Short Term Rescue Study of Olanzapine
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.
Development and marketing of new therapies for bipolar disorders (BD) has typically entailed
 performing double-blind placebo-controlled trials in acute mania maintenance studies and more
 recently acute depression studies. 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. 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.

 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.
Inclusion Criteria:Patients must meet the following criteria to be eligible to participate
 in the study:

 -  Male or female outpatients, 18 to 70 years of age

 -  Female patients of childbearing potential must be using a medically accepted means of
 contraception

 -  Able to communicate intelligently with the investigator, and study coordinator

 -  Able to give informed consent

 -  DSM-IV diagnosis of bipolar I, bipolar II, cyclothymic disorder or bipolar disorder
 not otherwise specified, experiencing an acute exacerbation of their illness at Visit
 1 (hypomania, subsyndromal depression, hypomania and subsyndromal depression,
 depression and hypomania, or depression if diagnosed with bipolar II) as verified by
 SCID-I/P

 -  CGI-BP Overall Severity score greater than or equal to mildly ill at Visit 1

 -  Must have been on prior medications for at least 2 weeks (6 weeks for fluoxetine)
 immediately prior to study entry Exclusion Criteria:Patients may not participate in
 the study if they have any of the following conditions:

 -  Pregnant, nursing, or intending to become pregnant during the study

 -  Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory,
 cardiovascular (including ischemic heart disease), endocrinologic, neurologic,
 immunologic, or hematologic disease such that hospitalization for the disease is
 anticipated within 3 months or death is anticipated within 3 years.

 -  A history of seizure disorder

 -  History of leukopenia without a clear and resolved etiology.

 -  DSM-IV substance (except nicotine or caffeine) dependence within the past month

 -  Judged clinically to be at serious suicidal risk

 -  Participation in clinical trial of another investigational drug within 1 month (30
 days) prior to study entry.

 -  Treatment with an injectable depot neuroleptic within less than one dosing interval
 between depot neuroleptic injections prior to study entry

 -  Treatment resistance, non-response, or intolerability with olanzapine by the
 investigator's judgment

 -  Treatment with clozapine within 3 months prior to study entry

 -  Treatment with remoxipride within 6 months (180 days) prior to study entry

 -  Treatment with an oral antipsychotic within 2 days prior to study entry

 -  A course of ECT (electroconvulsive therapy) in the preceding 4 weeks

 -  Excluded mood symptoms noted in Table 1 [of protocol]

 -  Unstable thyroid pathology and treatment-initiated or altered within the past 3 months

 -  Meet criteria for antisocial personality disorder