National Advisory Mental Health Council Minutes of the 227th Meeting
January 13-14, 2011
Department of Health and Human Services
Public Health Service
National Institutes of Health
National Institute of Mental Health
The National Advisory Mental Health Council (NAMHC) convened its 227th meeting in closed session to review grant applications at 11:00 a.m. on January 13, 2011, at the Neuroscience Center in Rockville, Maryland, and adjourned at approximately 5:00 p.m. (see appendix A: Review of Applications). The NAMHC reconvened for an open policy session on January 14, 2011, in Building 31C, National Institutes of Health (NIH), from 8:30 a.m. until adjournment at approximately 12:35 p.m. In accordance with Public Law 92-463, the policy session was open to the public. Thomas R. Insel, M.D., Director, National Institute of Mental Health (NIMH), chaired the meeting.
Council Members Present at the Grant Review and/or Open Policy Sessions
(See Appendix B: Council Roster)
Chairperson: Thomas R. Insel, M.D.
Executive Secretary: Jane A. Steinberg, Ph.D.
- David G. Amaral, Ph.D.
- Carl C. Bell, M.D.
- Robert Desimone, Ph.D.
- Ralph J. DiClemente, Ph.D.
- Howard B. Eichenbaum, Ph.D. (via teleconference)
- Daniel H. Geschwind, M.D., Ph.D.
- Portia E. Iversen
- Kay Redfield Jamison, Ph.D.
- David A. Lewis, M.D.
- Roberto Lewis-Fernandez, M.D.
- Thomas H. McGlashan, M.D. (via teleconference)
- Steven M. Paul, M.D.
- Rhonda Robinson Beale, M.D.
- Carla Shatz, Ph.D.
- Ad Hoc Members:
- Eric D. Jarvis, Ph.D.
- John W. Newcomer, M.D.
- Gregory E. Simon, M.D., M.P.H.
- Ex Officio Member:
- Ira Katz, M.D., Ph.D., Department of Veterans Affairs
- Liaison Representative at the Open Policy Session:
- A. Kathryn Power, M.Ed., Director, Center for Mental Health Services, Substance Abuse and Mental Health Services Administration (SAMHSA)
- Others Present at the Open Policy Session:
- Jeanette Colgan, Purple Communications
- Yoshie Davison, American Academy of Child and Adolescent Psychiatry
- Karl Deisseroth, Stanford University
- James Finley, National Association of Social Workers
- Kathryn Foxhall, Freelance Writer
- Gardiner Harris, New York Times
- Danielle Hunter, Dixon Group
- Patrick Hendry, Mental Health America
- Alan Kraut, Association for Psychological Science
- Lisette Madalena, Purple Communications
- Sara Maddox, Science Writer
- Anne Michaels, National Foundation for Mental Health
- Mortimer Mishkin, NIMH
- Richard Nakamura, NIMH
- Paula Skedsvold, Federation of Associations in Behavioral and Brain Sciences
- Michelle Rodriguez, Social & Scientific Systems, Inc.
- Kevin Roy, IKON Public Affairs
- Angela Sharpe, Consortium of Social Science Association
- Andrew Sperling, National Alliance on Mental Health
- Lisa Stand, National Alliance to End Homelessness
- Cynthia Thomas, Executive Reporters
- Tracy Todd, American Association for Marriage and Family Health
Open Policy Session: Call to Order and Opening Remarks
NIMH Director Thomas R. Insel, M.D., called the open policy session to order and welcomed all in attendance. Dr. Insel welcomed Kathryn Power, M.Ed., Director of the Center for Mental Health Services, Substance Abuse and Mental Health Services Administration (SAMHSA), and noted that the Council is looking forward to working with her on a number of cross-HHS initiatives. Dr. Insel also introduced Eric Jarvis, Ph.D., John Newcomer, M.D., and Greg Simon, M.D., M.P.H., three ad hoc members of Council participating in the meeting.
Approval of the Minutes of the Previous Council Meeting
Turning to the minutes of the September 2010 Council meeting, Dr. Insel asked if Council members had revisions or comments on the minutes. Hearing none, the minutes were approved unanimously.
NIMH Director’s Report
Scientific Management Review Board: Two Important Recommendations
NIH’s Scientific Management Review Board (SMRB) has issued recommendations regarding the creation of a new Institute focusing on substance use, abuse, and addiction research and related public health initiatives. This new Institute would integrate the relevant research portfolios from the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and other NIH Institutes and Centers (ICs). NIH accepted the proposed realignment of these NIH programs into a single, new Institute devoted to addiction. A task force is charged with looking carefully across the NIH’s 27 ICs to determine which programs could be moved into the proposed Institute.
In addition, the SMRB has recommended that NIH establish a new Center devoted to advancing translational sciences. As currently envisioned, the central role of the proposed National Center for Advancing Translational Sciences (NCATS) would be to establish a focused, integrated and systematic approach for building new bridges to link basic discovery research with diagnostics and therapeutics development. NCATS would be formed initially by integrating selected translational research programs now located within the National Human Genome Research Institute, the National Center for Research Resources and the NIH Director’s Common Fund. Another component may be the new Cures Acceleration Network, which was authorized by the Affordable Care Act, but has not yet received Congressional appropriation. The working goal is to launch NCATS by October 2011. A comment period has been opened by NIH Director Francis Collins, M.D., Ph.D.
The NIH Common Fund , enacted into law by Congress through the NIH Reform Act of 2006, encourages collaboration across NIH ICs to support cross-cutting, high-impact programs. Along with the National Institute on Aging, NIMH is leading a trans-NIH effort on health economics and the science of health care reform. The Health Maintenance Organization (HMO) Collaboratory Program is an effort designed to conduct large epidemiological practical trials that take advantage of existing structures, such as those at the National Cancer Institute and the National Heart, Lung and Blood Institute, to create a platform for certain kinds of science that can provide rapid answers. The NIH HMO Collaboratory effort will help poise NIH to support new collaborative biomedical research, as well as health care system reform.
Dr. Insel presented the design for the Porter Neuroscience Center that will house the NIH intramural neurosciences programs. The 500,000-square foot building has an expected completion date of 2013. NIMH will have approximately 20,000 to 25,000 square feet of new space, representing a new era in neuroscience research for the NIMH Division of Intramural Research Program (DIRP).
