Sequential Treatment of Pediatric MDD to Increase Remission and Prevent Relapse

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00612313
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 144
• Location: 1
• Arms: 2
• Duration (Months): 71
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

This study will compare the effectiveness of fluoxetine alone with the effectiveness of fluoxetine with cognitive behavioral therapy in increasing recovery and preventing relapse in youth with major depressive disorder.

Condition or Disease	Intervention/Treatment	Phase
Depression	Drug: Fluoxetine; Behavioral: Relapse prevention cognitive behavioral therapy (CBT)	N/A

Detailed Description

Major depressive disorder (MDD) is a serious psychiatric disorder that affects approximately 1 out of every 12 to 15 children and adolescents. Depression can cause problems with school, family, and friends, and if left untreated, these difficulties can persist into adulthood. Treatments using antidepressants and forms of psychotherapy have been shown to be effective in reducing symptoms of depression. However, many youth experience a return of depressive symptoms within 1 to 2 years of remission. Recent studies have shown that adding cognitive behavioral therapy (CBT), a form of psychotherapy that focuses on behavioral modification, to initial antidepressant treatment may increase remission and reduce relapse rates. This study will compare the effectiveness of fluoxetine alone versus fluoxetine plus added CBT in increasing recovery and preventing relapse in youth with MDD.

Participation in this study will last 78 weeks. Potential participants will undergo initial screening, which will include interviews and questionnaires about mood, behavior, and medical history; vital sign measurements; a meeting with a psychiatrist; and lab draws and/or urine drug or pregnancy tests if indicated by the psychiatrist. All eligible participants will then begin 6 weeks of treatment with fluoxetine. During this 6-week period, participants will attend weekly study visits, which will include vital sign measurements, questionnaires on symptoms and mood, and medication dosage adjustments. At Week 6, participants will be evaluated by an independent evaluator who will determine whether their depression has significantly improved. Participants who have not improved with fluoxetine will end their study participation and will be provided with recommendations for other treatment options.

All participants who have shown significant improvement will continue to receive fluoxetine for another 24 weeks, for a total of 30 weeks of treatment. Half of these participants will be randomly assigned to additionally receive CBT for the remaining 24 weeks. All participants will attend study visits that will occur every other week for 3 months and then monthly for 3 months. These visits will last 20 to 30 minutes and will include vital sign measurements and questions about mood and behavior. Participants receiving CBT will also attend 10 to 12 CBT sessions, which will last 50 minutes each and will occur weekly for the first 4 weeks, every other week for 1.5 months, and monthly for the last 3 months. The CBT sessions will involve both individual child and parent-child sessions, which will focus on modifying depressive thoughts, feelings, and behaviors. Participants will undergo repeat evaluations with the independent evaluator at Weeks 12, 18, 24, 30, 52, and 78.

Study Design

• Study Type: Interventional
• Actual Enrollment: 144 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Pediatric MDD: Sequential Treatment With Fluoxetine and Relapse Prevention
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Continued medication alone Participants will receive antidepressant treatment with fluoxetine for 30 weeks	Drug: Fluoxetine; Participants will take 10 to 40 mg per day of fluoxetine for 30 weeks.; Other Names: Prozac
Experimental: Continued medication plus CBT Participants will receive antidepressant treatment with fluoxetine for 30 weeks plus relapse prevention cognitive behavioral therapy for the last 24 weeks of treatment	Drug: Fluoxetine; Participants will take 10 to 40 mg per day of fluoxetine for 30 weeks.; Other Names: Prozac ; Behavioral: Relapse prevention cognitive behavioral therapy (CBT); After the first 6 weeks of treatment with fluoxetine, some participants will be assigned to additionally receive relapse prevention CBT for the remaining 24 weeks of treatment. These participants will attend 10 to 12 CBT sessions, during which they will learn specific skills to reduce and prevent the occurrence of residual depressive symptoms.; Other Names: CBT

Outcome Measures

Primary Outcome Measures

1. Time to Remission [30 weeks]

   Remission is defined as CDRS-R <=28. Timing of remission is based on clinical assessment using the CDRS-R and K-Life to identify the week at which point the patient remitted.

