Effects of Bupropion Versus Escitalopram on Reward Circuitry and Motivational Deficits in Patients With Major Depression and Increased Inflammation and Anhedonia
Phase: PHASE4
Conditions: Major Depression
Sponsor: Emory University

Protocol 
 
Title: Eﬀects of Bupropion versus Escitalopram on Reward Circuitry and 
MoƟvaƟonal Deﬁcits in PaƟents with Major Depression and Increased 
InﬂammaƟon and Anhedonia 
 
NCT Number: NCT04352101 
 
Protocol date: July 27, 2022 

Emory IRB00117673
PI: AH Miller 
Sponsor: NIMH
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1. Title: Effects of Bupropion versus Escitalopram on Reward Circuitry and Motivational
Deficits in Patients with Major Depression and Increased Inflammation and Anhedonia
Principle Investigators: Andrew H. Miller MD and Jennifer C. Felger, PhD
Co-Investigators: Ebrahim Haroon MD, Michael Treadway, PhD, Bobbi Woolwine, MSW
Version 7_Mod_31:  July 27, 2022
2. Précis/Abstract: 
The overall objective of the proposed research is to determine the mechanism of action of an 
antidepressant of known efficacy and tie this mechanism of action to a specific biomarker, ultimately 
supporting precision medicine in the treatment of major depression (MD). More specifically, the proposed 
research 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. Work by our group and others has demonstrated that 
administration of inflammatory stimuli to humans is associated with significant decreases in neural activity 
in the ventral striatum in association with symptoms of anhedonia. In studies in laboratory animals and 
humans, these effects of inflammation appear to be secondary to decreased dopamine (DA) 
neurotransmission. Data also indicate that MD patients with higher inflammation as indexed by C-reactive 
protein (CRP) exhibit lower FC between the DA-rich ventral striatum and ventromedial prefrontal cortex in 
association with motivational deficits and anhedonia that can be reversed by a DAergic drug (L-DOPA). 
Further relevant to the proposed research, in a recent clinical trial, depressed patients with increased 
inflammation (CRP≥1mg/L) showed a poor response to the selective serotonin reuptake inhibitor (SSRI) 
escitalopram alone, while treatment response was markedly increased in escitalopram-treated patients 
with the addition of bupropion. Bupropion is a DA reuptake inhibitor that exhibits ~25% occupancy of the 
DA transporter at therapeutic doses and increases DA neurotransmission in animal models. Taken 
together, these data suggest that inflammation affects DAergic pathways to disrupt reward-related circuits 
in depressed patients, leading to motivational deficits. Moreover, in the context of inflammation, drugs that 
target DA may be more efficacious than SSRIs. Thus, the current 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 DA (e.g. bupropion) might be a better choice for depressed patients with 
increased inflammation and anhedonia than an 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 FC in reward-related circuits at baseline, 4 and 
8 weeks along with objective and clinical assessments of RDoC positive (motivational) valence constructs 
at baseline and 2, 4, 6 and 8 weeks. We hypothesize that patients who receive bupropion versus 
escitalopram will exhibit increased FC between ventral striatum and ventromedial prefrontal cortex in 
association with decreased motivational deficits and anhedonia. This pilot study will provide foundational 
data for design of larger mechanistic clinical trials that will establish the mechanism of action of 
conventional antidepressants and determine whether biomarkers of inflammation can be used to facilitate 
antidepressant choice, increase antidepressant efficacy and ultimately personalize antidepressant 
treatment.    
3. Introduction and Background: 
Inflammatory Biomarkers May Reveal Differential Responsiveness to Conventional Antidepressants
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 
~10% of US adults and being the leading cause of disability worldwide.1, 2 Despite availability of several 
classes of antidepressant medications, initial treatment response is low (~30%), and ~1/3 of depressed 
patients are non-responsive to conventional antidepressant therapies.3-5 Although extensive reviews of 
the literature suggest that available antidepressant medications are equally effective,6, 7 recent studies 
suggest that there may be differential responsiveness to conventional antidepressants among subgroups 
of depressed patients.8, 9 

Emory IRB00117673
PI: AH Miller 
Sponsor: NIMH
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One subgroup of depressed patients who may exhibit differential antidepressant responsiveness are 
those with increased markers of inflammation. A meta-analysis on inflammation and treatment response 
suggests that patients with increased inflammation respond poorly to conventional antidepressants.10 
Nevertheless, as part of this literature, two large community-based trials of over 300 subjects found that 
patients with increased inflammation as indexed by a C-reactive protein (CRP) ≥1mg/L responded 
significantly better to the norepinephrine (NE) and dopamine (DA) reuptake inhibitors, nortriptyline and 
bupropion than the selective serotonin reuptake inhibitor (SSRI) escitalopram, which showed better 
efficacy in patients with low inflammation.8, 9 Indeed, in one of these studies, the SSRI escitalopram led to 
57% remission in depressed patients with low inflammation (CRP <1mg/L), whereas in patients with 
higher inflammation (CRP≥1mg/L), the remission rate with escitalopram alone was below 30%.8 Addition 
of bupropion to escitalopram in patients with high inflammation increased the remission rate to 51%.8 
These data 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 CRP. 
However, all studies examining the impact of inflammation on antidepressant treatment response have 
been post hoc in nature, and no study has prospectively examined whether a priori subgrouping of 
depressed patients by inflammatory status predicts response to conventional antidepressants.  In 
addition, the mechanism by which bupropion or nortriptyline vs an SSRI may increase antidepressant 
responsiveness in patients with increased inflammation is unknown. This proposal is designed to address 
both of these gaps in the literature.
Differential Antidepressant Responsiveness May Relate to the Impact of Inflammation on Monoamine 
Transporter Activity and Dopamine and Dopamine-Related Reward Circuitry
Inflammatory cytokines including interleukin (IL)-1beta and tumor necrosis factor (TNF) increase 
expression and function of the serotonin transporter (SERT) through activation of p38 mitogen activated 
protein kinase (MAPK) pathways.11, 12 For example, administration of the inflammatory stimulus 
lipopolysaccharide (LPS) to wild-type mice increased reuptake and clearance of serotonin while inducing 
depressive-like behavior; effects that were completely reversed by a p38 MAPK inhibitor or the use of IL-1 
receptor deficient mice.12  Interestingly, similar effects of IL-1, TNF and LPS were found on the NE 
transporter (NET), but not the DA transporter (DAT). These data suggest that inflammation may sabotage 
SSRIs (and possibly SNRIs) by increasing the activity and function of the very targets of these drugs (the 
transporters). Thus, the impact of inflammation on SERT and NET suggest that drugs that inhibit DAT 
may be more effective in states of high inflammation.  
In addition to the effects of inflammation on the SERT and NET, data support that inflammation may 
affect behavior in part through decreasing DA availability and disrupting DA-mediated reward pathways. 
Chronic administration of IFN-alpha is associated with blunted responses in the DA-rich ventral striatum 
(VS) to reward anticipation using functional magnetic resonance imaging (fMRI).13 In addition, IFN-alpha 
treatment of patients with hepatitis C decreases DA release within the striatum as measured by 
[18F]Dopa binding using PET.13 Other inflammatory stimuli including endotoxin and typhoid vaccination 
administered to healthy volunteers also decrease neural activity in the VS in response to rewarding 
stimuli using fMRI.14-16 Consistent with these neuroimaging findings, studies using in vivo microdialysis in 
VS have demonstrated that chronic administration of IFN-alpha to non-human primates is associated with 
significant decreases in extracellular DA both at baseline and following stimulation with potassium or 
amphetamine.  It should be noted that subchronic administration of IFN-alpha (2 weeks) and acute 
administration of LPS can increase DA release, possibly related to the timing of inflammatory exposure.17-
19 Interestingly, chronic effects of IFN-alpha on extracellular DA release were reversed by the DA 
precursor L-DOPA administered via reverse microdialysis.20 Decreases in extracellular DA were also 
found in rodents administered interleukin (IL)-6 and sampling from the nucleus accumbens.21 Consistent 
with the effects of inflammation on striatal neural activity and DA and their role in motivated behavior, 
inflammation also produces concomitant effects on behaviors relevant to motivation including effort 
expenditure for reward. For example, using a concurrent choice paradigm in rodents, acute administration 
of IL-1beta or IL-6 was associated with a shift away from preferred foods that required effort in favor of 
less desirable food that was freely available.21, 22 Similar inhibitory effects of inflammatory stimuli on 
effortful behavior occur in rodents,23 non-human primates,17 and humans.24 
Relative to patients with MD, previous studies by our group have shown that higher endogenous 
inflammation indexed by CRP in medically stable MD patients is associated with lower functional 
connectivity (FC) between ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC) in 

