Major Depressive Disorder
Conditions
Keywords
Depression, Geriatrics, Elderly, MRI, Antidepressants
Brief 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.
Detailed description
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 response. 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 processing speed. 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.
Interventions
DRUGEscitalopram
Escitalopram 10-20mg daily
DRUGBupropion XL
Bupropion XL 150-450mg daily
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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-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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Remission of Depression | From Baseline up to Week 16 | Montgomery-Asberg Depression Rating Scale (MADRS) is a clinician-rated measure of depression severity. Higher scores indicate greater depression severity, ranging 0-60. This will be used to define remission as a final score of 7 or less |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Depression Severity, Clinician Rated | Baseline to week 8 | Depression severity was measured by a study clinician using the MADRS. Higher scores indicate greater depression severity, ranging 0-60. Change calculated as Final MADRS - Baseline MADRS, so a negative score means greater improvement. |
| Change in Depression Severity, Self Rated | Baseline to week 8 | Self-rated depression severity was measured by the Quick Inventory of Depressive Symptoms, Self-Rated (QIDS-SR16). The QIDS-SR16 is a self-report of depression severity ranging from 0-27, with higher scores indicating greater depression severity. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Apathy Evaluation Scale (AES) | Baseline and Week 8 | The AES is a self-report scale of apathy symptoms. The scale ranges from 18-72, with higher scores indicating greater levels of apathy. Change is calculated as final AES score - baseline AES score, so a more negative value indicates greater improvement in that symptom. |
| Ruminative Response Scale (RRS) | Baseline and Week 8 | The RRS is a self-report questionnaire assessing rumination, or responding to distress by passively focusing on the possible causes and consequences of one's distress. The RRS ranges from scores of 0-66, with higher scores indicating greater severity of rumination. Change is calculated as final RRS score - baseline RRS score, so a negative change indicates improvement in this symptom. |
Countries
United States
Participant flow
Recruitment details
Enrollment opened in April 2015, with the first participant enrolled in June 2015. Enrollment remained open through March 2020. Recruitment involved outpatients at Vanderbilt University Medical Center, recruited through clinical referrals and community advertisements.
Pre-assignment details
Participants enrolled while on an antidepressant medication had that medication discontinued over several weeks. At least two weeks elapsed between last antidepressant use and randomization. Participants enrolled at screening were excluded from the study before baseline and randomization due to a) identification of potential MRI contraindications or b) remission of depression symptoms before the baseline visit.
Participants by arm
| Arm | Count |
|---|---|
| Blinded Escitalopram / Open-Label Bupropion 8 weeks of blinded escitalopram. Remission status then assessed. If not remitting, blinded escitalopram is stopped and participants begin 8 weeks of open-label bupropion xl
Escitalopram: Escitalopram 10-20mg daily
Bupropion XL: Bupropion XL 150-450mg daily | 63 |
| Blinded Placebo / Open-Label Bupropion 8 weeks of blinded placebo. Remission status then assessed. If not remitting, blinded escitalopram is stopped and participants begin 8 weeks of open-label bupropion xl
Placebo: 1-2 tablets daily
Bupropion XL: Bupropion XL 150-450mg daily | 32 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase 1: Blinded Escitalopram or Placebo | Adverse Event | 3 | 5 |
| Phase 1: Blinded Escitalopram or Placebo | Withdrawal by Subject | 1 | 0 |
| Phase 1: Blinded Escitalopram or Placebo | Worsening Depression | 0 | 4 |
| Phase 2: Open-Label Bupropion | Adverse Event | 2 | 7 |
| Phase 2: Open-Label Bupropion | Lost to Follow-up | 1 | 0 |
| Phase 2: Open-Label Bupropion | Worsening Depression | 0 | 1 |
Baseline characteristics
| Characteristic | Blinded Placebo / Open-Label Bupropion | Total | Blinded Escitalopram / Open-Label Bupropion |
|---|---|---|---|
| Age, Continuous | 66.44 years STANDARD_DEVIATION 4.81 | 66.40 years STANDARD_DEVIATION 4.82 | 66.38 years STANDARD_DEVIATION 4.86 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 90 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Mini-Mental State Exam (MMSE) Score | 29.22 units on a scale STANDARD_DEVIATION 1.21 | 29.36 units on a scale STANDARD_DEVIATION 1 | 29.43 units on a scale STANDARD_DEVIATION 0.87 |
| Montgomery Asberg Depression Rating Scale (MADRS) | 25.78 units on a scale STANDARD_DEVIATION 6.29 | 26.14 units on a scale STANDARD_DEVIATION 5.44 | 26.32 units on a scale STANDARD_DEVIATION 5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 85 Participants | 56 Participants |
| Region of Enrollment United States | 32 participants | 95 participants | 63 participants |
| Sex: Female, Male Female | 20 Participants | 56 Participants | 36 Participants |
| Sex: Female, Male Male | 12 Participants | 39 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 63 | 0 / 32 | 0 / 41 |
| other Total, other adverse events | 39 / 63 | 13 / 32 | 27 / 41 |
| serious Total, serious adverse events | 1 / 63 | 1 / 32 | 1 / 41 |
Outcome results
Primary
Number of Patients With Remission of Depression
Montgomery-Asberg Depression Rating Scale (MADRS) is a clinician-rated measure of depression severity. Higher scores indicate greater depression severity, ranging 0-60. This will be used to define remission as a final score of 7 or less
Time frame: From Baseline up to Week 16
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Blinded Escitalopram / Open-Label Bupropion | Number of Patients With Remission of Depression | 37 Participants |
| Blinded Placebo / Open-Label Bupropion | Number of Patients With Remission of Depression | 13 Participants |
Comparison: Statistical analyses utilized a logistic regression model with remission status (defined as final MADRS \<= 7) as the dependent variable. The independent variable of interest was treatment arm assignment, and the model included age, sex, and baseline depression severity by MADRS as covariates.p-value: 0.0689Regression, Logistic
Secondary
Change in Depression Severity, Clinician Rated
Depression severity was measured by a study clinician using the MADRS. Higher scores indicate greater depression severity, ranging 0-60. Change calculated as Final MADRS - Baseline MADRS, so a negative score means greater improvement.
