It can be difficult to achieve remission in individuals with late-life depression (LLD) and
they often require aggressive treatment. This challenge is in part due to age-related
vascular changes that are common in LLD. Successful antidepressant treatment involve changes
across affective, cognitive, and default mode networks. We hypothesize that in LLD, vascular
disease adversely affects response to antidepressants by disrupting connectivity of these
networks. The primary goal of this project is to characterize how focal vascular damage
affects regional connectivity and response to antidepressants. Based on past work and pilot
data, we a priori focus on the cingulum bundle and uncinate fasciculus. These key fiber
bundles connect frontal, temporal, and cingulate regions involved in cognition and affective
responses. Our central hypothesis is that ischemic damage to the cingulum bundle and
uncinate fasciculus contributes to structural and functional connectivity deficits of those
tracts. This results in a disconnection effect that alters the function of connected
regions. In turn, this increases the risk of a poor response to antidepressants.
Our approach is to enroll up to 130 adults over age 60 years with a diagnosis of Major
Depressive Disorder. Subjects will complete clinical evaluation, cognitive testing, and
MRI/functional MRI (fMRI) sessions, including an fMRI emotional oddball task that includes
attentional and affective components. Participants will be stratified by cerebral lesion
severity and randomized in a 2:1 ratio to a double-blinded 8-week trial of escitalopram or
matching placebo. Those who do not remit will transition to an 8-week trial of open-label
bupropion, an antidepressant with a different mechanism of action. This will allow us to
determine if different and distinct circuit deficits affect response to antidepressants with
different mechanisms of action while also accounting for the placebo response.
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
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
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.
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.
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
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