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association with anhedonia and motivational deficits including decreased effort expenditure for reward 
(see preliminary data).25 These studies indicate that increased chronic endogenous inflammation in 
patients with MD leads to similar changes in reward circuitry and motivation as chronic exogenously 
administered inflammatory stimuli. 
Bupropion is a Viable Candidate Antidepressant to Test in MD Patients with Increased Inflammation
There are several reasons that bupropion might have increased efficacy in MD patients with increased 
inflammation.26 First, as noted above, bupropion in combination with escitalopram was shown to rescue 
treatment remission in patients with CRP ≥1mg/L, increasing treatment remission from less than 30% to 
over 50%.  Furthermore, in human studies, bupropion (300mg/d) occupies the DAT by as much as 25% 
using displacement of radiolabeled DAT ligands.27, 28 One study reported 14% DAT occupancy with 
bupropion, although several confounds of the study design including a lower dosing regimen make 
interpretation of these data difficult.29 Of note, in non-human primates, an acute IV bolus of 5mg/kg of 
bupropion led to ~85% DAT occupancy in striatum.30 In addition, several studies in rodents demonstrated 
that bupropion increases extracellular DA in striatum and nucleus accumbens in a dose and time-
dependent manner.31, 32 Moreover, intraperitoneal administration of bupropion increased effort-based 
motivation for food rewards in association with pre- and post-synaptic markers of increased DA 
transmission.33 Finally, bupropion (but not fluoxetine or desipramine) reversed the inhibitory effects on 
effort-based motivation by tetrabenazine, a drug that depletes accumbens DA.34 Taken together, these 
data support the choice of bupropion as a reasonable candidate to increase FC within DA-related reward 
circuitry and increase motivation in depressed patients with increased inflammation and anhedonia. It 
should be noted that while nortriptyline also exhibited efficacy in MD patients with high inflammation, it is 
unclear whether these effects were related to reported effects of NET inhibition on increasing DA release 
in frontal cortex.35 Interestingly, in a systematic review of conventional antidepressants for smoking 
cessation, only bupropion and nortriptyline exhibited significant efficacy, suggesting some overlap on their 
effects on reward-related pathways.36 Nevertheless, given the strong evidence of the impact of 
inflammation on DA neurotransmission, we chose to proceed with a medication that had more clear-cut 
effects on DA (bupropion), as opposed to a drug that is a norepinephrine reuptake inhibitor. Of note, there 
are other drugs that have more selective and potentially more potent effects on DA than bupropion 
(obviating effects of bupropion on NE reuptake and the related inhibitory impact of NE on microglial 
activation and proinflammatory cytokine production37).  Nevertheless, bupropion is an FDA-approved drug 
of known efficacy in the treatment of depression (a requirement of the funding mechanism to which this 
proposal is directed – see Introduction).    
Working Model and Hypothesis
Bupropion vs escitalopram will 
increase FC between DA-rich 
reward regions in the VS and 
cortical reward regions in the 
vmPFC and improve 
associated RDoC positive 
valence constructs including 
effort-based motivational 
deficits in MD patients with 
increased inflammation and 
anhedonia.
4. Objectives: (Primary and secondary aims)
The goal of the proposed research is to establish the mechanism of action of an antidepressant 
medication with known efficacy and to tie this mechanism to a biomarker of inflammation. Specifically, we 
plan to determine whether bupropion (vs escitalopram) can increase functional connectivity (FC) within 
reward-related circuitry and improve motivational deficits in patients with major depression (MD) and both 
increased inflammation and anhedonia. Recent studies suggest that increased inflammation [as indexed 
by the inflammatory biomarker C-reactive protein (CRP)] is associated with a poor response to serotonin 
reuptake inhibitors including escitalopram. However, in a recent study, the treatment response to 
escitalopram in patients with increased CRP (≥1mg/L) was almost doubled with the addition of bupropion. 
Bupropion is a DA reuptake inhibitor that exhibits ~25% occupancy of the DA transporter at therapeutic 
doses and increases DA neurotransmission in animal models. These data suggest that the subgroup of 

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Sponsor: NIMH
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depressed patients with increased inflammation may have unique responsiveness to drugs that target 
DA. Indeed, preclinical and clinical studies demonstrate that chronic administration of inflammatory stimuli 
leads to decreased DA availability in ventral striatum (VS) in association with decreased VS activation to 
rewarding stimuli. In addition, higher inflammation as reflected by CRP is directly linked to lower FC 
between the DA-rich VS and the ventromedial prefrontal cortex (vmPFC) in MD patients using resting 
state fMRI. These inflammation-related decreases in VS-vmPFC FC in depressed patients in turn were 
associated with motivational deficits consistent with an impact of inflammation on RDoC positive valence 
constructs. Our preliminary data also indicate that administration of the DA-ergic drug L-DOPA increases 
VS-vmPFC FC (and effort-based motivation) in MD patients with high (CRP>2mg/L) but not low 
(CRP≤2mg/L) inflammation, using a longitudinal pre- post- neuroimaging design. These data suggest that 
this circuit and the related behaviors may be especially responsive to DA’ergic medications. Thus, the 
relationship between CRP and resting state FC within classic reward circuitry in MD patients provides a 
unique opportunity whereby a functional target in the brain can be used to establish whether there exists 
differential responsiveness to currently available antidepressants that can be revealed by an inflammatory 
biomarker (CRP) that is regularly used in clinical practice.  Accordingly, this proposal will employ a 
match/mismatch design, wherein patients with MD and increased inflammation (CRP>2mg/L) and 
anhedonia will be randomized to bupropion (match) or escitalopram (mismatch). A cut-off of CRP>2mg/L 
will be used because it predicted increased FC in response to L-DOPA and serves as an excellent 
translational proxy for a composite of inflammatory mediators in periphery and brain. CRP>2mg/L has 
also been used in the cardiovascular literature as a threshold for treatment of inflammation. Increased 
anhedonia will be defined as a score of 2 or greater on item 1 of the PHQ-9. . To examine FC in reward-
related circuitry, fMRI will be conducted at baseline and after 4 and 8 weeks of treatment. We hypothesize 
that bupropion (vs escitalopram) will increase FC within reward circuitry in association with improved 
objective and clinical measures of motivation in patients with high inflammation and anhedonia at 
baseline. To test this hypothesis, these aims are proposed:
Specific Aim 1. To determine whether bupropion (vs escitalopram) will increase functional connectivity in 
reward circuitry in MD patients with high inflammation and anhedonia. Fifty patients (n=50) with a CRP 
>2mg/L and an anhedonia score ≥ 2 on item #1 of the PHQ-9 will be stratified by sex and randomized to 8 
weeks of bupropion XL up to 300mg/d or escitalopram up to 20 mg/d (as tolerated). FC between VS-
vmPFC will be examined at baseline and after 4 and 8 weeks using resting state and task-based fMRI. 
Hypothesis 1: Bupropion vs escitalopram will increase VS-vmPFC FC in MD patients with high CRP and 
anhedonia. 
Specific Aim 2. To determine whether bupropion (vs escitalopram) will improve motivational deficits in MD 
patients with high inflammation and anhedonia. Objective and clinical measures of RDoC positive valence 
(motivational) constructs will be assessed in the subjects in Aim 1 at baseline and after 2, 4, 6 and 8 
weeks of treatment with bupropion or escitalopram by the Effort-Expenditure for Rewards Task (EEfRT) 
and the clinician-administered Snaith Hamilton Pleasure Scale and self-report Mood and Pleasure Scale. 
Hypothesis 2a: Bupropion vs escitalopram will increase the probability of making high effort choices on 
the EEfRT and improve scores on clinical and self-reported assessments of motivation. Hypothesis 2b: 
Improvement in VS-vmPFC connectivity will correlate with increased high effort choices on the EEfRT and 
improved scores on clinical and self-reported assessments of motivation.
Specific Aim 3 (Exploratory). To determine whether bupropion (vs escitalopram) will improve overall 
depressive symptoms in MD patients with high inflammation and anhedonia. Depressive symptom 
severity will be assessed by the Hamilton Depression Rating Scale-17 (HAM-D-17) at baseline and after 
weeks 2, 4, 6 and 8 of treatment in subjects noted in Aim 1. Hypothesis 3: Bupropion vs escitalopram will 
improve depression severity in MD patients with high CRP and anhedonia at baseline.  
In sum, by demonstrating the ability of bupropion vs escitalopram to increase FC in reward circuitry and 
reduce motivational deficits in MD patients with increased inflammation and anhedonia, this pilot study 
will not only help establish a mechanism of action for bupropion but will also help provide an important 
foundation for preferentially using bupropion (and other medications that target DA) in patients with 
increased inflammatory biomarkers such as CRP and anhedonia, thus supporting precision medicine 
using available antidepressants. 

