Shaun M. Eack, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Functional assessment in schizophrenia has become a recent NIMH priority (PA-05-037). The cognitive deficits associated with the illness are potentially important factors limiting functional recovery from the disorder. Research has suggested that deficits in social cognition may be particularly important to functional outcome. Unfortunately, reliable and valid social-cognitive assessments are sparse. The broad goal of this research is to contribute to the ongoing efforts of elucidating the functional significance of social-cognitive deficits in schizophrenia and the relevance of such deficits as specific targets for future schizophrenia treatments, through the examination of a promising measure of social cognition. Specifically, this project proposes to conduct a preliminary investigation on the use of the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT), a promising ability-based measure of emotional intelligence (and also included in the NIMH-MATRICS battery), for assessing social cognition in schizophrenia. This will be accomplished by utilizing longitudinal data from an ongoing trial of Cognitive Enhancement Therapy to estimate the reliability, validity, and longitudinal contribution to functional outcome of the MSCEIT as applied to individuals with schizophrenia. Results will be used to propose a systematic plan of research to conduct a more comprehensive validation of the MSCEIT and initiate the development of treatments to remediate social-cognitive deficits evinced by this instrument that have direct bearing on functional outcome. The results of this research have the potential to make an important public health contribution by pointing to the importance of social-cognitive deficits to social and functional disability in schizophrenia, and providing a preliminary systematic evaluation of a promising instrument to measure these deficits. These results will be used to contribute to ongoing scientific efforts to understand the cognitive correlates of functional disability in schizophrenia and develop targeted treatment strategies to improve social and behavioral outcomes among this population. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Substance use comorbidity is among the most frequent and disabling problems experienced by persons with schizophrenia, and a key treatment priority for NIDA. As many as 65% of people with schizophrenia experience significant problems with substance use, most frequently cannabis, and these individuals have the worst course, outcomes, and quality of life. While advances in integrated psychiatric and substance use treatment and specific behavioral interventions for people with severe mental illness have led to better standards of care, remarkably few effective treatments exist that specifically target the unique needs of individuals with schizophrenia and comorbid substance use problems. Impairments in cognition and affect regulation, currently unresponsive to pharmacotherapy, are major contributors to the exceedingly high rates of cannabis and other substance misuse in schizophrenia and highlight the need for targeted cognitive and affective remediation programs for this population. To date, however, no cognitive remediation approach has been adapted to the unique needs of schizophrenia patients with significant substance use comorbidity. In response to RFA-DA-10-007, "Cognitive Remediation Approaches to Improve Drug Abuse Treatment Outcomes," we propose to take the first step in integrating, adapting, and preliminarily testing a cognitive remediation (Cognitive Enhancement Therapy [CET]) and affect regulation (Personal Therapy [PT]) intervention for cannabis misusing patients with schizophrenia. Both of these psychosocial interventions have been rigorously tested in large samples of individuals with schizophrenia who do not experience substance use problems, and have been shown to be highly effective at remediating the untreated cognitive and affective impairments that can lead this population to use drugs. This project will now integrate and adapt these interventions, and conduct an initial examination of their feasibility, acceptability, and efficacy in a sample of 32 schizophrenia patients with significant cannabis use problems, the most frequent drug of abuse in this population. Patients will be randomized to CET/PT plus treatment as usual (TAU) or TAU alone and treated for 18 months. Treatment adherence, attendance, and satisfaction data will be collected throughout the trial to assess the feasibility and acceptability of CET/PT for cannabis misusing schizophrenia patients. In addition, comprehensive assessments of substance use, functioning, cognitive, and affective outcomes will be administered prior to treatment, and at 9 and 18 months, to estimate the efficacy of CET/PT on critical outcomes. It is expected that the findings from this project will provide strong support for the acceptability, feasibility, and efficacy of CET/PT for cannabis misusing schizophrenia patients that will justify the conduct of a more definitive trial and ultimately result in a significant treatment advance for the many individuals with schizophrenia who experience comorbid substance use problems. PUBLIC HEALTH RELEVANCE: The use of drugs, most commonly cannabis, is a frequent and highly disabling problem in schizophrenia that places a significant burden on society, and for which few effective treatments exist. Underlying these problems are untreated impairments in cognition and affect regulation, which drive many patients to use drugs. This project is of significant public health relevance in that it proposes to bring an evidence-based cognitive remediation (Cognitive Enhancement Therapy) and affect regulation (Personal Therapy) intervention to bear on this major public health problem, in an effort to advance the treatment of significant substance use comorbidity in schizophrenia and reduce the burden of these disorders on the individuals who suffer from them, their families, and society.

