Professional Coalition for Research Progress: 2017 Meeting
The National Institute of Mental Health (NIMH) convened the eighth Professional Coalition for Research Progress (Coalition) Meeting on Thursday, March 30, 2017, in Bethesda, Maryland. The meeting served as an opportunity for representatives from professional organizations with an interest in NIMH research to hear about advances in mental health research, current and new research directions, and strategies for NIMH. Participants networked with colleagues, interacted with – and expressed their views directly to – the NIMH Director, Joshua Gordon, M.D., Ph.D., and senior level NIMH staff. Speakers included Sarah H. Lisanby, M.D., and Bruce Cuthbert, Ph.D. This document provides a summary of the meeting highlights. Please see the meeting agenda and participant roster for additional information.
State of the NIMH
Joshua Gordon, M.D., Ph.D., Director, NIMH
Dr. Gordon remarked that the Coalition meeting was an important opportunity for him to hear from NIMH stakeholders. As he moves toward completing his first year as NIMH Director, he continues to listen across the broad constituency of NIMH. He aims to understand research concerns, gaps in knowledge, as well as what NIMH is doing well and where NIMH can improve. He said he was eager to hear from attendees about issues important to professional associations that relate to the priorities of the Institute. Moving to the state of NIMH, Dr. Gordon noted that Dr. Francis Collins has been held over as NIH Director under the new Administration. He also reviewed a number of staff updates, including the appointment of Shelli Avenevoli, Ph.D., as NIMH Deputy Director, and the return of Dr. Cuthbert as Director of the Research Domain Criteria (RDoC) Unit. Dr. Gordon said that the new HHS Secretary, Thomas E. Price, M.D., indicated that mental health issues are a priority for him. As NIMH Director, Dr. Gordon said he looks forward to working with the transition team to ensure that improving mental health through research remains a priority.
Dr. Gordon briefly reviewed the 21st Century Cures Act, that authorized 10 years of research on various innovative initiatives, and includes a number of important mental health and substance use provisions. The Cures Act authorizes funding for the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative; the Precision Medicine Initiative (PMI) and its All of Us Research Program; the Regenerative Medicine Innovation Project, and the Cancer Moonshot Initiative. Dr. Gordon also described the Adolescent Brain Cognitive Development (ABCD) Study – a collaborative longitudinal study of brain development and child health in the United States which will recruit 15,000 9- and 10-year-olds who will be followed with serial MRI and behavioral assessments for 10 years. A database will be created for studying the neurobiological, environmental, and genomic basis of behavioral change through adolescence.
To achieve the NIMH mission of transforming the understanding and treatment of mental illnesses in order to pave the way for prevention, recovery, and cure, Dr. Gordon emphasized that the number one priority for NIMH is to support excellent science. He emphasized that funding decisions for research are based on proposed study design, adherence to the highest standards of rigor, and potential impact on the field. Dr. Gordon noted that excellent science requires diversity in subject matter, workforce, research participants, and timeframes. In fact, such diversity is the cornerstone of a strong and balanced research portfolio. Dr. Gordon emphasized the importance of investing in research across diverse timeframes; research that has the potential to yield results or improve clinical care over the short, medium, and long term. Dr. Gordon highlighted several examples. In the short term, suicide prevention research, such as predicting risk and screening in emergency departments (ED), could result in significant decreases in suicide events. In the medium term, research on techniques to manipulate neural circuits could be applied to the treatment of mental illnesses in humans. In the long term, computational and theoretical approaches to psychiatry are needed to refine treatments. In fact, computational modeling that incorporates clinical data to build predictive biomarkers, or a framework for diagnosis, could transform mental health care.
Following these opening comments, participants discussed a number of issues, including the need for more translation of basic neuroscience findings into treatments and pointed to basic science often operating in siloes as a contributing roadblock to translation. They also expressed interest in opportunities for research collaboration and concerns about diversity. Participants noted that many interventions have been developed without regard to cultural context. Dr. Gordon agreed that more must be done to study specific populations and said that big data approaches may help.