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Sponsor: NIMH
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5. Study design and methods: 
Study Population: Fifty male and female subjects ages 25-55 will be randomized to obtain 40 with 
complete data (20% projected attrition). Subjects will be recruited from a community sample of MD 
patients through social media. 
Participant Selection
Inclusion Criteria: a. willing and able to give written or virtual informed consent; b. men or women, 25-55 
years of age or at PI’s discretion; c. a primary diagnosis of DSM-V MD or Bipolar II current episode, 
depressed, as diagnosed by the SCID- Structured Clinical Interview for DSM-V Axis I Disorders (SCID-V) 
V; d. score of  >10 on the PHQ-9 and a score of 2 or greater on item #1 of the PHQ-9; e. 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 f. CRP>2mg/L, and g. IDS-SR anhedonia subscale (Items 8,19,21) score ≥5.
Exclusion Criteria: a. current autoimmune disorder; b. history of hepatitis B or C infection or human 
immunodeficiency virus infection; c. history of any type of cancer requiring treatment with more than minor 
surgery; d. unstable cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic disease (as 
determined by physical examination and laboratory testing); e. history of any (non-mood-related) 
psychotic disorder; active psychotic symptoms of any type; history of Bipolar I Disorder; substance 
abuse/dependence within 6 months of study entry (as determined by SCID) or any 2 year period of 
continued substance abuse; f. an active eating disorder  or antisocial personality disorder; g. a history of a 
cognitive disorder unless otherwise approved by the PI; h. pregnancy or lactation; i. chronic use of non-
steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg of aspirin), glucocorticoid containing 
medications; j. use of NSAIDS or oral glucocorticoids at any time during the study; k. any contraindication 
for MRI scanning; l. failure of more than 2 antidepressant trials in the current episode; m. Intolerance of 
bupropion or escitalopram and n. BMI >40 (to exclude severe obesity). Due to the high co-morbidity 
between anxiety disorders and depression, we plan to include patients with anxiety-related disorders 
excluding 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. m. 
sexually active participants will be asked not to become pregnant during study participation. Pregnancy 
tests will be conducted at screening, baseline,and treatment weeks 4 and 8.
Description of Study Procedures
Appointment Scheduling & Reminders: All participants will be given the opportunity to receive 
appointment reminders and scheduling information via text message on their mobile phones. If the 
subject consents to this form of communication, study staff may use OhMD Texting Service to 
communicate with participants. This platform provides a Desktop and Mobile Version of OhMD for the 
research team to securely communicate with participants and maintain subject confidentiality. This 
service will only be used for communicating relevant appointment information and never used for PHI. 
Participants will receive the following text message from the study team upon first contact: “Please do 
NOT send any personal information via text. You may call the study team at 404-727-8229 to discuss any 
personal or health details.” Any PHI received via text message will be reported to the IRB as a potential 
breach of confidentiality.
Screening: Screening will include: (1) Past psychiatric history and current symptom severity by clinical 
interview and using a modified Structured Clinical Interview for DSM-V (SCID-V),38 and the PHQ-9 39 (2) 
Psychiatric treatment history in current episode using the MGH Antidepressant Treatment Response 
Questionnaire (ATRQ),40 (3) Medical history from patient interview and review of medical records, (4) 
Complete medical and neurological examination (5) Screening laboratory evaluation, (6) Vital signs, 
height and weight and (7) hsCRP (obtained twice over a 2-week period at the P.I’s discretion as per 
AHA/CDC guidelines to establish stability, and along with physical examination and laboratory testing to 
rule out acute inflammation or infection (which may influence DA neurotransmission). The PI may request 
to perform a rapid CRP test at screening using the Diazyme hsCRP POC Test Kit. This kit produces rapid 
results using a finger prick method to collect 20μl of blood and is intended for the in vitro quantitative 
determination of C-reactive protein. Screening laboratory evaluations may be repeated at PI’s or PI 
designee’s discretion. Additional assessments will be conducted if more than 4 weeks from screening, 
unless otherwise approved by the PI, study physician or PI’s designee.

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Baseline and Study Procedures: After screening, subjects will undergo fMRI and behavioral assessments 
at baseline followed by stratification by sex and double-blind randomization to either bupropion XL 
150mg/d or escitalopram 10mg/d as indicated in Table 1. The randomization scheme will be implemented 
by research pharmacy, and all patients and study staff will be blinded to treatment assignment. Patients 
will be randomized in blocks of 4. After 2 weeks, subjects with a HDRS-17_>7_will be increased to 
bupropion XL 300mg/d or escitalopram 20mg/d as tolerated.  fMRI scanning and behavioral assessments 
will be repeated at 4 and 8 weeks. Vital signs, safety labs, urine toxicology and adverse events will be 
collected as indicated in Table 1. The primary outcome (Aim 1) will be targeted VS-vmPFC FC as detailed 
below. Secondary outcomes (Aim 2) will include RDoC positive valence constructs including objective 
assessments of effort-based decision making and clinician-administered and self-report assessments of 
motivation/anhedonia (see below). Additional (exploratory) outcomes will include treatment response over 
time and adverse events. 
Virtual
Visit 1
Visit 2
Visit 3
Visit 
4
Visit 
5
Virtual
Visit 
6
Assessments
Intake
Screen 
A
Screen 
B
Base-
line A
Base-
line B
Wk 2
Wk 4
Wk 6
Wk 8
Consent
X
PHQ-9, Medical / 
Psychiatric Screening*** 
X
[X]
[X]
FERN MRI Screening 
Form***
[X]
X
X
X
ATRQ,  Medical History, 
SCID V-modified (Mood, 
Anxiety, PTSD modules), 
Bipolarity index
X
Laboratory Eval*, 
Urinalysis, height weight***
X
Rapid CRP (Finger Stick)***
X
X
Physical Exam 
X
Vital Signs
X
X
X
X
X
X
Adverse events**, 
Concomitant Meds***
X
X
X
X
X
X
X
X
Urine toxicology screen, 
pregnancy test***
X
X
X
X
Research bloods†
X
X
X
Neurocognitive Battery
X
X
X
X
EEfRT (computer-based)
X 
X
X
X
X
Demographics, habits, CTQ
X
MAP, IDS-SR, STAI, BAI, 
PCL-5, PSS
X
X
X
X
X
fMRI
X
X
X
SHAPS-C, CSSRS, CGI
X
X
X
X
X
HAM-A [Baseline only]****, 
HAM-D-17
X
X
X
X
Randomization to 
bupropion / escitalopram 
X
Table 1. Schedule of Study Procedures and Assessments

