Dynamics of Inflammation and Its Blockade on Motivational Circuitry in Depression
Phase: PHASE4
Conditions: Depression
Sponsor: Emory University

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Dynamics of Inflammation and its Blockade on Motivational 
Circuitry in Depression 
 
 
NCT03006393 
 
Date: July 6th, 2020 
 
IRB00087941 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Research Protocol 
 
Title of Protocol: Dynamics of Inflammation and its Blockade on Motivational Circuitry 
in Depression  
 
Short Title: Infliximab 
 
Principal Investigator:  Michael Treadway, Ph.D., Assistant Professor, Department of 
Psychology 
 
Correspondence: 
 
Michael T. Treadway, Ph.D. 
Department of Psychology  
36 Eagle Row, Room 491 
(404) 727-3166 (office) 
(404) 727-7541 (lab) 
mtreadway@emory.edu 
 
Abstract 
Motivational anhedonia–a subset of anhedonic symptoms involving dopamine-linked 
impairments in effort- based decision-making, reward anticipation and reinforcement 
learning–are common in psychiatric disorders such as major depression, and are 
notoriously difficult to treat. In recent years, these symptoms have been associated with 
alterations in dopaminergic corticostriatal circuitry, yet the underlying causes of this 
circuit dysfunction remain unknown. One candidate mechanism is inflammation; 
increased inflammatory cytokines have been reliably found in depressed patients, and 
administration of inflammatory cytokines or cytokine inducers has been shown to foment 
depressive symptoms of apathy, anhedonia and fatigue. In addition, inflammatory 
cytokines have been found to disrupt dopamine synthesis, alter basal-ganglia metabolism, 
and blunt striatal responsivity during reward anticipation. To date, however, the majority 
of data supporting the relationship between cytokines and symptoms in patients with 
major depression and other disorders is correlational in nature, and thus alternative 
experimental strategies are required to elucidate causal relationships. One strategy is to 
block inflammatory cytokines in a sample of depressed patients with high inflammation 
so as to determine which symptom domains are most affected and through which 
molecular pathways. The current study will assess neuroimaging measures of 
corticostriatal circuitry before and after a placebo-controlled pharmacologic blockade of 
inflammation in 80 depressed patients (n = 40 per group) recruited to ensure high levels 
of peripheral inflammation [C-reaction protein (CRP) > 3mg/L]. We will also recruit two 
comparison samples consisting of  20 depressed patients with low levels of peripheral 
inflammation [CRP <2mg/L] and 40 healthy controls. Primary aims are to evaluate 
whether 1) corticostriatal function during reward motivation and anticipation are 
associated with change in peripheral inflammation following pharmacologic blockade 
relative to placebo 2) the temporal dynamics of change in inflammation, gene- 
expression, reward motivation and reinforcement learning behavior and motivational 

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symptoms assessed at baseline, and 24 hours, 3 days, 1 week and two weeks post 
infliximab infusion, and 3) test an integrative multi- level path model to determine 
whether change in corticostriatal circuitry following inflammation blockade mediates the 
relationship between change in inflammation and change in motivational anhedonia 
symptoms. These data will provide further validation of inflammatory cytokines as 
therapeutic targets for motivational symptoms in depression and will define symptom 
targets and biomarkers of response for future studies. 
 
Introduction and Background  
Development of new treatments for major depression has been substantially hindered by 
the marked heterogeneity of the disorder, leaving remission rates as low as 33% with 
conventional antidepressant therapies.
24 To address this problem, the National Institute of 
Mental Health (NIMH) has emphasized transdiagnostic approaches focused on 
identifying pathophysiological mechanisms for specific symptoms, rather than disorders 
as a whole. Anhedonia and other reward-related symptoms represent an excellent 
opportunity for this type of translational neuroscience approach, given the vast basic 
science literature from which to draw upon.
25 Additionally, anhedonic symptoms reflect 
an area of critical need as they frequently fail to respond to widely available psychosocial 
and pharmacological treatments.
26,27  
To date, however, application of this important preclinical work to humans has 
been hampered by the enormous heterogeneity in psychiatric disorders, and the reliance 
on clinical symptom definitions that are underspecified for the purposes of identifying 
their neurobiological mechanisms. For example, the DSM-V (p. 163) states that 
individuals meeting criteria for anhedonia “may report feeling less interested in hobbies, 
‘not caring anymore,’ or not feeling any enjoyment in activities that were previously 
considered pleasurable.” In other words, clinical assessment of anhedonia does not 
discriminate between a decrease in motivation and a reduction in experienced pleasure. 
However, a wealth of preclinical data suggest that this distinction is crucial for purposes 
of specifying the neural processes involved in motivation and pleasure, with dopamine-
dependent corticostriatal function implicated in the former
28-30 but not the latter.
31,32 In 
addition to distinct substrates, these different sub-domains of anhedonia likely have 
distinct etiopathophysiologies. Indeed, as summarized below, there is excellent evidence 
to suggest that one path towards the development of an anhedonic presentation is the 
effect of inflammation on dopaminergic circuits and subsequent corticostriatal 
dysfunction resulting in impaired motivation, anticipation and reinforcement learning 
(referred to herein as “motivational anhedonia”
6).  
The goal of the proposed research is to establish the validity of an inflammation-
dependent path towards the development of motivational anhedonia. Importantly, we do 
not propose this model as a means of accounting for all forms of anhedonic symptoms; 
rather, we suggest this as a possible mechanism that may occur in the context of high 
inflammation and altered dopamine-dependent corticostriatal network functions  
Objectives. There are three primary aims of this study, each of which generates one or 
more hypotheses to consider and explore in the protocol design. These are elaborated on 

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below. 
Aim 1: Determine the relationship between inflammation and corticostriatal circuit 
function in patients with major depression and high inflammation before and after a 
placebo-controlled anti-inflammatory challenge. 
80 medication-free depressed patients pre-selected for high inflammation (CRP >3mg/L), 
20 medication-free depressed patients with low inflammation (CRP<2mg/L), and 40 
healthy controls will be enrolled. fMRI assessments of corticostriatal circuit function 
during effort-based decision-making, reward anticipation and reward attainment will be 
assessed using the EEfRT21, MID22, and a Reinforcement Learning (RL)23 task, 
respectively, at baseline and 2 weeks after double-blind, random assignment to receive 
administration of the TNF antagonist infliximab or placebo (n = 40 per group). Peripheral 
protein and gene expression markers of inflammation will also be assessed.  Hypothesis 1a: 
Infliximab-induced decreases in inflammation will predict pre-post increases in neural 
activity in ventral striatal and vmPFC during the EEfRT and, MID tasks, as well as 
increased prediction-error signals in ventral striatum during the reward attainment. 
Hypothesis 1b: Decreases in inflammation will additionally be associated with pre-post 
increases in vmPFC–striatal connectivity during the EEfRT task. 
 
Aim 2: Determine the temporal dynamics of change in CRP and interleukin-6 (IL-6) and 
change in behavioral and clinical measures of motivational anhedonia in depressed 
patients before and after an anti-inflammatory challenge. 
Behavioral measures of effort-based decision-making and reinforcement learning as well 
as symptoms of anhedonia will be collected in the subjects in Aim 1 at 4 time-points 
before and after anti-inflammatory challenge with infliximab or placebo: baseline (pre), 
24 hours post-infusion, 3 days, 1 week, and 2 weeks. Peripheral protein and gene 
expression markers of inflammation will also be assessed at each time point. Hypothesis 2: 
Individual differences in the magnitude of infliximab-induced decreases in plasma CRP 
and (IL-6) as well gene expression changes in TNF signaling pathways will be associated 
with reduced motivational anhedonia as assessed by behavioral and clinical measures. 
Aim 3: Explore the inter-relationship among inflammation, corticostriatal circuit function 
and reward motivation using path analysis. Hypothesis 3: Across all subjects, the 
association between change in peripheral inflammation and symptoms of motivational 
anhedonia following inflammation blockade or placebo will be mediated by changes in 
corticostriatal circuitry (ventral striatal BOLD signal & striatal-vmPFC connectivity). 
Mediation will be assessed using a well-validated bootstrapping procedure for indirect 
effects analysis. We will also test a model of moderated-mediation to examine whether 
indirect mediational effects of changes in corticostriatal circuitry are moderated by 
treatment with infliximab or placebo. 
 
STUDY PROTOCOL AND METHODS.  
 
Virtual Study Visits: Due to COVID-19, the informed consent process, clinical interview, 
neuropsychiatric assessments, task administration, and self-report surveys may be 
completed virtually with trained research staff using Emory’s HIPPA-Compliant Zoom 
Account and REDCap. Participants will be paid $15/hour for time spent in study visits on 

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Zoom. Please see the updated TReAD Lab Suicide Policy for information specific to 
virtual study visits.  
 The overall procedure for this study is summarized in the table, below.  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Description of Study Procedures 
 
Research Evaluation Clinic: Some subjects in this study will be recruited after 
completion of a separate “evaluation clinic protocol”, in which screening will be 
conducted to assess a subject’s eligibility to participate in this study and/or others. 
Screening may include a structured clinical interview, administration of self-reports and 
computer tasks, physical examination and EKG, urine drug and/or pregnancy screen, and 
blood work (CBC with differential platelet count, comprehensive metabolic panel, etc.). 
This pre-screening process will take place at the Behavioral Immunology screening 
Figure 1. 
Legend: PE = physical examination; MD = major depression; SCID = structured clinical interview for DSM-V; QIDS-SR = 
16-item Quick Inventory of Depressive Symptoms; MMSE = Mini Mental State Examination; C-SSR = Columbia Suicide 
Severity Rating Scale; CRP = C-reactive protein; INFLIX = infliximab; PBO = placebo; MRI = magnetic resonance 
imaging; Psych Ass. =  Interviewer based assessments using the SCID Mood Disorders module, MGH Antidepressant 
Treatment Response Questionnaire (ATRQ), Mini Mental State Examination (MMSE), SCID substance abuse modules, 
and Columbia Suicide Severity Rating scale (C-SSR). Self-report questionnaires will include the Multidimensional 
Fatigue Inventory (MFI), Inventory of Depressive Symptoms Self-Report (IDS-SR), 16-item Quick Inventory of 
Depressive Symptoms (QIDS-16 SR), Snaith-Hamilton Pleasure Scale (SHAPS), Fatigue Severity Scale (FSS), Mood 
and Pleasure scale (MAP-SR), and Positive Affect/Negative Affect Scale - Now (PANAS-X) Immune Eval = blood draw 
for assessment of plasma concentrations of TNF-alpha, sTNF RI and R2, IL-1, IL-1ra, IL-6, sIL-6R and CRP, intracellular 
TNF-alpha expression and NF-κB activity; the kynurenine to tryptophan ratio Adv. Events = clinician-based assessment 
of medication side effects/adverse events. 
Schema/Study Summary 

