Clinical trial NCT04723147
Conditions: Depression Anhedonia
Keywords: Depression Anhedonia
Sponsor: Emory University
Start date: 2021-01-29; Completion date: 2023-10-11
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this 6-week, double-blind, placebo-controlled, crossover study is to explore new treatment options for people with depression who have high inflammation and anhedonia. Thirty-five male and female participants with depression, between the ages of 25-55 years of age, will be randomized to two study tracks (A and B) to receive both placebo and three doses of L-DOPA, given in different orders. Increases or decreases in each dose will occur gradually over 6 weeks of the study. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing and functional MRI (fMRI) scans as part of the study. The total length of participation is about 2 months.

Detailed description:
Depression is a widespread disorder (lifetime prevalence \>20%). Current antidepressant medications are effective for many patients; however, more than 30% fail to respond. Of the patients that do respond to treatment, some continue to suffer with primary symptoms of depression like an inability to experience pleasure, called anhedonia. In this regard, one biological pathway that may contribute to symptoms of depression and particularly anhedonia is inflammation.

The purpose of this 6-week, double-blind, placebo-controlled, crossover study is to explore new treatment options for people with depression who have high inflammation and anhedonia. Despite evidence of low dopamine function in patients with depression, the ability of existing dopaminergic therapies, like L-DOPA, to affect brain circuits in depression has yet to be explored. This study will help determine the best dose of an FDA-approved medication, Sinemet (L-DOPA) that might be used in the future to treat sub-groups of depressed individuals.

Forty male and female participants with depression, between the ages of 25-55 years of age, will be randomized to two study tracks (A and B) to receive both placebo and three doses of L-DOPA, given in different orders. Increases or decreases in each dose will occur gradually over 6 weeks of the study. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing and functional MRI (fMRI) scans as part of the study. The total length of participation is about 2 months.

Arms: arm 1: Participants will receive first Carbidopa Levodopa at doses ranging from 150 to 450 mg administered at a ratio of 1 mg carbidopa for every 4 mg L-DOPA with a starting dose of 150 mg/day with dose escalation 150 mg/day per week to a final dose of 450 mg/day; and then placebo. arm 2: Participants will receive first placebo, and then Carbidopa Levodopa (L-DOPA) at doses ranging from 150 to 450 mg administered at a ratio of 1 mg carbidopa for every 4 mg L-DOPA with a starting dose of 150 mg/day with dose escalation 150 mg/day per week to a final dose of 450 mg/day.
Interventions: intervention 1: Carbidopa Levodopa intervention 2: Placebo
Intervention descriptions: intervention 1: Patients will receive L-DOPA at doses ranging from 150 to 450 mg administered at a ratio of 1 mg carbidopa for every 4 mg L-DOPA. Starting dose is 150 mg/day with dose escalation 150 mg/day per week to a final dose of 450 mg/day intervention 2: A placebo is a sugar pill that has no therapeutic effect and will be administered orally. Participants will receive 1 placebo tablet matching the Carbidopa Levodopa tablet.

Protocol documents:
Prot_SAP_001.pdf: 
Title: Dopaminergic Therapy for Inflammation-Related Anhedonia in 
Depression
NCT #: NCT04723147
Date: 08/23/2023


 PROTOCOL TITLE:   Dopaminergic Therapy for Inflammation-Related Anhedonia in Depression.
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PROTOCOL TITLE:   Dopaminergic Therapy for Inflammation-Related Anhedonia in Depression.
PRINCIPAL INVESTIGATOR:
Jennifer C. Felger, PhD
Emory University                                                                                                                              
Department of Psychiatry and Behavioral Sciences
                                                                                                                               
EXTERNAL (NON-EMORY) COLLABORATORS N/A ☐:                                                                   N/A) 
VERSION:  #9: August 23rd, 2023 .
FUNDING SOURCE: NIMH R61 Award.
REVISION HISTORY
Revision #
Version 
Date
Summary of Changes
2
04/10/20
Revisions from initial IRB review
3
12/30/20
Revision of recruitment procedures (now virtual and in-
person) before start of recruitment; provide additional 
study details; add personnel
4
12/30/20
Revisions requested for Modification #3
5
01/28/21
Fix errors in reimbursement table 
6
06/16/21
Revisions of travel compensation (reduce mileage 
coverage to 30 miles from 50 miles)
7
11/02/21
Revisions to the visit order of screening data collection
8
7/11/22
HAM-A instrument removed from Baseline Visit.
9
8/23/23
Clarified language regarding repeat CRP testing, clarified 
method of screening and monitoring of suicide, and 
clarified/fixed typos for HAM-D and IDS-SR in Table 2.


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Table of Contents
1.0
Study Summary....................................................................................................................3
2.0
Objectives............................................................................................................................3
3.0
Background..........................................................................................................................5
4.0
Study Endpoints *................................................................................................................7
5.0
Study Intervention/Investigational Agent ...........................................................................8
6.0
Procedures Involved* ........................................................................................................10
7.0
Data and Specimen Banking* N/A ☐.................................................................................20
8.0
Sharing of Results with Participants* ................................................................................21
9.0
Study Timelines*................................................................................................................22
10.0
Inclusion and Exclusion Criteria*.......................................................................................22
11.0
Vulnerable Populations* N/A ☐X......................................................................................22
12.0
Local Number of Participants ............................................................................................24
13.0
Recruitment Methods........................................................................................................24
14.0
Withdrawal of Participants*..............................................................................................25
15.0
Risks to Participants*.........................................................................................................28
16.0
Potential Benefits to Participants*....................................................................................29
17.0
Data Management* and Confidentiality ...........................................................................29
18.0
Provisions to Monitor the Data to Ensure the Safety of Participants*..............................34
19.0
Provisions to Protect the Privacy Interests of Participants................................................34
20.0
Economic Burden to Participants ......................................................................................35
21.0
Consent Process.................................................................................................................35
22.0
Process to Document Consent in Writing..........................................................................35
23.0
Setting................................................................................................................................36
24.0
Resources Available...........................................................................................................39
25.0
Multi-Site Research when Emory is the Lead Site*N/A ☐X ..............................................43
26.0
References.........................................................................................................................43


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1.0
Study Summary
Study Title
Dopaminergic Therapy for Inflammation-Related Anhedonia in 
Depression
Study Design
6-week randomized, double-blind, placebo-controlled 
crossover
Primary Objective
To determine a daily dosing strategy for the dopamine 
precursor, levodopa (L-DOPA), that will increase functional 
connectivity (FC) in ventral striatum to ventromedial prefrontal 
cortex (VS-vmPFC) reward circuitry in major depressive 
disorder (MDD) patients with high inflammation and 
anhedonia. 
Secondary Objective(s)
Data regarding safety and tolerability, and preliminary data on 
the potential for L-DOPA to improve anhedonia and motivation 
will also be collected. 
Additional behavioral, biologic and MRI measures (at 
baseline) will be collected for use as predictors of response 
and to enhance interpretation of results.
Research 
Intervention(s)/Interactions
L-DOPA; placebo
Study Population
Medically stable and medication-free adults (ages 25-55) with 
Major Depressive Disorder, plasma CRP >2 mg/L, and high 
anhedonia (score >/=2 on the anhedonia question of Patient 
Health Questionnaire [PHQ]-9)
Sample Size
35
Study Duration for 
individual participants
>8 Visits; ~8 week duration
Study Specific 
Abbreviations/ Definitions 
Levodopa (L-DOPA) 
Major depressive disorder (MDD)
Functional connectivity (FC)
C-reactive protein (CRP)
Ventral striatum to ventromedial prefrontal cortex (VS-vmPFC)
Funding Source (if any)
NIMH R61 Grant (R61MH121625)
2.0
Objectives


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The primary objective of the proposed research is to determine a daily dosing strategy for the 
dopamine precursor, levodopa (L-DOPA), that will increase 
functional connectivity (FC) in ventral striatum to ventromedial 
prefrontal cortex (VS-vmPFC) reward circuitry in major depressive 
disorder (MDD) patients with high inflammation and anhedonia. 
More than 30% of patients with MDD fail to achieve remission with 
conventional antidepressants and even responders exhibit 
significant residual symptoms including anhedonia. Inflammation is 
elevated in a significant portion of patients with MDD, particularly in 
those patients who are resistant to conventional antidepressant 
therapies. Preclinical and clinical findings indicate that inflammation 
can affect striatal dopamine availability and release, to contribute to 
symptoms of anhedonia and reduced motivation. We have 
previously reported a relationship between inflammation and FC in 
dopaminergic reward circuitry in patients with MDD whereby patients 
with increased inflammation, as defined by plasma C-reactive 
protein (CRP), exhibited lower VS-vmPFC FC. This VS-vmPFC FC 
was in turn correlated with symptoms of anhedonia. Clinical and 
translational evidence from our group and others suggests that 
inflammation impacts corticostriatal circuits by decreasing the 
synthesis and availability of dopamine. Our preliminary data 
demonstrate that VS-vmPFC FC connectivity was increased after 
acute administration of L-DOPA compared to placebo in patients 
with high CRP (indexed as CRP >2 mg/L), indicating that increasing dopamine with L-DOPA 
can reverse the impact of inflammation on this circuit. The dopamine precursor, L-DOPA, is 
taken up in the brain and rapidly converted to dopamine by DOPA decarboxylase. Despite 
evidence of reduced dopamine availability in MDD, little work has explored the potential for L-
DOPA to improve anhedonia and motivation in MDD. By building on our previous work 
demonstrating a functional link between decreased dopamine availability and impaired FC in 
reward circuits of MDD patients with high inflammation, this study will test the hypothesis that 
treatment with L-DOPA will improve depressive symptoms in MDD patients with high 
inflammation and anhedonia by increasing FC in reward circuitry and improving motivation. 
In order to obtain 30 study completers (~10-15% expected attrition rate), 35 medication-free, 
medically-stable and otherwise psychiatrically healthy adults (25-55 yrs) with 1) current MDD 
per DSM-V criteria, 2) plasma CRP >2 mg/L, and 3) score ≥5 on an anhedonia subscale of the 
Inventory of Depressive Symptomatology-Self-Report (IDS-SR), will be randomized to two study 
tracks (A and B) to receive both placebo and L-DOPA (starting dose of 150 mg/day with dose 
escalation 150 mg/day per week to a final dose of 450 mg/day) in a 6-week, double-blind, 
placebo-controlled, crossover study (see Figure 1). Patients will undergo resting-state 
functional magnetic resonance imaging (fMRI) at baseline, after 1-week of placebo, and after 1-
week at each dose of L-DOPA to establish target engagement in the brain for L-DOPA versus 
placebo to improve FC in reward circuity. Symptoms of anhedonia and an objective measure of 
motivation will be assessed as preliminary data regarding L-DOPA effects on behavior in 
relation to change in FC. Additional behavioral, biologic and MRI measures will be collected at 
baseline for use as predictors of response and to enhance interpretation of results. Safety and 
tolerability and data on the effect of L-DOPA on anhedonia and motivation in relation to target 
engagement in the brain (FC) will also be assessed. 
Aim 1: To determine whether L-DOPA increases VS-vmPFC functional connectivity in MDD 
patients with high CRP (>2 mg/L) and anhedonia. 
Figure 1. R61 Study Design
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Hypothesis 1:  L-DOPA versus placebo will increase VS-vmPFC FC along with plasma L-DOPA 
levels, and with maximal effects at higher doses. 
Exploratory aims: To obtain information on the dosing and tolerability of L-DOPA in our patient 
population, while collecting preliminary data on whether L-DOPA-sensitive fMRI FC brain 
biomarkers are affected in association with improvement in anhedonia and motivation.
Exploratory hypotheses: L-DOPA will be well-tolerated in otherwise medically-stable MDD 
adults with CRP >2mg/L and anhedonia at all doses tested, and improvement in FC in reward 
circuitry will occur in association with improved motivation and motor slowing.
3.0
Background
Depression is common, affecting ~10 million in the US alone, and confers a personal and 
societal burden. More than 30% of patients with major depressive disorder (MDD) fail to achieve 
remission with conventional antidepressants, and even responders exhibit significant residual 
symptoms including anhedonia.1-4 Therefore, new conceptual frameworks are needed to reveal 
pathophysiologic pathways and neurobiological targets for development of novel treatments for 
subgroups of MDD patients who are not sufficiently responsive to existing therapies. Relevant in 
this regard, one pathophysiologic pathway thought to contribute to symptoms of depression and 
particularly anhedonia is inflammation.5-7 A significant proportion of patients with MDD are 
reliably found to exhibit increased inflammatory markers in both the periphery and central 
nervous system, as measured by inflammatory cytokines and acute phase reactants such as C-
reactive protein (CRP).8-11 
Elevated CRP and other 
peripheral blood markers of 
inflammation have also been 
found to predict future 
development of depressive 
symptoms,12-14 and patients 
with high levels of 
inflammatory markers are 
more resistant to standard 
antidepressants such as 
selective serotonin reuptake 
inhibitors (SSRIs).5,15-19 
Working Model and Study 
Overview. Administration of 
inflammatory stimuli or 
cytokines to laboratory animals and humans affects reward pathways in the brain to lead to 
anhedonia and reduced motivation, which has been shown to be mediated by reduced 
synthesis and availability of striatal dopamine.20-25 We recently reported a relationship between 
increased inflammation (as defined by plasma CRP) and low functional connectivity between 
the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC), key structures that 
receive mesolimbic dopamine input,26 in patients with MDD, in association with increased 
anhedonia.27 Furthermore, our preliminary results also indicate that VS-vmPFC FC in MDD 
patients can be increased by acute administration of the dopamine precursor levodopa (L-
DOPA) in association with improved motivation, but only in patients with high inflammation. 
Together these findings indicate that MDD patients with high inflammation have low striatal 
dopamine availability that drives decreased FC in reward circuitry and increased 
anhedonia/reduced motivation (Figure 2A).7 These data also support our hypothesis that VS-
vmPFC FC in these patients can be strengthened by L-DOPA administration to lead to reduced 
anhedonia and improved motivation (Figure 2B). 
This study will determine a daily dosing strategy for L-DOPA that will increase FC in VS-vmPFC 
reward circuitry in a 6-week randomized, double-blind, placebo-controlled, crossover study with 
3 doses of L-DOPA in the R61. Data regarding the potential for L-DOPA to improve anhedonia 
Figure 2. Working Model
BH4-tetrahydrobiopterin; CRP-C-reactive protein; DDC-dopadecarboxylase; FC-functional 
connectivity; L-DOPA- levodopa; Phe-phenylalanine; PH-Phehydroxylase; ROS-reactive 
oxygen species; Tyr-tyrosine; TH-Tyrhydroxylase; vmPFC- ventromedial prefrontal cortex; VS- 
t
l t i t
XPH2 dih d
th
t
i
(+)
(-)


