Major depressive disorder (MDD) is a serious illness that affects a person's body, mood, and thoughts. The symptoms of MDD can interfere with a person's ability to work, study, sleep, eat, and enjoy activities that were once pleasurable. Antidepressant medications and psychotherapy are among the effective treatments for MDD. Individuals often respond to one type of treatment, but not another. Currently, however, doctors have no way of pre-determining which individuals will most benefit from which treatments. In the absence of practical predictors of MDD treatment response, the potential efficacy of existing MDD treatments is limited. This study will identify factors that may predict MDD treatment response by comparing the effectiveness of a selective serotonin reuptake inhibitor (SSRI), a serotonin norepinephrine reuptake inhibitor (SNRI), and cognitive behavioral therapy in people with MDD.

Participants in this 14-week, double-blind study will be randomly assigned to receive duloxetine (SNRI), escitalopram (SSRI), or cognitive behavioral therapy. Duloxetine and escitalopram are two medications that are approved by the Food and Drug Administration for the treatment of depression. Cognitive behavioral therapy is a talking therapy that is also used to treat depression. All participants assigned to take duloxetine or escitalopram will receive treatment weekly for 8 weeks, and then every other week for the remainder of the study. Participants assigned to cognitive behavioral therapy will attend therapy sessions twice a week for the first 4 weeks, and then once a week for the remainder of the study. The following assessments will be performed for all participants at each visit: vital sign and weight measurements; clinician assessments; and self-report questionnaires. Additionally, blood samples will be taken at three visits and an electrocardiogram will be performed at screening. A functional magnetic resonance imaging (fMRI) scan will be performed at selected times. Upon study completion, all participants will have the option to participate in a 1-year follow-up study or obtain a referral for treatment with another physician.

Inclusion Criteria:

• Current DSM-IV diagnosis of major depressive episode, as determined by Structured Clinical Interview for DSM-IV (SCID-IV)
• Primary diagnosis of MDD, based on prominence of symptoms and target for intervention (comorbid anxiety disorders, except obsessive-compulsive disorder [OCD], will not be criteria for exclusion)
• Score of at least 18 on the 17-item Hamilton Rating Scale for Depression (HAM-D17)
• Agrees to use an effective form of contraception and/or double barrier method

Exclusion Criteria:

• Previously treated for major depression with either medication or psychotherapy
• Current psychosis, dementia, eating disorder, or dissociative disorder
• History of bipolar disorder (I and II) or schizophrenia
• Alcohol or drug dependence within 3 months prior to study entry or current alcohol or drug abuse (excluding nicotine and caffeine), as assessed by medical history and urine drug screening
• Requires neuroleptic or mood stabilizer therapy in addition to depression treatment
• Presence of any acute or chronic medical disorder that could affect successful completion of the trial
• Medical contraindications that would preclude treatment with escitalopram or duloxetine
• Presence of practical issues that would likely prevent completion of the study (e.g., planned geographical relocation)
• Pregnant or breastfeeding
• Medical conditions that could prevent the safe use of MRI (e.g., pacemaker, aneurysm clips, neurostimulators, cochlear implants, metal in eyes, or other implants; steel worker)
• Medical conditions that could prevent the safe completion of a dexamethasone-corticotropin releasing factor (Dex-CRF) test (e.g., current asthma, uncontrolled hypertension, abnormalities in EKG, anemia, known allergies against drugs or sheep)