DepressionPhase 4NCT02562430
Neurobiological Underpinnings of Placebo Response in Depression
A Phase 4 study testing Welbutrin XL in people with Depression, run by Massachusetts General Hospital at 1 site in United States.
Trial summary
In summary, the proposed research is novel with respect to design, technology, and its multi-level integration probing psychological and neurobiological constructs assumed to be crucially implicated in placebo response and has significant clinical and research implications for the future. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Depression
- What is being tested?
- Welbutrin XL
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 76 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2016to Aug 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 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- In addition to fulfilling the diagnostic criteria for MDD, the following conditions must be met for patient eligibility:
- Written informed consent
- Men or women aged 18 to 60 years old
- A score of 16 or greater on the Hamilton Depression Rating Scale -32 items (HAM-D- 32)
- Continuing to meet criteria for current MDD at baseline and Clinical Global Impression Improvement (CGI) scores ≤ 3 (i.e. minimally improved or less) from the screen to the baseline visit
- Only one failed one prior antidepressant in the current episode or are currently taking an antidepressant as defined by the MGH-ATRQ, in the current episode and are willing to take bupropion or placebo as augmentation, since we are using subjects as their own controls and we are comparing changes within subjects. Subjects with secondary anxiety disorders, like panic, GAD or simple phobia will be allowed, in order to make the population studied more representative of the general population of MDD.
Who cannot join
- Pregnant women or women of child bearing potential not using a medically accepted means of contraception.
- Serious suicide or homicide risk.
- Unstable medical illnesses, any history of seizure disorder.
- The following DSM-IV diagnoses: a) organic mental disorders; b) substance use disorders, including alcohol abuse, within the last year; c) psychotic disorders; d) bipolar disorder; e) acute bereavement; f) severe borderline or antisocial personality disorder; g) history of eating disorder unless if in remission for ≥5 years prior to screening and presenting no current electrolyte abnormalities; h) current primary diagnoses of panic disorder, social phobia, PTSD, GAD, or OCD; i) mood congruent or mood incongruent psychotic features.
- History of hepatic impairment or congestive heart failure.
- Any history of abuse of stimulants or opiates.
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- Currently taking any exclusionary medications (i.e., antipsychotics, anticonvulsants, stimulants, dopaminergic agents), potential augmenting agents (e.g., T3, SAMe, St. John's Wort, lithium,). Gabapentin and pregabalin are allowed. Patients must have either no antidepressant treatment or stable (for at least 4 weeks prior to screening). No dose changes are allowed during the study. Monoamine oxidase inhibitors are excluded. Concomitant use of trazodone (up to 200 mg daily) is allowed. In agreement with patient's treating provider and under clinical monitoring, exclusionary drugs can be tapered and washed out prior to baseline visit.
- Any investigational psychotropic drug within the last year.
- Subjects who have not responded to two or more antidepressant trials of adequate doses (e.g., fluoxetine 40 mg/day or higher) and duration (e.g., ≥6 weeks) over the past five years according to the ATRQ.
- History of inadequate response/poor tolerability to bupropion.
- Subjects with medical contraindications to bupropion (e.g., history of seizures, uncontrolled electrolyte imbalance due to eating disorders, etc.) unless stable for 8 weeks prior to screening and there will be no changes during participation in the study.
- Any unstable concomitant form of psychotherapy (depression-focused). Concomitant psychotherapy would be allowed if the frequency and the modality have been stable for the 8 weeks prior to screening and there will be no changes during the participation to the study
- Receiving or have received during the index episode VNS, ECT or rTMS.
- Color-blindness for blue or green (see fMRI task).
Trial locations and contacts
1 site in 1 country.
