# Psychosocial Research at NIMH: A Primer

September 8, 2016

The following questions and answers explore a variety of topics related to psychosocial research at NIMH, and specifically how NIMH is actively supporting psychosocial research through a variety of mechanisms and processes.

Responses were prepared under the supervision of Dr. Bruce Cuthbert, Acting Director of NIMH, and reflect the considered judgments of a large number of NIMH staff from many Divisions and Offices in the Institute.

### Topic List

                  - Balancing a Psychosocial and Biological Research Portfolio
                  - Experimental Therapeutics Approach to Clinical Research
                  - Funding Mechanisms for Clinical Trials
                  - Support of Treatment Process Research
                  - Addressing Social, Community, and Organizational Influences in Mental Health Services Research
                  - Funding Research of Developmental Influences on Mental Health
                  - Commitment to Training Future Clinician Scientists

### Psychosocial Research Q & A

**1. What role does NIMH see for research that tests domains of function (and dysfunction) and mechanisms that are not measured with primarily biological markers or indices? More generally, how will NIMH ensure that it maintains a reasonably balanced portfolio so that multiple psychosocial and biological levels of analysis are considered, both alone and in interaction?**

According to the mission of the NIMH Research Domain Criteria (RDoC) initiative, the goal of RDoC is not to reduce the understanding of disorders to circuits (or to molecular/cellular processes), but rather to integrate and synthesize multiple measures to lead to a more comprehensive understanding of the constructs in the RDoC matrix, and in turn, to the symptoms to which they relate. As such, NIMH priorities should not be inferred by counting the number of columns representing units of analysis in the RDoC matrix. Rather, the matrix is a way to envision how each level of complexity is part of a whole organism responding to the environment. Progress in treating heart disease would not have advanced as it has if the genes and molecules underlying heart function had not been the object of research. That does not mean that understanding the effects of a sedentary lifestyle, diet, and smoking are not important, and that counseling to increase exercise is not worth testing, but the relationship of risk factors to the heart, and which treatments are effective and why, would be less well understood without a fine-grained understanding of heart function. While scientists can continue to do research on symptom management, behavior—such as how behavior is shaped and changed by the environment, including family, personal experiences, and society—is a manifestation of processes taking place in a physical and exceedingly complex organ.

That said, NIMH is very interested in the development of better ways to measure behavior, cognitive/affective processes, and self-reports of experience. For instance, two workgroups convened under the auspices of the National Advisory Mental Health Council (NAMHC) are working on different aspects of this challenge. One workgroup is focused on Opportunities and Challenges of Developing Information Technologies on Behavioral and Social Science Clinical Research. This workgroup has been charged with addressing how new mHealth technologies can be used to obtain more objective and precise measurements of many different types of behavior, social processes, and daily functioning, particularly those relevant to quantitative assessments for use in diagnosis and outcome studies. Further, such technologies could be used to help predict and prevent mental illnesses and improve the quality of mental health practice. A second workgroup on Tasks and Measures for Research Domain Criteria, has been convened to develop a list of well-specified tasks, paradigms, and measures for investigators to consider when conducting research involving RDoC constructs, with particular attention to reliability, validity, and ease of use. This workgroup will recommend promising measures as common data elements across studies that can facilitate data mining in the RDoC database**(**RDoCdb**).**In addition, NIMH co-sponsored a workshop with the Biomarkers Consortium ** of the Foundation for the NIH (FNIH) to work toward consensus on the standardization of reward-processing tasks that can be used for laboratory studies and clinical outcome measures. These examples illustrate that NIMH is as interested in behavior and functional measures as in fostering new biological approaches.

Further, NIMH is actively supporting efforts to enhance behavioral research in actual practice contexts. As addressed in several responses below, NIMH has issued funding opportunities and is supporting ongoing projects encompassing treatment and services research, including: assessing psychotherapy quality; suicide prevention; and, research aimed at developing ways to improve access and quality of care for underserved populations. With respect to clinical trials, NIMH’s clinical trials web pages note that NIMH is emphasizing an experimental therapeutic approach in which studies must include an examination of a defined intervention “target.” Targets are not limited to molecular or biological entities, but can encompass cognitive or emotional processes for psychotherapeutic interventions, provider behavior, decision-making or organizational policies, or behaviors for services interventions.