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and motivation will also be collected. Milestones for R61: To establish target engagement in the 
brain, we expect that at least one of 3 doses of L-DOPA will produce a mean increase in VS-
vmPFC FC that is ≥20% higher than that of placebo. 
This study aims to address an unmet need to investigate novel therapeutic strategies that may 
be targeted to sub-populations of patients with MDD based on a known pathophysiology that 
can be identified by a combination of peripheral blood and behavioral biomarkers. Despite 
evidence of low dopamine function in MDD,3,28,29 the ability of existing dopaminergic therapies 
with well-characterized pharmacology, like L-DOPA, to affect brain circuits in MDD has yet to be 
explored. Further novelty and innovation exist in targeting such therapies to MDD patients with 
high inflammation and anhedonia, a population frequently reported-on but understudied in 
experimental medicine or clinical trials. The choice of L-DOPA for this study is particularly well-
matched to this target population as inflammation is known to impede dopamine synthesis (see 
Figure 2), which is rapidly increased by the dopamine precursor, L-DOPA. Therefore, this work 
involving a dopamine agonist with known pharmacology will not only test a potential new 
therapy30 but will also provide the foundation for the development of novel dopaminergic 
therapies for the ~30-50% of MDD patients with high inflammation19,31-35 who are less 
responsive to conventional antidepressants like SSRIs.5,15-19
Inflammation Impacts Reward Circuitry through Decreased Dopamine Synthesis and 
Availability. Numerous neuroimaging studies in subjects peripherally administered cytokines or 
other inflammatory stimuli (either as clinical therapy or in laboratory experiments) have found 
that inflammation preferentially affects corticostriatal circuitry that is relevant to anhedonia and 
motivation, as well as psychomotor speed.21,22,36-39 For example, functional magnetic resonance 
imaging (fMRI) has demonstrated decreased ventral striatal neural activation to hedonic reward 
in patients administered the inflammatory cytokine interferon (IFN)-α to treat hepatitis C, which 
correlated with reduced motivation and activity.21 Typhoid vaccination and endotoxin 
administered in the laboratory to healthy subjects produced similar effects on the basal ganglia, 
including decreased neural activation of the ventral striatum to hedonic reward and decreased 
corticostriatal FC, which also correlated with symptoms of anhedonia and psychomotor 
slowing.22,38-40 Positron emission tomography (PET) neuroimaging investigating cytokine effects 
on dopamine metabolism revealed increased uptake and decreased turnover (indirect measures 
of dopamine capacity and release) of radiolabeled L-DOPA, [18F]fluorodopa, in the caudate, 
putamen, and ventral striatum of IFN-α-treated patients.21 Our translational work in non-human 
primates and studies in rodents have directly linked the effects of inflammation on corticostriatal 
reward circuits to decreased availability and release of striatal dopamine.20,24,41,42 Indeed, we 
conducted in vivo microdialysis and PET neuroimaging with [11C]raclopride displacement 
following amphetamine challenge in IFN-α-treated monkeys.20 Results indicated that stimulated 
dopamine release was decreased in the striatum (including nucleus accumbens) after chronic 
administration of IFN-α, and decreased dopamine release, as measured by in vivo 
microdialysis, was correlated with reduced effort-based sucrose consumption.20 A primary 
pathway by which inflammation impacts dopamine is by decreasing the availability of 
tetrahydrobiopterin (BH4), an enzyme co-factor required for synthesis of dopamine via the 
conversion of phenylalanine to tyrosine and tyrosine to L-DOPA (see Figure 1).43 We and 
others have observed evidence of reduced BH4 activity in patients administered IFN-α, which 
correlated with decreased cerebrospinal concentrations of dopamine and increased depressive 
symptoms.23,44 To examine whether inflammation reduces availability of dopamine by depleting 
dopamine precursors, we administered L-DOPA via reverse in vivo microdialysis to monkeys 
treated with chronic IFN-α, and the inflammation-induced reductions in striatal dopamine release 
were restored by L-DOPA.24 Therefore, pharmacological agents that improve dopamine 
synthesis may effectively treat anhedonia and reduced motivation in MDD patients with high 
inflammation.
Pharmacology of L-DOPA and Potential to Improve Reward Circuit Function, Motivation 
and Anhedonia in Depression with High Inflammation. Unlike dopamine itself, L-DOPA 
crosses the blood-brain-barrier (BBB) and is rapidly converted to dopamine by DOPA 


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decarboxylase (DDC) then packaged and either stored or released from presynaptic 
dopaminergic terminals. L-DOPA is currently used in combination with carbidopa (which does 
not cross the BBB) to increase dopamine transmission in dopamine-deficient patients with 
Parkinson’s disease (PD) or dopamine-mediated sleep movement disorders like restless legs 
syndrome (RLS).45,46 Carbidopa blocks the conversion of L-DOPA to dopamine in the periphery, 
allowing more L-DOPA to be taken up by the brain and to reduce peripheral side effects from 
dopamine receptor activation. In addition to having known pharmacology, the pharmacokinetics 
of L-DOPA and its effects on brain dopamine are well established.24,47 Despite evidence of 
reduced dopamine availability in depression,24 little work has explored the potential for 
dopaminergic therapies like L-DOPA to improve anhedonia and motivation in MDD. Case series 
beginning in the 1960s report improved depressive symptoms with L-DOPA monotherapy or 
augmentation, particularly in patients considered to have a slowed or “retarded” phenotype of 
depression.48-51 In new onset PD, L-DOPA was shown to improve symptoms in 28 out of 31 
patients with a mean decrease in the Hamilton Depression Rating Scale (HAM-D) of 11.7,52 
whereas others have reported beneficial effects on depressive symptoms, quality of life and/or 
cognitive performance.53-55 With regard to hedonic tone and motivation, L-DOPA increased the 
frequency by which healthy subjects chose high-probability gains in an instrumental learning 
task.56  Similarly, L-DOPA selectively improved motivation for (wanting), versus sensitivity for 
(liking) or learning about, reward in mice with a genetic depletion of dopamine.57 These findings 
support the hypothesis that L-DOPA is able to improve motivation, particularly in subjects with 
low dopamine synthesis and availability. Agents that increase dopamine signaling, such as the 
dopamine receptor agonist pramipexole, have demonstrated efficacy in treatment-resistant 
depression,58,59 and MDD patients with moderately increased CRP (≥1 mg/L) were found to 
exhibit a robust response to the combination of a SSRI plus bupropion (an antidepressant with 
stimulant properties) compared to a poor response to the SSRI alone.19 These findings provide 
support for our hypothesis that MDD patients with high inflammation, who are often resistant to 
SSRIs, may be especially responsive to dopaminergic therapies. However, dopamine receptor 
agonists bind to receptors for other systems such as serotonin,60 and bupropion is not specific 
for the dopamine transporter.61 Furthermore, inflammation is thought to decrease dopamine 
neurotransmission by interfering with rate-limiting aspects of dopamine synthesis that occur 
upstream of the conversion of L-DOPA to dopamine by DDC. Thus, L-DOPA is the most direct 
and specific pharmacological approach to increase dopamine transmission and improve 
corticostriatal reward circuits in association with behavior in MDD patients with high 
inflammation who may exhibit a fundamental depletion of dopamine availability. Accordingly, L-
DOPA is the most appropriate compound for the R61/R33 mechanism as it is 1) well-matched to 
the underlying mechanism and 2) will isolate a specific dopaminergic effect in the target 
population, which will have implications for development of novel therapeutics, or the targeting 
of existing compounds like bupropion,19,62 pramipexole58 or even L-DOPAf30 (as will be explored 
in the R33) to patients with MDD, high inflammation and anhedonia. The R33 can then inform 
future studies that examine L-DOPA as a monotherapy or adjunct and compare the response to 
other dopaminergic therapies (or SSRIs) and in low CRP patients. 
4.0
Study Endpoints *
Milestone for R61: Target Engagement of Brain. Targeted VS-vmPFC connectivity will serve 
as the primary outcome and will be assessed for determining the Go/No-Go Criteria. Targeted 
FC for each subject and treatment condition will be calculated as the degree of correlation in 
activity between a 3mm3 radius sphere in VS27,65 and the vmPFC ROI identified as being 
reward-sensitive in neuroimaging meta-analyses105 (MNI coordinates x=0, y=44, z=-8, cluster 
size=1408 mm3 and encompassing parts of BA11 and ventral BA32 of ACC) or other similar 
ROIs used to define vmPFC in our previous work.27,64,65,106  This method will ensure rigor and 
reproducibility and application of results to potential future trials because the seeds and ROI 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 after each dose of L-DOPA or placebo compared to baseline will be calculated. 


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FC between bilateral VS seeds and the vmPFC ROI will be examined separately and change in 
FC in either the right or left VS can contribute to meeting the Go/No-Go criteria. However, based 
on our previous work in MDD and IFN-a-induced depression21,27 and our preliminary studies, we 
anticipate that this change will be more pronounced on the left side. Response may also be 
strongest in subjects with greatest bioavailability of L-DOPA. If more than 1 dose of L-DOPA 
meets criteria, % of patients and mean number of reported side effects will be compared across 
doses to determine the effective dose that was most tolerated by patients. If doses are similarly 
tolerated, % change in behavior (EEfRT > anhedonia) will be used. Statistical significance, ES 
or sensitivity analyses may be used to assist with selection of the optimal dose. 
Additional Analyses for Publication and Dissemination: Brain Target- Targeted FC Z scores 
(as described above) will be entered into linear regression models including clinical covariates 
(see below) and both conservative (Bonferroni) and powerful (Fisher LSD) post-hoc analyses to 
asses change in FC across the 3 doses of L-DOPA compared to placebo and to each other. 
Linear models will also be used to determine whether FC increases as a function of increasing 
plasma L-DOPA, and whether patients with low bioavailability exhibit low ΔFC. In addition to the 
targeted FC that will be used to assess Go/No-Go criteria, hypothesis-driven and data-driven 
whole-brain analysis will also be explored and compared before and after L-DOPA and placebo. 
Consistent with our previous data, these analyses will include VS seed-to-voxel-wise 
comparisons of L-DOPA versus placebo, as well as network analyses using GBC and PBNA, as 
a secondary outcome measure and to identify other circuits that may be affected by L-DOPA. 
For all analyses, concentration of CRP and final dose will be explored as a linear predictor of 
response to L-DOPA. Clinical covariates such as age, sex, race, BMI and ATQR and/or 
bipolarity scores will be explored as potential confounders or moderators of L-DOPA effects on 
FC. Integration of Brain and Behavior: As described for FC, linear regression models and post-
hoc analyses will be used to asses change in behavioral outcomes across the 3 doses of L-
DOPA compared to baseline, to placebo and to each other, and whether response was modified 
by plasma bioavailability of L-DOPA, CRP, cytokine or sex hormone concentrations, or clinical 
covariates. Random intercept linear mixed models will be used to assess whether change in FC 
predicts change in anhedonia and motivation and in relation to clinical covariates. Overall 
depression scores and SHAPS-C and MAP-SR will be explored as secondary outcomes. 
Summary scores for dose-response (e.g. AUC) may be used to assess relationships among 
variables. 
5.0
Study Intervention/Investigational Agent
Description: Carbidopa-levodopa (Sinemet) is a combination of two drugs, 
L-DOPA and carbidopa. Carbidopa-levodopa is used primarily in the 
treatment of Parkinson's disease (although it is also FDA approved for other 
movement disorders such as Restless Legs Syndrome). Parkinson's 
disease is believed to be caused by low levels of dopamine in certain parts 
of the brain. When L-DOPA is taken orally, it crosses into the brain through 
the "blood- brain barrier." Once it crosses, it is converted to dopamine. The 
resulting increase in brain dopamine concentrations is believed to modulate 
nerve conduction and improve movement impairments. Carbidopa does not 
cross the blood-brain barrier. Carbidopa is added to L-DOPA to prevent its 
breakdown before crossing into the brain. The addition of carbidopa allows 
lower doses of L-DOPA to be used. This reduces the risk of side effects 
from L-DOPA such as nausea and vomiting. Nausea and vomiting are 
frequent side-effects of taking levodopa, and often improve with increasing 
time on medication. This combination medicine was approved by the FDA 
in 1988. Carbidopa-levodopa is taken several times per day for treatment of 
Parkinson’s disease, up to 800 mg daily. Patients in this study will receive 
L-DOPA at doses ranging from 150 to 450 mg administered with at a ratio 
of 1 mg carbidopa for every 4 mg L-DOPA. Our preliminary data using 


