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Dopaminergic Effects of Adjunctive Aripiprazole on the Brain in Treatment-Resistant Depression

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ClinicalTrials.gov Identifier: NCT00953745
Recruitment Status : Completed
First Posted : August 6, 2009
Results First Posted : April 19, 2018
Last Update Posted : April 19, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Washington University School of Medicine

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Participant);   Primary Purpose: Other
Condition Major Depressive Disorder
Interventions Drug: Escitalopram
Drug: Aripiprazole
Drug: Placebo Capsule
Drug: Placebo Tablet
Enrollment 43

Recruitment Details  
Pre-assignment Details  
Arm/Group Title Depressed Participants Control Participants
Hide Arm/Group Description

Subjects with treatment-resistant depression (TRD) will receive escitalopram combined with an adjunctive placebo capsule for 8 weeks.

Subjects who fail to respond will continue to receive escitalopram and additionally change to receive a placebo tablet resembling the active augmentation agent Aripiprazole (ARP) for 2 weeks.

Non-depressed, age- and sex-matched subjects without a DSM-IV Axis I diagnosis will serve as controls. They will not receive antidepressant, ARP, or any drug augmentation and will be used to compare the pre-ARP and post-ARP treatment brain images to draw conclusions about the pre-treatment state (depression) and post-treatment state (depression responders).
Period Title: Phase 1: 8 Weeks Escitalopram + Placebo
Started 37 6
Completed 24 6
Not Completed 13 0
Reason Not Completed
Pregnancy             1             0
Withdrawal by Subject             2             0
Lost to Follow-up             3             0
Adverse Event             1             0
Screen failures             6             0
Period Title: Phase 2: 2 Weeks Escitalopram + Placebo
Started 18 0
Completed 17 0
Not Completed 1 0
Reason Not Completed
Pregnancy             1             0
Period Title: ARP Phase: 6 Weeks Escitalopram + ARP
Started 17 0
Completed 17 0
Not Completed 0 0
Arm/Group Title Depressed Participants Control Participants Total
Hide Arm/Group Description

Subjects with treatment-resistant depression (TRD) will receive escitalopram combined with an adjunctive placebo capsule for 8 weeks.

Subjects who fail to respond will continue to receive escitalopram and additionally change to receive a placebo tablet resembling the active augmentation agent Aripiprazole (ARP) for 2 weeks.

Subjects who fail to respond to escitalopram after the 2 phase placebo treatment will enter the ARP augmentation phase of the study and will receive escitalopram augmentation with ARP.

Subjects will have 3 neuroimaging scans: F-DOPA PET, raclopride PET, and functional MRI conducted after 10 weeks of treatment and repeated after 6 weeks of ARP treatment.

Non-depressed, age- and sex-matched subjects without a DSM-IV Axis I diagnosis will serve as controls. They will not receive antidepressant, ARP, or any drug augmentation and will be used to compare the pre-ARP and post-ARP treatment brain images to draw conclusions about the pre-treatment state (depression) and post-treatment state (depression responders). Total of all reporting groups
Overall Number of Baseline Participants 37 6 43
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 37 participants 6 participants 43 participants
41.69
(19 to 54)
45.67
(31 to 54)
42.27
(19 to 54)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 37 participants 6 participants 43 participants
Female
27
  73.0%
5
  83.3%
32
  74.4%
Male
10
  27.0%
1
  16.7%
11
  25.6%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 37 participants 6 participants 43 participants
37 6 43
1.Primary Outcome
Title Fluorodopa Uptake Values in Brain Images of Aripiprazole Augmentation Responders
Hide Description A ratio of the image derived radioactivity concentration and the whole body concentration of the injected radioactivity specifically in a cluster within the right medial caudate (see data below).
Time Frame Week 10 and Week 16 (6 weeks of combined therapy)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The outcome purpose was to examine mechanism of action of aripiprazole in responders versus nonresponders. Control subjects were age and gender matched to study subjects and underwent one set of scans (fMRI, raclopride and FOPA PET scans) for use as a comparison group for quality control on a non-depressed population and not for data analysis.
Arm/Group Title ARP Responders ARP Non-Responders
Hide Arm/Group Description:

Subjects who fail to respond to escitalopram after the 2 phase placebo treatment will enter the ARP augmentation phase of the study and will receive escitalopram augmentation with ARP. ARP Responders will have had a 50% or greater drop in their MADRS scores from baseline.

Subjects will have 3 neuroimaging scans: F-DOPA PET, raclopride PET, and functional MRI conducted after 10 weeks of treatment and repeated after 6 weeks of ARP treatment.

Subjects who fail to respond to escitalopram after the 2 phase placebo treatment will enter the ARP augmentation phase of the study and will receive escitalopram augmentation with ARP. ARP Responders will have had a 50% or greater drop in their MADRS scores from baseline.

Subjects will have 3 neuroimaging scans: F-DOPA PET, raclopride PET, and functional MRI conducted after 10 weeks of treatment and repeated after 6 weeks of ARP treatment.

