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

Primary Purpose

Major Depressive Disorder

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Escitalopram
Aripiprazole
Placebo Capsule
Placebo Tablet
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Major Depressive Disorder focused on measuring Depression, Neuroimaging, Aripiprazole, Mood disorder, PET Scan, fMRI

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

Treatment Group

Inclusion Criteria:

  1. Subjects with known history of MDD verified using the Mini International Neuropsychiatric Interview and a Hamilton Depression Rating Scale 17-item score of at least 18
  2. Subjects must have failed to respond to one previous adequate dose-duration trial of antidepressant therapy
  3. Must complete the MRI screening tool and demonstrate ability to receive an MRI
  4. For entry into the ARP augmentation phase the subject must be a non-responder to the escitalopram phase as demonstrated by a MADRS score at week 10, that is not reduced by greater than 50% from baseline.

Exclusion Criteria:

  1. Subjects cannot be smokers
  2. No significant history of anxiety disorder
  3. Cannot be pregnant or lactating and sexually active women of childbearing potential must use a medically accepted means of contraception
  4. The following DSM-IV diagnoses are excluded: Organic mental disorder; substance abuse/dependence, including alcohol, active within the last year; schizophrenia, paranoid or delusional disorders; other psychotic disorders; panic disorder; generalized anxiety disorder; obsessive-compulsive disorder, or post-traumatic stress disorder; bipolar disorder; bulimia nervosa; anorexia nervosa
  5. Subjects with serious suicidal risks
  6. Subjects who have taken any antidepressant medication other than escitalopram within 5 half lives, of the most recent antidepressant taken
  7. Subjects involved in any other form of treatment for depression
  8. Subjects who have demonstrated any previous inadequate antidepressant response to electroconvulsive therapy (ECT)
  9. Subjects who have received ECT for the current depression episode
  10. Subjects who have been hospitalized within 4 weeks of the study
  11. Subjects who have received treatment with a monoaminoxidase inhibitor within 2 weeks of enrollment
  12. Subjects with a known allergy, hypersensitivity, or previous unresponsiveness to aripiprazole or known intolerance to any study medications
  13. Subjects with a history of participation in any investigational medication trial in the past month
  14. A positive drug screen or substance use disorder in the past 12 months
  15. History of any thyroid pathology
  16. History of serotonin syndrome or neuroleptic malignant syndrome
  17. History of seizure disorder
  18. Subjects who have participated in a trial using PET scans in the past 12 months and in any trial in the past 30 days.

Control Group

Inclusion Criteria:

  1. Ages 18-55 matched to a study subject
  2. Must be a healthy subject with no significant medical history
  3. Must complete the MRI screening tool and demonstrate ability to receive an MRI

Exclusion Criteria:

  1. Cannot be a smoker
  2. Cannot be pregnant or lactating and sexually active women of childbearing potential must use a medically accepted means of contraception
  3. Any DSM-IV or II diagnosis as assessed by the MINI
  4. Subjects with a positive drug screen or substance use disorder in the past 12 months

Sites / Locations

  • Washington University in St. Louis, School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

No Intervention

Arm Label

Depressed Participants

Control Participants

Arm Description

Subjects with treatment-resistant depression (TRD) will be administered the Hamilton Depression Rating Scale (HAM-D 17) for entry and 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 as quality control to compare the pre-ARP and post-ARP treatment brain images.

Outcomes

Primary Outcome Measures

Fluorodopa Uptake Values in Brain Images of Aripiprazole Augmentation Responders
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).

Secondary Outcome Measures

Depression Symptom Change on The Montgomery-Åsberg Depression Rating (MADRS) Scale Between ARP Responders and Non-responders.
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.

Full Information

First Posted
August 4, 2009
Last Updated
April 17, 2018
Sponsor
Washington University School of Medicine
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT00953745
Brief Title
Dopaminergic Effects of Adjunctive Aripiprazole on the Brain in Treatment-Resistant Depression
Official Title
Dopaminergic Effects of Adjunctive Aripiprazole on the Brain in Treatment-Resistant Depression: A Raclopride/F-DOPA Positron Emission Tomography and Functional MRI Study
Study Type
Interventional

2. Study Status

Record Verification Date
April 2018
Overall Recruitment Status
Completed
Study Start Date
May 2009 (undefined)
Primary Completion Date
June 2012 (Actual)
Study Completion Date
December 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Aripiprazole has been approved by the FDA for augmenting ineffective/partially effective oral antidepressant therapy in patients suffering from major depression. The mechanism by which this augmentation is achieved is not known. This study has been designed to test the hypothesis that the primary mechanism of action of aripiprazole (ARP) antidepressant augmentation is through the dopaminergic pathway. Two positron emission tomography (PET) scan procedures and a functional magnetic resonance imaging (fMRI) scan will be used to test this hypothesis.
Detailed Description
This study is designed to help understand the mechanism of action of ARP in major depressive disorder (MDD) augmentation. Subjects will undergo exposure to an existing antidepressant (Lexapro 10-20mg) for 10 weeks; subjects failing to completely respond to the monotherapy antidepressant treatment will receive augmentation with ARP for six weeks. Two placebo phases are included in which the subjects will receive one placebo along with the Lexapro for the first 6 weeks and a second placebo along with Lexapro for the next two weeks. A baseline brain imaging series (MRI and 2 PET/CT scans) will be obtained at week 10, prior to starting the aripiprazole, on subjects not responding to Lexapro. A second series of images will be obtained at the end of the six weeks of ARP augmentation. The neuroimaging will consist of fMRI, a raclopride PET scan, and a fluoro-dopa PET scan. Ten normal control subjects will not receive any treatment. They will be age and gender matched to study subjects and undergo one set of scans (fMRI,raclopride and FOPA PET scans) to use as comparison group for quality control on a non-depressed population and not for data analysis.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder
Keywords
Depression, Neuroimaging, Aripiprazole, Mood disorder, PET Scan, fMRI