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clinic, where subjects who are determined to be eligible for this study will be referred to 
study staff.  An overview of the study may initially be provided in person or over the 
phone by study clinicians or trained study staff after a subject has completed the 
evaluation protocol and consented to be contacted about other studies. Before enrollment 
of a subject, study staff will review the screening test results and medical record of a 
referred subject to ensure he or she is medically healthy and eligible to participate. Any 
screening tests and procedures necessary to verify eligibility not performed through the 
Research Evaluation Clinic will be administered for a subject as a part of this protocol. 
Subjects who are recruited through this route may not undergo some of the procedures 
described under the “Pre-Screening” and “Screening” visits if these were completed 
through the Research Evaluation Clinic and the results were still valid through 
completion of the study protocol. Screening tests and procedures may be repeated during 
the study as needed if the validity of a test has expired before completion of the study 
visits. For example, an EKG performed through the Research Evaluation Clinic could be 
deemed sufficient to assess for safety criteria for this study, if performed within a 
reasonable amount of time before study enrollment (under advisement of PI and co-
investigators). However, a serum pregnancy test would be completed during screening 
for this study regardless of whether a test was previously performed as a part of the other 
protocol. Serum Pregnancy will be repeated on infusion date, regardless of the date of the 
last negative result.  
 
Pre-Screening: To obviate the full screening assessment, an initial CRP and QIDS-16 SR 
will be obtained before embarking on the full screening process. 
 
Following pre-screening, participants will be scheduled to complete one or more 
screening appointments. The procedures described under “Screening” may be divided 
between multiple visits depending on subject scheduling and preference, staff 
availability, and other factors. Screening visits will occur at the Emory Department of 
Psychology and/or the Emory Clinics and Emory University Hospital. If screening is 
performed in a single visit, it will occur at the locations listed above. 
 
Screening: Subjects potentially qualified for enrollment will undergo a screening 
evaluation after written informed consent. Screening will involve a subject interview and 
evaluation, as well as obtained collateral history and data from other sources (i.e., 
medical records, referring physician). Screening will include the following assessments: 
(1) Assessment of past psychiatric history and current symptom severity using a) the 
Structured Clinical Interview for DSM-V (SCID-V) and QIDS-16 SR, (2) Assessment of 
past and current psychiatric treatment history, (3) Evaluation of medical history obtained 
from interview of the patient and review of pertinent medical records, (4) Complete 
medical and neurological examination, (5) Screening laboratory evaluations as described 
in “medical exclusionary criteria” above, (6) Height and weight (provided to the 
pharmacy to calculate appropriate infliximab dose), and (7) CRP. We anticipate that 50 
full-screens will be required annually to enroll 16-20 subjects per year.  
 
Randomization and Blinding:  

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A list containing the randomly generated sequence of assignments to infliximab or 
placebo will be maintained in the Emory University Investigational Drug Service 
pharmacy. Independent pharmacists will dispense either infliximab or placebo in a 250ml 
saline bag according to the randomization list. Subjects will be stratified on the basis of 
sex to obviate any confounding effect of gender on the outcome variables. Study 
personnel responsible for administering the infusion, conducting psychiatric evaluations, 
conducting medical assessments, drawing blood and performing lab analyses will be 
blinded to subject group assignment. In the event of a significant adverse reaction to the 
study medication, the study blind will be broken if medically necessary, and the subject 
will be referred for appropriate medical care. Unblinded subjects will be discontinued 
from the protocol. Based on our previous experience, infliximab was well-tolerated with 
no serious adverse events, no differences in side effects compared to placebo, and no 
ability to be distinguished from placebo by patients or staff.20 
 
Important Note: In some cases, an FDA-approved infliximab biosimilar, Inflectra 
(infliximab-dyyb) may be used in place of infliximab. Please note at each place where 
infliximab is referenced in this protocol that Inflectra may be used as its substitute.  
 
Phone Calls:  
If a participant misses a study visit, a study staff member will contact that participant to 
determine the reason behind the missed visit and will actively follow up with him or her 
as appropriate until the conclusion of the study (at the 30 day follow-up call).  
 
 
Healthy Controls and Low CRP Depressed Patients: 
Healthy controls and low CRP depressed patients will go through a pre-screen and 
screening process that will consist of psychiatric evaluations, research and safety labs, 
baseline assessments (clinician-rated assessments, self-reports, behavioral tasks) and will 
take part in one scan visit. In total, these participants will take part in up to 3 study visits 
(prescreening, screening, scan visit); however, some participants may request to 
consolidate their visits into just 2 study visits (prescreening, screen/scan visit).  
 
Healthy controls and low CRP depressed patients will undergo all research-related 
screening procedures that high CRP patients would undergo but will not receive a 
Quantiferon Gold TB Test, EKG or Chest X-Ray, as these are only required in order to 
ensure safety and suitability for the study drug. Healthy controls and low CRP depressed 
patients will not receive an infusion of either drug or placebo. 
 
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.96 All patients 
will be evaluated by the SCID as part of the screening process. In addition to providing 
information for inclusion/exclusion purposes, the SCID will provide data about relevant 
psychiatric covariates including number of past major depressive episodes, length of the 
current episode and presence of co-morbid anxiety disorders and/or dysthymia. Substance 

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abstinence will be additionally confirmed by urine drug screen at multiple points over the 
course of the study. 
 
The MGH Antidepressant Treatment Response Questionnaire (ATRQ)97: 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 resistance98 Degree of resistance will be used as a covariate in relevant 
statistical analyses. 
 
Mini-Mental State Exam (MMSE) is a 27-item interviewer-administered questionnaire 
widely used for the evaluation of general cognitive functioning and identification of altered 
mental status. At screening, subjects will be excluded for score ≤24, indicating evidence of 
more than mild cognitive impairment.95 
 
Bipolarity Index (BI): Bipolarity will be measured as a continuous variable using the 
NIMH funded Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-
BD) study.99 The STEP-BD computed bipolarity index scores by rating the patient’s 
profile relative to five traits characteristic of Bipolar I disorder, including episode 
characteristics, age of onset, course of illness/associated features, response to treatment 
and family history. The Bipolarity Index (BI) assigns common clinical features along 
each of five dimensions using a 0–20 score, where 20 points represents the presence of 
traits considered most characteristics of Bipolar I Disorder.  
 
Hamilton Rating Scale for Depression (HAM-D): The HAM-D is a 21-item 
interviewer-administered questionnaire widely used for the evaluation of severity of 
symptoms of depression.144 This clinician-rated assessment may be administered at the 
PI’s discretion. 
 
Wide Range Achievement Test (W-RAT3): The WRAT III is a very brief screening 
measure for achievement. It covers reading recognition, spelling, and arithmetic. It 
contains very easy beginning items (letter reading, basic counting, and dictation of 
letters) followed by spelling, pronouncing words, and written math problems. 
 
Note: Neuroimaging Measures and Computer tasks will be drawn from the tasks listed 
below. Participants will be required to complete a selection of these tasks. 
 
Neuroimaging Measures  
 
All neuroimaging will be acquired on a 3T Siemens Prisma magnetom scanner with a 32-
channel headcoil. Collection of structural and functional data includes: a 13-s localizer 
scan; an “auto-align scout” scan that uses a reference database to ensure consistent slice 
positioning across subjects; a rapidly acquired (~2 min), T1-weighted, multi-echo 
MPRAGE volume for structural analysis and localization of fMRI data (0.8 mm isotropic 
voxels; TR = 2.3 s; flip angle = 8 deg; TE1 = 3.15 ms; 224 slices); and multiband echo 

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planar imaging for task-related fMRI data (2x2x2.5 mm voxels; TR = 1.0 s; TE = 30 ms; 
flip angle = 46 deg; 56 transverse slices, no skip). This last sequence is re-used to acquire 
task-evoked fMRI data. The scanning session may also include diffusion tensor imaging 
(DTI) and MR spectroscopy (MRS) scans. All neuroimaging data will be analyzed in 
SPM using standard preprocessing routines involving realignment/motion-correction, co-
registration, normalization and smoothing with a 6mm Gaussian kernel.  
 
fMRI-adapted EEfRT (approx. 15-20 min) Assessment of reward motivation will be 
accomplished using an fMRI-adapted version of the EEfRT task. During each trial, 
subjects are presented with a choice between two levels of task difficulty, a High Effort 
option and a Low Effort option, which require different amounts of speeded manual 
button pressing for differing levels of monetary reward. The reward magnitude for a No 
Effort option remains constant ($1.00), while the reward magnitude for the High Effort 
option varies from $1.00 to $5.00. Additionally, the amount of effort required for the 
High Effort option will vary between 20%, 50%, 80% and 100% of the subject’s max 
effort (set for each individual prior to scan). The task will use a rapid event-related design 
with an exponential jitter between trials drawn from a Poisson distribution in order to 
optimize HRF estimation. Responses will be made using MRI-compatible button-boxes 
and images will be presented on a rear projection screen visible with a mirror mounted on 
the head coil.  
 
After the scan, subjects will be asked to complete a “post-scan” effort task. This task will 
present the same trial options the subject viewed and decided on in the scanner (e.g., 
$3.70 for 80% max effort or $1 for no effort). The subject may then choose to re-select 
the choice previously made or change it, and then complete the effortful button pressing 
or not (depending on the choice made). 
 
Main Effects Analysis: Based on subject choices, indifference curves for each level of 
effort will first be established using a logistic model, and then fit to a parabolic 
discounting effort function where the subjective value (SV) of each choice is defined as 
SV = Reward / (1-k*effort2). A parabolic discounting function is used based on prior 
work suggesting superior fits for effort-discounting as compared to hyperbolic or 
exponential functions 89. Per-trial subjective values will then be used as a parametric 
regressor in a first-level model, such differences in subjective value between the high and 
low effort options will be modeled against BOLD signal for each subject. Single-subject 
parametric contrast maps will then be entered into an RFX GLM, which is expected to 
isolate areas of vmPFC and striatum.  
 
Note: For this task, participants will be instructed that they may complete the EEfRT 
“post-scan” task during a mandatory 30-minute observation period, to follow the MRI 
scan session. In reality, an observation period is not needed after an MRI scan. This 
instruction will help ensure that participants do not believe that visit length is dependent 
choices made in the EEfRT post-scan task. Once all study procedures are complete at the 
14-day follow up visit, this will be explained to participants and a debriefing form will be 
provided.    
  