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* Laboratory evaluation will include the comprehensive metabolic panel, thyroid-stimulating hormone (TSH), 
CBC with diff, and plasma CRP. 
** Adverse events will be recorded at each visit after study enrollment (Baseline A until Week 8).
§ Compliance check will be conducted starting at Week 2 until Week 8.
# Medication dosage will be adjusted upward to 2 pills at Week 2 or Week 4 as needed based on tolerability.
[]To be completed if needed
***These assessments may be conducted at the Emory Behavioral Immunology program research 
screening clinic  
****HAM-A instrument removed from Baseline visit on 7/5/22.
Criteria for Study Discontinuation (“Stopping Rules”): 
Individual:
To reduce the risks associated with active treatment, all subjects will be monitored carefully for the 
development of adverse events as well as worsening of their condition. Between signing consent and 
completing the screening assessment, a period of no more than 2 weeks will pass until baseline. Subjects 
will be closely evaluated throughout the study both virtually and during study visits for worsening of 
psychiatric symptoms. Moreover, all patients are provided 24/7 access to study personnel in the event of 
an emergency. Subjects will be discontinued at any point for any of the following: 1) the development of 
significant suicidal ideation, plan or intent as determined by spontaneous subject report or as determined 
by CSSRS,41 2) the development of psychotic or catatonic symptoms, 3) a 25% increase from baseline of 
HAM-D-17 score, 4) missing more than 2 consecutive doses of medication more than once during the 
study, and 5) positive pregnancy test. Subjects requiring discontinuation will be referred for further 
evaluation and treatment by one of the study psychiatrists. 
Study:
1) If more than two individuals experience a reportable serious adverse event related to study procedures 
within a six-month period, the study will be stopped and reviewed by the DSMB.
Neuropsychiatric Assessments
Structured Clinical Interview for DSM-V Axis I Disorders (SCID-V) is a semi-structured clinical interview 
that provides a wide range of DSM-V diagnoses.42 All patients will be evaluated by  a modified SCID as 
part of the screening process. In addition to providing information for inclusion/exclusion purposes, the 
SCID will provide data about psychiatric predictors of treatment response, including number of past major 
depressive episodes, length of the current episode and presence of co-morbid anxiety disorders and/or 
dysthymia. 
The MGH Antidepressant Treatment Response Questionnaire (ATRQ):43 The ATRQ provides specific 
criteria for adequate dose and adequate length of a trial for it to be considered a failure, thus allowing 
clinicians to systematically collect data aimed at assessing degree of treatment-resistance of the MD 
episode. The data obtained can then be used to calculate a score using the MGH Staging Method (MGH-
S) to classify degree of treatment resistance.40 Degree of resistance will be used as a covariate in 
relevant statistical analyses and to exclude severely treatment resistant subjects.44 Severity of clinical 
condition and improvement in overall clinical state over the study period will be evaluated at each 
assessment with the Clinical Global Impressions Scale (CGI)45. Inventory of Depressive Symptoms-Self 
Report (IDS-SR) is a 30-item self-report instrument with excellent psychometric properties that was 
designed to measure symptom constructs including psychomotor retardation, fatigue and anhedonia 
consistent with current DSM nosology. MRI neuroimaging: Scans will be carried out in Emory’s Facility for 
Education and Research in Neuroscience (FERN) on a Siemens Trim Trio 3T scanner and 32-channel 
head coil using the following protocols. Anatomic images: High-resolution T1 weighted images 46 will be 
obtained for co-registration with fMRI data. A localizer scan will be used to orient the 3D volume scan. 
Medication dispensing 
/compliance check§ 
X
X
X
X
X
Adjustment of medication#
X
X
X
Discharge/discharge 
planning
X
X
X

