Major Depression
Conditions
Keywords
Inflammation
Brief summary
This study is designed to determine whether bupropion (vs escitalopram) increases functional connectivity (FC) within reward-related neurocircuits and decreases motivational deficits in depressed patients with increased inflammation and anhedonia. Participants will be randomized to take bupropion extended release (XL) or escitalopram for 8 weeks.
Detailed description
The goal of the proposed research is to determine the mechanism of action of an antidepressant of known efficacy (bupropion) and to tie this mechanism of action to a biomarker of inflammation in support of precision medicine for the treatment of major depression (MD). MD is a devastating disease affecting approximately 10% of US adults and being the leading cause of disability worldwide. Despite availability of several classes of antidepressant medications, initial treatment response is low (around 30%), and approximately 1/3 of depressed patients are non-responsive to conventional antidepressant therapies. Although extensive reviews of the literature suggest that available antidepressant medications are equally effective, recent studies suggest that there may be differential responsiveness to conventional antidepressants among subgroups of depressed patients. One subgroup of depressed patients who may exhibit differential antidepressant responsiveness are those with increased markers of inflammation. Data from previous studies support the notion that differential responsiveness to conventional antidepressants exists and may be revealed by pretreatment levels of inflammation as indexed by the inflammatory biomarker C-reactive protein (CRP). This study proposes to use a mechanistic clinical trial design with drugs of known efficacy to take the first step toward establishing whether antidepressants that target dopamine (e.g. bupropion) might be a better choice for depressed patients with increased inflammation and anhedonia than an selective serotonin reuptake inhibitor (SSRI). Accordingly, 50 depressed patients with a CRP\>2mg/L and increased anhedonia will be randomized to 8 weeks of bupropion or escitalopram in order to analyze data from 40 patients (accounting for drop outs). All depressed patients will undergo functional magnetic resonance imaging (fMRI) to examine functional connectivity in reward-related circuits at baseline and 4 and 8 weeks along with objective and clinical assessments of Research Domain Criteria (RDoC) positive (motivational) valence constructs at baseline and 2, 4, 6 and 8 weeks. The researchers hypothesize that patients who receive bupropion versus escitalopram will exhibit increased functional connectivity between ventral striatum and ventromedial prefrontal cortex in association with decreased motivational deficits and anhedonia.
Interventions
DRUGBupropion XL
Participants will take 150 milligrams per day (mg/d) of bupropion XL for two weeks, then the dose will be increased to 300mg/d, as tolerated, for the remaining 6 weeks of the study.
DRUGEscitalopram
Participants will take 10mg/d of escitalopram for two weeks, then the dose will be increased to 20mg/d, as tolerated, for the remaining 6 weeks of the study.
Sponsors
National Institute of Mental Health (NIMH)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
25 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* willing and able to give written informed consent * a primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders (DSM-V) MD, current as diagnosed by the Structured Clinical Interview for DSM-V Axis I Disorders (SCID-V) * score of ≥16 on the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) * off all antidepressant or other psychotropic therapy (e.g. mood stabilizers, antipsychotics, and sedative hypnotics) for at least 4 weeks prior to baseline visit (8 weeks for fluoxetine); concomitant administration of up to 2 mg of clonazepam or its equivalent per day will be allowed, but not within 12 hours of study assessments * CRP\>2mg/L * Inventory of Depressive Symptomatology (IDS-SR) anhedonia subscale score ≥5
Exclusion criteria