United States1 site
Depression Clinical and Research Program at Massachusetts General Hospital
Boston, Massachusetts, 02114
About this study
In summary, the proposed research is novel with respect to design, technology, and its multi-level integration probing psychological and neurobiological constructs assumed to be crucially implicated in placebo response and has significant clinical and research implications for the future. Specifically, the future implications include: 1) identification of biomarkers and biosignatures of placebo responders, 2) new possibilities to understanding and manipulating the system, 3) possibly decreasing or eliminating a major confounder in clinical trials and drug development, and 4) refining treatments with novel drugs that decrease (in clinical trial) or increase (in clinical practice) the placebo response.
Read the detailed description
The objective of this pilot study is to investigate possible dopaminergic mechanisms underlying the placebo response in MDD.
We expect that mesolimbic DA mechanisms implicated in reward anticipation, reinforcement learning, and expectation play a critical role in mediating placebo responses in MDD. A better understanding of the neurobiological basis of placebo has enormous potential on different levels. On a clinical level, the understanding of placebo mechanisms could lead to a number of applications for therapeutic purposes, such as developing drugs that could enhance the effects of a therapeutic relationship or accelerate the onset of action of an antidepressant by manipulating the placebo-related mechanisms, even if the patient is hopeless or severely anhedonic. On a level of clinical trial innovation, if we confirm the role of dopamine in placebo response and we comprehend how the placebo response mechanistically takes place, this could lead to developing new drugs that could block the placebo effects in clinical trial participants and greatly decrease if not eliminate the placebo effect nested even in those subject who are drug responders, therefore increasing the effect size and decreasing the sample size of studies. Moreover if we can identify biosignatures of placebo effect and use them to predict response, we could potentially enrich samples with subjects who are less likely to be placebo responders and again this would result in increased signal detection in a clinical trial. Finally, with this initial study we plan to lay the foundation for other studies to investigate how this dopaminergic circuitry is affected by other treatments, such as psychotherapy, and what are the changes that are similar or different between antidepressants, placebo and specific forms of psychotherapy, transcranial magnetic stimulation, electroconvulsive therapy or deep brain stimulation.
- Conditions
- Depression
- Being tested
- Welbutrin XL, Placebo
- Keywords
- Placebo response
- Medical subject headings
- Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Welbutrin XLDrug
Also called Buproprion XL
12.5% of participants will receive Welbutrin XL in phase 1 of the study.
PlaceboDrug
Also called Sugar pill
87.5% of subjects will be randomized to placebo in phase 1 of the study.
| Study group | Role | What they receive |
|---|---|---|
| Active Treatment | Experimental | 12.5 % will be randomized to Welbutrin XL in phase 1 of the study. Receives: Drug: Welbutrin XL |
| Placebo Group | Active comparator | 87.5% will be randomized to receive placebo in phase 1 of the study. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
HAM-D 32
The HAM-D-32 (Hamilton Depression Rating Scale) scores can range between 0 and 124, with higher scores indicating more severe depression. Total score was reported here.
Measured: 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Sep 2015 (estimated)
- Study startAug 2016
- Primary completionAug 2022
- Study completionAug 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 DepressionStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe 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
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 76 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Cristina Cusin, MD, Massachusetts General Hospital
- Investigators
- Cristina Cusin, MD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02562430
- Sponsor's protocol ID
- 2014P000889
- Status last verified
- Dec 2025
- First submitted
- 25 Sep 2015
- Last updated
- 14 May 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 14 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neurobiological Underpinnings of Placebo Response in Depression
- ClinicalTrials.gov ID
- NCT02562430
- Acronym / sponsor ID
- 2014P000889
- Conditions
- Depression
- Keywords
- Placebo response
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 76 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Study start
- Aug 2016
- Primary completion
- Aug 2022 (actual)
- Study completion
- Aug 2022 (actual)
- First posted
- 29 Sep 2015 (estimated)
- Results
- Posted 14 May 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
In summary, the proposed research is novel with respect to design, technology, and its multi-level integration probing psychological and neurobiological constructs assumed to be crucially implicated in placebo response and has significant clinical and research implications for the future. Specifically, the future implications include: 1) identification of biomarkers and biosignatures of placebo responders, 2) new possibilities to understanding and manipulating the system, 3) possibly decreasing or eliminating a major confounder in clinical trials and drug development, and 4) refining treatments with novel drugs that decrease (in clinical trial) or increase (in clinical practice) the placebo response.