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Resting fMRI BOLD: Resting bold will be acquired before and after treatment using phase-encoding 
directions of opposite polarity (anterior-posterior) for distortion correction. Sequences will be optimized for 
signal-to-noise ratio and sensitivity to head motion, and collected over ~15 minutes.47 Data will be 
analyzed with standard preprocessing protocols in AFNI (http://afni.nimh.nih.gov/) and SPM12 
(www.fil.ion.ucl.ac.uk/spm12/), including slice-timing correction, realignment/motion-correction, anat-to-epi 
co-registration, and 5mm spatial smoothing.25, 48, 49 Resting BOLD analysis will also include nuisance 
signal regression (head motion, cerebral spinal fluid, and white matter) and band pass filtering 
(0.009Hz<f<0.08Hz). Individual’s fMRI data will be normalized into a standard stereotaxic space, MNI 
template with 1mm3 resolution. MIDT: MIDT will be used to assess FC50-52 during reward anticipation. 
This widely-used task for assessing reward function in psychiatric patients53-55 is one of the few imaging 
reward tasks with established test-retest reliability.56 Monetary outcome depended on patient 
performance in a simple reaction time task by pressing a button in response to a visual target stimulus. 
The “anticipatory delay,” ~4000 m, occurs after presentation of a pseudo-randomly distributed cue to 
inform participants whether a given trial will allow them to win or lose money (reward: +$; loss: -$; no 
incentive: 0$; averaging ~$2) but prior to the target stimulus, has reliably been shown to robustly activate 
ventral striatum.53, 57, 58 Participants will complete 2 functional runs of 70 trials each (140 trials total) over 
~20 minutes.50, 52 FC during each anticipation condition will be assessed using beta-series correlation59 
shown to be both powerful and sensitive for assessing task-modulated connectivity60, 61 and has been 
used with MIDT.50, 52 Task-based fMRI - Faces Task: This is a task that has been developed to measure 
brain activity in response to viewing of fearful and neutral faces. For the duration of the task, patients will 
be instructed to passively view faces as they appear on the screen. The task lasts 5 minutes and 
proceeds as follows: 15 blocks of 16 trial face stimuli are presented in pseudorandom order. Each block 
contains 8 fearful faces and 8 neutral faces presented in random order. Each face stimulus is presented 
for 500ms, followed by a 500ms presentation of a fixation cross. After every 10th block, a 10,000ms rest 
period is presented. The task has been designed to minimize patient discomfort and enhance 
cooperation. If at any time a patient experiences negative or unpleasant reaction, they will be removed 
from the scanner. The addition of these tests does not add to the overall risk to patient safety. DTI: At the 
first visit, a cmrr_mbep2d_bold protocol over ~12 minutes will be used calculated fractional anisotropy 
(FA) maps for each voxel using 3DSlicer.
Targeted FC will serve as the primary outcome and will be calculated as the degree of correlation 
in activity between a 3mm3 radius sphere in VS (see Fig. 1A)25, 62 and the vmPFC cluster identified as 
being reward-sensitive in neuroimaging meta-analyses63 and as used to define vmPFC in our previous 
work (MNI coordinates x=0, y=44, z=-8, cluster size=1408 mm3 and encompassing parts of BA11 and 
ventral BA32 of ACC).25, 62, 64 This method will ensure rigor and reproducibility and application of results to 
potential future trials because the seeds and ROI cluster are predefined as opposed to those derived from 
whole-brain and data-driven analyses which are determined based on the specific patient sample. Z-
scores will be extracted and the change in mean FC values compared to baseline will be calculated. FC 
between bilateral VS seeds and the vmPFC ROI will be examined separately and treatment-driven 
change in FC in either the right or left VS will be considered in the analysis. However, based on our 
previous work in MD and IFN-alpha-induced depression 13, 25 and preliminary studies above, we anticipate 
that changes in FC will be more pronounced on the left side. Additional Analyses for Publication and 
Dissemination: In addition to the targeted FC that will serve as the primary outcome, hypothesis-driven 
and data-driven whole-brain analysis will also be explored and compared before and after L-DOPA and 
placebo. Consistent with our previously published data,65  these analyses will include VS seed-to-voxel-
wise comparisons of bupropion versus escitalopram, as well as network analyses using GBC and PBNA, 
as a secondary outcome measure and to identify other circuits that may be differentially affected by the 
two treatments. For all analyses, concentration of CRP and final dose will be explored as linear predictors 
of response.
Assessments of Positive Valence (Motivational) Constructs
Objective: Effort-Expenditure for Rewards Task (EEfRT):  The EEfRT task is a multi-trial game in which 
participants are given an opportunity to choose different task difficulty levels to obtain monetary 
rewards.66 The task is 20 min, and first 50 trials are analyzed. The proportion of hard-task choices across 
each level of probability is calculated. Lower proportions of hard task choices indicate decreased 
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Clinician-Rated: Snaith-Hamilton Pleasure Scale (SHAPS-C): The SHAPS-C is a 14-item clinician-
administered scale that assesses hedonic tone.67, 68 In a previous study examining hedonic capacity, 
confirmatory factor analysis revealed a Hedonic Capacity factor that was largely defined by the SHAPS.68, 
69 Clinical Global Impression (CGI): The CGI provides an overall clinician-determined summary measure 
of improvement that incorporates all available information, including the patient's history, psychosocial 
circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function45.
Self-Report: Mood and Pleasure Scale (MAP): The mood and pleasure scale 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.70 
Assessments of Depression: Clinician-Rated: Hamilton Depression Rating Scale (HAM-D-17): The HAM-D-
17 is a 17-item, clinician-administered scale, that rates severity of depression.71 
Self-Report: Inventory of Depressive Symptoms- Self Reported: The IDS-SR is a 30-item self-report 
instrument with excellent psychometric properties that was designed to measure symptom 
constructs including psychomotor retardation, fatigue and anhedonia consistent with current DSM 
nosology
Assessments of Anxiety:
Hamilton Anxiety Rating Scale (HAM-A): The HAM-A is a 14-item clinician-administered scale that 
assesses the severity of symptoms of anxiety72.
Beck Anxiety Inventory (BAI): The BAI is a 21-item self-report measure of anxiety symptoms, rated on a 
4-point Likert scale73 modified to be based on the patient's experience in the past week. 
State-Trait Anxiety Inventory (STAI) State Scale: This 20-item self-report scale is used to measure current 
anxiety symptoms.
PTSD Checklist for DSM-5 (PCL-5): The PCL-5 is a The PCL-5 is a 20-item self-report measure that 
assesses the 20 DSM-5 symptoms of PTSD, rated on a 5-point Likert scale74 modified to be based on the 
patient's experience in the past week. 
Perceived Stress Scale (PSS): The PSS is a self-report scale measuring the perception of stress. The 
items are designed to predict how uncontrollable, unpredictable, and overloaded the subjects find their 
lives. Safety and Tolerability
Adverse Event Recording: All adverse events will be coded in standard MeDRA terms (Version 14.1), and 
whether events are expected and study-related will be determined by the study PI or designee. In 
addition, severity and start and end dates will be recorded as well as any evidence of unanticipated 
problems. This information will be provided to the Department of Psychiatry and Behavioral Sciences 
DSMB and IRB annually as described in the Human Subjects Section.
6. Participant selection:
Recruitment and Informed Consent Process
Male and female subjects with depression will be recruited from local (inter-Departmental) referrals, 
medical record queries and/or social media recruitment campaign(s). Subjects in this study may also be 
referred from our Behavioral Immunology Program “Recruitment Clinic” protocol, Psychiatric Research 
Screening Clinic: IRB0000075162, which uses the screening strategy for this protocol to recruit and 
screen patients with depression for our active studies through IRB approved social media campaigns. An 
overview of the study will initially be provided in person or over the phone by study clinicians or trained 
study staff.  A telephone prescreening interview may be conducted on candidates providing verbal 
consent. If a subject shows interest in the study, research staff members will describe the general 
procedures involved and will answer relevant questions. If a subject remains interested in participation, 
the detailed nature, purpose, procedures, benefits, risks of, and alternatives to this research study will be 
explained to each subject and written informed consent will be obtained by a study clinician or designee, 
by virtual consent utilizing the REDCap platform or in a private office space.. To ensure comprehension of 
the informed consent information, the clinician will allow time for adequate consent review and 
questioning. Informed consent will be documented on the Institutional Review Board-approved form. A 
copy of the signed consent form will be given to the participant or accessible to the participant following 
virtual consent provided in a REDCap ICF document link and the original document filed in a central study 
consent binder. Subject casebooks will be in electronic format in the REDCap database The consent 
binder(s) and. select regulatory information gathered as part of the study will be kept in a locked office 
and/or cabinet.
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A telephone screen interview or RedCap Survey may be conducted with study referrals following verbal 
consent. Candidates eligible to proceed with the study process will be scheduled for an appointment to 
see a study clinician in a virtual appointment or in an on campus office visit. 
Virtual intake and onsite screening
Trained personnel will obtain either virtual or written informed consent from candidates prior to initiating 
study procedures. Virtual consents will be obtained using the Emory IRB approved REDCap Platform. 
Virtual interviews will be conducted by use of ZOOM, a video conferencing service endorsed by Emory 
University for HIPPA compliant patient encounters. Screening information will be collected by interview 
and evaluation, as well as obtaining collateral history and data from other relevant sources (e. g. medical 
records, referring physician). Screening will include the following assessments: (1) History of medical and 
psychiatric conditions (2) screening laboratory evaluations, (3) subject height and weight measurements 
and waist circumference obtained by staff 4) Concomitant Medications 5) Adverse Events 6) MRI Safety 
Form 7) Demographics and 8) assessments below:
Childhood Trauma Questionnaire (CTQ): The CTQ is a standardized, retrospective 28-item self-report 
inventory that measures the severity of different types of childhood trauma. Participants will not be 
excluded for history of childhood trauma. 
Habits: The Habits form is a brief questionnaire that assesses a subject’s daily smoking, caffeine and 
alcohol consumption, and exercise patterns.
Laboratory Variables
Research bloods will be collected between 9-11AM by venipuncture into EDTA-containing vacutainer 
tubes using standard sterile technique. Plasma for the evaluation of concentrations of CRP will be 
obtained along with additional plasma, buffy coat and a tempus tube for future studies. Plasma and buffy 
coat will be removed separately, aliquoted into siliconized polypropylene tubes, and stored at -80°C until 
batched assay of CRP. Bloods will also be collected by venipuncture into Tempus mRNA tubes and 
directly placed in freezer storage at -20C. In order to collect immune cells for future analyses, we will 
additionally collect 10 ml of whole blood in EDTA at room temperature for immune cell extraction. Some 
de-identified samples may be sent to other labs for additional analysis for future studies.
C-reactive protein (CRP): Plasma CRP will be assessed with a high sensitivity turbidimetric assay. 
Sensitivity is 0.18 mg/L, range of measure is 0.2 to 80 mg/L, and functional sensitivity (at 20% CV) is 0.2 
mg/ L.
7. Management of MRI Incidental Findings
The purpose of these scans is not to make a clinical determination of patients’ brain health.  However, if 
any incidental finding is noticed during the scan, the information will be provided to patients or their 
medical provider-of-record for further management.  Incidental findings are those abnormalities seen in 
patients’ brain images during the scanning process, which may or may not be of clinical importance.  
Follow-up of the scan findings will be the responsibility of the patients’ Healthcare provider-of-record. 
8. Sources of Materials: Research material will be derived from clinician-administered and self-report 
questionnaires, blood, urine, and fMRI scans. Material for evaluating baseline medical status and subject 
safety prior to randomization will be obtained from blood and urine. Data to be recorded from subjects will 
include standardized ratings of emotional, cognitive and physical symptoms, as well as clinical information 
derived from medical records when available, interviews with the subject, referring physicians and family 
members when relevant. Data will be obtained from peripheral blood, including complete metabolic panel, 
CBC with differential, urine pregnancy test, plasma concentrations of hs-CRP.  Data obtained from urine will 
include urinalysis, toxicology screen and pregnancy testing. Clinical data that will be used to assess 
eligibility and safety will be collected via virtual or in person interviews and documented by study clinicians. 
Standardized clinician-administered and self-report questionnaires will be administered and collected by 
study physicians or study personnel. Blood and urine samples at screening will be obtained by the study 
team/or trained nurses. Blood and urine for the baseline assessment and subsequent assessment at week -
4 and 8 will also be obtained by the study personnel or trained staff. 
All data, including questionnaires and blood and urine samples will be coded by unique identifying 
numbers. Subjects’ names will not appear elsewhere in any form that would link them specifically to data 
except in the REDCap database accessed by approved study personnel. Subject name and identifying 
number will be kept in a locked office or in the secure REDCap database. Only approved study team 
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data will not be provided information from which they could identify subjects by name. Only the identifying 
number will be used during fMRI scanning and post processing. 
All information will be obtained solely to determine eligibility for study participation or for research 
purposes or to monitor subject safety. Nevertheless, any abnormalities uncovered will be reported to the 
subject and his/her treating physician for follow-up or will be used by study clinicians to determine 
appropriate medical care in the case of adverse events.
9. Data Collection and Management: The data management team will use REDCap.75 REDCap allows 
database construction, an interface for collecting data, data validation, and automated export procedures 
for data downloads to statistical packages (SPSS, SAS, Stata, R). Dr. Miller is currently using REDCap 
for 3 of his currently funded projects, and he and his staff have extensive experience with its usage.
10. Statistical Analyses
Aim 1: To determine whether bupropion (vs escitalopram) will increase FC in reward circuitry. 
Hypothesis 1: Bupropion vs escitalopram will increase VS-vmPFC FC in depressed patients with high
CRP and anhedonia at baseline. Primary Endpoint: Targeted VS-vmPFC FC at 8 weeks. Predictors: 
group (bupropion vs escitalopram), time (baseline, 8 weeks), and group x time interactions. Covariates: 
Primary: Age, sex, BMI, race. Additional covariates: Number of depressive episodes, length of current 
depressive episode (in months), treatment trials (ATRQ), age of onset, and family history of depression 
(yes/no), weeks on targeted dose of medication. Analysis Plan: Subjects will be randomized to two 
different treatment groups and scanned across two visits. Consequently, a factorial mixed-effects models 
for repeated measures (MMRM) will be employed with group, time and group x time interaction on 
targeted VS-vmPFC FC as fixed effects and each subject's baseline (identity) as random effects. Linear 
and multi-level mixed effects will be evaluated using both unstructured and autoregressive covariance 
structures and restricted maximum likelihood estimation and will be used to predict random effects (slope 
and intercept) in addition to fixed effects, optimized using Bayesian Information Criteria (BIC). Primary 
and additional covariates will be entered in all models as random variables after testing for significant 
associations. Given the inherently noisy nature of the covariates, model tuning to optimize the balance 
between explanatory (r2) and noise variables (root mean square error) will be undertaken to select the 
most parsimonious models using BIC. The MMRM will also be augmented using Elastic net generalized 
regression models using group||time nesting approaches. Models will be selected using model 
comparison metrics. All analyses will be conducted in accordance with published guidelines.76 Exploratory 
analysis: A similar analysis as indicated above will be conducted on fMRI scans conducted at 4 weeks. 
The 4-week scan will be conducted based on the rapid effects seen with dopamine agonists in our 
preliminary studies with L-dopa (data not shown).
Aim 2. To determine whether bupropion (vs escitalopram) will improve motivational deficits. 
Hypothesis 2a: Bupropion vs escitalopram will improve objective and clinical assessments of motivation in 
depressed patients with high CRP and anhedonia at baseline. Secondary Endpoints: EEfRT, SHAPS-C 
and MAP. Predictors and Covariates: Same as above. Analysis plan: MMRM with random intercepts will 
be used to examine effects of group, time and group x time interaction controlling for variations in 
baseline scores. Relevant covariates as indicated in Aim 1 will be included in these analyses as 
described above.
Hypothesis 2b: Improvement in VS-vmPFC FC will correlate with improved objective and clinical 
assessments of motivation. Analysis plan: Multivariate regression models will be used to examine linear 
associations between primary (VS-vmPFC FC) and secondary endpoints (EEfRT, SHAPS-C and MAP). 
Models will be adjusted for relevant covariates as indicated above. Separate analyses will be run for each 
behavioral outcome of motivation. Type I errors as a result of multiple testing will be controlled by Family-
Wise Error correction.77
Aim 3. To determine whether bupropion (vs escitalopram) will improve depression severity.
Hypothesis 3 (Exploratory): Bupropion vs escitalopram will improve depressive symptoms in MD patients 
with baseline high CRP and anhedonia. Analysis plan: MMRM will be used to examine effects of group, 
time and their interaction on depression severity using the HAM-D-17. Relevant covariates as in Aim1 will 
be included. 
Interim Analysis: After 16 subjects have completed the study, the blind will be broken by Dr. Miller, and an 
effect size estimation will be made of between group differences in VS-vmPFC FC.* If the effect size is 
less than Cohen’s d =0.3 at both fMRI time points (weeks 4 and 8), the study will be terminated.  If the 
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focusing on the fMRI time point with the largest effect size.  If the between group difference in VS-vmPFC 
FC is >0.6 (Cohen’s d), the possibility of using the data as proof-of-concept for a larger trial will be 
discussed with the study sponsor (NIMH).
* Due to slow recruitment secondary to COVID 19, we have decided to conduct the interim 
analysis at 16 subjects as opposed to 20.
11. Power Analysis
Hypothesis 1: Our preliminary data from 
depressed (major depression – MD) patients 
with high inflammation (CRP >2 mg/L, n=7) 
administered a dopaminergic agent, L-DOPA, 
and placebo control was used to estimate the 
anticipated change in VS-vmPFC FC in 
response to treatment (bupropion) and control 
(escitalopram) conditions in the proposed 
study. The expected change in FC in response 
to bupropion and escitalopram (the within-
subject effects of these conditions) was then 
used to calculate the effect size (ES) and 
sample size per group that will be required to 
detect a significant difference between the 
response to bupropion versus escitalopram 
(the between-subjects effect) with alpha= 0.05 
and power >0.80. Accordingly, based on the 
mean and standard deviation for the change in 
FC after L-DOPA (0.20.16), we can expect a 
large ES for the expected within-subject 
effects of bupropion (Cohen’s dz = 1.25, which 
would require only 8 subjects to detect). Based 
on the mean and standard deviation for the change in FC after placebo (0.070.10), we expected a 
medium effect size for the effects of escitalopram (Cohen’s dz = 0.7), representing ~30-40% increase in 
FC and consistent with a ~30% placebo effect commonly observed in trials in MD patients.78 Based on 
these expected within-subject effects for our treatment and control groups and the corresponding mean 
and standard deviations from our preliminary data, we estimate the between-group effect of the response 
to bupropion and response to escitalopram to have an ES Cohen’s d = 0.97, which would require a total 
sample size of 36 (18 per group) for power >0.8 at alpha=0.05. Using 5000-fold resampling, with alpha = 
0.05, sample power= 0.8, sample sizes of 18 per group (total sample size= 36) was large enough to 
estimate group differences. Figure 1 presents a graphical representation of the total sample sizes 
required for between-subject group comparisons of the FC response to bupropion versus escitalopram 
across the full range of power, demonstrating >80% power at the proposed total sample size of n=40.
Hypothesis 2: For hypothesis 2a, the expect difference in motivation after bupropion versus escitalopram 
is based on the improvement in the EEfRT that has been previously established to be clinically and 
pharmacologically meaningful (10% change,79, 80 representing a 0.10 increase in probability of hard 
choice choices) and standard deviations from our preliminary data for the EEfRT in MD patients. Thus, we 
expect a 0.10  0.10 difference in mean probability of hard choices after bupropion compared to placebo 
and a medium to large ES (Cohen’s d = 1.0), which will require a total sample size of 34 subjects (17 per 
group) for power >0.8 at alpha=0.05. For hypothesis 2b, our preliminary data on the relationship between 
VS-vmPFC FC and motivation, as measured by the EEfRT, demonstrated a correlation coefficient (r) of 
0.43 (r2 = 0.185). We expect a similar effect size for the relationship between change of FC and change in 
motivation and will need a sample size of 37 subjects to detect an overall relationship between change in 
FC and motivation with power >0.8 at alpha=0.05. Therefore, based on our sample size of n=40 (20 per 
group) we will have at least 80% power to detect significant differences for the proposed hypotheses to 
be tested under both Aims 1 and 2 at alpha=0.05. 
12. Potential Study Risks: There are 5 major areas of potential risk in the proposed study stemming 
from 1) neuropsychiatric assessments, 2) blood drawing, 3) fMRI scanning, 4) medication administration, 
and 5) loss of confidentiality. Neuropsychiatric assessments may uncover strong and potentially 
Figure 1: Estimated power for between-subject 
comparisons of the FC response to bupropion versus 
escitalopram. Sample size (x-axis) and power (y-axis) 
for ES (d) = 0.97. The proposed total sample size of 
40 (dashed line, n=20 per group) will yeild power >0.8.