During the discussion period, participants also expressed concerns regarding the decline in implementation and dissemination research that has coincided with the rise of experimental therapeutics approach and RDoC, and challenges associated with the peer review process – specifically noting that child-specific sections are being subsumed in the review process and that in the move toward experimental therapeutics, many of the multisite trials for the treatment of children with mental disorders have stopped. Dr. Avenevoli suggested that part of this may actually be a shift to specific, smaller applications focused on RDoC or the R21/R61 trials involving behavioral interventions in children. In response, Dr. Gordon said that we will need to reevaluate disorders such as schizophrenia that have been historically thought of as adult disorders, and he stressed the importance of identifying and addressing roadblocks to inform the next generation of pediatric researchers.
Experimental Therapeutics Approach to Interventions
Sarah H. Lisanby, M.D., Director, Division of Translational Research, NIMH
Dr. Lisanby began by explaining the experimental therapeutics approach to interventions, a strategy for translating scientific discovery into novel treatments for mental health conditions. She outlined the current challenges to translation, including relative lack of novel molecular targets, multiple gene conditions, long developmental pathways not easily modeled in animals, and the inability to directly, noninvasively measure the human brain. These challenges often lead to failure in the intervention development pipeline. The experimental therapeutics approach is meant to secure the pipeline by addressing the leading causes of intervention development failure. Dr. Lisanby reviewed the basic framework of the approach: Target Engagement – the intervention (medication, psychosocial intervention, device, or biological intervention) can reach the target; Mechanism of Action – the intervention causes a change in the relevant brain activity or mental process; and Proof of Concept – shows that the change in that mechanism is associated with the change in the clinical phenomenon that was the target of the intervention. This approach is highlighted in a series of Requests for Applications (RFAs) that were recently revised to allow more specification and detail about the range of therapeutic interventions of interest. Dr. Lisanby described the role of RDoC in identifying translatable biomarkers but noted that both RDoC and the Diagnostic and Statistical Manual of Mental Disorders (DSM) can be used to identify targets.
Experimental Therapeutics Guided Discussion
NIMH staff, Mi Hillefors, M.D., Ph.D., and Meg Grabb, Ph.D., led a guided discussion on the experimental therapeutics approach. Discussion topics included how to accelerate the identification of translatable targets and foster the development of therapeutic interventions that lack a strong industry base; how RDoC can inform experimental therapeutics; the value of national networks of organizations in supporting adequately powered clinical trials to evaluate targets and promising treatments; and how to capitalize on shared resources to support trial implementation and monitoring. Participants acknowledged some of the difficulties of using the experimental therapeutics approach, such as complex diseases and multiple genes. However, they noted this complexity may also provide opportunity to identify more targets. Promising new targets may encourage cross-discipline research and lead to more translational discovery. Collaboration is especially important for small-scale behavioral work, and the group suggested that NIMH could promote registries and practice-based research networks (PBRNs) to share resources and train the next generation of investigators. Participants voiced a need to bridge the DSM, International Classification of Disease (ICD), and RDoC systems to inform translatable targets. Additionally, participants noted it would be helpful for the Center for Medicare and Medicaid Services (CMS) and the Food and Drug Administration (FDA) to accept the validity of RDoC for payment. Dr. Cuthbert commented that FDA is open to the RDoC approach. Finally, participants emphasized getting the message out that enrolling in clinical trials advances science.
Research Domain Criteria Update
Bruce Cuthbert, Ph.D., Director, Research Domain Criteria Unit, NIMH
Dr. Cuthbert provided an overview of RDoC, which aims to develop a framework for studying psychopathology based on dimensions of observable behavior and neurobiological measures and to address the need for standards and guidelines for evaluating research grants in psychopathology if the DSM/ICD system is not used. He reviewed the RDoC framework, explaining that mental health disorders are increasingly understood to be disorders of neurodevelopment and that more than half of funded RDoC grants involve developmental aspects. As such, there is a need to study the effects of the environment as it interacts with neurodevelopment. It is only within these crucial frames of development and environment that we can look at the domains of function and the units of analysis across which they are measured. Dr. Cuthbert reviewed the RDoC matrix and pointed out how function and circuit overlap in the RDoC construct. Being that RDoC is a practical rubric that is always under construction, future activities aim to incorporate big data; short-term longitudinal studies showing trajectories; a move toward pre-emption and prevention; and the use of formal computational approaches. Dr. Cuthbert also outlined the clinical consequences of the RDoC approach. Discussion questions included: Whether the emphasis should be more on clinical trials or services research? How to keep the matrix fluid and updated? What will the developmental and environmental components of RDoC will include? How to best employ computational approaches? What resources are needed to maintain cutting-edge definitions of the constructs?