**2. The new funding process for NIMH clinical trials requires a mechanism of action to be specified before funding will be considered. Researchers may be interested to know how future funding for intervention research could be impacted by this new model for clinical trials. How does NIMH address the concern that development of innovative new treatments could be hindered if funding is no longer available for more “traditional” clinical trials? Does NIMH have plans to ensure that important treatment advances will not be overlooked when a target engagement test “fails” (e.g., if therapy A shows promise of efficacy despite posited mechanism B being incorrect)?**

First, some background: Based on recommendations outlined in the 2010 National Advisory Mental Health Council (NAMHC) report, “From Discovery to Cure,” and the need for cost-effective development of novel interventions, NIMH has shifted away from a traditional approach to clinical trials. The traditional approach, in which researchers studied the clinical outcomes of an intervention without assessing whether the intervention altered a well-defined target, established current, well-accepted treatments such as exposure therapy and dialectical behavior therapy. However, it is well known that these treatments are not effective for all patients and that overall outcomes have not improved palpably in recent decades, potentially due to the lack of new interventions or better matching of patients to available treatments. Additional limitations to the traditional approach include: costly failures to replicate positive results in larger trials; difficulty in determining the reasons for negative results; low yield in terms of identifying disease or intervention mechanisms due to an exclusive focus on symptom change and clinical endpoints; and, the expensive and very lengthy practice of first establishing multi-component psychosocial treatments followed by years of “unpacking” studies.

As a result, in 2014 NIMH launched a new experimental therapeutics approach to clinical trials and  introduced a set of Funding Opportunity Announcements (FOAs) to support clinical trials research spanning novel intervention development, efficacy testing, and effectiveness testing in community practice settings. NIMH also established new requirements for timelines, trial registration, publication, and data sharing for the clinical trials program.

The experimental therapeutics approach, widely accepted for drug development, is equally relevant to psychosocial treatment development. In many ways, this approach is consistent with traditional, empirical methods for developing behavioral and psychosocial interventions. Such interventions are based on psychopathology research that identifies potentially mutable factors associated with etiology, maintenance, severity and/or course of disorders; importantly, the new strategy emphasized that these factors may be considered in psychological terms (e.g., attention, impulsivity). Intervention strategies that map onto these targets are designed to determine if manipulation of putative targets leads to clinical improvement. Clinical trials should ideally be informative even when interventions are not efficacious. Such information is consistent with the goal of learning more about mental illnesses and providing critical information on effective dose and duration of treatment, both of which are necessary for developing evidence-based treatment models.

In the experimental therapeutics approach, the intervention is first used as a tool to validate and engage the target. Under this mechanism-based approach to intervention development and testing, the object is to design and conduct the trial to be maximally informative regarding the viability of both the target and intervention strategy. Accordingly, the trial should ideally be designed to address well-selected targets (i.e., targets that have been empirically linked to the development, maintenance, severity, and/or course of the clinical problem); should incorporate well-validated measures of the target (including the use of multiple measures that span multiple units of analysis, as appropriate and feasible, to enhance detection of intervention-induced changes in the target); and, should be designed with careful attention to optimizing the intervention delivery (e.g., with attention to operationalizing and maximizing fidelity, and with careful attention to “dose” optimization [i.e., in a psychological context, typical length and duration of sessions]). The test of target engagement informs a “Go/No Go” decision about whether or not to proceed to examine the clinical effects of the intervention. A fully powered and expensive test of efficacy is not pursued without evidence of target engagement and a preliminary signal of efficacy. This approach optimizes the value of clinical trials regardless of clinical outcomes.

The experimental therapeutics approach is in its sixth funding cycle and, moving forward, NIMH plans to continue to implement this approach. NIMH recognizes there may be challenges to finding the most promising target for new innovative interventions, and will continue to evaluate the effectiveness of the experimental medicine approach and examine key issues across all modalities of clinical trials to ensure inclusion of exciting and innovative interventions and to establish standards that enable researchers to meet the criteria for such an approach.

