INCLUSION CRITERIA:
Males or females 18 to 60 years of age;
Diagnosis: DSM-IV Bipolar I Disorder, current episode manic or mixed with or without psychotic features as determined by SCID-P. This criteria includes the following diagnoses: 296.4X, Bipolar I Disorder, Most Recent Episode Manic, and 296.6X, Bipolar I Disorder, Most Recent Episode Mixed;
YMRS greater than or equal to 20 at Visits 1 and 2;
No decrease in total score of YMRS of greater than or equal to 20% during washout (between Visits 1 and 2);
Meet criteria for treatment resistance.
Patients must have experienced at least two manic or mixed episodes within five years prior to study entry and one manic or mixed episode being within the last 12 months (not including the current episode); DSM-IV rapid cyclers will be permitted to participate in this study;
Each patient must have a level of understanding sufficient to agree to all the tests required by the protocol;
Each patient must understand the nature of the study and must sign an informed consent document. It is recommended, but not required, that an NIH Advanced Directive form be completed.
EXCLUSION CRITERIA:
WBC count is less than 3500/mm(3) or history of a myeloproliferative disorder.
History of meeting criteria for DSM-IV criteria for schizophrenia or other psychotic disorder;
History of DSM-IV substance abuse, including alcohol within the last three months and substance dependence (except nicotine and caffeine) within the past 5 years;
Acute or unstable medical illnesses, (e.g., delirium, metastatic cancer, unstable diabetes, decompensated cardiac, hepatic, renal or pulmonary disease, or stroke or myocardial infarction within the last six months);
Current pregnancy or plan to become pregnant during the first three months (the duration of the study) in woman of childbearing age; breast-feeding in woman with infants;
Previous treatment with clozapine;
History of seizures;
History of leukopenia or agranulocytosis;
Uncorrected hypo- or hyperthyroidism;
Elevated thyroid stimulating hormone (TSH) greater than or equal to 5.0 micro U/ml;
Concomitant use carbamazepine or other concomitant medication with primarily CNS activity; Has received an investigational drug within 30 days of enrollment.
Has received an antidepressant within 4 weeks prior to Visit 1 (8 weeks for fluoxetine);
Treatment with an oral antipsychotic drug within 5 half-lives prior to Visit 2;
No course of ECT (electroconvulsive therapy) within the preceding 4 weeks to Visit 1;
Treatment with an injectable depot neuroleptic within less than one dosing interval prior to Visit 1;
Is actively suicidal, and/or has a score of 3 or more on item 3 of the HAMD;
Has an acute or chronic illness likely to impair drug absorption, distribution, metabolism or excretion;
General MRI exclusion criteria.
Warren Grant Magnuson Clinical Center (CC)