Dr. Insel noted that the NAMHC’s Interventions Workgroup report, “From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illness,” has been influential in terms of the discussions around what NIMH should be doing in the realm of therapeutics—going beyond basic biology to hasten early interventions. It is important to consider tailoring interventions to make the biggest impact on individuals and on public health.
Dr. Insel commented that since last January, many of the larger pharmaceutical companies have moved out of the psychiatric or neuropsychiatric drug development, because it is too expensive and too difficult and has a high failure rate. He described this move as a great paradox, as there are many exciting scientific opportunities that can be pursued at this time. In addition, coming out of the genomics revolution, there is a whole set of new targets available.
Dr. Insel noted that NIH is currently operating under a continuing resolution (CR) that expires on March 4, 2011. The CR provides for funding at fiscal year (FY) 2010 enacted levels, which is $1.489 billion for NIMH. The FY 2011 President’s budget request, submitted to Congress last winter, included $1.540 billion for NIMH, which would represent an increase of $50.6 million or 3.39 percent over the FY 2010 level. While Congress has not yet passed a budget for FY 2011, the President’s request continues to be the starting point for negotiations. The House Budget Committee, within the next few days, is expected to renew consideration of an FY 2011 budget by establishing spending targets, which would be followed by consideration by the House Appropriations Committee. Between now and the expiration of the current CR, we anticipate that Congress will pass either another short-term CR, a CR for the full remainder of FY 2011, or a new budget for the remainder of FY 2011 reflecting a compromise between the President’s request and Congress.
While operating under a CR, in accordance with NIH policy, NIMH has been issuing non-competing research grant awards at 90 percent of the previously committed level, and the Institute plans to continue this practice until a final FY 2011 appropriation is enacted. This is consistent with practice during the CRs of FYs 2006-2010. NIMH is assuming a funding level below the FY 2010 budget with regard to new and competing applications. Under these constraints, we will not be issuing awards for grants beyond the 10th percentile. NIMH will consider adjustments to these levels once the final appropriation is enacted.
Steven M. Paul, M.D. said that although pharmaceutical companies’ investments in psychiatric drugs do not look too promising, the situation may not be as bleak as some believe. NIH and NIMH in particular can be great catalysts. There are ways of de-risking ventures and thereby increasing interest of pharmaceutical companies. Dr. Paul encouraged the Institute to continue drug discovery efforts and noted that, in fact, today’s selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs) would not be available if it were not for research sponsored by NIMH.
Kathryn Power, M.Ed., said that leadership is important in articulating a vision. In a strategy group, it is important to include not only the other operating divisions of HHS but also incorporate the Department of Veterans Affairs and the Department of Defense, because their research capability and prevention and intervention strategies that would be helpful to the overall goal. She also noted that when she and Carl Bell, M.D., were at the Carter Center this year, former Congressman Patrick Kennedy talked about his vision of the future of neuroscience. She said that such a vision could be included as part of the Institute’s discussion around strategy and NIMH’s leadership role.
Dr. Jarvis said he liked the idea of having a program at NIH that goes from bench to bedside, and that it should be utilized as a model not just for drug development, but also for going from bench to bedside generally in the neurosciences— beyond drug targets to include other kinds of molecules, proteins, and more. He inquired as to how such initiatives could be initiated and balanced during a time of workforce decline.
Dr. Insel said that both a short-term and a long-term strategy are needed and noted that he sees this as a scientific question that will involve adhering to the highest standards to make sure that NIH and NIMH are pursuing truly promising molecules or enzymatic steps in a signaling cascade, as examples.
Carla Shatz, Ph.D. said the possibility that only 10 percent of grants could be funded in the coming year is sobering. She noted that the core strength of NIMH and NIH is to fund research and to permit breakthroughs that will ultimately lead to treatments. One never knows where these discoveries will come from, but by funding high-level research, the possibility of a breakthrough is increased. The pharmaceutical companies and biotechnology companies are not entirely writing off neuroscience; there are companies that continue to have significant interests in neuroscience. Thus, it may be useful to identify a number of these companies and ask whether it would be possible to create an industry-government partnership to move forward.
She expressed concern about funding and how significant cuts will affect new investigators, new grants, and new ideas as well as the impact on the attitudes of young scientists who are pursuing research careers. Many other countries are investing enormous amounts of money in supporting their research enterprise, and we are training extremely talented young people who are now being recruited to head major research enterprises in other countries such as China and Germany. Dr. Shatz also expressed concern about our ability to retain the best and the brightest in this country to ensure that we are investing in our future.
Roberto Lewis-Fernandez, M.D. encouraged investment both in new targets and in making existing interventions—psychosocial and pharmaceutical—more effective and more effectively disseminated. Dr. Lewis-Fernandez expressed concern that biological interventions have an organized lobby and cost incentives. Psychosocial treatments do not have a strong lobby, and the cost incentive may not be as clear; yet, these are marvelous treatments that should be incentivized as well.
Robert Desimone, Ph.D. said that now is the time to be investing in the technologies to understand how genes affect circuits related to behavior rather than going the pharmacological route.
David A. Lewis, M.D. commented that while it is possible to find ways to do the same thing for slightly less money, it’s also important to rethink how to do things in a different way that may be more effective and cost-efficient. He emphasized the importance of rethinking the approaches taken.
Rhonda Robinson Beale, M.D. noted that it is important to remember that we are in a time of financial crisis, and this has caused a situation that will result in the demand for changes in health care, particularly in the way it is structured. NIMH has had a tremendous role in advancing the understanding around other therapeutics involving psychosocial issues. The adoption of drugs is quick, and the pharmaceutical companies have learned how to do that well; but the adoption of psychosocial therapies is not as quick, and the adoption of evidence-based treatments is very poor. There should be a focus on methodologies that advance the ability to administer those evidence-based treatments in a personalized manner.
Dr. Insel thanked Council members for their input and commented that this discussion has been very helpful and will continue to be an ongoing conversation both internally and at upcoming Council meetings.
