept presented by Dr. Ferrante focuses on deep learning by integrating data-driven models with physically realistic models of neurons or by labeling features of the model with semantic information. Another approach is to learn from complementary models. If this type of technology can be used in closed-loop modulation of behaviors, some of the issues relevant to understanding complex behaviors can be addressed and interventions tailored to optimize outcome. He provided an example where behavioral and neural activities in a mouse decision-making model could be recorded, categorized, and fused to identify the atomic component of the behavior and identify ways to modify the model to affect the behavior.

With this concept, the NIMH would seek proof of concept studies in animals or humans with invasive or non-invasive neurotechnology. A satellite symposium will take place on November 10, 2017 to inform this possible Funding Opportunity Announcement (FOA). A collaboration with the Defense Advanced Research Projects Agency (DARPA) and their utilization of XAI in defense applications is possible as well. These approaches may provide solutions (where, when, and how to stimulate to change behavior) and explanations (why one stimulation works and another does not) to enable a greater understanding of the circuit-level determinants of behaviors by creating new breakthroughs in multimodal data analytics and the generation of new unbiased brain theories.

NIMH Psychoactive Drug Screening Program

Jamie Driscoll, B.A., Division of Neuroscience and Basic Behavioral Science

Ms. Driscoll discussed the continuation of the productive NIMH Psychoactive Drug Screening Program (PDSP) contract. The global burden and unmet medical need for serious mental health disorders is high, but many companies are reducing efforts in psychiatric drug discovery. As drug discovery efforts move to the academic sector, there is a need for high-quality data on the activity and selectivity of chemical probes and therapeutic leads. The PDSP provides a key resource for CNS drug discovery and basic science efforts supporting target identification and validation, screening, and lead optimization. Approval is being sought to re-compete the PDSP contract for another five-year period (2018-2023).

The PDSP focuses on using state-of-the-art, novel, high throughput screening and counter-screening of compounds submitted from investigators in the field as well as assays of more than 400 molecular targets. The PDSP also supports the development of innovative assays and support databases for the mining of pharmacological data. For the current contract period, the PDSP receives requests from over 100 NIMH or NIMH-funded investigators annually and screens about 4,000 compounds in over 200,000 assays. The PDSP generally receives more requests than it can support.

Pharmacological data in the form of a Ki database is provided to the research community. It is one of the largest publicly available pharmacology databases, receiving over 200,000 queries per month. By providing a centralized resource, the PDSP results in significant cost-savings to the NIMH as compared to funding this work through individual grants. Over 700 papers in drug, basic neuroscience, and technology development cited PDSP in the last five years.

Discussion

The Council unanimously passed the motion to approve the nine concepts.

Public Comment

Dr. Michael Byer of M-3 Information, LLC stated that he visits NIMH each year on behalf of his colleagues, Robert Post and Larry Culpepper, to discuss progress in mental health and primary care, including regulatory restrictions and findings from patient data generated in primary care settings. As a disclosure, M3 is a self-funded research collaborative focusing on a multi-condition screen. Their research was conducted at the University of North Carolina and authored by a group including Dr. David Rubinow.

Dr. Byer stated that the symptoms query includes bipolar, anxiety, post-traumatic stress disorder, and depression. It allows a comorbid view of data to better build symptom clusters to recognize patterns. Examples of clusters that point to major problems include suicide by veterans and youth experiencing nightmares, bipolar disorder, and anxiety and pain management.

Dr. Byer indicated that Laboratory Corporation of America (LabCorp) is working with M3 to produce a standardized test that is diagnostic at the symptom level. If a patient presents with a mix of symptoms, the conversation with the doctor could be personalized and organized to provide relief at the symptom not diagnosis level. Interventions have been shown to be equally as valuable as medicine.

Dr. Byer said that primary care has never had a metric to use measurement-based care to better identify and follow patients. He stated that because their research extends beyond depression, M3 was 83 percent predictive of any mental health condition. Dr. Byer claimed that this is superior to the Patient Health Questionnaire score for depression, which is only 47 percent predictive as patients may be suffering from other mental illnesses.

