Neurobiological Underpinnings of Placebo Response in Depression

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.

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).