National Institute of Mental Health Support for Cognitive Treatment Development in Schizophrenia: A Narrative Review

Abstract

For several decades the National Institute of Mental Health (NIMH) has supported basic and translational research into cognitive impairment in schizophrenia. This article describes the Institute’s ongoing commitment to cognitive assessment and intervention research, as reflected by three signature initiatives—Measurement and Treatment Research to Improve Cognition in Schizophrenia; Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia; and Research Domain Criteria—and related funding announcements that span basic experimental studies, efficacy and comparative effectiveness trials, and implementation research designed to promote cognitive healthcare in real-world treatment settings. We discuss how trends in science and public health policy since the early 2000s have influenced NIMH treatment development activities, resulting in greater attention to (1) inclusive teams that reflect end-user perspectives on the utility of proposed studies; (2) measurement of discrete neurocognitive processes to inform targeted interventions; (3) clinical trials that produce useful information about putative illness mechanisms, promising treatment targets, and downstream clinical effects; and (4) “productive urgency” in pursuing feasible and effective cognitive interventions for psychosis. Programs employing these principles have catalyzed cognitive measurement, drug development, and behavioral intervention approaches that aim to improve neurocognition and community functioning among persons with schizophrenia. NIMH will maintain support for innovative and impactful investigator-initiated research that advances patient-centered, clinically effective, and continuously improving cognitive health care for persons with psychotic disorders.

Introduction

In 1992, the Schizophrenia Bulletin published several prescient articles and commentaries on the theme of cognitive therapy for schizophrenia.^1–7 These papers signaled fresh interest in interventions for improving attention, memory, learning, and problem-solving among persons with schizophrenia, and considered a variety of biobehavioral approaches to promote greater clinical, social, and vocational recovery. The authors’ perspectives on key questions about cognitive interventions (eg, cognitive targets, mechanisms of treatment effects, and implementation barriers); clinical research methods (eg, ecologically valid measures, trial designs, and mediation analyses); and alliances to promote uptake of effective practices (eg, partnerships between service users, family members, clinicians, and scientists) foreshadowed later efforts by the National Institute of Mental Health (NIMH) to promote cognitive treatment development in psychosis.

The present article summarizes NIMH initiatives since the early 2000s that aimed to facilitate cognitive intervention research for schizophrenia and related disorders. We first describe external developments between 1997 and 2003 that motivated NIMH to explore new tactics for stimulating treatment development research. We then examine specific NIMH initiatives between 2002 and 2012 that catalyzed cognitive measurement, drug development, and rehabilitation research aimed at improving neurocognition and community functioning in schizophrenia. Next, we consider recent science and policy developments intended to speed treatment development research along the discovery-translation-implementation pathway. We conclude by summarizing lessons that may benefit future efforts to advance patient-centered, clinically effective, and continuously improving cognitive health care for persons with psychotic disorders.

External Influences, 1997–2003

NIMH is the lead government agency in the United States for research on mental disorders. In setting its scientific priorities, the Institute considers input from diverse external sources, including other federal agencies, the extramural research community, advocacy and professional organizations, clinical providers and health system administrators, and persons who use mental health services. The period between 1997 and 2003 was a fertile time for interaction, with synergistic initiatives by the US Surgeon General, a Presidential Commission, and the Director of the National Institutes of Health (NIH) that convened diverse constituents to consider mental health and clinical research ecosystems and to recommend strategies for improving links between science and services.

The Surgeon General’s Report on Mental Health,⁸ initiated in 1997, was an ambitious effort to summarize scientific evidence underlying the epidemiology, diagnosis, and treatment of mental disorders, and to describe gaps between what is known through research and application of advances in real-world settings. Based on an extensive review of the literature, the report conveyed optimism about the research supporting the efficacy and range of treatments available for many disorders. While the Surgeon General recommended strongly that people seek help for mental disorders,⁹ the report highlighted important areas of scientific uncertainty. The Surgeon General called for continued investment in mental health research, emphasizing integrative neuroscience and molecular genetics studies to identify novel targets for pharmacologic and psychosocial interventions as well as new approaches to health services implementation research.

The President’s New Freedom Commission on Mental Health (2002–2003) extended the Surgeon General’s analysis to include a comprehensive study of the US mental health service delivery system across public and private sectors.¹⁰ The Commission recognized enormous progress in the scientific study of interventions for mental disorders but noted an absence of cures and spotty implementation of evidence-based services in real-world settings. The Commission’s final report advocated a major, long-term commitment to basic research to promote recovery and resilience, and ultimately to cure and prevent mental illness. It also emphasized the need for applied research to study the dissemination, implementation, effectiveness, and sustainment of evidence-based interventions in communities, and to speed testing of emerging innovations in field settings.¹¹