DESCRIPTION (provided by applicant): Schizophrenia is a severe and persistent psychiatric disorder that is characterized by significant impairments in cognitive function. Deficits in social cognition, or the ability to process, interpret, and regulate socio-emotional information, have been recently shown to be key rate-limiting factors to functional recovery from the illness, making them critical targets for treatment. Social-cognitive impairments reflect a presumed deficit in fronto-temporal brain function, and are unresponsive to extant pharmacologic interventions. Recently, a comprehensive cognitive rehabilitation approach known as Cognitive Enhancement Therapy (CET) has been shown to greatly improve social cognition in two NIH-supported clinical trials with schizophrenia patients. The beneficial effects of CET presumably reflect a change in underlying brain function, and when applied early in the course of illness CET may be able to capitalize on a neuroplasticity reserve to alter functional brain deficits. Indeed, we have recently shown that social-cognitive improvement in CET is associated with an enhanced structural integrity of fronto-temporal brain networks in the early course of the disorder. Beyond these initial observations, however, remarkably little is known about the neurobiologic effects of social-cognitive rehabilitation on brain function in schizophrenia. Research on the neurobiologic effects of psychosocial interventions is aligned with the NIMH priority goal of identifying neural mechanisms of psychiatric treatments, yet such studies have rarely been conducted in schizophrenia due to a lack of translational investigators trained in both intervention and neuroscience research. The purpose of this Mentored Patient-Oriented Career Development Award (K23) is to provide the applicant, a trained social worker and psychosocial interventionist, with the skills in neuroscience needed to bridge the fields of psychosocial treatment and neuroscience research in schizophrenia. The long-term goal of the applicant is to advance the treatment of schizophrenia through evaluating the effects of psychosocial interventions on the brain and developing novel psychosocial treatments to enhance brain function in the disorder. To accomplish this long-term goal, a multidisciplinary training plan has been developed to provide the applicant with complementary expertise in: (1) neuroanatomy and the neurobiology of schizophrenia; (2) social-cognitive and affective neuroscience, and (3) functional neuroimaging methods. The applicant will receive mentoring in a strong multidisciplinary environment from accomplished experts in the field of neuroscience, which will be combined with formal training and coursework designed to develop his expertise in translational neuroscience methods and approaches. A complementary research plan will conduct a cross-sectional, post-treatment outcomes study of the effects of CET on social-cognitive brain function in 32 patients in the early course of schizophrenia. This research plan will proceed by first characterizing the nature of deficits in brain function during social-cognitie processing in early course schizophrenia patients (N = 16) and matched healthy controls (N = 16) using a field standard functional neuroimaging paradigm of emotion perception, along with two novel social cognition paradigms of perspective-taking and emotion regulation. Subsequently, 16 patients in the early course of schizophrenia who have been treated with CET in a ongoing clinical service at the institution will be studied along with 16 carefully matched early course patients who have not been exposed to CET. Post-treatment functional neuroimaging data using the emotion perception, perspective-taking, and emotion regulation paradigms will be collected on both CET-exposed and CET non-exposed patients to examine the effects of the intervention on fronto-temporal brain function and connectivity. Together, these activities will support an R01 application to conduct a subsequent longitudinal randomized trial of CET effects on social-cognitive brain function, and provide the unique training and research experiences needed to enable the applicant to achieve his long-term goal of becoming an independent investigator of the effects psychosocial treatment on the brain in schizophrenia. Results from this area of investigation are expected to lead to new discoveries regarding brain plasticity in schizophrenia, identify the neural mechanisms that can support social-cognitive enhancement, and pave the way for refining existing and developing increasingly effective interventions for this highly disabling condition.

? DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) is characterized by marked impairments in social and non-social cognitive ability that persist well into adulthood and contribute to significant functional disability. The treatment of ASD has focused almost exclusively on children, and few empirically supported interventions are available to address the core cognitive and functional challenges individuals with ASD face as they transition to adulthood. Cognitive rehabilitation has emerged as a set of systematic approaches to the remediation of cognitive impairments that hold considerable promise for the treatment of cognitive deficits in autism, yet adequately-powered and rigorously controlled studies of these interventions have not been conducted in this population. Cognitive Enhancement Therapy (CET) represents one of the most promising cognitive rehabilitation approaches for adult ASD due to its comprehensive and developmental approach to targeting neurocognitive and social-cognitive impairments as well as its established efficacy in schizophrenia, a disorder characterized by similar cognitive deficits. With support from NIMH, we have recently demonstrated the feasibility of adapting CET to adults with ASD, and evidence is emerging from our initial, small-scale randomized trial of CET in this population indicating target engagement on diverse areas of cognition with substantial downstream benefits to functional outcomes. Excitingly, these improvements in cognition associated with CET also appear to be supported by underlying neuroplastic changes in fronto-temporal brain function and connectivity. Such evidence suggests that CET has considerable promise as an evidence-based cognitive rehabilitation intervention for adult ASD, and it is critical that these early findings are followe-up with an adequately-powered efficacy trial. In response to the psychosocial intervention focus of PA-13-216, Research on Autism Spectrum Disorders, this project proposes to conduct a randomized-controlled efficacy trial of CET in 100 verbal adults with ASD. Participants will be randomized to CET or an Enriched Supportive Therapy (EST) control condition and treated for 18 months. Specific aims of the project are to (1) evaluate the comparative effectiveness of CET versus EST on diverse cognitive and behavioral outcomes to assess target engagement and functional impact, (2) examine the effects of CET on fronto-medial temporal brain function and connectivity to elucidate the neural mechanisms of cognitive enhancement in this population, and (3) use personal and neurobiological indicators to explore heterogeneity in treatment response and identify moderators indicative of individuals most likely to benefit from CET. The proposed project will result in the largest psychosocial intervention study in adult ASD, and the first adequately-powered study of a promising cognitive rehabilitation approach for this population. If successful, this project will provide a major step forward in making interventions available for adults with ASD, and will demonstrate the plasticity of the adult ASD brain and its responsiveness to cognitive rehabilitation, paving the way for a new generation of treatments in autism.

? DESCRIPTION (provided by applicant): Schizophrenia is a severe and disabling mental health condition that exacts considerable burden on the individuals who live with the disorder, their family members, and society. Impairments in social and non- social cognition are leading contributors to disability in schizophrenia, and while these deficits are currently untreated by antipsychotic medication, evidence has supported the efficacy of psychosocial cognitive rehabilitation interventions in treating cognitive impairments in the disorder. The early application of these treatments soon after individuals develop the illness has shown particular promise for producing cognitive and functional improvements that stand to alter the long-term trajectory of schizophrenia by preventing chronic disability and capitalizing on early neuroplasticity reserves. Cognitive Enhancement Therapy (CET) is one such approach to cognitive rehabilitation that uniquely targets deficits in neurocognitive and social-cognitive function, and has been shown to lead to considerable improvements in social and vocational functioning, and to exert a neuroprotective effect against gray matter loss, when applied early in schizophrenia. Despite the promise of early intervention with cognitive rehabilitation, no evidence is available on the long-term durability of its effects in either chronic or early course schizophrenia patients, and thus the ability of cognitive rehabilitation treatments, such as CET, to alter the neurobiologic and functional trajectory of the illness is not known. This project proposes to conduct a 10-year follow-up study of the 58 patients who participated in a randomized- controlled trial of CET for early course schizophrenia, in order to provide evidence on the potential long-term benefits of early intervention with cognitive rehabilitation in the disorder. Early course participants in this trial were randomized to CET or an active Enriched Supportive Therapy (EST) and treated for up to two years, with annual cognitive, functional outcome, and neuroimaging assessments. Individuals are now approaching 10- years since completing this trial, and many have remained in the Pittsburgh area and connected with known treatment systems, providing the unique opportunity to examine the long-term impact of CET on the disorder. All available patients who were randomized and received some exposure to their psychosocial treatment condition will be recruited back for this study. Comprehensive cognitive and behavioral data will be collected on neuropsychological function, social cognition, psychopathology, and functional outcome to examine the durability of the previously observed benefits of CET in this sample of early course patients with schizophrenia. In addition, structural neuroimaging assessments will be conducted to examine whether the neuroprotective effects of CET compared to EST found at the end of active treatment have been maintained. Together, this project will provide the first comprehensive evidence of the long-term durability of early cognitive rehabilitation in schizophrenia, and will generate critical information on the ability of CET to alter the long-term disability trajectory of the illness, which could have a profound impact on patients with schizophrenia and society.