* history of any autoimmune disorder * history of hepatitis B or C infection or human immunodeficiency virus infection * history of any type of cancer requiring treatment with more than minor surgery * unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic disease (as determined by physical examination and laboratory testing) * history of any (non-mood-related) psychotic disorder; active psychotic symptoms of any type; substance abuse/dependence within 6 months of study entry (as determined by SCID) * an active eating disorder or antisocial personality disorder * a history of a cognitive disorder or ≤28 on the Mini-Mental State Exam unless otherwise approved by the PI * pregnancy or lactation * chronic use of non-steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg of aspirin), glucocorticoid containing medications * use of NSAIDS or oral glucocorticoids at any time during the study * any contraindication for MRI scanning * failure of more than 2 antidepressant trials in the current episode * Intolerance of bupropion or escitalopram * BMI \>40 (to exclude severe obesity) * due to the high co-morbidity between anxiety disorders and depression, the study team plans to include patients with anxiety-related disorders excluding obsessive-compulsive disorder (OCD) if depression is the primary diagnosis. Patients with stable medical conditions and on medications for those conditions will not be excluded. Concomitant administration of up to 2 mg of clonazepam or its equivalent per day will be allowed, but not within 12 hours of study assessments. * sexually active participants are required to use medically approved birth control methods as defined in the Birth Control Method Form for the duration of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Targeted Ventromedial Prefrontal Cortex-Ventral Striatal (vmPFC-VS) Functional Connectivity (FC) | Baseline, Week 4, Week 8 | Targeted FC is calculated as the degree of correlation in activity between a 3mm3 radius sphere in VS and the vmPFC cluster identified as being reward-sensitive in neuroimaging meta-analyses and as used to define vmPFC in previous work. Subject-level correlations for degree of vmPFC-VS FC is Fisher's Z transformed {Z(R)=0.5ln\[(1+R)/(1-R)\]}, a standard method for calculating fMRI functional connectivity, whereby greater Z-scores reflected stronger correlated functional magnetic resonance imaging (fMRI) activity (i.e., higher VS-vmPFC connectivity). For each study timepoint, Z-scores will be extracted and the change in mean FC values compared to baseline will be calculated. The central value is 0, and the standard deviation depends on the sample variance. Increasing values indicate increasing connectivity between the indicated brain regions (VS and vmPFC). There are no relevant thresholds, and there is no direct interpretation of results in terms of clinical improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT) | Baseline, Week 2, Week 4, Week 8 | The Effort-Expenditure for Rewards Task (EEfRT) is a computer-based multi-trial game to assess motivation. Participants are given an opportunity to choose different task difficulty levels to obtain monetary rewards (easy tasks have low rewards while hard tasks have higher rewards). Each trial has a high, medium, or low probability of success, and this information is given to the participant when they are deciding between easy and hard tasks. The task lasts for 20 minutes, and first 50 trials are analyzed. The proportion of hard-task choices across each level of probability is calculated. Possible values range between 0 to1 with 1 being a better outcome indicating the mean probability of making a hard (high effort) choice. Lower proportions of hard task choices indicate decreased motivation. |
| Snaith-Hamilton Pleasure Scale (SHAPS-C) Score | Baseline, Week 2, Week 4, Week 6, Week 8 | The SHAPS-C is a 14-item clinician-administered scale assessing the amount of pleasure during common daily activities that the participant has experienced in the past week. Responses are given on a scale of 1 to 4 where 1 = lots of pleasure and 4 = no pleasure. Total scores range from 14 to 56 with lower scores indicating greater enjoyment of activities. |
| Motivation and Pleasure Scale-Self-Report (MAP-SR) Score | Baseline, Week 2, Week 4, Week 6, Week 8 | The MAP-SR is an 18-item self-report inventory that has been validated in psychiatric populations and is designed to disentangle motivational and consummatory components of everyday activities over a 24-hr period. Responses are given on a 5-point scale where 0 = no pleasure or motivation and 4 = extreme pleasure or motivation. Total scores range from 0 to 72 and higher scores indicate greater motivation and pleasure during everyday activities. |
| Inventory of Depressive Symptomatology - Self-Report (IDS-SR) | Baseline, Week 2, Week 4, Week 6, Week 8 | The IDS-SR is a 30-item self-reported measurement of depression severity. Responses are given on a 4-point scale where 0 = no problems and 3 = severe problems. Total scores are based on 28 items and range from 0 to 84 with higher scores indicating more severe symptoms of depression. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the Emory Clinic in Atlanta, Georgia, USA. Participant enrollment began September 23, 2020 and the final follow-up assessment occurred July 25, 2022.
