Allopurinol Add-on Treatment for Refractory Mania

Bipolar disorder is a severe mental disorder with episodes of mania and depression. Current
medications for mania can have significant side effects, high costs and the need for blood
monitoring. The purpose of this research study is to study the effectiveness of allopurinol,
in combination with lithium or valproic acid or carbamazepine, for treatment-resistant
bipolar mania and mixed mania. This research study is designed to test the safety and/or
effectiveness of allopurinol that has been approved by the U.S. Food and Drug Administration
(FDA) for recurrent calcium renal calculus, gout, hyperuricemia (cancer and tumor lysis
syndrome), but it is not approved for use in treatment-resistant bipolar mania or mixed
mania.

Participants in this double-blind study will be randomly assigned to one of two study groups.
The first group will receive the study medication of allopurinol while the second group will
receive a placebo. These will be taken in conjunction with current medications and doses. The
study will last for 7 weeks (an initial screening, a baseline visit and 4 follow-up visits at
weeks 1,2,4, and 6). The initial screening visit will be used to determine whether or not the
subject is able to participate in the study. The following will be conducted during the
screening visit: Review of medical and psychiatric history along with standard psychiatric
assessment exams; Physical examination, including review of prior and current medications and
adverse drug effects; An electrocardiogram (ECG) - a painless test which is done by attaching
straps or pads to your limbs and chest and recording the electrical pattern of your heart,
will be done to record your heart rhythm; About 5 tablespoons of blood will be drawn to
assess basic laboratory values that show if you are healthy enough to participate in the
study; Blood levels of lithium, valproic acid, and/or carbamazepine will be measured; A urine
sample will be collected to test for the presence of illegal drugs and for pregnancy test (if
you are a female of child-bearing potential); Collection of demographic data (e.g., age,
gender, marital status, social and vocational status) and other information including health
beliefs, and knowledge of illness. At the baseline visit the participant will be given
questionnaires related to mood, quality of life, disability, medications, and side effects.
The participant's vitals (temperature, weight, heart rate, and blood pressure) will be
measured. The participant will be randomized to treatment (300 mg of allopurinol/day) or
placebo. After week one at the Week 1 visit, those that have tolerated the dosage of
allopurinol will get an increased dosage. The participant will also complete a set of
questionnaires. Vitals will be taken. The remaining follow-up visits will be similar to visit
one except that there will be no more increases in dosage; Week 2 will include a blood draw
to measure levels of lithium, valproic acid, and/or carbamazepine in the participant's blood,
and the final visit at Week 6 will in addition include a blood draw, and exit physical exam,
and a urine sample will be collected.

Inclusion Criteria:

- Subjects must be between ages 18 and 70.

- Subjects must meet DSM-IV criteria for bipolar disorder, most recent episode manic or
mixed, at the time of screening confirmed by the Mini International Neuropsychiatric
Interview (MINI).

- Subjects must be taking at least one medication for mania (lithium, valproic acid,
carbamazepine) at a therapeutic dose for at least 4 weeks.

- Subjects must have non-response or partial response to medications as evidenced by
Young Mania Rating Scale (YMRS) score greater than or equal to 14 at screening and at
baseline.

- Female subjects must be either postmenopausal for at least 1 year, surgically sterile,
abstinent or practicing an effective method of birth control if sexually active.
Female subjects must also have a negative urine pregnancy test at screening, baseline
and other time points throughout the study.

- Subjects must be able and willing to comply with self-administration of medication or
have consistent help/support available.

- Subjects must have signed an informed consent document indicating that they understand
the purpose of and procedures required for the study and are willing to participate in
the study.

- Subjects must be able and willing to meet or perform study requirements (e.g. answer
self-administered questionnaires).

- Subjects must be willing to allow study staff to contact subject's regular
psychiatrist while the subject is in the study.

Exclusion Criteria:

- Subjects who are unable to provide informed consent.

- Subjects with a serious, unstable medical illness (such as cardiovascular,
respiratory, neurologic, hematologic, renal, hepatic, endocrine, immunologic, or other
systemic illness), a history of cerebrovascular disease, uncontrolled diabetes
mellitus or AIDS. Subjects with chronic illness must be stable and otherwise
physically healthy on the basis of a physical examination, medical history,
electrocardiogram and the results of blood biochemistry, hematology tests and a
urinalysis.

- Subjects with a history of substance abuse or dependence (excluding nicotine and
caffeine) according to DSM-IV criteria within last 4 weeks.

- Subjects taking azathioprine, mercaptopurine, apalcillin, and/or amoxicillin.

- Subjects taking dopamine agonists and/or anti-psychotics.

- Subjects who have been intoxicated with alcohol or illicit drugs within 3 days prior
to baseline.

- Subjects with a history of severe pre-existing gastrointestinal narrowing or inability
to swallow oral study medication whole with the aid of water.

- Female subjects who are pregnant or nursing.

- Subjects who have previously participated in this study.

- Subjects with an anticipated life expectancy of 6 months or less.

- Subjects who have received an experimental drug or used an experimental medical device
within 1 month of screening.