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

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.

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