Frontal Hypoperfusion Effects on Antidepressant Outcomes in Late-Life Depression

Major Depressive Disorder Clinical Trial

Official title:

Frontal Hypoperfusion Effects on Antidepressant Outcomes in Late-Life Depression (R21)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01896934
• Other study ID #: 130360
• Secondary ID: R21MH099218-01A1
• Status: Completed
• Phase: Phase 4
• First received: July 1, 2013
• Last updated: July 15, 2016
• Start date: July 2013
• Est. completion date: June 2016

Study information

• Verified date: July 2016
• Source: Vanderbilt University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 60 Years and older

Eligibility

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

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Intervention

Drug:
• Sertraline
50-200mg daily

Locations

Country	Name	City	State
United States	Vanderbilt University	Nashville	Tennessee

Sponsors (2)

Lead Sponsor	Collaborator
Vanderbilt University	National Institute of Mental Health (NIMH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	MRI Arterial Spin Labeling (ASL)	This is a noninvasive approach to measuring cerebral perfusion. We will examine pre-treatment measures to determine if they predict subsequent response to sertraline as measured by the MADRS and QIDS-SR16	Baseline	No
Primary	Remission of depression	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.	Week 12	No
Secondary	Change in depression severity	Change in depression severity will be measured by the MADRS and the Quick Inventory of Depressive Symptoms, Self-Rated (QIDS-SR16). The QIDS-SR16 is a self-report measure of depression severity.	Baseline to week 12, measured every 2 weeks	No