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acute administration of 250 mg L-DOPA to MDD patients with CRP >2mg/L 
increased corticostriatal FC in reward circuitry as measured by fMRI (the 
primary study outcome) without only mild adverse events that are 
anticipated during initial exposure to the medication, primarily nausea (with 
vomiting in some patients). Other common symptoms that were 
experienced included headache and drowsiness or lightheadedness. 
Furthermore, in a similar recent study in aged adults with depression (>/=60 
years),30 L-DOPA administered at the same doses proposed herein (also 1 
week at each dose) decreased depressive symptoms and was well-
tolerated. Indeed, the percent of patients reporting nausea (the most 
common symptom) decreased from 19.4% in Week 1 to 9.1% in Week 3, 
despite dose increases by 150 mg/week. Symptoms of headache and 
drowsiness occurred in less than 10% of patients throughout the duration of 
the study, and insomnia occurred in 8% in the first week which decreased 
to 3% in week 3. Moreover, patients were monitored for dyskinesias (a 
common symptom in Parkinson’s Disease that may be specific to 
neurodegenerative disease pathology) and scores were 0.0 at Week 3 for 
all subjects. 
Table 1. Expected Frequency and Duration of Common Anticipate Mild 
Adverse Events Associated with L-DOPA
Anticipated Mild Adverse Events 
Associated with L-DOPA
Approximate 
Expected Frequency
Anticipated Expected 
Duration
Nausea (may include vomiting in 
some patients)
20-30%
10-20%
~10% or less
First few days
First few weeks
After week 3
Insomnia
~10%
~5% or less
First week
After the first week
Headache
~5-10%
Anytime during treatment
Lightheadedness, dizziness or 
drowsiness
~5-10%
Anytime during treatment
The following rare but serious side effects have also been reported 
following the use of chronic high doses of L-DOPA for treatment of 
Parkinson’s disease: easy bleeding/bruising, signs of infection (e.g., fever, 
persistent sore throat), tingling of the hands/feet, vision changes (e.g., 
blurred/double vision), chest pain, seizures, vomit that looks like coffee 
grounds, black/tarry stools, unusual muscle stiffness, severe confusion, 
sweating, fast/irregular heartbeat, rapid breath or trouble breathing, painful 
or prolonged erection in males, rash, itching/swelling (especially of the 
face/tongue/throat), and severe dizziness. Transient and mild side effects 
that may occur following acute administration of the doses used in this 
study include: dizziness, nausea, vomiting, increased sleepiness or trouble 
sleeping, and headache. L-DOPA may also increased eye 
blinking/twitching, cause fainting, mental/mood changes, and worsening of 
involuntary movements/spasms.
5.1
Drug/Device Handling: L-DOPA and placebo will be dispensed to by Emory 
Investigational Drug Services (IDS) under an IDS-SOP and delivered to the 
principal investigator or study team member. The principal investigator or 


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health care providers on his/her research team will provide the medicine to 
the subjects. To maintain blinding during dose escalation and across tracks, 
study medication will be dispensed to each participant at their weekly 
follow-up visits. In order to assist participants and the monitoring of 
adherence, medication will be dispensed in blister packs and all unused 
medication will be returned to the pharmacy. Compliance will be monitored 
and recorded. Falling below 85% compliance on more than one week may 
be grounds for dismissal.
5.2
N/A. Investigator Justification for IND Exemption is attached.
6.0
Procedures Involved*
6.1
Full participation in this study will require a minimum of 9 visits, including, 1) 
at least two screening visits (Screen A and B, which may be conducted on 
the same day), 2) baseline blood draws and behavioral assessments, and 
fMRI scan, 3) 4 follow-up visits during dose-escalation of L-DOPA or 
washout to placebo that include blood, fMRI scan and behavioral 
assessments, and 4) two follow-up visits without scans to collect self-report 
and safety and tolerability information. An initial intake visit (to be 
conducted on the phone or virtually) will also be conducted either within the 
study (after study consent) or prior to study consent within our Behavioral 
Immunology Program Screening Clinic. At screening (in-person visit to 
occur after study consent), patients will receive a physical examination and 
laboratory testing (blood sampling) and will be requested to provide detailed 
information on past medical and psychiatric history and treatment, as well 
as current symptom status. Height, weight and vital signs will be recorded. 
Some aspects of laboratory testing (blood work and urinalysis) and medical 
and psychiatric history may be collected in the Screening Clinic to help 
match participants to this or other ongoing studies. During screening, a 
fasting research blood sample (18 ml total) may be collected (along with 
blood draw for additional safety labs and/or CRP measurement if needed) 
as a Pre-Baseline assessment. Research blood will be used for 
measurement of plasma inflammatory markers, mRNA gene expression for 
inflammatory signaling pathways, circulating and mRNA gene expression 
markers related to metabolism and endocrine hormones, and buffy coat to 
examine polymorphisms in relevant inflammatory proteins. Pre-Baseline 
assessments will be collected during the Screen B visit, and will also 
include practice neurocognitive and motivation assessments.
Eligibility for completing further screening and Pre-Baseline assessments: 
The PI or PI’s designee will review information collected from the initial 
intake/consent visit and any subsequent screening to determine whether 
subjects are eligible to proceed with further screening and collection of Pre-
Baseline assessments based on the following:
(1) Attainment of informed consent 
(2) Psychiatric clinician has determined presence of current depressive 
symptoms at intake with PHQ9 score >10, unless otherwise approved by 
the principal investigator or PI’s designee


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(3) The patient has not informed study staff or the psychiatric clinician of 
any condition that, in the opinion of the PI or PI’s designee, would make the 
patient unsuitable for or unable to complete further screening 
Following the in-person screening visits and Pre-Baseline data collection, 
the patient will undergo the Baseline visit including MRI scan and 
randomization. At the Baseline visit, urine will be obtained for toxicology 
and pregnancy testing (where appropriate) and a fMRI scan will be 
performed. Subjects will receive standardized clinician-administered 
interviews and ratings for psychiatric symptoms, will be asked to fill out self-
report questionnaires and will undergo objective tests of motivation and 
motor activity. Blood will also be drawn for the measurement of 
inflammatory marker/hormone levels after the scan procedures, and 
patients will receive study medication. At the end of each indicated week of 
treatment (7 days after each dose change in weeks 1, 3, 4 and 6), subjects 
will undergo fMRI scans, receive standardized clinician-administered 
interviews and ratings for psychiatric symptoms, will be asked to fill out self-
report questionnaires, have blood drawn for L-DOPA concentrations and 
inflammatory markers, urine will be obtained for toxicology, and pregnancy 
testing, and will perform objective tests of motivation/motor activity. Safety 
and tolerability will also be assessed. For follow up visits at weeks 2 and 5, 
patients will either be seen in person (where possible) or virtually to fill out 
self-report questionnaires, height, weight and vital signs will be recorded 
(in-person only), update psychiatric symptoms, and safety and tolerability 
will be assessed. If the visit occurs virtually, medication will be mailed to the 
participant and unused medication will be returned at the next in-person 
visit.
Table 2. Schedule of Study Procedures and Assessments. 
Assessments
Intake/
Consent
Screen A
Screen B-
(Incl. Pre-      
Baseline       
Assess.)
Baseline
Weeks
1, 3, 4, 6
Weeks 
2 & 5
Consent, Intake Registration Form, PHQ-9 
[Intake or Screen A, optional at Screen B], 
Med-Psych Prescreen Form, History of 
Chronic Conditions, Medication Avoidance 
List*
X
[X]
[X]
SCID V-modified (Mood, Anxiety, PTSD 
modules), Bipolarity index, ATRQ, Clinical 
Review for Screening**
X
[X]
[X]
C-reactive protein (CRP), Rapid CRP Finger 
Prick [if necessary to verify CRP]*
X
[X]
[X]
MRI Safety Screening, Anti-nuclear AB, TSH, 
Serum Pregnancy (hCG), Hepatitis B surface 
antigen, Hepatitis C antibody, HIV 
antigen/antibody* 
X
[X]
EKG
X
[X]
Urine pregnancy test*
[X]
X
X
[X]
Physical Exam
X


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*These assessments may be conducted in the Emory behavioral Immunology 
Program research screening clinic
** A Clinical Review will be conducted if more than 2 weeks from last assessment 
or as an update to SCID modules conducted in the Behavioral Immunology 
Program within the past 6 months
***HAM-A removed from Baseline visit on 7/11/22.
[] to be completed if needed
6.2
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. All patients will be evaluated 
by a modified version of the SCID as part of the screening process. These 
interviews will primarily be conducted virtually. 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. At screening 
and at each visit, a standardized clinician interview will also be used to 
assess or monitor symptoms of mania/hypomania, substance abuse (also 
confirmed by urine toxicology screen), alcohol use, dyskinesia, and 
gambling (a potential symptom of dopaminergic medications like L-DOPA).
The MGH Antidepressant Treatment Response Questionnaire (ATRQ): 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. Degree of resistance will be used as a 
Adverse Events, Concomitant Medications* 
X
X
X
X
X
X
Vital Signs, weight, height [screen only], waist-
hip ratio [screen only]
X
X
X
X
[X]
CBC with differential, urinalysis w/ micro, 
comprehensive metabolic panel*
X
[X]
Urine toxicology
X
[X]
X
X
[X]
Demographic Data, Habits, CTQ, IDS-SR
X
Randomization (Track A or Track B)
X
Study Medication Dispensing, Dose Change 
and/or Compliance Check
X
X
X
Research Blood (fasting)
X
Research Blood (Non-Fasting)
X
X
HAM-D item #3, Columbia Suicide Severity 
Rating Scale (CSSRS), Clinical Review for 
Follow Up, Dyskinesia Symptom Review
X
X
X
Psychiatric Assessments (HAM-D, SHAPS-C), 
HAM-A [Baseline only, optional for all other 
visits]***
X
X
X
Self-Report Forms (IDS-SR/IDS-Anhedonia, 
MAPS-SR, BAI, STAI, PSS, PCL-5, Habits)
X
X
X
EEfRT (Motivation), Neurocognitive Testing
X
X
X
MRI Scan
X
X


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covariate in relevant statistical analyses and to exclude severely treatment 
resistant subjects (>3 adequate failed trials). 
MRI neuroimaging: Scans will be carried out in Emory University’s Facility 
for Education & Research in Neuroscience (FERN) on a Trim Trio scanner 
and 32-channel head coil. T1 weighted anatomic images will  be collected 
with MPRAGE148 or a similar high-resolution sequence for co-registration 
with fMRI data after a localizer. fMRI BOLD for resting and task-based 
functional connectivity: A multi-echo (ME) ep2 BOLD sequence will be 
optimized to provide high signal-to-noise ratio in regions of interest that is 
maintained during minor incidences of head motion. Resting ME BOLD will 
be acquired over ~10 min, and task fMRI will involve two scans of ~10 
minutes each. For resting bold, a single acquisition of phase-encoding in 
the opposite direction of polarity (anterior-posterior) for distortion correction 
will be collected over ~ 30 seconds.149 Data will be analyzed with standard 
preprocessing protocols in AFNI and SPM1. Individual’s fMRI data will be 
normalized into a standard stereotaxic space, Montreal Neurological 
Institute (MNI) template with 1mm3 resolution. MIDT: MIDT will be used to 
assess FC95,152,153 during reward anticipation. This widely-used task for 
assessing reward function in psychiatric patients154-156 is one of the few 
imaging reward tasks with established test-retest reliability.157 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.154,158,159 Participants will complete 2 
functional runs of 70 trials each (140 trials total) over ~20 minutes.95,152 FC 
during each anticipation condition will be assessed for comparison. 
Exploratory Measures (baseline only) - DTI: Inflammation may have 
consequences on white matter fiber tracts necessary to maintain neural 
connections.163 Though not a primary outcome, DTI will be collected at the 
1st scan to determine whether decreased structural connectivity in key basal 
ganglia outflow tracts predict or confound L-DOPA response.164,165 Briefly, 
diffusion weighted images will be acquired over ~5 min, with an image 
acquired in the opposite polar direction for ~30 seconds. Faces task: This 
task that has been developed to measure brain activity in response to 
viewing of fearful and neutral faces and will be collected at the 1st scan. 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
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 