The NIH Roadmap initiative, launched by the NIH Director in 2002–2003, reexamined the NIH research portfolio to identify scientific gaps and to consider novel methods, technologies, and large-scale projects to transform the process of medical research.¹² The Roadmap engaged hundreds of NIH staff, extramural scientists, and the lay public in a deliberative process of assessing scientific challenges, enumerating roadblocks to progress, and proposing bold ideas to increase the efficiency and impact of biomedical research. Three major themes—ie, new pathways to discovery, research teams of the future, and reengineering the clinical research enterprise—organized initiatives to promote state-of-the-art technologies, interdisciplinary team science, and clinical research via academic-community partnerships. Collectively, these programs aimed to speed the movement of research from the laboratory to the patient’s bedside within a decade.¹³

Impact of External Initiatives on NIMH Treatment Development Activities

NIMH leaders and scientist administrators engaged actively in committees, work groups, and public meetings that supported the Surgeon General’s Report, the President’s New Freedom Commission, and the NIH Roadmap process. NIMH staff contributed to planning, convening, synthesizing, and reporting activities, learned new approaches from government and private sector partners, and adopted several best practices in subsequent cognitive treatment development efforts:

Include Key Partners.

All 3 external projects recognized the need for broad input and new partnerships to understand and address complex medical problems.^8,10,12 In addition to representatives from academia and government, nontraditional experts were included, such as persons with lived experience, professionals with practical experience in organizing, delivering, and financing mental health services, and representatives of private foundations and patient advocacy organizations. The Surgeon General’s report⁸ and the NIH Roadmap¹² advocated stronger partnerships with biotechnology and pharmaceutical industries and greater collaboration between federal agencies with shared responsibilities for developing, regulating, and delivering evidence-based treatments.

Promote Transparency.

The New Freedom Commission utilized several tactics to increase transparency, including open meetings, regular opportunities for public input, and timely reports from subcommittees and the overall Commission.¹¹ For example, monthly working meetings included open deliberation and dedicated time for public testimony from advocacy groups, professional organizations, and members of the public. In addition, an interactive public website encouraged participation outside in-person meetings; over 2300 individuals submitted comments, concerns, and ideas for consideration. Finally, detailed reports from 15 subcommittees were made available, along with an interim progress report¹⁴ that generated spirited commentary that influenced the final phase of the Commission’s work.

Encourage “Productive Urgency”.

The cadence, operations, and deliverables of the President’s New Freedom Commission and the NIH Roadmap set new standards for rapid policy analysis and strategic planning. Aggressive one-year timelines were established to direct effort to urgent problems in mental health delivery systems¹¹ as well as respond to heightened public expectations for NIH-supported research.¹² Subcommittees and working groups, comprised of government and private sector experts with relevant expertise, tackled key issues in parallel, with overall coordination of efforts by Commissioners and NIH leaders, respectively. This formula was successful in generating understandable goals, concrete recommendations, and performance benchmarks for assessing the impact of new initiatives.^13,15 The urgency, efficiency, and productivity that characterized these initiatives influenced NIMH’s ensuing efforts to spur cognitive treatment development research in schizophrenia.

NIMH Cognitive Treatment Development Initiatives, 2002–2012

The Surgeon General’s report identified cognitive dysfunction as a key feature of schizophrenia and noted a paucity of evidence-based treatments for cognitive symptoms.⁸ Hyman and Fenton¹⁶ echoed these observations and suggested cognitive impairment as a “test case” for new approaches to schizophrenia therapeutics. Specifically, they proposed a framework for drug and psychosocial intervention development that would (1) dissect schizophrenia into component symptom complexes such as cognitive deficits; (2) develop measures to define new clinical targets as endpoints in human clinical trials; (3) direct interventions at the narrower clinical targets; (4) employ novel experimental designs to evaluate efficacy and clinical significance; and (5) draw on cognitive neuroscience and neuroimaging research to clarify neural mechanisms involved in cognition and to develop objective biomarkers for cognitive deficits. Hyman’s and Fenton’s commentary signaled a new approach to assessment and treatment development in schizophrenia that influenced NIMH initiatives over a 10-year period.

Measurement and Treatment Research to Improve Cognition in Schizophrenia

In 2002, NIMH announced the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, a multiyear effort to identify and remedy barriers to drug development and testing for cognition in schizophrenia.¹⁷ Following a competitive selection process, a contract was awarded to UCLA (Stephen Marder and Michael Green, co-principal investigators) to engage the pharmaceutical industry, the academic community, and government agencies, including the US Food and Drug Administration (FDA), in a consensus-oriented process to identify cognitive targets for intervention; select reliable and valid neuropsychological measures to assess cognition as a dependent variable in treatment trials; propose experimental designs to establish the efficacy of agents to enhance cognition in schizophrenia; and identify potential molecular targets for new therapeutic agents. The contract mechanism allowed a high level of collaboration between NIMH staff and the MATRICS team to pursue these goals. Importantly, coordinated efforts between NIMH leaders and MATRICS investigators spurred conversations and new alliances among key actors in the drug development space, including psychopharmacologists,¹⁸ the FDA,¹⁹ and persons with lived experience.²⁰