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Monetary Incentive Delay Task (approx. 15 min): Assessment of reward anticipation 
will be achieved using the Monetary Incentive Delay Task.22 This is one of the most 
widely-used tasks for assessing reward function in psychiatric populations,8,10,100 and is one 
of the few imaging reward tasks with established test-retest reliability.91 Briefly, during this 
task participants have the opportunity to win or lose money by making a rapid button 
press in response to a target visual stimulus. The primary epoch of interest is the 
“anticipatory delay” – a period of ~2000ms that occurs after participants have been 
informed how much money they can win or lose on a given trial, but prior to the 
presentation of the target. This epoch has repeatedly been associated with robust ventral 
striatal activity10,22,101-103 and shows excellent test-retest reliability. Participants will 
complete 2 functional runs of 90 trials each, resulting in a total of 180 trials (72 win; 72 
loss, 36 no-change), with evenly distributed reward magnitudes of $0.20, $1.00 and $5.00.  
An optional variant of this task may involve an additional cue at the beginning of each trial 
signifying different ranges of possible reward values with the precise amount for each trial 
revealed only at the outcome phase.   
 
Main Effects Analysis: Primary contrasts of interest will focus on reward anticipation, 
and include Win > Neutral trials, Loss > Neutral trials, and Win > Loss trials. We will 
additionally examine these contrasts after restricting Win and Loss trials to only high 
reward amounts ($5.00).  
 
Adaptive MID (one run AdaptMID; approx. 9-10 min.  Total run time approx. 18-
20 min.): The adaptive MID task was designed to show how brain value signals adapt to 
the specific context that a person is experiencing.  The AdaptMID includes both training 
and a test phase.  During training subjects will see stimuli identical to what they see in the 
test portion.  Subjects are first shown a cue signal informing them of the context they are 
in.  The two contexts are low context rewards, where the trial could be worth $0.25 or 
$1.00, and high context rewards, where the trial could be worth $1.00 or $4.00.  The 
contexts are indicated by either one “+” symbol (low) or by three “+” symbols 
(high).  After the cue there is a jittered delay (mean 2.84 sec.) and the reward amount is 
displayed to them ($0.25, $1.00, or $4.00).  The lower value option and higher value 
option are displayed an equal number of times within each context. After all of the cue 
information has been presented there is an anticipation phase delay (mean 2.36 sec.) 
before a target appears.  A target red box flashes briefly on the screen and the subject’s 
role is to quickly press a button before the box disappears.  An accurate response results 
in a “hit” and the subject is rewarded the amount shown previously.  An inaccurate 
response results in a “miss” and the subject is not rewarded.  The subject is shown 
feedback on whether they hit or missed, and how much money they earned if any.  The 
primary dependent variables are how subjects respond to low and high contextual 
situations and whether the reward amount revealed is the low value or high value within 
that context. The AdaptMID will be administered as two runs with a novel order of trials 
for each of the runs.  
 
Gamble Task (approx. 30 min): To examine the relationship between chosen certain 
rewards the expected values of chosen gambles, the difference between experienced and 
predicted rewards and happiness; we have added a Gamble Task. During this task, 

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participants will have the option of selecting between a certain choice and a gamble choice, 
with equal probabilities of the two outcomes. There will between 50 and 150 trials with an 
equal proportion of three trial types: mixed (a certain amount of $0 with a gain and loss 
amount), gain (with a certain gain or a gamble with $0 and a larger loss), and loss (with a 
certain loss or a gain of $0 and a greater loss). Further, participants will be asked to rate 
their current level of happiness after every three trials. Also, before and after the task is 
complete, participants will be asked to measure their life happiness. Previous studies by 
Rutledge et. al. have demonstrated that this technique can be used to establish a relationship 
between task earnings and happiness. Further, fMRI measures have demonstrated a 
relationship between ventral striatum activities with happiness ratings from this task.  
 
RL Task (approx. 15-20 min): To examine effects of infliximab on neural responses to 
reward attainment we have added an instrumental conditioning task (90 trials). Trials for 
this task involve a 3s cue presentation during which subjects choose between two abstract 
stimuli, followed by an exponentially jittered delay, and then a 3s feedback presentation 
with positive (monetary win), negative (monetary loss) or neutral outcomes. Behavioral 
responses will be analyzed by fitting a standard reinforcement learning (Q-learning) 
model104  to each subject’s sequence of choices. Based on individual choices and 
outcomes for each trial, the Q-learning algorithm will compute the expected values (Q) of 
choosing a given stimulus: Qt = Qt-1 + alpha*RPEt, where RPEt = Rewardt - Qt-1 and 
alpha represents the learning rate.104 Model-based expected values will be related to 
subject choices using a softmax selection rule105 to determine learning-rate parameters 
and generate behavioral RPE values for each trial, consistent with past studies from our 
group (Preliminary Study 5) and others.23,106 We note that while some past work has 
suggested minor test-retest reliability issues with fMRI RL tasks107, these have only been 
observed using task designs with a very low number of trials (~25 as compared to 90 in 
the current proposal), which likely produce less reliable measurements for purposes of 
repeated assessments. 
 
Main Effects Analysis: Primary contrasts of interest will focus on parametric modulation 
of RPE during reward attainment reward, which is expected to robustly recruit ventral 
striatal activity. 
 
Delay-discounting Task (approx. 5-15 min): Participants are presented with choices 
between receiving one reward amount now, and a different reward amount that will be 
delivered some number of days later. Reward values will range between approximately 
$5.00 to $50.00, and number of days will range between today and 52 weeks.  To ensure 
the ecological validity of this task, participants will be told that two of the choices they 
made will be added to their final compensation, with this added payment received either 
at the end of the study or some days later (depending on the choice made by the 
participant). 
 
Main Effects Analysis: Primary contrasts of interest will focus on the parametric 
modulation of reward amount and delay of reward. 
 
Ramping Task (approx. 10 min/run, 20 min total): In this task, subjects will be trained on 
different computerized mazes with varying difficulties/lengths. There will be a group of 

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easy mazes and a group of hard mazes. After a subject has sufficiently learned the mazes 
(defined as reaching the end of a maze by a specified goal time), he or she will begin the task 
itself. In this task, subjects may be exposed to different trial types, like “navigate” and 
“passive viewing”. In “navigate” trials, subjects will have to reach the end of the maze for a 
varying known or unknown reward amount (ranging from $0-10). Trials may be set to 
“time out” after a predetermined period of time has elapsed to ensure subject compliance 
and performance. In “passive viewing” trials, subjects will watch as they are navigated 
through the maze without needing to actively respond or move.   
 
Main Effects Analysis: Primary contrasts of interest will focus on the parametric modulation 
of reward amount and effort differences between ‘passive viewing’ and ‘navigate’ trial 
types. 
 
Behavioral Assessments of Reward Motivation and Reinforcement Learning 
 
Behavioral Effort-Expenditure for Rewards Task (behEEfRT; approx. 20-25 min): 
The behEEfRT task is a multi-trial game in which participants are given an opportunity 
on each trial to choose between two different task difficulty levels in order to obtain 
monetary rewards.21 For all trials, participants make repeated manual button presses 
within a short period of time. Each button press raises the level of a virtual ‘‘bar’’ viewed 
onscreen by the participant. Participants are eligible to win the money allotted for each 
trial if they raise the bar to the ‘‘top’’ within the prescribed time period. Each trial 
presents subjects with a choice between two levels of task difficulty, a ‘high-effort’ and 
‘low-effort’ task that require different amounts of speeded button pressing. Reward 
magnitudes for the high effort task vary between $1.24 and $4.33, while reward 
magnitudes for the low effort task remain constant ($1.00). Trials also vary in terms of 3 
levels of probability of winning the amount associated with the choice selected. Subjects 
participate in the task for about 20 minutes and the first 50 trials are used for analysis.  
For statistical analyses the proportion of hard-task choices across each level of 
probability is calculated. Lower proportions of hard task choices indicate decreased 
motivation for monetary rewards. The EEfRT will be administered 5 times. The task has 
excellent test-retest reliability (test-retest r > 0.85), and has been successfully used in 
prior multi-session studies with similar time intervals between administrations. 43,108  
 
Probabilistic Stimulus Selection Task (PST; approx. 15-20 min): The PST was 
designed to differentiate between “go” and “no-go” reinforcement learning and has been 
validated tested using a bio-realistic model of basal ganglia function, and empirical data 
in humans.37,109,110 The PST includes a training phase and a test phase. During training, 
participants are presented with three different stimuli pairs (AB, CD, EF) in random 
order, and are instructed to choose one. After each choice, participants are informed if 
their selection was “correct” or “incorrect.” Correct/incorrect feedback is probabilistic 
such that for AB trials, A is correct 80% of the time and B 20%; for CD trials C is correct 
70% and D 30%, and for EF trials, E is correct 60% and F 40%. After subject behavior 
demonstrates that they have accurately learned the “correct” option for each stimulus 
pair, they enter the testing phase. In this phase, subjects are presented with novel pairs 
involving either the A stimulus (AC, AD, etc.) or B stimulus (BC, BD, etc.). Since A 
always has the highest probability of being correct across all stimuli (80%), the extent 

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that subjects choose A in this novel pairs represents a learned “go” association. 
Conversely, since the B stimulus has the lowest probability of being correct (20%), the 
extent to which subjects do NOT choose B in the novel pairs indicates a “no-go” 
association. The primary dependent variables are the proportions of correct go and no-go 
trials during the testing phase. The PST will be administered 5 times with a novel stimuli 
set used each time, consistent with past repeated measures designs using the PST.111  
 
Go No-Go Variant Task (approx. 32 min): On each trial of this task, one of four possible 
fractal images is briefly presented to the subject. Each represents the combination between 
action (either “go” or “no-go”, carried out by button pressing or withholding button 
pressing), and valance at outcome (either win or lose). Action will be required in response 
to a circle that follows the fractal image, after a brief variable delay. The circle will appear 
on the screen for approximately 500-2500ms. In go trials, subjects will be asked to indicate 
which side of the screen the circle appeared on, by pressing a button. Subjects must make a 
response within a brief amount of time (e.g. 700 ms). In no-go trials, subjects will simply 
be asked to withhold any response. After a short delay, the outcome will be presented to a 
subject (win, loss, or neutral). A green upward symbol indicates a win of $1, a red 
downward symbol indicates a loss of $1, and a horizontal bar indicates an absence of win 
or loss. In “go to win” trials, a correct button press is rewarded. In “go to avoid losing” 
trials, a correctly avoided button press avoids punishment. In “no-go to” win trials, 
withholding the button press leads to reward. In “no-go to avoid losing” trials, withholding 
a button press avoids punishment. The outcome will be designed in a probabilistic manner, 
so that 70% of correct responses are rewarded in win trials and 70% of correct responses 
are not punished in lose trials. On 50% of trials, target detection and outcome will be 
omitted. Participants will be asked to complete 4 blocks of this task, each approximately 8 
minutes in length. 
 
