Effects of Cerebral Hypoperfusion and Its Reversal on Late-Life Depression

This study will examine how magnetic resonance imaging (MRI) measures of cerebral perfusion relate to antidepressant response. There are two phases to the study. In the first phase, we will examine how cerebral perfusion is related to response to sertraline, a commonly used antidepressant. In the second phase, we will examine individuals who do not respond to sertraline or other selective serotonin reuptake inhibitors (SSRI). We will examine if candesartan, an ARB, improves depression and if it does so by improving cerebral perfusion. After providing informed consent, participants will undergo medical and psychiatric screening. Participants determined to be eligible at the screen will proceed to a baseline evaluation, which will include brief cognitive neuropsychological testing and MRI. Participants will then begin open-label sertraline for eight weeks (baseline to week 8). Dosing will begin at 50mg daily and, based on response and tolerability, can increase up to the FDA approved maximum dose of 200mg daily. After the eight weeks, participants will be re-evaluated and complete another MRI. Those who respond to sertraline and experience remission of their depression will end their study participation. Those who do not experience remission will continue to the phase 2 open-label candesartan arm. The candesartan arm will last for 12 weeks (week 8 to week 20). Dosing will begin at 4mg daily and can increase to a maximum dose of 32mg, based on tolerability and response. Participants will be monitored closely, and other antihypertensive medications adjusted to avoid low blood pressure. At the end of the 12-week trial, participants will again complete MRI and neuropsychological testing. Their study participation will then end.