This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our long term studies of first episode schizophrenia patients have clearly indicated excellent initial responsiveness of positive psychotic symptoms to treatment with conventional antipsychotic medications. However, in the years immediately following this initial good response, morbidity increases: cognitive functioning improves with treatment but remains impaired in multiple domains, social/occupational adjustment is poor or worse for 25% of the patients, 15% develop a deficit state and the incidence of tardive dyskinesia is 6% per year of conventional antipsychotic exposure. Relapses, often multiple ones, are the rule and are usually precipitated by medication noncompliance. Prevention of this morbidity is the major clinical challenge in treating first episode patients and is the focus of this application. There is some evidence that the second generation antipsychotic drugs may have superior efficacy in these outcome domains. However, these newer agents have been studied primarily in chronic and/or treatment resistant patient samples and there are virtually no long term studies or studies comparing the new drugs with one another. We propose to study them in the population which has the potential for maximum responsiveness and long term benefit-patients with schizophrenia who are being treated for the first time. We also propose to incorporate neuroimaging methods to evaluate the contribution of structural brain alterations, dopamine (D2) receptor occupancy and serotonin function to variability in response to treatment. Specifically, we will randomly assign first episode patients to treatment with olanzapine or risperidone. Treatment will be for 3 years. Outcome measures for the initial episode will include psychopathology (positive, negative and affective symptoms), side effects, neurocognition (executive function, memory and attention), social and occupational function and service utilization. The effects on long term course will be measured in terms of frequency and timing of relapses, level of recovery from subsequent episodes and prospectively assessed course of psychopathology, neurocognitive function, social/vocational function and service utilization. Neuroimaging studies will include a structural Magnetic Resonance Imaging Scan and Positron Emission Tomography (PET) scans of serotonin function at baseline and after sixteen weeks of treatment and PET scans of D2 receptor occupancy after sixteen weeks of treatment. The results will provide a basis for informed treatment choices for clinicians as well as address the crucial question of the potential of the new treatments to improve the longitudinal course of this devastating illness. The incorporation of neuroimaging methods with the clinical infrastructure will enable us to examine physiological mechanisms that underlie treatment response and resistance.
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