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disturbing feelings about the subject’s past or present emotional state. The risks of blood drawing include 
discomfort, bruising, infection, bleeding, and fainting. Undergoing fMRI scanning poses no more risk than 
undergoing a routine MRI scan. Physical discomfort due to lying in the scanner, occasional headaches 
due to scanner sounds and previously unrecognized claustrophobic attacks are the prominent adverse 
effects of the procedure. Use of bupropion has been associated with several side effects including 
anorexia, dry mouth, rash, sweating, tinnitus, tremors, hypertension and seizures. Use of escitalopram 
has been associated with appetite changes, headache, sweating, indigestion, nausea, tremors and 
sexual dysfunction.  Both drugs can induce mania and suicidal ideation. Finally, there is a risk of loss of 
confidentiality. Confidentiality of all subjects will be protected per institutional and NIH and other federal 
requirements, and as described in greater detail below.
Alternatives to study participation include not participating in the proposed study. Although both 
medications to be used in this study have demonstrated efficacy in major depression, there are an array 
of other demonstrated effective treatments for depression including but not limited to: other selective 
serotonergic antidepressants (i.e. fluoxetine, paroxetine, etc.), serotonin-norepinephrine reuptake 
inhibitors (i.e. venlafaxine, duloxetine), atypical antidepressants (i.e. mirtazapine, nefazodone), tricyclic 
antidepressants, monoamine oxidase inhibitors, electroconvulsive therapy (ECT) and psychotherapy (i.e. 
interpersonal and cognitive behavioral therapies). Risks and side effects of these agents vary in type and 
severity depending on class, but include sexual dysfunction, gastrointestinal distress, anxiety, 
anticholinergic symptoms, induction of mania, suicidal ideation and potential lethality in overdose. 
Common risks of ECT include short term memory loss, head and body aches and risks related to 
anesthesia. Benefits of antidepressants and ECT include documented efficacy in the treatment of 
depression. In addition to approved modalities, trials of novel treatments for more severe depressions are 
ongoing and include the use of vagal nerve stimulation and deep brain stimulation. Benefits of these 
modalities may include efficacy for patients who have failed traditional agents. Risks include the 
possibility that these modalities are not effective. There are also surgery-related risks of infection and 
anesthesia involved with these modalities. 
At screening, study clinicians will discuss benefits and side effects of these alternative treatments 
with subjects compared to the risks and potential benefits of study participation. 
13. Adequacy of Protection Against Risks: 
Recruitment and Informed Consent:
Subjects will be recruited from social media campaigns including Facebook and Instagram. An 
overview of the study will initially be provided over the phone by study clinicians. If a subject shows 
interest in the study, research staff members will describe the general procedures involved and will 
answer relevant questions. If a subject remains interested in participation, the detailed nature, purpose, 
procedures, benefits risks of, and alternatives to this research study will be explained to each subject and 
written informed consent will be obtained by the study clinician or designee who provides this information. 
Informed consent will be documented on an Emory Institutional Review Board-approved form. A copy of 
the signed form will be given to the subject and a copy will be placed in a case-book containing relevant 
demographic data for the subject. Of note, because this case-book will contain personal identifiers (i.e. 
name), it will be kept will be kept in a locked office or in a password protected REDCap electronic 
casebook
Protection Against Risk:
Every effort will be taken to prevent injury or distress that may result from this study. 
Neuropsychiatric Assessments:
Care will be taken to avoid bringing about undue psychological distress during the neuropsychiatric 
interviews. This will be accomplished by using trained raters (clinicians) for all neuropsychiatric 
assessments. If a subject becomes unduly distressed, Drs. Miller or Haroon will be immediately 
contacted, and an appropriate clinical intervention plan will be developed. Drs. Miller and Haroon are 
Board Certified psychiatrists and have many years of clinical experience in a wide variety of treatment 
settings, including emergency, consultation-liaison, inpatient and outpatient psychiatry.  In cases where 
patients need extra time to collect their thoughts and emotions, mental health clinicians will be available 
for emotional support after all interviews.
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Standard sterile procedure for blood withdrawal will be used. Blood draws will be conducted by clinicians 
with significant experience in the technique. In addition, the volume of blood withdrawn for this study will 
not exceed 200 ml over a maximum 8-week period (from screening to study completion). 
fMRI scans: 
To minimize discomfort during the fMRI scanning, patients will be provided with a head cushion and ear 
plugs. Patients will also be informed about the progress of the procedure through a remote microphone. 
In the case of patients developing acute anxiety or panic the scanning session will be terminated and 
patient provided enough support to cope with the feelings induced by the scanner. 
Bupropion or Escitalopram Treatment:
Risks and side effects of these medications vary in type and severity depending on the drug, but include 
gastrointestinal distress, headaches, sexual dysfunction, anxiety, high blood pressure, induction of mania, 
suicidal ideation, seizures and potential lethality in overdose. To reduce the risks associated with active 
treatment, all subjects will be monitored carefully for the development of adverse events as well as 
worsening of their condition. Specific indications for discontinuation between screening and baseline will 
include any of the following at the PI’s discretion: 1) the development of significant suicidal ideation, plan 
or intent as determined by spontaneous subject report or as determined by CSSRS,41 2) the development 
of psychotic, manic/hypomanic or catatonic symptoms, 3) a 25% increase from baseline of HAM-D-17-17 
score, 4) missing more than 2 consecutive doses of medication more than once during the study, and 5) a 
positive pregnancy test at any point during the study. Other criteria for discontinuation between screening 
and the baseline visit include: hospitalization for any reason or a clinical judgment that a subject is an 
imminent threat to self or others. Upon discontinuation, subjects will be immediately evaluated by a study 
psychiatrist and determination of the appropriate level of care, including emergency hospitalization, will be 
determined. Subjects with non-urgent symptoms but who disqualify for further participation and who are in 
active treatment will be referred to their primary psychiatric physician. Participants will be required to 
identify a primary care or psychiatric physician at study entry to ensure seamless psychiatric care 
following study completion. All depressed subjects without a current psychiatrist will be offered an 
appropriate referral. The unblinded study physician may break the treatment blind following study 
completion or early termination from study participation. Participants with adequate treatment response at 
study completion may receive a 4 week supply of identified study medication.  At the end of the study, or 
in the event of Early Termination, patients not achieving a 50% or greater treatment response as 
measured by the Ham-D-17 total score, they will be given a prescription to continue medication for 1 
tablet daily for 7 days before stopping the medication (if on 2 pills of study medication at the end of the 
study). An individualized plan will be crafted for each subject to ensure psychiatric back-up should 
emergency psychiatric care be required after hours or on weekends. During the treatment study itself, 
subjects will be discontinued at any point for any of the following: 1) the development of significant 
suicidal ideation, plan or intent as determined by spontaneous subject report or as determined by the 
Columbia Suicide Severity Rating Scale, 2) the development of psychotic or catatonic symptoms, 3) a 
25% increase from baseline of HAM-D-17 score, 4) missing more than 2 consecutive doses of medication 
more than once during the study and 5) positive pregnancy test at any point during the study. Subjects 
requiring discontinuation will be referred for further evaluation and treatment by one of the study 
psychiatrists as described above.
Confidentiality and Data Management: 
Loss of confidentiality is a risk of research participation. Every effort will be made to maintain subject 
confidentiality throughout the study. All project personnel, including those involved in data entry, have 
completed an on-line course in human subjects’ protection for patient-related research with regular 
recertification. Each subject will be assigned a unique ID number. Data entry forms will be developed 
using the REDcap database system developed at the Vanderbilt Institute for Clinical and Translational 
Research (CTSA). REDCap (Research Electronic Data Capture) is an Oracle-based, secure, password-
protected, HIPAA-compliant, web-based application designed to support data capture for research 
studies. REDCap provides: 1) an intuitive interface for data entry (with intrinsic data validation); 2) audit 
trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless 
data downloads to common statistical packages (SPSS, SAS, Stata, R); 4) procedures for importing data 
from external sources; 5) Real-time data cleaning and validation; 6) Automatic field computation; 7) Data 
dropdowns for choice lists (including condition selections based on earlier responses); 8) Data entry 
warnings for out of range or missing values; and 9) Electronic scheduling. Data entry can be performed 