2. Relapse [Measured at Weeks 12, 18, 24, and 30]

   Relapse was defined as: 1) CDRS-R score >=40 with a history of 2 weeks of clinical deterioration or 2) CDRS-R<40, but with a 2 week history of significant clinical deterioration.

3. Remission [Measured at Weeks 12, 18, 24, and 30]

   Remission is defined as CDRS-R <=28.

Secondary Outcome Measures

1. K-Life (Time Well) [30 weeks]

   K-Life interview was conducted at Weeks 6, 12, 18, 24, and 30, with ratings for depressive illness for each week throughout the study. Ratings definitions: 1=Normal, no residual symptoms; 2=Presence of 1 or more symptosm in no more than mild degree; 3=Considerably less psychopathology than full criteria, but still obvious evidence of disorder with no more than moderate impairment; 4=Does not meet full criteria, but has major symptoms or impairment from the disorder; 5=Meets full criteria, but no extreme impairment; 6=Meets full criteria, and either has prominent psychotic symptoms or extreme impairment. Time well is defined as each week the depression rating was a 1 or 2. Percent time well was defined as each week the depression rating was a 1 or 2 divided by the total number of weeks in the study. Statistic: anova

2. Remission [Weeks 52 and 78]

   Remission is defined as CDRS-R <=28 (up through week 30) or at least 8 consecutive weeks of a K-Life rating of 1 or 2. Timing of remission is based on clinical assessment using the CDRS-R and K-Life to identify the week at which point the patient remitted.

3. Relapse [Weeks 52 and 78]

   Up through week 30, relapse was defined as: 1) CDRS-R score >=40 with a history of 2 weeks of clinical deterioration or 2) CDRS-R<40, but with a 2 week history of significant clinical deterioration. From week 31-78, relapse was assessed using the K-Life. Relapse was defined as at least 2 weeks of a K-Life rating of 5 or 6; participants may also be identified as relapsing with a K-Life rating of 4 if the rating was for several weeks and not strictly related to stressful life events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Primary diagnosis of nonpsychotic MDD (single or recurrent) for at least 4 weeks before study entry

• In good general medical health

• Normal intelligence

Exclusion Criteria:

• Lifetime history of any psychotic disorder, including psychotic depression

• Lifetime history of bipolar I and II disorders

• Alcohol or substance dependence within the 6 months before study entry

• Anorexia nervosa or bulimia within the 6 months before study entry

• Pregnant or breastfeeding females, or sexually active females not using medically acceptable means of birth control (e.g., IUD, birth control pills, barrier devices)

• Chronic medical illness (medically unstable and requires regular medication that may interfere with treatment interventions)

• Concurrent medication(s) with psychotropic effects (e.g., anticonvulsants, steroids, etc.) other than stable ADHD medication

• First degree relatives with bipolar I disorder

• Severe suicidal ideation or previous history of serious suicide attempt within this episode

• Prior failure to respond to an adequate treatment with fluoxetine (defined as at least 40 mg/day for 4 weeks)

• Non-English speaking

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Medical Center of Dallas, Outpatient Psychiatry Clinic	Dallas	Texas	United States	75235

Sponsors and Collaborators

• University of Texas Southwestern Medical Center
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Graham J. Emslie, MD, University of Texas, Southwestern Medical Center at Dallas
• Principal Investigator: Beth D. Kennard, PsyD, University of Texas, Southwestern Medical Center at Dallas

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Graham Emslie, Professor of Psychiatry, University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT00612313
• Other Study ID Numbers: R01MH039188-01; R01MH039188-01; DSIR 84-CTS; NCT00599300
• First Posted: Feb 11, 2008
• Last Update Posted: Jan 7, 2016
• Last Verified: Dec 1, 2015

• Keywords provided by Graham Emslie, Professor of Psychiatry, University of Texas Southwestern Medical Center: Major Depressive Disorder; MDD; Children; Adolescents; Antidepressant; CBT
• Additional relevant MeSH terms: Recurrence; Depression; Fluoxetine

Study Results

Participant Flow

Recruitment Details	200 participants began acute phase open-label treatment with fluoxetine. Of these, 144 entered the randomized control study. Results data presented are for 144 participants randomized.