If mental health can be inserted into primary care at the level of a chronic condition, with a score that is destigmatizing, it can be discussed with patients as part of a collaborative effort. Dr. Byer stated that M3 would be willing to share their datasets with anyone interested in studying mental health in primary care settings, early recognition, and pattern clustering. Dr. Byer stated that the organization just completed a Federally Qualified Health Center in New York where 52 percent of the patients were screened to have mental health conditions other than depression. The suicides in the dormitory of 200 individuals decreased from eight per year to none as a result of querying and discussion. Dr. Byer thanked the Council for the opportunity to present the work of M3 and concluded that primary care is an ideal place to bend the curve. Dr. Gordon thanked Dr. Byer for his comments and sharing the latest research on the resource developed by M3.

Dr. Krystal expressed his concern regarding the new administration’s proposed 21 percent NIH budget cut and major budget cuts to the National Science Foundation (NSF) and SAMHSA. Dr. Krystal expressed his belief that the cuts would be absolutely devastating to efforts to save lives, reduce suffering, and ameliorate disability associated with mental illnesses and all other medical conditions. It would lessen any effort to develop and sustain a meaningful scientific workforce and would yield other indirect problems and false solutions. As an example, he stated that reducing the indirect cost rate on grants is a false way to redistribute money and sustain the grant workforce. Cuts to the indirect cost to universities would only serve to further undermine the ability to conduct research within these organizations, leading to an erosion of the national research mission.

Ms. Tanya Shy introduced herself as a parent who lost her daughter to suicide two years ago at the age of 26. She remarked that she found the Council discussion interesting and was learning from the information presented. She works in education and formerly worked at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) under Dr. Reid Lyon. She encouraged the Council to think outside the box as the national suicide rate is increasing. She lost a friend to suicide this past spring and amongst her colleagues, frequently hears of families who have lost members or friends to suicide. She is looking forward to reviewing the Final Report of the Council Workgroup on Opportunities and Challenges of Developing Information Technologies. She was also interested in XAI and the combined utilization of mobile technology, XAI, and cognitive tutors. Although she agreed that the proposed budget cuts were serious, she suggested considering the use of technology to assist providers in the delivery of better care. Dr. Gordon thanked Ms. Shy for her comments and stated that the best ideas come from outside the box, from extramural investigators.

Hearing no further comments from the public, Dr. Gordon adjourned the open session at 12:20 p.m.

Joshua A. Gordon, M.D., Ph.D.

Appendix A

Summary of Primary MH Applications Reviewed

Council: May 2017

IRG Recommendation
Category	Scored #	Scored Direct Cost $	Not Scored (NRFC) #	Not Scored (NRFC) Direct Cost $	Other #	Other Direct Cost $	Total #	Total Direct Cost $
Research	649	$885,360,794	524	$581,680,864	15	$7,108,895	1188	$1,474,150,553
Research Training	0	$0.00	0	$0	0	$0.00	0	$0.00
Career	76	$58,534,426	40	$31,744,095	1	$201,371	117	$90,479,892
Other	0	$0.00	0	$0.00	0	$0.00	0	$0.00
Totals	725	$943,895,220	564	$613,424,959	16	$7,310,266	1305	$1,564,630,445

Appendix B

Department of Health and Human Services
National Institutes of Health
National Institutes of Health
National Advisory Mental Health Council
(Terms end 9/30 of designated year)

Chairperson

• Joshua A. Gordon, M.D., Ph.D.
  Director
  National Institute of Mental Health
  Bethesda, MD

Executive Secretary

• Jean Noronha, Ph.D.
  Director
  Division of Extramural Activities
  National Institute of Mental Health
  Bethesda, MD

Members

• Tami D. Benton, M.D. Ad Hoc (Pending)
  Psychiatrist-in-Chief
  Department of Child and Adolescent Psychiatry
  And Behavioral Sciences
  Children’s Hospital of Philadelphia
  Philadelphia, PA

