Connectivity Affecting the Antidepressant REsponse Study

Individuals with late-life depression (LLD) experience high levels of disability, mortality,
and poor responses to antidepressants. The MRI hallmark of 'vascular depression' in this
population is significant ischemic white matter lesion (WML) severity, a finding associated
with poor antidepressant outcomes. Despite observations of diffuse white matter disease in
LLD, we propose in our "disconnection hypothesis" that focal damage to fiber tracts
negatively affects the function of connected regions, resultantly contributing to cognitive
deficits and clinical symptoms such as depression severity and negativity bias. Focal WMLs
may also reduce the likelihood of an antidepressant response when the specific antidepressant
used acts on neurotransmitter systems projecting through the damaged fiber tract. This
implies that the effect of tract damage on clinical response may differ between drugs with
different mechanism of action.

We propose that the cingulum bundle (CB) and uncinate fasciculus (UF) are key tracts in LLD
as they are components of cognitive, affective and default mode networks and contain
monoamine neurotransmitter projections. Supporting our model, past work implicates CB and UF
deficits in LLD and our new pilot data associates tract damage with poor antidepressant
response.

In a cohort of up to 130 depressed elders we will test our central hypotheses: a) focal CB
and UF WMLs disrupt connectivity and function of connected regions and contribute to
cognitive deficits and affective symptoms; and b) antidepressants acting on neurotransmitter
systems projecting through these tracts will be less effective.

Overall Study Design: After obtaining informed consent, we will assess for eligibility.
Individuals who meet eligibility criteria will complete neuropsychological testing and a
one-hour magnetic resonance imaging (MRI). Subjects will then be randomized in a 2:1 ratio to
receive either blinded escitalopram or identical placebo. After 8 weeks of study drug, they
will be assessed for remission. Those whose depression has remitted will end their study
participation. Those who remain symptomatic will be transitioned to open-label bupropion for
8 weeks, after which their participation will end. We will work with participants on plans
for clinical care after the study and will offer two additional visits to facilitate that
transition.

Specific Aim 1: To characterize the effect of cingulum bundle (CB) and uncinate fasciculus
(UF) WMLs on tract connectivity, function of connected regions, and the cognitive and
affective presentation of LLD.

Hypothesis 1: Greater CB WML volume is associated with a) reduced resting-state connectivity
of frontal, temporal, and cingulate regions and b) deficits in attention, memory and
processing speed.

Hypothesis 2: Greater UF WML volume is associated with a) reduced resting state functional
connectivity between frontocingulate and medial temporal regions, and b) greater depression
severity and negativity bias.

Exploratory Hypothesis: Greater CB WML volume is associated with failure of anterior and
posterior default mode network nodes to deactivate during attentional components of the fMRI
task. Greater UF WML volume is associated with greater medial temporal reactivity during the
functional MRI task.

Specific Aim 2: To determine whether deficits in tract structural / functional connectivity
predict nonremission to antidepressant treatments and if these relationships vary based on
antidepressant mechanism of action.

Hypothesis 3: Nonremission to escitalopram will be predicted by: a) greater WML volume in the
CB and UF, and b) reduced resting functional connectivity between structures connected by the
CB and UF. Greater WML severity and reduced functional connectivity in these tracts will not
significantly predict response to placebo.

Hypothesis 4: Nonremission to bupropion will be predicted by a) greater WML volume in the UF
but not CB, and b) reduced resting functional connectivity deficits between structures
connected by the UF but not CB.

Exploratory Aims: Expl. Aim 1) To determine if specific cognitive measures may serve as
markers of focal tract WML damage. Expl. Aim 2) To use whole-brain multimodal imaging
approaches to examine how connectivity differences in other brain regions may also predict
nonremission to antidepressants.

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 ≥ 24.

5. Fluent in English.

Exclusion Criteria:

1. Current or past diagnoses of other Axis I psychiatric disorders, except for
generalized anxiety disorder (GAD) symptoms occurring during a depressive episode

2. History of alcohol or drug dependence or abuse in the last three years

3. History of developmental disorder or IQ score < 70

4. Presence of acute suicidality

5. Acute grief (< 1 month)

6. Current or past psychosis

7. Primary neurological disorder, including but not limited to dementia, stroke, brain
tumors, epilepsy, Parkinson's disease, or demyelinating diseases

8. MRI contraindications

9. Any physical or intellectual disability adversely affecting ability to complete
assessments

10. Electroconvulsive therapy in last 6 months

11. Use of antidepressant medications or other psychotropic medications in the last 4
weeks (or the last 6 weeks for fluoxetine). Occasional use of benzodiazepines or
non-benzodiazepine sedatives (such as zolpidem, eszopiclone, or zaleplon) during this
period is allowable.

12. A failed therapeutic trial of escitalopram in the current depressive episode (defined
as at least 6 weeks of treatment at a daily dose of 10mg or higher)

13. Known allergy or hypersensitivity to escitalopram or bupropion

14. Current or planned psychotherapy