January 10–11, 2008
Department of Health and Human Services
Public Health Service
National Institutes of Health
Hational Institute of Mental Health
The National Advisory Mental Health Council (NAMHC) convened its 217th meeting in closed session to review grant applications at 11:00 a.m. on January 10, 2008, 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 session the following day, January 11, 2008, in Building 31C, National Institutes of Health, Bethesda, Maryland, from 8:30 a.m. until adjournment at 12:45 p.m. In accordance with Public Law 92-463, the open 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)
- Council Members:
- Elizabeth Childs, M.D., P.C.
- Jonathan D. Cohen, M.D., Ph.D.
- Robert Desimone, Ph.D.
- Raquel E. Gur, M.D., Ph.D.
- Peter J. Hollenbeck, Ph.D.
- Dilip V. Jeste, M.D.
- Norwood Knight-Richardson, M.D., M.B.A.
- Helena C. Kraemer, Ph.D.
- Pat R. Levitt, Ph.D.
- David A. Lewis, M.D.
- John S. March, M.D., M.P.H.
- Enola K. Proctor, Ph.D.
- Suzanne E. Vogel-Scibilia, M.D.
- Thomas R. Insel, M.D.
- Executive Secretary
- Jane A. Steinberg, Ph.D.
- Liaison Representative Present at the Open Policy Session:
- Pamela Fischer, Ph.D., representing A. Kathryn Power, Center for Mental Health Services (CMHS), Substance Abuse and Mental Health Services Administration (SAMHSA)
- Others Present:
- Brian Altman, Suicide Prevention Action Network USA
- Carol Alter, Academy for Psychosomatic Medicine
- Kevin Beverly, Social and Scientific Systems
- Gabriella Bosa, National Council
- Andrea Browning, Society for Research in Child Development
- Thomas Bryant, National Foundation for Mental Health
- Lindsey Dartt, National Alliance on Mental Health
- Debra Derr, Executive Reporters, Transcriptionist
- Marci Giang, Council on Social Work Education
- Martin Gittelman, NYU School of Medicine
- Elizabeth Hoffman, American Psychological Association
- Jenny Jones, Council on Social Work Education — Minority Fellowship Program
- Marc Lerro, Eating Disorders Coalition
- James McNulty, National Alliance on Mental Illness
- Anne Michaels, National Foundation on Mental Health
- Paula Moore, LRP Publications
- Diane Morales, Mental Health America
- Gerald Overman, College of Psychiatric and Neurologic Pharmacists
- Amy Pollick, Association for Psychological Sciences
- Darrel Regier, American Psychiatric Institute for Research and Education
- Kristen Ricchetti, Society for Women’s Health Research
- Michelle Rodrigues, SRI International Inc
- Bette Runck, Science Writer
- Viviana Simon, Society for Women’s Health Research
- Jane Tilly, Alzheimer’s Association
- Barbara Wanchisen, Federation of Behavioral, Psychological and Cognitive Sciences
- Joan Levy Zlotnik, Institute for the Advancement of Social Work Research
Open Policy Session: Call to Order and Opening Remarks
NIMH Director, Thomas R. Insel, M.D., called the open policy session to order, welcoming all in attendance. He introduced two new Council members: Robert Desimone, Ph.D., Director of the McGovern Institute for Brain Research at the Massachusetts Institute of Technology and former Scientific Director of the NIMH Intramural Research Program (IRP); and David Lewis, M.D., Director of the Translational Neuroscience Program and an endowed Professor in translational neuroscience in the Department of Psychiatry at the University of Pittsburgh.Dr. Insel also introduced Pamela Fischer, Ph.D., representing SAMHSA.
Approval of the Minutes for the Previous Council Meeting
Turning to the minutes of the September 2007 Council meeting, Dr. Insel asked if Council members had revisions or comments on the minutes. Hearing none, the minutes were unanimously approved.
Roadmap: Dr. Insel updated the Council on the progress of the NIH Roadmap, which began in 2003. Its purpose is to serve as an incubator for novel science across all NIH Institutes and Centers (ICs). The initiatives selected, epigenomics and microbiome, are revolutionary approaches that are relevant to NIMH. Requests for applications (RFAs) were recently issued for research on epigenomics, i.e., proteins and other factors that modify gene expression. The Roadmap effort is directed at developing the needed tools for epigenomics. The novel area of microbiomics involves the study of the DNA of the microbial DNA that “live on us, in us, and around us” by using new genomic technology. Microbial DNA, Dr. Insel said, is thought to exceed human DNA by at least 10 times in the human body. Discussion of the next phase of the Roadmap, version 2.0, will begin at the end of this year, when the next set of initiatives will be generated.
Public Access: Public access of NIH supported research will increase as a result of the passage of the Consolidated Appropriations Act, which was signed by the President on December 26, 2007. Previously, NIH had encouraged NIH grantees to submit final peer reviewed manuscripts within a year of publication to PubMed Central, which is a centralized database managed by the National Center for Biotechnology Information within the National Library of Medicine. Under the Consolidated Appropriations Act, submission is required, not voluntary. The Howard Hughes Institute in the United Kingdom already has such a requirement and at least 90 percent of manuscripts generated with National Research Council funding go into a public access database. The NIH Office of Extramural Research will be issuing specific instructions in the near future.
Peer Review: Final recommendations from the committee examining the NIH peer review system are expected in the next 2 months. Discussion at the Advisory Committee to the Director in December made it clear that the changes will be major, with the goal of supporting more innovative research. The current system may not be completely overhauled, but experiments will be undertaken to explore different ways of soliciting and reviewing grants and different ways of supporting innovation.
