Neurobiological Underpinnings of Placebo Response in Depression

NCT ID: NCT02562430

Last Updated: 2022-09-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 73 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-08-31
• Study Completion Date: 2022-08-31

Brief 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. 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.

Conditions

Depression

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Active Treatment

12.5 % will be randomized to Welbutrin XL in phase 1 of the study.

Group Type: EXPERIMENTAL

Welbutrin XL

Intervention Type: DRUG

12.5% of participants will receive Welbutrin XL in phase 1 of the study.

Placebo Group

87.5% will be randomized to receive placebo in phase 1 of the study.

Group Type: ACTIVE_COMPARATOR

Placebo

Intervention Type: DRUG

87.5% of subjects will be randomized to placebo in phase 1 of the study.

Interventions

Welbutrin XL

12.5% of participants will receive Welbutrin XL in phase 1 of the study.

Intervention Type: DRUG

Placebo

87.5% of subjects will be randomized to placebo in phase 1 of the study.

Intervention Type: DRUG

Other Intervention Names

Buproprion XL; Sugar pill

Eligibility Criteria

Inclusion Criteria

In addition to fulfilling the diagnostic criteria for MDD, the following conditions must be met for patient eligibility:

1. Written informed consent

2. Men or women aged 18 to 60 years old

3. A score of 16 or greater on the Hamilton Depression Rating Scale -32 items (HAM-D- 32)

4. 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

5. 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.

Exclusion Criteria

1. Pregnant women or women of child bearing potential not using a medically accepted means of contraception.

2. Serious suicide or homicide risk.

3. Unstable medical illnesses, any history of seizure disorder.

4. 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.

5. History of hepatic impairment or congestive heart failure.

6. Any history of abuse of stimulants or opiates.

7. 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.

8. Any investigational psychotropic drug within the last year.

9. 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.

10. History of inadequate response/poor tolerability to bupropion.

11. 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.

12. 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

13. Receiving or have received during the index episode VNS, ECT or rTMS.

14. Color-blindness for blue or green (see fMRI task).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Cristina Cusin, MD

Staff Psychiatrist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Cristina Cusin, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Depression Clinical and Research Program at Massachusetts General Hospital

Boston, Massachusetts, United States

Countries

United States

Other Identifiers

2014P000889

Identifier Type: -

Identifier Source: org_study_id