While there are many effective options for treating a major depressive episode, there are no clinical markers that predict the likelihood of remission with an initial trial of either an antidepressant medication or psychotherapy. More critically, there are also no reliable predictors that might anticipate failure to such standard treatments either alone or in combination. This project will characterize imaging-based brain subtypes that distinguish groups of depressed patients who later remit or not to SSRI pharmacotherapy or cognitive behavior therapy (CBT), respectively. To define these subtypes, a prospectively-treated cohort of 100 patients will be randomized to receive either escitalopram (s-CIT) or CBT for the first 12 weeks, with non-remitters to either first treatment crossed over to receive an additional 12 weeks of treatment with combined treatment. Non-remitters to both treatments will thus define a relatively treatment resistant third subgroup. Resting-state 18F-fluoro-deoxyglucose (FDG) positron emission tomography (PET) scans will be acquired prior to initiating antidepressant therapy, with pre-treatment scan patterns associated with three possible outcomes (CBT remission, s-CIT remission, and non-remission to both) assessed using multivariate analytic methods. A second PET scan, acquired early in the treatment course, will be used to assess the likelihood of response to the specific treatment first assigned. The proposed studies are a first step towards defining brain-based biomarkers predictive of differential treatment outcome in major depression; most critically, patterns distinguishing patients at risk for treatment resistance. Identification of such biomarkers has additional implications for future testing of novel therapies in patients with distinct brain signatures, including development of evidence-based treatment algorithms for individual patients.

SPECIFIC AIMS Aim 1. To define baseline regional glucose metabolic patterns (measured using FDG PET) associated with differential clinical remission to each of two well-established, randomly delivered first-line antidepressant treatments-the SSRI escitalopram (s-CIT) or cognitive behavioral therapy (CBT) with cross-over treatment for non-remitters (sequential course of treatment model).

Aim 2. To define metabolic change patterns, occurring early in the course of both s-CIT and CBT, associated with successful and unsuccessful clinical remission to each intervention.

Inclusion Criteria:

• Male or female patients between the ages of 18 and 60. (no subjects with first episode over age 50. This is an attempt to exclude patients with 'vascular depression' who have a potentially different pathophysiology and treatment response compared to idiopathic MDD.
• DSM-IV criteria for unipolar Major Depressive Disorder.
• HAM-D (24 item) score >/= 18 at Screening, >/= 15 at Baseline.
• Co-morbid conditions (other than those listed under exclusion criteria below) will be accepted as long as MDD is the primary diagnosis (based on predominance and sequential development of symptoms).
• Acceptable method of birth control (oral contraceptives, Depo-Provera, Norplant, condoms with spermicide. A vasectomy is acceptable in the framework of a stable monogamous relationship. Sexually inactive women must agree to contraception if they become sexually active during the study.
• Educational level, degree of understanding and reliability so that participation is feasible.
• Informed consent to participate and comply in the study.

Exclusion Criteria:

• Known neurological disorders or documented head injury.

• Serious and unstable medical illnesses including diabetes, cardiovascular disease and cancer.

• Medical conditions with known mood changes (endocrine, autoimmune disorders)

• Co-morbid DSM-IV Axis I Diagnoses

  1. Lifetime history of Bipolar Disorder, Schizophrenia, and other Psychotic Disorders, or Obsessive Compulsive Disorder
  2. Alcohol abuse or dependence within the past six months, psychoactive substance abuse or dependence within the past six months.
  3. Clinical evidence of a severe Personality Disorder that would impede participation or completion of a controlled trial.

• ECT within the past 6 months.

• Previous failure to achieve a much improved status on CGI-Improvement (the equivalent of >50% symptom reduction) with a course of CBT (defined as a minimum of 8 sessions during 8 weeks of a specified manual-driven therapy by a CBT trained therapist) or escitalopram (defined as a minimum of 6 weeks with the dose of 10 mgs achieved for at least 2 weeks)

• Use of concomitant medications with the exception of:

  1. Maintenance/prophylactic meds for stable medical conditions
  2. Ambien 5-10 mgs may be prescribed for occasional use (up to a single dose a week for insomnia, as long as it is not the night before a clinic visit, PET/fMRI study or ratings.
  3. Antidepressants will be discontinued for 7 days prior to the screening visit, which will be a minimum of a week before the baseline scan (5 weeks for fluoxetine, protryptyline).

• Current treatment with weekly individual or group psychotherapy targeted at the depressive symptoms, including psychodynamic, interpersonal or cognitive-behavioral.

• Currently responding to medication treatment, without clinical reasons to change (e.g. side effects). Will not enroll a subject who wishes to discontinue an effective treatment for the sake of participation in the research.

• Woman who are pregnant, breast feeding or intending to become pregnant during the course of the study.

• Contraindications for MRI: pacemaker, aneurysm clips, neurostimulators, cochlear implants, metal in eyes, steel worker, or other implants.