Major Depressive Disorder
Conditions
Keywords
Depression, Antidepressants, Elderly, Geriatrics
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). 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.
Interventions
DRUGSertraline
50-200mg daily
Sponsors
National Institute of Mental Health (NIMH)
Vanderbilt University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Remission of Depression | 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
| Measure | Time frame | Description |
|---|---|---|
| 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 depression severity will be measured by the clinician-rated Montgomery Asberg Depression Rating Scale (MADRS), range of 0-60, with higher scores indicating more severe depression |
| Change in Patient-rated Depression Severity | Assessed every 2 weeks from baseline to week 12, change from baseline to week 12 is reported | Change in depression severity measured by the patient-rated Quick Inventory of Depressive Symptoms, Self-Rated (QIDS-SR16). The QIDS-SR16 is a self-report measure of depression severity with a range of 0-27, with higher scores indicative of more severe depression. |
Countries
United States
Participant flow
Pre-assignment details
Participants taking ineffective antidepressant medications underwent a washout period. 10 recruited individuals were withdrawn after screening for a) concomitant medications (N=2), b) depression not severe (N=4), c) MRI contraindications (N=4)
Participants by arm
| Arm | Count |
|---|---|
| Sertraline 50-200mg daily | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Sertraline |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 68.05 years STANDARD_DEVIATION 7.15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Montgomery-Asberg Depression Rating Scale | 27.43 units on a scale STANDARD_DEVIATION 4.8 |
| Quick Inventory of Depressive Symptoms | 11.94 units on a scale STANDARD_DEVIATION 4.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 21 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 21 |
| other Total, other adverse events | 14 / 21 |
| serious Total, serious adverse events | 0 / 21 |
Outcome results
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.
Time frame: Week 12
Population: Individuals achieving remission of depression, defined as MADRS score of 7 or less.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sertraline | Remission of Depression | 10 Participants |
Secondary
Change in Clinician-rated Depression Severity
Change in depression severity will be measured by the clinician-rated Montgomery Asberg Depression Rating Scale (MADRS), range of 0-60, with higher scores indicating more severe depression
Time frame: Assessed every 2 weeks from baseline to week 12, change from baseline to week 12 is reported
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sertraline | Change in Clinician-rated Depression Severity | 16.14 units on a scale | Standard Deviation 9.84 |
Secondary
Change in Patient-rated Depression Severity
Change in depression severity measured by the patient-rated Quick Inventory of Depressive Symptoms, Self-Rated (QIDS-SR16). The QIDS-SR16 is a self-report measure of depression severity with a range of 0-27, with higher scores indicative of more severe depression.
Time frame: Assessed every 2 weeks from baseline to week 12, change from baseline to week 12 is reported
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sertraline | Change in Patient-rated Depression Severity | 3.82 units on a scale | Standard Error 6.04 |