This was an initial unfunded pilot project stopped after similar studies were funded.

The long-term goal is to determine if decreased blood flow to the brain (cerebral hypoperfusion) is predictive of antidepressant outcomes in late-life depression (LLD). Studies in younger adult report that successful antidepressant treatment is associated with increases in cerebral blood flow, with no change in blood flow being observed in nonresponders. Thus cerebral hypoperfusion may be a biomarker of poor response to antidepressants. In LLD, this may occur secondarily to underlying vascular disease. If LLD is characterized by cerebral hypoperfusion and it does have predictive power to identify individuals who will poorly respond to conventional antidepressants, this would support the study of interventions that improve cerebral perfusion and may improve antidepressant outcomes.

As an initial step in this research, this pilot study will utilize MRI to examine if resting blood flow deficits predict and persist with antidepressant nonremission in an elderly population. The rationale for this proposal is that it will guide the design and power requirements of a larger, definitive trial examining the relationship between cerebral perfusion and depression outcomes. Importantly, support for this mechanism being linked to LLD would also support studies examining the antidepressant efficacy of drugs that may improve cerebral perfusion.

The primary purpose of this pilot study is a) to demonstrate feasibility by recruiting, scanning, and treating depressed elders; and b) to acquire preliminary data for competitive grant submissions.

SPECIFIC AIM: To use MRI to test for differences in cerebral perfusion between individuals who do and do not remit to a 8-week course of sertraline.

After providing informed consent, participants will complete brain MRI and memory testing. If they are currently taking an antidepressant and are not doing well on it, they will be taken off it. Participants will then start sertraline, a commercially available antidepressants. They will be monitored for response and side effects for 8 weeks and doses adjusted as needed. After the study, we will examine how differences in brain blood flow may predict who does and does not respond to sertraline.

Inclusion Criteria:

• Age 60 years or older.
• Current diagnosis of major depressive disorder (DSM-IV-TR), recurrent or chronic, without psychotic features
• Minimum depression severity of Montgomery Asberg Depression Rating Scale (MADRS) score ≥ 15
• Cognitively intact by Montreal Cognitive Assessment (MoCA) score ≥ 23
• Ability to read and write English

Exclusion Criteria:

• Other current or past psychiatric diagnoses
• Any use of illicit substances or abuse of prescription medications
• Presence of acute suicidality
• Current or past psychotic symptoms
• Known primary neurological disorder, including dementia
• Chronic untreated medical disorders where treatment is warranted
• Any contraindication to MRI, such as metal in the body
• Electroconvulsive therapy in the last 6 months
• Use of antidepressants or other psychiatric medications in the last month.
• Known allergy to sertraline
• A failed therapeutic trial of sertraline in the current depressive episode
• Current or planned psychotherapy