Prevention of Relapse & Recurrence of Bipolar Depression

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT00961961
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 177
• Locations: 2
• Arms: 4
• Actual Duration (Months): 86
• Patients Per Site: 88.5
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: Lithium / Fluoxetine; Drug: Lithium / Placebo	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 177 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Prevention of Relapse & Recurrence of Bipolar Depression
• Actual Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Relapse of Major Depressive Episode Within 1 Year [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.

Secondary Outcome Measures

1. Number of Participants With an Onset of a Manic Episode Within 1 Year [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.

2. Number of Participants With an Onset of a Hypomanic Episode Within 1 Year [1 Year]

   Onsets of a hypomanic episodes were ascertained with the clinician-rated Hypomania Interview Guide and associated scoring rules.

3. Number of Participants With the Onset of a Sub-Syndromal Mood Conversion Episode Within 1 Year [1 Year]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rush University Medical Center	Chicago	Illinois	United States	60612
2	Depression Research Unit	Philadelphia	Pennsylvania	United States	19104-3309

Sponsors and Collaborators

• University of Pennsylvania
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Robert J. DeRubeis, PhD, University of Pennsylvania
• Principal Investigator: John M Zajecka, MD, Rush University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• DeRubeis Lab Web Page

Publications

None provided.

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT00961961
• Other Study ID Numbers: R01MH080097; R01MH080097; R01MH080098
• First Posted: Aug 19, 2009
• Last Update Posted: Oct 19, 2020
• Last Verified: Sep 1, 2020

• Keywords provided by University of Pennsylvania: Bipolar Disorder; Manic Depression; Major Depressive Episode; Mania; Hypomania; Long Term Treatment
• Additional relevant MeSH terms: Recurrence; Depression; Bipolar Disorder; Lithium Carbonate; Fluoxetine

Study Results

Participant Flow

Pre-assignment Detail	Phase I was an open label treatment, of Lithium and Fluoxetine, of all enrolled patients. Those who met criteria for response after 12 weeks were randomized to one of two Phase II (double-blinded) arms: Lithium plus Fluoxetine Lithium plus Placebo

Arm/Group Title	Lithium Plus Fluoxetine Phase I	Lithium Plus Placebo Phase I	Lithium Plus Fluoxetine Phase II	Lithium Plus Placebo Phase II
Arm/Group Description	Lithium / Fluoxetine: Individualized Daily Dosage	This is a placeholder arm. No participants were given Placebo in Phase I.	One of the two randomly assigned groups, each of which continued on Lithium Double-blind assignment to continue on Fluoxetine (this group)	One of the two randomly assigned groups, each of which continued on Lithium Double-blind assignment to switch from Fluoxetine to Placebo (this group)
Period Title: Phase I
STARTED	177	0	0	0
COMPLETED	51	0	0	0
NOT COMPLETED	126	0	0	0
Period Title: Phase I
STARTED	0	0	29	22
COMPLETED	0	0	17	14
NOT COMPLETED	0	0	12	8

Baseline Characteristics

Arm/Group Title	Lithium Plus Fluoxetine Phase I	Lithium Plus Placebo Phase I	Lithium Plus Fluoxetine Phase II	Lithium Plus Placebo Phase II	Total
Arm/Group Description	All eligible and consenting participants began in this open phase. Therefore baseline characteristics are only relevant for this category.	No participant was begun on Placebo. Lithium Plus Placebo was a real condition only after randomization, in Phase II. Baseline characteristics for all participants are listed under Lithium plus Fluoxetine Phase I.	This is a subset of patients whose baseline characteristics are listed under Lithium plus Fluoxetine Phase I.	This is a subset of patients whose baseline characteristics are listed under Lithium plus Fluoxetine Phase I.	Total of all reporting groups
Overall Participants	177	0	0	0	177
Age (Count of Participants)
<=18 years	0 0%	0 NaN	0 NaN	0 NaN	0 0%
Between 18 and 65 years	175 98.9%	0 NaN	0 NaN	0 NaN	175 98.9%
>=65 years	2 1.1%	0 NaN	0 NaN	0 NaN	2 1.1%
Sex: Female, Male (Count of Participants)
Female	90 50.8%	0 NaN	0 NaN	0 NaN	90 50.8%
Male	87 49.2%	0 NaN	0 NaN	0 NaN	87 49.2%
Region of Enrollment (participants) [Number]
United States	177 100%	177 Infinity

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Relapse of Major Depressive Episode Within 1 Year
Description	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.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The analyses are relevant only during Phase II. The comparisons are between those assigned to one of the two randomized Phase II conditions.

