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Context Cognitive rehabilitation has shown efficacy for improving cognition in patients with schizophrenia, but the underlying neurobiologic changes that occur during these treatments and support cognitive improvement are not well known. Objective To examine differential changes in brain morphology in early schizophrenia during cognitive rehabilitation versus supportive therapy. Design A 2-year, randomized-controlled trial with annual structural magnetic resonance imaging and cognitive assessments. Setting An outpatient research clinic at a university-based medical center providing comprehensive care services for patients with severe mental illness. Patients A total of 53 symptomatically stable, but cognitively disabled outpatients in the early course of schizophrenia or schizoaffective disorder. Interventions Cognitive enhancement therapy is an integrated approach to the remediation of cognitive impairments in schizophrenia that utilizes computer-assisted neurocognitive training and group-based social-cognitive exercises. Enriched supportive therapy is an illness management approach that provides psychoeducation and teaches applied coping strategies. Main Outcome Measures Broad areas of frontal and temporal gray matter change were analyzed using longitudinal voxel-based morphometry methods employing mixed-effects models, followed by volumetric analyses of regions demonstrating significant differential changes between treatment groups. Results Patients receiving cognitive enhancement therapy demonstrated significantly greater preservation of gray matter volume over the course of two years in the left hippocampus, parahippocampal gyrus, and fusiform gyrus, and significantly greater gray matter increases in the left amygdala (all corrected P < .040), compared with those receiving enriched supportive therapy. Less gray matter loss in the left parahippocampal and fusiform gyrus, and greater gray matter increases in the left amygdala were significantly related to improved cognition and mediated the beneficial cognitive effects of cognitive enhancement therapy. Conclusion Cognitive enhancement therapy may offer neurobiologic protective and enhancing effects in early schizophrenia that are associated with improved long-term cognitive outcomes. Trial Registration clinicaltrials.gov Identifier: NCT00167362

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Background: Deficits in social cognition and neurocognition are believed to underlie schizophrenia disability. Attempts at rehabilitation have had circumscribed effects on cognition, without concurrent improvement in broad aspects of behavior and adjustment.Objective: To determine the differential effects of cognitive enhancement therapy (a recovery-phase intervention) on cognition and behavior compared with stateof-the-art enriched supportive therapy.Design: A 2-year, randomized controlled trial with neuropsychological and behavioral assessments completed at baseline and at 12 and 24 months.

As part of a long-term study in schizophrenia, a model of family intervention has been developed which attempts to diminish relapse rates of schizophrenic patients. This model reflects theoretical and research findings which suggest that certain patients have a "core psychological deficit" that might increase vulnerability to external stimuli. While a program of maintenance chemotherapy attempts to decreae patient vulnerability, a series of highly structured, supportive, psycho-educational family interventions are aimed at de-intensifying the family environment in which the patient lives.