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.

Inclusion Criteria:

- Diagnosis of schizophrenia or schizoaffective disorder

- Current medication regimen that includes any combination of first generation
neuroleptics, for at least 30 days

- Referring psychiatrist agrees to transfer primary psychiatric care and medication
prescription to the study doctor, for the duration of patient's participation in the
study

Exclusion Criteria:

- Significant auditory/visual impairment that would interfere with study procedures

- Lack of aptitude in English that may interfere with the administration of the tests

- Current use of psychoactive substances that may affect attention (e.g. Amoxetine,
Methylphenidate)

- Deviations from the prescription regimen not approved by study doctor

- Changes in the regimen of antipsychotics not included in the study's protocol

- Chart diagnosis of any other medical or neuropsychiatric illnesses known to impair
brain function (e.g. mental retardation, traumatic brain injury, seizure disorder).

- Pregnant or breast-feeding females.

- Use of alcohol or drugs 4 weeks prior to beginning of study.

- For participants with history of substance dependence (excluding nicotine and
caffeine) use of illicit substances (e.g. marijuana or crack) during study
participation.

- Use of a depot antipsychotic within 4 weeks prior to baseline

- History or evidence of a medical or neurological condition that would expose the
subject to an undue risk of a significant adverse event or interfere with study
assessments

- Clinically significant abnormal laboratory test results at screening