Comparative Effectiveness Study for Bipolar Disorder

Mood stabilizers, medications that prevent future mood episodes, are the foundation for
treatment of bipolar disorder. While all published bipolar disorder treatment guidelines
recommend that pharmacotherapy should include mood stabilizers for long-term maintenance
treatment, no randomized comparative effectiveness studies have examined the real-world
advantages and disadvantages of the newer second generation antipsychotic (SGA) mood
stabilizers compared to the classic mood stabilizers, such as lithium (Li). No studies have
looked at the effectiveness of SGAs compared to mood stabilizers when used in the context of
other medications required to manage bipolar patients, since bipolar disorder patients take a
median of 3 medications for optimal outcomes. Quetiapine (QTP) is the most extensively
studied, broadly efficacious and the most widely prescribed SGA for bipolar disorder. The
classic mood stabilizer Li has the largest evidence base for treating bipolar disorder, but
has been largely supplanted by the SGAs.

Thus, this study compares symptomatic benefits and adverse effect burden between a QTP
foundation with adjunctive personalized treatments (QTP+APT) and a mood stabilizer foundation
consisting of Li with APT (Li+APT). APT will include any other medication needed with the
following exceptions: the QTP+APT cannot receive Li and the Li+APT group cannot receive an
antipsychotic. If, however, participants clinically require a switch to, or the addition of
any other SGA or mood stabilizer, then those medications can be added as a rescue strategy
that will be carefully recorded. Consistent with an effectiveness trial, participants will be
able to continue in the study if they require a rescue treatment. The specific plan is a
randomized, open, two arm, comparative effectiveness study of QTP+APT vs. Li+APT treatment
for 6 months across 10 sites.

In summary, this comparative effectiveness study compares fundamentally different acute and
continuation treatments for bipolar disorder. The investigators address the key question of
whether to use a prototypical mood stabilizing SGA (i.e., QTP) or the classical mood
stabilizer Li as the foundational treatment in the context of other necessary adjunctive
personalized treatments (APT).

Inclusion Criteria:

1. Meets DSM-IV criteria for BD I or II, which is the primary focus of treatment

2. Able to give written informed consent

3. Age > to 18 years and < 68 years

4. Women of child bearing potential must agree to use adequate contraception (e.g. oral
contraceptives, intrauterine device, barrier methods, or total abstinence from
intercourse; Depo Provera is acceptable if it is started 3 months prior to
enrollment), inform their doctor at the earliest possible time of their plans to
conceive, and to understand the risks of lithium and other study treatments to the
fetus and infant

5. Currently symptomatic, as defined as a Clinical Global Impression - Bipolar Disorder
Overall Severity (CGI-BP-S) score of at least 3 (mild)

6. If currently taking an SGA, participants would be required to be willing to either
discontinue or switch to QTP

7. Willing to be randomized to either QTP+APT or Li+APT.

Exclusion Criteria:

1. Unwilling or unable to comply with study requirements

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

3. Patients who have had intolerable side effects with QTP or Li

4. Patients whose clinical status requires inpatient care

5. Drug/alcohol dependence within the past 30 days

6. Pregnancy as determined by urine pregnancy test or breastfeeding

7. History of nonresponse to Li at a serum level of ≥ 1.0 mEq/L ≥ 8 weeks

8. History of nonresponse to QTP at doses of at least 600 mg ≥ 8 weeks.