The STAR*D project will enroll 4,000 outpatients (ages 18 -75) diagnosed with nonpsychotic Major Depressive Disorder. Participants will be initially treated (open label) with citalopram, the Level 1 treatment, for a minimum of 8 weeks. Patients who experience minimal benefit will be strongly encouraged to complete 12 weeks of treatment in order to maximize the chances of symptom remission (unless no benefit at all is seen after 8 weeks). All participants will also receive a brief depression educational program.

At each level change, participants will be asked to indicate the unacceptability of the potential treatment strategies (e.g, to augment or to switch medications). Participants will then be eligible for random assignment to one of the acceptable and medically safe treatment options.

Level 2: Participants who either did not have an adequate response to or could not tolerate citalopram are eligible for Level 2. The Level 2 treatment strategies are:

i) Medication and Psychotherapy Switch: switch to sertraline, venlafaxineXR, bupropionSR, or cognitive therapy (CT).

ii) Medication and Psychotherapy Augmentation: add to citalopram either a) buspirone, b) bupropionSR, or c) CT.

iii) Medication Only Switch or Medication Only Augmentation options are available for participants for whom CT is unacceptable.

iv)Psychotherapy Only Switch or Psychotherapy Only Augmentation options are available for participants for whom additional medication is unacceptable at this point in the study (participants must be willing to continue citalopram)

Level 2A: Participants without a satisfactory response to their Level 2 treatment are eligible for random assignment to additional treatment at Level 2A (if medically safe and acceptable). Level 2A is included so that all participants entering Level 3 have had an opportunity to respond to at least 2 medications. Level 2A consists of Medication Switch to one of two antidepressant medications (venlafaxineXR or bupropion SR).

Level 3: Participants without satisfactory response to Level 2 and,if appropriate Level 2A, are eligible for random assignment to one of the following treatments (if acceptable and medically safe):

i) Medication Switch to: a) mirtazapine or b) nortriptyline, a tricyclic antidepressant.

ii) Medication Augmentation: Add (to current Level 2 or Level 2A medication) either: a) lithium or b) thyroid hormone (T3).

Level 4: Participants without an adequate response to Level 3 are eligible for random assignment to Level 4 treatment (if acceptable and medically safe). Level 4 includes two Medication Switch options: to tranylcypromine [a monoamine oxidase inhibitor (MAOI)], or to mirtazapine plus venlafaxineXR.

After Level 4, participants without an adequate response will discuss other acceptable treatment options with their physician.

Once an adequate response is achieved at Levels 2, 2A, 3 or 4, participants are eligible to enter the 12-month follow-up, during which time they will remain on their current treatment(s) and will be asked about their symptoms and other relevant information monthly by telephone. ONLY PATIENTS BEING TREATED AT THE PARTICIPATING CLINICS ARE ELIGIBLE FOR THIS STUDY.