Frontal Hypoperfusion Effects on Antidepressant Outcomes in Late-Life Depression (R21)
Trial Snapshot
- Phase
- Phase 4
- Status
- Completed
- Sponsor
- Vanderbilt University
- Enrollment
- 31
- Locations
- 1
- Primary Endpoint
- Remission of Depression
Study Overview
Brief Summary
The long-term goal of this line of research is to determine if decreased vascular reactivity and frontal hypoperfusion is associated with poor response antidepressants. Such perfusion deficits could contribute to antidepressant nonresponse as they would hinder improvements in dorsal system metabolism seen with antidepressant treatment. The objective of the current proposal is to determine if decreased vascular reactivity and frontal hypoperfusion in depressed elders predicts and persists with antidepressant nonremission. The investigators will pursue the primary aim testing the hypothesis that decreased reactivity and hypoperfusion, specifically in the dorsolateral prefrontal cortex and dorsal anterior cingulate cortex, predict antidepressant nonremission. The investigators will enroll 40 depressed elders who will complete clinical, cognitive, and MRI assessments before and after a 12-week open-label antidepressant trial of sertraline.
Detailed Description
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).
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Basic Science
- Masking
- None
Eligibility Criteria
- Ages
- 60 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age 60 years or older.
- •Current diagnosis of major depressive disorder (DSM-IV-TR), single episode, recurrent or chronic, without psychotic features, as detected by MINI and clinical exam.
- •Minimum MADRS score ≥
- •Mini-Mental State Exam ≥
- •Ability to read and write English.
Exclusion Criteria
- •Current or past diagnoses of other Axis I psychiatric disorders, including panic disorder and substance dependence.
- •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.
- •Presence of acute suicidality
- •Current or past psychosis
- •Known primary neurological disorder, including dementia, brain tumors, epilepsy, Parkinson's disease, or demyelinating diseases
- •Chronic untreated medical disorders (including but not limited to hypertension, hyperlipidemia, fibromyalgia, hypothyroidism, or any other disorder) where treatment is warranted
- •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.
- •Any physical or intellectual disability affecting completion of assessments
- •MRI contraindications
- •Electroconvulsive therapy in last 6 months
- •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.
- •Known allergy or hypersensitivity to sertraline
- •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)
- •Current or planned psychotherapy
Arms & Interventions
Sertraline
50-200mg daily
Intervention: Sertraline (Drug)
Outcomes
Primary Outcomes
Remission of Depression
Time Frame: Week 12
Montgomery-Asberg Depression Rating Scale (MADRS) is a measure of depression severity. This will be used to define remission as a score of 7 or less.
Secondary Outcomes
- Change in Clinician-rated Depression Severity(Assessed every 2 weeks from baseline to week 12, change from baseline to week 12 is reported)
- Change in Patient-rated Depression Severity(Assessed every 2 weeks from baseline to week 12, change from baseline to week 12 is reported)
Investigators
Warren Taylor
Associate Professor of Psychiatry
Vanderbilt University