Federal funding now and in the future: How child psychiatry can succeed

1. Federal funding now and in the future: How child psychiatry can succeed Christopher Sarampote, PhD Director, Office of Training and Career Development Division of Developmental Translational Research, NIMH

2. Disclosures • Dr. Sarampote is a full-time employee of the National Institutes of Mental Health, with no conflicts of interest to disclose

3. Agenda • Overview of NIMH structure and priorities • The Role of the Research Domain Criteria Project (RDoC) in NIMH research funding • NIMH’s updated priorities and strategies for clinical trials research • Final thoughts

4. NIMH Divisions Mission: To transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure Adult Translational (DATR) Neuroscience & Basic Behavioral (DNBBS) Services & Interventions (DSIR) Intramural Research (DIRP) Developmental Translational (DDTR) AIDS/HIV (DAR) Extramural Activities (DEA)

5. Training at NIMH • Training awards by career stage: F, K • T32 institutional awards K01, K08 K23 F30 F31 R36 F32 K02 K24 Award Types K99 / R00 Postdoc Phase High School/ Undergraduate Student Graduate/ Medical Student Independent Investigator MD/PhD PhD Faculty Position Career Stage Diversity and Reentry Research Supplements

6. NIMH Strategic Plan (2008) • Strategic Objective 1: Promote discovery in the brain and behavioral sciences to fuel research on the causes of mental disorders • Strategic Objective 2: Chart mental illness trajectories to determine when, where, and how to intervene • Strategic Objective 3: Develop new and better interventions for mental disorders that incorporate the diverse needs and circumstances of people with mental illness • Strategic Objective 4: Strengthen the public health impact of NIMH-supported research

7. Strategic Objective #1: Promote Discovery in the Brain and Behavioral Sciences to Fuel Research on the Causes of Mental Disorders GenesNeural CircuitsBehaviorDisease Phenotype Meyer-Lindenberg & Weinberger, Nature Rev Neurosci, 2006

8. Strategic Objective #2: Chart Mental Illness Trajectories to Determine When, Where and How to Intervene Healthy Gray Matter Maturation Age 4 Age 10 Childhood Onset Schizophrenia Gray Matter Loss Adult P-value Adapted from: Thompson et al, Proc Natl Acad Sci, 2001 & Gogtay et al, Arch Gen Psychiatry, 2004

9. Strategic Objective #3: Develop New and Better Interventions for Mental Disorders that Incorporate the Diverse Needs and Circumstances of People with Mental Illness • Strategy 3.1: Further develop innovative interventions and designs for intervention studies • Strategy 3.2: Expand and deepen the focus to personalize intervention research • Strategy 3.3: Strengthen the application of mental health interventions in diverse care settings by examining community and intervention delivery approaches and how they may affect intervention outcomes • Strategy 3.4: Identify and systematically study elements of personalized mental health care

10. Strategic Objective #4: Strengthen the Public Health Impact of NIMH-Supported Research 26.2% Impact Gap % U.S. Adults 10.8% 3.5% Adapted from: Kessler et al, Arch Gen Psychiatry, 2005 & Wang et al, Arch Gen Psychiatry, 2006

11. Strategic Objective #4 Research Priorities • Effectiveness of mental health preventative, treatment and rehabilitative interventions, alone or in combination, for children and adolescents • Services organization, delivery and related health economics • Clinical epidemiology of mental disorders across all clinical and service settings • Dissemination and Implentation • Development of innovative ways of disseminating information to stakeholders (e.g., new technologies, multimedia approaches) • Novel methods of Development to address the multidimensional components of dissemination and implementation (consumer, practitioner, clinic, state) • Implementation studies of addressing organizational outcomes around sustainability

12. Mental Disorders: A Neurodevelopmental Perspective JAMA May 7, 2014 Vol 311(17)

13. Early Prediction & Preemption Challenge: Identify and delineate disease processes early in neurodevelopment, before the onset of symptoms.

14. Division of Developmental Translational Research • Neurobiological Mechanisms • Neurobiological, genetic, experiential influences • Biologically based markers • Dimensional Phenotypic Measurement • Sex Differences • Developmental Trajectories • Integrative longitudinal models of risk • Sensitive periods in development • Early identification and prediction

15. Guiding Framework I. Delineate Risk – Enhance Prediction II. Identify biomarkers and mechanisms of risk/illness Priorities III. Chart trajectories of illness across development IV. Develop innovative, personalized interventions Development: Maturation/Sensitive Periods

16. State of the Science Prediction Mechanism Trajectories Intervention Underrepresented Developing Active

17. Research Domain Criteria (RDoC)

18. Research Domain Criteria (RDoC) • Current psychiatric diagnosis strengths: • Clusters of signs & symptoms • Utility at a time of limited knowledge in genetics, neuroscience, behavioral science • Clinically useful: clinical phenotypes, course of disorders • Increased reliability (since DSM-III) • Dissemination throughout medical, legal, social services systems • Suboptimal for research: • Emphasis on reliability over validity • Heterogeneity of disorders • Extensive co-morbidity • Antedates current knowledge of brain and behavior • Difficult to relate diagnoses to genes, particular circuits, or basic behavioral mechanisms

19. RDoC (cont) • Uncoupling of research questions from DSM categories might be required to develop an understanding of psychopathology founded in the integration of biology and psychology • Translational approach to link mechanisms and symptoms • Dimensional approach involving multiple levels of analysis • Framework to study mechanisms that cut across traditional diagnostic categories • Goals: • Integration of biological and psychological constructs • New treatment targets • Creation of an “Information Commons” • Increasing share of NIMH-funded research

