Sequential Multiple Assignment Treatment for Bipolar Disorder

This open methods advancement study will randomize BD patients with clinically significant
symptoms to treatment with one of two mood stabilizers (MS), lithium [LI] or divalproex
[DV]. Those who develop protocol defined depression will then be randomized to a MS alone,
MS + quetiapine [QT] or MS + lamotrigine [LM]. A SMART strategy employs a rule for adding
new treatments based on each patient's current illness state and response during the trial,
mimicking the adaptive nature of treatment selection which occurs in clinical settings, but
in a controlled way which allows application of causal inference. By using early indices of
response to dynamically alter treatment decisions to improve outcome, SMART eliminates
unmeasured confounders associated with treatment decisions that are not randomized, as
occurs in data mining exercises and in other non-randomized decisions in studies which
randomize one variable at baseline. This sequential adaptive design represents a
methodological innovation in bipolar trial history which will have particular implications
for effectiveness studies.

Specific Aim A.1: Assess the feasibility of a SMART design in the conduct of an
effectiveness study over 26 weeks in patients with BD.

Aim A.2 Compare the effectiveness of LI to DV as a primary component of treatment for BD
over 26 weeks.

Aim A.3: Assess the effectiveness of MS + QT and MS + LM versus MS in subjects who develop
depression.

A4. Exploratory Aims: 1.Determine the effects of ethnicity, language facility, education and
stress as moderators of treatment outcomes; 2. Explore the use of novel statistical
methodologies to more informatively characterize illness trajectories in response to the
interventions. In the aggregate these aims also will clarify whether the SMART confirms
results provided by traditional, single point randomized controlled trials (RCTs).

Inclusion Criteria:

- DSM-IV TR diagnosis BD I or II as assessed by MINI PLUS

- Male or female ≥ 18 years old

- Currently symptomatic with a CGI-BP-S ≥3 for mania/hypomania &/or depression for ≥ 2
weeks

- One of the following indicators of recent active illness: a depressive or manic or
hypomanic or mixed episode in the past 12 months

- If female of child bearing age must use effective birth control.

Exclusion Criteria:

- Unwilling or unable to comply with study requirements

- Renal impairment (serum creatinine > 1.5 mg/dL)

- If maintained on thyroid medication must be euthyroid for at least 1 month before
Visit 1

- Patients who have had intolerable side effects to QT, LI, DV, or LM

- Patients whose clinical status requires inpatient care

- Drug/alcohol dependence within the past 30 days

- Pregnancy as determined by serum pregnancy test or breastfeeding

- History of poor response to LI at a serum LI of ≥ 0.5 mEq/L or DV at a serum level of
≥ 45 mg/dL for at least 2 weeks.