Zyprexa and Task Engagement in Schizophrenia

Objectives: Olanzapine (OLZ) has emerged as one of the promising pharmacologic interventions that not only improves psychotic symptoms but may also target ability to sustain attention on cognitive tests. Pupillary response, as measured by degree of pupil constriction, and visual scanning patterns are unique methods of quantifying attention by gauging the level of psychophysiologic engagement on a visual task. It is reasonable to expect that if a treatment for attention problems is effective, then this will be reflected in more efficient allocation of psychophysiologic attentional resources as measured by pupillometry. Primary purpose of this pilot study is to demonstrate efficacy of switching to OLZ for improving task engagement in schizophrenia. Secondary objectives are to demonstrate improved attention in response to OLZ translates to improved attentional allocation strategies and vocational readiness, and demonstrate efficacy of OLZ as agent that enhances ability to benefit from cognitive training. The proposed study will examine functional implications of improved attention in patients taking OLZ, and it will test the hypothesis that mechanism of this functional improvement is through process of engagement as measured by pupillometry and functional behavioral measures.

Research Design and Methodology: This is an industry-sponsored, investigator initiated trial with 18 patients in an open-label design over 24-month period. Participants will be adult outpatients (ages 18 to 55) with a diagnosis of schizophrenia or schizoaffective disorder who are on any regimen of "typical" antipsychotics. They will be randomly assigned to one of two conditions: 1) Olanzapine Group (OLZ-G). Subjects assigned to the OLZ condition will be switched to OLZ from their previous medication so OLZ is the only antipsychotic medication part of their regimen. Following switch to OLZ, subjects will be enrolled in a twice weekly, 20-session cognitive training program that is specifically designed to target attention deficits and promote active engagement. 2) "Typicals" Group (TYP-G). Subjects assigned to the "typicals" condition will continue with their medication regimen throughout the course of the study as they are enrolled in the same cognitive training program. Research questions are: Compared to participants on any combination of "typical" medications, we hypothesize that persons with schizophrenia on OLZ will (a) show significantly improved performance on psychophysiologic measure of task engagement, (b) show greater engagement in cognitive training, and (c) show greater improvement in attention on vocational task. Primary efficacy measure will be an ASL H6 Series head-mounted optics pupillometer to measure task engagement as function of pupil dilation and visual scanning patterns. Secondary efficacy measures will include computer software specifically developed to assess on-task behavior on computer exercises, brief neuropsychological test battery, global behavior and symptom inventories, and functional assessment of treatment motivation.