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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

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.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Drug: Escitalopram Drug: Aripiprazole Drug: Placebo Capsule Drug: Placebo Tablet Not Applicable

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 43 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention 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: Single (Participant)
Primary Purpose: Other
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 Start Date : May 2009
Actual Primary Completion Date : June 2012
Actual Study Completion Date : December 2012

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Active Comparator: Depressed Participants

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.

Drug: Escitalopram
All subjects will begin on escitalopram and placebo for 8 weeks
Other Name: Lexapro
Drug: Aripiprazole
Subjects who fail to respond to Escitalopram will continue on Escitalopram and augment with active Aripiprazole.
Other Name: Abilify
Drug: Placebo Capsule
All subjects will begin on escitalopram and placebo capsule for 8 weeks.
Drug: Placebo Tablet
After 8 weeks, subjects will be given a 2 week supply of escitalopram and placebo tablet.
No Intervention: Control Participants
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.



Primary Outcome Measures :
  1. Fluorodopa Uptake Values in Brain Images of Aripiprazole Augmentation Responders [ Time Frame: Week 10 and Week 16 (6 weeks of combined therapy) ]
    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 :
  1. Depression Symptom Change on The Montgomery-Åsberg Depression Rating (MADRS) Scale Between ARP Responders and Non-responders. [ Time Frame: Week 10 and Week 16 (6 weeks of combined therapy) ]
    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.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00953745


Locations
United States, Missouri
Washington University in St. Louis, School of Medicine
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Bristol-Myers Squibb
Investigators
Principal Investigator: Charles R Conway, MD Washington University School of Medicine

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00953745     History of Changes
Other Study ID Numbers: 201101790-2
First Posted: August 6, 2009    Key Record Dates
Results First Posted: April 19, 2018
Last Update Posted: April 19, 2018
Last Verified: April 2018

Keywords provided by Washington University School of Medicine:
Depression
Neuroimaging
Aripiprazole
Mood disorder
PET Scan
fMRI

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Major
Depressive Disorder, Treatment-Resistant
Behavioral Symptoms
Mood Disorders
Mental Disorders
Aripiprazole
Raclopride
Citalopram
Dexetimide
Dopamine
Dopamine Agents
Dopamine Agonists
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Antidepressive Agents, Second-Generation
Antidepressive Agents
Antiparkinson Agents
Anti-Dyskinesia Agents
Parasympatholytics