Prevention of Relapse & Recurrence of Bipolar Depression

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the long-term use of combined antidepressant plus mood stabilizer therapy is superior to mood stabilizer therapy alone in preventing the relapse and recurrence of bipolar depression.

Detailed Description
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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.

Official Title
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Prevention of Relapse & Recurrence of Bipolar Depression

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Lithium / Fluoxetine
* Drug: Lithium / Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Lithium plus Fluoxetine Phase I<br>All participants were started in this arm. Those who met criteria for entry into Phase II were then randomized to one of the two Phase II arms. | Drug: Lithium / Fluoxetine<br>* Individualized Daily Dosage<br>* Other names: Lithium Carbonate / Prozac;|
| Other: Lithium plus Placebo Phase I<br>No participants began their participation on Lithium plus Placebo. | Drug: Lithium / Placebo<br>* Individualized Daily Dosage<br>* Other names: Lithium Carbonate / Sugar Pill;|
| Experimental: Lithium plus Fluoxetine Phase II<br>Patients who responded to Lithium plus Fluoxetine in Phase I and were randomized to continue on both compounds. | Drug: Lithium / Fluoxetine<br>* Individualized Daily Dosage<br>* Other names: Lithium Carbonate / Prozac;|
| Placebo Comparator: Lithium plus Placebo Phase II<br>Patients who responded to Lithium plus Fluoxetine in Phase I and were randomized to switch from Fluoxetine to placebo. | Drug: Lithium / Placebo<br>* Individualized Daily Dosage<br>* Other names: Lithium Carbonate / Sugar Pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Relapse of Major Depressive Episode Within 1 Year | Patients who were randomized to one of the Phase II conditions were interviewed once each month. If they met criteria for a relapse of a Major Depressive Episode, this was considered the study outcome. If they participated for the full year of Phase II without a documented relapse, they were considered a completer. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Onset of a Manic Episode Within 1 Year | Onsets of a manic episodes were ascertained with the clinician-rated Young Mania Rating Scale (YMRS). The YMRS covers 11 symptom groups over the previous 48 hours. Four of the items are rated on a scale from 0 to 4; the other 4 are rated on a scale of 0 to 8. A score of 12 or above indicates a manic episode. | 1 Year | 
| Number of Participants With an Onset of a Hypomanic Episode Within 1 Year | Onsets of a hypomanic episodes were ascertained with the clinician-rated Hypomania Interview Guide and associated scoring rules. | 1 Year | 
| Number of Participants With the Onset of a Sub-Syndromal Mood Conversion Episode Within 1 Year |  | 1 Year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar Disorder, Manic Depression, Major Depressive Episode, Mania, Hypomania, Long Term Treatment