Detailed description
The objective of this pilot study is to investigate possible dopaminergic mechanisms underlying the placebo response in MDD.
We expect that mesolimbic DA mechanisms implicated in reward anticipation, reinforcement learning, and expectation play a critical role in mediating placebo responses in MDD. A better understanding of the neurobiological basis of placebo has enormous potential on different levels. On a clinical level, the understanding of placebo mechanisms could lead to a number of applications for therapeutic purposes, such as developing drugs that could enhance the effects of a therapeutic relationship or accelerate the onset of action of an antidepressant by manipulating the placebo-related mechanisms, even if the patient is hopeless or severely anhedonic. On a level of clinical trial innovation, if we confirm the role of dopamine in placebo response and we comprehend how the placebo response mechanistically takes place, this could lead to developing new drugs that could block the placebo effects in clinical trial participants and greatly decrease if not eliminate the placebo effect nested even in those subject who are drug responders, therefore increasing the effect size and decreasing the sample size of studies. Moreover if we can identify biosignatures of placebo effect and use them to predict response, we could potentially enrich samples with subjects who are less likely to be placebo responders and again this would result in increased signal detection in a clinical trial. Finally, with this initial study we plan to lay the foundation for other studies to investigate how this dopaminergic circuitry is affected by other treatments, such as psychotherapy, and what are the changes that are similar or different between antidepressants, placebo and specific forms of psychotherapy, transcranial magnetic stimulation, electroconvulsive therapy or deep brain stimulation.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Active Treatment | Experimental | Drug: Welbutrin XL12.5 % will be randomized to Welbutrin XL in phase 1 of the study. |
| Placebo Group | Active comparator | Drug: Placebo87.5% will be randomized to receive placebo in phase 1 of the study. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- In addition to fulfilling the diagnostic criteria for MDD, the following conditions must be met for patient eligibility:
- Written informed consent
- Men or women aged 18 to 60 years old
- A score of 16 or greater on the Hamilton Depression Rating Scale -32 items (HAM-D- 32)
- Continuing to meet criteria for current MDD at baseline and Clinical Global Impression Improvement (CGI) scores ≤ 3 (i.e. minimally improved or less) from the screen to the baseline visit
Key exclusion criteria (14 listed)
- Pregnant women or women of child bearing potential not using a medically accepted means of contraception.
- Serious suicide or homicide risk.
- Unstable medical illnesses, any history of seizure disorder.
- The following DSM-IV diagnoses: a) organic mental disorders; b) substance use disorders, including alcohol abuse, within the last year; c) psychotic disorders; d) bipolar disorder; e) acute bereavement; f) severe borderline or antisocial personality disorder; g) history of eating disorder unless if in remission for ≥5 years prior to screening and presenting no current electrolyte abnormalities; h) current primary diagnoses of panic disorder, social phobia, PTSD, GAD, or OCD; i) mood congruent or mood incongruent psychotic features.
- History of hepatic impairment or congestive heart failure.
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 |
|---|---|---|
| Welbutrin XLAlso: Buproprion XL12.5% of participants will receive Welbutrin XL in phase 1 of the study. | Drug | Active Treatment |
| PlaceboAlso: Sugar pill87.5% of subjects will be randomized to placebo in phase 1 of the study. | Drug | Placebo Group |
Primary outcome
HAM-D 32
Time frame: 8 weeks
The HAM-D-32 (Hamilton Depression Rating Scale) scores can range between 0 and 124, with higher scores indicating more severe depression. Total score was reported here.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 May 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
Cristina Cusin, MD principal investigator
Massachusetts General Hospital
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 Welbutrin XL in people with Depression, run by Massachusetts General Hospital 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 14 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 14 May 2026. 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 14 May 2026). 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?
HAM-D 32 (time frame: 8 weeks). 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 14 May 2026.