Behavioral Assessment of Emotional Memory Pre/Post-Infusion  
 
Emotional Memory Task: To examine the effects of infliximab on emotional memory, 
we have added a two-part (i.e., encoding & retrieval) emotional memory task that may be 
performed before and after the infusion.  Participants will complete the two-part 
emotional memory task before the infusion and again after the infusion. We will use 360 
happy, angry, and neutral faces selected from the Carnegie Mellon University Multi-PIE 
Face Database (Gross et al., 2010) as stimuli. All images will be cropped to ovoid shape 
in order to remove distinctive hairstyles, jewelry, or clothing. During encoding, we will 
present each participant with 90 images of faces: 30 happy faces, 30 angry faces, and 30 
neutral faces. On each trial, the participant will view the face for 2 seconds before 
indicating by button press whether the expression is happy, angry or neutral—the 
participant will have an additional 2 seconds to make this judgment. Trials will be 
separated by a jittered intertrial interval (ITI) during which time a fixation cross will be 
presented (mean duration: 2 seconds; range: 1-5 seconds). Thus, the total trial time will 
by 6 seconds, on average, for a total encoding time of about 10 minutes (including time 
for setup and brief instructions). On the following day (or as close to the following day as 
possible we will administer a recognition memory test for the faces. Briefly, participants 
will view the 90 “old” faces from the encoding session mixed with 90 “new” faces—

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lures—and will be asked to indicate whether each face is old or new and also how 
confident they are in their judgment (4 seconds). A fixation ITI will again separate the 
trials (mean: 2 seconds). Given 180 faces and an average trial length of 6 seconds, the 
recognition test is expected to last about 25 minutes. Identical procedures will be used 
before and after treatment with infliximab, with different faces presented at each session. 
 
We will first analyze the recognition memory data by computing d’, which is a signal 
detection measure of memory accuracy unconfounded by response bias; d’ is calculated 
as Z(hit rate) – Z(false alarm rate). Next, we will submit the d’ data to a 2 Treatment (pre, 
post) x 3 Emotion (happy, angry, neutral) repeated measures ANOVA. We expect to 
obtain a significant Treatment x Emotion interaction. We further predict that follow-up t-
tests will reveal significantly better memory for angry vs. happy faces before treatment, 
but no difference between angry and happy faces after treatment (i.e., memory for happy 
faces will be selectively improved by treatment with infliximab). Furthermore, we expect 
a series of “post minus pre” within-subject t-tests to show no effect of treatment on 
memory for neutral or angry faces, but a positive effect of treatment on memory for 
happy faces. If possible, we will seek to correlate any observed change in memory for 
happy faces with measures of improved dopamine function. We predict that depressed 
adults will show poor memory for positive relative to negative stimuli before treatment, 
but that memory for positive stimuli will improve significantly after treatment. 
 
Behavioral Assessments of Psychomotor Slowing 
 
Finger Tapping Task (FTT): This task uses a specially adapted tapper that the subject 
taps as fast as possible using the index finger.  The subject is given 5 consecutive 10-
second trials for the preferred and non-preferred hands.  The finger tapping score is the 
mean of 5 trials and is computed for each hand.  Performance norms have been 
established, and scores have been shown to be stable over time.112 The FTT is designed to 
assess subtle motor impairment and is altered in subjects with basal ganglia disorders and 
lesions.113     
 
Reaction Time Task (RTT)(CANTAB): The RTT provides measures of simple and 
choice movement and 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. Movement times on the CANTAB reaction time 
task have been shown to be slowed during IFN-alpha treatment and correlate with IFN-
alpha-induced depression and fatigue.114   
 
Digit Symbol Task (DST): The Digit Symbol 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.115 This test is one of the most frequently 
used in neuropsychology and relevant norms and test-retest reliability have been well 
established.112 Performance on the Digit Symbol Test has been found to correlate with 

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subcortical atrophy in disorders involving the basal ganglia including Huntington’s 
disease and multiple sclerosis.116,117 
 
Self-Report Assessments 
 
Snaith-Hamilton Pleasure Scale (SHAPS): The SHAPS is a 14-item self-report scale 
that assesses hedonic tone.121 The items 1,4,8 and 9 refer to interests, items 3 and 10 to 
food and drink, items 2,7,13 and 14 to social interaction and items 5,6,11 and 12 to 
sensory experiences.122  
 
Multidimensional Fatigue Inventory (MFI): is a 20-item self-report instrument designed 
to measure fatigue, covering the dimensions General Fatigue (GF), Physical Fatigue (PF), 
Mental Fatigue (MF), Reduced Motivation (RM) and Reduced Activity (RA).123 Separate 
scores for each of these five dimensions are generated from the MFI. We will only use the 
score from the RM dimension in this domain. The Reduced Motivation score from the 
MFI has been shown to highly correlate with reduced neural activation in the ventral 
striatum to a reward task during IFN-alpha administration as determined by fMRI.124  
 
Motivation and Pleasure Scale: The mood and pleasure questionnaire is a recently-
developed 18-item self-report inventory that was created to disentangle state-wise 
motivational and consummatory components of everyday activities over a 24-hour period, 
and has been previously validated as a measure of reward-related symptoms in psychiatric 
populations.125 This scale will be used to assess self-reported changes in motivational 
anhedonic symptoms before and after inflammation blockade.  
 
PANAS-X: The Positive Affect/Negative Affect Scale (PANAS) is a widely used measure 
of in-the-moment aspects of positive and negative affectivity126, and will be used as an 
additional measure of self-reported changes in anhedonic symptoms following 
inflammation blockade.  
 
Fatigue Severity Scale (FSS): is a 9-item self-report scale that is one of the best known 
and most used fatigue scales. It has high internal consistency, has good test–retest 
reliability and is sensitive to change with time and treatment. It has been used in multiple 
medically ill populations as well as in those with primary depression.127,128 
 
Inventory of Depressive Symptoms-Self Report (IDS-SR) is a 30-item self-report 
instrument with excellent psychometric properties that was designed to measure symptom 
constructs consistent with current DSM nosology and that has been widely used as a self-
report outcome measure of depression in treatment trials.94,118 
 
Apathy Motivation Index (AMI): is an 18-item self-report index of apathy and 
motivation. It provides a useful means of probing different mechanisms underlying sub-
clinical lack of motivation in otherwise healthy individuals. It covers motivation within 
three dissociable domains: cognitive, emotional/affective and behavioral. This index will 
take about 5 minutes to complete. 
 

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Apathy Evaluation Scale (AES): The AES addresses characteristics of goal directed 
behavior that reflects apathy including behavioral, cognitive and emotional indicators. It 
consists of 18 items; Items are scored on 4-point Likert scale with descriptors for the 
“self” version (not at all true, slightly true, somewhat true, very true). It takes 
approximately 10 minutes to complete. 
 
Childhood Trauma Questionnaire (CTQ): The self-report questionnaire includes a 28-
item test that measures 5 types of maltreatment – emotional, physical, and sexual abuse, 
and emotional and physical neglect and assesses individual's understanding of their 
childhood trauma. This questionnaire should take about 5 minutes to complete. 
 
Dysfunctional Attitudes Scale – Short Form (DAS-SF): is a self-report questionnaire 
containing nine items taken from the original DAS, using item-response analysis to 
provide an efficient and accurate assessment of dysfunctional attitudes. It is designed to 
negative self-belief construct. This questionnaire should take about 5 minutes to 
complete. 
 
HEXACO: HEXACO Personality Inventory-Revised, an instrument that assesses the six 
major dimensions of personality, Honesty-Humility, Emotionality, eXtraversion, 
Agreeableness (versus Anger), Conscientiousness, and Openness to Experience.  
 
Perceived Stress Scale (PSS): The Perceived Stress Scale (PSS) is the most widely used 
psychological instrument for measuring the perception of stress. It is a measure of the 
degree to which situations in one’s life are appraised as stressful. Items were designed to 
tap how unpredictable, uncontrollable, and overloaded respondents find their lives. The 
scale also includes a number of direct queries about current levels of experienced stress.  
 
UCLA Loneliness Scale: A 20-item scale designed to measure one’s subjective feelings 
of loneliness as well as feelings of social isolation. Participants rate each item on a scale 
from 1 (Never) to 4 (Often). This measure is a revised version of the original UCLA 
Loneliness Scale.   
 
State-Trait Anxiety Inventory (STAI): The State-Trait Anxiety Inventory (STAI) is a 
commonly used measure of trait and state anxiety (Spielberger, Gorsuch, Lushene, Vagg, 
& Jacobs, 1983). It can be used in clinical settings to diagnose anxiety and to distinguish 
it from depressive syndromes. It also is often used in research as an indicator of caregiver 
distress 
Form Y, its most popular version, has 20 items for assessing trait anxiety and 20 for state 
anxiety. State anxiety items include: “I am tense; I am worried” and “I feel calm; I feel 
secure.” Trait anxiety items include: “I worry too much over something that really 
doesn’t matter” and “I am content; I am a steady person.” All items are rated on a 4-point 
scale (e.g., from “Almost Never” to “Almost Always”). Higher scores indicate greater 
anxiety. 
 
Stress and Adversity Inventory (STRAIN): The STRAIN, or Stress 
and Adversity Inventory, is a NIMH/RDoC-recommended instrument that efficiently and 

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reliably assesses a person’s cumulative exposure to stress over the life course. The 
measure is entirely online and systematically inquires about a diverse array of acute life 
events (e.g., deaths of relatives, job losses, negative health events) and chronic 
difficulties (e.g., ongoing health problems, work problems, relationship problems, 
financial problems, etc.) that have implications for human health and well-being. 
Stressors occurring in early life (e.g., childhood maltreatment or neglect, parental 
loss/separation, etc.) are also queried in detail. Respondents are asked to rate the severity, 
frequency, timing, and duration of each stressor they endorse. The average time needed to 
complete the STRAIN is 25 minutes, with a range of approximately 18-30 minutes based 
on the population being interviewed. 
 