Overall Number of Participants Analyzed 11 3
Mean (Standard Deviation)
Unit of Measure: FDOPA ratio in the right medial caudate
Week 10 1.297  (0.176) 1.363  (0.180)
Week 16 1.333  (0.175) 1.350  (0.252)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ARP Responders
Comments A region of increased relative Fluorodopa (FDOPA) uptake in the right medial caudate was anticipated for the aripiprazole augmentation responders over the 6 weeks of augmentation treatment (Weeks 10-16).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.029
Comments paired t-test thresholded at cluster level significance of p=0.001; family-wise error multiple comparisons corrected
Method t-test, 1 sided
Comments [Not Specified]
2.Secondary Outcome
Title Depression Symptom Change on The Montgomery–Åsberg Depression Rating (MADRS) Scale Between ARP Responders and Non-responders.
Hide Description Montgomery–Åsberg Depression Rating (MADRS) Scale scores compared between the 6 week Aripiprazole augmentation groups (responds vs. non-responders). Total range of the MADRS is 0 to 60, with a score of greater than 34 indicating severe depression, 20-34 indicating moderate depression, 7-19 mild depression, and 0-6 normal or absent of symptoms.
Time Frame Week 10 and Week 16 (6 weeks of combined therapy)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
MADRS score comparison between ARP responders and nonresponders.
Arm/Group Title ARP Responders ARP Non-Responders
Hide Arm/Group Description:
Subjects who fail to respond to escitalopram after the 2 phase placebo treatment will enter the ARP augmentation phase of the study and will receive escitalopram augmentation with ARP. ARP Responders will have had a 50% or greater drop in their MADRS scores from baseline.
Subjects who fail to respond to escitalopram after the 2 phase placebo treatment will enter the ARP augmentation phase of the study and will receive escitalopram augmentation with ARP. ARP non-responders will not have had a 50% or greater drop in their MADRS scores from baseline.
Overall Number of Participants Analyzed 11 3
Mean (Standard Deviation)
Unit of Measure: score on the MADRS scale
Week 10 27.9  (5.6) 31.7  (12.7)
Week 16 6.5  (3.0) 25.3  (5.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ARP Responders
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection ARP Non-Responders
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.366
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Depressed Participants Control Participants
Hide Arm/Group Description

Subjects with treatment-resistant depression (TRD) will receive escitalopram combined with an adjunctive placebo capsule for 8 weeks.

Subjects who fail to respond will continue to receive escitalopram and additionally change to receive a placebo tablet resembling the active augmentation agent Aripiprazole (ARP) for 2 weeks.

Subjects who fail to respond to escitalopram after the 2 phase placebo treatment will enter the ARP augmentation phase of the study and will receive escitalopram augmentation with ARP.

Subjects will have 3 neuroimaging scans: F-DOPA PET, raclopride PET, and functional MRI conducted after 10 weeks of treatment and repeated after 6 weeks of ARP treatment.

Non-depressed, age- and sex-matched subjects without a DSM-IV Axis I diagnosis will serve as controls. They will not receive antidepressant, ARP, or any drug augmentation and will be used to compare the pre-ARP and post-ARP treatment brain images to draw conclusions about the pre-treatment state (depression) and post-treatment state (depression responders).
All-Cause Mortality
Depressed Participants Control Participants
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Depressed Participants Control Participants
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/37 (5.41%)      0/6 (0.00%)    
Pregnancy, puerperium and perinatal conditions     
Birth of a baby (deception by subject) [1]  1/27 (3.70%)  1 0/6 (0.00%)  0
Pregnancy [2]  1/27 (3.70%)  1 0/6 (0.00%)  0
[1]
Subject documented as non pregnant/breast-feeding. Five urine pregnancy tests conducted within 10 weeks prior to the birth of her full term baby; all were negative (subject provided fake urine). Terminated from study upon date of discovery.
[2]
Occurred ~4 weeks after start of escitalopram; continued an additional 4 weeks. Admitted noncompliance to use of acceptable birth control method. Terminated from study. Subject reported escitalopram discontinuation and delivery of a healthy baby.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Depressed Participants Control Participants
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   24/37 (64.86%)      0/6 (0.00%)    
Ear and labyrinth disorders     
Lightheadedness  2/37 (5.41%)  0/6 (0.00%) 
Dizziness  3/37 (8.11%)  0/6 (0.00%) 
Gastrointestinal disorders     
Nausea  7/37 (18.92%)  0/6 (0.00%) 
Constipation  2/37 (5.41%)  0/6 (0.00%) 
Nervous system disorders     
Increased fatigue  11/37 (29.73%)  0/6 (0.00%) 
Akathisia  4/37 (10.81%)  0/6 (0.00%) 
Insomnia  2/37 (5.41%)  0/6 (0.00%) 
Headache  5/37 (13.51%)  0/6 (0.00%) 
Increased sweating  2/37 (5.41%)  0/6 (0.00%) 
Restlessness  4/37 (10.81%)  0/6 (0.00%) 
Decreased libido  3/37 (8.11%)  0/6 (0.00%) 
Vivid dreaming  4/37 (10.81%)  0/6 (0.00%) 
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Dr. Charles R. Conway, MD
Organization: Washington University School of Medicine
Phone: 314-362-7566
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00953745     History of Changes
Other Study ID Numbers: 201101790-2
First Submitted: August 4, 2009
First Posted: August 6, 2009
Results First Submitted: January 20, 2016
Results First Posted: April 19, 2018
Last Update Posted: April 19, 2018