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anywhere using the internet and provides 128-bit SSL security. All electronic data will include unique 
patient identifiers to maintain patient confidentiality Any protected personal health information will be 
stored in a restricted access area or a password protected electronic casebook in REDCap System. The 
link between identifying information (e.g., name, contact information) and project data stored on a 
password-protected computer or in source documentation accessible only to the PIs and to the project 
coordinators, who will be making appointments and assigning research personnel to meet with the 
participant. Paper forms will be stored in locked file cabinets accessible only to study personnel.
Stopping Rules:
Subjects will be closely evaluated throughout the study for worsening of psychiatric symptoms. Subjects 
will be discontinued at any point for any of the following at the PI’s discretion: 1) the development of 
significant suicidal ideation, plan or intent as determined by spontaneous subject report or as determined 
by CSSRS,41 2) the development of psychotic, manic/hypomanic or catatonic symptoms, 3) a 25% 
increase from baseline of HAM-D-17 score, 4) missing more than 2 doses of medication more than once 
during the study, and 5 a positive pregnancy test at any time during the study. Subjects requiring 
discontinuation will be referred for further evaluation and treatment by one of the study psychiatrists or 
clinicians. 
Compensation to Participants:
Participants will receive up to $400-$1500 for participation of the study. Participants will be compensated 
using ClinCard. The ClinCard is a web based, reloadable, debit card that automates reimbursements for 
clinical research participants. An additional $25 will be provided to cover travel expenses for participants 
that travel equal to or greater than 50 miles to Atlanta. Candidates deemed ineligible by virtual 
evaluation(s)prior to the first in person office visit will not be compensated.
Visit
Total Amount 
Amount put on Clincard 
immediately after visit 
Amount put on Clincard at 
the end of study participation
Intake (Virtual when possible)
No Payment
No Payment
No Payment
(Visit Total)
Visit 1 (Screen A)
Screening lab work, UDS, Preg Test, 
AEs, Concomitant Meds 
$50*
$50*
(Visit Total)
$50
Visit 2 (Screen B & Baseline A)
Physical Exam, Rapid CRP, Vitals, 
research bloods, urine toxicology and 
pregnancy test, self-report surveys
$50
$50
Computer Task (depending on choice 
made on the computer)
$5-$10
$5-$10
(Visit Total)
$55-$60
Visit 3 (Baseline B)
Medical and psychiatric assessments, 
vitals, self-report surveys and 
medication check and randomization 
and medication administration 
$50
$50
Computer Task (depending on choice 
made on the computer)
$5-$30
$5-$30
Complete Scan
$200
$200
Incomplete Scan
$25**
$25**
(Visit Total)
$80-$280
Visit 4 (Week 2)
Medical and psychiatric assessments, 
self-report surveys and medication 
check
$50
$50