Index of Race-Related Stress (IRRS): The IRRS is a 46-item instrument developed 
according to the theoretical framework of daily hassles (R. S. Lazarus & S. Folkman, 1984) 
and integrated with P. Essed's (1990) concept of everyday racism. The self-report survey 
takes approximately 10 minutes to complete. 
 
Menstrual Cycle Questionnaire: Female participants may be asked to complete a short 
form with the following information: first day of last period, usual length of menstrual 
cycle, approximate onset of next period, and use of hormone contraceptives or hormone 
therapy. This self-report may be administered at the PI’s discretion. 
 
Demographics Questionnaire: Participants will be asked to complete a short form with 
basic demographic information like race, income level, and years of education. 
 
Mobile Assessments 
At the end of a participant’s screening appointment, we may ask him or her to 
install a mobile application on their cell phone to complete assessments from 
home. The application is free of charge and can be deleted at any time if the 
subject decides not to continue. If the subject does decide not to continue, we will 
stop collecting data from him or her upon notice of withdrawal. Each day, 
following the screening visit (up to 2 weeks following the last study visit [30-day 
Follow-Up Call]) we may send a notification to the subject (via phone or email) to 
complete a variety of computer tasks and/or short surveys through the application. 
Subjects may be asked to complete experiments at various points during the day 
or will be free to complete experiments as frequently as desired, depending on the 
study design. These will include a subset of the same measures used for the 
behavioral components of the study (described in detail elsewhere in the 
protocol).  
 
Insomnia Severity Index: Participants may be asked to complete a short form with 
information about their sleeping habits. 
 
Laboratory and Biological Variables:  
 
Blood collection: At the designated assessments, blood will be collected by venipuncture 
into EDTA-containing vacutainer tubes using standard sterile technique. Some research 

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blood may be collected by point of care testing. Plasma for the evaluation of plasma 
concentrations of cytokines and their receptors as well as CRP will be obtained by 
centrifugation of whole blood at 1000 x g for 10 minutes at 4°C. Plasma will be removed 
and aliquoted into siliconized polypropylene tubes and stored at -80°C until batch assay. 
Blood for mRNA analyses will be collected in Tempus tubes and stored at -80°C for later 
RNA extraction. In order to further assess immune cell profiles, we will also collect 
approximately 10 ml of whole blood in EDTA at room temperature for immune cell 
extraction at Infusion Visit, 24-Hour Visit, and 14-Day Visit.  
 
Plasma cytokines and soluble cytokine receptors: Customized Fluorokine MAP 
Multiplex Human Biomarker Panels (R&D Systems, Minneapolis, MN) will be used to 
measure plasma IL-1ra, IL-6, sIL-6R, IL-10, TNF-alpha, sTNFR2 and MCP-1. These 
inflammatory markers were chosen based on their reliable changes in depression and/or 
their relationship to symptoms of anhedonia and corticostriatal function in subjects 
administered inflammatory cytokines and cytokine inducers.14,16,129 Each determination 
requires 50-100 μl, and all samples will be assayed in duplicate according to 
manufacturer’s instructions. Quality control plasma of both low and high cytokine 
concentrations will be included with every assay. The mean inter- and intra-assay 
coefficients of variation for control samples are reliably 10% or less.    
 
C-reactive protein (CRP): Plasma CRP will be assessed with a high sensitivity 
turbidimetric assay. Sensitivity of the assay is rated at 0.18 mg/L, range of measure is 0.2 
to 80 mg/L, and functional sensitivity (at 20% CV) is 0.2 mg/ L. 
 
Gene Expression: RNA will be isolated from Tempus tubes using 5 Prime PerfectPure 
RNA Blood kit (Gaithersburg, MD).  RNA quality will be verified using the Agilent 
Bioanalyzer, and only samples with a RIN factor >7.0 will be included.  Samples will be 
analyzed in the Emory Integrated Genomic Core for gene expression analysis using an 
Illumina platform (Illumina, San Diego, CA). Raw microarray scan files from the Illumina 
HT-12 v4.0 arrays will be exported using the Illumina Beadstudio program and loaded into 
R for downstream analysis (http://www.R-project.org). The data will be transformed and 
normalized using the variance stabilizing normalization method.130 An Illumina probe 
detection p-value of <0.01 in 5% of the individuals will be used to filter non-expressed 
transcripts which will be excluded from all subsequent analyses. To correct for 
confounding due to batch effects, the expression profiles will be normalized using ComBat, 
an empirical Bayes method for batch correction.131 The results will be corrected for 
multiple testing using the permutation of regressor residuals test as implemented in the R 
package glmperm (http://cran.r-project.org/web/packages/glmperm/ index.html).132   
 
Urine Samples: At one of the study visits where a urine sample is collected, up to 
500mL of urine may be collected and sent to a collaborating laboratory led by study Co-
Investigator Zhexing Wen. The collaborator will use cells from this urine sample to 
create induced pluripotent stem cells (iPSC). Over the past decade, researchers—
including Dr. Wen (Wen, et al., 2014; Tang, et al., 2016; Wen et al., 2016)—have 
harnessed the power of cellular-reprogramming technologies to turn differentiated cells in 
the adult, like those found in urine or skin, into induced pluripotent stem cells (iPSCs). 

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Importantly, patient-derived iPSCs feature the same mutations as those found in the 
donor individual (Wen et al., 2016). Thus, researchers can use these cells to model a 
condition or disease in the context of an individual person. A description of how the cells 
will be used is laid out in detail in the consent form. If the amount of sample collected is 
not sufficient or a sample cannot be collected at a visit, additional samples may be 
collected at following visits while the participant is enrolled in the study. If the amount of 
sample collected is not sufficient or a sample cannot be collected at a visit, additional 
samples may be collected at following visits (if applicable) while the participant is 
enrolled in the study. If the sample collected is not sufficient or if a sample is not 
collected, participants may be asked to come back to the laboratory to provide a sample. 
Participants will have an opportunity to indicate consent for re-contact for this purpose in 
the study consent form. 
 
 
Participants 
 
140 medically stable male and female subjects between the ages of 21 and 65 will be 
included in this study. Subjects will meet criteria for current major depression (MD) or be 
recruited as healthy controls. MD subjects will be further screened based on levels of 
peripheral inflammation as determined by plasma CRP concentrations. The high CRP 
patient group (n=80) will have a CRP greater than 3mg/L at screening whereas the low 
CRP patient group (n=20) will have a CRP less than 2mg/L.  Healthy controls (n=40) will 
also be recruited. Based on a screening failure rate of 30-50% and a dropout rate of 10%, 
we anticipate that including up to 350 subjects (65 full screens per year) will provide 140 
subjects for final data analysis.  Because this study is not a treatment trial, only subjects 
who complete all study procedures will be included in the analysis. This will be determined 
at the PI’s discretion. Subjects will continue to be enrolled until 140 completers are 
included.  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 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.  
 
Subjects may be recruited after completion of an “evaluation clinic protocol” within the 
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine 
and from advertising in radio, television, Internet (Facebook) and print media.  
Alternatively, subjects may also express interest in the study directly to our lab personnel 
without first going through the Behavioral Immunology Research Evaluation Clinic. These 
participants may contact the lab through our master prescreen survey (see 
TReADLab_MasterPrescreen.pdf), phone, or email to request additional information. This 
information is provided on our website, clinicaltrials.gov and through our social media 
(Facebook, Instagram, Twitter) platforms. The evaluation clinic protocol evaluates 
potential subjects for appropriateness for participation in several on-going trials of various 
modalities for major depression. Most frequently, subjects come to these clinics as a result 
of referral from their primary physicians or as a result of seeing/hearing advertisements. An 

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overview of the study will initially be provided in person or over the phone by study 
clinicians. If a subject shows interest in the study, research staff members will describe the 
general procedures involved and will answer relevant questions. If a subject remains 
interested in participation, the detailed nature, purpose, procedures, benefits risks of, and 
alternatives to this research study will be explained to each subject, and written informed 
consent will be obtained by the study clinician who provides this information. Informed 
consent will be documented on an Emory Institutional Review Board-approved form. A 
copy of the signed form will be given to the subject and a copy will be placed in a casebook 
containing relevant demographic data for the subject. Of note, because this casebook will 
contain personal identifiers (i.e. name), it will be kept separate from any data gathered as 
part of the study, and will be kept in a locked office. Some participants may elect to 
complete all screening and infusion-related visits under IRB Protocol #90667, Infliximab-
Glutamate Study, PI Dr. Andrew Miller, and participate in the task-based MRI visits only 
as part of this study. These participants will sign a consent form (MRI-Only Version) under 
the current protocol (IRB87941) only for completion of the fMRI study visits (Baseline, 
14-Day) and be paid under this protocol for those visits. 
 
To compensate for time required for participation, inconvenience and travel expenses, 
high CRP MDD patients will receive $100 after completion of an outpatient 24-Hour 
visit (OPTIONAL), $60 for a 3-Day visit, and $200 for an optional 7-Day (OPTIONAL) 
visit post infusion. Subjects will receive $100 for the pre-screening visit, and $100 for 
screening procedures ($50 for each screening visit). Subjects will receive $410 for the 
infusion visit, and $310 for the study visit at 14 days (due to the MRI scan). Subjects may 
have the option of completing the MRI scan portion of the infusion visit one day before 
infusion. If they do so, the compensation for the MRI scan will be paid as a separate visit. 
During the visits where subjects undergo an MRI scan (on the day of infusion and at 14 
days after infusion), subjects will have the opportunity to earn an additional $150 per 
visit based on choices and performance on the computer tasks. At visits 3 and 7 days after 
infusion, subjects will have the opportunity to earn an additional $50 based on task 
choices and performance, making the total amount possible from task performance at 
study visits $400.  
 
MRI-Only Participants will be paid up to $800 for the MRI related visits and task 
compensation, detailed below. 
 
 
 
 
 
 
 
 
 
 
 
 
Lab Visits 
Total Amount Earned 
Baseline Task-Based fMRI Visit 
$250 
14-Day Task-Based fMRI Visit 
$250 
Task Performance 
Total Amount Possible 
Baseline Task-Based fMRI Visit 
Up to $150 
14-Day Task-Based fMRI Visit 
Up to $150 
Minimum for Task-Based fMRI Study 
Procedures 
 
Maximum for Task-Based fMRI Study 
Procedures 
$500 
 
$800 

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Healthy controls and low CRP depressed patients will receive $100 for the screening visit 
and $100 for the scan visit. Subjects will also have the opportunity to earn an addition $50 
on the scan visit based on choices and performances in the computer tasks.  
 
