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Priorities for Strategy 3.1

Updated: January 2019

Develop new treatments based on discoveries in genomics, neuroscience, and behavioral science

NIMH encourages an experimental therapeutics approach to treatment development, based on the translation of basic science and new developments in bioengineering and technical developments into intervention targets and strategies, with the goal of demonstrating target engagement and identifying doses at which the intervention has the optimal effect on the putative target. For cognitive, behavioral, and other psychosocial interventions, appropriate dosing parameters may include intensity, frequency, or duration. For brain stimulation interventions, appropriate parameters should include the spatial, temporal, and contextual parameters of the delivered dose.  Pharmacologic agents should be selected based on biology of the target, known CNS penetration, and the ability to provide evidence of a specific pharmacologic effect in human brain. Parameters contributing to optimization of target engagement may include selectivity of the agent and temporal relationship between exposure and brain activity. Once target engagement is demonstrated, additional proof-of-concept research would then address whether intervention-induced changes in the target are associated with the anticipated clinical benefit. Examples of potential targets for intervention include, but are not limited to, domains of behavior (not limited to RDoC domains), and specific brain circuits underlying functional deficits or symptoms. Importantly, effective targeting may be directed within or across diagnostic categories. Larger trials, beyond early-stage intervention development and testing, would next serve to reconfirm target engagement and further assess its clinical impact. This experimental therapeutics framework, with its focus on mechanism-informed intervention development and testing, is intended to facilitate matching interventions to individuals’ specific deficits and needs, in order to advance the objective of developing more precise intervention approaches.  It is also designed to increase the scientific impact of the work, whether or not the results support therapeutic efficacy, by testing hypotheses regarding mechanisms underlying mental illnesses. The experimental therapeutics framework also recognizes that clinical targets may differ qualitatively and quantitatively across childhood, adolescence, and into late life. Therefore, there needs to be strong scientific premise for selecting a clinical target within a particular age range (the same clinical target may not be appropriate across the age ranges). Likewise, the dose of intervention that is safe and effective for target engagement may be age- or developmentally dependent, and should be systematically established in advance of efficacy testing.  

NIMH encourages applications that identify new targets for intervention, and that develop new treatments based on these targets. Consistent with the principles of experimental therapeutics, clinical trials can be used to investigate a disease mechanism such that the study is informative not only about the intervention, but also about the psychopathology. In general, NIMH will consider applications that follow the experimental therapeutics paradigm, and expects strong empirical justification for adaptation or augmentation trials.

Research Priorities

  1. Identify and validate new targets for treatment development that underlie disease mechanisms. 

    Priority areas include:

    1. Developing and validating behavioral, neurobiological, and physiological measures as translational cross-species assays to evaluate therapeutic candidates and target-mediated effects on circuits linked to functional domains disrupted in mental illnesses. Behavioral measures should be empirically linked with specific brain circuits (such as those associated with wanting or liking, or striatal reward pathways).
    2. Translating innovative methods contributing to basic discoveries and advancements in neuroscience into assays for a range of applications, from accelerating basic discovery to target identification and therapeutic development.
    3. Identifying novel targets (e.g., receptors and signaling molecules, circuit-based targets, brain areas and activity rhythms such as neural oscillations, plasticity mechanisms, neurodevelopmental processes, cognitive processes, behaviors) and further developing emerging therapeutic target approaches (e.g., allosteric modulators, neuromodulation, transcriptional regulators, modulators of protein-protein interactions, learning mechanisms, social communication processes).
    4. Developing novel treatments that target specific neural or psychological systems critical for core domains of cognitive and emotional function relevant to mental illnesses, including those that cut across diagnostic categories.
    5. Identifying intervention targets appropriate to the developmental stage across the lifespan and subsequently identifying interventions that can selectively modify the CNS or functional domains with potential to improve symptoms. Both pediatric and geriatric intervention testing are a priority.
    6. Identifying, using computational methods and remote sensors, behavioral markers of subjective states, thought processes, and internal perceptions derived from temporally dense passive sensing of naturalistic behaviors.
    7. Identifying neural activity patterns associated with behavioral markers of subjective states, thought processes, and internal perceptions through the temporal linking of neural activity recording with passive sensing of behavior, with high temporal and spatial resolution.
    8. Testing the efficacy of novel treatments in improving clinical symptoms, core domains of cognitive and emotional functions, and outcomes, while identifying potential mechanisms and/or mediators.

  2. Develop and validate new metrics for target engagement that are feasible for use in clinical trials. 

    Priority areas include:

    1. Improving existing tools and developing new methods for reliably and objectively measuring the engagement of treatment targets, including development of new PET ligands, new neuroimaging methods (such as interleaved imaging), perturbation imaging (interleaving of imaging with stimulation), and behavioral measures.
    2. Developing tools to assess, in humans, the effects of novel and existing interventions on activity across circuits contributing to functional domains impacted in mental illnesses.
    3. Developing or improving existing non-invasive tools to assess target engagement of novel therapeutic candidates in children and adolescents.
    4. Using novel tools and methodologies to evaluate whether an intervention engages its putative target and the impact of target engagement on clinical benefits (i.e., validating the target), and whether an intervention has satisfactory tolerability and feasibility.

  3. Develop objective surrogate measures of outcome and clinical change that extend beyond symptoms, to assess if target mechanisms underlying general health and quality of life have been modified by treatments.

    Priority areas include:

    1. Developing objective, standardized measures of real-world functional outcomes across a range of pathologies and populations that vary in phase of illness (or RDoC-defined components of mental disorders), age, sex, and ethnicity/race, educational, and socioeconomic backgrounds. 
    2. Developing validated proxy measures or markers that are relatively brief and inexpensive for use in multi-modal assessments in outcomes research.
    3. Developing or improving existing non-invasive measures to objectively track effects of novel therapeutics on brain circuit plasticity, side effects, and clinical symptoms/functional effects in children and adolescents, and across development.
    4. Developing metrics that can be used to determine the value and efficiency of intervention strategies.
    5. Developing and assessing novel mobile technology/digital health tools to enable objective measurement of behavior in naturalistic environments.