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

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to compare the efficacy and tolerability of quetiapine versus divalproex extended-release administered in a rapid oral loading fashion in the treatment of acute episodes of mania or mixed mania in bipolar disorder. Three hypotheses will be tested: Hypothesis 1: treatment ( 3 weeks) of divalproex extended-release is similar to quetiapine in the symptomatic control of mania or mixed mania Hypothesis 2: divalproex extended-release orally loaded may produce significant improvements in symptoms of mania sooner than quetiapine Hypothesis 3: divalproex extended-release may produce significantly less sedation

Detailed Description
-----------------
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.

Official Title
-----------------
A Single-Blind, Randomized, Naturalistic Pilot Study, Comparison of Divalproex ER and Quetiapine for Adults With Acute Mania or Mixed Episodes

Conditions
-----------------
Bipolar Disorder

Intervention / Treatment
-----------------
* Drug: divalproex ER
* Drug: quetiapine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: For inclusion, patients must fulfill all of the following criteria at enrollment: Provide written informed consent before initiation of any study-related procedures 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) Male or female, at least 18 years old YMRS score equal to or greater than 17 and a CGI of 4 (moderate) or greater. 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: Known intolerance or lack of response to quetiapine fumarate or Divalproex ER as judged by the investigator. Unwilling or not able to provide informed consent 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. History of schizophrenia or schizoaffective disorder Treatment with a depot antipsychotic within 1 treatment cycle 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 A female subject who is pregnant or lactating 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. Hospitalized for more than 1 week for current episode at the screen 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. Known diagnosis of dementia or MCI

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 Divalproex ER<br>Divalproex ER | Drug: divalproex ER<br>* Dose: 30mg per kg, rounded to nearest 500mg, dosed PO QHS. Adjustments made through trial to obtain serum valproic acid levels of 85-125 mcg/ml<br>* Other names: Depakote ER;|
| Active Comparator: 2 Quetiapine Fumarate<br>quetiapine fumarate | Drug: quetiapine<br>* Dose: 200mg PO QHS, titrated up to therapeutic dose of 600-800mg.<br>* Other names: Seroquel;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Measure: Young Mania Rating Scale (YMRS) Primary Endpoint: Day 7 | Minimum: 0 Maximum: 60 Higher scores indicate worse outcome | Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Young Mania Rating Scale (YMRS) Secondary Endpoints |  | weekly - Day 3, 14, 21 | 
| Clinical Global Impression: Severity (CGI:S) |  | each visit | 
| Clinical Global Impression: Improvement (CGI:I) |  | each week/visit | 
| Readiness to Discharge Questionnaire (RDQ) |  | each week/visit in the hospital | 
| Montgomery-Asberg Depression Rating Scale (MADRS) |  | each week/visit | 
| Behavioral Activity Rating Scale (BARS) |  | each week/visit | 
| Extrapyramidal Symptoms Rating Scale (ESRS) |  | each week/visit | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
quetiapine, divalproex