CAARE: Connectivity Affecting the Antidepressant REsponse Study

• Sponsor: Vanderbilt University Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02332291
• Collaborator: (none)
• Enrollment: 95
• Location: 1
• Arms: 2
• Actual Duration (Months): 64
• Patients Per Site Per Month: 1.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Escitalopram; Drug: Bupropion XL	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 95 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Connectivity Affecting the Antidepressant REsponse (The CAARE Study)
• Actual Study Start Date: Apr 1, 2015
• Actual Primary Completion Date: Aug 1, 2020
• Actual Study Completion Date: Aug 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Blinded Escitalopram / Open-Label Bupropion 8 weeks of blinded escitalopram, followed by 8 weeks of open-label bupropion xl for nonremitters	Drug: Escitalopram; Escitalopram 10-20mg daily; Other Names: Lexapro ; Drug: Bupropion XL; Bupropion XL 150-450mg daily; Other Names: Wellbutrin XL
Placebo Comparator: Blinded Placebo / Open-Label Bupropion 8 weeks of blinded placebo, followed by 8 weeks of open-label bupropion xl for nonremitters.	Drug: Bupropion XL; Bupropion XL 150-450mg daily; Other Names: Wellbutrin XL

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. Change in Depression Severity, Clinician Rated [Week 8 to week 16]

   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.

4. Change in Depression Severity, Self Rated [Week 8 to week 16]

   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.

Other Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 60 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt Psychiatric Hospital	Nashville	Tennessee	United States	37212

Sponsors and Collaborators

• Vanderbilt University Medical Center

Investigators

• Principal Investigator: Warren D Taylor, MD, MHSc, Vanderbilt University Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 10, 2020
• Informed Consent Form - Nov 7, 2019

More Information

Publications

None provided.

• Responsible Party: Warren Taylor, Professor of Psychiatry, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT02332291
• Other Study ID Numbers: 141137
• First Posted: Jan 6, 2015
• Last Update Posted: Sep 21, 2021
• Last Verified: Aug 1, 2021

• Keywords provided by Warren Taylor, Professor of Psychiatry, Vanderbilt University Medical Center: Depression; Geriatrics; Elderly; MRI; Antidepressants
• Additional relevant MeSH terms: Depressive Disorder; Depressive Disorder, Major; Citalopram; Bupropion

Study Results

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 Detail

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.

Arm/Group Title	Blinded Escitalopram / Open-Label Bupropion	Blinded Placebo / Open-Label Bupropion
Arm/Group Description	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	8 weeks of blinded placebo. Remission status then assessed. If not remitting, blinded placebo is stopped and participants begin 8 weeks of open-label bupropion xl Placebo: 1-2 tablets daily Bupropion XL: Bupropion XL 150-450mg daily
Period Title: Phase 1: Blinded Escitalopram or Placebo
STARTED	63	32
COMPLETED	59	23
NOT COMPLETED	4	9
Period Title: Phase 1: Blinded Escitalopram or Placebo
STARTED	22	19
COMPLETED	19	11
NOT COMPLETED	3	8

Baseline Characteristics

Arm/Group Title	Blinded Escitalopram / Open-Label Bupropion	Blinded Placebo / Open-Label Bupropion	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	63	32	95
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.38 (4.86)	66.44 (4.81)	66.40 (4.82)
Sex: Female, Male (Count of Participants)
Female	36 57.1%	20 62.5%	56 58.9%
Male	27 42.9%	12 37.5%	39 41.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 6.3%	1 3.1%	5 5.3%
Not Hispanic or Latino	59 93.7%	31 96.9%	90 94.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 6.3%	3 9.4%	7 7.4%
White	56 88.9%	29 90.6%	85 89.5%
More than one race	3 4.8%	0 0%	3 3.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	63 100%	32 100%	95 100%
Montgomery Asberg Depression Rating Scale (MADRS) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	26.32 (5.00)	25.78 (6.29)	26.14 (5.44)
Mini-Mental State Exam (MMSE) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	29.43 (0.87)	29.22 (1.21)	29.36 (1.0)

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Remission of Depression
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Blinded Escitalopram / Open-Label Bupropion	Blinded Placebo / Open-Label Bupropion
Arm/Group Description	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	8 weeks of blinded placebo. Remission status then assessed. If not remitting, blinded placebo is stopped and participants begin 8 weeks of open-label bupropion xl Placebo: 1-2 tablets daily Bupropion XL: Bupropion XL 150-450mg daily
Measure Participants	63	32
Count of Participants [Participants]	37 58.7%	13 40.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Blinded Escitalopram / Open-Label Bupropion, Blinded Placebo / Open-Label Bupropion
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0689
	Comments	The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was < 0.05.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio, log
	Estimated Value	0.8642
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.4750
	Estimation Comments