Neuroscience Blueprint: The Neuroscience Blueprint, a collaborative effort of 16 ICs with an interest in neuroscience, was launched in 2005. The focus in 2007 was neurodegeneration; in 2008, the focus is neurodevelopment, and there already are several RFAs out on this subject. The focus in 2009 will be neuroplasticity. After 2009, the subject of interest has not been decided and ideas are welcome. One possibility is taking on a grand challenge such that the focus would not be specific to any one disease but would ideally provide either better translation, better tools, or a mechanism that would transform the current approach to the science underlying disease across all of the ICs.
Budget: The budget appropriated for NIMH for 2008 is $1,405 million. After several months of negotiations, the final budget included a 0.1 percent increase over 2007; this is the fifth year that NIMH has had a subinflationary budget. By contrast, inflation for biomedical research has been running between 3.5 and 4.5 percent and is estimated to be 3.7 percent this year. A conservative estimate is that NIMH has lost about 10.9 percent of its purchasing power since 2004, and this will continue in 2008.
Dr. Insel pointed out that the average cost of grants has crept up over the last decade. Although the cost was supposed to have been held flat in 2007, research project grants averaged $350,000, up from $324,000 in 2006, not including the cost of centers or training grants. The increase occurred despite an average 10-percent cut in all new research project grants. The FY08 appropriation level allows for a 1 percent inflationary increase to non-competing research grant awards in 2008, a target that will be very difficult to meet.
It is likely that NIMH will be able to fund only about 500 new and competing applications in 2008, down from 620 applications funded in 2007. The success rate will continue to decline unless new management strategies are devised. The success rate for NIMH grant applicants–that is, the probability that any given application will be funded with as many as three reviews–was close to 30 percent for ongoing principal investigators in 2003. The success rate for all applicants was 27 percent that year. For 2008, the comparable rates are likely to be less than 18 percent. With the current budget, the research community will have to expect fewer grants and, probably, less money per grant relative to the growth we had seen in the last few years.
NIMH is committed to trying to make sure that these reductions do not result in the loss of a generation of investigators. The aggregate number of new principal investigators has been about 95 over the last 5 years. In 2007, 98 new principal investigators were funded, but that number is likely to decline to about 91 in 2008. In answer to a question from Dr. Vogel-Scibilia, Dr. Insel said that approximately 80 to 90 new investigators were funded each year before 1995, when the doubling of NIH budgets began. By 2001, the number had reached 144 but had dropped precipitously to 86 2 years later.
Genomics and Mental Health
Dr. Insel introduced Francis Collins, M.D., Director of the National Human Genome Research Institute (NHGRI). He was recently awarded the Presidential Medal of Freedom, the highest honor given to a U.S. citizen, an honor rarely awarded to a scientist.
Dr. Collins began his presentation by noting that in the 3 years since he last addressed the NAMHC, the approach that genomics offers for understanding the pathogenesis of common disease has advanced significantly. Given the phenomenal and unprecedented opportunities, it is unfortunate that current budgets require austerity, Dr. Collins said. A major focus since the sequencing of the human genome has been to understand human genetic variation well enough to be able to pursue common diseases that are not inherited in simple Mendelian ways. One strategy, the case-control association study, can now be done across the entire genome. Using that strategy, scientists identify individuals who are affected by a variant and those who are unaffected and then note the skewing of the distribution of the variant between the two groups. On occasion, association studies of a candidate gene yielded useful findings. More often, studies of candidate genes for common diseases such as schizophrenia and bipolar illness prove frustrating.
Five years ago, a more comprehensive approach was devised. It required a complete catalog of the single nucleotide polymorphisms (SNPs) in the genome, as well as at least a thousand cases and controls to have sufficient power to be able to see a subtle difference in frequencies of variations between cases and controls. The very large number of comparisons would entail sacrificing statistical validity. In addition, the genotyping alone would be prohibitively expensive: about 20 billion genotypes would be needed at 50 cents a genotype. This hypothetical strategy seemed unrealistic and unapproachable until recently, when technological and scientific advances have made it feasible.
A major reason is the result of the International HapMap Project, an ambitious international effort led by the NIH that is assembling a comprehensive map of human genetic variation. Instead of analyzing 10 million SNPs, variations are examined in haplotypes, the regions of variants that tend to be inherited together. Thus, a much smaller set of genotypes can be studied — 300,000 to 500,000 — and can serve as proxies for the rest. A huge amount of lab work and associated costs are thereby avoided. New, more efficient genotyping technology has also resulted in a reduction in cost from about 50 cents per genotype down to about a tenth of a cent. At the same time, the quality and speed of genotyping has improved. Given these developments, genome wide association studies (GWAS) can now be done on a much smaller list of SNPs. And the cost of an association analysis is now well under $1 million, whereas it would have been $10 billion before.
In 2005, the first success story for this HapMap based GWAS was age related macular degeneration. In 2006, three more associations were found. By 2007, the associations number in the hundreds. Science magazine, recognizing this unprecedented development, announced that the breakthrough of the year in all of science in 2007 was human genetic variation, the discovery of which is shedding light on common diseases.
