Naturalistic Study, Comparison of Divalproex Extended Release (ER) and Quetiapine for Adults With Acute Mania or Mixed Episodes

This will be a rater-blinded, head-to-head comparison (no placebo) of divalproex ER and
quetiapine in patients with symptoms of an active manic or mixed mania (symptoms of mania and
depression). Forty subjects are expected to be enrolled. After screening for eligibility,
eligible subjects will be randomized while hospitalized in a 1:1 ratio into 2 treatment
groups: divalproex ER or quetiapine. Depakote® ER will be given orally at 30 mg/kg day
initially taken at night and rounded up to nearest 500 mg dose with adjustments made through
the trial as needed to obtain serum valproic acid levels of 85-125 mcg/ml. Quetiapine will be
given orally at an initial dose of 200mg/day on Day 1, and titrate up to 800 mg/day. The
duration of the study will be 21 days from baseline and the total number of visits including
screening is five. Patients will be released from the hospital once stable and visits for the
study will then take place on an outpatient basis.

Inclusion Criteria:

For inclusion, patients must fulfill all of the following criteria at enrollment:

1. Provide written informed consent before initiation of any study-related procedures

2. A diagnosis of Bipolar I Disorder, Most Recent Episode Manic (296.4x), or Bipolar I
Disorder, Most Recent Episode Mixed (296.5x), with or without psychotic features, as
defined by Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition
(DSMIV)

3. Male or female, at least 18 years old

4. YMRS score equal to or greater than 17 and a CGI of 4 (moderate) or greater.

5. Female patients of childbearing potential must be using a reliable method of
contraception. Reliable methods of contraception include hormonal contraceptives
(e.g., oral contraceptive or long-term injectable or implantable hormonal
contraceptive), double-barrier methods (e.g., condom and diaphragm, condom and foam,
condom and sponge), intrauterine devices, and tubal ligation.

Exclusion Criteria:

1. Known intolerance or lack of response to quetiapine fumarate or Divalproex ER as
judged by the investigator.

2. Unwilling or not able to provide informed consent

3. Positive urine toxicology result on screening for cocaine, phencyclidine (PCP),
opiates or amphetamines that confirms the current manic/mixed episode is better
accounted by a substance intoxication or withdrawal as judged by PI.

4. History of schizophrenia or schizoaffective disorder

5. Treatment with a depot antipsychotic within 1 treatment cycle

6. Unstable medical condition including hepatic, renal, gastroenterologic, neurologic,
immunologic, or hematologic diseases that is deemed by the principle investigator to
likely to result in hospitalization in 6 months or death within one year

7. A female subject who is pregnant or lactating

8. Lorazepam will be provided for agitation and insomnia as needed for rescue only. Not
to exceed 6 mg in the first 7 days; Not to exceed 4 mg for the next 3 days and note to
exceed 2 mg/day for the remainder of the study. Those that require a greater amount of
Lorazepam will be excluded.

9. Hospitalized for more than 1 week for current episode at the screen

10. Substance or alcohol dependence at enrollment and within the three months prior to
enrollment (except dependence in full remission, and except for caffeine or nicotine
dependence), as defined by DSM-IV criteria.

11. Known diagnosis of dementia or MCI