Biennial Report on the Inclusion of Women and Minorities in NIMH Research
Pamela Collins, M.D., M.P.H., Director of the Office for Research on Disparities and Global Mental Health, presented the FY 2009 and FY 2010 data regarding the inclusion of women and minorities in NIMH-funded clinical research. The NIH Revitalization Act of 1993 mandated a biennial report describing the manner in which NIH Institutes have complied with its requirements. NIH guidelines ensure that women and minorities are included in NIH-funded clinical research and that NIH-defined Phase III clinical trials are carried out in a manner sufficient to examine differential effects of both females and males, as well as individuals of diverse racial and ethnic groups.1
In FY 2009, 942 NIMH-funded extramural studies enrolled 2,223,100 human subjects. This aggregate data include a very large study involving United States Air Force (USAF) recruits enrolling approximately 1.8 million human subjects. This study appears to have skewed the NIMH inclusion data (73 percent male participants) as this study recruited a high percentage of male participants. In order to get an understanding of recruitment in more typical NIMH studies, it is important to consider the NIMH enrollment data excluding this large USAF study. When this study is excluded, the rate of participation is somewhat higher among females (56 percent) than males (44 percent), and Asian (8.6 percent) and Black (29.2 percent) participants are somewhat overrepresented relative to their representation in the U.S. population.1 On the other hand, Hispanic (8.5 percent) and White (48.0 percent) participants are represented at rates lower than their representation in the U.S. population.2 However, when looking only at studies recruiting domestic populations, the percentage of Black participants drops to 16 percent, and the rate of Hispanic participation increases to over 11 percent. In FY 2010, 1087 NIMH-funded extramural studies enrolled 2,349,704 human subjects. A similar trend in Black and Asian recruitment is found when examining only domestic studies.
Regarding NIMH Division of Intramural Research Programs, NIMH reported on 90 research protocols for FY 2009 and FY 2010. NIMH enrolled more females and Black participants as compared to NIH as a whole in FY 2009; however, NIMH enrolled fewer Asians and Whites than NIH in FY 2009. While the rate of enrollment of Hispanic participants was slightly higher for NIMH than NIH in FY 2009, the rate of Hispanic participation remains low, at less than 5 percent in both FY 2009 and FY 2010. The aggregate data from NIH is not yet available for FY 2010.
Dr. Robinson Beale said she was struck by the consistently low percentage of Hispanics that are included in the studies. Dr. Collins agreed that this is a problem across NIH and needs to be addressed.
Dr. Jarvis talked about the differences in social ethnicity versus genetic ethnicity and suggested NIMH consider the use of an inexpensive genetic tests that would allow for the identification of some kind of genetic ethnicity that may affect outcomes.
Dr. Lewis-Fernandez mentioned that one of the priorities of the Division of AIDS Research (DAR) is to conduct research with minority communities. He wondered what these numbers would look like for the other Divisions within the Institute, if the numbers from DAR were removed. Dr. Collins said that in looking at the Phase III research protocols for the domestic non-AIDS numbers, Black and African-American participation is about 21 percent in the non-AIDS group and Hispanic participation is 14 percent in the non-AIDS group—similar to all NIMH studies.
Following Dr. Collins’ presentation, Council members voted their concurrence that the data are in compliance with the NIH inclusion rules.
Diversity in the Workforce
Dr. Collins reported that NIH is continuing its efforts to increase the diversity of the NIH-funded scientific workforce. In reviewing the race and ethnicity reported by Principal Investigators (PIs) funded in FY 2009, Whites and Asian Americans are overrepresented compared to their representation in the US population, and Hispanic Americans are underrepresented in research portfolios as PIs.
Dr. Collins examined the NIMH portfolio in terms of NIH Research Project Grant Program (R01) PIs from 2004 to 2010, commenting that the trajectory for Asian investigators has improved somewhat during this time frame. That said, the number of Black investigators has steadily decreased since 2007. Upon examination of the NIH numbers, she noted a rapid increase in Asian investigators and a somewhat similar trajectory for Hispanic investigators. NIMH was ahead of NIH (in terms of diversity) as a whole in 2004, but the NIMH numbers have decreased since then and are now aligned with the NIH-wide numbers. A snapshot of FY 2010 NIH-funded R01 investigators shows that about 5 percent of investigators self-report their race/ethnicity as an underrepresented group.
Dr. Collins also discussed training initiatives focused on diversifying the NIMH workforce, including the Director’s Pathfinder Award, an American Recovery and Reinvestment Act of 2009 (ARRA)-supported initiative (about $12 million) for which awards already have been made. This initiative focused on highly innovative approaches to diversifying the scientific workforce. NIMH is also focused on creating diversity and leadership in the next generation of mental health researchers.
In response to a question regarding the decreased numbers of Black investigators, Dr. Insel said one hypothesis is that as NIMH has moved from social science to neuroscience, some diversity has been lost, and that the one place where a large number of minority Ph.D.s can be found is in the social sciences. There is a need to understand these numbers better and to think about how to turn them around. Dr. Insel made note of a recent editorial in Science by Dr. Freeman Hrabowski about workforce diversity. In the editorial, Dr. Hrabowski, who chaired the Institute of Medicine (IOM) effort in this area, makes the argument that ethnic and racial minorities are the fastest growing sector of the population; because this is the direction of the future, there is a need to identify a way to capture this growing wave.
Portia Iversen suggested examining the increased involvement of women in research. Dr. Shatz added that tracking women, especially at NIMH, would help disassociate ethnicity from this issue of change in support for the social sciences, because it is an area in which women traditionally have been interested.
Dr. Insel said that the IOM report “Expanding Underrepresented Minority Participation: America’s Science and Technology Talent at the Crossroads” makes clear that the numbers show students who enter undergraduate school thinking they want to go into science often end up doing something completely different, and this is where the challenge may be. Dr. Insel noted that the current representation is unacceptable and is a problem that needs to be addressed. Efforts must be doubled and programs are being launched to promote change. In addition, NIMH will monitor the numbers in order to change direction so that in 2013 and 2015 a different picture can be shared.