20. RDoC (cont)

21. Updated NIMH Clinical Trials Priorities

22. Updated Clinical Trials Priorities & Strategies • Limited recent progress at identifying new drug/psychosocial targets and novel strategies. • Efficacy findings from small trials often do not hold up. • Standard intervention testing focused on symptom change outcomes yields limited information about disease/intervention mechanisms (e.g., in the event of a failed trial). • Limited understanding about potential targets/mechanisms (for pharmacological, behavioral/psychotherapeutic, and other modalities) has impeded efforts to develop novel targets/strategies or optimize existing approaches (e.g., to enhance potency or efficiency). NIMH Director’s Blog (http://www.nimh.nih.gov/about/director/index.shtml): Februrary 27, 2014, “A New Approach to Clinical Trials”; June 12, 2012, “Experimental Medicine”; December 14, 2011, “Treatment Development: The Past 50 Years”

23. Rationale for Updated Priorities & Strategies Experimental Therapeutics…. • Future trials will follow an experimental medicine approach in which interventions serve not only as potential treatments, but as probes to generate information about the mechanisms underlying a disorder. • Trial proposals will need to identify a target or mediator (and specify a corresponding plan to assess target engagement). • For treatment development, the assessment of target engagement informs a “go/no-go” decision: only if the intervention adequately engages the target, further research then addresses whether intervention-related changes in the target affect clinical outcomes. • Positive results require not only that an intervention ameliorated a symptom, but that it had a demonstrable effect on a target, such as a neural pathway implicated in the disorder or a key cognitive operation. NIMH Director’s Blog (http://www.nimh.nih.gov/about/director/index.shtml), Februrary 27, 2014, “A New Approach to Clinical Trials”; June 12, 2012, “Experimental Medicine”; December 14, 2011: “Treatment Development: The Past 50 Years”

24. Updated Priorities & Strategies –Overall Approach Beginning with applications submitted for the June 5, 2014 submission date and all subsequent applicable deadlines, NIMH will not accept R01, R21, or R03 applications that include clinical trials of potential therapies for mental disorders, under: • NIH parent R01 FOA PA-13-302 • NIH parent R21 FOA PA-13-303 • NIH Parent R03 FOA PA-13-304, • … and subsequent reissuances of these FOAs. NOT-MH-14-007 NIMH Policy for Submission of Applications Containing Clinical Trials February 25, 2014

25. Updated Priorities & Strategies –Overall Approach Discontinuation of Former Clinical Trials FOAs: NOT-MH-13-023: NIMH Announces Discontinuation of PAR-12-071 "Collaborative R34s for Pilot Studies of Innovative Treatments in Mental Disorders (Collaborative R34) " NOT-MH-14-009: Notice to Discontinue Participation of NIMH in PAR-12-279 "Pilot Intervention and Services Grants (R34)" NOT-MH-14-008: NIMH announces the expiration of PAR-12-278 "Collaborative R01s for Clinical and Services Studies of Mental Disorders and AIDS (Collaborative R01)"

26. Clinical Trial Pipeline and New NIMH Funding Initiatives First in Human (Drugs) Confirmatory Efficacy Effectiveness, Dissemination Exploratory Experimental Therapeutics Target engagement R21/R33 Exploratory Clinical Trials of Novel Interventions for Mental Disorders R34 Pilot Effectiveness Studies and Services Research Grants TBD Companion R33 Exploratory Clinical Trials of Novel Interventions for Mental Disorders R01 Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions U01 (New Chemical Entities) First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders Collaborative R01 Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions

27. NIMH Fast-Fail Trials • Aims: 1.) quickly identify compounds that merit more extensive testing; 2.) identify targets in the brain for the development of additional candidate compounds • Conduct trials in small, human samples (10-30 subjects) to assess: • Does the compound engage a target in the brain (e.g., a specific receptor in brain cells or alter signaling in the brain by a specific neurotransmitter?) • Does it measurably alter a feature of the brain function (e.g., test of memory, cognition or attention?) • Teams • Andrew Krystal, MD: Duke University – Mood and Anxiety Spectrum Disorders • Jeffrey Lieberman, MD: Research Foundation for Mental Hygiene – Psychotic Spectrum Disorders • James McCracken, MD: UCLA – Autism Spectrum Disorders • D

28. Final Thoughts • Advances in basic neuroscience (neuroscience, genetics, basic behavioral) offer unprecedented opportunities to elucidate the pathophysiology of disorders • A mechanistic approach to disorders and their underlying components is essential to both the understanding of mental illness and its treatment • Early prediction and preventative intervention of mental illness before behavioral symptoms present is a high research priority • New biomarkers of risk and targets for intervention are needed to develop new strategies for treatment and prevention • Team science and collaboration that draws on basic and clinical disciplines is necessary to advance the field • Reproducibility and transparency of findings are crucial to ensuring the impact of our research • Awareness of NIMH research priorities is critical to successful grant funding

29. Research Priorities • Institute Priorities on Website: NIMH Strategic Plan • Division Description & Priorities on Webpage • Funding Opportunity Announcements (FOAs), also known as PA and RFA • Scientific Meetings/Workshop Reports (webpage) and NAMHC Workgroup Reports (webpage) • NAMHC Concept Clearances Sources of Information

30. Concept Clearances