Prevention of Relapse & Recurrence of Bipolar Depression

September 23, 2020 updated by: University of Pennsylvania
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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

177

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Rush University Medical Center
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104-3309
        • Depression Research Unit

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
OTHER: Lithium plus Fluoxetine Phase I
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
Individualized Daily Dosage
Other Names:
  • Lithium Carbonate / Prozac
OTHER: Lithium plus Placebo Phase I
No participants began their participation on Lithium plus Placebo.
Drug: Lithium / Placebo
Individualized Daily Dosage
Other Names:
  • Lithium Carbonate / Sugar Pill
EXPERIMENTAL: Lithium plus Fluoxetine Phase II
Patients who responded to Lithium plus Fluoxetine in Phase I and were randomized to continue on both compounds.
Drug: Lithium / Fluoxetine
Individualized Daily Dosage
Other Names:
  • Lithium Carbonate / Prozac
PLACEBO_COMPARATOR: Lithium plus Placebo Phase II
Patients who responded to Lithium plus Fluoxetine in Phase I and were randomized to switch from Fluoxetine to placebo.
Drug: Lithium / Placebo
Individualized Daily Dosage
Other Names:
  • Lithium Carbonate / Sugar Pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Relapse of Major Depressive Episode Within 1 Year
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 1 Year
1 Year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Pennsylvania

Collaborators

National Institute of Mental Health (NIMH)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

July 1, 2009

Primary Completion (ACTUAL)

September 1, 2016

Study Completion (ACTUAL)

September 1, 2016

Study Registration Dates

First Submitted

August 18, 2009

First Submitted That Met QC Criteria

August 18, 2009

First Posted (ESTIMATE)

August 19, 2009

Study Record Updates

Last Update Posted (ACTUAL)

October 19, 2020

Last Update Submitted That Met QC Criteria

September 23, 2020

Last Verified

September 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • R01MH080097 (NIH)
  • R01MH080098 (NIH)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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