7. PROJECT SUMMARY/ABSTRACT Schizophrenia is one of the most disabling of all psychiatric conditions, and places significant burden on the individuals who experience the disorder, as well as their family members and society. Advances in pharmacotherapy and psychosocial interventions have led to significant reductions in hospitalization and psychotic symptoms, and have provided opportunities for affected individuals to become more integrated members of the community. Despite this significant progress, many individuals with schizophrenia remain markedly disabled by persistent negative symptoms, including lack of motivation, social withdrawal, emotional blunting, and poverty of speech. These negative symptoms are untreated by current pharmacotherapies and are notoriously unresponsive to existing interventions, leaving patients and family members with little to no options for treatment. Recently, there has been growing appreciation of the overlap between cognitive and negative symptoms in schizophrenia, and psychosocial studies of cognitive remediation have begun to show promise in treating negative symptoms by utilizing computer- and group-based exercises to enhance social and non-social cognition. We have preliminarily observed in post-hoc analyses of three separate randomized- controlled trials that Cognitive Enhancement Therapy (CET), an evidence-based cognitive remediation approach for schizophrenia, can result in significant reductions in broad negative symptom domains. Further, neurocognitive and social-cognitive improvement appear to underlie these symptom reductions, and point to the enhancement of cognition as one of the most promising approaches for treating negative symptoms in schizophrenia. To date, however, adequately designed trials of cognitive remediation interventions have yet to be conducted in patients with moderate-to-severe and persistent negative symptoms to confirm these effects. In response to RFA-MH-18-707, Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders, this project proposes to conduct a confirmatory efficacy trial to examine the efficacy of CET for the treatment of schizophrenia patients with significant and persistent negative symptoms. A total of 75 stabilized schizophrenia outpatients with moderate-to-severe persistent negative symptoms will be randomized to 18 months of CET or an active, enriched supportive therapy control. Comprehensive data on persistent negative symptoms, social and non-social cognition, and functional outcome will be collected prior to treatment and at frequent 6-month intervals to (1) confirm the efficacy of CET for improving persistent negative symptoms; (2) confirm the impact of cognitive target engagement on reduced negative symptoms; and (3) examine the short-term durability of CET effects on negative symptoms and functioning. The results of this project are expected to establish promising new avenues for the treatment of persistent negative symptoms in the condition, and to significantly reduce the personal and public health burden associated with schizophrenia.

7. PROJECT SUMMARY/ABSTRACT Developmental disabilities (DD), including autism spectrum disorder (ASD), Down syndrome, Fragile X syndrome, and other intellectual and developmental disabilities are heterogeneous neurodevelopmental disorders that place considerable burden on individuals, families, and society. Although most research on DD has focused on children, these conditions are life-long with few established treatments to support functioning in adulthood. As a result, many adults with DD experience significant functional impairment represented by low rates of employment, severe social dysfunction and isolation, and a limited ability to live independently and experience autonomy in adult life. The development of interventions to improve adult functional outcomes in social, employment, and independent living domains across DD has lagged far behind those developed for children. A key factor limiting the development of treatments to improve adult functioning in DD is the lack of validated assessments of functional outcome applicable to adulthood. Current studies either use measures relevant to childhood with limited applicability to and treatment sensitivity in adults, or fail to assess this important domain, greatly restricting knowledge on how adult functioning can be improved in DD. We have shown in preliminary studies with adults with ASD that it is possible to develop measures of functional outcome in adulthood that have greater validity and are more sensitive to treatment effects than existing measures adapted from childhood. In response to this major gap in adult outcome measurement in DD and PAR-18-039, ?Outcome Measures for Use in Treatment Trials of Individuals with Intellectual and Developmental Disabilities?, this project proposes to use NIH PROMIS methods to develop and validate proxy- and self-report versions of the Adult Functioning Scale (AFS) for assessing functional outcomes in social, employment, and independent living domains in adults with DD. A pool of potential items will be generated based on our conceptual model, functional outcome measures used in other populations, and input from expert and stakeholder panels. This item pool will then be completed by two calibration samples: Proxy reporters (e.g., parents, clinicians, group home staff) for 1000 adults with DD representative of the full range of verbal and intellectual functioning in DD and 1000 self-reporting adults with DD (N = 500 with ASD, N = 500 with other DD). Advanced psychometric analytics employing exploratory and confirmatory factor analysis and item response theory models will be used to create final calibrated item banks (and static short forms) of the AFS suitable for broad use in clinical trials across heterogeneous DD. The reliability and validity of the AFS caregiver and self-report versions will be examined in the calibration samples, along with a 4-week retest subsample (N = 200). Sensitivity to treatment- related changes will be assessed in longitudinal intervention studies of inpatient and outpatient samples of adults with DD. The results will validate the first measure of functional outcome for use in clinical trials in adult DD and will pave the way for treatment advances to improve functioning in this underserved population.