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Goal 3: Strive for Prevention and Cures

Man talking with female counselor

We need to develop better ways to prevent and treat mental illnesses. To achieve that goal, we need validated targets for interventions, improved methods to match interventions to individuals and populations, including marginalized and underserved communities, and strategies for scaling interventions for the greatest public health impact. Interventions encompass prevention and treatment, and include all therapeutic modalities (e.g., pharmacologic, psychosocial, behavioral, device-based, biologics).

Robust clinical studies require testable hypotheses on how an intervention will engage a relevant target. Targets can include molecular processes; synaptic- and circuit-level regions or networks; neural systems; cognitive, emotional, and interpersonal processes; and, provider behavior, decision-making, and organizational policies and behaviors. Interventions should aim to modify targets, based on a hypothesis that such modification will result in improved symptoms, behavior, or functional outcomes. Evaluating the relationship between modification of targets and clinical outcomes allows us to fine-tune our understanding of mental illnesses and helps us to prioritize the most promising interventions. This idea underlies NIMH’s experimental therapeutics approach by which interventions serve not only as potential therapies or preventive strategies, but also as probes to generate objective information about mechanisms of illness and/or resilience so that information from a research study has scientific value, irrespective of the intervention’s success.

Precision in mental health care means that individuals and populations will receive preventive and treatment interventions that are optimally matched to their characteristics and needs, across disease stages, across diagnostic categories, and across the lifespan. Optimizing interventions will not only require consideration of symptoms and functioning, but also a broader consideration of etiologies, intervention, preferences of patients and families, and the contexts of intervention delivery.

NIMH supports the development and testing of preventive as well as treatment interventions, recognizing that most mental illnesses begin well before adulthood and often before symptoms appear or daily functioning is impaired. We need preventive interventions for delivery early in the course of illness and early in life for at-risk individuals, plus treatment interventions to mitigate mental illnesses and associated dysfunction at the earliest possible opportunity. NIMH encourages the development and testing of preventive and early interventions that can be delivered in a developmentally appropriate manner (e.g., at known sensitive periods and at key transitions) as early in life as possible and early in the illness course, to prevent or forestall mental illnesses and associated dysfunction.

The following Objectives further define this Goal:

Doctor holding nasal spray bottle

The focus of an experimental therapeutics approach is not only on testing whether new interventions show clinical benefit, but also on understanding whether interventions work through the presumed mechanisms by altering the selected targets. If they do work, larger clinical trials would serve to reconfirm target engagement and further assess clinical impact of the potential intervention. If the interventions do not work in the expected manner, negative results are likewise scientifically informative and fundamental to refining the intervention.

The experimental therapeutics framework also recognizes that clinical targets may differ qualitatively and quantitatively throughout the life course. Therefore, there needs to be a strong scientific premise for selecting clinical targets within a particular age range. Additionally, the dose of an intervention that is safe and effective for target engagement may be age- or developmental stage-dependent and should be systematically established in advance of efficacy testing. It is also recognized that multiple targets may need to be engaged to exert beneficial outcomes.

To more effectively develop new prevention and treatment interventions based on novel genomic, neurological, and behavioral advancements, NIMH will support research that employs the following Strategies:

Interest areas include:

  1. Enhancing the predictive value of preclinical assays used to select targets, drug candidates, circuit-based or cognitive/behavioral interventions, devices, and biologics for clinical development.
  2. Developing and optimizing novel prevention and intervention strategies and evaluating the functional impact of target engagement, demonstrating the optimal dose needed to achieve functional impact.
  3. Developing and optimizing novel pharmacological, or psychosocial, device-based, or biologic therapeutic candidates that selectively engage therapeutic targets of interest.
  4. Identifying prevention and intervention targets appropriate to an individual’s age and stage of illness, and testing interventions to modify those targets to prevent or improve symptoms. Putative targets should be based on scientific discoveries that advance our understanding of the mechanisms and trajectories of mental resilience and illnesses.
  5. Developing promising therapeutic candidates into treatment approaches that target specific molecular, cellular, neural circuit, or psychological mechanisms driving core domains of cognitive, behavioral, and affective function that are disrupted in mental illnesses, including those that cut across diagnostic categories.
  6. Developing novel preventive interventions based on an understanding of risk and protection at the level of the individual and within a developmental and environmental context, and testing whether targeting proximal risk and protective factors, or intervening factors that reduce risk, result in promoting health and decreased onset of the illness.