Dr. Collins highlighted the Genetic Association Information Network (GAIN), a public private partnership now underway among NIH, the Foundation for NIH, and the private sector. With GAIN resources, investigators who had already collected cases and controls have access to free genotyping; in return, after nine months of exclusive rights to publish their findings, they make their data (genotypes and phenotypes) available to other qualified investigators. The GAIN project selected six projects, four of which examine mental disorders: attention deficit hyperactivity disorder (ADHD), major depression, schizophrenia, and bipolar disease. The genotyping is nearly complete for these projects, and data analysis is well underway for two of them.
Dr. Collins pointed out that GAIN has become a model for NIH policy on GWAS and open access to other large and complex datasets. All of the output from GAIN and other studies are being deposited in the Database of Genotype and Phenotype (dbGaP), which was developed by the NIH National Center for Biotechnology Information. Investigators who want access to the data can apply to this clearinghouse. Policies are in place to ensure that secondary uses of the data comply with original consents and protect the privacy and confidentiality of the participants.
The GWAS may provide insight into new drug targets, Dr. Collins said. Most of the genes discovered in the last couple of years had not previously been considered relevant. These genes offer exciting new possibilities of approaching therapeutics for many common diseases, including psychiatric illnesses, although the process of getting an FDA approved drug will be long. In addition to the implications for therapeutics, diagnosis can become more precise as soon as validated variations associated with disease are discovered. How to apply that knowledge in the standard practice of medicine is the subject of considerable debate because many of the genes’ effects are modest. Although the clinical usefulness of genomics may be years away, its value for understanding pathogenesis is near at hand.
During the discussion that followed Dr. Collins’s presentation, Dr. Kraemer recommended that association studies measure effect size, which provides more valuable information than p values. Dr. Collins agreed and said that, in general, effect sizes for these variants are being reported as odds ratios. Most are about 1.2 to 1.3 — maybe as much as 1.5 or 1.6 — except for macular degeneration, where a variant has been found that has a large effect.
Dr. Collins said that odds ratios are useful in predicting a person’s future risk of disease because they indicate the predictive strength of a genetic variation. But they are irrelevant to understanding pathogenesis. The variant simply points to a gene, a protein, and a pathway, not how involved they are. Two of the 10 susceptibility genes found for diabetes had very small odds ratios, yet they were the drug targets for two of the major classes of drugs currently used to treat diabetes. It is likely that there are some powerful drug targets in the long list of new discoveries, but it is not clear which ones they are.
Dr. Kraemer pointed out that the mediation of genes by environmental factors may be very important in explaining a relationship. Dr. Collins agreed, noting that studies must be as empowered in the collection of environmental exposure data as they are in the collection of genetic data. The Genes Environment Initiative brings together environmental and genetic researchers in collaborations that have not been seen before. Dr. Levitt noted that many of the challenges will entail to the functional domains, which are likely to be in regulatory regions. He asked if technology will soon make it possible to examine those regions more rapidly than is now possible. Dr. Collins said that part of an ongoing effort known as the Encyclopedia of DNA Elements (ENCODE) Project is to identify and characterize functional elements in the human genome experimentally. Discussions are underway about which core set of cell lines should be included. In addition, a possible Roadmap initiative is to develop a publicly accessible set of carefully characterized human tissues for doing research on gene expression in those tissues and genotypes.
Dr. Jeste suggested that studies be undertaken on the genetics of health and well-being because health is not merely absence of disease. Dr. Collins said that such studies are a “grand challenge.” It would be especially interesting to look at exceptionally healthy people, particularly those who have had an environmental exposure normally associated with pathology but have evaded it. Although such studies have not yet gotten off the ground, the National Institute on Aging has a big investment in research on the genetics of exceptional longevity. Other possible studies could be done in the obese or long-term smokers who have somehow evaded negative consequences for their health. Dr. Insel said that in the mental health framework, the genetics of resilience is also of interest.
Dr. Insel asked for advice about managing expectations. The GAIN schizophrenia and bipolar projects are nearly finished. The ADHD and depression projects are underway. It is possible that nothing impressive will emerge from the several thousand sample cases and controls that have been collected. The depression data appear to show completely novel, interesting findings, although the data need to be clarified and replicated. Absent are the kind of findings in many other disorders, which are either common variants with large effects or multiple, very clear common variants of high statistical significance. Dr. Collins acknowledged that the first set of cases and controls have not yielded important findings for other diseases as well. He said that larger samples are needed; the findings in diabetes, for example, would not have been positive if the studies had been limited to a couple of thousand samples. It is quite clear that schizophrenia, bipolar disorder, and ADHD are not purely environmental conditions. If the heritability has not yet been found by this approach, then presumably it is hiding in some other form. The ability to look at copy number variation is advancing quickly; in this strategy, large segments of DNA may be duplicated or deleted; variation in expression comes not from a point mutation but on a very large copy number effect. If that approach does not yield results, then it might be prudent to look for those rare variants of large effect that are missed by the current effort but which might very well be, for some diseases, the major contributor.
Dr. Collins said that following the successive steps may be necessary to arrive at definitive data on which variants are involved in disease. He appealed to the group not to become discouraged by the early failures to find such evidence. Dr. Insel noted that the most recent American Journal of Human Genetics published three independent studies that found the identical gene for autism. Such developments provide reason for hope. Healthy skepticism is warranted; however because particularly in psychiatric genetics, false leads have abounded. It is likely that large samples will be needed to pinpoint the genes involved in psychiatric illnesses.
In closing, Dr. Collins acknowledged Kathy Kopnisky, Ph.D., who recently left NIMH to become his new Chief of Staff.
NIMH Strategic Plan
Dr. Insel reminded Council of the four objectives outlined in the strategic plan.