2. Secondary Outcome

Title	Change in Depression Severity, Clinician Rated
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Blinded Escitalopram	Blinded Placebo
Arm/Group Description	8 weeks of blinded escitalopram. Escitalopram: Escitalopram 10-20mg daily	8 weeks of blinded placebo. Placebo: 1-2 tablets daily
Measure Participants	63	32
Mean (Standard Deviation) [score on a scale]	-13.90 (9.38)	-6.09 (8.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Blinded Escitalopram / Open-Label Bupropion, Blinded Placebo / Open-Label Bupropion
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was p < 0.05.
	Method	Mixed Models Analysis
	Comments	344 degrees of freedom
Method of Estimation	Estimation Parameter	Slope, fixed effect
	Estimated Value	-1.066
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.264
	Estimation Comments

3. Secondary Outcome

Title	Change in Depression Severity, Self Rated
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Blinded Escitalopram	Blinded Placebo
Arm/Group Description	8 weeks of blinded escitalopram. Escitalopram: Escitalopram 10-20mg daily	8 weeks of blinded placebo. Placebo: 1-2 tablets daily
Measure Participants	63	32
Mean (Standard Deviation) [units on a scale]	-4.87 (5.33)	-2.09 (4.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Blinded Escitalopram / Open-Label Bupropion, Blinded Placebo / Open-Label Bupropion
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0483
	Comments	The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was < 0.05.
	Method	Mixed Models Analysis
	Comments	150 degrees of freedom
Method of Estimation	Estimation Parameter	Slope, fixed effects
	Estimated Value	-0.3117
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1566
	Estimation Comments

4. Secondary Outcome

Title	Change in Depression Severity, Clinician Rated
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open-label Bupropion XL
Arm/Group Description	Bupropion XL was administered open-label for 8 weeks with flexible dosing. Bupropion XL: Bupropion XL 150-450mg daily
Measure Participants	41
Mean (Standard Deviation) [units on a scale]	-8.75 (8.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Blinded Escitalopram / Open-Label Bupropion
	Comments	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.
	Type of Statistical Test	Other
	Comments	Analyses tested for effects of time in this one-arm, open-label study phase.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was p < 0.05.
	Method	Mixed Models Analysis
	Comments	128 degrees of freedom
Method of Estimation	Estimation Parameter	Slope, fixed effect
	Estimated Value	-1.186
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.181
	Estimation Comments

5. Secondary Outcome

Title	Change in Depression Severity, Self Rated
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open-label Bupropion XL
Arm/Group Description	Bupropion XL was administered open-label for 8 weeks with flexible dosing. Bupropion XL: Bupropion XL 150-450mg daily
Measure Participants	41
Mean (Standard Deviation) [units on a scale]	-2.83 (3.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Blinded Escitalopram / Open-Label Bupropion
	Comments	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.
	Type of Statistical Test	Other
	Comments	Analyses tested for effects of time in this one-arm, open-label study phase.
Statistical Test of Hypothesis	p-Value	0.0123
	Comments	The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was p < 0.05.
	Method	Mixed Models Analysis
	Comments	61 degrees of freedom
Method of Estimation	Estimation Parameter	Slope, fixed effects
	Estimated Value	-0.2342
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0908
	Estimation Comments

6. Other Pre-specified Outcome

Title	Apathy Evaluation Scale (AES)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Blinded Escitalopram	Blinded Placebo
Arm/Group Description	8 weeks of blinded escitalopram. Escitalopram: Escitalopram 10-20mg daily	8 weeks of blinded placebo. Placebo: 1-2 tablets daily
Measure Participants	50	22
Mean (Standard Deviation) [units on a scale]	-4.52 (7.72)	-3.00 (8.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Blinded Escitalopram / Open-Label Bupropion, Blinded Placebo / Open-Label Bupropion
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.742
	Comments	The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was p < 0.05.
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-0.636
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.924
	Estimation Comments

7. Other Pre-specified Outcome

Title	Ruminative Response Scale (RRS)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Blinded Escitalopram	Blinded Placebo
Arm/Group Description	8 weeks of blinded escitalopram. Escitalopram: Escitalopram 10-20mg daily	8 weeks of blinded placebo. Placebo: 1-2 tablets daily
Measure Participants	49	22
Mean (Standard Deviation) [units on a scale]	-10.27 (9.96)	-5.41 (10.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Blinded Escitalopram / Open-Label Bupropion, Blinded Placebo / Open-Label Bupropion
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0232
	Comments	The p-value was not adjusted for multiple comparisons. The a priori threshold for statistical significance was p < 0.05.
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-5.4705
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.352
	Estimation Comments

