Major late life depression (LLD) is an important health problem with a large and growing number of affected individuals. A significant subset of patients with LLD, particularly those with vascular depression, have abnormalities in certain parts of the brain that are evident on MRI scans and may be associated with poor acute and long-term response to antidepressant treatment. Studies have also indicated that LLD patients frequently have frontal lobe dysfunction. A longitudinal study with the antidepressant nortriptyline has demonstrated that frontal lobe dysfunction is associated with poor acute response and a greater risk for recurrence of LLD. However, it is not known if this finding applies to other antidepressants. This study will be the first clinical trial to simultaneously test the effects of specific brain and psychological factors on course of response, remission rate, and other measures of health outcomes in people with LLD.

Participants are treated with sertraline for 12 weeks. During this period, participants undergo cognitive testing, MRI, electrocardiogram (EKG), and laboratory tests. Study visits occur every 2 weeks.

Adults 60+ with major depression.

Inclusion Criteria:

1. Ages 60+
2. DSM-IV criteria for MDD
3. Hamilton Depression Rating Scale score >18
4. No MRI contraindications, e.g. foreign metallic implants, pacemaker
5. Medication free of any psychotropic drug except as otherwise noted for set washout period (see D.2.1)
6. Mini Mental Status Exam score <21
7. No unstable medical disorders (requiring immediate medical attention)
8. Ability to give informed consent
9. English speaking

Exclusion Criteria:

1. Age <60
2. Does not meet DSM-IV criteria for MDD
3. Hamilton Depression Rating Scale score <18
4. MRI contraindications e.g. foreign metallic implants, pacemaker
5. Psychotropic drug use other than zolpidem and lorazepam, prn within 2 weeks of entry
6. Mini Mental Status Exam score >21, or known primary neurological disorders including Dementia of the Alzheimer type, Parkinson's Disease, multiple sclerosis, seizure disorder.
7. Unstable medical disorders, uncorrected hypothyroidism, or any condition that in the investigators opinion makes the patients unsuitable for a trial
8. Cannot give informed consent
9. Does not speak English