- Promote discovery in the brain and behavioral sciences to fuel research on the causes of schizophrenia, depression, and other mental disorders.
- Chart mental illness trajectories to determine when, where, and how to intervene.
- Develop new and better interventions for mental disorders that incorporate the diverse needs and circumstances of people with mental illness.
- Strengthen the public health impact of NIMH-supported research.
Dr. Insel reported that the draft strategic plan issued last fall for public comment elicited more than 500 responses. The comments about the strategic plan came in from a wide range of mental health researchers and professionals, people with mental illness and their families, and the entire spectrum of professional and advocacy organizations. After a comprehensive review of all the comments, three major themes emerged:
- Research should focus on alternatives to pharmacological treatments, and disorders should not be addressed solely as biological in origin.
- More focus needs to be given to behavioral and social science research, as well as the environmental factors associated with mental illness.
- NIMH should focus on recovery and self-management, including studying new practices and services specifically targeted to these areas.
Dr. Insel invited additional comments from Council members. Dr. Proctor asked whether the strategic plan would prepare NIMH to support research into gene environment interactions. Dr. Insel said that the topic, which is increasingly being referred to as epigenetics, is directed at understanding how the environment affects function by changing gene expression. The field has begun to develop the tools for looking at genomic tags to study long term effects on the patterns of gene expression and ultimately the patterns of brain development that result in vulnerability to mental disorders.
Dr. Levitt said that the NIH Blueprint highlights a natural tension between the disciplines of the physical and biological sciences on one hand and the social and educational sciences on the other. It is important to use the Blueprint to facilitate the process of encouraging these disciplines to work together.
Dr. Cohen agreed with Dr. Levitt’s remarks. He added that collaboration to advance methodological discoveries is also needed. Similar methodologies are needed for analyzing neuroimaging datasets as are needed for the genetic analysis discussed by Dr. Collins. Both types of study involve huge numbers of data points and must deal with the problems of multiple comparisons and multivariate versus univariate analyses. It might be efficient to find out the fundamental mathematical problems in analyzing huge datasets and then tweak the tools rather than having to rediscover the basic principles of analysis de novo each time. Dr. Insel agreed, noting that the strategic plan is meant to provide a blueprint for transforming the science, rather than to suggest small incremental changes.
Dr. Gur pointed out that NIMH supported the development of common tools for genetic studies and suggested that similar tools are needed to measure environmental stress so that researchers can take advantage of the samples collected for genetic studies. Dr. Insel said that NIMH has about 70,000 DNA samples and cell lines currently in the repository. What is missing are common phenotypic measures or a consensus for obtaining them. That approach is being developed in autism but is not underway as systematically in other disorders. With a consensus battery for data collection, more cross study comparisons would be possible.
Dr. March emphasized the need for a new kind of interventional research. Our research needs to explore how effective treatments can be disseminated. How do these treatments act within the framework of how the brain learns? Are the systems that are involved in adult neuroplasticity or learning the same systems that are targets of these cognitive behavioral interventions? Dr. Insel said that Dr. March had captured what the strategic plan was trying to do.
Dr. Hollenbeck said he wanted to underline the importance of the fourth objective of the strategic plan. Services research and innovation will be simply an academic exercise unless there is a focus on dissemination and implementation research. The delivery system is almost inevitably more complex and perhaps more expensive for mental health issues than for other diseases, such as heart disease. But if only 3½ percent of adults with heart disease were effectively treated, research on those treatments would not be considered successful.
In answer to a question from Dr. Childs, Dr. Insel said he thinks the strategic plan crystallizes discussions the Council has been having over the last 5 years. By creating a formal plan, the mission and vision of the Institute are explicated. Action plans for every division will be based on the plan’s objectives. One difficulty is to find a measurement of the success of this plan. More thought is needed to develop the measures of impact and success.
NAMHC Workgroup on Neurodevelopment: Update on Activities and Workgroup Recommendations
Progress of the Council Workgroup on Neurodevelopment was described by Dr. Levitt, who, together with Dr. March, chaired the workgroup. He noted that the developmental basis of mental illness has been recognized for more than 100 years, although that recognition has come primarily through inference and epidemiological studies. The mechanisms by which alterations in development lead to mental illness are still a black box. Dr. Levitt reminded Council of its charge to the workgroup:
- Integrate developmental neuroscience, behavioral science, and psychopathology to forge a deeper understanding of the pathways leading to mental illnesses?
- Stimulate the discovery of the molecular, genetic, experiential, and environmental underpinnings of mental illnesses in development?
- Foster translational science to improve indicators of risk, to specify causal mechanisms, and to develop effective preemptive interventions?
- Use training, research resources, and infrastructure support to speed scientific discovery and produce a diverse workforce of translational researchers?
The workgroup’s rapid schedule began last May with the review of the NIMH research portfolio and will conclude with the final report. In describing the discussion of the first question posed in the workgroup charge, Dr. Levitt credited Dr. March with pointing out that scientists tend to gravitate to research opportunities that are intriguing. The workgroup proposes to define the field of translational developmental neuroscience as an organizing novel discipline. To understand developmental etiology, it is necessary to study developmental time periods in the context of integrating basic and translational approaches.