Arm/Group Title	Continued Medication Alone	Continued Medication Plus CBT
Arm/Group Description	n=69 Participants will receive antidepressant treatment with fluoxetine for 30 weeks Fluoxetine: Participants will take 10 to 40 mg per day of fluoxetine for 30 weeks.	n=75 Participants will receive antidepressant treatment with fluoxetine for 30 weeks plus relapse prevention cognitive behavioral therapy for the last 24 weeks of treatment Fluoxetine: Participants will take 10 to 40 mg per day of fluoxetine for 30 weeks. Relapse prevention cognitive behavioral therapy (CBT): After the first 6 weeks of treatment with fluoxetine, some participants will be assigned to additionally receive relapse prevention CBT for the remaining 24 weeks of treatment. These participants will attend 10 to 12 CBT sessions, during which they will learn specific skills to reduce and prevent the occurrence of residual depressive symptoms.
Period Title: Overall Study
STARTED	69	75
COMPLETED	52	62
NOT COMPLETED	17	13

Baseline Characteristics

Arm/Group Title	Continued Medication Alone	Continued Medication Plus CBT	Total
Arm/Group Description	Participants received antidepressant treatment with fluoxetine for 30 weeks Fluoxetine: Participants will take 10 to 40 mg per day of fluoxetine for 30 weeks.	Participants received antidepressant treatment with fluoxetine for 30 weeks plus relapse prevention cognitive behavioral therapy for the last 24 weeks of treatment Fluoxetine: Participants will take 10 to 40 mg per day of fluoxetine for 30 weeks. Relapse prevention cognitive behavioral therapy (CBT): After the first 6 weeks of treatment with fluoxetine, these participants were assigned to additionally receive relapse prevention CBT for the remaining 24 weeks of treatment. These participants attended 10 to 12 CBT sessions, during which they will learn specific skills to reduce and prevent the occurrence of residual depressive symptoms.	Total of all reporting groups
Overall Participants	69	75	144
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	14.2 (2.4)	13.5 (2.7)	13.8 (2.6)
Sex: Female, Male (Count of Participants)
Female	39 56.5%	38 50.7%	77 53.5%
Male	30 43.5%	37 49.3%	67 46.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	20 29%	23 30.7%	43 29.9%
Not Hispanic or Latino	49 71%	52 69.3%	101 70.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.4%	0 0%	1 0.7%
Asian	0 0%	1 1.3%	1 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	7 10.1%	8 10.7%	15 10.4%
White	54 78.3%	64 85.3%	118 81.9%
More than one race	7 10.1%	2 2.7%	9 6.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	69 100%	75 100%	144 100%
Baseline CDRS-R (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	59.2 (7.0)	56.8 (7.1)	58.0 (7.2)
Baseline CGI Severity (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.3 (0.69)	5.1 (0.7)	5.2 (0.7)

Outcome Measures

1. Primary Outcome

Title	Time to Remission
Description	Remission is defined as CDRS-R <=28. Timing of remission is based on clinical assessment using the CDRS-R and K-Life to identify the week at which point the patient remitted.
Time Frame	30 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Continued Medication Alone	Continued Medication Plus CBT
Arm/Group Description	Participants received antidepressant treatment with fluoxetine for 30 weeks Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks.	Participants received antidepressant treatment with fluoxetine for 30 weeks plus relapse prevention cognitive behavioral therapy for the last 24 weeks of treatment Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks. Relapse prevention cognitive behavioral therapy (CBT): After the first 6 weeks of treatment with fluoxetine, these participants were assigned to additionally receive relapse prevention CBT for the remaining 24 weeks of treatment. These participants will attend 10 to 12 CBT sessions, during which they learned specific skills to reduce and prevent the occurrence of residual depressive symptoms.
Measure Participants	69	75
Mean (Standard Error) [weeks]	13.67 (1.17)	11.33 (0.95)

2. Primary Outcome

Title	Relapse
Description	Relapse was defined as: 1) CDRS-R score >=40 with a history of 2 weeks of clinical deterioration or 2) CDRS-R<40, but with a 2 week history of significant clinical deterioration.
Time Frame	Measured at Weeks 12, 18, 24, and 30

Outcome Measure Data

Analysis Population Description

Only participants who achieved remission were analyzed for relapse rates, as only remitted patients can experience a relapse of depression.

