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

NCT ID: NCT00953745

Last Updated: 2018-04-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 43 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-05-31
• Study Completion Date: 2012-12-31

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.

Conditions

Major Depressive Disorder

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Escitalopram

Intervention Type: DRUG

All subjects will begin on escitalopram and placebo for 8 weeks

Aripiprazole

Intervention Type: DRUG

Subjects who fail to respond to Escitalopram will continue on Escitalopram and augment with active Aripiprazole.

Placebo Capsule

Intervention Type: DRUG

All subjects will begin on escitalopram and placebo capsule for 8 weeks.

Placebo Tablet

Intervention Type: DRUG

After 8 weeks, subjects will be given a 2 week supply of escitalopram and placebo tablet.

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Escitalopram

All subjects will begin on escitalopram and placebo for 8 weeks

Intervention Type: DRUG

Aripiprazole

Subjects who fail to respond to Escitalopram will continue on Escitalopram and augment with active Aripiprazole.

Intervention Type: DRUG

Placebo Capsule

All subjects will begin on escitalopram and placebo capsule for 8 weeks.

Intervention Type: DRUG

Placebo Tablet

After 8 weeks, subjects will be given a 2 week supply of escitalopram and placebo tablet.

Intervention Type: DRUG

Other Intervention Names

Lexapro; Abilify

Eligibility Criteria

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.

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. 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

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Bristol-Myers Squibb

INDUSTRY

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Charles R Conway, MD

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Washington University in St. Louis, School of Medicine

St Louis, Missouri, United States

Countries

United States

Other Identifiers

201101790-2

Identifier Type: -

Identifier Source: org_study_id