Toward a Balanced Research Portfolio
Joshua Gordon, M.D., Ph.D., Director, NIMH
Dr. Gordon began by noting that a balanced research portfolio is based on diversity in scientific workforce, study participants, subject matter, and timeframes. In the short term, we must look to those who are dealing with these disorders and underwrite research that will help ensure broad access to the most effective, currently available treatments. For the medium and long term, we need to build the knowledge base that will lead to transformative treatments in the future and fully investigate new treatment targets and methods as they arise. Dr. Gordon highlighted current NIMH priorities, the experimental therapeutics approach to developing and testing interventions, RDoC, and the complementary data-driven approaches. He noted a need to emphasize genomics research. Discussion questions included: What factors should be considered when determining portfolio balance? How can NIMH balance the portfolio to ensure a pipeline of translation from basic to translational science to intervention and implementation and back? How to determine the best science? How to communicate portfolio balance?
RDoC and Portfolio Balance Concurrent Guided Discussion Reports
In discussing the question of whether RDoC should be pushed faster and harder in real-world clinical applications, the RDoC group (guided by Uma Vaidyanathan, Ph.D., and Jenni Pacheco, Ph.D.) noted that although RDoC is about research, it is important to expand it to clinical work, but to do so cautiously and clearly. Keeping the matrix updated should be done in an open science, community-driven—but controlled—manner; however, it should not be controlled to the point that it becomes a dogmatic framework. Participants suggested that interpretive guidelines, such as narrative case studies, would be helpful. They also noted the importance of identifying where potential points of failure may exist as the beginning of psychopathology. Participants thought that computational measures should be included in RDoC, and stressed the value of embedding the common data elements across registries to inform the matrix. It was also suggested that training mechanisms are needed to help bring investigators up to speed.
The portfolio balance group discussion (guided by Dr. Avenevoli) focused on the cultural context of research, the diversity of researchers and research participants, disparities, and the need for more balance in research involving children and adolescents and among different stages of investigators. Participants noted that it is important to promote young and diverse investigators to keep the career development pipeline going. Some participants said that there is a perception that the portfolio is more loaded on the basic end, and they suggested that evaluating the long-term potential of basic research may be the best approach to achieving balance, although this may risk the loss of innovation that cannot be identified up front. Some large initiatives can cross the translational continuum to help create balance and ensure a robust pipeline, but there are advantages to an ongoing portfolio balance process that goes beyond RFAs and brings the community together to identify areas of need. They also supported looking at the impact of the research on public health. Participants indicated their willingness to engage in NIMH’s communication and information dissemination efforts.
Following the group reports, participants engaged in continued discussion on both topics. They noted that more data are needed for RDoC and that this data should be provided through multiple categories/categorization schemes. The challenges involved in ensuring sufficient funding and training/mentoring of early- and mid-stage scientists were also of common interest, and some possible approaches were suggested to support investigators from diverse backgrounds. Dr. Gordon said that NIMH has been engaging in an ongoing push to rebalance funding for early investigators and that having arrested the long-term decline in funding in this area, the focus has now shifted to mid-stage scientists. He emphasized that whatever approaches are taken to meet these challenges, they must connect with NIMH’s mission of doing excellent science and supporting innovation.
Discussion, Questions & Answers
Dr. Gordon received several questions regarding the focus of his efforts going forward in his first year as Director and the ongoing transition. In response, he said that he will be attending professional and advocacy group meetings, meeting with other stakeholder groups, talking to members of Congress with an interest in mental health, and working to learn more about the priorities of the administration regarding mental health. In addition, NIMH will hold workgroups and workshops in the three priority areas discussed earlier, which may result in a number of reports, funding announcements, and more. Dr. Gordon concluded by emphasizing the important role of professional organizations in this and other NIMH efforts, and he thanked all who attended the day’s meeting for sharing their valuable ideas, knowledge, and expertise.