A recent NIMH Leadership update at an NAMHC meeting noted some concerns from the field related to clinical trial efforts. Some misconceptions are that NIMH is not interested in funding clinical trials; that NIMH is only interested in biological targets; and, that NIMH has no interest in optimizing current therapies. To address the concern that potentially valuable interventions could be prematurely abandoned if the hypothesized target is incorrect, NIMH encourages further investigation of the mechanisms of action of such effective treatments to refine future target selection. For instance, in the example posited in the question (therapy A shows promise but mechanism B is incorrect) it would be reasonable for an investigator to submit a grant application to test a new hypothesis regarding a different mechanism (and thus, different target) for therapy A.

**3. Does NIMH accept clinical trials applications under the R01 funding mechanism? If not, does NIMH plan to offer such funding?  What does NIMH see as the appropriate balance between NIMH-initiated and investigator-initiated research to most effectively reduce the burden of mental illness?**

NIMH recognizes the need to improve interventions for mental illnesses across the entire range of modalities. Intervention development in the pharmaceutical industry has been so slow that few viable new targets and few effective medications exist. Further, innovative psychosocial interventions require validation of measures of fidelity before being disseminated or reimbursed in the new healthcare environment. In addition, replication of positive results in larger trials is costly, and NIMH is constrained by limited funding and a budget that has lagged well behind inflation over the last decade. Based on the need to develop novel interventions with fewer dollars, and following recommendations by the National Advisory Mental Health Council (NAMHC), NIMH continues to move toward an experimental therapeutics approach to clinical trials.

While NIMH does not accept clinical trials applications under the standard NIH parent R01, R21, and R03 mechanisms (see NOT-MH-14-007 **), current NIMH clinical trials Funding Opportunity Announcements (FOAs) use similar grant mechanisms specifically designed for NIMH clinical trials. The reason for this policy is to ensure that grant applications for clinical trials follow the experimental therapeutics approach as the field becomes conversant with the new guidelines. These clinical trials FOAs support the full pipeline of intervention development and efficacy testing. They support research on preventive, therapeutic, and services interventions across the full range of modalities including psychosocial, pharmacological, device-based, and combination approaches. As well, these FOAs are not prescriptive with regard to the focus of the intervention research, and encourage research across the developmental spectrum and across all mental illnesses addressed by NIMH (as well as Research Domain Criteria [RDoC]-themed studies). Functionally, this suite of FOAs is capable of supporting the full range of clinical trials research that would otherwise be submitted as investigator-initiated applications. NIMH believes these clinical trials FOAs will facilitate the movement of interventions through the pipeline so that more promising interventions make it to full-scale efficacy and effectiveness testing.

An internal NIMH committee meets regularly to review the response to, and yield from, the current clinical trials FOAs. Committee members consider such issues as whether there are a sufficient number of novel targets available for testing, and whether RDoC constructs are being integrated into clinical trials. This committee evaluates how well current funding strategies meet the needs for research on preventive, therapeutic, and services interventions. At this point, NIMH plans to maintain the experimental therapeutics approach; in addition, NIMH might potentially develop separate drug/device and psychosocial intervention FOAs, and might consider companion FOAs to fill gaps. NIMH will also work to improve communication and outreach by providing webinars and conference presentations for applicants about clinical trials, and will work to ensure a consistent understanding of this approach by grant reviewers.

**4. To what extent, and in what ways, does NIMH envision supporting treatment process research, including questions about the roles that clients, therapists, settings, and relationships, as well as social and cultural contexts, play in achieving treatment outcomes?**

As stated in the NIMH Strategic Plan for Research, NIMH values the importance of supporting research to enhance the practical relevance of effectiveness research, taking into account how client-, therapist-, and setting-level factors impact the outcomes of interventions in practice settings. NIMH is engaged in numerous efforts to address the processes of intervention to identify approaches that work in real-world environments and to ensure that effective treatment elements are translated from research to practice.

