Major DepressionPhase 4NCT04352101
Bupropion Versus Escitalopram on Reward Circuitry and Motivational Deficits
A Phase 4 study testing Bupropion XL and Escitalopram in people with Major Depression, run by Emory University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 25 to 55 years
- Conditions the study is for
- Major Depression
- What is being tested?
- Bupropion XL and Escitalopram
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 1 siteUnited States
- Study dates
- 23 Sep 2020to 25 Jul 2022
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 25 to 55 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 16Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Effects of Bupropion Versus Escitalopram on Reward Circuitry and Motivational Deficits in Patients With Major Depression and Increased Inflammation and Anhedonia
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.
Read the 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.
- Conditions
- Major Depression
- Being tested
- Bupropion XL, Escitalopram
- Keywords
- Inflammation
- Medical subject headings
- Depressive Disorder, Major, Inflammation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Bupropion XLDrug
Also called Wellbutrin
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.
EscitalopramDrug
Also called Lexapro
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.
| Study group | Role | What they receive |
|---|---|---|
| Bupropion | Experimental | Participants randomized to take bupropion for 8 weeks. Receives: Drug: Bupropion XL |
| Escitalopram | Active comparator | Participants randomized to take escitalopram for 8 weeks. Receives: Drug: Escitalopram |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline, Week 4, Week 8
Secondary outcomes (4)
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.
Measured: Baseline, Week 2, Week 4, Week 8
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.
Measured: Baseline, Week 2, Week 4, Week 6, Week 8
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.
Measured: Baseline, Week 2, Week 4, Week 6, Week 8
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.
Measured: Baseline, Week 2, Week 4, Week 6, Week 8
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Apr 2020
- Study start23 Sep 2020
- Primary completion25 Jul 2022
- Study completion25 Jul 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Major DepressionStudies of the same condition, open and under way.
- More trials run by Emory UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Emory University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Responsible party
- Principal investigator, Andrew H Miller, Emory University
- Investigators
- Andrew Miller, MD, Principal investigator, Emory University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04352101
- Sponsor's protocol ID
- IRB00117673
- Other IDs
- 1R21MH121891
- Status last verified
- Dec 2023
- First submitted
- 16 Apr 2020
- Last updated
- 29 Dec 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The database generated by the study will be made available to the broader research community upon request accompanied by documentation of local institutional review board (IRB) approval. Investigators will provide relevant protocols and published phenotypic and clinical data upon request.
Study at a glance
From the registry record, last updated by the sponsor on 29 Dec 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Bupropion Versus Escitalopram on Reward Circuitry and Motivational Deficits in Patients With Major Depression and Increased Inflammation and Anhedonia
- ClinicalTrials.gov ID
- NCT04352101
- Acronym / sponsor ID
- IRB00117673
- Conditions
- Major Depression
- Keywords
- Inflammation
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 18 participants (actual)
- Lead sponsor
- Emory UniversityUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- 23 Sep 2020 (actual)
- Primary completion
- 25 Jul 2022 (actual)
- Study completion
- 25 Jul 2022 (actual)
- First posted
- 20 Apr 2020 (actual)
- Results
- Posted 29 Dec 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Bupropion | Experimental | Drug: Bupropion XLParticipants randomized to take bupropion for 8 weeks. |
| Escitalopram | Active comparator | Drug: EscitalopramParticipants randomized to take escitalopram for 8 weeks. |
Who may qualify
- Ages
- 25 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (16 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Bupropion XLAlso: WellbutrinParticipants 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. | Drug | Bupropion |
| EscitalopramAlso: LexaproParticipants 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. | Drug | Escitalopram |
Primary outcome
Change in Targeted Ventromedial Prefrontal Cortex-Ventral Striatal (vmPFC-VS) Functional Connectivity (FC)
Time frame: 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.
4 secondary outcomes
Proportion of Hard-Task Choices During the Effort-Expenditure for Rewards Task (EEfRT)
Time frame: Baseline, Week 2, Week 4, Week 8
Snaith-Hamilton Pleasure Scale (SHAPS-C) Score
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Motivation and Pleasure Scale-Self-Report (MAP-SR) Score
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Inventory of Depressive Symptomatology - Self-Report (IDS-SR)
Time frame: Baseline, Week 2, Week 4, Week 6, Week 8
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Dec 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. The database generated by the study will be made available to the broader research community upon request accompanied by documentation of local institutional review board (IRB) approval. Investigators will provide relevant protocols and published phenotypic and clinical data upon request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andrew Miller, MD principal investigator
Emory University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Bupropion XL and Escitalopram in people with Major Depression, run by Emory University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Dec 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Targeted Ventromedial Prefrontal Cortex-Ventral Striatal (vmPFC-VS) Functional Connectivity (FC) (time frame: Baseline, Week 4, Week 8). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Dec 2023.