The MATRICS team convened 6 interlocking conferences over a 2-year period, with timely reports that conveyed the focus, process, and outcomes of each meeting.^{18,19,21–23} Concrete achievements that sprang from these activities include the following:

• The MATRICS Consensus Cognitive Battery (MCCB) was developed using quantitative analyses and expert consensus methods and was field tested in a 5-site psychometric and validation study.²⁴ To facilitate interpretation of results using a common scaling across tests, the MCCB was co-normed using data obtained from a representative US community sample.²⁵

• To meet the FDA’s requirement for functionally meaningful co-primary measures in cognitive intervention trials, 4 potential measures were evaluated alongside the MCCB for reliability, utility, practicality, and relationship to cognitive performance.²⁶

• In 2005, the NIMH National Advisory Mental Health Council (NAMHC) and the FDA recommended the MCCB as the standard cognitive performance battery in clinical trials of potential cognition-enhancing interventions.²⁴

• The MCCB has been translated into over 39 languages²⁷ and is now widely used to assess neurocognition in schizophrenia clinical studies. Since 2004, the MCCB has been cited in ~500 scientific publications and included as an outcome measure in ~170 clinical studies registered in ClinicalTrials.gov.

• The FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia¹⁹ developed guidelines for subject selection, co-primary outcome measures, and statistical approaches for clinical trials involving cognitive-enhancing drugs, which were later updated based on practical experience.²⁸

The MATRICS initiative was successful in catalyzing studies of procognitive drugs in schizophrenia, but new medications have proved elusive.²⁹ Green et al^30,31 reviewed cognitive intervention studies launched since MATRICS and identified several methodological factors that may hinder efforts to identify efficacious drugs. Those authors also noted broader scientific issues that impede drug discovery, including our incomplete understanding of the pathophysiology of cognitive impairment and error variance attributed to clinical and functional heterogeneity across schizophrenia spectrum disorders.³¹ Two ensuing NIMH initiatives considered these important scientific considerations in turn.

Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia

The final meeting of the MATRICS program focused on new preclinical and clinical research approaches for assessing and improving cognition in schizophrenia.²³ A strong case was made for applying methods derived from experimental cognitive psychology and cognitive neuroscience to examine the integrity of specific cognitive systems implicated in schizophrenia and to directly measure the effects of drugs on cognition-related brain activity.³² Responding to these recommendations, Cameron Carter and Deanna Barch proposed the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) conference series³³ and were awarded consecutive research conference grants to articulate a neuroscience research agenda that would extend the work started by MATRICS.

Between 2007 and 2011 the CNTRICS steering committee organized 7 meetings that brought together experts from the basic and clinical sciences, researchers from academia and industry who use animal models, and individuals with experience in clinical trials, psychometrics, and cognitive rehabilitation in schizophrenia to explore potential benefits of using constructs, tasks, and tools from cognitive neuroscience to better understand and treat cognitive impairments in psychosis.^34,35 Interactive surveys, quantitative summaries, and consensus-building methods were employed across meetings to identify cognitive systems and component processes that could serve as targets for measurement and treatment development; to address psychometric issues relevant for adapting experimental cognitive tasks for use in clinical trials; to select candidate experimental tasks that measure key cognitive constructs implicated in schizophrenia; to consider promising imaging biomarkers for use in cognitive treatment development research; and to facilitate development of translational animal model paradigms for exploring cognitive and affective constructs. In addition, the steering committee introduced an innovative buddy system that paired prominent cognitive neuroscientists with well-known clinical researchers with schizophrenia expertise to maintain a patient-centered focus in CNTRICS deliberations.

Midway through the CNTRICS process, NIMH published a funding opportunity announcement to solicit proposals for research aimed at adapting and optimizing experimental cognitive measures for use in treatment trials of schizophrenia (RFA-MH-08-090). Among the studies selected for funding, a 5-site collaborative project came together as the “Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRaCS) Consortium.” CNTRaCS investigators proposed a transdisciplinary approach for (1) cognitive task selection; (2) adaptation of validated paradigms for clinical research; (3) psychometric evaluation of new measures; and (4) maintaining construct validity of modified tasks. Since 2008, CNTRaCS has pursued translational measurement development for cognitive constructs identified in CNTRICS (ie, goal maintenance; relational encoding and retrieval in episodic memory; gain control; visual integration; working memory; and reinforcement learning) and produced a variety of cognitive neuroscience-based approaches for clinical research studies, including imaging biomarkers.³⁶

