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Strategic Objective 3

Strategic Objective 3 lays out the next steps in the research continuum for identifying better preventive and therapeutic interventions, and for tailoring such interventions to the individual.

Strategic Objective 3: Strive for Prevention and Cures

There is little doubt that we need better biomedical and psychosocialtreatments for mental illnesses. A recent study29 demonstrates how mental illnesses are a leading source of disability, with disability increasing since 1990 despite a concomitant rise in the use of pharmacologic treatments.30 Although there are many commercially successful medications for anxiety, depression, and psychosis, they are largely variations of existing compounds; few represent true breakthroughs in efficacy.31 For many serious clinical challenges, such as PTSD, the core symptoms of autism, the cognitive deficits of schizophrenia, and anorexia nervosa, to name a few, we lack effective medications altogether. There has been more success recently in the development of psychosocial interventions, with important progress in such challenging conditions as borderline personality disorder and anorexia nervosa. However, even the most effective psychotherapeutic interventions, like cognitive behavioral therapy for mood and anxiety disorders, do not work for everyone. A successful path to better treatments requires more precise diagnostics, validated targets, strategies for individualization, and mechanisms for scaling interventions for broad impact.

More precise diagnostics should emerge from the RDoC project. By reconceptualizing the scientific study of mental illnesses in an integrative and dimensional way, we are forging a path to a future where measures of an individual’s genetic, neural, physiological, and behavioral states will form the basis of an increasingly specific and informative diagnosis. RDoC-based classifications should facilitate the identification and validation of biomarkers for subtypes of mental illness and for response to specific interventions. NIMH envisions such biomarkers as integral to a better system of care where care providers have the objective tools needed to diagnose, tailor treatment, and monitor response systematically. If successful, RDoC will not only deconstruct current categories like major depressive disorder into several subtypes requiring different treatments, it will also identify dimensions like anhedonia that span several current categories and might be addressed by new interventions.

For illnesses in other areas of medicine, increased understanding of their biological bases has transformed previously dire diagnoses into manageable, if chronic, illnesses. For example, we have seen dramatic improvements in remission rates for specific types of cancer and large drops in mortality rates from cardiovascular disease. We have not seen equivalent improvements for mental illnesses, which can be no less deadly or disabling. NIMH now requires that clinical trials identify the target (e.g., a neural pathway or a cognitive domain) of the treatment being studied and measure the extent to which a given dose of the intervention affects the target. This approach uses interventions not only as potential treatments, but as tools to probe the mechanisms that may underlie an individual’s disorder. This target-focused strategy is designed to quickly identify those interventions that merit more extensive testing and to identify targets for additional candidate interventions. The promise of better treatments, whether pharmacological, psychosocial, device-based, or a combination of the three, depends on clinical trials that rapidly validate or, as importantly, reject specific mechanisms.

Intervention research has historically focused on the elimination or reduction of symptoms of mental illnesses. Alleviating symptoms, although vital, may not address the totality of a person’s quality of life. Therefore, NIMH will work toward person-centered approaches that take into consideration the individual’s precise diagnosis (using an RDoC approach), environmental and cultural factors, characteristics of the interventions (including their efficacy, tolerability, and availability), and the individual’s characteristics and preferences (including those captured in person-centered treatment plans).

We are in a dynamic period of change for mental health care. With new legislation affecting health care, new stakeholders, and new ways to conduct clinical research, the traditional intervention development “pipeline” is being transformed. NIMH will focus on intervention research with the greatest potential to transform practice and public health. NIMH envisions individuals receiving the most effective treatment at the earliest opportunity, with maximal impact on health outcomes and daily life. Treatment should be accessible across socioeconomic levels and among diverse groups (e.g., sex, gender, age, racial, ethnic, cultural), usable in diverse settings and with individuals with a range of illness severity and treatment responsiveness.

To further develop interventions that are based on precision medicine and are efficacious for the greatest number of people, NIMH will employ the following strategies:

While past pharmacological treatments have focused on monoamine transporters and neurotransmitter receptors, and psychotherapies have been based on traditional learning theory, new discoveries are revealing a diverse range of potential targets for new interventions. The challenge is to test these potential mechanisms rapidly to rule in or rule out the target as a mechanism of the illness. This requires that the intervention engage the target and test its efficacy for reducing symptoms. New interventions are especially needed for those syndromes causing the greatest disability, and new measures are needed to assess reductions in disability. To implement this strategy, NIMH will support research to:

  • Identify and validate new targets for treatment development that underlie disease mechanisms.
  • Develop and validate new metrics for target engagement that are feasible for use in clinical trials.
  • 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.

Clinical trials in mental health have traditionally focused on individuals with diagnoses made on the basis of symptoms rather than stratifying individuals into subgroups based on behavioral or biological factors. As a result, clinical trials include highly heterogeneous groups and efficacy for a subgroup may be obscured. A relevant analogy here is to compare this situation with testing the efficacy of an antibiotic in everyone with a fever. Going forward, the quest for better treatments will depend on new diagnostics, such as RDoC domains, that identify subgroups with common etiologies or other features sensitive to treatment. To implement this strategy, NIMH will support research to:

  • Develop valid and innovative biomarkers to detect subgroups of individuals sharing common etiologies—whether within or across traditional diagnostic categories—as well as aspects of emotion, cognition, and social behavior that predict clinical response.
  • Foster personalized interventions and strategies for sequencing or combining existing and novel interventions that are optimal for specific phases of disease progression (e.g., prodromal, initial onset, chronic), different stages of development (e.g., early childhood, adolescence, adulthood, late life), and other individual characteristics.
  • Develop and refine alternative research designs and analytic approaches that can be used to test precise interventions.

NIMH strives to support intervention research that maximally improves the lives and functioning of people with mental illnesses. While most interventions are developed in academic settings, their value depends on translating successful outcomes to community practice settings. Moving from clinical research to clinical practice has been a challenge for both biomedical and psychosocial interventions. But this stage of translation can be accelerated by research, including research on the bundling of previously validated interventions to optimize their impact in community practice settings. This approach promises to move community practice beyond the single-pill or single-treatment approach. This aspect of translation, sometimes called T2, can be leveraged by partnerships with other funders such as PCORI and the Clinical and Translational Science Awards program. Once such outcomes are optimized in pragmatic trials, they are ready for yet broader implementation in a variety of service settings and health care system models. To implement this strategy, NIMH will support research to:

  • Develop and test bundled intervention components (each validated individually in prior research) that have the greatest impact on patients’ lives and functioning.
  • Together with key stakeholders, including patient, provider, payer, and other research funding groups, conduct efficient pragmatic trials that employ new tools to rapidly identify, engage, assess, and follow participants in the context of routine care.
  • Enhance the practical relevance of effectiveness research, taking into account how patient-, provider-, and organizational-level factors impact the outcomes of interventions in practice settings.