Arm/Group Title	Lithium Plus Fluoxetine Phase I	Lithium Plus Placebo Phase I	Lithium Plus Fluoxetine Phase II	Lithium Plus Placebo Phase II
Arm/Group Description	The outcome measures, including this one, are only relevant in Phase II. Thus there will be zeroes in this category.	The outcome measures, including this one, are only relevant in Phase II. Thus there will be zeroes in this category.	Participants randomized to this condition remained on active medications. However, the fluoxetine pills were made to look like the placebo pills, to maintain the double-blind.	Participants randomized to this condition were switched from fluoxetine to placebo. However, the placebo pills were made to look like the fluoxetine pills, to maintain the double-blind.
Measure Participants	0	0	29	22
Count of Participants [Participants]	4 2.3%	5 Infinity

2. Secondary Outcome

Title	Number of Participants With an Onset of a Manic Episode Within 1 Year
Description	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.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

This and other outcomes are only relevant in the double-blind Phase II of the study.

Arm/Group Title	Lithium Plus Fluoxetine Phase I	Lithium Plus Placebo Phase I	Lithium Plus Fluoxetine Phase II	Lithium Plus Placebo Phase II
Arm/Group Description	This is not a relevant category for this outcome. This outcome is only assessed in Phase II.	This is not a relevant category for this outcome. This outcome is only assessed in Phase II.	Includes participants who completed Phase I and were assigned randomly to continue on their medications in Phase II (double-blind, as the fluoxetine and placebo were identical in appearance.	Includes participants who completed Phase I and were assigned randomly to switch from fluoxetine to placebo in Phase II (double-blind, as the fluoxetine and placebo were identical in appearance).
Measure Participants	0	0	29	22
Count of Participants [Participants]	0 0%	0 NaN	0 NaN	0 NaN

3. Secondary Outcome

Title	Number of Participants With an Onset of a Hypomanic Episode Within 1 Year
Description	Onsets of a hypomanic episodes were ascertained with the clinician-rated Hypomania Interview Guide and associated scoring rules.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

These are the patients who were randomly assigned, after responding to the medications provided in Phase I, to either remain on the same regime or have their fluoxetine switched to placebo.

Arm/Group Title	Lithium Plus Fluoxetine Phase I	Lithium Plus Placebo Phase I	Lithium Plus Fluoxetine Phase II	Lithium Plus Placebo Phase II
Arm/Group Description	All participants began with both medications in Phase I, which led into Phase II.	No participant was on placebo in Phase I. Only during Phase II.	Participants randomized to this condition remained on active medications. However, the fluoxetine pills were made to look like the placebo pills, to maintain the double-blind.	Participants randomized to this condition were switched from fluoxetine to placebo. However, the fluoxetine pills were made to look like the placebo pills, to maintain the double-blind.
Measure Participants	0	0	29	22
Count of Participants [Participants]	0 0%	0 NaN	0 NaN	0 NaN

4. Secondary Outcome

Title	Number of Participants With the Onset of a Sub-Syndromal Mood Conversion Episode Within 1 Year
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

This was not a diagnosis that was recognized widely in the profession. Procedures for ascertaining such episodes were not consistent across the two performance sites. As a consequence the data obtained to document this outcome were unreliable.