Optogenetics and Mental Health: Development and Application
Dr. Insel introduced Karl Deisseroth, M.D., Ph.D., Associate Professor of Bioengineering and Associate Professor of Psychiatry and Behavioral Sciences at Stanford University. Dr. Deisseroth has developed optical neuroengineering technologies, called optogenetics, for noninvasive imaging and control of brain circuits in real-time. Optogenetics combines genetic and optical methods to affect function of well-defined events in specific cells of living tissue, through the precise delivery of light into tissues. The optogenetics approach inserts a single gene that encodes for a light-activated product into brain cells, thereby allowing for precise control of the cells’ functioning. Because light scatters—particularly in myelinated tissue—to counter this effect, Dr. Deisseroth and colleagues developed fiber optic-based methods to constrain the scattering for more precise access to deep brain structures. The whole assembly weighs less than two grams and can be carried on the head of a freely moving mouse.
Readouts are designed to obtain a fine level of detail, including behavioral detail. One kind of readout, called an optetrode, obtains a millisecond-precision electrical readout from a circuit while delivering millisecond-precision optical control. Another kind of readout involves functional magnetic resonance imaging (fMRI). Dr. Deisseroth has begun to turn his attention to integrating the global and noninvasive aspects of fMRI with optogenetic control of a defined population of cells, such as the dopamine neurons, which has not been possible by other means. Dr. Deisseroth paused to provide a history of the molecular engineering work required to make optogenetics possible.
Dr. Deisseroth went on to describe work being done, both in his own laboratory and at others, on the use of different types of lights and complementary genes, particularly the use of red light, which scatters less and penetrates more deeply, and channel proteins, called opsins. He noted that Dr. Desimone and his colleagues recently showed that one could insert channel red opsin into the brains of awake macaques and thereby drive spiking. So-called ‘step function’ opsins can deliver a single blue light pulse in an awake macaque and get elevated spiking that can be turned off with a yellow pulse of light. Dr. Deisseroth also reviewed advances using different opsins.
Dr. Deisseroth emphasized the importance of precision targeting of brain cells to all areas of neuroscience and mental health research. In order to achieve such precision and advance the field, it will be necessary to leverage other NIH resources, such as the Cre driver lines. He commented that at this point, the range of researchers who are now becoming interested in optogenetics, including non-neuroscientists, has created a demand for teaching and training. Tools have been sent to more than 800 laboratories worldwide, and many thousands of people are working with them across a variety of systems and are now even moving into some non-excitable and non-neuronal cells. Hands-on training has an enormous impact, and he has been providing training in his laboratory to researchers across all career phases. Tools can be found at www.optogenetics.org.
In response to a question about the possible use of fiber optics in treatment, Dr. Deisseroth said that although he has not explored the possibility in his laboratory, he sees no fundamental barrier regarding optical devices for treatment. Nevertheless, Dr. Insel said that the idea of putting a fiber optic cable into a human brain may always be a challenging one; he asked if a noninvasive method, such as a magnetic stimulus, could be used, rather than a light-sensitive channel. He also asked if anybody else was thinking about other ways of activating inhibiting channels through other kinds of proteins.
Dr. Deisseroth said that the key idea implicit in the question is maintaining the temporal precision of light. There are other combinations of chemicals and chemical genetic strategies through which one can get cell type specificity, but maintaining a temporal precision is very important. He said that in thinking about what other form of energy delivery could be introduced that might penetrate more deeply but still maintain a millisecond precision, it may be that a magnetic pulse could be used; or one also could do away with optical hardware in some senses, even with the opsins.
Dr. Jarvis remarked that it seemed like Dr. Deisseroth began this project looking for a way to control neurons to answer a question in psychiatry. He wondered, looking back on it now, whether Dr. Deisseroth sees himself continuing in the same direction or in other directions to find ways to develop novel tools to answer many different questions.
Dr. Deisseroth said his work is helping him to understand more deeply what kinds of processes may be dysfunctional in his patients with autism spectrum disorder. He said the goal is to understand the biological basis of psychiatric disease more profoundly. He commented that they are working on expanding the diversity of the animal models involved.
Insights from a Lifetime in the Neurosciences
Dr. Insel introduced Mortimer Mishkin, Ph.D., Acting Chief of the NIMH Laboratory of Neuropsychology, who in mid-November became the first member of the NIMH DIRP to receive the highest honor given to an American scientist by the U.S. government—the National Medal of Science. Dr. Mishkin’s contributions to science were honored at a White House ceremony.
Dr. Insel noted that due in large part to work spearheaded by Dr. Mishkin, science now understands much about the pathways for vision, hearing and touch, and about how those processing streams connect with brain structures important for memory. In nonhuman primates, Dr. Mishkin’s team discovered that the brain uses divergent pathways to process two different types of memory. Cognitive memory—recollection of events and new information—is processed by a separate circuit from behavioral memory—skills and habits. The cognitive memory circuit courses from the sensory streams through the brain’s limbic lobe—an emotion hub—while behavioral memory detours through the basal ganglia. In collaboration with British colleagues, Dr. Mishkin has recently applied these insights toward improved understanding and care of children with amnesia.
Dr. Mishkin said he was happy to have this opportunity to thank so many people for the support that he has received throughout his career at NIH, which began in 1955. He said he could not have had a more satisfying career than the one he has had at NIMH. Dr. Insel noted that over the past decade Dr. Mishkin has completely transformed the area of auditory processing in the brain, providing a wonderful role model for everyone to move into completely new areas of research, open up new ventures and new frontiers, and push the edge of science. He thanked Dr. Mishkin for all he has done, including his leadership and extraordinary scientific accomplishments.
Dimensional Approaches to Research Classifications
Linda Brady, Ph.D., Director, Division of Neuroscience and Basic Behavioral Science, commented that Strategy 1.4 of the NIMH Strategic Plan is to develop new ways of classifying mental disorders based on dimensions of neurobiological measures and observable behaviors. This initiative, “Dimensional Approaches to Research Classification,” is designed to foster studies of pathophysiology and psychopathology consistent with the Research Domain Criteria (RDoC) approach to classification on the basis of dimensionally defined constructs. The initiative would support awards for projects with clinical populations that are designed to explicate specified dimensions of functioning that cut across traditional diagnostic categories, using multiple levels of analysis. In contrast to typical clinical studies, the independent variable might be selected from any level of analysis (e.g., genetic, functional neuroimaging, responses to behavioral tests), and dependent variables from one or more other levels of analysis. The goal of the research projects is to study how measurements in different systems interrelate in defining a given functional dimension, and to examine functional outcomes and symptoms of behavior and neurobiology. This initiative will be directed toward the RDoC specifications that have been established to date: working memory and dimensions involving aversive motivational constructs such as fear, distress, and aggression/anger. The initiative is expected to generate substantive research on mechanisms related to disorders that involve these constructs and will also serve to catalyze interest in NIMH’s new approach to classification.