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Fig. 1A) and the vmPFC cluster identified as being reward-sensitive in 
neuroimaging meta-analyses 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) or other similar 
ROIs used to define vmPFC in our previous work.27,64,65,106 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 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, 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: The EEfRT28,167,168: was developed by Co-I, Dr. Treadway. 
EEfRT is a suggested measure under the RDoC Domain: Positive Valence 
Systems > Construct: Reward Valuation, and can detect dose-dependent 
increases in effort expenditure for reward in response to dopaminergic 
drugs.169 EEfRT is well-matched to detecting effects of inflammation on 
motivation considering previous studies in rodents and non-human primates 
showing that inflammation may target effort expenditure for reward as 
opposed to simply affecting the ability to experience pleasure.20,138,139 As 
described, EEfRT performance correlated with both the IDS anhedonia 
subscale and with VS-vmPFC FC in our preliminary data. In this multi-trial 
game, participants are given an opportunity to choose between two 
different task difficulty levels in order to obtain monetary rewards by 
repeated manual button presses within a short time.170 Button presses 
raises a virtual ‘‘bar’’ viewed onscreen. If they raise the bar to the ‘‘top’’ 
within the prescribed time, they are eligible to win the allotted money. Each 
trial presents the subject with a choice between two levels of task difficulty, 
a ‘hard task’ and an ‘easy task’ and 3 probabilities of winning. Subjects 
participate in the task for 20 minutes and the first 50 trials are analyzed by 
calculating proportion of hard-task choices across each level of probability. 
Lower proportions of hard task choices indicate decreased motivation. 
Clinician-Rated Scales for Depression and Anhedonia: 
Snaith-Hamilton Pleasure Scale (SHAPS-C): The SHAPS-C is a 14-item 
clinician-administered scale that assesses hedonic tone.104,176  In a previous 


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study examining hedonic capacity, confirmatory factor analysis revealed a 
Hedonic Capacity factor that was largely defined by the SHAPS. Hamilton 
Depression Rating Scale (HAM-D-17): The HAM-D-17 is a 17-item, 
clinician-administered scale, that rates severity of depression.70 Patient 
Health Questionnaire (PHQ)-9: The PHQ9 is a clinician administered 
assessment covering the 2 core (depressed mood, anhedonia) symptoms 
of depression plus 7 additional symptoms that will be used for screening 
purposes.
Self-Report Assessments of Depression and Anhedonia: 
Anhedonia subscale of IDS-SR: correlates with the SHAPS,27,104 but probes 
not only capacity for pleasure and response to desired events, but also 
interest in work and activities,27,65,73,104 which may more closely approximate 
motivational aspects of anhedonia.177 We have established relationships 
between this scale and both FC and performance on the EEfRT. 
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.178
Additional Measures of Lifestyle, Stress, Anxiety and PTSD Symptom 
Severity:
Hamilton Anxiety Rating Scale (HAM-A): The HAM-A is a 14-item clinician-
administered scale that assesses the severity of symptoms of anxiety71.
Beck Anxiety Inventory (BAI): The BAI is a 21-item self-report measure of 
anxiety symptoms, rated on a 4-point Likert scale72 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 scale73 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.
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.
Neurocognitive Tasks: Additional Measures of Psychomotor Speed 
and Goal-Directed Behavior
Finger Tapping Task (FTT): This task uses a specially adapted tapper that 
the subject is asked to tap as fast as possible using the index finger.  The 
subject is given 5 consecutive 10-second trials for both the preferred and 


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non-preferred hands.  The finger tapping score is the mean of the 5 trials 
and is computed for each hand.  
Reaction Time Task (CANTAB): The reaction time test includes simple and 
choice reaction time tasks and is divided into 5 stages requiring 
increasingly complex chains of responses and providing distinction between 
reaction (or decision) time and movement latencies (3). 
Trail Making Tests A (TMT): is a commonly used neuropsychological 
measure with updated norms. Part A (TMT-A) requires the patient to 
connect numbered circles in order and reflects a measure of basic attention 
and processing speed. 
Digit Symbol Task (DSST): The Digit Symbol Substitution Task is a subtest 
of the Wechsler Adult Intelligence Scale (WAIS) and consists of rows of 
blank squares, each printed with a randomly assigned number. The test 
involves graphimotor speed, visual scanning and memory, with about half 
of the variance being accounted for by graphimotor speed, a third by visual 
scanning and 4-5% by memory.
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.
6.3
Protection Against Risk: 
Every effort will be taken to prevent injury or distress that may result from 
this study. 
Recruitment and Informed Consent:
•
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: IRB00075162, 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 including Facebook and Instagram. An overview of the study will 
initially be provided virtually or over the phone by study clinicians. A 
telephone or virtual 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 the study clinician or their 
appropriately trained designee who will provide this information by virtual 
consent utilizing the Emory IRB approved REDCap platform or in a private 


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office space. To ensure comprehension of the informed consent 
information, the clinician will allow time for adequate consent review and 
questioning. Virtual interviews will be conducted by use of ZOOM, a video 
conferencing service endorsed by Emory University for HIPPA compliant 
patient encounters. 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 or accessible to the participant following virtual consent 
provided in a REDCap ICF document link. The original document will be 
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.
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. In the event 
that a subject becomes unduly distressed, Dr. Miller will be immediately 
contacted, and an appropriate clinical intervention plan will be developed. 
Drs. Miller and is a Board-Certified psychiatrist, and has 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.
Blood Draws: 
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 400 
ml over a ~8-week period (from screening to study completion). 
Rapid CRP test: 
May be conducted at screening using the Diazyme hsCRP POC (or 
comparable) Test Kit. The kits produce 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, 
including rapid CRP, may be repeated at PI’s or PI designee’s discretion.
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. 
L-DOPA Treatment:
To reduce the risks associated with treatment, all subjects will be monitored 
carefully for the development of adverse events as well as worsening of 
their condition. Although it remains unclear what risk chronic therapy with L-


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DOPA will have in depression, and risks are assumed to be small, 
procedures will be put in place to ensure that any risks associated with 
receiving L-DOPA are minimized. At screening, subjects will be carefully 
evaluated for the presence of any medical conditions that might increase 
the risk of an adverse events (for example cardiovascular issues uncovered 
by EKG). Subjects will be evaluated by medical personnel weekly during 
treatment and will be available 24/7 if problems arise. All procedures will be 
conducted in the Emory University Hospital facilities where emergency 
assistance will be available if needed. Between signing consent and 
completing the screening assessment, a period of no more than 2 weeks 
will pass until baseline, and during this period either the patient will be 
taken off-study, or a study clinician or their designee will contact and 
valuate the subject every 7 days to ensure that symptoms haven’t 
worsened appreciably or that suicidal ideation has not developed. In the 
case of either of these eventualities, subjects will be discontinued from the 
study immediately and appropriate psychiatric referral will be made. 
Specific indications for discontinuation between screening and baseline will 
include any of the following: 1) the development of suicidal ideation or 
attempt assessed by spontaneous subject report or by scoring >3 on the 
HAM-D suicide item [item #3]) at any assessment or 2) the development of 
psychotic or catatonic symptoms at any assessment. 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. Subjects will be evaluated for the 
appropriate level of care, including emergency hospitalization if indicated. 
Subjects with non-emergent symptoms but who disqualify for further 
participation will be referred back to their primary psychiatric physician. 
Appropriate follow-up care will be arranged for subjects not in active 
psychiatric treatment. 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. Upon completion of the study 
protocol, all depressed subjects without a current psychiatrist will be offered 
an appropriate referral. 
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 
annual recertification. Each subject will be assigned a unique ID number 
that will be used in all data files and on all measures in place of personal 
identifiers. 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 


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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 anywhere using the internet and 
provides 128-bit SSL security. All electronic and hard entry forms will 
include unique patient identifiers to maintain patient confidentiality and will 
not relate to the patient in any way. Any protected personal health 
information will be encrypted and stored separately. The only link between 
identifying information (e.g., name, contact information) and project data will 
be in a key stored on a password-protected computer 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.
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
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: 1) the development of significant suicidal ideation, plan or 
intent as determined by spontaneous subject report or as determined by 
scoring >3 on the HAM-D suicide item [item #3], 2) the development of 
psychotic or catatonic symptoms, or 3) a 25% increase from baseline of 
HAM-D score, 4) below 85% compliance on more than one week 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. All unanticipated and/or serious adverse events or problems 
will be reported to the DSMB, IRB and NIH and we will follow their 
recommendations for stopping the overall study. 
6.4
Research material will be derived from clinician-administered and self-
report questionnaires, blood, urine, objective behavioral tests 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, 


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serum 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 interview and documented by study clinicians. Standardized 
clinician-administered and self-report questionnaires will be administered 
and collected by study physicians or study coordinator. Blood and urine 
samples at screening will be obtained by the study coordinator and nursing 
staff. Blood and urine for the baseline assessment and follow up visits will 
also be obtained by nursing 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. Subject 
name and identifying number will be kept on separate forms in a locked 
office separate from data files. Only the study coordinator and study 
physicians will have access to subject identities. Research personnel 
analyzing blood data or entering data into the database 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.
6.5
Because we do not anticipate any serious adverse events attributed to L-
DOPA in this study, and because both tracks of study participation involve 
dose de-escalation at the end of study, we do not anticipate a need to 
conduct long-term follow up. 
7.0
Data and Specimen Banking* N/A ☐
7.1
De-identified plasma samples and buffy coat (collected from 2, 6cc tubes 
EDTA whole blood at 4 degree) for inflammatory markers and L-DOPA 
concentrations, and Tempus tubes for mRNA (from ~3-4 cc blood) will be 
collected in this study at baseline and Weeks 1, 3, 4 and 6. 10mL samples 
(in EDTA at RT) will also be collected for immune cell extraction. Samples 
will be stored in the -80-degree freezers (or liquid nitrogen for immune cells) 
in the Behavioral Immunology Program Laboratory on the 5th Floor of 
Clinical B at Emory. Samples will be analyzed by the PI and the Laboratory 
Research Associate or other laboratory personnel that are approved on this 
protocol, or sent to core laboratories within Emory University for analysis 
(i.e. the Genomics Core lab, Biomarker Core Laboratory) or elsewhere (see 
section 17.4). 
7.2
Samples will be de-identified and only the study personnel approved on this 
protocol will have access to the samples or to the data that is associated 
with the identifier for each sample.
7.3
External investigators may obtain specimens and the associated de-
identified clinical data for research purposes only through a Materials 
Transfer Agreement to be prepared and approved by the Emory 
Technology Transfer Office and the Emory Office of Sponsored Programs.


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8.0
Sharing of Results with Participants*
8.1
The results of screening laboratory tests conducted by EML will become part 
of each participant’s Emory Healthcare medical record and will be shared 
with them. Other results such as computer tests, medical and psychiatric 
history, health status updates, questionnaires, urine drug screen results, 
research lab work for looking at inflammation, and MRI scans are not 
intended for clinical use and will be kept only in a research record. These 
results will not be placed in their Emory Healthcare medical record and will 
not be reported to participants or to other healthcare providers who may be 
providing them treatment.
The Principal Investigator and research staff may also share PHI or results with 
the following parties to help conduct the study or to ensure safety or regulatory 
compliance:
1.
Emory offices that are part of the Human Research Participant Protection 
Program and those that are involved in study administration and billing.  
These include the Emory IRB, the Emory Research and Healthcare 
Compliance Offices, and the Emory Office for Clinical Research. 
2.
Government agencies that regulate the research including: Office for 
Human Research Protections; Food and Drug Administration.
3.
Public health agencies including the sponsor of the study, the National 
Institute of Mental Health (NIMH).
4.
Research monitors and reviewer.
5.
Accreditation agencies.
8.2
The fMRI scans that will be completed as data for this study are not 
designed to detect or diagnose problems of the brain. A radiologist will not 
be reading the scans. However, it is still possible that we will see something 
on a structural scan that is potentially abnormal. If this happens, we will 
discuss it with the participants. 
8.3
During the consent process, participants will be informed that they will 
receive the results of their screening laboratory tests performed by EML. 
Participants will also be informed that their other results (i.e. computerized 
testing, psychiatric evaluations, as described above) are not intended to be 
clinical or diagnostic and will not be reported. They will also be informed 
that although MRI scans are also not diagnostic, will not be reviewed by a 
radiologist, and that fMRI results will not be reported, they will be informed 
that if an abnormality is observed during collection of MRI data, this finding 
will be discussed with them by the PI, Study Physician or their designee. 
Participants will have the option to opt out of receiving their lab results or 
being alerted to any incidental findings.
8.4
This study is not deigned to provide treatment and does not include a 
budget for the diagnosis or treatment of incidental findings uncovered 
during participation in this research. The study team will discuss the 
screening laboratory results with the participant, including going over values 
that are outside of the normal range. Patients with abnormal results will be 
advised to schedule a visit with their primary care or treating physician. If 
potential abnormalities are observed during MRI scans, the participants will 
be informed that a potential structural abnormality was observed and that it 