Participants by arm
| Arm | Count |
|---|---|
| Bupropion Participants randomized to take bupropion for 8 weeks. Participants took 150 milligrams per day (mg/d) of bupropion XL for two weeks, then the dose increased to 300mg/d, as tolerated, for the remaining 6 weeks of the study. | 10 |
| Escitalopram Participants randomized to take escitalopram for 8 weeks. Participants took 10mg/d of escitalopram for two weeks, then the dose increased to 20mg/d, as tolerated, for the remaining 6 weeks of the study. | 8 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 2 | 1 |
Baseline characteristics
| Characteristic | Bupropion | Total | Escitalopram |
|---|---|---|---|
| Age, Continuous | 39.6 years STANDARD_DEVIATION 10 | 40.4 years STANDARD_DEVIATION 9.9 | 41.5 years STANDARD_DEVIATION 10.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 16 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| 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 | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 8 Participants | 14 Participants | 6 Participants |
| Region of Enrollment United States | 10 participants | 18 participants | 8 participants |
| Sex: Female, Male Female | 8 Participants | 14 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 8 |
| other Total, other adverse events | 6 / 10 | 6 / 8 |
| serious Total, serious adverse events | 0 / 10 | 0 / 8 |
Outcome results
Primary
Change in Targeted Ventromedial Prefrontal Cortex-Ventral Striatal (vmPFC-VS) Functional Connectivity (FC)
Targeted FC is calculated as the degree of correlation in activity between a 3mm3 radius sphere in VS and the vmPFC cluster identified as being reward-sensitive in neuroimaging meta-analyses and as used to define vmPFC in previous work. Subject-level correlations for degree of vmPFC-VS FC is Fisher's Z transformed {Z(R)=0.5ln\[(1+R)/(1-R)\]}, a standard method for calculating fMRI functional connectivity, whereby greater Z-scores reflected stronger correlated functional magnetic resonance imaging (fMRI) activity (i.e., higher VS-vmPFC connectivity). For each study timepoint, Z-scores will be extracted and the change in mean FC values compared to baseline will be calculated. The central value is 0, and the standard deviation depends on the sample variance. Increasing values indicate increasing connectivity between the indicated brain regions (VS and vmPFC). There are no relevant thresholds, and there is no direct interpretation of results in terms of clinical improvement.
Time frame: Baseline, Week 4, Week 8
Population: This analysis includes participants with available and analyzable fMRI scans both at baseline and post-treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bupropion | Change in Targeted Ventromedial Prefrontal Cortex-Ventral Striatal (vmPFC-VS) Functional Connectivity (FC) | Baseline to Week 4 | 0.02 Z-score | Standard Deviation 0.14 |
| Bupropion | Change in Targeted Ventromedial Prefrontal Cortex-Ventral Striatal (vmPFC-VS) Functional Connectivity (FC) | Baseline to Week 8 | 0.02 Z-score | Standard Deviation 0.2 |
| Escitalopram | Change in Targeted Ventromedial Prefrontal Cortex-Ventral Striatal (vmPFC-VS) Functional Connectivity (FC) | Baseline to Week 4 | -0.13 Z-score | Standard Deviation 0.16 |
| Escitalopram | Change in Targeted Ventromedial Prefrontal Cortex-Ventral Striatal (vmPFC-VS) Functional Connectivity (FC) | Baseline to Week 8 | 0.09 Z-score | Standard Deviation 0.19 |
Secondary
Inventory of Depressive Symptomatology - Self-Report (IDS-SR)
The IDS-SR is a 30-item self-reported measurement of depression severity. Responses are given on a 4-point scale where 0 = no problems and 3 = severe problems. Total scores are based on 28 items and range from 0 to 84 with higher scores indicating more severe symptoms of depression.
