Connectivity Affecting the Antidepressant REsponse Study
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Intervention: Escitalopram; Bupropion XL
Intervention description: Escitalopram 10-20mg daily; Bupropion XL 150-450mg daily
Intervention MeSH terms: Bupropion; Escitalopram
Phase: Phase 4
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 95.0
Sex: All
Minimum age: 60 Years
Healthy volunteers: No
Keywords: Depression; Geriatrics; Elderly; MRI; Antidepressants

Summary:

      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.
    

Eligibility criteria:

        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-International
             Neuropsychiatric Inventory (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 Intelligence Quotient 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