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is recommended that they schedule an appointment with their primary care 
doctor or a specialist, if applicable. 
9.0
Study Timelines*
Because our programs are currently running longitudinal experimental medicine studies and 
clinical trials, and because we are already administering L-DOPA to a similar MDD population, 
we expect that start up and training can be completed in the 1st quarter of the project, and that 
we will be able to study 5 patients by the end of the 2nd quarter. Start up and training will 
include: a. Study team orientation, b. setting up of data bases, c. IRB approval and stamped 
10.0
Inclusion and Exclusion Criteria*
10.1 Seventy medically-stable male and female subjects between the ages of 25 
and 55 will be enrolled in this study in order to obtain 35 qualified subjects 
for the R61 study. All subjects will meet criteria for current major 
depression. All subjects will have a plasma hs-CRP concentration >2 mg/L 
and a score ≥2 on the anhedonia item from the PHQ-9 at screening. During 
screening, CRP will be measured at least twice over a 1 to 2-week interval 
per AHA/CDC guidelines, and additional testing will occur at 1 to 2-week 
intervals in patients with CRP >10 mg/L as needed to determine stability 
and/or, along with exam and lab tests, rule out acute infection. Based on a 
screening failure rate of up ~50%, we anticipate that enrolling and 
screening 70 subjects (35 per year) will provide 35 qualified subjects for 
inclusion in the study. AT screening, participants will undergo laboratory 
testing (for safety labs including coagulation parameters and determination 
of the absence of unstable medical illness including infection, thyroid 
disease and autoimmune disorder).  Electrocardiogram (EKG to rule out 
cardiac contraindications to L-DOPA) will also be conducted followed by a 
complete psychiatric examination (conducted by a trained clinician) 
including detailed information on past psychiatric history and treatment, as 
well as current symptom status. There will be no exclusions for 
race/ethnicity and minority populations, and women will be actively 
recruited. Indeed, based on our previous work ~65% of the sample will be 
female. We will make active attempts to enroll minority patients in a 
Year 1 (R61)
Year 2 (R61)
Year 3 (R33)
Year 4 (R33)
Year 5 (R33)
Table 3: Timeline 
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Q1
Q2
Q3
Q4
Start-up & training
X
X
Accrual (completers)
5
10
15
20
25
30
5
10
20
25
30
35
40
45
50
55
60
Cytokine/image analysis
X
X
X
X
X
X
X
X
Gene expression (R61)
X
DSMB report
X
X
X
X
X
Annual reports NIH/IRB
X
X
X
X
X
Final data cleaning
X
X
X
X
X
X
X
X
X
X
Final analysis 
X
X
X
X
X
X
X
Decision on Go/No-Go criteria
X
X


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proportion that is reflective of the areas surrounding Atlanta from which 
patients will be recruited. No patients will be enrolled from vulnerable 
populations, including neonates, children, prisoners, or institutionalized 
individuals. No use will be made of fetal tissue.
10.2
Inclusion Criteria: a. willing and able to give written informed 
consent; b. men or women, 25-55 years of age; c. a primary diagnosis of 
DSM-V MD, current, as diagnosed by the SCID-V; d. score of >10 on the 
Patient Hospital Questionnaire (PHQ-9); e. off all antidepressant or other 
psychotropic therapy (e.g. mood stabilizers, antipsychotics, anxiolytics, and 
sedative hypnotics) for at least 4 weeks prior to baseline visit (8 weeks for 
fluoxetine) f. CRP ≥2 mg/L, g. PHQ-9 anhedonia score ≥2.
Exclusion Criteria: a. history or evidence (clinical or laboratory) of an autoimmune 
disorder ; b. history or evidence (clinical or laboratory) 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, EKG and laboratory testing); e. history of any (non-mood-
related) psychotic disorder; active psychotic symptoms of any type; history or 
current bipolar disorder; history or current gambling disorder; substance 
abuse/dependence within 6 months of study entry (as determined by standardized 
clinician interview); f. active suicidal plan as determined by self-report (question #9 
on the PHQ-9) and clinician interview (SCID); g. an active eating disorder (except 
for patients with binge eating disorder in whom binging is clearly associated with 
worsening of mood symptoms) ; h. a history of a cognitive disorder or traumatic 
head injury involving loss of consciousness; i. pregnancy or lactation; j. chronic use 
of non-steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg of aspirin), 
glucocorticoid containing medications or statins; k. use of NSAIDS, glucocorticoids, 
or statins at any time during the study; l. urine toxicology screen is positive for 
drugs of abuse, m. any contraindication for MRI scanning; n. intolerance, sensitivity 
or contraindication to carbidopa-levodopa (including history of narrow-angle 
glaucoma, melanoma, gastric and/or duodenal ulcers, bleeding disorders, or 
frequent migraines). Due to the high co-morbidity between anxiety disorders and 
depression, we plan to include patients with comorbid dysthymia and/or anxiety-
related disorders excluding OCD if depression is the primary diagnosis. Enrolled 
subjects may also have a comorbid personality disorder (except for subjects who 
meet criteria for antisocial personality disorder or with a history recurrent 
hospitalizations and/or recurrent suicidal behavior due to the personality disorder). 
Patients with stable medical conditions and on medications/treatments for those 
conditions will not be excluded.
10.3 INCLUSION OF WOMEN, MINORITIES, AND CHILDREN
a. Recruitment of minorities: Eligible subjects will be offered the opportunity to participate 
regardless of gender or minority status. We appreciate that minority groups tend to be under-
represented in research samples and under-treated for mood and anxiety disorders. Therefore, 
we will recruit minority patients to ensure that the subject sample represents the community. 
Census estimates from 2017 for Atlanta, GA, were 40.1% white, 52.4% African American, 0.3% 
American Indian and Alaskan Native, 4% Asian, and <1% Native Hawaiian and other Pacific 
Islander; Hispanic or Latino were 4.8%. There will be two factors that will determine recruitment 
of minorities into the current study. First, although Emory University is located in Atlanta, we 
tend to draw participants regionally; therefore, recruitment is more likely to reflect the minority 


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distribution of Georgia, which is similar to that of the larger Metro-Atlanta population. 
Specifically, these distributions are as follows: 60.8% white, 32.2% African American, 0.5% 
American Indian and Alaskan Native, 4.2% Asian, and <1% Native Hawaiian and other Pacific 
Islander; Hispanic or Latino were 9.6%. Second, the prevalence rate of depression among non-
Hispanic whites (17.9%) is higher than Hispanic whites (13.5%) and African Americans (10.8%) 
(Breslau J, et al. Psychological Med 2006; 36:57-68). Based on these factors, we anticipate 
recruitment of minorities with the following distribution: 60-65% white, 30-35% Black or African 
American, 1-2% American Indian and Alaskan Native, 3-5% Asian, <1% Native Hawaiian and 
other Pacific Islander, 2.1% Two or More Races, and 6-8% Hispanic or Latino. 
Efforts to boost minority enrollment: The following efforts will be undertaken to help maintain 
minority enrollment: 1) Advertisements in African American or Hispanic television or radio 
programs, 2) Advertisements in African American or Hispanic-Latino newspapers, 3) Advertising 
in Emory-affiliated clinics serving communities with high representation of African Americans 
and Hispanic-Latino groups (e.g. Grady Hospital), and 4) targeting of our online Advertisement 
campaign to minority social media users. Recruitment of minorities will be assessed quarterly 
and approaches adjusted accordingly.
b. Inclusion of women: Consistent with NIH policy, women will be included in this study. 
Women typically comprise approximately 65% of subjects at Emory, distributed over racial and 
ethnic categories similar to men. Furthermore, epidemiological studies have found that 
depression is much more prevalent in women than men, with a risk ratio of roughly 2:1 (e.g. 
Kessler, J Affect Disord, 2003, 74:5-13). Higher enrollment of women than men will more closely 
approximate the prevalence of depression, making this study sample more representative of 
and generalizable to the population of depressed patients from which it samples. In addition, 
because of the potential interactive effects of sex with inflammation and depression, recruitment 
of women will be assessed quarterly to ensure adequate representation. 
c. Inclusion of Children: 
In order to limit the variability of the primary outcome variables (neuroimaging and behavioral), 
we have chosen to limit the age range from 25-55, reflecting +/- ~1-2 standard deviations from 
the mean age (40 years) in our previously published patient samples. This design consideration 
precludes the inclusion of children (and older adults), limiting variability contributed by potential 
neurodevelopmental and neurodegenerative factors on brain connections (a primary outcome of 
this study). Furthermore, the relationship between inflammatory markers, dopamine and reward 
responsivity has not been established in children. The study will also exclude younger adults 
(<25 years) due to the unknown risk of treating subjects in an age range where the brain is still 
be developing. 
11.0
Vulnerable Populations* N/A ☐
N/A
12.0
Local Number of Participants
12.1 Seventy medically-stable male and female subjects between the ages of 25 
and 55 will be enrolled in this study in order to obtain 35 qualified subjects 
to be randomized for the R61 study.
12.2 Thus, n=70 will be enrolled for screening, and n=35 will be randomized in 
order to obtain and analyze data from n=30 study completers when 
considering a ~10-15% attrition rate.
13.0
Recruitment Methods


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13.1 Recruitment will be made through the use of contact lists, databases or 
other pre-screening resources, advertisements, outreach, media/social 
media, and referral networks or groups.
13.2 Community recruitment will encompass the Metro Atlanta are as well as 
regionally through north and central Georgia.
13.3 We use primarily online advertising to identify interested participants. 
Approximately 500 potential participants will be screened by phone per year 
to yield 200 face-to- face prescreens (to be conducted through our program 
recruitment center) and 35 subjects per year (n=70 total) for enrollment and 
full screening for this study. As part of daily recruitment monitoring, the 
study team records all advertisement responses and contacts and 
schedules potentially eligible participants.
13.4 We use primarily Facebook, Google and Instagram campaigns with the 
advertising materials attached.
13.5 Participant reimbursement:
Table 4. Schedule of Reimbursement 
Visit
Total Amount 
Amount put on Clincard 
immediately after visit
Amount put on 
Clincard at the end of 
study participation
Intake (phone or virtual)
No Payment
No Payment
(Visit Total)
n/a
Screening A*
Rapid CRP, Vitals and BMI, 
MRI Safety Questionnaire,
Urine Toxicology Screen, 
Serum Pregnancy Test, 
Screening Labs, EKG, SCID 
and Clinician Assessments 
(may be done virtually or 
as part of intake)  
$50
$50
(Visit Total)
$50
$50
Screening B and Pre-
Baseline 
Physical Exam, CRP, Fasting 
Blood, Demographics and 
Report Forms, Practice 
Neurocognitive
$50
$50
Practice Computer 
Motivation Tasks In and 
Out of Scanner (depending 
on choices made in task)
$5-$10
$5-$10
(Visit Total)
$55-60
$55-60
Visit 1 (Baseline)
Medical and Psychiatric 
Update, Urine Toxicology, 
Urine Pregnancy, Self-
report Surveys, 
Neurocognitive Tasks, 
$50
$50


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Research Bloods, 
Medication Dispense
Complete Scan (~1 hr)
$100
$100
Incomplete Scan
$25**
$25**
Computer Motivation Task 
in Scanner (depending on 
choices made in task)
$0-$20
$0-$20
Computer Motivation Task 
Out of Scanner (depending 
on choices made in task)
$5-$10
$5-$10
(Visit Total)
$25-$180
$25-$80
$0-$100
Visit 2 (Week 1)
Medical and Psychiatric 
Update, Urine Toxicology, 
Urine Pregnancy, Self-
report Surveys, 
Neurocognitive Tasks, 
Research Bloods, 
Medication Check and 
Dispense (as tolerated)
$50
$50
Complete Scan
$100
$100
Incomplete Scan
$25**
$25**
Computer Motivation Task 
in Scanner (depending on 
choices made in task)
$0-$20
$0-$20
Computer Motivation Task 
Out of Scanner (depending 
on choices made in task)
$5-$10
$5-$10
(Visit Total)
$25-$180
$25-$80
$0-$100
Visit 3 (Week 2)
Medical and Psychiatric 
Update, Urine Toxicology 
and Pregnancy (in-person 
only), Self-report Surveys, 
Medication Check and 
Dispense 
$50
$50
(Visit Total)
$50
$50
Week 4 (Week 3)
Medical and Psychiatric 
Update, Urine Toxicology, 
Urine Pregnancy, Self-
report Surveys, 
Neurocognitive Tasks, 
Research Bloods, 
Medication Check and 
Dispense
$50
$50
Complete Scan (~45 min)
$100
$100
Incomplete Scan
$25**
$25**
Computer Motivation Task 
in Scanner (depending on 
choices made in task)
$0-$20
$0-$20
Computer Motivation Task 
Out of Scanner (depending 
on choices made in task)
$5-$10
$5-$10
(Visit Total)
$25-$180
$25-$80
$0-$100


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Visit 5 (Week 4)
Medical and Psychiatric 
Update, Urine Toxicology, 
Urine Pregnancy, Self-
report Surveys, 
Neurocognitive Tasks, 
Research Bloods, 
Medication Check and 
Dispense
$50
$50
Complete Scan (~45 min)
$100
$100
Incomplete Scan
$25**
$25**
Computer Motivation Task 
in Scanner (depending on 
choices made in task)
$0-$20
$0-$20
Computer Motivation Task 
Out of Scanner (depending 
on choices made in task)
$5-$10
$5-$10
(Visit Total)
$25-$180
$25-$80
$0-$100
Visit 6 (Week 5)
Medical and Psychiatric 
Update, Urine Toxicology 
and Pregnancy (in-person 
only), Self-report Surveys, 
Medication Check and 
Dispense
$50
$50
(Visit Total)
$50
$50
Visit 7 (Week 6)
Medical and Psychiatric 
Update, Urine Toxicology, 
Urine Pregnancy, Self-
report Surveys, 
Neurocognitive Tasks, 
Research Bloods, 
Medication Check
$50
$50
Complete Scan (~45 min)
$100
$100
Incomplete Scan
$25**
$25**
Computer Motivation Task 
in Scanner (depending on 
choices made in task)
$0-$20
$0-$20
Computer Motivation Task 
Out of Scanner (depending 
on choices made in task)
$5-$10
$5-$10
(Visit Total)
$25-$180
$25-$80
$0-$100
Completed Study 
Compensation
$980-$1110
*=These visits may be combined into a single screening visit with combined compensation
**= Unable to complete scan leading to termination from the study
Participants will also receive tokens for parking expenses incurred at EUH, and an 
additional $25 will be provided to cover travel expenses for participants that travel equal 
to or greater than 30 miles one way to Atlanta.


