Prevention of Relapse & Recurrence of Bipolar Depression

Recurrence of Bipolar I (BP I) major depressive episode (MDE), is now recognized as a major
mental health problem. Recurrent BP I MDE is a disorder with no satisfactory therapy, and
its treatment remains a challenge to clinicians. To date, initial and long-term therapy of
BP I MDE has been based on un-validated practice guidelines. These guidelines recommend
limiting antidepressant drug (AD) use during initial therapy of BP I MDE, and completely
avoiding AD use during long-term therapy. There is, however, no empirical evidence to
suggest that mood stabilizer (MS) monotherapy is superior to combined MS plus AD therapy in
preventing recurrent BP I MDE. Nor is there evidence to suggest that long-term MS plus AD
therapy results in more manic switch episodes. We present evidence that AD-induced mania
during long-term therapy of BP I MDE has been over-estimated, and that long-term use of MS
plus AD therapy may be superior to MS therapy alone in preventing recurrent BP I MDE. In
this study, we will ask: "Does continuation therapy with combined lithium plus fluoxetine
result in fewer MDE relapses and recurrences vs. lithium monotherapy?" To answer this
question, patients with BP I MDE will receive combined lithium plus fluoxetine therapy for 8
weeks. Responders who stay well for an additional 4 weeks of consolidation therapy will then
be randomized to double-blind continuation therapy with either (i) combined lithium plus
fluoxetine, or (ii) lithium alone (following fluoxetine taper and discontinuation) for an
additional 50 weeks. We hypothesize that long-term lithium plus fluoxetine therapy will
result in fewer MDE relapses and recurrences vs. lithium monotherapy. We will also ask:
"What is the relative safety, tolerability, and frequency of syndromal and sub-syndromal
manic, hypomanic, and mixed state conversions during continuation treatment with combined
lithium plus fluoxetine vs. lithium monotherapy?" To answer this question, we will measure:
the frequency, severity, and duration of syndromal and sub-syndromal manic, hypomanic, and
mixed state conversions; frequency, severity, and duration of treatment-emergent adverse
events; frequency of treatment discontinuation; time to onset of first syndromal and
sub-syndromal conversion event; time to first treatment intervention of each syndromal and
sub-syndromal conversion event; and, time to onset of increase in suicidal ideation event.
We hypothesize that lithium plus fluoxetine therapy will result in a similar frequency of
syndromal and sub-syndromal conversion events, and a similar frequency of treatment-emergent
adverse events. We further hypothesize that lithium plus fluoxetine therapy will result in
fewer suicide ideation events and fewer study discontinuations vs. lithium monotherapy. We
believe that the results of this trial may have an important public health impact on the
current practice guidelines for treating BP I MDE.

Inclusion Criteria:

- Men/women (all races and ethnicity)

- Age at least 18 years old

- Bipolar Type I Disorder

- Current Major Depressive Episode

- Able to understand and provide signed informed consent

Exclusion Criteria:

- Current alcohol or drug abuse

- Alcohol or drug dependence within 3 months

- Allergic to Fluoxetine or Lithium

- Unstable medical condition (e.g., uncontrolled thyroid, renal, cardiovascular
disease)

- Pregnant or nursing women

- Women of child-bearing potential unwilling to use a medically acceptable form of
contraception

- Actively suicidal

- Requiring hospitalization

- Use of medication contraindicated with lithium or fluoxetine

- Unable to participate in a year-long trial