7. Study Design

Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
This study is designed to help understand the mechanism of action of aripiprazole in MDD augmentation. Subjects will undergo exposure to en an existing antidepressant (Lexapro 10-20mg) for 10 weeks; subjects failing to completely respond to the monotherapy antidepressant treatment will receive augmentation with aripiprazole for six weeks. We have included two placebo phases to the study in which the subjects received one placebo along with the Lexapro for the first 6 weeks and a second placebo along with Lexapro for the next two weeks (weeks 7 and 8). This double placebo design is to ensure that subjects receiving aripiprazole augmentation have a legitimate response (non-placebo) to the aripiprazole augmentation. Since the N of this study is small and a small % of patients with placebo response could skew the imaging data significantly, the use of a double placebo prior to the start of the true aripiprazole augmentation should reduce or eliminate a placebo response.
Masking
Participant
Allocation
Non-Randomized
Enrollment
43 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Depressed Participants
Arm Type
Active Comparator
Arm Description
Subjects with treatment-resistant depression (TRD) will be administered the Hamilton Depression Rating Scale (HAM-D 17) for entry and 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.
Arm Title
Control Participants
Arm Type
No Intervention
Arm Description
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 as quality control to compare the pre-ARP and post-ARP treatment brain images.
Intervention Type
Drug
Intervention Name(s)
Escitalopram
Other Intervention Name(s)
Lexapro
Intervention Description
All subjects will begin on escitalopram and placebo for 8 weeks
Intervention Type
Drug
Intervention Name(s)
Aripiprazole
Other Intervention Name(s)
Abilify
Intervention Description
Subjects who fail to respond to Escitalopram will continue on Escitalopram and augment with active Aripiprazole.
Intervention Type
Drug
Intervention Name(s)
Placebo Capsule
Intervention Description
All subjects will begin on escitalopram and placebo capsule for 8 weeks.
Intervention Type
Drug
Intervention Name(s)
Placebo Tablet
Intervention Description
After 8 weeks, subjects will be given a 2 week supply of escitalopram and placebo tablet.
Primary Outcome Measure Information:
Title
Fluorodopa Uptake Values in Brain Images of Aripiprazole Augmentation Responders
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)
Secondary Outcome Measure Information:
Title
Depression Symptom Change on The Montgomery-Åsberg Depression Rating (MADRS) Scale Between ARP Responders and Non-responders.
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Treatment Group Inclusion Criteria: Subjects with known history of MDD verified using the Mini International Neuropsychiatric Interview and a Hamilton Depression Rating Scale 17-item score of at least 18 Subjects must have failed to respond to one previous adequate dose-duration trial of antidepressant therapy Must complete the MRI screening tool and demonstrate ability to receive an MRI For entry into the ARP augmentation phase the subject must be a non-responder to the escitalopram phase as demonstrated by a MADRS score at week 10, that is not reduced by greater than 50% from baseline. Exclusion Criteria: Subjects cannot be smokers No significant history of anxiety disorder Cannot be pregnant or lactating and sexually active women of childbearing potential must use a medically accepted means of contraception The following DSM-IV diagnoses are excluded: Organic mental disorder; substance abuse/dependence, including alcohol, active within the last year; schizophrenia, paranoid or delusional disorders; other psychotic disorders; panic disorder; generalized anxiety disorder; obsessive-compulsive disorder, or post-traumatic stress disorder; bipolar disorder; bulimia nervosa; anorexia nervosa Subjects with serious suicidal risks Subjects who have taken any antidepressant medication other than escitalopram within 5 half lives, of the most recent antidepressant taken Subjects involved in any other form of treatment for depression Subjects who have demonstrated any previous inadequate antidepressant response to electroconvulsive therapy (ECT) Subjects who have received ECT for the current depression episode Subjects who have been hospitalized within 4 weeks of the study Subjects who have received treatment with a monoaminoxidase inhibitor within 2 weeks of enrollment Subjects with a known allergy, hypersensitivity, or previous unresponsiveness to aripiprazole or known intolerance to any study medications Subjects with a history of participation in any investigational medication trial in the past month A positive drug screen or substance use disorder in the past 12 months History of any thyroid pathology History of serotonin syndrome or neuroleptic malignant syndrome History of seizure disorder Subjects who have participated in a trial using PET scans in the past 12 months and in any trial in the past 30 days. Control Group Inclusion Criteria: Ages 18-55 matched to a study subject Must be a healthy subject with no significant medical history Must complete the MRI screening tool and demonstrate ability to receive an MRI Exclusion Criteria: Cannot be a smoker Cannot be pregnant or lactating and sexually active women of childbearing potential must use a medically accepted means of contraception Any DSM-IV or II diagnosis as assessed by the MINI Subjects with a positive drug screen or substance use disorder in the past 12 months
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Charles R Conway, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University in St. Louis, School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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