Quetiapine XR for Cognitive and Functional Disability in Clinically Stable Patients With Bipolar Disorder

In contrast to previous conceptions of bipolar disorder as an illness where cognitive
impairments were limited to manic and depressed episodes, it has become clear that cognitive
impairments are common in clinically stable bipolar patients.

Quetiapine has been reported to have beneficial cognitive effects in several randomized
controlled trials in schizophrenia. It has not yet been studied in bipolar disorder, but
promising results from the use of extended release quetiapine for the maintenance treatment
of bipolar disorder suggests that its cognitive benefits could be detected. Moreover,
quetiapine has been shown to have direct beneficial effects on performance-based measures of
social competence in schizophrenia and to improve quality of life (QoL) in bipolar
depression. We propose to study quetiapine augmentation of mood stabilizer monotherapy in
clinically stable patients with bipolar disorder. This will be a randomized, placebo
controlled trial, with attentional impairments as the primary outcome and other cognitive
performance variables and measures of social and everyday living skills, as well as
subjective QoL, as the secondary outcomes.

An additional possible benefit of quetiapine treatment, and one that is directly relevant to
neuropsychological performance, is that of increased activity of cortical norepinephrine
(NE). Thus, in studies of cognitive enhancement with quetiapine, examination of cortical
NE neet occupancy will be of substantial interest.

General Background: This will be a three site study which will include Emory University
(Coordinating site), Duke University, and University of Toronto. We choose to have three
sites so that the difficult task of recruiting clinically stable patients with bipolar can
be accomplished quickly and the study can be completed within a two-year time frame.

Subjects: We will recruit 100 patients for this study. Fifty percent of them will receive
active treatment with quetiapine XR. All participants will meet diagnostic criteria for
bipolar I disorder and have medical record-based evidence of at least one previous manic or
mixed episode. They will be clinically stable, as evidence by meeting criteria for low
scores on both the Young Mania Rating Scale (YMRS) and the Montgomery-Asberg Depression
rating scale (MADRS). They will also be receiving therapy with mood stabilizers, either
lithium or an approved mood stabilizing agent.

Visit Schedule: This is a 10 week study with a six-week active treatment protocol. All
interested patients who meet study entry criteria will be screened for stability four and
two weeks prior to the baseline assessment. Patients will also be re-assessed for stability
at baseline. Patients who fail to meet entry criteria at baseline can come back for a
second screening after 2 and 4 weeks.

Throughout treatment, medication adjustments will be limited to changes of less than 25%
during this time period.

Assessments: Cognitive assessments will be performed at baseline, week 2 and week 6 of
active treatment.

Clinical Assessments will be performed at screening and rescreening, baseline, weeks 2 and
6.

Biological Measures: Bloods for NE net occupancy will be drawn at baseline, week 2, and
week 6. We will also screen for levels of other medications that may interfere with
accurate measures of NE net occupancy. These include, Venlafexine, Duloxetine, Paroxetine,
and Desipramine / imipramine. Serum levels of quetiapine at all three assessments will also
be examined.

Cognitive Assessments:

We will focus our cognitive assessment on the types of cognitive impairments previously
reported in bipolar disorder. Our focus will be on attention, episodic memory, processing
speed, and working memory. This same instrumentation has proven able to detect sedation as
well, so that we can use the results of our assessment to identify any potential adverse
sedation effects.