• Randy D. Blakely, Ph.D. Ad Hoc (Pending)
  Professor
  Department of Biomedical Sciences
  Charles E. Schmidt College of Medicine
  Florida Atlantic University
  Jupiter, FL

• David A. Brent, M.D. (17)
  Academic Chief
  Child & Adolescent Psychiatry
  Endowed Chair in Suicide Studies
  Professor of Psychiatry, Pediatrics and Epidemiology
  Director, Services for Teens at Risk
  University of Pittsburgh School of Medicine
  Pittsburgh, PA

• Benjamin G. Druss, M.D., M.P.H. (18)
  Rosalynn Carter Chair in Mental Health and Professor
  Department of Health Policy and Management
  Rollins School of Public Health
  Emory University
  Atlanta, GA

• Ian H. Gotlib, Ph.D. Ad Hoc (Pending)
  David Starr Jordan Professor and Chair
  Department of Psychology
  Stanford University
  Stanford, CA

• Alan E. Greenberg, M.D., M.P.H. Ad Hoc (Pending)
  Professor and Chair
  Department of Epidemiology and Biostatistics
  School of Public Health
  George Washington University
  Washington, DC

• David C. Henderson, M.D. Ad Hoc (Pending)
  Chair
  Department of Psychiatry
  Boston University School of Medicine
  Boston, MA

• Michael F. Hogan, Ph.D. (18)
  Consultant and Advisor
  Hogan Health Solutions LLC
  Delmar, NY

• Richard L. Huganir, Ph.D. (17)
  Professor and Director
  Department of Neuroscience
  Investigator, Howard Hughes Medical Institute
  Co-Director, Brain Science Institute
  The Johns Hopkins University School of Medicine
  Baltimore, MD

• Lisa H. Jaycox, Ph.D. Ad Hoc (Pending)
  Senior Behavioral Scientist
  Health Program
  Rand Corporation
  Arlington, VA

• John H. Krystal, M.D. (19)
  Robert L. McNeil, Jr. Professor of Translational Research
  Chair, Professor of Neurobiology
  Chief of Psychiatry, Yale-New Haven Hospital
  Department of Psychiatry
  Yale University School of Medicine
  New Haven, CT

• Marsha M. Linehan, Ph.D. (17)
  Professor and Director
  Behavioral Research and Therapy Clinics
  Department of Psychology
  University of Washington
  Seattle, WA

• Gregory A. Miller, Ph.D. Ad Hoc (Pending)
  Professor and Chair
  Department of Psychology
  University of California, Los Angeles
  Los Angeles, CA

• Maria A. Oquendo, M.D. (17)
  Vice Chair for Education
  Professor of Psychiatry
  Department of Psychiatry
  Columbia University
  New York State Psychiatric Institute
  New York, NY

• Rhonda Robinson Beale, M.D. (19)
  Senior Vice President and Chief Medical Officer
  Blue Cross of Idaho
  Meridian, ID

• Elyn R. Saks, J.D., Ph.D. Ad Hoc (Pending)
  Orrin B. Evans Professor of Law
  Gould School of Law
  University of Southern California
  Los Angeles, CA

• Hyong Un, M.D. (17)
  Head of EAP & Chief Psychiatric Officer
  AETNA
  Blue Bell, PA

• Christopher A. Walsh, M.D. (19)
  Chief, Division of Genetics and Genomics
  Boston Children’s Hospital
  Bullard Professor of Pediatrics and Neurology
  Harvard Medical School
  Boston, MA

Ex Officio Members

Office of the Secretary, DHHS

• Thomas E. Price, M.D.
  Secretary
  Department of Health and Human Services
  Washington, DC

National Institutes of Health

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

Department of Veterans Affairs

• Amy M. Kilbourne, Ph.D., M.P.H.
  Director
  Quality Enhancement Research Initiative
  Health Services Research & Development
  Department of Veterans Affairs, Ann Arbor
  Ann Arbor, MI

Department of Defense

• Vacant

Liaison Representative

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