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Population: This analysis includes participants who were still participating in the study at the indicated study visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bupropion | Inventory of Depressive Symptomatology - Self-Report (IDS-SR) | Week 2 | 30.222 Score on a scale | Standard Deviation 8.729 |
| Bupropion | Inventory of Depressive Symptomatology - Self-Report (IDS-SR) | Week 6 | 25.000 Score on a scale | Standard Deviation 11.464 |
| Bupropion | Inventory of Depressive Symptomatology - Self-Report (IDS-SR) | Baseline | 38.800 Score on a scale | Standard Deviation 9.942 |
| Bupropion | Inventory of Depressive Symptomatology - Self-Report (IDS-SR) | Week 8 | 23.875 Score on a scale | Standard Deviation 11.532 |
| Bupropion | Inventory of Depressive Symptomatology - Self-Report (IDS-SR) | Week 4 | 23.556 Score on a scale | Standard Deviation 11.577 |
| Escitalopram | Inventory of Depressive Symptomatology - Self-Report (IDS-SR) | Week 8 | 18.143 Score on a scale | Standard Deviation 12.734 |
| Escitalopram | Inventory of Depressive Symptomatology - Self-Report (IDS-SR) | Week 2 | 30.250 Score on a scale | Standard Deviation 9.407 |
| Escitalopram | Inventory of Depressive Symptomatology - Self-Report (IDS-SR) | Week 4 | 21.500 Score on a scale | Standard Deviation 9.258 |
| Escitalopram | Inventory of Depressive Symptomatology - Self-Report (IDS-SR) | Week 6 | 16.250 Score on a scale | Standard Deviation 11.235 |
| Escitalopram | Inventory of Depressive Symptomatology - Self-Report (IDS-SR) | Baseline | 42.250 Score on a scale | Standard Deviation 7.906 |
Secondary
Motivation and Pleasure Scale-Self-Report (MAP-SR) Score
The MAP-SR is an 18-item self-report inventory that has been validated in psychiatric populations and is designed to disentangle motivational and consummatory components of everyday activities over a 24-hr period. Responses are given on a 5-point scale where 0 = no pleasure or motivation and 4 = extreme pleasure or motivation. Total scores range from 0 to 72 and higher scores indicate greater motivation and pleasure during everyday activities.
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Population: This analysis includes participants who were still participating in the study at the indicated study visit. One participant in the Bupropion group did not complete this assessment at the Week 4 visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bupropion | Motivation and Pleasure Scale-Self-Report (MAP-SR) Score | Week 2 | 29.333 Score on a scale | Standard Deviation 8.846 |
| Bupropion | Motivation and Pleasure Scale-Self-Report (MAP-SR) Score | Week 6 | 37.250 Score on a scale | Standard Deviation 8.876 |
| Bupropion | Motivation and Pleasure Scale-Self-Report (MAP-SR) Score | Week 4 | 35.250 Score on a scale | Standard Deviation 9.254 |
| Bupropion | Motivation and Pleasure Scale-Self-Report (MAP-SR) Score | Week 8 | 38.000 Score on a scale | Standard Deviation 10.529 |
| Bupropion | Motivation and Pleasure Scale-Self-Report (MAP-SR) Score | Baseline | 27.800 Score on a scale | Standard Deviation 7.829 |
| Escitalopram | Motivation and Pleasure Scale-Self-Report (MAP-SR) Score | Week 8 | 45.714 Score on a scale | Standard Deviation 9.232 |
| Escitalopram | Motivation and Pleasure Scale-Self-Report (MAP-SR) Score | Baseline | 28.000 Score on a scale | Standard Deviation 8.211 |
| Escitalopram | Motivation and Pleasure Scale-Self-Report (MAP-SR) Score | Week 2 | 34.875 Score on a scale | Standard Deviation 8.493 |
| Escitalopram | Motivation and Pleasure Scale-Self-Report (MAP-SR) Score | Week 4 | 42.500 Score on a scale | Standard Deviation 11.199 |
| Escitalopram | Motivation and Pleasure Scale-Self-Report (MAP-SR) Score | Week 6 | 44.750 Score on a scale | Standard Deviation 9.852 |
Secondary
Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT)
The Effort-Expenditure for Rewards Task (EEfRT) is a computer-based multi-trial game to assess motivation. Participants are given an opportunity to choose different task difficulty levels to obtain monetary rewards (easy tasks have low rewards while hard tasks have higher rewards). Each trial has a high, medium, or low probability of success, and this information is given to the participant when they are deciding between easy and hard tasks. The task lasts for 20 minutes, and first 50 trials are analyzed. The proportion of hard-task choices across each level of probability is calculated. Possible values range between 0 to1 with 1 being a better outcome indicating the mean probability of making a hard (high effort) choice. Lower proportions of hard task choices indicate decreased motivation.
