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.

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