Together, CNTRICS and CNTRaCS achieved the respective goals of establishing a neuroscience research agenda for cognitive treatment development in schizophrenia and adapting validated laboratory tasks of cognitive operations for use in clinical trials. Over 60 scientific publications describe the scientific discourse that occurred during CNTRICS meetings as well as methods, results, and products from the CNTRaCS research program. Cognitive task paradigms developed by CNTRaCS are freely available to the field and industry (https://cntracs.ucdavis.edu/), including tasks and associated computational models appropriate for clinical trials as well as research conducted within the NIMH Research Domain Criteria framework.³⁷

Research Domain Criteria

NIMH launched the Research Domain Criteria (RDoC) initiative in 2009 to provide a framework for research that explores novel ways of characterizing and classifying mental disorders. The rationale for this new approach was that the ecosystem of research funding, peer review of grant applications and scientific publications, and regulatory activities was over-focused on studies of highly heterogenous mental disorders as defined in longstanding diagnostic systems. The overarching RDoC hypothesis is that mental disorders may be better understood if the tools and concepts of modern behavioral neuroscience are used to dissect heterogeneity within psychopathology and assess functional domains that could be targeted for treatment in a more precise and individualized way.

The RDoC framework was informed by a series of workshops in 2010–2012—and an additional workshop in 2018—which closely modeled the MATRICS and CNTRICS meetings. These workshops engaged over 200 leading scientists and NIMH staff in discussions of the RDoC approach and the development of a set of exemplar constructs and associated elements that provide a shared vocabulary for this scientific endeavor. The first workshops focused on Working Memory³⁸ and Cognitive Systems,³⁹ built directly on the knowledge base created by CNTRICS. These workshops adopted CNTRICS’ focus on integrating knowledge from cognitive and affective neuroscience into novel approaches for translational research, a focus that persisted throughout the workshop series. In contrast to MATRICS, NIMH did not develop a formal battery of specified tasks for assessing RDoC domains but instead encouraged investigators to flexibly select measures that are fit for purpose. Participants in this series of formative RDoC workshops populated the RDoC matrix with exemplars of tasks and tools, including several CNTRaCS tasks, which could be used to assess constructs related to RDoC cognitive systems domains.

NIMH has published 19 RDoC-focused funding opportunity announcements since 2011. More than one hundred research projects adopting RDoC principles have been funded, along with many others awarded under other NIH funding mechanisms. Among these grants are several projects that examine cognitive constructs such as language⁴⁰ and perception⁴¹ in psychosis which may lead to novel treatment targets or outcome measures. Most recently, the NIMH RDoC Unit launched the Individually Measured Phenotypes to Advance Computational Translation in Mental Health (IMPACT-MH) initiative (RFA-MH-23-105). Projects supported through IMPACT-MH will combine data from cognitive tasks and device-based behavioral measures with electronic health records information to derive novel clinical signatures that can be assessed at the individual level to improve clinical decision-making and predict clinical outcomes.

NIMH Workshop on Cognitive Training in Mental Disorders

During the period when MATRICS/CNTRICS/RDoC initiatives were being developed (2002–2012), NIMH observed growing interest among extramural scientists for nonpharmacologic cognitive training and rehabilitation interventions, with successful research proposals involving patients from diverse diagnostic categories and across developmental stages. In addition, an annual conference sponsored by the Columbia University Irving Medical Center brought together researchers, clinicians, and healthcare administrators to share experiences and perspectives on cognitive remediation in psychiatry and to focus attention on emerging translational, clinical, and implementation research questions.⁴² To learn from the expanding cadre of cognitive interventionists, NIMH convened a state-of-the-science meeting in 2012 to review evidence for the efficacy of cognitive training approaches across psychiatric illnesses, including schizophrenia, and to identify knowledge gaps, new research opportunities, and examples of research-to-practice implementation.⁴³ The workshop included investigators from academia, military research agencies, and the NIMH Intramural Research Program; representatives of digital health companies, state mental health authorities, and community behavioral health systems; and health scientist administrators from several NIH institutes. Approximately one-quarter of participants were veterans of the MATRICS, CNTRICS, and/or RDoC initiatives, which provided valuable scientific continuity.

For purposes of the workshop, cognitive training (CT) was differentiated from other behavioral and psychosocial interventions that address problematic cognitions as part of a broader therapeutic approach, such as cognitive behavioral therapy or psychoeducation. CT was defined more precisely as “an intervention that uses specifically designed and behaviorally constrained cognitive or socio-affective learning events, delivered in a scalable and reproducible manner, to potentially improve neural system operations.”⁴⁴ The workshop addressed the current state of knowledge regarding (1) the neuroscience basis for cognitive, affective, and neural processes targeted by CT; (2) evidence of CT efficacy for improving neurocognitive processes and functioning; (3) hypothesized mechanisms of CT treatment effects; (4) approaches that combine CT with other treatment modalities; (5) predictors of treatment response; and (6) what has been learned from efforts to implement CT in clinical practice.