In answer to the second question, the workgroup suggests that NIMH stimulate the discovery of molecular, genetic, experiential, and environmental underpinnings of mental illness in development by working with NIH to develop tools and approaches. Among them are tools for rapid in vivo gene manipulation and analysis; methodologies in high-throughput analysis of cell function that are adaptable to basic laboratories; adaptation of methods to examine transcriptional regulatory mechanisms in the brain; expansions of banking and database efforts to include microRNA, splice variants, and a transcriptional atlas in the nonhuman primate and in human development; and robust partnerships with advocacy groups and community leadership to enhance the collection and analysis of large, ethnically diverse biomaterials and patient cohorts.
The third question involves fostering translational science to improve indicators of risk, to specify causal mechanisms, and to develop effective preemptive interventions. The workgroup recommended establishing creative, behaviorally validated tasks for use across developmental time points and species; and testing state-of-the-art cognitive and affective neuroscience assessments in the clinic to advance diagnostics and interventions. It also appears essential to enhance interdisciplinary collaboration by creating opportunities for effective cross-disciplinary communication among grantees and NIMH staff/programs; establishing a basic neurodevelopment branch in the IRP; using modern technologies to exchange knowledge effectively; and collaborating with patient advocacy groups.
The fourth question concerns the use of training and research resources and infrastructure support to speed scientific discoveries. Dr. Levitt acknowledged that tight budgets make such undertakings challenging. The workgroup recommended attracting clinician-scientists, particularly in the fields of developmental pediatrics and pediatric neurology. Other recommendations are to integrate research and training initiatives and to provide exposure to translational opportunities and new technologies through summer institutes, mini-sabbaticals, and technical applications institutes.
Following Dr. Levitt’s presentation, Dr. March added that if mental illness is to be prevented or cured, it is essential to have early developmental trajectory based research. The workgroup recommendations are designed to highlight where the interesting opportunities are in science. A new field emerges when the scientific opportunities ripen, and they ripen in a way that requires collaborations across disciplines, across areas of science (e.g., cellular, molecular systems, neuroscience) and across platforms. Dr. Gur, another member of the workgroup, said that the workgroup itself was an excellent example of how the integration of basic and clinical scientists can occur.
Dr. Kraemer, addressing methodological concerns, said that in the last 10 years there has been enormous progress in analyzing longitudinal data, but many Ph.D. and M.D. scientists are not trained in these new methods. It will be necessary to train investigators who conduct longitudinal research, such as neurodevelopmental work. Dr. Levitt said that the workgroup report does underscore the need for increasing use of complex bioinformatics and biostatistical approaches.
Dr. Kraemer also raised the problem of getting longitudinal studies approved and funded. It is unlikely that these studies will achieve their full goals in a five year funding period; if a renewal is not obtained, the cohort is interrupted and the infrastructure of the study may be lost. She suggested that new review mechanisms may be needed for this type of study. Dr. Insel said that the report makes the point that, particularly in neuroimaging in childhood illnesses, it is necessary to shift from studying the destination to studying the journey to look at how the brain changes over time.
Dr. March agreed that traditional funding mechanisms may not be sufficient for the new field of translational developmental neuroscience, where studies will require teams made up of scientists doing cellular, molecular, and systems neuroscience, developmental epidemiology, and biostatistics, as well as clinicians. Studies are needed that go from animal models into humans. To carry out the parallel studies in clinical populations and in animal model systems, it may be necessary to develop different funding mechanisms or to rely more heavily on contracts as were used with the large clinical trial networks of the past few years.
The Council then unanimously concurred with the recommendations of the workgroup. Dr. Insel thanked the workgroup and acknowledged the significant contributions of Dr. Jane Steinberg and other NIMH staff.
Novel Interventions for Neurodevelopmental Disorders
Judith M. Rumsey, Ph.D., Program Chief within the Neurodevelopmental Disorders Branch of the Division of Developmental Translational Research, described an initiative that seeks to stimulate the development of novel interventions for neurodevelopmental disorders, with the aims of improving various domains of functioning that are impaired across disorders and of altering developmental trajectories. Early onset disorders such as autism spectrum disorders, childhood-onset schizophrenia, ADHD, OCD, and Tourette’s syndrome frequently result in lifelong impairment despite treatment with existing approaches. The phenotypic variability within disorders, their comorbidities, and shared domains of impairment provide a rationale for the development of novel therapeutic approaches that may well hold potential for application across disorders.
Dr. Rumsey described a few examples of the types of studies that might be supported under this initiative such as novel medications or drug combinations or new applications of existing medication regimens; novel behavioral therapies based on recent neuroscience findings; adaptive computerized cognitive training; neurofeedback using real time functional MRI or other indicators of brain activity; therapeutic noninvasive neurostimulation; and treatments that incorporate the use of new technologies, such as virtual reality or robotics.
In the discussion that followed Dr. Rumsey’s presentation, Dr. Levitt suggested including childhood-onset bipolar disorder as a target of this initiative. Dr. Vogel-Scibilia agreed. Dr. Rumsey agreed and noted that regulation of emotion is one of the domains of functioning that may be addressed under this initiative.
In response to concerns about the age of potential subjects, Dr. Rumsey said that adolescent subjects were not excluded given the chronicity of these disorders. Nevertheless, she said, most of the study subjects will probably be younger children.
Dr. March applauded the initiative and suggested that emphasis should be placed on developing trajectory based rather than cross sectional interventions or studies that involve some state change. He also said that if the aim is to go after intermediate phenotypes that are shared across disorders, some attention might be given to defining those intermediate phenotypes so that they can be studied in parallel in animal models where possible.