Interest areas include:

  1. Developing and validating quantitative behavioral and neurophysiological measures of target engagement in humans and animals as translational assays linked to functional domains disrupted in and across mental illnesses.
  2. Developing and optimizing reliable and objective measures of target engagement and intervention on brain (molecular, cellular, circuit) function, side effects, clinical symptoms, and functional outcomes that can be implemented in clinical trials.
  3. Testing novel behavioral markers and their associated neural activity patterns as potential stratification measures. Such testing might include computational and bioinformatics approaches and remote sensors.
  4. Optimizing and validating real world outcome measures, including patient-reported outcomes, for use across clinical populations. Such measures may take into account illness phase, age, sex, race, ethnicity, culture, education, socioeconomic background, and other factors.
  5. Developing and assessing novel mobile technology and digital health tools to enable objective measurement of behavior and intervention effects on symptom expression, functional outcomes, and quality of life in naturalistic environments.
  6. Developing valid proxy measures or markers that are relatively brief and cost-effective for use in outcomes research.
  7. Applying quantitative methods, algorithms, and metrics to assess the value and efficiency of intervention strategies.

Female patient receiving transcranial magnetic stimulation on her brain from male doctor

Clinical trials have traditionally focused on diagnostic status and symptom severity. Inattention to the complex topography of intervention targets, and to individual differences in psychopathology and intervention needs and preferences, can limit the value of findings and their potential uptake in routine practice. Strategies should focus on functional outcomes, considered within the context of an individual’s development stage, environment, and cultural context. 

Personalized mental health interventions mean that people should receive preventive and treatment interventions optimally matched to their needs. Optimizing interventions will not only require consideration of symptoms and functioning, but also a broader consideration of genetic, environmental, developmental, and cultural factors, and functional deficits and needs. Optimal care will also require consideration of the characteristics of population stratification or the candidate interventions and characteristics of providers and settings. Efficient research designs are needed to examine approaches for optimizing interventions for individuals, families, communities, populations, and settings.

To better tailor existing interventions to optimize outcomes, NIMH will support research that employs the following Strategies:

Interest areas include:

  1. Investigating heterogeneity in, and mechanisms of, response to existing efficacious prevention and treatment interventions to inform personalized interventions that address specific outcomes.
  2. Investigating strategies for sequencing or combining interventions that are optimal for individuals in the context of phases of disease progression, stages of development, and other characteristics.
  3. Establishing the safety and efficacy of efficacious therapeutic interventions developed for adult populations in children and the elderly, as well as women at various phases of the reproductive cycle (including menarche, the menstrual cycle, all stages of pregnancy, and menopause), while testing targets and target engagement specific to these populations.
  4. Running prospective studies of known efficacious interventions to identify moderator variables and objective biomarkers, digital phenotypes, composite biomarkers, and/or multi-modality derived biotypes.
  5. Developing multi-modal intervention strategies that combine the simultaneous application of established or novel pharmacological, psychosocial, biologic, and/or neuromodulation interventions to selectively access specific therapeutic targets through synergistic action.

Interest areas include:

  1. Developing and refining research methods that can be used to advance personalized interventions, including computational algorithms for prescriptive approaches and innovative trial designs.
  2. Reanalyzing or conducting meta-analyses using individual or aggregated clinical trials, patient registries, electronic health records, or other existing clinical data sets to identify moderators that might serve as tailoring variables for interventions.
  3. Applying innovative computational approaches (e.g., machine learning, artificial intelligence, pattern classification techniques, predictive analytics) to multiple streams of data (e.g., routinely collected standardized measures in electronic health records, sensor-based data, social media/device use metrics) using existing data sources to inform targets and timing for interventions and to facilitate clinical decision-making.
  4. Developing and using innovative trial designs and data collection strategies to test personalized strategies that incorporate tailoring variables (e.g., clinical data, biomarkers, behavioral markers derived from passive sensing of naturalistic behaviors, patient response history) into participant assignment.