Adverse Events

Time Frame	Adverse event data were collected during participants' duration in the study following randomization. This lasted for 8 weeks for the randomized, blinded escitalopram or placebo phase, and an additional 8 weeks for individuals progressing into the subsequent open-label bupropion phase.
Arm/Group Title	Blinded Escitalopram		Blinded Placebo		Open-Label Bupropion
Arm/Group Description	8 weeks of blinded escitalopram Escitalopram: Escitalopram 10-20mg daily		8 weeks of blinded placebo Placebo: Placebo 1-2 tablets daily		8-weeks of open-label treatment with bupropion following initial randomization phase for individuals who did not remit to treatment with either blinded escitalopram or placebo. Bupropion XL: Bupropion XL 150-450mg daily
All Cause Mortality
	Blinded Escitalopram		Blinded Placebo		Open-Label Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/63 (0%)		0/32 (0%)		0/41 (0%)
Serious Adverse Events
	Blinded Escitalopram		Blinded Placebo		Open-Label Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/63 (1.6%)		1/32 (3.1%)		1/41 (2.4%)
Gastrointestinal disorders
Gastrointestinal bleeding	1/63 (1.6%)	1	0/32 (0%)	0	0/41 (0%)	0
General disorders
Dehydration	1/63 (1.6%)	1	0/32 (0%)	0	0/41 (0%)	0
Infections and infestations
Pyelonephritis	0/63 (0%)	0	0/32 (0%)	0	1/41 (2.4%)	1
Nervous system disorders
Stroke, ischemic	0/63 (0%)	0	1/32 (3.1%)	1	0/41 (0%)	0
Other (Not Including Serious) Adverse Events
	Blinded Escitalopram		Blinded Placebo		Open-Label Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/63 (61.9%)		13/32 (40.6%)		27/41 (65.9%)
Cardiac disorders
Irregular Heartbeat	0/63 (0%)	0	0/32 (0%)	0	1/41 (2.4%)	1
Ear and labyrinth disorders
Tinnitus	0/63 (0%)	0	0/32 (0%)	0	2/41 (4.9%)	2
Eye disorders
Blurred vision	1/63 (1.6%)	1	0/32 (0%)	0	0/41 (0%)	0
Diplopia	1/63 (1.6%)	1	0/32 (0%)	0	0/41 (0%)	0
Gastrointestinal disorders
Constipation	1/63 (1.6%)	1	0/32 (0%)	0	1/41 (2.4%)	1
Diarrhea	6/63 (9.5%)	6	1/32 (3.1%)	1	2/41 (4.9%)	2
Nausea	8/63 (12.7%)	8	2/32 (6.3%)	2	1/41 (2.4%)	1
Appetite loss	2/63 (3.2%)	2	0/32 (0%)	0	0/41 (0%)	0
General disorders
Dry mouth	0/63 (0%)	0	1/32 (3.1%)	1	1/41 (2.4%)	1
Diaphoresis	2/63 (3.2%)	2	0/32 (0%)	0	0/41 (0%)	0
Fatigue	8/63 (12.7%)	8	1/32 (3.1%)	1	0/41 (0%)	0
Hot flashes	1/63 (1.6%)	1	0/32 (0%)	0	0/41 (0%)	0
Infections and infestations
Urinary Tract Infection	0/63 (0%)	0	0/32 (0%)	0	1/41 (2.4%)	1
Upper Respiratory Infection	3/63 (4.8%)	3	1/32 (3.1%)	1	0/41 (0%)	0
Injury, poisoning and procedural complications
Minor Environmental Injury	0/63 (0%)	0	1/32 (3.1%)	1	1/41 (2.4%)	1
Fall	1/63 (1.6%)	1	0/32 (0%)	0	0/41 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia / Myalgia	2/63 (3.2%)	2	1/32 (3.1%)	1	0/41 (0%)	0
Nervous system disorders
Dizziness / Lightheaded	5/63 (7.9%)	5	2/32 (6.3%)	2	2/41 (4.9%)	2
Headache	3/63 (4.8%)	3	1/32 (3.1%)	1	1/41 (2.4%)	1
Paresthesia	0/63 (0%)	0	1/32 (3.1%)	1	1/41 (2.4%)	1
Psychiatric disorders
Anxiety / Tension	2/63 (3.2%)	2	1/32 (3.1%)	1	8/41 (19.5%)	8
Irritability	0/63 (0%)	0	2/32 (6.3%)	2	4/41 (9.8%)	4
Insomnia	0/63 (0%)	0	0/32 (0%)	0	1/41 (2.4%)	1
Increased dreaming	3/63 (4.8%)	3	0/32 (0%)	0	3/41 (7.3%)	3
Renal and urinary disorders
Urinary Retention	0/63 (0%)	0	0/32 (0%)	0	1/41 (2.4%)	1
Reproductive system and breast disorders
Sexual dysfunction	7/63 (11.1%)	7	0/32 (0%)	0	0/41 (0%)	0
Skin and subcutaneous tissue disorders
Diaphoresis	2/63 (3.2%)	2	0/32 (0%)	0	0/41 (0%)	0
Vascular disorders
Edema, peripheral	0/63 (0%)	0	1/32 (3.1%)	1	0/41 (0%)	0

Limitations/Caveats

Single-site study; some missing data for self-report other outcome data

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.