A Double-Blind, Placebo-Controlled Study of Aripiprazole Adjunctive to Antidepressant Therapy

Inclusion Criteria

• Patients able to give informed consent, and/or consent obtained from a legally acceptable representative (as required by IRB/IEC), prior to the initiation of any protocol required procedures.
• Patients must be able to understand the nature of the study, agree to comply with the prescribed dosage regimens, report for regularly scheduled office visits, and communicate to study personnel about adverse events and concomitant medication use.
• Patients with a diagnosis of major depressive episode as defined by DSM-IV-TR criteria, based on the SCID-I/P; their major depressive episode must be deemed "valid" using the SAFER criteria interview administered by remote, independent raters.
• Patients who have reported a history for the current depressive episode of an inadequate response to at least one and no more than three adequate antidepressant treatments. An inadequate response is defined as less than a 50% reduction in depressive symptom severity, as assessed by the MGH ATRQ administered by remote, independent raters. An adequate trial is defined as an antidepressant treatment for at least 6 weeks duration at least at a minimum dose as specified in the MGH ATRQ.
• Patients must have a HAM-D17 ≥ 18 at the end of the screening phase to qualify for inclusion. The HAM-D17 will be administered by the study clinicians at the screening and baseline visits, and by remote, independent raters during the screening phase at the time of the SAFER interview.
• Patients must be able to be reliably rated on the psychiatric scales required by the protocol.
• Men and women, ages 18 to 65 Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.

WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea ³ 12 consecutive months; or women on hormone replacement therapy [HRT] with documented serum follicle stimulating hormone [FSH] level > 35 mIU/mL). Even women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential.

WOCBP must have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.

• Meet DSM-IV criteria (by Structured Clinical Interview for DSM-IV - SCID-I/P) for MDD, current;
• Quick Inventory of Depressive Symptomatology - Self-Rated (QIDS-SR) (22) score of at least 16 at both screen and baseline visits;
• Treated with an SSRI at adequate doses (defined as 20mg/day or more of fluoxetine, citalopram; paroxetine 30mg/day or more or 37.5 mg/day or more of paroxetine CR; 10 mg/day or more of escitalopram, 50mg/day or more of sertraline, and 150 mg/day or more of venlafaxine) during the current episode for at least 8 weeks, with the same, adequate dose over the last 4 weeks;
• Between the screen and baseline visit, patients must be documented prospectively to have received a stable dose of their SSRI or venlafaxine for at least 2 weeks.

Additional criteria for defining response and non-response for patients in Phase 2 eligible for the pooling of the data with all the patients in Phase 1. Among patients pre-randomized to receive placebo in both phases or to receive placebo in Phase 1 and aripiprazole in phase 2, only those meeting non-response criteria will be added to the primary efficacy sample:

• Placebo non-resp