The NIMH commitment to effectiveness research for treatment, preventive, and services interventions is highlighted by several funding opportunity announcements (FOAs; e.g., MH-16-410 **, MH-16-415 **, MH-16-420 **) that emphasize the importance of research regarding how patient/client characteristics impact the intervention process and response. This emphasis is consistent with the widely observed fact that even the most effective, evidence-based interventions do not work for everyone. The focus on detecting moderators of intervention response that might inform strategies to tailor interventions corresponds with the broader goal to develop and test more prescriptive, personalized strategies.

NIMH also recognizes the importance of understanding how therapist- and setting-level factors impact the delivery and efficacy of interventions. NIMH solicits research studies that test or compare client-, therapist-, or setting-level services interventions designed to promote service access, use, engagement, and retention, or to improve quality or outcomes of care. Importantly, NIMH supports effectiveness research that incorporates approaches to reduce empirically documented outcome disparities experienced by people in specific subgroups, as emphasized in the NIMH Strategic Plan.

Effectiveness research on quality of care is of vital importance to the NIMH mission. One current FOA (MH-17-500 **) solicits research focused on the assessment of psychotherapy process and quality in community practice settings. The goal is to develop assessment tools and strategies that can be used to characterize the delivery of psychotherapy. Metrics of quality derived in this effort need to be psychometrically rigorous, feasible for use in practice settings, and useful for advancing efforts at training, supervision, quality monitoring, and/or quality improvement.

NIMH also funds research on specific strategies for training therapists to promote initial competence, sustain high-quality therapy, and promote patient outcomes. For example, a currently funded two-site trial (MH-10-6536 **; MH-10-6657 **) is examining whether the addition of an outcome monitoring and therapist feedback system improves outcomes among youth treated for mood and anxiety disorders.

Other ongoing or planned NIMH efforts on the effectiveness of interventions include projects aimed specifically at particular social and cultural contexts: these include the Suicide Prevention for at-Risk Individuals in Transition (SPIRIT)  project aimed at suicide prevention in the justice system, and Reducing the Incidence of Suicide in Indigenous Groups – Strengths United through Networks (RISING SUN), aimed at reducing suicide in underserved, minority communities.****

**5. How will NIMH’s future research agenda contribute to an improved understanding of social and community influences on mental health, as well as organizational and structural influences on access to mental health services?**

As outlined in the NIMH Strategic Plan for Research, Strategic Objective 4 addresses NIMH’s commitment to services research to optimize the organization and delivery of evidence-based treatments. To strengthen the public health impact of its research, NIMH partners with payers, regulators, and decision makers to determine what research will provide the requisite evidence for improving outcomes in practice.

As an example of the NIMH approach to intervention development research, the Recovery After an Initial Schizophrenia Episode (RAISE) initiative utilized coordinated specialty care (CSC), a team-based intervention designed to improve outcomes for individuals experiencing first episode psychosis. Results demonstrated that CSC is efficacious, cost-effective, and adaptable in community treatment settings. Building on the success of RAISE, NIMH is planning an intervention and prevention initiative for youth. The Early Psychosis Intervention Network (EPINET) will use a learning health care model to optimize care for youth at high risk to reduce the incidence of psychosis.

NIMH strives to leverage its research through collaborations with other federal agencies. For instance, the success of RAISE prompted Congress to allocate an additional $25 million dollars in each of fiscal years (FYs) 2014 and 2015, and $50 million in FY 2016, to the Community Mental Health Block Grant Program administered by the Substance Abuse and Mental Health Services Administration (SAMHSA). Congress instructed SAMHSA to set these funds aside to assist states in establishing evidence-based treatment programs following the RAISE CSC model for first episode psychosis. The legislation specifically directed NIMH and SAMHSA to collaborate on providing guidance to states regarding the principles of CSC, and to evaluate the implementation of the new treatment programs. In addition, the Centers for Medicare and Medicaid Services, working together with NIMH and SAMHSA, approved reimbursement for the CSC model for first episode psychosis, promoting dissemination and accessibility for this important intervention. Following this successful model, pilot studies for other applications involving NIMH-SAMHSA collaboration are in development.