Keshavan et al. summarized the workshop’s presentations, discussions, and recommendations for future research.⁴⁴ The authors concluded that “overall, the evidence thus far supports the neurobiological rationale and the efficacy of cognitive training in schizophrenia, but replication of positive results is needed; many questions remain with regard to therapeutic mechanisms, key therapeutic ingredients, and approaches to dissemination in routine clinical settings.” Several considerations for the design of CT trials echo lessons from the MATRICS initiative^29,31; ie, the importance of detailed participant characterization, including baseline cognitive functioning; choosing appropriate inclusion/exclusion criteria; measuring specific (vs global) cognitive operations as treatment targets and outcomes; and accounting for mediators, moderators, and mechanisms of treatment effects. Other recommendations emphasized up-front attention to end-user perspectives, clinical workflows, and provider requirements in intended delivery settings, and including outcome measures that are meaningful to healthcare policymakers. Together, these recommendations encouraged best practices for advancing interventions that target core neurocognitive operations necessary for clinical, social, and educational/vocational recovery, and for positioning new interventions for rapid adoption in clinical practice.

Impact of NIMH Cognitive Treatment Development Initiatives

The MATRICS, CNTRICS, and RDoC initiatives were largely successful in replicating the inclusiveness, transparency, and productive urgency that characterized the Surgeon General’s Report, the President’s New Freedom Commission, and the NIH Roadmap. Each NIMH initiative brought together diverse constituents to work through complex scientific questions, and through progressive encounters, to establish a common framework and vocabulary for analyzing problems and imagining potential solutions. Frederick Frese, a respected mental health “prosumer,” contributed significantly to the MATRICS Neurocognition Committee²⁴ as a champion of recovery principles²⁰ and stigma-free, nonpejorative language about cognition in schizophrenia.⁴⁵ The unique value of this lived experience perspective prompted NIMH to encourage similar engagement with service users in subsequent research initiatives, as described below.

The cadence of MATRICS, CNTRICS, and RDoC meetings, the continuity of participants across initiatives, and new collaborations among diverse partners fostered interdisciplinary teams that later tackled translational research goals. The co-creation of new research concepts, methods, and products by such teams were essential factors in generating broad enthusiasm for cognitive treatment activities in schizophrenia. Indeed, ~750 scientific papers, review articles, and book chapters have been published since 2002 that are based on MATRICS, CNTRICS, or RDoC contributions to the assessment and treatment of cognitive symptoms in schizophrenia.

Science and Policy Trends, 2013–2023

Between 2002 and 2012, NIMH-supported initiatives created momentum for neuroscience-based studies in schizophrenia that focused on illness mechanisms and targeted interventions based on mechanistic insights. A small number of competitive funding opportunities incentivized the development of new assessment tools and clinical trial methods, but most funded studies used traditional grant mechanisms to support investigator-initiated projects. In the subsequent decade, new science and NIMH policy developments influenced trends in cognitive intervention research, including new expectations for clinical trials and implementation of science studies.

Experimental Therapeutics Paradigm for Clinical Trials

By 2010, major pharmaceutical companies had exited the field of psychiatry, citing poor understanding of disease mechanisms, a lack of biomarkers and valid animal models, and high failure rates in clinical trials.^46,47 The dramatic change in industry priorities prompted NIMH to seek guidance on how to better align basic, clinical, and intervention research to support pharmacologic treatment development. The NAMHC workgroup report, “From Discovery to Cure”⁴⁸ recommended several changes to the NIMH clinical trials portfolio to accelerate translational efforts, including a shift towards an experimental therapeutics model, “in which interventions are used as probes of disease mechanisms as well as tests of efficacy.”⁴⁹

Since 2014, NIMH has solicited clinical trial applications through a dedicated set of funding announcements that cover the intervention development pipeline, including first-in-human and early-stage clinical trials of novel investigational drugs or devices; pilot research to develop and test innovative psychosocial interventions; confirmatory efficacy trials; and comparative effectiveness trials. In each case, an experimental therapeutics approach is required, where projects (1) identify a mechanistic target or mediator for the intervention being tested; (2) measure the intervention’s impact on the hypothesized target; and (3) examine whether changes in targets are associated with changes in distal clinical or services outcomes. Trials designed in this manner are informative for basic, translational, and intervention research in that studies produce useful information about putative illness mechanisms, promising treatment targets, and downstream clinical effects.

Implementation and Sustainment of Evidence-Based Interventions

Reports from the Surgeon General,⁸ the President’s New Freedom Commission,¹⁰ the Institute of Medicine,⁵⁰ and a NAMHC workgroup on mental health services research⁵¹ all noted long delays between the reporting of scientific findings and the translation of new knowledge into clinical practice. To address this “implementation gap,” NIMH began promoting deployment-focused approaches to intervention development, testing, and dissemination,⁵² starting with the Recovery After an Initial Schizophrenia Episode (RAISE) initiative.⁵³ Subsequent deployment-focused studies have considered the perspective of end-users (eg, service users, clinicians, health care administrators, and payers) and characteristics of the ultimate delivery settings (eg, workforce capacity, training resources, clinical workflows) to help ensure that proposed interventions are feasible and scalable, and that research results are actionable for improving practice.

