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.

Inclusion Criteria:

1. Age 60 years or older

2. Diagnosis of Major Depressive Disorder, single or recurrent episode, without
psychotic features by Diagnostic and Statistical Manual IV Text Revision (DSMIV-TR)
criteria

3. Presence of hypertension (defined as systolic > 140 or diastolic > 90 or currently
receiving antihypertensive therapy)

4. Minimum depression severity of ≥ 15 on the Montgomery-Asberg Depression Rating Scale
(MADRS)

5. Cognitively intact or with mild cognitive deficits, with a minimum score ≥ 23 on the
Montreal Cognitive Assessment (MoCA).

Exclusion Criteria:

1. Other psychiatric Axis I disorders

2. Acute suicidality

3. Electroconvulsive therapy in the last 6 months

4. Primary neurological disorder, including dementia and stroke

5. Significant cardiovascular disease, specifically diagnosis of congestive heart
failure, known bilateral renal artery stenosis, symptomatic hypotension, or critical
aortic or mitral stenosis

6. Myocardial infarction or open-heart surgery in last 6 weeks

7. Serum creatinine ≥ 265 micromol /L

8. Serum potassium ≥ 5.5 mmol/L

9. MRI contraindications

10. Known allergy to sertraline or candesartan specifically or known allergy to other
SSRIs or ARBs.

11. History of prolonged (> 3 weeks) or self-described severe discontinuation syndrome in
the past after stopping an antidepressant.

12. Current use of an angiotensin receptor blocker

13. Current or planned psychotherapy

14. Need for continuous oxygen use or any medical disorder where the hypercapnia
challenge would be contraindicated or put the subject at increased risk. This would
include acute respiratory disease, chronic angina, or other unstable cardiac
conditions.