Short Term Rescue Study of Olanzapine
We will assess the effect of olanzapine compared to placebo added to prior treatment on CGI-S in a one-week randomized double-blind study. We will also assess the effect of olanzapine added to prior treatment on CGI-S in an eight-week open treatment study. In addition, we will assess the effect of olanzapine on Young Mania Rating Scale (YMRS), Hamilton and Montgomery-Asberg Depression Rating Scales (HDRS, and MADRS), and Hamilton Anxiety Rating Scales (HARS) in the above paradigms. We will also assess the influence of presentation severity (CGI-S) and polarity (mood elevation versus depression) on olanzapine response. Finally, we will assess safety and tolerability of olanzapine in the above paradigms.
We hypothesize that in diverse mild syndromal and subsyndromal exacerbations of BD in outpatients, randomized double-blind flexibly dosed olanzapine added to prior treatment (including no treatment) will yield greater CGI-S improvement than placebo by the end of one week, and that such improvement will persist over one week of open continuation treatment.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||Double-Blind Placebo-Controlled Olanzapine Add-on Therapy in the Treatment of Acute Syndromal and Subsyndromal Exacerbations in Bipolar Disorders|
- CGI-S [ Time Frame: prior week ] [ Designated as safety issue: No ]
- YMRS [ Time Frame: prior week ] [ Designated as safety issue: Yes ]
- Hamilton and Montgomery-Asberg Depression Rating Scales (HDRS, and MADRS) [ Time Frame: Prior week ] [ Designated as safety issue: No ]
- Hamilton Anxiety Rating Scales (HARS) [ Time Frame: Prior week ] [ Designated as safety issue: No ]
|Study Start Date:||July 2005|
|Study Completion Date:||June 2010|
|Primary Completion Date:||June 2010 (Final data collection date for primary outcome measure)|
Olanzapine/Zyprexa 2.5 mg up to 8 per day for 1 week
Placebo Comparator: Placebo
Development and marketing of new therapies for bipolar disorders (BD) has typically entailed performing double-blind placebo-controlled trials in acute mania 1, 2, maintenance studies 3, 4, and more recently acute depression studies 5. Such an approach addresses BD primarily in terms of episodes and has the strength of studying levels of pathology sufficiently high to permit detection of treatment effects, and guiding clinicians when they encounter syndromal mood episodes. However, this approach has the important limitation of not addressing an important unmet clinical need, namely the management of subsyndromal symptoms. Indeed, emerging data suggest that in BD subsyndromal symptoms compared to syndromal episodes are far more pervasive 6, 7. Also such an approach runs the risk of not paying sufficient attention to the disorder construct, in a sense permitting preoccupation with syndromal episodes to carry more importance than the disorder.
Our group has published a novel open study of olanzapine in diverse exacerbations of BD 8. Twenty-five bipolar disorder [14 bipolar I (BPI), 10 bipolar II (BPII) and one bipolar disorder not otherwise specified (BP NOS)] outpatients received open olanzapine (15 adjunctive, 10 monotherapy). Thirteen had elevated (11 syndromal, two subsyndromal) and 12 depressed (four syndromal, eight subsyndromal) mood symptoms of at least mild severity, with Clinical Global Impression-Severity (CGI-S) scores of at least 3. Only one had psychotic symptoms. With open olanzapine (15 adjunctive, 10 monotherapy), overall symptom severity (CGI-S) as well as mood elevation (Young Mania Rating Scale), depression (Hamilton and Montgomery-Asberg Depression Rating Scales), and anxiety (Hamilton Anxiety Rating Scale), rapidly decreased (significantly by days 2-3). Patients with the greatest baseline severity (CGI-S) had the greatest improvement. Fifteen of 25 (60%) patients responded. Time to consistent response was bimodal, with five early (by 0.5 +/- 0.3 weeks) and 10 late (by 7.0 +/- 1.9 weeks) responders. Early compared with late responders had 51% lower final olanzapine doses. Olanzapine was generally well tolerated, with sedation and weight gain the most common adverse effects. Thus, olanzapine appeared effective in diverse exacerbations of BD in outpatients. Controlled studies are warranted to further explore these preliminary observations.
|United States, California|
|Stanford University School of Medicine|
|Stanford, California, United States, 94305|
|Principal Investigator:||Terence Arthur Ketter||Stanford University|