This is an application for a K23-Mentored Patient-Oriented Research Career Development Award entitled "Efficacy of a Cognitive Remediation Treatment Program for Bipolar Disorder". The candidate is an instructor and assistant research psychologist at McLean Hospital/Harvard Medical School with a background in neurocognitive and behavioral deficits in patients with psychosis and at risk populations. Clinically, the candidate has focused on treatment of adults with severe and persistent mental illness, including patients with schizophrenia (SZ), schizoaffective disorder (SZA), and bipolar disorder (BD). The candidate's work in cognitive phenotypes of psychotic illness and her clinical interests have converged on an interest in the implementation of novel treatment approaches to address cognitive dysfunction in psychosis. She now aims to apply her research and clinical experience to psychosocial clinical trials work specifically targeting neurocognitive dysfunction in patients with BD with psychosis and, ultimately, other psychotic illnesses. Cognitive dysfunction is increasingly recognized as a major feature of BD, present by illness onset, persistent into euthymia, and associated with functional outcome. Deficits are qualitatively similar to those seen in SZ, and may be quantitatively similar in some patient groups (50-55), e.g. in patients with a history of psychosis. Despite strong associations between cognitive impairment and functional outcomes in BD, treatment for these symptoms at present is inadequate. Pharmacotherapies do little to address cognitive symptoms, and may even worsen them. Psychosocial cognitive remediation (CR) treatments have been developed to target these symptoms and their functional correlates, and have shown early promise in patients with SZ in improving both neurocognition and community functioning. However, despite the overlap of neurocognitive deficits between patients with SZ and BD, no studies to date have extended neuroscience- based CR to patients with BD. The present proposal aims to assess the efficacy of CR treatment in patients with BD with a history of psychosis using a 70-hour CR paradigm compared to a dose- matched computer-based control. It is hypothesized that patients in the CR group will exhibit improvements in cognitive and community functioning compared to controls, which will persist during a 6-month durability phase. Additionally, putative mechanisms of functional change will be examined, including mediator effects of cognitive and clinical change on community functioning. 130 patients with BD with a history of psychosis recruited from the Psychotic Disorders Programs at McLean Hospital will be randomized into either the CR or computer control group. CR will be administered using the PositScience Brain Fitness and InSight programs, neuroscience-based training programs that have shown early promise in patients with SZ and are used actively by the Mentor (Dr. Keshavan) and an Advisor (Dr. Vinogradov) on this project. Participants will be assessed on measures of clinical, cognitive, and community functioning at baseline, following the 70-hour treatment or control phase, and again 6 months later. This project is in keeping with the NIH's stated strategic priorities for improving mental health outcomes in patients and strengthening the impact of NIMH-supported research on public health, with specific recommendations for broad implementation of effective psychosocial interventions. The candidate's research examining neurocognition across diagnoses and over time, and her pilot work examining CR in patients with psychosis indicate that a) patients with BD exhibit significant and persistent neurocognitive deficits, b) CR is well-tolerated in patients with BD with psychosis, c) the candidate has access to patients who are appropriate for the proposed study, and d) the candidate can develop and implement longitudinal and treatment-outcome studies of neurocognition in patients with psychotic illness. As an instructor and assistant research psychologist at McLean Hospital/Harvard Medical School, the candidate is well positioned to continue to develop her work toward a career as an independent investigator. She has gained extensive experience with patient oriented research, and now seeks additional training in clinical trials work, CR techniques, quantitative methods, and cognitive neuroscience techniques (including neuroimaging) in order to develop expertise in CR clinical trials and a knowledge base in cognitive neuroscience. Training in these areas is necessary for the development of her academic identity as a clinical scientist conducting independent investigations of CR in BD and other major psychotic illnesses. Additionally, in future work the candidate aims to develop collaborations with experts in cognitive neuroscience and imaging toward identifying mechanisms of cognitive change after CR treatment. The candidate has assembled a team of mentors and advisors for this project who are experts in CR (including the use of the CR programs selected for the present proposal), clinical trails, outcomes in bipolar disorder, quantitative methods in longitudinal research, and cognitive neuroscience and neuroimaging, and with whom she has demonstrated effective and productive collaborations. Additionally, a number of courses have been selected in key training areas, and are available to her through Harvard and its affiliates. Together with the rich training environment of McLean Hospital - Harvard's largest psychiatric training site - the above mentorship and didactics will allow the candidate to develop the skills and expertise necessary to transition to an independent research career, and, by the end of the award period, to develop next phase research projects and secure federal funding in order to undertake them.

Public Health Relevance

Cognitive deficits represent a core feature of bipolar disorder and are closely associated with functional outcome in patients;however, current medication therapies do little to address these symptoms. Cognitive remediation is a computer-based non-medication treatment targeting cognitive deficits that has shown promise in patients with schizophrenia but has not yet been studied in patients with bipolar disorder. The proposed study will evaluate cognitive remediation in patients with bipolar disorder and its effects on cognitive deficits and community functioning in an attempt to improve outcomes for patients with this disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Mentored Patient-Oriented Research Career Development Award (K23)
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Interventions Committee for Adult Disorders (ITVA)
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Wynne, Debra K
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Mclean Hospital
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Lewandowski, Kathryn E; Ongür, Dost; Sperry, Sarah H et al. (2015) Myelin vs axon abnormalities in white matter in bipolar disorder. Neuropsychopharmacology 40:1243-9
Lewandowski, K E; Sperry, S H; Cohen, B M et al. (2014) Cognitive variability in psychotic disorders: a cross-diagnostic cluster analysis. Psychol Med 44:3239-48
Lewandowski, Kathryn E; Sperry, Sarah H; Malloy, Mary C et al. (2014) Age as a predictor of cognitive decline in bipolar disorder. Am J Geriatr Psychiatry 22:1462-8
Lewandowski, Kathryn E; Cohen, Bruce M; Keshavan, Matcheri S et al. (2013) Neuropsychological functioning predicts community outcomes in affective and non-affective psychoses: a 6-month follow-up. Schizophr Res 148:34-7
Lewandowski, Kathryn E; Cohen, Bruce M; Keshavan, Matcheri S et al. (2011) Relationship of neurocognitive deficits to diagnosis and symptoms across affective and non-affective psychoses. Schizophr Res 133:212-7