Individuals who choose to participate in the daily assessment portion of this study on 
their mobile phones, will receive an additional $2-10 dollars for each day of mobile 
assessments completed. The exact compensation received will be based on their choices 
and performance in the task(s) on the mobile app. If a participant completes 3 days of 
assessments, they could receive between $6 and $30. If they complete 7 days of 
assessments, they could receive between $14 and $70, and so on. Participants will be 
prompted to complete two days prior to the infusion visit and 8 days following infusion 
visit, making the max amount possible $100 based on task performance. Subjects who 
complete at least 8 out of 10 days will receive an additional $50 as a completion bonus. 
Total possible compensation from the mobile assessments is $150. 
 
If requested by the PI or designee to return for follow-up assessments (i.e. repeat 
measures or confirm eligibility/safety), compensation will be provided at a rate of 
$25/hour. 
 
Subjects who travel over 30 miles to participate in study-related activities may receive an 
additional payment as compensation for time and travel, at the discretion of the PI or 
designee.   
 
Participants who agree to be re-contacted for an additional urine or blood sample and 
come to the laboratory to provide the sample will be compensated an additional $30 for 
their time. 
 
Note: Participants may be compensated by cash, check or Emory ClinCard (see below) 
for their time and efforts in the study. If participants are compensated by check or Emory 
ClinCard, they will be asked to fill out a tax form, including mailing address and Social 
Security or Taxpayer Identification Number, in order to be reimbursed. Subjects will be 
informed that they are able to decline payment if there are concerns around 
confidentiality, or that they can talk to the study team to see if there are other payment 
options (i.e., cash). If subjects elect to receive payment via the Emory ClinCard, 
compensation earned from task performance will be paid at the end of study participation. 
If participants elect to be paid via check, all funds will be paid at the conclusion of the 
study. 
• 
The payment card (Emory ClinCard) is a prepaid debit card issued to 
participants for free. It can be used exactly like a Mastercard. Study staff 
load money onto the individual's card electronically every time they need to 
be paid. The card scheme is run by Greenphire, an independent company 
specializing in payments for research studies and clinical trials. To issue the 
card, we need to provide Greenphire with some of the participant's personal 
information including SSN, Name, DOB, and Address. Banks and other 
financial institutions can access this information if they need to verify the 

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participant's identity when using the card. If a participant wants to receive 
e-mail or text alerts when payments are made, we will ask them to provide 
an e-mail or phone number. All of this information will be stored on 
computers owned by Greenphire. Greenphire will not have access to any 
other information collected during this study. Full instructions about using 
the card will be provided to the participant when it is issued. 
• 
It will be explained to the participant that payment by check would involve study-
related mail coming to his or her house, which may be seen by others in the 
household.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
Total Amount Earned 
PRE-SCREENING 
$100 
Visit Total 
$100 
SCREENING VISIT(S) 
 
Visit A 
$50 
Visit B 
$50 
Visit Total 
$100 
INFUSION VISIT(S) 
 
fMRI 
$250 
Infusion 
$100 
Scheduled Assessment 
$60 
Visit Total 
$410 
24-HOUR VISIT (OPTIONAL) 
 
Scheduled Assessments 
$100 
Visit Total 
$100 
3-DAY VISIT 
 
Scheduled Assessments 
$60 
Visit Total 
$60 
7-DAY VISIT (OPTIONAL) 
 
Scheduled Assessments 
$200 
Visit Total 
$200 
14-DAY VISIT 
 
fMRI 
$250 
Scheduled Assessments 
$60 
Visit Total 
$310 
TASK PERFORMANCE 
 
Infusion Visit 
Up to $150 
3-Day Visit 
Up to $50 
7-Day Visit (OPTIONAL) 
Up to $50 
14-Day Visit 
Up to $150 
Assessment Total 
Up to $400 
MOBILE APP (Optional) 
 
Pre-Infusion Assessments (2 Days) 
$4-20 
Post-Infusion Assessments (8 Days) 
$16-80 
80% Completion Bonus (8 of 10 Days) 
$50 
Assessment Total 
Up to $150 
Minimum Over Course of Study 
 
Maximum Over Course of Study 
$880 
 
$1,730 

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The inclusion and exclusion criteria for this study were formed on the basis of two 
general concerns: participant safety and data quality. Criteria related to participant safety 
(as indicated in the table below) will be assessed for each enrolled participant using 
study-specific eligibility checklists. These can be accessed through the eIRB smartform 
for this study. For data quality criteria, assessments may rely on participant self-report or 
observations by the PI or designee. In certain cases, not all data quality criteria are 
necessary, and exclusion criteria that solely affect data quality may be waived at the 
discretion of the PI or his designee. Inclusion and exclusion criteria that ONLY affect 
data quality (as indicated below) will be enforced at the discretion of the PI or designee. 
Inclusion/Exclusion criteria related to participant safety will never be waived. 
 
Inclusion Criteria for High CRP Depressed Subject Safety 
 
1. All subjects will be fully ambulatory and in good medical health.  
a. Note: By DSM-V definition of depression, subjects will report impairment 
in ability to carry out daily activities as a result of their major depression. 
2. Subjects will be able to read and understand English. 
3. Women must be postmenopausal (no menstrual period for a minimum of 2 years) 
or surgically sterilized and/or have a negative serum pregnancy test on entry in the 
study and negative urine pregnancy tests throughout the study (performed at each 
visit after Screening). Additional serum pregnancy tests will be completed at the 
Infusion and 14-Day Visits.  
4. Men and women of childbearing potential must use adequate birth control measures 
(e.g., abstinence, oral contraceptives, intrauterine device, barrier method with 
spermicide, implantable or injectable contraceptives or surgical sterilization) for 
the duration of the study and should continue such precautions for 6 months after 
receiving the last infusion. Participants will also be required to abstain from sexual 
intercourse for two weeks prior to the schedule infusion visit. Appropriate methods 
will be documented and on a Birth Control Method Form and signed by both the 
participant and the PI, NP, or designee (see Birth Control Method Form). 
5. The following are considered eligible according to the following tuberculosis 
(TB) screening criteria: 
 
a. 
Have no history of latent or active TB prior to screening. 
b. 
Have no signs or symptoms suggestive of active TB upon medical history 
and/or physical examination. 
c. 
Have had no recent close contact with a person with active TB or, if there has 
been such contact, will be referred to a physician specializing in TB to 
undergo additional evaluation to rule out infection. The candidate will be 
excluded from study participation if the specialist diagnoses active TB and or 
determines TB treatment is warranted.  

Version: 07062020 
24
d. 
Have a chest radiograph (both posterior-anterior and lateral views), taken 
within 3 months prior to the first administration of study agent and read by a 
qualified radiologist, with no evidence of current active TB or old inactive 
TB.  
e. 
History of negative PPD test; or documentation of a negative blood test 
(Quantiferon-TB-Gold). Any candidate testing positive for tuberculosis in the 
medical screening evaluation, will be excluded from study participation. 
Inclusion Criteria for High CRP Depressed Data Quality 
 
1. Patients will have a primary diagnosis of DSM-V MD current, or Bipolar, 
depressed type as diagnosed by the SCID-V 
a. Individuals meeting criteria for both PTSD and MDD will only be included 
if depression is the primary diagnosis. 
2. Subjects will have a CRP of > 3 mg/L.  
3. Subjects will be required to be off all antidepressant therapy for a period of at least 
8 weeks prior to the baseline visit.  
a. Note: Subjects must agree to maintain this treatment status until the final 
assessment is complete.  
4. Subjects will be between the ages of 21-65. 
6. Able to comfortably fit in MRI scanner. 
 
Exclusion Criteria for High CRP Depressed Subject Safety 
 
1. Subjects will be excluded for any prior use of a TNF-alpha antagonist (i.e. 
etanercept, infliximab, adalimimub) and/or use of any other immunosuppressant 
agent (i.e. systemic corticosteroids or anti-proliferative agents such as 
methotrexate) within one year of study entry. 
2. Subjects taking more than 2 mg of lorazepam (or equivalent benzodiazepine) for 
one month daily at the time of study participation will be excluded. 
3. Subjects will be required not to use anti-inflammatory agents, non-steroidal anti-
inflammatory agents (NSAIDs) (excluding 81mg of aspirin), glucocorticoid 
containing medicines or statins, or COX-2 inhibitors during the study as these 
agents may interfere with assessment of the relationship between inflammatory 
markers and treatment response.  
a. Note: Acetaminophen will be allowed. 
4. Potential subjects will be excluded for a history of any of the following conditions: 
a. Abnormal electrocardiogram 
b. Auto-immune condition as confirmed by laboratory testing (i.e. 
rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, 
lupus) 
c. History of significant infectious sequelae, including but not limited to, 
abscess or sepsis 

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25
d. Infection within one month prior to screening that required antibiotic or 
antiviral therapy 
e. History of a cognitive disorder or ≤ 24 on the Mini-Mental State Exam 
(MMSE), unless otherwise approved by PI or his designee  
f. Unstable cardiovascular or endocrinologic disease (as determined by 
physical examination and/or laboratory testing) 
g. Any other current or past medical condition that might increase the risk of 
infliximab-related adverse events 
5. Potential subjects will be excluded for any of the following conditions: 
a. Active suicidal ideation defined as a score of >3 on Columbia Suicide 
Severity Rating Scale (C-SSR).   
i. Note: PI will be consulted if score is > 1 
b. Suicide attempt within six months of study entry 
c. Schizophrenia or Schizoaffective Disorder 
d. Active eating disorder unless limited to binge eating in the context of a 
mood disorder and in absence of purging 
e. Comorbid PTSD and MDD where MDD is the secondary diagnosis 
f. History of any (non-mood related) psychotic disorder or active psychotic 
symptoms of any type 
6. Subjects will have had no infectious illnesses for one month prior to infusion. 
Should a subject develop an infection (i.e. flu, upper respiratory viral infection) 
between screening and infusion, the infusion will be delayed until 4 weeks after 
resolution of symptoms. As noted above, patients with a chronic infectious 
condition or with a past history of serious infectious complications will be 
excluded. 
7. Subjects will be excluded for any evidence on laboratory testing (or by history) of 
hematologic, renal or hepatic abnormality. Subjects will be excluded if the anti-
nuclear antibody (ANA) test indicates the presence of a possible autoimmune 
disease.  
Inclusion Criteria for Low CRP Depressed Patients & Health Controls for Safety 
1. All subjects will be fully ambulatory and in good medical health.  
a. Note: By DSM-V definition of depression, subjects will report impairment 
in ability to carry out daily activities as a result of their major depression. 
2. Subjects will be able to read and understand English. 
3. Women must be postmenopausal (no menstrual period for a minimum of 1 year) or 
surgically sterilized and/or have a negative serum pregnancy test on entry in the 
study and negative urine pregnancy tests throughout the study (performed at each 
visit after the serum pregnancy test is completed).   
 