This approach is elaborated in current NIMH research initiatives aimed at accelerating the implementation and continuous improvement of new practices in diverse, real-world healthcare settings, including the ALACRITY Research Centers⁵⁴ program, EPINET Research Networks,⁵⁵ and funding announcements for comparative effectiveness trials (eg, PAR-21-130; PAR-21-131). Through these initiatives, NIMH strongly encourages meaningful involvement of mental health service users and family members in multiple roles throughout the research enterprise. For example, serving as a principal or co-principal investigator of a research project; membership in a project’s executive committee or external advisory group; as a practice-partner member of a transdisciplinary research team; or as a research participant whose lived experience perspectives are systematically assessed via qualitative and/or quantitative methods.

Impact of Experimental Therapeutics and Implementation of Science Funding Announcements

Extramural scientists have successfully pivoted to experimental therapeutics trials to test cognitive interventions for persons with psychotic disorders, as evidenced by research grant projects awarded across all stages of the intervention pipeline. Many funded projects are taking cognitive treatment in new directions, including (1) interventions that target social cognitive processes; (2) approaches that combine cognitive training with other therapies to improve neurocognitive outcomes or promote generalization of training effects (eg, procognitive medications, neuromodulation techniques, aerobic exercise, or behavioral skills training); (3) studies that integrate cognitive interventions into treatment programs for early psychosis; and (4) efforts to address heterogeneity in neurocognitive functioning through personalized cognitive training.

Several deployment-focused implementation projects are examining the adoption and sustainment of cognitive training interventions in real-world community settings. For example, one ALACRITY Center subproject focuses on improving the accessibility and personalization of cognitive remediation for schizophrenia in publicly funded outpatient mental health clinics (P50MH115843). An EPINET network project is testing the feasibility and real-world effectiveness of a neuroscience-informed cognitive training program that pairs social cognitive training with a research-supported mobile application to improve outcomes in first-episode psychosis (R01MH120589). A third implementation project is testing an environmental intervention to bypass cognitive and motivational difficulties associated with schizophrenia to increase adherence to medications and improve functional outcomes among persons receiving treatment in community mental health centers (R01MH11701).

Reflections and Considerations for Future Research

Cognitive treatment development in the United States has progressed substantially since 1992, when thought leaders debated whether cognitive intervention in schizophrenia was possible and if so, how clinical studies should proceed.^1–7 In the ensuing decades, NIMH has employed both top-down and bottom-up approaches to support basic, translational, and implementation research in cognitive treatment for psychosis. The MATRICS, CNTRICS, and RDoC initiatives illustrate the former tactic, where NIMH staff collaborated closely with extramural scientists and others to organize a neuroscience research agenda around cognitive therapeutics. These efforts over a 10-year period helped to cultivate a vibrant learning community that embraced the challenges of delineating cognitive systems implicated in schizophrenia and developing new animal models, clinical assessments, and intervention methods. Afterwards, NIMH shifted its focus to standing funding announcements designed to support innovative and impactful investigator-initiated research projects. Over the past decade, the science supporting cognitive treatment efficacy and implementation has advanced and evolved, propelled by the interests, creativity, and energy of the extramural research community.

Partnerships with other government agencies, industry, and persons with lived experience have grown over time and continue to benefit NIMH treatment development activities. For example, the Accelerating Medicines Partnership Program for Schizophrenia (AMP SCZ)⁵⁶ is a public-private endeavor between NIMH, the FDA, the European Medicines Agency, pharmaceutical companies, and other private-sector partners to generate tools that will aid the development of early-stage treatments for people who are at risk for schizophrenia. Persons with lived experience contribute to the leadership and operation of AMP SCZ, which has enriched both the science and real-world relevance of the project.^57,58 This aspect of AMP SCZ is consistent with NIMH’s expanded vision of team science, which includes individuals with lived experience, family members, frontline clinicians, and payers as colleagues in clinical research efforts.^54,55 It is also an Institute priority to include members of historically underrepresented groups in team science, ie, persons from racial, ethnic, and sexual and gender minority groups as well as individuals from lower socioeconomic strata.

Collectively, external influences and NIMH initiatives have helped set a direction for the next phase of science-to-service research in cognitive treatment for persons with psychotic disorders. The 2023 White House Report on Mental Health Research Priorities,⁵⁹ developed to address the mental health crisis exacerbated by the COVID-19 pandemic, provides additional guidance. For example, the White House Report calls for new scientific efforts to (1) support and expand the supply, capacity, and diversity of the mental health workforce; (2) increase the availability, quality, and impact of evidence-based services across a range of settings; (3) foster long-term engagement in care and recovery among persons receiving mental health treatments; and (4) develop and test strategies for provider training, supervision, and performance feedback to ensure sustained implementation of high-quality interventions. To reduce mental health disparities and advance equity, the Report encourages research that addresses social determinants of health, applies community-based participatory methods to ensure the responsiveness of interventions, and oversamples members of historically underrepresented groups in mental health studies.