Arm/Group Title	Continued Medication Alone	Continued Medication Plus CBT
Arm/Group Description	Participants will receive antidepressant treatment with fluoxetine for 30 weeks Fluoxetine: Participants will take 10 to 40 mg per day of fluoxetine for 30 weeks.	Participants will receive antidepressant treatment with fluoxetine for 30 weeks plus relapse prevention cognitive behavioral therapy for the last 24 weeks of treatment Fluoxetine: Participants will take 10 to 40 mg per day of fluoxetine for 30 weeks. Relapse prevention cognitive behavioral therapy (CBT): After the first 6 weeks of treatment with fluoxetine, some participants will be assigned to additionally receive relapse prevention CBT for the remaining 24 weeks of treatment. These participants will attend 10 to 12 CBT sessions, during which they will learn specific skills to reduce and prevent the occurrence of residual depressive symptoms.
Measure Participants	52	64
Week 12	3	1
Week 18	10	3.5
Week 24	20.5	7
Week 30	26.5	9

3. Secondary Outcome

Title	K-Life (Time Well)
Description	K-Life interview was conducted at Weeks 6, 12, 18, 24, and 30, with ratings for depressive illness for each week throughout the study. Ratings definitions: 1=Normal, no residual symptoms; 2=Presence of 1 or more symptosm in no more than mild degree; 3=Considerably less psychopathology than full criteria, but still obvious evidence of disorder with no more than moderate impairment; 4=Does not meet full criteria, but has major symptoms or impairment from the disorder; 5=Meets full criteria, but no extreme impairment; 6=Meets full criteria, and either has prominent psychotic symptoms or extreme impairment. Time well is defined as each week the depression rating was a 1 or 2. Percent time well was defined as each week the depression rating was a 1 or 2 divided by the total number of weeks in the study. Statistic: anova
Time Frame	30 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Continued Medication Alone	Continued Medication Plus CBT
Arm/Group Description	Participants received antidepressant treatment with fluoxetine for 30 weeks Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks. n=69	Participants received antidepressant treatment with fluoxetine for 30 weeks plus relapse prevention cognitive behavioral therapy for the last 24 weeks of treatment Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks. Relapse prevention cognitive behavioral therapy (CBT): After the first 6 weeks of treatment with fluoxetine, these participants were assigned to additionally receive relapse prevention CBT for the remaining 24 weeks of treatment. These participants will attend 10 to 12 CBT sessions, during which they learned specific skills to reduce and prevent the occurrence of residual depressive symptoms. n=75
Measure Participants	69	75
Mean (Standard Deviation) [Weeks spent well]	12.8 (9.5)	16.0 (9.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Continued Medication Alone, Continued Medication Plus CBT
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.02
	Comments	The estimated rate of time spent well was evaluated using a Poisson regression with adjustment for CDRS-R score at the end of the acute phase, age group, and gender.
	Method	Regression, Poisson
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	9.7
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Differencein percentages represents estimated percentage for medication management + CBT Arm minus estimated percentage for medication management only Arm.

4. Secondary Outcome

Title	Remission
Description	Remission is defined as CDRS-R <=28 (up through week 30) or at least 8 consecutive weeks of a K-Life rating of 1 or 2. Timing of remission is based on clinical assessment using the CDRS-R and K-Life to identify the week at which point the patient remitted.
Time Frame	Weeks 52 and 78

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Continued Medication Alone	Continued Medication Plus CBT
Arm/Group Description	Participants received antidepressant treatment with fluoxetine for 30 weeks Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks. Treatment was uncontrolled after week 30.	Participants received antidepressant treatment with fluoxetine for 30 weeks plus relapse prevention cognitive behavioral therapy for the last 24 weeks of treatment Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks. Relapse prevention cognitive behavioral therapy (CBT): After the first 6 weeks of treatment with fluoxetine, these participants were assigned to additionally receive relapse prevention CBT for the remaining 24 weeks of treatment. These participants will attend 10 to 12 CBT sessions, during which they learned specific skills to reduce and prevent the occurrence of residual depressive symptoms. Treatment was uncontrolled after week 30.
Measure Participants	69	75
Week 52	89	94
Week 78	92	96