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Computer Task (depending on choice 
made on the computer)
$5-$10
$5-$10
(Visit Total)
$55-$60
Visit 5 (Week 4)
Medical and psychiatric assessments, 
urine toxicology, self-report surveys 
and medication check
$50
$50
Computer Task (depending on choice 
made on the computer)
$5-$30
$5-$30
Complete Scan
$150
$150
Incomplete Scan
$25**
$25**
(Visit Total)
$80-$230
Virtual (Week 6)
$25
$25
(Visit Total)
$25
Visit 6 (Week 8)
Medical and psychiatric assessments, 
research bloods, urine toxicology, 
self-report surveys and medication 
check
$50
$50
Computer Task (depending on choice 
made on the computer)
$5-$30
$5-$30
Complete Scan
$150
$150
Incomplete Scan
$25**
$25**
(Visit Total)
$80-$230
Total Study Compensation
$425-$935
*Screening visit may be divided across 2 visits and paid $25 per visit 
**Unable to complete scan leading to termination from the study
Potential benefits of the proposed research to the subjects and others:
The direct benefits of study participation will include receiving a psychiatric and medical evaluation, including 
standard blood and urine-based laboratory tests and MRI scan. In addition, subjects will all receive an active 
treatment with known efficacy. Subjects will also have the chance to contribute to a scientific investigation, 
which may be of benefit to future patients. Benefits to others may include gaining significant knowledge 
regarding the role of inflammatory activation in the pathophysiology and treatment of depression. As a result 
of this knowledge, this study may contribute to personalization of therapeutic strategies for patients with 
major depression. 
Given the low risk involved with blood drawing, psychiatric assessments and fMRI scanning 
coupled with the likelihood that many patients will obtain at least some symptomatic benefit, we feel that the 
risks of the study are reasonable in relationship to the benefits of study participation.
Importance of the knowledge to be gained:
Successful treatment modalities both arise from, and contribute to, our understanding of disease 
pathophysiology. Mounting data indicate that depression is associated with evidence of 
immune/inflammatory activation, and that patients with major depression may be especially likely to 
demonstrate increased proinflammatory cytokine production/release. Furthermore, alterations in 
dopamine neurotransmission have been demonstrated extensively in individuals exposed to inflammatory 
stimuli, and patients with major depression have been shown to exhibit inflammation-associated 
alterations in functional connectivity within dopamine-related reward circuitry. Nevertheless, studies 
conducted to date have not explored whether currently available antidepressant treatments have 

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differential effectiveness in reversing inflammation-related brain changes and whether any observed 
differential effects on the brain are manifested in behavior. Understanding the mechanisms by which 
conventional antidepressant treatments interact with immune-related pathologies may not only lead to 
new treatments for depression but also may help guide antidepressant choice by measuring inflammatory 
state prior to treatment. For these reasons, we feel that risks to subjects are reasonable in relationship to 
the value of the knowledge (both theoretical and practical) to be gained.
Investigational Drug Status
All drugs to be used in this study (bupropion and escitalopram) are FDA-approved for the treatment of 
depression and will be used at doses and duration recommended in the package inserts of these 
medications. 
14. Data and Safety Monitoring Plan (DSMP)
The DSMB for this study will consist of Larry Tune, M.D. Chairman, Boadie Dunlop, M.D., Tanja Mletzko, 
M.S. and Marian Evatt, M.D. Each of these clinical researchers has agreed to serve as the external 
DSMB for investigator-initiated clinical trials conducted by Emory researchers in the Department of 
Psychiatry & Behavioral Sciences. If the DSMB requires additional specialized expertise to evaluate 
safety issues related to the performance of this study, a relevant specialist will be consulted by the 
DSMB. The frequency of the Department of Psychiatry and Behavioral Sciences DSMB review for this 
protocol will be once every year based on IRB recommendations consistent with the assessed risk status 
of the study. 
Procedures and Responsibilities of the Emory DSMB
Prior to each DSMB meeting, the data manager/research coordinator will prepare a report to be reviewed 
during that meeting. The report will include the number of participants who signed consent for the study 
and were randomized, the number of post-randomization dropouts, reasons for these dropouts, and any 
safety concerns, adverse events, etc. An up-to-date consent form may be provided, as well as a summary 
of measures taken to protect confidentiality (e.g., data storage, use of coded ID numbers, etc.) The PIs 
will also prepare a report summarizing any new data/evidence that might alter the risk/benefit ratio for 
participating in the study (e.g., newly published studies, etc.). Data will be presented to the DSMB in such 
a way as to maintain patient confidentiality.
Based on the information provided to the Department of Psychiatry and Behavioral Sciences DSMB, once 
every year the DSMB will issue a letter to the PI to be included in the annual Emory IRB Continuing 
Review submission. The letter will inform the Emory IRB that the study is approved to proceed or state 
any safety related concerns expressed by the committee.  Reports will not specifically disclose the 
treatment arm of the study for relevant subjects unless this disclosure is required for safety reasons. 
PI and designated trained study personnel will review all pertinent aspects of study conduct 
including patient safety, compliance with protocol, data collection and efficacy. Periodic chart monitoring 
will be conducted by study personnel to validate integrity of the data.
Adverse Event Reporting
Note that any adverse event or serious adverse event (SAE) meeting Emory IRB criteria for on 
Unanticipated Problem will be reported to the Emory IRB and the study DSMB according to standard 
regulations. The IRB defines a serious adverse event as: “any adverse experiences occurring that result 
in any of the following outcomes: death, a life-threatening adverse experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. For the purposes of this policy, death is never expected.” According to the Emory 
IRB, an AE meets criteria for an Unanticipated Problem (UP) if all of the following criteria are met: 1) The 
AE is unexpected 1) the AE is related or possibly related to participation in the research 3) the AE 
suggests that the research places subjects or others at a greater risk of harm that was previously know. 

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