Integrating Multi-Dimensional Data to Explore Mechanisms Underlying Psychiatric Phenotypes
Dr. Brady described a second initiative,”Integrating Multi-Dimensional Data to Explore Mechanisms Underlying Psychiatric Phenotypes,” which involves the integration of multidimensional datasets. The RDoC initiative discussed earlier leads into this because it establishes a paradigm for the effort. Recent NIMH investments have led to an enormous depth of genomic data, extensive brain imaging data, and new clinical assessments to define the etiology, pathophysiology, and trajectories of mental disorders. Although many bioinformatics tools are available, existing tools do not offer effective means to integrate the breadth of data types collected across these studies, which may include neuroimaging data, physiological data, clinical data, and genomic data. Neither are the available tools capable of offering efficient statistical analyses of multi-dimensional data for diagnostic or outcomes research. Therefore, a biologically grounded approach is needed to reduce the plausible combination of genomic regions and various types of phenotypes in order to effect a drastic reduction in the number of statistical tests needed to reach meaningful conclusions.
This initiative will support the development of holistic analytical approaches to model biological systems accurately, using data from various platforms. NIMH expects newly developed analytical tools will help establish links between biological networks, environmental factors, and downstream psychiatric phenotypes, which will ultimately provide a foundation for identifying new diagnostic tools and personalized therapeutic methods.
David G. Amaral, Ph.D. said that the first concept presented is an important way to understand psychiatric disorders. He said that in trying to understand multidisciplinary approaches to autism, a limitation has been the lack of creative integrative approaches to bring the data together to summarize them and that a bioinformatics approach would be helpful.
Dr. Simon commented that he is enthusiastic about the idea of moving from the traditional diagnostic classifications to these dimensional measures. He said that he is especially enthusiastic about moving from the dimensional measures to measures of observable behavior, measurable performance, and physiologic states. He encouraged thinking about the technological revolutions of the past few years, as the use of technology could not only improve the validity of the measurements but also dramatically reduce costs. Dr. Desimone agreed, noting that laboratory-based measures often miss critical data regarding a person’s ability to function in society.
Dr. Geschwind said that the data analysis works well for these large-scale projects that serve as shared resources. He emphasized that there is a lot of this kind of data and noted that critical issues include using these techniques and data-mining tools to actually address those data, and the need for standardization and integration of the data.
Dr. Robinson Beale said that she did not hear standardization as part of the methodology used, although she recognizes that it will be very difficult because there is a need to find the key domains and the items within the domains, before standardization can be initiated.
Neurodevelopmental Trajectories in Children at Familial Risk for Schizophrenia or Bipolar Disorder
Shelli Avenevoli, Ph.D., Branch Chief in the Division of Developmental Translational Research, described an initiative titled “Neurodevelopmental Trajectories in Children at Familial Risk for Schizophrenia or Bipolar Disorder.” This initiative intends to encourage collaborative research applications to conduct a coordinated, multi-site, multi-modal longitudinal study charting middle childhood (ages 6–12 years) trajectories of brain, cognitive, and affective development among those at high and low familial risk for schizophrenia or bipolar disorder, before the onset of prodromal symptoms.
Existing evidence suggests that serious mental illness is rooted in early development. In spite of this knowledge, significant gaps remain in our understanding of brain and behavioral trajectories before the onset of prodromal symptoms. Specifically, there are few prospective studies that (a) commence sufficiently early to identify developmental aberrations that precede syndrome onset; (b) assess more than two time points to define and track trajectories from healthy development to illness; or (c) collectively evaluate brain changes in structure, function, and connectivity across development. Mapping the trajectories of brain and behavioral development during middle childhood (ages 6–12 years) will fill a critical gap in our knowledge of the course of illness across development and may identify sensitive periods that are amenable to early intervention (addressing Strategic Objective 2 of the NIMH Strategic Plan).
This initiative focuses on neurodevelopmental trajectories among those at high and low familial risk for schizophrenia or bipolar disorder. Although schizophrenia and bipolar disorder share many clinical symptoms and genetic risk factors, there is evidence supporting distinct neural circuitry. Longitudinal study of the neurodevelopmental trajectories of these disorders may enable the detection of unique biosignatures, points of divergence in development, and opportunities for intervention.
Expected outcomes include neurodevelopmental maps of brain maturation during the middle childhood period; development of a standardized assessment battery and methods; increased knowledge of the links between brain maturation and cognitive and affective development during middle childhood; and the identification of targets and timing to inform efforts to intervene before the onset of illness.
In response to a multiple questions regarding the age range of middle childhood (age 6–12), Dr. Avenevoli commented that an analysis of the NIMH portfolio in this area was conducted. This analysis revealed a gap in that many funded studies start in adolescence, but that there was limited work in middle childhood. Following the cohorts currently enrolled in early developmental studies would be useful, but Dr. Avenevoli noted that studies in middle childhood may be foundational in the sense that they would inform other studies that start at earlier ages.
When asked about offering supplements to ongoing studies to expand the scope to this age range, Dr. Avenevoli noted that NIMH supports a large portfolio in schizophrenia and bipolar disease, but due to time constraints and the 5-year grant cycle, following a sample longitudinally from birth (or a very early age) has many challenges.
Dr. Desimone noted that traditionally a longitudinal study covering all of childhood could effectively be conducted within the NIMH DIRP, because the children could be followed for a longer period than during the traditional grant cycle (5 years) and all of the data would not necessarily need to be published before grant renewal time. Dr. Desimone also noted the challenges realized with the rapid pace of technology development, particularly in the area of imaging. This can markedly affect data and represents a challenge for longitudinal and extramural studies.
Ms. Power offered her congratulations for focusing on this age group and commented that this is an important group in terms of the services intervention cycle.