Inclusion Criteria for Low CRP Depressed Patients & Healthy Controls for Data 
Quality 
 
1. Patients will have a primary diagnosis of DSM-V MD current, or Bipolar, 
depressed type as diagnosed by the SCID-V  

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26
a. If subject is a Healthy Control, then no diagnosis for current disorder will 
be present 
b. Low CRP patients meeting criteria for both PTSD and MDD will only be 
included if depression is the primary diagnosis. 
2. Patients will have a CRP of < 2 mg/L.  
a. Healthy Controls will not be ruled out for CRP, but this information will be 
collected 
3. Patients will be required to be off all antidepressant therapy for a period of at least 
8 weeks prior to the baseline visit.  
a. Note: Subjects must agree to maintain this treatment status until the final 
assessment is complete.  
4. Subjects will be between the ages of 21-65. 
6. Able to comfortably fit in MRI scanner. 
 
Exclusion Criteria for Low CRP Depressed Patients & Healthy Controls 
1. Subjects will be excluded for any prior use of a TNF-alpha antagonist (i.e. 
etanercept, infliximab, adalimimub) and/or use of any other immunosuppressant 
agent (i.e. systemic corticosteroids or anti-proliferative agents such as 
methotrexate) within one year of study entry. 
2. Subjects taking more than 2 mg of lorazepam (or equivalent benzodiazepine) for 
one month daily at the time of study participation will be excluded. 
3. Subjects will be required not to use anti-inflammatory agents, non-steroidal anti-
inflammatory agents (NSAIDs) (excluding 81mg of aspirin), glucocorticoid 
containing medicines or statins, or COX-2 inhibitors during the study as these 
agents may interfere with assessment of the relationship between inflammatory 
markers and treatment response.  
a. Note: Acetaminophen will be allowed. 
4. Potential subjects will be excluded for a history of any of the following conditions: 
a. Auto-immune condition as confirmed by laboratory testing (i.e. 
rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, 
lupus) 
b. History of significant infectious sequelae, including but not limited to, 
abscess or sepsis 
c. Infection within one month prior to screening that required antibiotic or 
antiviral therapy 
d. History of a cognitive disorder or ≤ 24 on the Mini-Mental State Exam 
(MMSE), unless otherwise approved by PI or his designee  
e. Unstable cardiovascular or endocrinologic disease (as determined by 
physical examination and/or laboratory testing) 
f. Any other current or past medical condition that might increase the risk of 
infliximab-related adverse events 
5. Potential patients will be excluded for any of the following conditions: 
a. Active suicidal ideation defined as a score of >3 on Columbia Suicide 
Severity Rating Scale (C-SSR).   
i. Note: PI will be consulted if score is > 1 
b. Suicide attempt within six months of study entry 

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27
c. Schizophrenia or Schizoaffective Disorder 
d. Comorbid PTSD and MDD where MDD is the secondary diagnosis 
e. Active eating disorder unless limited to binge eating in the context of a 
mood disorder and in absence of purging 
f. History of any (non-mood related) psychotic disorder or active psychotic 
symptoms of any type 
6. Subjects will have had no infectious illnesses for one month prior to study 
enrollment. Should a subject develop an infection (i.e. flu, upper respiratory viral 
infection) between screening and infusion, the infusion will be delayed until 4 
weeks after resolution of symptoms. As noted above, patients with a chronic 
infectious condition or with a past history of serious infectious complications will 
be excluded. 
7. Subjects will be excluded for any evidence on laboratory testing (or by history) of 
hematologic, renal or hepatic abnormality. Subjects will be excluded if the anti-
nuclear antibody (ANA) test indicates the presence of a possible autoimmune 
disease.  
 
All Subjects (High CRP MDD, Low CRP MDD, Healthy Controls): Study-
Specific Exclusion Criteria 
a. Have had any previous treatment with monoclonal antibodies or antibody 
fragments. 
b. History of receiving human/murine recombinant products or a known 
allergy to murine products. A known allergy to murine product is an 
exclusion criterion. 
c. Documentation of seropositive for human immunodeficiency virus (HIV). 
Any candidate testing positive for HIV, in the medical screening 
evaluation, will be excluded from study participation. 
d. Documentation of a positive test for hepatitis B surface antigen or 
hepatitis C.  Any candidate testing positive for hepatitis B or hepatitis C, 
in the medical screening evaluation, will be excluded from study 
participation. 
e. Are unable or unwilling to undergo multiple venipunctures because of 
poor tolerability or lack of easy access. 
f. Use of any investigational drug within 30 days prior to screening or within 
5 half-lives of the investigational agent, whichever is longer.  
g. Presence of a transplanted solid organ (with the exception of a corneal 
transplant > 3 months prior to screening).  
h. Have a concomitant diagnosis or history of congestive heart failure. 
i. Have a history of alcohol or substance abuse within the preceding 6 
months that, in the opinion of the investigator, may increase the risks 

Version: 07062020 
28
associated with study participation or study agent administration, or may 
interfere with interpretation of results. (As determined by SCID) 
j. Have a known history of serious infections (e.g., hepatitis, pneumonia, or 
pyelonephritis) in the previous 3 months. 
k. Have or have had an opportunistic infection (e.g., herpes zoster [shingles], 
cytomegalovirus, Pneumocystis carinii, aspergillosis, histoplasmosis, or 
mycobacteria other than TB) within 6 months prior to screening. 
l. Have a history of lymphoproliferative disease, including lymphoma or 
signs suggestive of possible lymphoproliferative disease such as 
lymphadenopathy of unusual size or location (e.g., nodes in the posterior 
triangle of the neck, infraclavicular, epitrochlear, or periaortic area), or 
splenomegaly. 
m. Currently have any known malignancy other than the condition being 
treated or have a history of malignancy within the previous 5 years, with 
the exception of basal cell or squamous cell carcinoma of the skin that has 
been fully excised with no evidence of recurrence. 
8. Any contraindication(s) to fMRI scanning (as assessed with standard MRI 
screening form from the Facility for Research and Education in Neuroscience 
(FERN)), including but not limited to: 
a. Cardiac pacemaker or pacemaker wires, 
b. Metallic particles in body, 
c. Vascular clips in the head, 
d. Previous neurosurgery, 
e. Prosthetic heart valves 
f. Claustrophobia. 
g. Notes: All MR-Safe Intra-Uterine Devices (IUDs) will be allowed 
 
Assessments to Evaluate Eligibility  
 
Laboratory values and other evaluations: The following medical evaluations will be 
obtained after consent is signed and prior to randomization: 
 Comprehensive metabolic panel,  
 HIV, Hepatitis B Surface Antigen, and Hepatitis C Antibody 
 Complete blood count with differential 
 C-Reactive Protein 

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29
 Serum pregnancy test 
 TSH 
 Urinalysis with microscopic 
 Anti-nuclear antibody (ANA). 
 Urine drug screen 
 Quantiferon-TB-Gold blood test prior to randomization to rule out tuberculosis - 
High CRP Patients Only 
 A complete physical examination will be performed and a medical history will be 
obtained prior to randomization. 
 An electrocardiogram (EKG) – High CRP Patients Only 
 A chest X-ray - High CRP Patients Only 
 
The following psychiatric instruments will be administered after consent is signed and 
prior to randomization to evaluate eligibility: 
 SCID 
 MMSE 
 ATRQ 
 C-SSR 
 Self-Reports: QIDS-16 SR, MFI, IDS-SR, PANAS-X, SHAPS, FSS, MAP-SR 
 
Early Detection of Active Tuberculosis (High CRP Patients Only): 
 
To aid in the early detection of TB reactivation or new TB infection during trial 
participation, subjects must be evaluated for signs and symptoms of active TB at 
scheduled visits or by telephone contact approximately every 8 to 12 weeks.  The 
following series of questions is suggested for use during the evaluation:  
“Have you had a new cough of > 14 days’ duration or a change in a chronic cough?” 
• “Have you had any of the following symptoms: 
− Persistent fever? 
− Unintentional weight loss? 
− Night sweats?” 
• “Have you had close contact with an individual with active TB?”  (If there is 
uncertainty as to whether a contact should be considered “close,” a physician 
specializing in TB should be consulted.) 
If the evaluation raises suspicion that a subject may have TB reactivation or new TB 
infection, an immediate and thorough investigation should be undertaken, including, 
where possible, consultation with a physician specializing in TB.   
 
Investigators should be aware that TB reactivation in immunocompromised subjects may 
present as disseminated disease or with extrapulmonary features.  Subjects with evidence 
of active TB must immediately discontinue study agent and should be referred for 
appropriate treatment. 
 

Version: 07062020 
30
Subjects who experience close contact with an individual with active TB during the 
conduct of the trial must have a repeat chest radiograph, a repeat tuberculin skin test, and, 
if possible, referral to a physician specializing in TB to determine the subject’s risk of 
developing active TB and whether treatment for latent TB is warranted.   
 
Note: The presence of comorbid dysthymia and/or an anxiety disorders (excluding 
Obsessive Compulsive Disorder and Post Traumatic Stress Disorder) will not disqualify 
subjects from enrollment as long as the mood disorder is the predominant diagnosis. 
Bipolar depressed patients will be included, given that these patients also commonly 
experience anhedonia and increased inflammation. Enrolled subjects may also have a 
comorbid personality disorder. Patients with stable medical conditions and on medications 
for those conditions will not be excluded.  
 
 
History and physical: 
At enrollment, a general medical history and comprehensive physical and 
neurological examinations will be obtained. Medical history evaluation will focus 
specifically on conditions that might represent an increased risk for receiving 
infliximab or that might confound results. Such conditions include, but are not 
limited to, tuberculosis, chronic infection, autoimmune condition, malignancy or 
neurological condition. Findings will inform eligibility.  
 