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14.0
Withdrawal of Participants*
14.1 Patients may be drawn from the research without their consent if they 
experience a severe adverse event thought to be attributed to the study 
procedures, due to repeat non-compliance with study procedures (2 or 
more of the same violation), worsening of depressive symptoms including 
suicidal ideation, or for any other reason that the PI or Study Physicians 
determine to be putting the participant at increased risk or jeopardizing 
integrity of the study data.
14.2 To withdraw a participant, the study team will contact the subject to inform 
them that they should discontinue use of all study medication and to 
schedule a follow-up visit for the participant to be assessed by study 
clinicians for medical and psychiatric safety. The participant will be asked to 
return all unused medication at this time, and a member of the study team 
will take them off study. If the patient is determined to be a potential risk to 
themselves or others on the call or in the final interview, Drs. Miller or 
Dunlop will be immediately contacted, and an appropriate clinical 
intervention plan will be developed. 
14.3 When participants withdraw from this study, they will be appropriately off-
studied and their participation will be terminated. Because this study is a 
mechanistic study to demonstrate target engagement using a within-in 
subject design, no partial withdrawal with continued data collection will be 
allowed for participants who miss their schedule MRI, blood and 
neurocognitive follow-up assessments.
15.0
Risks to Participants*
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 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. L-DOPA may cause nausea or 
vomiting, and carbidopa is co-administered with the L-DOPA as a combination pill to reduce 
side effects. Common symptoms are most pronounced after the first few doses of L-DOPA and 
may also include dizziness or headache. L-DOPA may also cause increased eye 
blinking/twitching, fainting, or worsening of involuntary movements and spasms. People who 
take high-doses of L-DOPA daily for Parkinson’s disease have reported more serious but rare 
symptoms such as dyskinesias, and these are not anticipated following the doses used in this 
study or in patients with depression who do not have neurodegeneration. Participants’ vital 
signs and adverse events will be monitored at weekly follow visits. If patients are unable to 
tolerate dose escalations, the study physician will provide the patient with a dose pack or bottle 
of one pill of study medication (containing 150 mg L-DOPA) a day for 3 days followed by study 
medication discontinuation. 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. 
Alternative options include not participating in the proposed study. In addition, an array of 
demonstrated effective treatments for depression exists and include, but are not limited to: 


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selective serotonergic antidepressants (i.e. fluoxetine, paroxetine, etc.), serotonin-norepinephrine 
reuptake inhibitors (i.e. venlafaxine, duloxetine), atypical antidepressants (i.e. bupropion, 
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 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.
16.0
Potential Benefits to Participants*
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. 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 and potential for use 
of novel dopaminergic therapies. 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 and 
the use of an intervention with only a mild side-effect profile and that has the potential to have 
some clinical benefit, we feel that the risks of the study are reasonable in relationship to the 
benefits of study participation.
17.0
Data Management* and Confidentiality
17.1 Statistical Analysis and Power
POWER ANALYSIS
Effect Size Estimations for Power and Go/No-Go Criteria: The relationship 
between VS-vmPFC FC and anhedonia from our previous dataset (n=48)27 
was used to estimate a clinically meaningful effect size (ES) for Go/No-Go 
criteria and power calculations. Mean FC scores for patients with high (≥5) 
versus low (<5) anhedonia scores indicated a 50% difference in FC scores. 
Of note, a 50% difference for FC in patients with low compared to high 
anhedonia was stable across the low and high ends of the 95% confidence 
interval of the means, as determined by 1000-repetition bootstrapping of 
the data. Therefore, we expect that L-DOPA will produce ≥50% increase in 
FC, corresponding to a mean difference of ~3 points on the anhedonia 
scale. We also anticipate a ~30% placebo response, consistent with the 
placebo response rate in MDD145 and with the percent change in FC after 
acute placebo administration in our preliminary data in patients with high 
CRP (32%). Therefore, we expect to observe a ≥20% separation between 
the L-DOPA and placebo responses, which will serve as Go/No-Go criteria 
for the R61. Based on a 20% difference in FC response between placebo 
and L-DOPA and the estimated standard deviation of this change based on 


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our preliminary data involving acute L-DOPA and placebo administration to 
high CRP patients (~1.5 x the mean difference between L-DOPA and 
placebo), an ES (Cohen’s dz for standardized differences) of 0.65 is 
anticipated. 
Power Analysis for R61 Go/No-Go Criteria: Based on our estimated ES of 
dz=0.65, 21 patients would be required for 80% and 28 patients would be 
required for 90% power. To account for uncertainty and bias, clinical 
covariates (age, sex, race and BMI) were also considered. Although none 
of the covariates exerted significant effects in the model, per se (all p-
values >0.05), they did improve the ES for the mean difference in placebo 
versus L-DOPA in our preliminary data. Based on this improvement, an ES 
dz=0.97 is estimated for the proposed separation of the means by ≥20% 
when including covariates in the model. A graphical analysis of the sample 
size across a full range of power at the proposed ESs (with and without 
covariates) is provided in Figure 1 as shown below. 
Figure 1. Estimated power for within subject comparisons of FC response 
to L-DOPA versus placebo in the R61 phase. Sample size (x-axis) and 
power values (y-axis) for ES (dz) of 0.97 (with covariates) and 0.65 (without 
covariates) are provided. Relevant to the power analysis of the study based 
on Go/No-Go criteria for difference in response to L-DOPA versus placebo, 
both the treatment effect alone and the treatment effect plus covariates will 
exhibit power >0.8 with the proposed sample size of 30 (dashed line).
A sample size of n=30 will also provide sufficient power for collecting 
preliminary information about the relationship between change in behavior 
and target engagement in the brain. For example, based on the correlation 
between EEfRT and change in VS-vmPFC FC after acute L-DOPA in our 
prelim data of r=0.6, we will have >95% power to detect significant 
correlations with 30 patients. 
Analytic strategy
Milestones (Go/No-Go Criteria)
0.4
0.6
0.8
1.0
20
40
60
0
n=30
Sample Size
Power (1-β)
0.65 (w/o covariates)
Effect size
0.97 (with covariates)


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Target Engagement in the Brain: VS-vmPFC FC using an objective, a 
priori analytic strategy, will serve as the target for physiologic response and 
functional improvement in the brain after administration of L-DOPA versus 
placebo. The relationship between VS-vmPFC FC and anhedonia from our 
previous dataset (n=48)27 and anticipate placebo response was used to 
estimate a clinically meaningful effect size (ES) for Go/No-Go criteria and 
power calculations (see Milestones). 
Milestone for Brain Target: At least 1 dose of L-DOPA will cause a 
mean increase in FC that is ≥20% higher than placebo. 
Power Analysis and Sample Size Estimation
Sample size was estimated to have adequate power to observe statistical 
significance based on our preliminary data and the proposed Go/No-Go 
criteria described above (see Power Analysis section for detail). For the 
R61 Phase, the proposed threshold criteria for the primary outcome of 
target engagement in the brain (VS-vmPFC FC) is a mean change with L-
DOPA from baseline of ≥20% greater than that of placebo. Based on the 
means and standard deviations from our previous work, a ≥20% difference 
in mean change in FC corresponds to a effect size (ES) of 0.65, indicating 
that with a 2-sided alpha=5%, a total of 30 patients (out of 35 that will be 
studied to account for potential drop-outs) will be required to have >90% 
power for statistical analysis (see Figure 1 in the Power Analysis section 
of Human Subjects for detail). Based on our preliminary data on the 
relationship between change in EEfRT performance and change in VS-
vmPFC FC after acute L-DOPA of r=0.6, we will have also have >95% 
power to detect correlations between change in FC and improvements in 
motivation, a secondary outcome to be explored.
Statistical Analysis
Target Engagement in the Brain for R61 Go/No-Go Criteria: Targeted 
VS-vmPFC connectivity will serve as the primary outcome and will be 
assessed for determining the Go/No-Go Criteria. Targeted fMRI FC will be 
calculated as the degree of correlation in activity using an a priori defined 
seed in VS and region of interest (ROI) in vmPFC (per the literature and our 
previous studies). 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. FC Z-scores will be extracted and the change in mean FC values 
after each dose of L-DOPA or placebo compared to baseline will be 
assessed. We expect that at least one dose of L-DOPA will increase VS-
vmPFC FC by ≥20% greater than placebo. If more than 1 dose of L-DOPA 
is able to engage the FC outcome at the proposed thresholds, the percent 
of patients and mean number of reported side effects will be compared 
across doses to determine the effective dose that was most tolerated by 
patients. If doses are similarly tolerated, the one with greatest impact on 
behavior (% change in behavior, EEfRT > anhedonia), or lowest dose 
meeting all of the above criteria, will be chosen. Statistical significance, ES 
or sensitivity analyses may be used to assist with selection of the optimal 
target dose of L-DOPA foe the R33 phase.


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Additional Analyses for Publication and Scientific Dissemination: 
Brain Target- Targeted FC Z scores (as described above) will be entered 
into linear regression models including clinical covariates and both 
conservative (Bonferroni) and powerful (Fisher LSD) post-hoc analyses to 
asses change in FC across the 4 doses of L-DOPA compared to baseline, 
placebo and to each other. Linear models will also be used to determine 
whether FC increases as a function of increasing plasma L-DOPA, and 
whether patients with low bioavailability exhibit low FC. Treatment 
resistance (as measured by ≥2 on the MGH-ATRQ) will also be assessed in 
linear models to determine whether it is associated with greater response to 
L-DOPA. In addition to the targeted FC that will be used to assess Go/No-
Go criteria, hypothesis-driven and data-driven whole-brain analysis will also 
be explored and compared before and after L-DOPA. Consistent with our 
previous data, these analyses will include VS seed-to-voxel-wise 
comparisons of L-DOPA versus placebo, as well as network analyses using 
GBC and PBNA, as a secondary outcome measures and to identify other 
circuits that may be affected by L-DOPA. For all analysis, concentration of 
CRP and final dose will be explored as a linear predictor of response to L-
DOPA. Clinical covariates such as age, sex, race and BMI will also be 
explored as potential confounders or mediators of L-DOPA effects on FC. 
As described for FC, linear regression models and post-hoc analyses will 
be used to asses change in behavioral outcomes across the 3 doses of L-
DOPA compared to baseline, placebo and to each other, and whether 
response was modified by plasma bioavailability of L-DOPA, CRP or 
cytokines concentrations or clinical covariates. Overall depression scores, 
SHAPS-C and MAP-SR will also be explored as an outcome. Integration of 
Brain and Behavior: Random intercept linear mixed models will be used to 
assess whether change in FC predicts change in anhedonia and motivation 
and in relation to clinical covariates. Overall depression scores and motor 
behaviors will also be explored as outcomes. Summary scores for dose-
response (e.g. area under the curve) may be used to assess relationships 
among variables.
Integration of Brain, Behavior and Inflammatory Markers: Whether 
plasma levels of inflammatory cytokines and their receptors at baseline, 
together in models with selection or when combined in a composite or 
principle component factor, predict FC and behavioral response with be 
assessed. There is some evidence that dopamine is anti-inflammatory, and 
change in inflammatory markers and their relationship with response to L-
DOPA over time will also be examined. Gene transcripts will be entered into 
linear regression models in R with change in FC and behavioral measures, 
and identified genes will be assessed in bioinformatic platforms as 
described in the methods to determine additional biological and 
inflammatory pathways that are associated with L-DOPA response. Other 
behaviors (e.g. locomotor behavior) and imaging markers (e.g. white matter 
fractional anisotropy) will also be explored as factors that moderate L-
DOPA-induced changes in FC, anhedonia and motivation, and depression 
scores.
17.2 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, 


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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 anywhere using the internet and provides 128-bit SSL security. 
All electronic and hard entry forms will include unique patient identifiers to 
maintain patient confidentiality and will not relate to the patient in any way. 
Any protected personal health information will be encrypted and stored 
separately. The only link between identifying information (e.g., name, 
contact information) and project data will be in a key stored on a password-
protected computer 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.
17.3 Data will be securely entered directly into REDCap. Data will be value 
checked with double entry. The PI and Co-I’s and their staff are currently 
using REDCap for their funded projects, and have extensive experience 
with its usage. No names or locating information will be entered in 
databases. Forms will be maintained in locked offices. Neuroimaging and 
neurocognitive data will be reviewed weekly and backed-up to local 
servers. Imaging data will be preprocessed using standard techniques to 
remove or control for artifact. Descriptive statistics will summarize central 
tendencies and variances of dependent variables, demographics and 
clinical characteristics. Log-transformation will be used for non-normally 
distributed data (i.e. inflammatory markers) and non-parametric tests will be 
used were appropriate.
17.4 De-identified plasma samples, immune cells and Tempus tubes for mRNA 
collected in this study will be stored in the -80-degree freezers in the 
Behavioral Immunology Program Laboratory on the 5th Floor of Clinical B at 
Emory. Samples will be analyzed by the PI and the Laboratory Research 
Associate or other laboratory personnel that are approved on this protocol, 
or sent to core laboratories within Emory University for analysis (i.e. the 
Genomics Core lab, Biomarker Core Laboratory). Samples will remain 
stored indefinitely to allow completion of all planned or future analyses. By 
storing samples for future analyses, we can do research for a long time 
without needing to ask for fresh samples from new patients. We anticipate 
transporting one sample per participant for each assay, but understand that 
there may be the need to repeat some analyses and additional tubes may 
need to be transported. Samples will be transported by laboratory personal 
who have completed the sample shipping certification class offered at 
Emory. In addition to analysis at Emory-affiliated core labs, we also expect 
to ship de-identified plasma samples to Brainsonline/Charles River (South 
San Francisco, CA) labs for measurement of concentrations of L-DOPA. 