Time frame: Baseline, Week 2, Week 4, Week 8
Population: One participant in the Bupropion group was excluded prior to completing this task, and another did not complete the task due to shoulder pain during the task. One participant in the Escitalopram group did not complete the task at the Week 4 visit because the visit was seen virtually (due to illness) and neuropsychological testing was not performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bupropion | Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT) | Baseline | 0.392 proportion of hard-task choices | Standard Deviation 0.257 |
| Bupropion | Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT) | Week 2 | 0.450 proportion of hard-task choices | Standard Deviation 0.316 |
| Bupropion | Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT) | Week 4 | 0.348 proportion of hard-task choices | Standard Deviation 0.207 |
| Bupropion | Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT) | Week 8 | 0.360 proportion of hard-task choices | Standard Deviation 0.229 |
| Escitalopram | Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT) | Week 8 | 0.323 proportion of hard-task choices | Standard Deviation 0.158 |
| Escitalopram | Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT) | Baseline | 0.450 proportion of hard-task choices | Standard Deviation 0.29 |
| Escitalopram | Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT) | Week 4 | 0.321 proportion of hard-task choices | Standard Deviation 0.215 |
| Escitalopram | Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT) | Week 2 | 0.385 proportion of hard-task choices | Standard Deviation 0.275 |
Secondary
Snaith-Hamilton Pleasure Scale (SHAPS-C) Score
The SHAPS-C is a 14-item clinician-administered scale assessing the amount of pleasure during common daily activities that the participant has experienced in the past week. Responses are given on a scale of 1 to 4 where 1 = lots of pleasure and 4 = no pleasure. Total scores range from 14 to 56 with lower scores indicating greater enjoyment of activities.
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Population: This analysis includes participants who were still participating in the study at the indicated study visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bupropion | Snaith-Hamilton Pleasure Scale (SHAPS-C) Score | Week 2 | 36.222 Score on a scale | Standard Deviation 6.629 |
| Bupropion | Snaith-Hamilton Pleasure Scale (SHAPS-C) Score | Week 6 | 35.375 Score on a scale | Standard Deviation 7.963 |
| Bupropion | Snaith-Hamilton Pleasure Scale (SHAPS-C) Score | Week 4 | 33.778 Score on a scale | Standard Deviation 9.68 |
| Bupropion | Snaith-Hamilton Pleasure Scale (SHAPS-C) Score | Week 8 | 32.125 Score on a scale | Standard Deviation 9.125 |
| Bupropion | Snaith-Hamilton Pleasure Scale (SHAPS-C) Score | Baseline | 39.400 Score on a scale | Standard Deviation 6.535 |
| Escitalopram | Snaith-Hamilton Pleasure Scale (SHAPS-C) Score | Week 8 | 24.857 Score on a scale | Standard Deviation 6.89 |
| Escitalopram | Snaith-Hamilton Pleasure Scale (SHAPS-C) Score | Baseline | 38.625 Score on a scale | Standard Deviation 2.2 |
| Escitalopram | Snaith-Hamilton Pleasure Scale (SHAPS-C) Score | Week 2 | 33.375 Score on a scale | Standard Deviation 4.534 |
| Escitalopram | Snaith-Hamilton Pleasure Scale (SHAPS-C) Score | Week 4 | 27.250 Score on a scale | Standard Deviation 3.196 |
| Escitalopram | Snaith-Hamilton Pleasure Scale (SHAPS-C) Score | Week 6 | 25.250 Score on a scale | Standard Deviation 4.559 |