NIMH is funding studies seeking to overcome barriers to treatment. Some focus on service delivery in non-specialty mental health settings including studies of jail diversion by police (MH-09-9268 **; MH-09-6744 **) and treatment of anxiety in community vocational rehabilitation settings (MH-10-2263 **; MH-10-2274 **). Other studies test strategies to overcome help-seeking barriers faced by vulnerable populations, such as low literacy (MH-09-6707 **), stigma and discrimination (MH-10-4381 **; MH-09-4310 **; MH-09-6795 **), cultural perspectives on illness and efficacy of treatment (MH-08-5653 **), homelessness (MH-08-4903 **), and continuity of care for transition age youth in low-resource communities (MH-10-2525 **). NIMH also funds research aimed at overcoming barriers to treatment created by limited provider availability, including service networks to enhance access to care (MH-10-1307 **), access and engagement through peer support (MH-10-2230 **; MH-10-1271 **; MH-10-2525 **), and strategies to prevent provider burn-out (MH-10-4201 **), along with studies examining telemedicine to expand reach and improve public health impact (MH-09-1208 **; MH-10-4363 **).

Research to improve dissemination and implementation of evidence-based interventions can radically alter the quality of care for all populations across the lifespan. Research addressing these priorities can help reduce the gap between research and practice. NIMH encourages research proposals that will advance dissemination and implementation of effective practices, and catalyze new approaches to narrow the gap between best practices and standard care.

**6. Does NIMH’s research portfolio include the study of developmental influences on mental health? In particular, will there be research devoted to prevention of mental illnesses at all ages? Will NIMH support research devoted to treatment development and dissemination for youth struggling with mental illnesses?**

NIMH strongly supports the current, generally accepted view that mental disorders are neurodevelopmental conditions that have their roots across childhood – from early life programming, to childhood experiences that confer risk or resilience, to important changes in the social environment, and in brain development across adolescence. As described in the NIMH Strategic Plan for Research, Strategic Objective 2 is aimed at understanding brain and behavioral development across the lifespan and in diverse populations to inform intervention. To achieve these goals, it is essential to identify time periods when the impact of experience is particularly strong. A focus on the early, pre-symptomatic phase of a mental illness is critical, as this may provide the best opportunity to identify individuals at high risk and intervene at the earliest possible time.

Predicting the onset of mental illnesses is essential to early intervention strategies. NIMH has a strong track record for funding prospective research aimed at identifying early symptoms and early makers of risk. For example, NIMH has funded (for more than 10 years) three large and ongoing prospective studies: The Bipolar Offspring Study (BIOS); the Longitudinal Assessment of Manic Symptoms study (LAMS); and, the Child Outcomes of Bipolar in Youth study (COBY). These studies have collectively provided foundational knowledge on the natural course and progressive stages of, prodrome (a high-risk syndrome preceding frank symptoms) of, early vulnerability for, and the predictive value of risk factors for, the development of bipolar disorders. Additionally, NIMH funded the North American Prodrome Longitudinal Study ** (NAPLS and NAPLS2: PMID 23043872 **) which investigated mechanisms and developed predictive algorithms combining behavioral and biological markers to identify individuals who are most likely to develop psychosis. NAPLS3 is now following a new sample over two years to map the developmental trajectories of brain-behavior relationships. This will help to generate further insights into mechanisms driving psychosis onset and refine predictive algorithms associated with progression to psychosis.

Bolstered by the success of the NAPLS project, NIMH is coordinating an effort to harmonize clinical, cognitive, neuroimaging, and genomics data collection across multiple international studies of individuals at risk for psychosis. In this Harmonization of At-Risk Multisite Observational Networks for Youth ** (HARMONY) project, data from 1,900 individuals at elevated risk for psychosis are expected to be evaluated using a harmonized battery. This effort will allow cross-validation of predictive data analytic methods to identify the extent to which risk factors and patterns of illness development are similar across cultural groups. Predictive algorithms emerging from projects like NAPLS and HARMONY will inform clinical efforts toward early intervention for psychotic episodes.