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18.0
Provisions to Monitor the Data to Ensure the Safety of Participants*
Because study subjects will be receiving a pharmacological intervention as part of this study 
protocol, we have elected to utilize a Data and Safety Monitoring Board as part of our data and 
safety monitoring plan. This board is described below:
Composition of the Emory DSMB
The Emory DSMB consists of Marian Evatt, M.D. from the Department of Neurology, Larry Tune, 
M.D., Chairman of the DSMB, Dr. Dunlop, Ms. Woolwine and David Goldsmith, 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. No persons involved in the operation of this study will review DSMB reports for the 
study. The frequency of Emory DSMB review for this protocol will be once every 12 months based 
on IRB recommendations consistent with the assessed risk status of the study. 
Procedures and Responsibilities of the Emory DSMB
In advance of the DSMB meeting, the data manager/research coordinators will prepare a an 
annual 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 will 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 Emory DSMB, once every 12 months the DSMB will 
issue a report to the Emory IRB that summarizes the following: All serious and unexpected 
adverse events or other unanticipated problems that involve risk to study participants, and 
whether these appear related to the study-based interventions or research assessment protocols. 
Reports will not specifically disclose the treatment arm of the study for relevant subjects unless 
this disclosure is required for safety reasons. Note that any serious adverse event (SAE) will be 
reported to the Emory IRB within 24 hours 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.”
The PIs will take responsibility for reporting any serious and unexpected adverse events in a 
timely fashion directly to the Emory DSMB. The PIs will also report serious and unexpected 
adverse events or other unanticipated study problems or variances to the Emory IRB. Actions 
taken by the IRB in response to adverse event reports will be immediately reported to the Emory 
DSMB.
19.0
Provisions to Protect the Privacy Interests of Participants
19.1 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 
annual recertification. Each subject will be assigned a unique ID number 
that will be used in all data files and on all measures in place of personal 
identifiers. Data entry forms will be developed using the REDcap database 


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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. All 
electronic and hard entry forms will include unique patient identifiers to 
maintain patient confidentiality and will not relate to the patient in any way. 
Any protected personal health information will be encrypted and stored 
separately. The only link between identifying information (e.g., name, 
contact information) and project data will be in a key stored on a password-
protected computer 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.
19.2 Care will be taken to avoid bringing about undue psychological distress to 
participants, particularly during the neuropsychiatric interviews. This will be 
accomplished by using trained raters (clinicians) for all neuropsychiatric 
assessments. In the event that a subject becomes unduly distressed, Drs. 
Miller or Dunlop will be immediately contacted, and an appropriate clinical 
intervention plan will be developed.
19.3 Only research team members approved on this protocol are allowed to 
access any sources of information about a participant. Approved team 
members may do so by accessing the casebooks, which are stored in 
locked file cabinets. The CRC, Director of Projects and Study physicians 
are also able to view a participant’s Emory Medical Record through Power 
Chart.
20.0
Economic Burden to Participants
No cost is incurred by the participant other than transportation expenses for study visits. 
an additional $25 will be provided to cover travel expenses for participants that travel 
equal to or greater than 50 miles one way to Atlanta.
21.0
Consent Process
If a subject shows interest 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 trained designee who provides this information in 
a private setting. 
22.0
Process to Document Consent in Writing
Written informed consent will be obtained by the study clinician or their appropriately 
trained designee who will provide this information by virtual consent utilizing the Emory 
IRB approved 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. Virtual interviews will be conducted by use of ZOOM, a video 
conferencing service endorsed by Emory University for HIPPA compliant patient 
encounters. 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 or 
accessible to the participant following virtual consent provided in a REDCap ICF 
document link. The original document will be 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 


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locked office and/or cabinet. Active participants will be asked to reconsent with a revised 
consent if an IRB approved modification is relevant to subjects’ participation.
23.0
Setting
This work will be conducted in the Emory Behavioral Immunology Program on the 5th floor of 
Clinic B, and using the following clinical, laboratory and imaging facilities as described below.
Office Space:  The Department of Psychiatry and Behavioral Sciences provides Dr. Felger with 
an office on the 4th floor of the Woodruff Memorial Research Building, which is down the hall 
from her laboratory space, shared equipment, and to the offices of Dr. Miller (Co-I and Study 
Physician) and Ms. Woolwine (Project Manager). Office and desk space for the dedicated 
laboratory manager, as well as clinical and laboratory staff and students, are provided in the 
laboratory spaces and adjacent clinical research areas. In addition, 3 offices are available for 
patient interviews, and one office area is available for storage of patient files and equipment. 
The Department of Psychiatry and Behavioral Sciences provides Dr. Dunlop with an office on 
the 3th floor of the Executive Park 12 (EP12) building. Dr. Treadway is Faculty of the 
Department of Psychology at Emory where he has laboratory and office space on the 4th floor of 
the Psychology and Interdisciplinary Sciences Building.
Laboratory Resources: 
The Emory University Hospital maintains a CLIA-Certified lab for the necessary clinical 
laboratory testing. Dr. Felger’s over 600 square feet of laboratory space is located on the 4th 
Floor of the Woodruff Memorial Research Building, and is part of the Emory Behavioral 
Immunology Program spaces. See Equipment for details. 
Clinical Resources:  
Emory University Hospital Clinical Research Site:
The proposed study will use the Emory University Hospital Clinical Research Network (CRN), 
which is part of the Georgia Clinical and Translational Science Alliance (GCTSA, formerly 
Atlanta CTSI) located in the Emory University Hospital. The GCTSA-CRN is staffed around the 
clock with trained research nurses, who are available to aid in the implementation of all protocol 
procedures.  It should be noted that GCTSA staff have extensive experience in conducting 
blood sampling procedures as proposed in this protocol and preparing the patients for LP.  More 
detailed information about the CRN includes:
Outpatient Care Area:  The outpatient area consists of two beds and four infusion recliners, an 
outpatient nursing station and a restroom.  There is a small waiting area in the hallway adjacent 
to the Outpatient Room. In addition, the GCTSA outpatient area offers attached lab services, 
where blood and CSF samples can be processed. The GCTSA has implemented NCATS cost 
recovery mandated for all CTSAs through fees for use of space, nursing and laboratory support. 
Statistical Core:  As an active GCTSA investigator, the Dr. Felger has access to the GCTSA 
statistics faculty and statistical software. FCTSA computers are connected to a local area 
network that allows sharing software, custom programs, data, and automatic backups of 
administrative files. Investigators can access their data from any personal computer at the CRN, 
as well as by dialing into the CRN system. 
The Mood and Anxiety Disorders Program (MAP): 
The Emory Mood and Anxiety Disorders Program directed by Co-Investigator, Dr. Boadie 
Dunlop, is the largest clinical research program in the Emory Department of Psychiatry and 
Behavioral Sciences, and will be the primary clinical site for this project. MAP has been 
conducting NIH- and industry-funded outpatient research trials of major depression, PTSD, 
social phobia, generalized anxiety disorder, obsessive-compulsive disorder and panic disorder 
for 15 years. Trials conducted by MAP include industry- and federally sponsored studies, 


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including the recently completed PReDICT study with a recruitment target of 400 treatment-
naïve MDD patients willing to be randomized to medication or psychotherapy. MAP personnel 
conduct telephone screening of approximately 1200 people per year for depressive or anxiety 
disorders, resulting in in-person evaluations of approximately 150-200 people per year who are 
interested in participating in clinical research. Potential research subjects contact MAP either 
through our telephone number or complete application forms located on the website for 
“emoryclinicaltrials”. The program is located on the third floor of the Executive Park 12 (EP12) 
building. MAP operates out of a suite of 12 offices, plus additional rooms for physical exams, 
phlebotomy, EKG, centrifugation, storage (including dry-ice storage equipment, and -20ºC and -
80ºC freezers), and a conference room. The program is fully equipped with modern desktop 
computers, printers, fax machines, photocopier, supplies, and video-taping equipment. The 
personnel have extensive clinical experience and all have been trained to conduct high-quality 
clinical research. There is plentiful free parking directly in front of the EP12 building, and a 
public transit bus stop directly in front of the EP12 building.
Additional Patient Referral Resources and Support: In addition to the MAP, patients will be 
obtained from multiple internal and external referral resources including the Emory Clinic, Grady 
Health System, and the Veterans Administration Medical Center (VAMC) as well as community 
psychiatrists. Advertisement will consist primarily of a social media advertising campaign, but 
may also include radio, television, and print advertising. We anticipate that up to 3 subjects per 
month will consent and qualify to undergo full screening for our study (~35 per year), and we will 
enroll approximately 1-2 patients per month. This estimate is based on current studies on 
depression in mood disorders research programs within the department. Relevant to this 
project, we consistently observe that at least 50% of patients exhibit increased C-reactive 
protein (i.e. CRP >2mg/L). 
Core Resources:
Biomedical Imaging Technology Center (BITC): Center for Systems Imaging 
(CSI)/Biomedical Imaging Technology Center (BITC): The BITC is part of the overall Emory CSI 
and the Wallace H. Coulter Department of Biomedical Engineering run jointly by Emory 
University and Georgia Institute of Technology. The BITC facility at Emory University Hospital is 
housed in approximately 3000 square feet of space. BITC is a core facility of the School of 
Medicine at Emory University. It was established to focus on the development and application of 
imaging technology, particularly magnetic resonance imaging (MRI). BITC is equipped with a 3 
Tesla Siemens Prisma whole-body MR system, and a 9.4T/21-cm Bruker animal MR 
imaging/spectroscopy system dedicated to research. In addition, a research agreement was 
reached with Siemens Medical System such that BITC will have full access to sequence 
programming software, technical details for data manipulation, and necessary technical support. 
This MRI system will be used for fMRI studies proposed in this project. The post processing will 
be conducted in a state-of-art computing facility consisting of a Linux-based 29 nodes 
computational cluster, disk array with a capacity of 131 TB, and an automated backup system. 
The core of the processing is accomplished by a Sun Grid Engine powered for maximum data 
processing efficiency. This state-of-the-art hardware setup is augmented with a number of 
software packages including Matlab, FSL, AFNI, Hammer, SPM5/8, IDL, LCMODEL, and 
Stimulation. In addition to the MRI system and computing facility, peripheral equipment including 
coils, monitoring systems, computers and software are also available in the center described as 
follows: 
RF coils:
CP_Head coil [Siemens]
64, 32 and 20- channel head array coils [Siemens]
Spinal Matrix coil [Siemens]


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2x Flexible Body Matrix coil [Siemens]
CP Extremity Coil (Knee coil) [Siemens]
CP Wrist Coil [Siemens]
Managed Peripheral Equipment:
In vivo Vital Sign Monitor (MRI compatible) -- ECG, SpO2, EtCO2, and HR (heart bit rate); also 
(upgraded to) provide external trigger signal and synchronized vital signal digital recording.
Homemade respiration belt monitoring/recording setup.
Homemade visual stimulation setup -- support computer video display mode 640x480 up to 
1280x1024. 
Homemade LED goggle -- visual stimulation.
Avotec Silent ScanTM Audio System -- PI-patient communication and acoustic stimulation.
Applied Science Laboratories eye-tracker -- pupil tracking.
Current Designs, Inc. optical button box -- non-audio patient response.
Home-made single large button -- simple response.
Home-made buzzer -- tactile stimulation.
Third Party Peripheral Equipment:
Biopac MP100 -- GSR recorder.
Including: ECG100C-MRI (for ECG), RSP100C (for respiration), EDA100C-MRI (for skin 
conductivity),
TSD160A (for animal respiration), STM100C (for electrical stimulation), and DTU200/300 (for 
cardiac and
respiration triggering).
BITC Cluster software available for MRI data processing
fMRI data processing - AFNI 
fMRI/DTI data processing - FMRIB Software Library
fMRI data processing for animal image - Stimulate 
MRI image converter/viewer - MRIcro
Post-processing software - LC Model
Echoplanar Spectroscopic Imaging - Developed at the University of Miami used in BITC with 
permission
Generic Scientific Calculation
Matlab
The Emory Integrated Genomics Core (EIGC): Dr. Zwick is the Scientific Director for the 
EIGC, which provides a host of genomic and related computational services for Emory 
Investigators. The EIGC is a CLIA-certified (CLIA # 11D1086150) laboratory located on the 7th 
floor of the Woodruff Memorial Research Building, with 2400 sq ft of dedicated wet-lab space 
and 500 sq ft of dedicated office space for bioinformatics. The EIGC’s laboratory areas include 
dedicated pre- and post-PCR spaces. The EIGC is composed of three divisions: CLIA, 
Research, and Computational. Each division provides specialized genomics and computational 
research services to Emory investigators. 
Biostatistics and Bioinformatics Shared Resource: The Biostatistics and Bioinformatics 
Shared Resource at Winship Cancer Institute is a shared resource that serves as a focal point 
from which Winship investigators may draw statistical expertise for planning, management and 
analysis of their studies. The Biostatistics core also develops, tests and implements various 
techniques of statistical analysis, including mathematical modeling, applicable to cancer 
research. Types of research supported include clinical trials, translational research, 