Translational Research for the Development of Novel Interventions for Mental Disorders
Ann Wagner, Ph.D., Branch Chief, Division of Developmental Translational Research, described the goal of this initiative as encouraging researchers to translate emerging findings on the neuroscience of mental disorders into novel non-pharmacological treatment approaches. The initiative, “Translational Research for the Development of Novel Interventions for Mental Disorders,” aims to increase our understanding of neural networks associated with mental disorders and the impact of experience at the neural level. It encourages biologically informed, novel approaches to engage and alter a target at the level of circuits, behaviors, cognitive/affective processes, or clinical symptom dimensions.
The NIMH Strategic Plan calls for the development of new or improved interventions for people with mental disorders in Strategy 3.1: Further develop innovative interventions and designs for intervention studies. The NAMHC’s workgroup report, “From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses,” also recognizes the gap between advances in understanding the neural circuitry and neurobiological mechanisms underlying mental disorders and the development of novel interventions.
This initiative addresses a specific gap in treatment development research at NIMH: the translation of biological and behavioral science findings into novel psychosocial (e.g., cognitive strategies and innovative behavioral approaches) and other non-pharmacological interventions (e.g., brain stimulation, protocols designed to enhance plasticity). Concurrent with an increasing understanding of neural networks associated with mental disorders, there is an increasing appreciation of the role of experience in neurodevelopment and the impact, at the neural level, of cognitive, behavioral, and other non-pharmacological interventions. Hence, there is great opportunity for translating this emerging knowledge into intervention strategies.
This initiative aims to speed the translation of emerging findings on the neuroscience of mental disorders into novel treatment approaches that will ultimately alter dysfunctional neural circuits and psychological processes underlying mental disorders to reduce symptoms and/or restore function.
Dr. Paul asked if NIMH is investing in technology development that would noninvasively stimulate the brain in some meaningful way. Dr. Wagner said that Small Business Innovation Research grants (SBIRs) and Small Business Technology Transfer grants (STTRs) provide technology development; this initiative would take such a technology and provide proof-of-concept at the point when it is ready for an Investigational Device Exemption. Dr. Insel clarified that “non-pharmacological” interventions might include a range of different interventions that would be of interest, so long as there is a rationale and a way of looking at a proof-of-concept.
In response to a request for clarification, Dr. Wagner described targets broadly (not just neurocircuits); rather than adapt existing interventions for a different population or age group, the initiative would encourage thinking about new targets based on the scientific findings of the underlying pathology.
Dr. Insel commented that this concept would serve as the bridge between cognitive neuroscience and treatment development.
Optimizing Fidelity of Empirically Supported Behavioral Treatments for Mental Disorders
Varda Shoham, Ph.D., Special Assistant to the Director, Division of Adult Translational Research and Treatment Development, described another potential initiative, “Optimizing Fidelity of Empirically Supported Behavioral Treatments (ESBTs) for Mental Disorders.” This initiative aims to support research that will enhance the fidelity, and ultimately the effectiveness, of empirically supported behavioral treatments (ESBT) for mental disorders, as implemented by community-based therapists. More specifically, it encourages research designed to develop and test (a) methods for assessing theory-derived ESBT fidelity components; and, (b) interventions that enhance and maintain the fidelity with which clinicians implement these ESBTs in community settings.
The recent NAMHC’s workgroup report, “From Discover to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses,” calls for optimizing current treatments. The NIMH Strategic Plan also recognizes the need for improving interventions for people with mental disorders and for the effective application of these treatments in community-based practice.
Although efficacious behavioral treatments for many mental disorders exist, studies suggest that many patients in community settings do not receive these ESBTs as intended by the treatment developers. A major factor in the widely acknowledged science-to-service gap is treatment fidelity. The fidelity of an ESBT is essential in the delivery of psychosocial interventions, as the integrity of the treatment depends disproportionally on clinician behavior. What the clinician does and does not do (based on an ESBT manual) defines a multi-component independent variable—the treatment itself—encompassing domains such as adherence, competence, and differentiation from other treatments. While successful fidelity acquisition and maintenance is feasible in randomized efficacy trials, little is known about how to extend effective methods of ESBT training and fidelity maintenance to community practice.
A sharpened focus on treatment fidelity and its outcome-related components has the potential to advance knowledge on how ESBTs work and how to make them more efficient. For example, the complex, multi-component nature of some ESBT treatment packages may itself pose a barrier to successful community implementation. In the absence of specific knowledge about which components relate most essentially to behavior change, a common practice is to train therapists in all elements of the package, emphasizing active and inert components equally.
This funding initiative supports research aiming to develop treatment-specific, multi-component fidelity measures; to examine component-outcome relationships; and to explore methods for enhancing and maintaining the most promising fidelity components. The ultimate goal of this initiative is to narrow the science-practice gap by making high-quality ESBTs more readily accessible to patients in the community.
Dr. Simon commented that one cannot improve what one cannot measure. He added that is the central question about improving the psychosocial treatments available to people worldwide. He would encourage a strong emphasis on scalable methods as well as an emphasis on conditions- or treatment-specific measures, together with universally applicable methods. That is, in trying to improve the delivery of behavioral health services across a range of conditions and treatments, it would be important to be able to say that the basic methods used to measure process and this information are the same even if the measures applied to the data collected are different.
Dr. Newcomer said to get to this ultimate goal one must target both the barriers to dissemination and implementation at the same time. He wondered if there is any synergy between Food and Drug Administration (FDA) efforts to overcome dissemination/implementation barriers, and what this initiative would be trying to achieve through these behavioral interventions. Dr. Insel agreed that FDA could be very helpful with the dissemination piece. He said that currently, NIH has a very active collaboration with FDA, which is interested in many NIH efforts.
Dr. Lewis-Fernandez said he thought the initiative is much needed and very important. He wished to emphasize that the methods as a whole could be useable across conditions and treatments. He said it also would be important to add treatment settings and populations so that it is useable across multiple types of groups.
Dr. Robinson Beale echoed the other comments of other Council members and wondered how much work is already being done in this realm. The American Psychological Association (APA) is starting to collect outcome tools and plans make them available to its members via the APA Web site. The gap is the provider seeing these tools and using them. Also, it is important to think about how to link with partners—organizations that are geared to the education of providers and that are doing certification and re-certification.
