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)
Developmental
(DDTR)
AIDS/HIV
(DAR)
Neuroscience &
Basic Behavioral
(DNBBS)
Services &
Interventions
(DSIR)
Intramural Research (DIRP)
Pre-Clinical/Basic Research  Psychopathology & Tx Development (1st in Human studies)  Effectiveness, Services, Implementation/Dissemination
Extramural Activities (DEA)

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

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. GenesNeural CircuitsBehaviorDisease Phenotype
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
Strategic Objective #1
Examples include:
Integrative approaches to understand neuro-functioning
Identify genetic and epigenetic components of pathophysiology
Identify biomarkers
Reconstruct mental disorders
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
Slide showing that gray matter brain loss in Childhood Onset Schizophrenia appears to be an exaggeration of the normal maturation process.  
Pink indicates greater brain matter loss.
Thompson et al, 2001, Proc Natl Acad Sci, 98,
Gogtay et al, 2004, Arch Gen Psych, 61,
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
Strategy 3.1: Further develop innovative interventions and designs for intervention studies:
Including translating basic science into novel interventions and novel targets and strategies
Strategy 3.2: Expand and deepen the focus to personalize intervention research
TO most efficiently deploy existing interventions and match individuals with current interventions that they are most likely to benefit from.
Strategy 3.3: Strengthen the application of mental health interventions By developing and testing more practice ready interventions that are scalable and disseminable and more likely to have an impact on practice and policy.

10. Strategic Objective #4: Strengthen the Public Health Impact of NIMH-Supported Research
26.2%
Impact Gap
% U.S. Adults
10.8%
12-month diagnosable disorders in the NCS-R
Goal of SO4 is to make more of an impact on public health, and make sure that everyone that is diagnosed with a disorder receives adequate treatment.
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)
MH Advisory Council workgroup report on neurodevelopmental research in 2008 recommended:
Research on how healthy trajectories become altered
Research on Characterization of sensitive periods of neurodevelopment that are open at specific times in development, which might be amenable or susceptible to the environment
Research on intervention research that would aim to bend trajectories of neurodevelopment early on, before the illness is apparent.
There are examples of these workgroup reports on the website, and we often use these to stimulate research in the area, so it is a good thing to keep your eyes on.

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

14. Division of Developmental Translational Research
TARGETED INTERVENTIONS
Targeted treatments
Preemptive strategies
Mechanisms of action
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 Priorities Development: Maturation/Sensitive Periods
Disease Origins
Pre-Symptomatic
Early Symptoms to Prodrome
Disease
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. Early Symptoms to Prodrome
State of the Science
Disease Origins
Pre-Symptomatic
Early Symptoms to Prodrome
Disease
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
Transition: What do we make of the fact that supposedly different disorders occur together -- clearly, they are not all different, so how do we go about sorting out the differences?

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).
Over the past few years, the NIMH DIRECTOR’s BLOG has highlighted some CONCERNS about:
--The TRADITIONAL APPROACH to intervention development and Testing
--The limited Yield from these traditional research approaches.
SPECIFICALLY…..
1—Limited progress at identifying new targets and novel strategies
2—Findings from EFFICACY trials are often INCONCLUSIVE or DO NOT HOLD UP
3—the MAIN focus on SYMPTOM CHANGE OUTCOMES yields little info about disease or intervention mechanisms.
4—Finally, across all intervention modalities (Pharm, Psyhosocial, other approaches), Limited understanding about mechanisms has been a RATE-LIMITING FACTOR in developing novel targets/strategies or optimizing existing approaches.
NIMH Director’s Blog ( 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.
CONSEQUENTLY, NIMH is adopting a more EXPLICIT EXPERIMENTAL THERAPEUTICS approach to intervention development and testing
The approach places a more UP-FRONT and CENTRAL FOCUS on INTEROGATING INTERVENTION TARGETS and MECHANISMs throughout ALL STAGES of INTERVENTION TESTING + DEVELOPMENT
UNDER THIS APPROACH
1—interventions serve not only as potential txs, but also as PROBES to generate information of relevant TARGETS and DISEASE mechanisms
2—ALL trials will be expected to identify targets and specify a plan to assess whether the intervention engages the target
3—for Tx development, the assessment of target engagement informs a GO/NO-GO decision: only if the tx engages the target, then further research would be conducted to see if tx-induced target changes are associated with clinical benefit
4—trials will need to be poised to demonstrate not only whether there was clinical benefit, but also whether the tx had a effect on a key target, such as a neural pathway or key cognitive operation implicated in the disorder.
NIMH Director’s Blog ( 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
NOT-MH
NIMH Policy for Submission of Applications Containing Clinical Trials
February 25, 2014
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
NIH parent R21 FOA PA
NIH Parent R03 FOA PA ,
… and subsequent reissuances of these FOAs.
As a first step to implementing these approaches, NIMH issued a notice that we will no longer accept TRIALS RESEARCH under the OMNIBUS, PARENT ANNOUCEMENTS for investigator-initiaied R01s, R21s, or R03s

25. Updated Priorities & Strategies –Overall Approach
Discontinuation of Former Clinical Trials FOAs:
NOT-MH : NIMH Announces Discontinuation of PAR "Collaborative R34s for Pilot Studies of Innovative Treatments in Mental Disorders (Collaborative R34) "
NOT-MH : Notice to Discontinue Participation of NIMH in PAR "Pilot Intervention and Services Grants (R34)"
We also issued GUIDE NOTICES to discontinue formers ANNOUNCEMENTS that were used to solicit trials research, including the R34 mechanisms and Collaborative R01.
NOT-MH : NIMH announces the expiration of PAR "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)
Exploratory Experimental Therapeutics
Target engagement
Confirmatory
Efficacy
Effectiveness,
Dissemination
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
The new set of FOAs include 6 announcements, including 3 FOAs to support novel treatment and 3 FOAS to support EFFECTIVENESS RESEARCH.
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. Sources of Information
Research Priorities
Sources of Information
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

30. Concept Clearances