Time frame: Baseline to week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinded Escitalopram / Open-Label Bupropion | Change in Depression Severity, Clinician Rated | -13.90 score on a scale | Standard Deviation 9.38 |
| Blinded Placebo / Open-Label Bupropion | Change in Depression Severity, Clinician Rated | -6.09 score on a scale | Standard Deviation 8.9 |
Comparison: Statistical analyses utilized mixed model. MADRS score was the repeated measures dependent variable. Independent variables included time, age, sex, and treatment assignment. The primary variable of interest for this analysis was an interaction term between time and treatment assignment. A statistically significant interaction term would indicate that one treatment arm experienced a greater change in MADRS score over time than the other treatment arm.p-value: 0.0001Mixed Models Analysis
Secondary
Change in Depression Severity, Clinician Rated
Change in depression severity will be measured by the MADRS. Higher scores indicate greater depression severity, ranging 0-60. Change calculated as Final MADRS - Baseline MADRS, so a negative score means greater improvement.
Time frame: Week 8 to week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinded Escitalopram / Open-Label Bupropion | Change in Depression Severity, Clinician Rated | -8.75 units on a scale | Standard Deviation 8.27 |
Comparison: Statistical analyses utilized mixed models, with MADRS score being the repeated measures dependent variable. Independent variables included time, age, and sex. The primary variable of interest was time, to indicate a change in depression severity over time with open-label treatment.p-value: <0.0001Mixed Models Analysis
Secondary
Change in Depression Severity, Self Rated
Self-rated depression severity was measured by the Quick Inventory of Depressive Symptoms, Self-Rated (QIDS-SR16). The QIDS-SR16 is a self-report of depression severity ranging from 0-27, with higher scores indicating greater depression severity.
Time frame: Baseline to week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinded Escitalopram / Open-Label Bupropion | Change in Depression Severity, Self Rated | -4.87 units on a scale | Standard Deviation 5.33 |
| Blinded Placebo / Open-Label Bupropion | Change in Depression Severity, Self Rated | -2.09 units on a scale | Standard Deviation 4.13 |
Comparison: Statistical analyses utilized mixed models, with QIDS score being the repeated measures dependent variable. Independent variables included time, age, sex, and treatment assignment. The primary variable of interest was an interaction term between time and treatment assignment.p-value: 0.0483Mixed Models Analysis
Secondary
Change in Depression Severity, Self Rated
Change in self-reported depression severity was measured by the Quick Inventory of Depressive Symptoms, Self-Rated (QIDS-SR16). This scale ranges from 0-27, with higher scores indicating greater depression severity. Change is calculated as final score less baseline score, so a negative value indicates a decrease in depression severity.
Time frame: Week 8 to week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinded Escitalopram / Open-Label Bupropion | Change in Depression Severity, Self Rated | -2.83 units on a scale | Standard Deviation 3.85 |
Comparison: Statistical analyses utilized mixed models, with QIDS score being the repeated measures dependent variable. Independent variables included time, age, and sex. The primary variable of interest was time, to indicate a change in depression severity over time with open-label treatment.p-value: 0.0123Mixed Models Analysis
Other Pre-specified
Apathy Evaluation Scale (AES)
The AES is a self-report scale of apathy symptoms. The scale ranges from 18-72, with higher scores indicating greater levels of apathy. Change is calculated as final AES score - baseline AES score, so a more negative value indicates greater improvement in that symptom.
Time frame: Baseline and Week 8
Population: Only 72 subjects out of possible 95 individuals included, as both baseline and week 8 AES data were missing for 23 participants who did not complete the self-report questionnaire.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinded Escitalopram / Open-Label Bupropion | Apathy Evaluation Scale (AES) | -4.52 units on a scale | Standard Deviation 7.72 |
| Blinded Placebo / Open-Label Bupropion | Apathy Evaluation Scale (AES) | -3.00 units on a scale | Standard Deviation 8.5 |
Comparison: Statistical analyses used a linear model. Final AES score at week 8 was the dependent variable. Independent variables included age, sex, baseline AES score, baseline MADRS score, and treatment assignment. Treatment assignment was the independent variable of interest.p-value: 0.742Regression, Linear
Other Pre-specified
Ruminative Response Scale (RRS)
The RRS is a self-report questionnaire assessing rumination, or responding to distress by passively focusing on the possible causes and consequences of one's distress. The RRS ranges from scores of 0-66, with higher scores indicating greater severity of rumination. Change is calculated as final RRS score - baseline RRS score, so a negative change indicates improvement in this symptom.
Time frame: Baseline and Week 8
Population: Only 71 participants out of a possible 95 were included in analyses as either baseline or week 8 RRS data were missing for the remaining 24 participants, who did not complete the questionnaire.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Blinded Escitalopram / Open-Label Bupropion | Ruminative Response Scale (RRS) | -10.27 units on a scale | Standard Deviation 9.96 |
| Blinded Placebo / Open-Label Bupropion | Ruminative Response Scale (RRS) | -5.41 units on a scale | Standard Deviation 10.22 |
Comparison: Statistical analyses used a linear regression model. Final RRS score at week 8 was the dependent variable. Independent variables included age, sex, baseline RRS score, baseline MADRS score, and treatment assignment. Treatment assignment was the independent variable of interest.p-value: 0.0232Regression, Linear