In another major NIMH-funded effort directed toward understanding adverse trajectories, the Philadelphia Neurodevelopmental Cohort (PMID 25858255 **) followed over 9,000 children admitted for a wide variety of reasons to a hospital network in Philadelphia. A retrospective analysis showed that children who went on to develop palpable psychotic symptoms in adolescence showed a lag of approximately one year of cognitive developmental age compared to typically developing children. The implications for more precisely identifying such at-risk children, and working toward effective preventive interventions, are clear and compelling.

As an example of prevention research, NIMH launched an initiative to intervene early and to continue to implement a prioritized research agenda for suicide prevention. The Emergency Department Screen for Teens at Risk for Suicide (ED-STARS) is poised to improve screening for risk of suicidality among youth. This effort represents NIMH’s continued commitment to determining the best methods to prevent suicide, particularly among high-risk populations. In May, 2016, NIMH convened a major workshop on RDoC approaches to suicide prevention; this workshop emphasized the risk that early adverse events pose for maladaptive behavioral and brain development, with subsequent risks for suicidal ideation and behaviors.

Understanding that early intervention and prevention efforts require evidence-based approaches to individual care, NIMH supports research that evaluates the effectiveness of psychosocial and other interventions for mental illnesses. NIMH encourages services research, including research to develop interventions to improve the quality and outcomes of care; organization and system-level interventions to enhance service delivery; and strategies for widespread dissemination and implementation for evidence-based treatments into routine care settings.

**7. How is NIMH working to ensure that the next generation of clinical scientists is well positioned to create large-scale treatments that could lead to visible reductions in health problems, for example, “tomorrow’s cognitive behavioral therapy (CBT)”? In particular, what is NIMH’s role in scientific clinical training and promoting innovative clinical researchers?**

NIMH is committed to research training and career development that prepares individuals to conduct innovative research in areas of program relevance that will advance the mission of the Institute. Training and development of future and current clinician scientists is designed to encourage innovation in the study of the origins and treatment of mental illnesses.

NIMH  supports training of clinician scientists through a variety of mechanisms, including Individual National Research Service Awards (NRSA) Predoctoral and Postdoctoral Fellowships (F30, F31, F32), Institutional NRSA Research Training Awards (T32), Mental Health Dissertation Research Grants to Increase Diversity (R36), Mentored Career Development Awards (K99/R00, K01, K08, K23), Mental Health Research Education Awards (R25), and Diversity and Re-Entry Supplements. All of these awards support research education and training that includes treatment efficacy and effectiveness research. NIMH has developed specific guidance for clinician scientists at a variety of career stages, which can be found on the NIMH Training webpages.

As one current example of the ongoing commitment to the training of clinician scientists, NIMH supports and collaborates with the Delaware Project on Clinical Science Training **, which aims to create best practices for training psychology graduate students, interns, and post-doctoral fellows studying mental illnesses. One particular aim of the Delaware Project is to train students in developing new treatments, as opposed to merely learning the current crop of empirically-supported interventions. In collaboration with representatives from the Delaware Project, NIMH staff members are currently developing a webinar series designed to create innovative training resources by bringing together basic scientists, treatment developers, and experts in dissemination and implementation. Each webinar in the series will illustrate NIMH’s Research Domain Criteria (RDoC) approach to studying and understanding psychopathology and NIMH’s experimental therapeutics approach to developing and testing interventions, as applied to psychosocial interventions.

In addition to the many training efforts originating at NIMH, NIH has recently published several notices about policies that will help to support new investigators, including an announcement that formal instruction in rigorous experimental design and transparency to enhance reproducibility will be required as part of institutional training grants (e.g., T32) and individual fellowships (e.g., F30, F31, F32) as early as fiscal year 2017 (NOT-OD-16034 **). In addition, NIH announced a new policy on salary and research cost allowances for clinically trained investigators (K08 and K23 awards; NOT-OD- 16032 **), effective early 2016. With this policy change, NIMH will contribute up to $100,000 toward the K08 or K23 awardees' salary to offset the requested level of effort that will be devoted to research and career development.

Looking toward a future filled with great advances in mental health research, NIMH remains committed to working with the scientific community to better understand future workforce needs and to inspire the next generation of committed scientists.