5. Secondary Outcome

Title	Relapse
Description	Up through week 30, relapse was defined as: 1) CDRS-R score >=40 with a history of 2 weeks of clinical deterioration or 2) CDRS-R<40, but with a 2 week history of significant clinical deterioration. From week 31-78, relapse was assessed using the K-Life. Relapse was defined as at least 2 weeks of a K-Life rating of 5 or 6; participants may also be identified as relapsing with a K-Life rating of 4 if the rating was for several weeks and not strictly related to stressful life events.
Time Frame	Weeks 52 and 78

Outcome Measure Data

Analysis Population Description

Only participants who achieved remission were analyzed for relapse rates, as only remitted patients can experience a relapse of depression.

Arm/Group Title	Continued Medication Alone	Continued Medication Plus CBT
Arm/Group Description	Participants received antidepressant treatment with fluoxetine for 30 weeks Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks. Treatment was uncontrolled after week 30.	Participants received antidepressant treatment with fluoxetine for 30 weeks plus relapse prevention cognitive behavioral therapy for the last 24 weeks of treatment Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks. Relapse prevention cognitive behavioral therapy (CBT): After the first 6 weeks of treatment with fluoxetine, these participants were assigned to additionally receive relapse prevention CBT for the remaining 24 weeks of treatment. These participants will attend 10 to 12 CBT sessions, during which they learned specific skills to reduce and prevent the occurrence of residual depressive symptoms. Treatment was uncontrolled after week 30.
Measure Participants	54	67
Week 52	49	27
Week 78	62	36

6. Primary Outcome

Title	Remission
Description	Remission is defined as CDRS-R <=28.
Time Frame	Measured at Weeks 12, 18, 24, and 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Continued Medication Alone	Continued Medication Plus CBT
Arm/Group Description	Participants received antidepressant treatment with fluoxetine for 30 weeks Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks.	Participants received antidepressant treatment with fluoxetine for 30 weeks plus relapse prevention cognitive behavioral therapy for the last 24 weeks of treatment Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks. Relapse prevention cognitive behavioral therapy (CBT): After the first 6 weeks of treatment with fluoxetine, these participants were assigned to additionally receive relapse prevention CBT for the remaining 24 weeks of treatment. These participants will attend 10 to 12 CBT sessions, during which they learned specific skills to reduce and prevent the occurrence of residual depressive symptoms.
Measure Participants	69	75
Week 12	59	68
Week 18	71	79
Week 24	80	86
Week 30	84	90

Adverse Events

Arm/Group Title	Continued Medication Alone		Continued Medication Plus CBT
Arm/Group Description	Participants received antidepressant treatment with fluoxetine for 30 weeks Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks. N=69		Participants received antidepressant treatment with fluoxetine for 30 weeks plus relapse prevention cognitive behavioral therapy for the last 24 weeks of treatment Fluoxetine: Participants took 10 to 40 mg per day of fluoxetine for 30 weeks. Relapse prevention cognitive behavioral therapy (CBT): After the first 6 weeks of treatment with fluoxetine, these participants were assigned to additionally receive relapse prevention CBT for the remaining 24 weeks of treatment. These participants will attend 10 to 12 CBT sessions, during which they learned specific skills to reduce and prevent the occurrence of residual depressive symptoms. N=75
All Cause Mortality
	Continued Medication Alone		Continued Medication Plus CBT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Continued Medication Alone		Continued Medication Plus CBT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/69 (10.1%)		9/75 (12%)
General disorders
Hospitalization for medical conditions	2/69 (2.9%)	2	3/75 (4%)	5
Psychiatric disorders
Hospitalization for Suicide Attempt	1/69 (1.4%)	1	0/75 (0%)	0
Hospitalization for Suicidal Ideation	3/69 (4.3%)	3	5/75 (6.7%)	5
Hospitalization for Agitation	1/69 (1.4%)	1	0/75 (0%)	0
Suicidal behavior that did not result in hospitalization	0/69 (0%)	0	1/75 (1.3%)	1
Other (Not Including Serious) Adverse Events
	Continued Medication Alone		Continued Medication Plus CBT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/69 (0%)		0/75 (0%)

Limitations/Caveats

Primary outcomes based on data through 30 weeks. Participants were not blinded to treatment assignment.

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.