Networks for Developing Post-Traumatic Stress Disorder (PTSD) Risk Assessment Tools
Farris Tuma, Sc.D., Program Chief within the Traumatic Stress Disorders Research Program of the Division of Adult Translational Research and Treatment Development, described an initiative that has developed out of a need to accelerate research in the prevention or preemption of PTSD given the recent reports of high rates of PTSD among veterans returning from current conflicts and among disaster survivors, terrorist survivors, shootings, and other forms of interpersonal violence and trauma.
Over a lifetime, exposure to traumatic events occurs at high levels. PTSD is among the most common conditions associated with trauma exposure, yet the majority of exposed and symptomatic persons naturally recover functioning. For those who do not recover, PTSD and related co-morbidity can be quite debilitating. While research into the pathophysiology of the disorder has opened avenues for preemptive intervention, we are currently unable to differentiate trauma survivors who will recover naturally from those who will develop enduring symptoms. The PTSD literature is rich with epidemiological studies of correlates and potential risk and resilience factors, as well as treatment and intervention studies. Among the factors isolated as predictors of recovery or failure of recovery after trauma are individual characteristics, demographic factors, prior history, and post-traumatic sequelae. None of these has proven adequate.
The proposed initiative would establish interdisciplinary teams or networks for exploratory studies combining, weighing, and sequencing measures of PTSD risk derived from existing data (past trials and epidemiological studies) and/or in the context of ongoing PTSD studies. The expected outcomes of the network(s) would be preliminary data on risk assessment tools that are sensitive to and balance statistical and clinical significance for future prediction and preemption studies and research to develop clinical decision tools. Teams are envisioned to include neuroscientists, geneticists, clinical researchers, psychometricians, and clinimetricians and to span several levels of analysis (e.g., molecular to behavioral).
Dr. Jeste suggested that NIMH might pool resources with the U.S. Department of Veterans Affairs, which is investing heavily in this area.
Dr. Kraemer suggested that documents related to the initiative should refer to “exploratory datasets” instead of “pilot data.” She also mentioned that in recent years cardiologists have substituted signal detection methods for the long-used logistic regression analysis. She recommended that new methods of classification be considered as they have proved to be more successful and useful to clinicians.
Dr. Knight Richardson emphasized the need to specify inclusion of variable symptom expression across ethnic and cultural populations. Such representation is particularly important for PTSD studies, because at some point a population can become so traumatized that the symptoms become accepted into the culture and can be missed by clinicians and researchers.
Dr. Hollenbeck asked about the quantity, quality, richness, and uniformity of existing data on PTSD risk. Dr. Tuma said that a wealth of information has been compiled across populations, communities, samples, points in time, and trauma types; some of it is methodologically rigorous. In addition, NIMH is funding several good, comprehensive studies, some of them prospective longitudinal studies.
Novel NeuroAIDS Therapies: Integrative Preclinical/Clinical Program
Dianne Rausch, Ph.D., Deputy Director of the Center for Mental Health Research on AIDS within the Division of AIDS and Health and Behavior Research, described an initiative that aims to support the development of novel therapeutics for preclinical and clinical neuroAIDS issues. She oriented Council to the fact that this initiative was previously undertaken with the National Institute of Allergy and Infectious Disease with NIMH co-sponsoring it; but it is now being presented as an NIMH initiative. The initiative will provide a targeted mechanism to promote research on the development and evaluation of innovative therapies to ameliorate the central nervous system (CNS) complications of HIV infection. It will foster preclinical studies and encourage the translation of innovative treatments from the bench to bedside. These will be collaborative agreements with heavy programmatic involvement.
Basic research on virus and host interactions is yielding new targets that can be evaluated in the clinic. NeuroAIDS research to date has shown that searching for new targets and treatments having immunomodulatory and neuroprotective properties is a promising endeavor. Although antiretroviral therapy has reduced the incidence of severe HIV associated dementia, the prevalence of milder forms of CNS complications is increasing.
The specific aims of the initiative are to develop and validate new therapeutic targets that interrupt molecular, cellular, and genetic factors or pathways that contribute to the CNS dysfunction; develop strategies or entities to eliminate CNS viral reservoirs, since the virus appears to reside in the brain with a low level of replication and potential damage; develop strategies to improve neuroimmune interactions and/or neural function; and develop gene transfer strategies to interfere with viral replication, spread, or secondary damage of HIV-1.
Recovery After an Initial Schizophrenic Episode (RAISE)
John Hsiao, M.D., Program Chief of the Adult Psychopharmacology Intervention Program within the Division of Service and Intervention Research, described a new initiative that has the goal of improving prognosis and long term outcome for people suffering from schizophrenia. Chronic deterioration and a lifetime of disability remain the norm for persons with chronic schizophrenia. Despite a half century of treatment research, it is clear that skills and abilities lost to chronic schizophrenia are rarely, if ever, regained. Unlike chronically ill patients, patients in their first episode of psychosis often respond very well to treatment, and many individuals are able to attain complete symptomatic remission. Treatment responsiveness changes over time with symptoms become less and less responsive over time; nonetheless, in current practice, management of the first year of illness differs little from management of the 20th year.
The unanswered question is whether aggressive, integrated, and sustained pharmacological, psychosocial, and rehabilitative intervention after an initial schizophrenic episode can forestall chronic disability. Not surprisingly, as patients deteriorate they require more and more attention, and much more is invested in treating chronically ill patients than in managing patients early in the course of illness. Perhaps the treatment goal during a first break should not be just suppressing hallucinations and delusions but also preventing deterioration and preserving function.
