Significant and widespread cognitive impairments are a core feature of schizophrenia, providing a windowinto underlying neuropathophysiology while serving as a robust predictor of long-term functional outcome.The recently completed Measurement and Treatment Research to Improve Cognition in Schizophrenia(MATRICS) project demonstrates the commitment of the NIMH to enhancing our understanding of cognitivedeficits in schizophrenia. Within the context of research in first episode schizophrenia at the Zucker HillsideHospital, neurocognition is considered both as a critical target of treatment and as a predictor or mediator ofillness course. The primary aims of this proposed CIDAR project involve the use of early neurocognitivemeasures to predict functional outcome during a 52-week controlled treatment algorithm, as well as acutesymptomatic response during the initial 12-week randomized clinical trial. At the same time, measurescollected over the course of this project will also serve as outcome variables for other projects in this CIDAR,including Project 2 (Magnetic Resonance Imaging) and Project 4 (Pharmacogenomics).We will utilize the MATRICS battery composite score to predict long-term (52-week) functional outcome inemployment, residential status, and social functioning. In addition to the traditional neuropsychologicalmeasures in the MATRICS battery, the proposed project will employ complementary methods, derived fromrecent cognitive neuroscience research. Such measures are designed to more specifically assess functionssensitive to dopaminergic tone and other aspects of prefrontal cortico-cortical and cortico-subcortical circuitscritical to illness and treatment. In particular, we aim to predict positive symptom response secondary todopaminergic modulation by second-generation antipsychotics, after 12- and 52-weeks of treatment, using aset of tests (N-Back working memory test, Competing Programs, and Intradimensional/Extradimensional SetShifting) that have been empirically demonstrated to be sensitive to dopamine manipulations and/or COMTgenotype. We also hypothesize that specific tasks tapping motivation and behavioral production will predictnegative symptom response, and semantic processing measures will predict disorganized symptoms.Finally, we will explore the possibility that early changes in cognition (between baseline and 12 weeks) mayalso be predictors of long term response and outcome, insofar as early improvement may reflect neuralplasticity phenomena related to symptom remission.
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