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

Major Depressive Disorder Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00953745
• Other study ID #: 201101790-2
• Status: Completed
• Phase: N/A
• First received: August 4, 2009
• Last updated: April 17, 2018
• Start date: May 2009
• Est. completion date: December 2012

Study information

• Verified date: April 2018
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: December 2012
• Est. primary completion date: June 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Depressive Disorder, Treatment-Resistant
• Major Depressive Disorder

Intervention

Drug:
• Escitalopram
All subjects will begin on escitalopram and placebo for 8 weeks
• Aripiprazole
Subjects who fail to respond to Escitalopram will continue on Escitalopram and augment with active Aripiprazole.
• Placebo Capsule
All subjects will begin on escitalopram and placebo capsule for 8 weeks.
• Placebo Tablet
After 8 weeks, subjects will be given a 2 week supply of escitalopram and placebo tablet.

Locations

Country	Name	City	State
United States	Washington University in St. Louis, School of Medicine	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	Bristol-Myers Squibb

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	Week 10 and Week 16 (6 weeks of combined therapy)
Secondary	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.	Week 10 and Week 16 (6 weeks of combined therapy)