The RAISE initiative will be a crucial first step towards answering this question. A single project will be supported to: (1) test the feasibility of recruiting and retaining newly diagnosed patients in a longitudinal trial; (2) develop the treatment model—a mix of pharmacological, psychological, and rehabilitative interventions—that is aimed at the preservation of function and maintenance of patient participation; and (3) determine the appropriate comparison group. This initiative will set the stage for a large-scale, definitive, randomized clinical trial.
During the discussion that followed Dr. Hsiao’s presentation, Dr. Knight Richardson again encouraged careful attention to cultural sensitivity. He suggested that research should be done on how to fashion models that work in rural America and include some study on the use and efficacy of telemedicine as a support for these interventions.
Dr. Childs applauded this initiative, commenting that early intervention could possibly change the trajectory of the illness and its downstream effects, and it would also be more humane.
In answer to a question from Dr. Kraemer, Dr. Hsiao said that the initiative would support preliminary studies to develop the intervention that might be used in a randomized clinical trial rather than the randomized clinical trial itself. The statistics, which will require an adaptive design, will be very complicated. Dr. Kraemer asked if observational studies, quasi experimental studies, and reviews of existing databases would be done. Dr. Hsiao said that the project would start with looking at the existing databases. The exact studies that would be done initially will depend on the consensus of opinion on the best way of approaching the problem. Dr. Insel encouraged thought to what data would be needed to affect policy so that an individual would be covered at the beginning of illness rather than after the fifth failure.
Dr. Jeste said that this project addresses an issue of great public health significance. He asked what kind of a control group will be used. Finding a control group that is scientifically appropriate will be difficult. One that uses “usual treatment” as a control criterion is problematic when what is usual varies significantly by setting. Dr. March said, from a public health perspective, the question is what should be the logical comparison condition for this optimized intervention. He also suggested that the investigators define a very large network with a stable infrastructure that can be used for several longitudinal studies, allowing for the patients to be phenotyped and genotyped, and potentially a subset could be imaged.
Dr. Gur said that since cognitive deficits in schizophrenia appear to be the best predictors of functional outcome, individuals with prodromal symptoms should be studied. When first episode patients present, they have a significant impairment of cognitive functioning when compared with healthy people in the community. She suggested forming partnerships with industry, which now has various cognitive enhancers in the pipeline. She also noted that cognitive psychosocial intervention will be needed as well.
Dr. Lewis suggested that the study be broadened to include all first-episode never-medicated psychosis, since about 40 percent have a nonschizophrenia psychotic disorder. He also asked whether there isn’t already a substantial literature on the feasibility of recruiting and retaining newly diagnosed patients. Dr. Hsiao replied that the existing data is not impressive. Pharmacological studies of first-episode patients tend to follow patients for a year at most. Several studies have been done outside the United States that use multi element interventions for first episodes and have, to date, followed patients for about 2 years.
Limited Competition for Data Deposition and Analysis of Genome-Wide Association Studies of Mental Disorders and Genomic Parsing of Bipolar Disorder and Schizophrenia: Studies of Large Cohorts in the U.S. and Across the Globe
Thomas Lehner, Ph.D., Branch Chief with the Genomics Research Branch within the Division of Neuroscience and Basic Behavioral Science, described two initiatives that have the potential to increase data and samples for psychiatric genetic studies. The first one is a limited competition for data deposition and analysis, which is part of the Psychiatric GWAS Consortium. Founded by the four GAIN principal investigators, the consortium has expanded to more than 30 investigators worldwide. To participate, a member must have whole-genome data and patient consents and must agree to joint analysis.
This initiative would provide some support for statistical analysis and the depositing of data on phenotypes and whole-genome genotypes into the dbGaP and NIMH repositories. This initiative is planned as a limited competition, meaning that it is open only to consortium members. Disorders currently represented are autism, ADHD, major depressive disorder, schizophrenia, and bipolar disorder.
The second initiative Dr. Lehner described would support the collection of samples and genomic studies of very large cohorts of people with bipolar and schizophrenia across the globe. The focus is on rapid sample collection. Two-to-five five-year projects will be supported. The plan is to start both initiatives in 2008.
Dr. Kraemer asked whether any provision had been made in the compilation of these datasets to follow up on control subjects who later developed the disorder; such information might be helpful in the future if developmental studies are done. She also asked it any information is available on age of onset. Dr. Lehner said that age of onset is known for the consortium samples. Controls in the NIMH database that later become ill are not currently followed. The second initiative does not necessarily require the collection of controls. He added that the false-negative rate in controls is high and this can contribute to the loss of precision of the estimates in statistical genetics, although it doesn’t destroy the study.
Dr. Gur again recommended that the samples should include subjects younger than 18 given the recommendations of the Council Workgroup on Neurodevelopment.
Following the discussion, the Council voted to approve all the concepts.
Dr. Martin Gittelman spoke on behalf of the American Association for Psychosocial Rehabilitation, a nongovernmental organization with the World Health Organization. He said his organization is concerned with the failures of the system of care for persons with serious mental illness. Particularly worrisome is the high mortality rate, especially among those with schizophrenia. Some research has shown that individuals with serious mental illness die 25 years before those who do not have such illnesses. It has been suggested that some of the second-generation antipsychotics may be associated with cardiovascular disease and diabetes. Research is needed to determine if these medications contribute to premature death. Dr. Gittelman suggested that more comparative studies between developed countries and the United States are needed.