Promoting Engagement in Care and Timely Antiretroviral Initiation Following HIV Diagnosis
Pathology of HIV-associated Neurodegeneration in Aging Populations on Long Term Antiretroviral Therapy
Dianne Rausch, Ph.D., Deputy Director, Center for Mental Health Research on AIDS within DAR, presented two concepts, both of which are responsive to the strategic planning processes for the Division. The first concept, “Promoting Engagement in Care and Timely Antiretroviral Initiation Following HIV Diagnosis,” aims to develop and test interventions to reduce the time between HIV diagnosis and achievement of first undetectable viral load among patients for whom antiretroviral therapy (ART) is indicated, as well as to reduce racial and ethnic disparities in HIV-treatment outcomes.
One third of the patients in this country who are HIV infected and know it are not fully engaged in primary care. Another third do not enter medical care within the first year of HIV diagnosis, and 15 percent of those who do and who are eligible for antiretroviral medications do not take them. This lack of treatment is associated with poor treatment outcomes, disease progression, and mortality. There also is a very high racial-ethnic disparity factor in HIV survival rates. The goal of this initiative is to advance U.S. research to improve medical care engagement particularly within 12 months following HIV diagnosis. The outcomes to be studied are rapid linkage to care for those diagnosed, improved patient retention, the initiation of more timely antiretroviral initiation, improved adherence, and reduced disparities. These interventions should target patients, providers, and the care systems.
The second concept is in the basic arena, titled “Pathology of HIV-associated Neurodegeneration in Aging Populations on Long Term Antiretroviral Therapy.” There has been a dramatic increase in the number of older persons living with HIV infection due in part to the improvements in antiretroviral therapy. The Centers for Disease Control and Prevention predict that more than half of HIV-infected individuals in the U.S. will be over 50 by 2015. This estimate includes both individuals who have been infected for a long time as well as newly infected and diagnosed individuals. Despite the wide use of antiretroviral therapy, the prevalence of HIV-Associated neurocognitive disorders (HAND) remains high.
The rationale for this concept is that the pathophysiology of HAND may be distinct in aging populations because of potential interactions with aging-associated diseases, as well as HIV-associated neurodegenerative processes and complications from long-term antiretroviral therapy. The goals will be to support research on elucidating mechanisms of the neuropathogenesis of HAND in the aging population in long-term care treatment settings, and ultimately, to develop better treatments. The research would focus on dysregulated expression of amyloid-beta and other molecules that may affect neurocognition in aging populations.
Kay Redfield Jamison, Ph.D. asked if there had been any study of a subgroup of people who are on these drugs and also are on drugs that might have some sort of neuroprotective effects, such as some of the mood stabilizers and antidepressants. Dr. Rausch said NIMH has a small portfolio in this area, but more work is needed.
In response to a question regarding evidence that patients with HIV or AIDS have any enhanced amyloid pathology, Dr. Rausch said there is some evidence that there is an earlier onset of Alzheimer’s disease in HIV-infected patients, although this area has not been well studied.
Grand Challenges in Global Mental Health
Creating Diversity and Leadership in the Next Generation of Mental Health Researchers
Determinants and Mechanisms of Prevalence Patterns of Common Mental Disorders in Diverse Populations
Pamela Collins, M.D., M.P.H., presented three concepts. The first, “Grand Challenges in Global Mental Health,” aims to support innovative research that will generate the major scientific advances needed to make a significant impact on the lives of people living with neuropsychiatric disorders worldwide. The goal is to support research to address barriers that, if removed, will have a significant impact on the prevention and treatment of mental disorders worldwide. While mental disorders account for a considerable proportion of the global burden of disease, despite the suffering and disability, there are relatively few resources allocated to fund the necessary research to prevent, preempt, and treat neuropsychiatric disorders. This initiative envisions research that prioritizes community engagement, considers the affordability of research products so they can be applicable to a variety of health systems, and enables access to the interventions or research products produced.
This initiative encourages research that uses a life course perspective to address questions that attend to the natural evolution of mental disorders and specific questions of prevention, preemption, and treatment relevant to children, adults, and the elderly. Scientific areas of interest include research examining the interaction between physical and mental health in producing patterns of disparities; cross-national comparisons of treatment delivery models for mental, neurological, and substance use disorders; and, the creation of a mental health toolkit for integration into broader health interventions for children in conflict settings.
The second initiative, “Creating Diversity and Leadership in the Next Generation of Mental Health Researchers,” aims to leverage existing infrastructure to support the career development and training of outstanding early career mental health researchers from disadvantaged backgrounds. The anticipated outcomes are: an increase in the number of faculty from disadvantaged backgrounds who are committed to academic careers in neuroscience research, clinical investigation, or mental health services research, and who will encourage and foster the development of succeeding classes of such scholars; the development of a cadre of mental health researchers grounded in the advanced methods and approaches needed to solve tough mental health problems; and, an increase in the number of researchers from disadvantaged backgrounds who receive research grant support from NIMH.
The third initiative, “Determinants and Mechanisms of Prevalence Patterns of Common Mental Disorders in Diverse Populations,” aims to stimulate research on the determinants and mechanisms over the life course that produce variation in the prevalence of common mental disorders (CMD) across diverse populations. It builds on what has been learned from collaborative psychiatric epidemiologic surveys that show substantial variation in the prevalence of CMD across diverse populations.
The nature and relevant timing of risk and protective factors, across and within groups, is not clearly known. Also, little is known about intermediate phenotypes and endophenotypes across diverse populations; basic discovery research in key domains and constructs across units of analysis could illuminate mechanisms. This initiative would stimulate research in two directions. One would build on what is understood from the epidemiologic studies to try to identify risk and protective factors across the life course that produce variation in CMD. The other would go deeper evaluating the differences in brain functioning and psychopathology by examining intermediate phenotypes and endophenotypes across diverse populations.
In response to a question regarding ongoing efforts at NIMH to increase the diversity of researchers, Dr. Collins noted that current programs would continue. NIMH has ongoing initiatives that focus on a number of underrepresented groups—including people with disabilities, people from socioeconomic disadvantaged backgrounds, and underrepresented racial and ethnic minority groups. She also noted an NIH-wide funding initiative through the NIH Blueprint for Neuroscience Research, namely the NIH Blueprint for Enhancing Neuroscience Diversity through Undergraduate Research Education Experiences initiative. This program is focused on an earlier stage of development—getting undergraduates involved in research and moving them through the pipeline.