These priorities are highly relevant to cognitive treatment of psychosis in the United States, where the cognitive intervention workforce is small, evidence-based programs are rarely available outside of academic research clinics, and few individuals with lived experience receive needed therapies. A forward-looking collaboration between the New York State Office of Mental Health (OMH) and Columbia University⁶⁰ addresses these limitations through a multiyear project to implement cognitive health services in state-operated outpatient clinics for persons with serious mental illness (SMI). In a series of richly detailed papers,^61–66 Medalia, Saperstein, and colleagues describe a systematic process for introducing cognitive remediation practices in large systems of psychiatric care. Their deployment-focused, phased, and data-driven approach stands out as a case study in implementation excellence.

Table 1 presents current views about the stages of successful implementation, as summarized in the National Implementation Research Network’s synthesis of implementation research and practice studies,⁶⁷ as well as best practices for promoting the adoption, installation, and sustainment of evidence-based programs,⁶⁸ per guidance provided by the Substance Abuse and Mental Health Services Administration regarding implementation of evidence-based programs. The New York State effort largely follows these recommendations, including (1) close collaboration between OMH officials, local facility personnel, and cognitive remediation experts on implementation choices, methods, and resources; (2) a standardized and sustainable staff training program that teaches evidence-based practices to busy clinicians and supports treatment fidelity; (3) program evaluation activities that support provision of high-quality care; and (4) treatment adaptations that meet the needs of a culturally diverse and multilingual SMI population. Several noteworthy features of the project include the following:

Table 1.

Stages of Implementation and Best Practices to Promote Adoption, Installation, and Continuity of Evidence-Based Programs

Implementation Stage	Recommended Actions
Exploration and adoption	Establish mechanisms to create and sustain strong partnerships with organizational leaders, managers, and front-line staff around selecting an appropriate evidence-based program, eliminating barriers to adoption, and supporting implementation efforts over time. Identify the target population and understand its needs, challenges, assets, and desired outcomes that are relevant to choosing an evidence-based program. Assess organizational capacity, including (a) financial resources to cover startup costs; (b) availability of space, equipment, and support services; and (c) ability to bill for new interventions. Evaluate workforce readiness and supports, including caseload standards, clinical workflows, staff recruitment and retention plans, and training and supervision requirements for new and current staff members. Determine feasible methods for monitoring treatment fidelity longitudinally, supporting continuous quality improvement of services, and measuring the impact of new programs on the population being served.
Program installation	Establish an Implementation Team comprised of subject matter experts, organizational leaders, and local “champions” who possess a strong understanding of the selected program, workplace culture, and structural and procedural changes necessary to implement the program. Create readiness for implementation by establishing space for the program, installing needed equipment, selecting personnel, and training staff in evidence-based practices. Anticipate the need for onsite coaching and ongoing supervision to support practitioners’ efforts to implement the new program with fidelity. Develop data management and billing systems to monitor treatment fidelity, track service delivery, and measure the effects of the program. Ensure engagement of clinical, administrative, and support staff and address issues regarding readiness and commitment to change.
Initial implementation	Use the Implementation Team to guide, manage, and reinforce organizational change processes and to maintain momentum of the initiative. Set realistic goals and expectations about implementation timelines, the incremental nature of progress, and the impact of new practices on patient outcomes. Provide evidence-based interventions to members of the target population, build caseloads, and start billing for new services. Collect quantitative and qualitative data to (a) reveal unforeseen barriers to implementation; (b) identify challenges to performing new skills and routines; and (c) communicate examples of successful application of evidence-based practices. Encourage onsite coaches to provide immediate feedback and technical assistance to practitioners to troubleshoot implementation problems, enhance skills development, build confidence, and increase positive perceptions of the program.
Full implementation	The Implementation Team stays engaged with organizational leaders, managers, and practitioners to sustain tangible commitment to the evidence-based program. Monitor referrals, patient enrollment, caseloads, services delivered, and funding streams to assure program viability. Maintain a skilled workforce through ongoing supervision, consultation, and targeted training activities. Assess whether the program is being implemented as intended (fidelity evaluation) and whether the program is working for the intended population (outcome evaluation).
Program austainability	Create a continuous feedback loop between high-level administrators, the Implementation Team, clinical providers, and service users about the relevance, feasibility, and effectiveness of the evidence-based program. Be alert for changes in organizational leadership or priorities, or external factors that might affect ongoing support for the evidence-based program. Track and troubleshoot problems with patient referrals, enrollment, services delivered, and billing to ensure financial stability for the program. Institutionalize a quality assurance system that includes regular review of fidelity and outcome data and uses findings to improve the quality and effectiveness of the program. Nurture staff morale by acknowledging implementation milestones, sharing positive results with clinical teams, and celebrating success with key shareholders.