Dr. Childs said that a study of morbidity and mortality of the entire population of the Massachusetts Department of Mental Health, about 30,000 individuals, found that persons with mental illness do appear to suffer premature death, on average 26 years prematurely. The primary cause of death was cardiovascular disease, exacerbated by diabetes, secondarily by lung cancer. Suicide was a very distant third cause. Analysis of the use of second-generation atypical antipsychotics suggests that the drugs were not the cause of premature death. Nonetheless, Dr. Childs agreed that more research is needed.
Brian Altman, J.D., Director of Public Policy and Program Development at the Suicide Prevention Action Network USA, a nongovernmental organization dedicated to preventing suicide through public education and awareness, community action, and Federal, state, and local grassroots advocacy, cited data on the high rates of attempted and completed suicide. He encouraged NIMH to take a more active role in preventing suicide by funding research leading to evidence based programs and treatments.
Mr. Jim McNulty, representing the National Alliance on Mental Illness (NAMI), said he was happy to hear of the Institute's receptiveness to reactions to the strategic plan, in particular the area of recovery and self advocacy and self management. The challenge now is turning the strategic plan into action, given the funding constraints.
Mr. McNulty said that NAMI would be very interested in the initiative presented by Dr. Hsiao, because it is timely and necessary to intervene after the first episode, or even before if possible. Most individuals participating in studies have been ill for several years before they receive serious treatment. A demonstration that early intervention can prevent the devastation that results from untreated mental illness would be a critical contribution to changes in public policy. NIMH must make sure that the research is done across cultures and ethnic groups.
Dr. Darrel Regier, representing the American Psychiatric Association (APA), said the strategic plan would be presented at the annual meeting of the APA in May, and he hoped that it would be accompanied by an emphasis on transitioning to evidence based care. Dr. Regier reported that the development of a revised Diagnostic and Statistical Manual is underway. The taskforce has been named, as have many of the workgroups; hundreds of advisors will be involved in the effort. Nearing completion is a series of conferences involving NIMH and its sister Institutes, together with 300 other participants, about half of whom are international colleagues. The APA would welcome the opportunity to provide an update on its efforts to translate research into newer and more effective phenotypes for use in the whole range of research in clinical care, Dr. Regier said.
Dr. Insel adjourned the 217th meeting of the NAMHC at approximately 12:45 p.m. on January 11, 2008.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Thomas R. Insel, M.D., Chairperson
Appendix A: Review of Applications
Review of Applications with Primary MH Assignment to NIMH
January 2008 Council
Date/Time Report Run: 01/10/2008 12:39
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Appendix B: Council Roster
(Terms end 9/30 of designated year)
Thomas R. Insel, M.D.
National Institute of Mental Health
Jane A. Steinberg, Ph.D. Director
Division of Extramural Activities
National Institute of Mental Health
- Carl C. Bell, M.D. (11)
President and CEO
Community Mental Health Council and Foundation, Inc.
- Glorisa J. Canino, Ph.D. (09)
Director, Behavioral Sciences Research Institute
University of Puerto Rico
Medical Sciences Campus
San Juan, PR
- Elizabeth Childs, M.D., P.C. (10)
- Jonathan D. Cohen, M.D., Ph.D. (08)
Eugene Higgins Professor of Psychology
Director, Princeton Neuroscience Institute
- Robert Desimone, Ph.D. (11)
Director, McGovern Institute for Brain Research
Massachusetts Institute of Technology
- 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, CA
- Raquel E. Gur, M.D., Ph.D. (08)
Director, Neuropsychiatry Section
University of Pennsylvania Medical Center
- Peter J. Hollenbeck, Ph.D. (08)
Professor of Biological Sciences
Department of Biological Sciences
West Lafayette, IN
- Dilip V. Jeste, M.D. (10)
Ester and Estelle Levi Chair in Aging
Distinguished Professor of Psychiatry and Neurosciences
University of California, San Diego
VA San Diego Healthcare System (116A-1)
La Jolla, CA
- Jeffrey A. Kelly, Ph.D. (08)
Professor of Psychiatry and Behavioral Medicine
Director, Center for AIDS Intervention Research (CAIR)
Medical College of Wisconsin
- Norwood Knight-Richardson, M.D., M.B.A. (09)
Vice Chairman of Department of Psychiatry
Director of the Public Psychiatry Training Program
Director of Oregon Health and Science University
Oregon Health and Science University
- Helena C. Kraemer, Ph.D. (08)
Department of Psychiatry and Behavioral Sciences
- Pat R. Levitt, Ph.D. (09)
Professor, Department of Pharmacology
and Director, Vanderbilt Kennedy Center for Research on Human Development
- David A. Lewis, M.D. (11)
Director, Translational Neuroscience Program
University of Pittsburgh
- John S. March, M.D., M.P.H. (10)
Professor and Chief
Department of Psychiatry
Child and Adolescent Psychiatry
Duke University Medical Center
- Enola K. Proctor, Ph.D. (10)
Frank J. Bruno Professor of Social Work Research
Washington University in St. Louis
St. Louis, MO
- Suzanne E. Vogel-Scibilia, M.D. (08)
Beaver County Psychiatric Services
Ex Officio Members
- Office of the Secretary, DHHS
Michael O. Leavitt
Department of Health and Human Services
- National Institutes of Health
Elias A. Zerhouni, M.D.
National Institutes of Health
- Veteran’s Affairs
Ira Katz, M.D., Ph.D.
Department of Veteran’s Affairs
Office of Mental Health Services
A. Kathryn Power, M.Ed.
Director, Center for Mental Health Services