With regard to the third initiative, Dr. Lewis-Fernandez commented that it is important to realize that many of these epidemiologic findings need to be understood in terms of their validity for particular groups. He noted that around the world, when using the same methodology, incredibly different rates of psychopathology result.
Dr. Simon said that regarding global challenges in mental health, it is important to emphasize the need to ensure that the research produces generalizable knowledge; this requires a more coordinated effort and more collaboration, especially when independently funding separate projects. There is a need, he said, to bring people together who have been funded independently to ask how their work is related and what can be learned from it.
Dr. Jarvis said that regarding the third initiative, it would be a good idea to look at genetic versus social differences. Regarding the issue of getting more investigators into mental health research, it is important to try to keep an open mind about the different mechanisms that could be used to make that happen.
Dr. Insel thanked both the presenters and Council members, and Council voted to unanimously approve all nine concept clearances that were presented. Dr. Insel reminded Council members and members of the public that the cleared concepts will be posted to the NIMH Web site and there will be opportunity for additional comment through those Web pages.
Dr. Insel noted that due to time constraints, the presentation by Dr. David Chambers, “Advancing Mental Health Services and Interventions Research through Information Technologies,” would need to be postponed until the May Council meeting.
There were no public comments.
Comments from Dr. Carl Bell
After serving three years as a member of NAMHC, Dr. Bell announced his resignation. Dr. Bell commented that there has not been sufficient attention to public health, prevention, and health promotion activities or to issues of diversity. Dr. Bell noted that the Institute’s shift in emphasis from dissemination, adaptation, and implementation of efficacious interventions to more basic science continues despite his efforts, and that he will now focus his energies on pursuing the deployment of the important interventions described in the Institute of Medicine’s 2009 Report titled, “Preventing Mental, Emotional, and Behavioral Disorders Among Young People: Progress and Possibilities.”
Dr. Insel said that Dr. Bell’s decision is respected, and that Dr. Bell has brought important insights to the Council and to the Institute. He also indicated that Dr. Bell would be missed and that the Institute will strive to find an individual to advise it in these important areas.
Dr. Insel adjourned the meeting at approximately 12:30 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Thomas R. Insel, M.D., Chairperson
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National Institutes of Health
National Institute of Mental Health
National Advisory Mental Health Council
(Terms end 9/30 of designated year)
Thomas R. Insel, M.D.
National Institute of Mental Health
Jean Noronha, Ph.D.
Division of Extramural Activities
National Institute of Mental Health
National Institutes of Health
- David G. Amaral, Ph.D. (12)
Department of Psychiatry
The M.I.N.D. Institute
University of California, Davis
- Carl C. Bell, M.D. (11)
President and CEO
Community Mental Health Council and Foundation, Inc.
- Robert Desimone, Ph.D. (11)
Director, McGovern Institute for Brain Research
Massachusetts Institute of Technology
- Ralph J. DiClemente, Ph.D. (12)
Department of Behavioral Sciences and Health Education
Rollins School of Public Health
- Howard B. Eichenbaum, Ph.D. (12)
Professor and Director
Center for Memory and Brain
Department of Psychology
- Daniel H. Geschwind, M.D., Ph.D. (11)
Gordon & Virginia MacDonald
Distinguished Chair in Human Genetics
Professor of Neurology & Psychiatry
University of California, Los Angeles
Los Angeles, California
- Portia E. Iversen (12)
Cure Autism Now Foundation and Autism Genetic Resource Exchange
Los Angeles, California
- Kay Redfield Jamison, Ph.D. (13)
The Dalio Family Professor in Mood Disorders
Professor of Psychiatry
Department of Psychiatry and Behavioral Sciences
The Johns Hopkins University School of Medicine
- Erich D. Jarvis, Ph.D. (Ad Hoc)
Department of Neurobiology
Duke University Medical Center
Durham, North Carolina
- David A. Lewis, M.D. (11)
Director, Translational Neuroscience Program
University of Pittsburgh
- Roberto Lewis-Fernandez, M.D. (13)
Professor of Clinical Psychiatry
Columbia University Director
NYS Center of Excellence for Cultural Competence and Hispanic a Treatment Program
NY State Psychiatric Institute NYSPI
New York, New York
- Thomas H. McGlashan, M.D. (12)
Department of Psychiatry
Yale University School of Medicine
New Haven, Connecticut
- John W. Newcomer, M.D. (Ad Hoc)
Senior Associate Dean for Clinical Research
Leonard M. Miller Professor of Psychiatry and Behavioral Sciences
Leonard M. Miller School of Medicine
University of Miami
- Steven M. Paul, M.D. (12)
Appel Alzheimer’s Disease Research Institute
Professor of Neurology (Neuroscience) and Psychiatry
Weill Medical College of Cornell University
New York, New York
- Rhonda Robinson Beale, M.D. (13)
Chief Medical Officer
Optum-Health Behavioral Solutions
- Carl Shatz, Ph.D. (13)
Professor of Biology and Neurobiology
James H. Clark Center
- Gregory E. Simon, MPH, M.D. (14)
Senior Scientific Investigator
Center for Health Studies/Behavioral Health Service
Group Health Cooperative
Ex Officio Members
- Office of the Secretary, DHHS
Department of Health and Human Services
- National Institutes of Health
Francis Collins, M.D., Ph.D.
National Institutes of Health
- Veterans Affairs
Ira Katz, M.D., Ph.D.
Department of Veterans Affairs
Office of Mental Health Services
- Department of Defense
John A. Ralph, Ph.D.
Commander, U.S. Navy
National Naval Medical Center
A. Kathryn Power, M.Ed.
Director, Center for Mental Health Services
- The U.S. Census Bureau’s 2000 Census indicates 3.6 percent of Census respondents identified as Asian and 12.3 percent of respondents identified as Black.
- The U.S. Census Bureau’s 2000 Census indicates 12.5 percent of respondents identified as Hispanic and 75.1 percent of respondents identified as White.