Note: Stages of implementation are based on the National Implementation Research Network’s synthesis of implementation research and practice studies.⁶⁷ Recommended actions are from guidance provided by the Substance Abuse and Mental Health Services Administration regarding implementation of evidence-based programs.⁶⁸.

• Cognitive remediation experts worked closely with OMH leaders and local clinic administrators to operationalize a public psychiatry model of cognitive health and to solve pragmatic questions about staffing models, clinical workflows, information technology needs, and billing practices.

• Cognitive remediation services were implemented in a staggered manner, starting with outpatient clinics serving adults with SMI diagnoses⁶¹ and later expanded to Coordinated Specialty Care (CSC) programs for first-episode psychosis.^62,63 The latter effort adopted recovery values, organizational principles, and implementation methods pioneered in the adult SMI programs, but modified them to address the needs and perspectives of younger service users.⁶⁴

• Workforce development programs were created to build broad and enduring support for cognitive remediation interventions. All clinical and support staff received education about cognitive health and recovery; selected clinicians received targeted training and ongoing supervision in cognitive assessment, treatment planning, and intervention practices. Train-the-trainer classes were established to maintain a pool of competent instructors to teach these skills to new clinicians, as needed.

• Clinicians collect program evaluation data as part of routine care; supervisors use these data to monitor treatment fidelity and troubleshoot implementation problems in real-time. Pragmatic measures of service utilization, dropout rates, and participant satisfaction confirm the fidelity, acceptability, and perceived effectiveness of cognitive remediation in state-operated clinics,⁶⁵ but also identify areas for further improvement.⁶⁶

The New York State implementation experiment responds to several research priorities outlined in the recent White House Report.⁵⁹ The initiative successfully expands the cognitive remediation workforce to include psychologists, nurses, physicians, social workers, and mental health counselors who work in community treatment settings. The public psychiatry model⁶¹ assures that almost all persons served in state-operated clinics for adults, and CSC programs for youth, are eligible to receive cognitive health services. Integrating cognitive remediation into existing multidisciplinary rehabilitation programs furthers OMH’s commitment to person-centered, recovery-oriented treatment that fosters patients’ independence and community engagement. Innovative methods for training clinicians, tracking their performance, and maintaining treatment fidelity are sustaining the implementation of high-quality interventions over time. Finally, the extension of cognitive health services into CSC programs illustrates the importance of involving end-users, eg, CSC service providers⁶² and persons with lived experience,⁶⁴ in developing interventions that are feasible to implement and responsive to the needs and preferences of the target population.

While these accomplishments are a clear step forward, further research in public sector settings is needed to (1) optimize the delivery of cognitive interventions (eg, increase referrals, participant enrollment, and service utilization); (2) eliminate potential inequalities in access, quality, or effectiveness of services for populations with health disparities⁶⁹; (3) evaluate the impact of cognitive interventions on objective measures of patients’ social, educational, and vocational functioning; and (4) determine the cost-effectiveness of combining cognitive remediation programs with traditional psychiatric rehabilitation services. These and similar practice-oriented research questions could be explored within a learning health care framework, where data collected as part of routine care are used to study the implementation, adaptation, and effectiveness of evidence-based interventions in public health clinics.⁷⁰ Such an approach ensures that research findings are directly relevant to representative sets of patients, clinicians, and health care system administrators, while clinical practice benefits from continuous data-driven improvement.⁷¹

Conclusions

Throughout 2024, NIMH is celebrating 75 years of basic, translational, and health services research that has deepened our understanding of mental disorders and broadened the therapeutic armamentarium. Cognitive intervention research for schizophrenia has featured prominently in the Institute’s scientific portfolio, with sequential treatment development initiatives over the past 2 decades. A core set of principles guided these efforts, including convening diverse learning communities, using structured encounters to establish a common scientific framework and vocabulary for understanding complex challenges, and creating funding opportunities that encourage interdisciplinary, deployment-focused studies. Increasingly, teams that partner translational scientists, implementation researchers, and mental health shareholders, eg, service users, family members, clinicians, payers, and policymakers, are developing and testing interventions that align with conditions encountered in real-world treatment systems. This approach holds promise for speeding the introduction of evidence-based practices in these settings, thereby narrowing the typical research-to-implementation gap.⁷² Going forward, science-to-service studies conducted within the learning health model will further accelerate progress toward clinically effective, continuously improving, and accessible cognitive health care for all persons with psychotic disorders.

Conflict of Interest

The authors have no conflicts of interest to disclose. The views expressed in this article do not necessarily represent the views of the National Institutes of Health, the Department of Health and Human Services, or the United States Government.