Frontal Hypoperfusion Effects on Antidepressant Outcomes in Late-Life Depression

The long-term goal of this line of research is to determine if in late-life depression
(LLD), cerebrovascular dysregulation is predictive of antidepressant outcomes. The
investigators hypothesize that vascular pathology resulting in reduced cerebrovascular
reactivity contributes to frontocingulate hypoperfusion. Such pathology would impair
neurovascular coupling and reduce the ability of the vasculature to improve frontocingulate
perfusion during antidepressant treatment. Thus decreased cerebrovascular reactivity and
perfusion may be a biomarker of antidepressant nonresponse. As an initial step in this
research, the current study will utilize MRI arterial spin labeling (ASL) to examine if
cerebrovascular reactivity deficits and resting cerebral blood flow (CBF) deficits predict
antidepressant nonremission in LLD. The rationale for this proposal is that it will identify
mechanisms by which vascular pathology may contribute to LLD. If the study hypotheses are
correct, this crucial next step will support studies examining antidepressant properties of
cardiovascular drugs that may reverse vascular pathology and improve perfusion.

The investigators will pursue our initial goal by examining ASL predictors of nonremission
to a 12-week trial of sertraline. Forty LLD subjects will complete MRI, cognitive testing,
and hyperintensity assessment. ASL measured CBF will be obtained during a hypercapnia
challenge and at rest with room air. This will help determine if deficits in cerebrovascular
reactivity (CVR) and/or resting and on-demand CBF measures predict nonremission.

AIM: To test for differences in CVR and CBF in dorsal frontal cognitive control regions
between individuals who do and do not remit to a 12-week course of sertraline (defined as
MADRS ≤ 7).

Hypothesis 1: Compared with remitters, during a hypercapnia challenge nonremitters will
exhibit less CVR in the dlPFC and dAC.

Hypothesis 2: Compared with remitters, while breathing room air nonremitters will exhibit
lower resting CBF in the dorsal anterior cingulate (dAC) and dorsolateral prefrontal cortex
(dlPFC).

Exploratory Aim: To examine the relationship between ASL measures (CVR to hypercapnia and
resting CBF during normoxia) and performance in cognitive domains implicated in LLD
treatment outcomes. For this Aim, we will focus on functions involving the dlPFC and dAC,
specifically executive function and processing speed.

The study will enroll patients from clinical referrals and response to advertisements. In
these cases, potential participants will call our study contact number. Study staff will
describe the study to them, including a description of the study entry criteria. Those who
continue to be interested will then be scheduled for an evaluation. After scheduling, a
study physician will review their electronic medical record to assure that potential
subjects meet entry criteria.

Following policies of the Vanderbilt University Health System Institutional Review Board,
written informed consent will be obtained and documented by the study's Research Coordinator
before any study-related procedures are performed. The study coordinator will review study
procedures and the consent form with each potential participant. Each individual may take as
much time as they like to decide if they do or do not wish to participate. There is no
randomization. All participants receive open-label sertraline.

An initial evaluation will determine eligibility, depression severity, and evaluate medical
and psychiatric history. Participants will also complete a detailed battery assessing
cognitive function. During this time they will also complete the one-hour MRI session, which
includes measurement of cerebral perfusion and vascular reactivity.

They will then begin the 12-week trial of open-label sertraline, allowing titration up to
the maximum dose of 200mg daily. At the end of the study participants will be referred for
ongoing clinical treatment.

Inclusion Criteria:

1. Age 60 years or older.

2. Current diagnosis of major depressive disorder (DSM-IV-TR), single episode, recurrent
or chronic, without psychotic features, as detected by MINI and clinical exam.

3. Minimum MADRS score ≥ 15.

4. Mini-Mental State Exam ≥ 22.

5. Ability to read and write English.

Exclusion Criteria:

1. Current or past diagnoses of other Axis I psychiatric disorders, including panic
disorder and substance dependence.

2. Any use of illicit substances (such as marijuana or cocaine) or abuse of prescription
medications (such as benzodiazepines or opiates) within the last three months.

3. Presence of acute suicidality

4. Current or past psychosis

5. Known primary neurological disorder, including dementia, brain tumors, epilepsy,
Parkinson's disease, or demyelinating diseases

6. Chronic untreated medical disorders (including but not limited to hypertension,
hyperlipidemia, fibromyalgia, hypothyroidism, or any other disorder) where treatment
is warranted

7. 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 active respiratory disease, chronic angina or other unstable cardiac
conditions.

8. Any physical or intellectual disability affecting completion of assessments

9. MRI contraindications

10. Electroconvulsive therapy in last 6 months

11. Use of fluoxetine in the last 6 weeks. Occasional use of benzodiazepines or
non-benzodiazepine sedatives (such as zolpidem, eszopiclone, or zaleplon) during the
last month is allowable.

12. Known allergy or hypersensitivity to sertraline

13. A failed therapeutic trial of sertraline in the current depressive episode (defined
as at least 6 weeks of treatment at a daily dose of 100mg or higher)

14. Current or planned psychotherapy