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epidemiology, behavioral, and basic science. This shared resource has Ph.D. and M.S. 
biostatisticians including whose primary appointments are in the Department of Biostatistics at 
Rollins School of Public Health of Emory University. 
The EIGC offers comprehensive bioinformatics pipelines and services for the analysis of 
genomics data contained within the Computational Division. Presently, standard analyses are 
carried out using the Emory Human Genetics Computer Cluster (HGCC) which is composed of 
1 head node and 20 compute nodes and serves multiple functions related to genomic projects, 
including running NGS analysis pipelines, high-performance and parallel computing, web 
application serving, and data storage. The cluster includes a 143 TB Penguin Computing RAID 
6 storage array for user files and data, a 32TB Advanced Clustering RAID 5 storage array for 
storing and processing NGS data, and a 22TB Apple Xserve RAID 51 storage array for serving 
web applications. A mix of 10 Gbps ethernet, 1 Gbps ethernet, and 4 Gbps fibre-channel 
switches are configured to provide a high-speed Storage Area Network (SAN). All storage 
arrays and compute nodes utilize the SAN for data transfer, and are configured to connect 
either via 10 Gbps high-speed network, or with dual-bonded connections to the 1 Gbps ethernet 
or 4 Gbps fibre-channel ports for increased bandwidth. The cluster runs Centos 5.7 64-bit 
operating system on all nodes. Configuration: One head node: 2 x 2.4 GHz 8-core CPUs, 64 GB 
RAM. One development and job-submission node: 2 x 2.4 GHz dual-core CPUs, 8GB RAM. 
Four compute nodes: 4 x 2.4 GHz 8-core CPUs, 256 GB RAM, 10 Gbps ethernet. Two compute 
nodes: 4 x 2.4 GHz quad-core CPUs, 24GB RAM, 2 x 1 Gbps ethernet. Fourteen compute 
nodes: 1 x 3 GHz dual-core CPU, 12 GB RAM, 1 Gbps ethernet. Sun Grid Engine is 
implemented for job submission. Four queues are implemented: shq - for short jobs requiring 
high memory, lhq - for long jobs requiring high memory, slq - short jobs requiring low memory, 
and llq - for long jobs requiring low memory. Short jobs are defined as those requiring 12 hours 
or less to complete. High memory jobs are defined as those requiring greater than 12GB RAM. 
The EIGC operates a custom EIGC Galaxy server for standard analyses. Galaxy is an 
open, web-based platform for accessible, reproducible, and transparent computational 
biomedical research. The Galaxy server will use flexible Emory University Isilon storage (up to 1 
petabyte total capacity) to store large datafiles and the EHPCC to process large computational 
jobs in parallel. Galaxy provides a wide variety of bioinformatic tools that allow users to analyze, 
manipulate, and visualize large genome-wide datasets from a wide variety of platforms, 
including microarrays and next-generation sequencing instruments.
Emory's Library & Information Technology Services (LITS) supports High Performance 
Computing (HPC) on campus through a relationship with Amazon Web Services (AWS) as a 
preferred vendor. The HPC team will meet directly with clients to help them set up an account, 
create a virtual private cloud (VPC) as well as Amazon Machine Images (AMI). The team also 
provides necessary training. The AWS Cloud provides a broad set of infrastructure services, 
such as computing power, storage options, networking and databases, delivered as a utility: on-
demand, available in minutes, with pay-as-you-go pricing.
Computer Resources:
See above. Available to the research staff in this application are 6 IBM desktop computers and 
2 laptop computers as well as 2 laser printers (one color), a FAX copier and a dedicated 
scanner.  The computers are all connected to the University server for internet access and are 
all available for data storage and management, statistical analyses, word processing and 
presentation graphics.  The project staff also has access to the Emory University Computing 
Center. The Center is available to the investigators via fiber-optic linked campus wide network 
and supports a wide array of software including a number of statistical packages such as SAS 
and SPSS.
24.0
Resources Available


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24.1 This project will be conducted using the resources described above. 
Recruitment and referral sources for subject recruitment will include paid 
online advertisement conducted through the Behavioral Immunology 
Program, where up to 500 subjects per year will be contacted to yield 200 
participants to be seen by our program for pre-screen followed by 35 
consents and full screens to be conducted for this study each year to yield 
35 patients randomized over 2 years. This recruitment method, which has 
been successful in our previous studies (including Dr. Felger’s ongoing R01 
study) will be supplemented by referrals from the clinical of Co-Investigator, 
Dr. Dunlop (see MAP clinic above). 
•
Anticipated effort of the faculty and staff involve on the project (may 
change at any time during the study in accordance with NIH 
requirements):
Principal Investigator Jennifer C. Felger, Ph.D., M.S. (3.6 calendar 
months, both years) Dr. Felger is an Associate Professor of 
Psychiatry and Behavioral Sciences at Emory University School of 
Medicine, and has been conducting clinical and translational research 
in behavioral immunology for over 10 years. As the team lead, she will 
be responsible for the overall administration and management of the 
study, and will maintain regular contact with all team members. She 
will work closely with the Project Manager/Director of Projects to hire, 
supervise, and train staff in clinical/study procedures, design all data 
collection instruments, and coordinate patient recruitment. She will 
consult with Dr. Miller, Dr. Dunlop and the Nurse Practitioner to review 
recruitment criteria and safety measures for all study participants. Dr. 
Felger will have weekly meetings with the Postdoctoral Fellow, and 
quarterly meetings with Dr. Treadway and Dr. Li, to ensure quality 
control of neuroimaging data acquisition and analysis. She will work 
with Dr. Treadway and the Postdoctoral Fellow on the implementation 
and analysis of performance-based reward tasks inside and outside of 
the scanner. Dr. Felger is the Laboratory Director for the Emory 
Behavioral Immunology program, and will oversee all specimen 
collection and bioassays performed by the research Specialist. Dr. 
Felger will work with Dr. Schettler, a statistician with extensive 
experience in psychiatry research, and the Postdoctoral Fellow to 
compile, analyze and upload/share (see Resource Sharing Plan) the 
collected data, and will prepare the results for presentation and 
publication. 
Co-Investigator Andrew H. Miller, M.D. (1.8 calendar months, both 
years) Dr. Miller is Professor of Psychiatry and Behavioral Sciences at 
Emory University School of Medicine, and will serve as the study 
physician during the R61 phase. He has over 20 experience in 
experimental medicine, psychoneuroimmunology research and clinical 
trials. He will determine if subjects are medically healthy, as 
demonstrated by a normal history and physical examination and 
laboratory testing. He will provide physician coverage for any medical 
or psychiatric problems that arise during subject assessments. He will 
review entry criteria for all patients (including screen failures) and will 
oversee the medical management of all study participants. He will 


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provide on-call availability to study participants 24/7. He also will be 
involved in data interpretation and manuscript preparation.
Co-Investigator Boadie W. Dunlop, M.D., M.S. (1.2 calendar months, 
both years) Dr. Dunlop is an Associate Professor of Psychiatry and 
Behavioral Sciences at Emory University and is the Director of the 
Mood and Anxiety Disorders Program (MAP) for the Department. 
During the R61 phase, Dr. Dunlop will assist with recruitment by 
referring participants from his clinic and research program into the 
study, and will serve the second (back-up) psychiatrist on the project. 
He will participate in writing up study findings for publication. 
Co-Investigator Michael T Treadway, Ph.D. (1.8 calendar months, 
both years) Dr. Treadway is an Associate Professor in the Department 
of Psychology at Emory University. Dr. Treadway has a background in 
cognitive neuroscience and clinical psychology, with specific training 
in methods of functional and structural magnetic resonance imaging 
and application of computational models to neuroimaging data. He is 
an expert in the evaluation of reward responsivity and has developed 
innovative strategies for measuring various aspects of reward 
processing, notably effort-based decision-making. As part of his 
research, he developed the Effort Expenditure for Rewards Task 
(EEfRT) task, which will be one of the tasks used in this proposal to 
assess reward valuation. Dr. Treadway will oversee the 
implementation of the performance-based reward tasks and will assist 
with determination of the quality of the data. He also has over 10 
years of neuroimaging experience, and will assist in the collection, 
analysis and interpretation of fMRI data, as well as the integration of 
imaging findings with the results of the EEfRT task outside of the 
scanner for presentation and publication.
Other Personnel
Director of Projects Bobbi J. Woolwine, M.S.W. (2.4 calendar months, 
both years) Ms. Woolwine is a well-trained research clinician with 25 
years of experience who will supervise the clinical 
interviews/assessments of study participants, and will assist Dr. 
Felger with regulatory oversight and study monitoring during the R61 
phase. She has worked closely with the Departmental and University 
Offices of Grants and Contracts and the Institutional Review Board to 
assure that all research activities are in compliance with appropriate 
university and other funding agency guidelines. She will help Dr. 
Felger to develop budgets and track expenditures. She will also assist 
with the writing of protocols, operational decision manuals, and 
provide documentation of these annual reports. The Project Manager 
will also assist Dr. Felger with the hiring and training of staff in 
clinical/study procedures, as well as advertisement and patient 
recruitment, and will oversee the flow from intake through the 
participation process.
TBD, Clinical Research Coordinator I (12 calendar months, both 
years) A Clinical Research Coordinator I (CRC) will be needed for 


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recruiting patients, scheduling patients for study procedures, and 
handling the day-to-day management of the study including 
maintaining the case report forms, entering data into the database, 
and screening of patients. The CRC will report directly to Dr. Felger.  
He/she will also assist in conducting standardized patient interviews 
and conducting the performance-based assessments under the 
supervision of Dr. Treadway. The CRC will conduct intake interviews, 
administer research rating scales with the validated instruments, and 
conduct vital signs measurements. He/she will assist the Research 
Interviewer in the phone and clinic screening of potential research 
participants. The CRC will also be responsible for recording adverse 
events, study variances and maintaining up-to-date charting and entry 
of clinical data into Red Cap. The CRC will help prepare reports for 
the DSMB and IRB, and help prepare and submit study modifications 
and renewals to the IRB. 
TBD Research Interviewer (6 calendar, both years)The primary role of 
the Research Interviewer will be to work with the PI, CRC, NP and 
Director of Projects to recruit study participants. He/she will conduct 
phone screens and participate in the initial intake interviews. The 
Research Interviewer will also assist the CRC and PIs in facilitating 
the flow of participants through the study protocols, maintaining 
patient records and preparing reports for the DSMB and IRB. 
TBD, Research Specialist (1.8 calendar months, both years)
The Research Specialist will be responsible for the overall 
management of the laboratory aspects of the project including the 
collection, processing and storing of all biological samples, and 
conducting assays of inflammatory markers. The Research Specialist 
will also be responsible for laboratory data entry, data proofing and 
cleaning, and developing reports and queries for manuscripts and 
progress reports. She/he will assist with data acquisition, chart 
cleaning, and data retrieval as needed.
This research will be conducted using the Facilities and Resources 
described above.
Availability of medical or psychological resources:
Psychological: 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. In the event that a subject becomes 
unduly distressed, Study Physicians Drs. Miller or Dunlop will be 
immediately contacted, and an appropriate clinical intervention plan 
will be developed. Drs. Miller and Dunlop 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.
Medical: At screening, subjects will be carefully evaluated for the 
presence of any medical conditions that might increase the risk of an 


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adverse events (for example cardiovascular issues uncovered by 
EKG). Subjects will be evaluated by medical personnel weekly during 
treatment and will be available 24/7 if problems arise. All procedures 
will be conducted in the Emory University Hospital facilities where 
emergency assistance will be available if needed. 
•
All personnel working on this study will complete appropriate CITI 
training modules including Good Clinical Practice. The CRCs working 
on the study will also complete a coordinator training class. Staff will 
be trained by the PI and designees (Study Physicians or Director of 
Projects) on all procedures, and adequate training for specific tasks 
will be documented in the delegation of authority log. After any 
approved modification to this protocol, the new protocol and IC will be 
circulated and discussed by study team. Each member will be asked 
to acknowledge key changes for written documentation that all staff 
and Investigators were appropriately educated.
25.0
Multi-Site Research when Emory is the Lead Site*N/A ☐ 
N/A
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ICF_000.pdf: 
Title: Dopaminergic Therapy for Inflammation-Related Anhedonia in Depression  
NCT#: NCT04723147 
Date: 04/28/2022


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