Effectiveness research aims to generate information for persons and families seeking care, providers, and policy makers about the interventions that benefit clients the most in real-world settings. Effectiveness research is most useful for informing practice or policy decisions when it addresses a condition that has substantial public health significance; when the practical benefit of the intervention can be justified when compared to existing approaches; when it is conducted in diverse, representative populations and contexts; when interventions are potentially scalable and could be disseminated into current practice; and when it assesses a broad array of stakeholder-relevant outcomes.

Effectiveness research is best implemented through efficient and innovative platforms and designs that advance treatment personalization in community practice settings. Deployment-focused models of intervention and services research, which consider the key characteristics of the settings and providers where interventions and services will be implemented, are critical. Consistent with the NIMH experimental therapeutic approach to intervention development and testing, there is a need for effectiveness trials that contribute to our overall understanding of therapeutic change mechanisms. Not only are these effectiveness trials beneficial when they test the impact of interventions on clinical endpoints, they are beneficial when they explicitly examine whether the intervention engages the targets that mediate the clinical benefit.

To better test intervention effectiveness in community practice settings, NIMH will support research that employs the following Strategies:

Interest areas include:

  1. Developing and testing approaches for implementing new indications and developing and testing adaptations or augmentations of evidence-based interventions when research suggests that a moderator or negative prognostic factor can be targeted to improve response substantially for a readily identifiable refractory subgroup.
  2. Testing combination and sequenced approaches to optimize effectiveness and safety, while minimizing unnecessary or off-label use of devices or psychotropic medications among children, adolescents, and adults.
  3. Developing and testing broadly relevant preventive/early interventions that target shared modifiable risk and protective factors and key domains of functioning (e.g., emotion regulation or other RDoC domains) and thereby change life trajectories and reduce risk for multiple mental illnesses.
  4. Focusing on strategies for addressing the needs of individuals and populations at risk for relapse/recurrence and for managing chronic disorders (e.g., post-acute phase interventions/service strategies that are matched to the stage of illness both in terms of the goals and approaches to maximize the chances of complete recovery and sustained remission).
  5. Developing and testing approaches that employ mobile health (mHealth) and other emerging technologies to boost the effectiveness of evidence-based interventions and to monitor health status.

Interest areas include:

  1. Conducting effectiveness trials that leverage practice-based research and other research investments to inform intervention development and increase the efficiency and relevance of effectiveness research, including identifying targets and optimal timing for intervention.
  2. Supporting refinement of preventive and treatment interventions for mental illnesses, while capitalizing on efficiencies to facilitate participant recruitment and data collection.
  3. Supporting practice-based research aimed at refining and testing efficacious preventive interventions (including broad, selective, indicated, and tiered approaches), so that they are scalable and can be sustainably implemented in pediatric-serving settings where preventive services are delivered (e.g., primary care settings, schools).
  4. Externally validating practice-based research across diverse populations and contexts to enhance the relevance and translation potential of trial results.

Interest areas include:

  1. Encouraging deployment-focused intervention and service models and effectiveness testing that consider the perspective of relevant stakeholders and key characteristics of intended intervention settings, to increase the likelihood that the interventions/services are feasible and scalable, and the research results will have utility for end users.
  2. Emphasizing hybrid effectiveness-implementation research that goes beyond examining the effect of interventions on symptomatic or functional outcomes and designing studies to address questions regarding how client-, provider-, community-, and organizational-level factors impact clinical outcomes, implementation, and scalability of research-generated interventions.
  3. Encouraging hybrid effectiveness-implementation trials across diverse settings to identify setting characteristics (e.g., workforce capacity, case mix) that impact intervention delivery and test strategies to sustain intervention effectiveness and quality of implementation in diverse settings.
  4. Examining novel applications of technology that can generalize across indications, target populations, and operating platforms, to facilitate the delivery of interventions and enhance their reach and therapeutic value.

Progress for Goal 3

Highlighting efforts to improve preventive and therapeutic interventions.