Arm/Group Title	Lithium Plus Fluoxetine	Lithium Plus Placebo	Lithium Plus Fluoxetine Phase II	Lithium Plus Placebo Phase II
Arm/Group Description	Lithium / Fluoxetine: Individualized Daily Dosage	Lithium / Placebo: Individualized Daily Dosage	Participants randomized to this condition remained on active medications. However, the fluoxetine pills were made to look like the placebo pills, to maintain the double-blind.	Participants randomized to this condition remained on active medications. However, the fluoxetine pills were made to look like the placebo pills, to maintain the double-blind.
Measure Participants	0	0	0	0

Adverse Events

Time Frame	15 months
Adverse Event Reporting Description	All events were noted during the first phase of the study.
Arm/Group Title	Lithium Plus Fluoxetine Phase I		Lithium Plus Placebo Phase I		Lithium Plus Fluoxetine Phase II		Lithium Plus Placebo Phase II
Arm/Group Description	This is the condition that all participants started in. They were given Lithium plus Fluoxetine and, if they responded, they were asked to accept random assignment to Phase II.		No one was on placebo in Phase I.		These are the patients randomly assigned to stay on the fluoxetine in Phase II.		These are the patients randomly assigned to switch to placebo from fluoxetine in Phase II.
All Cause Mortality
	Lithium Plus Fluoxetine Phase I		Lithium Plus Placebo Phase I		Lithium Plus Fluoxetine Phase II		Lithium Plus Placebo Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/177 (0%)		0/0 (NaN)		0/29 (0%)		0/22 (0%)
Serious Adverse Events
	Lithium Plus Fluoxetine Phase I		Lithium Plus Placebo Phase I		Lithium Plus Fluoxetine Phase II		Lithium Plus Placebo Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/177 (11.3%)		0/0 (NaN)		0/29 (0%)		0/22 (0%)
Gastrointestinal disorders
Elevated Creatinine	1/177 (0.6%)	1	1/0 (Infinity)	1	0/29 (0%)	1	0/22 (0%)	1
Unable to swallow pills	1/177 (0.6%)	1	1/0 (Infinity)	1	0/29 (0%)	1	0/22 (0%)	1
Nausea	1/177 (0.6%)	1	1/0 (Infinity)	1	0/29 (0%)	1	0/22 (0%)	1
General disorders
Hospitalized for dehydration	1/177 (0.6%)	1	1/0 (Infinity)	1	0/29 (0%)	1	0/22 (0%)	1
Musculoskeletal and connective tissue disorders
Muscle stiffness	1/177 (0.6%)	1	1/0 (Infinity)	1	0/29 (0%)	1	0/22 (0%)	1
Nervous system disorders
Lethargy, cognitive dulling	3/177 (1.7%)	3	3/0 (Infinity)	3	0/29 (0%)	3	0/22 (0%)	3
Tremors	3/177 (1.7%)	3	3/0 (Infinity)	3	0/29 (0%)	3	0/22 (0%)	3
Psychiatric disorders
Suicide ideation	2/177 (1.1%)	2	2/0 (Infinity)	2	0/29 (0%)	2	0/22 (0%)	2
Acute mood disturbance	2/177 (1.1%)	2	2/0 (Infinity)	2	0/29 (0%)	2	0/22 (0%)	2
Hospitalized for overdose of benzodiazepines	2/177 (1.1%)	2	2/0 (Infinity)	2	0/29 (0%)	2	0/22 (0%)	2
Hospitalized for acute alcohol abuse	1/177 (0.6%)	1	1/0 (Infinity)	1	0/29 (0%)	1	0/22 (0%)	1
Hospitalized for acute substance abuse	1/177 (0.6%)	2	1/0 (Infinity)	2	0/29 (0%)	2	0/22 (0%)	2
Skin and subcutaneous tissue disorders
Skin rash	1/177 (0.6%)	1	1/0 (Infinity)	1	0/29 (0%)	1	0/22 (0%)	1
Other (Not Including Serious) Adverse Events
	Lithium Plus Fluoxetine Phase I		Lithium Plus Placebo Phase I		Lithium Plus Fluoxetine Phase II		Lithium Plus Placebo Phase II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/177 (0%)		0/0 (NaN)		0/29 (0%)		0/22 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.