Mandatory laboratory assessments: 
The following labs will be evaluated to assess study eligibility prior to 
randomization: comprehensive metabolic panel, complete blood count with 
differential, antinuclear antibody (ANA), TSH, HIV, Hepatitis B Surface Antibody 
and Hepatitis C Antibody, urinalysis with microscopic, and a serum pregnancy test 
(if applicable). A tuberculosis blood test (Quantiferon-TB-Gold) will be drawn to 
rule out tuberculosis. A chest x-ray will be obtained, and an electrocardiogram will 
be obtained. Plasma concentrations of high-sensitivity CRP will be measured. A 
urine drug screen will also be performed.  
 
Healthy Controls and Low CRP Patients will not obtain a TB-Gold test, chest x-
ray, or EKG as they will not be infused with the study drug. 
 
Other assessments: 
The pretreatment evaluation will also include interviewer-administered 
questionnaires: the mood and substance abuse modules from the Structured Clinical 
Interview for DSM-V (SCID), the Bipolarity Index (BI), the Mini Mental State 
Examination (MMSE), the Columbia Suicide Severity Rating Scale (C-SSR), and 
the Massachusetts General Hospital Staging (MGH-S) questionnaire (to evaluate 
degree of treatment resistance). To qualify for entry, subjects will meet criteria for 
current major depression by SCID, will have a score of > 24 on the MMSE, will a 
score of <4 on the C-SSR, indicating no active suicidal ideation and will have a 
MGH-S score of 2 or greater.  

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31
Note: If a score >1 is recorded on the C-SSR scale, the PI will be notified 
to determine if further evaluation is needed.  
Healthy Controls should have no current diagnoses as confirmed by the above 
measures. 
 
Registration/Randomization. 
 
Where and when to call:  
Subjects may be recruited through the Behavioral Immunology Program in the 
Department of Psychiatry and Behavioral Sciences. In addition, the program has an 
ongoing recruitment program utilizing IRB-approved advertisements. Registration 
will occur in person either in the offices of the Behavioral Immunology Program or 
the laboratory of the PI. If questions arise subjects will be able to call the P.I., 
Michael T. Treadway, at (404) 727-3166. Some participants may also express 
interest in the study directly to our lab personnel without first going through the 
Behavioral Immunology Research Evaluation Clinic. These participants may 
contact the lab through our master prescreen survey, phone, or email to request 
additional information. This information is provided on our website, 
clinicaltrials.gov and through our social media (Facebook, Instagram, Twitter) 
platforms. 
 
Information to provide at entry:  
Prior to entry, at the time of obtaining consent, it will be explained to high CRP 
depressed patients that if they meet entry criteria they will be randomized to receive 
one infusion of either infliximab or placebo (salt water) in a random manner (like 
flipping a coin) and that neither they nor personnel who interact with them will 
know which they received. It will be explained that they will be followed at 24 
hours, 3 days, 7 days, 14 days, and one month after infusion for changes in 
depressive symptoms and/or for the development of physical side effects to the 
medication. Study visits may deviate from these time points or be split into multiple 
visits at the approval of the PI to accommodate scheduling needs. Subjects will be 
given the Medication Guide for REMICADE® (infliximab) from Janssen Biotech, 
Inc. as well as the Drug Summary for REMICADE® (infliximab) from the 
Physicians Desk Reference (PDR). A schedule of each subject’s participation will 
be given at study entry. Names and numbers to contact with complaints or in case 
of an adverse event will be provided at this time. There are some medications that 
subjects will be asked to avoid during the study. Subjects will be given a take-home 
instruction sheet, which will explain in detail which medications to avoid. This 
sheet will also instruct subjects to contact study staff if they start antibiotics or any 
new medications while in the study. The sheet includes contact information for the 
study coordinators, and will also tell subjects what to do in the event of an after-
hours concern or emergency. 
 
Infusion (High CRP Depressed Patients Only) 
 

Version: 07062020 
32
Infusion protocol: Blinded infusions of infliximab or placebo will be conducted at the 
ACTSI or an infusion center at the Emory Clinic. Infusions will be performed following a 
standard protocol. Specifically, intravenous access will be obtained in a sterile manner and 
infliximab (5 mg/kg body weight) or placebo will be administered over an approximate 2-
hour period. Subjects will be monitored during the infusion and for approximately 10-20 
minutes (or longer if deemed clinically necessary) after completion for the development of 
anaphylaxis (allergic reaction). Significant anaphylactic reactions requiring treatment 
occur in less than 1% of patients receiving an initial dose of infliximab. All aspects of the 
infusion will be overseen by a trained nurse, and a physician will be available should 
subjects develop anaphylaxis during the infusion. A standard protocol is in place in the 
infusion center for the treatment of anaphylaxis.  
 
Under advisement of the study physicians, NP, and nurses at the infusion site, subjects may 
be administered a premedication prior to the infusion to prevent a possible hypersensitivity 
reaction. Subjects may be administered one of the premedications listed below at least 30 
minutes before the infusion.  
 
1. Acetaminophen (Tylenol) 650mg PO 
2. Diphenhydramine (Benadryl) 25mg or 50mg PO or IV 
3. Famotidine (Pepcid) 20mg IV push 
 
In the event of an infusion-related drug hypersensitivity reaction a standard protocol will 
be followed at the infusion site.  
 
 
Blinding/Randomization/Placebo Preparation: A list containing the randomly generated 
sequence of assignments to infliximab or placebo will be maintained in the Emory 
University Investigational Drug Service pharmacy. Treatment allocation will occur when 
a patient is eligible for the study and the consent for randomization has been obtained. If a 
subject drops prior to receiving the initial infusion, he/she will not be included in data 
analyses and his/her randomization assignment will “roll over” to the next recruited 
subject. The research pharmacist with the Emory Investigational Drug Service will be 
responsible for preparing the infusion bag with either infliximab or normal saline based on 
the pre-determined order of the randomization list. Infusion bags with infliximab will be 
indistinguishable from bags with normal saline (placebo). Study personnel responsible for 
administering the infusion, conducting psychiatric evaluations, conducting medical 
assessments, drawing blood and performing lab analyses will be blinded to subject group 
assignment. In the event of a significant adverse reaction to the study medication, the study 
blind will be immediately broken by the unblinded study physician or research pharmacist 
and the subject will be referred for appropriate medical care. Such adverse reactions 
include, but are not limited to, anaphylaxis during infusion, serum sickness or development 
of symptoms of infection. 
 
 
 
 
 

Version: 07062020 
33
Graphical Display of Study Procedures 
Assessment 
Pre-
Screening
4  
Screening: 
Part A or 
Part B1,4     
Optional 
Scan 
Visit3 
Infusion 
(Infliximab or 
Placebo) 
 
Optio
nal 24 
hours 
3 
days 
 
Opti
onal 
7 
days 
 
14 days 
 
30 
day 
F/U 
Call 
 
 
Clinician-Rated Assessments 
SCID 
 
X 
 
 
 
 
 
 
 
Bipolarity Index 
 
X 
 
 
 
 
 
 
 
MMSE 
 
X 
 
 
 
 
 
 
 
ATRQ 
 
X 
 
 
 
 
 
 
 
Substance Use 
Assessment 
 
 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSR 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Self-Report Questionnaires 
IDS-SR, PANAS-X 
 
X 
 
X 
X 
X 
X 
X 
 
SHAPS, FSS, MAP-SR, 
MFI 
 
X 
 
 
 
X 
X 
X 
 
QIDS-16 SR 
X 
 
 
 
 
 
 
 
 
Behavioral Assessments 
behEEfRT,  Go No-
Go, FTT, RTT, DST2 
 
X 
 
 
 
X 
X 
X 
 
Medical Assessments Related to Safety 
Medical F/U 
Assessment 
 
 
 
 
X 
X 
X 
X 
 
Physical Examination 
 
X 
 
X 
 
 
 
X 
 
Medical History 
 
X 
 
X 
 
 
 
 
 
Vital signs 
 
X 
 
X 
X 
X 
X 
X 
 
Height, weight (BMI) 
waist circumference 
 
X 
 
X 
 
 
 
 
 
EKG, CXR 
 
X 
 
 
 
 
 
 
 
Serum Pregnancy 
Test (if applicable) 
 
X 
 
X 
 
 
 
X 
 
Urine Pregnancy Test 
(if applicable) 
 
 
X 
X 
X 
X 
X 
X 
 
Comprehensive 
Metabolic Panel 
 
X 
 
X (Optional) 
 
 
 
X 
(Optional) 
 
HIV, Hepatitis B 
Surface Antigen, and 
Hepatitis C Antibody 
 
 
X 
 
 
 
 
 
 
 
TSH 
 
X 
 
 
 
 
 
 
 

Version: 07062020 
34
 
1Following pre-screening, participants will be scheduled to complete one or more screening appointments. 
The procedures described under “Screening” may be divided among these visits depending on subject 
scheduling and preference, staff availability, and other factors. Screening visits will occur at the Emory 
Department of Psychology and/or the Emory Clinics and Emory University Hospital. If screening is 
performed in a single visit, it will occur at the locations listed above. Follow up appointments may deviate 
from the specified “3-Day”, “7-Day”, and “14-Day” dates or be split into multiple dates within a range 
approved by the PI in order to accommodate scheduling of the participant and study staff. 
2Behavioral assessments may be skipped in the interest of time on visit days where visit length exceeds what 
was scheduled 
3Subjects may be asked to or may prefer to complete the MRI scan portion of the infusion visit one day prior 
to the infusion. 
4Bolded “X’s” signify prescreening and screening procedures healthy controls and low CRP depressed 
controls will undergo.   
 
Issues Related to Questionnaires, Rating Scales and Interviews: 
1. A copy of each questionnaire that will be used in this study has been included 
with this IRB submission. 
2. Time required for questionnaire completion: On average the SCID will require 
90 minutes for completion. This may vary depending on the particular participant. 
Questionnaires and interviews for the screening visits will require approximately 
3½ hours. Completion of questionnaires and interviews for the infusion visit 
through the visit at 14 days will take approximately 1½ hours. The QIDS-16 SR 
Anti-nuclear 
Antibody (ANA) 
 
X 
 
 
 
 
 
 
 
Quantiferon TB Gold 
 
X 
 
 
 
 
 
 
 
CBC with differential 
 
X 
 
X 
X 
X 
X 
X 
 
Urinalysis with 
microscopic 
 
X 
 
X 
 
 
 
X 
 
 
Medical Assessments Related to Research 
Laboratory Testing 
 
 
 X 
X 
X 
X 
X 
X 
X 
 
Plasma CRP 
(assessed by finger 
stick and/or blood 
draw) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fluorokine MAP 
Multiplex Human 
Biomarker Panel, 
mRNA 
 
 
X 
X 
X 
X 
X 
X 
 
Immune Cell Analysis 
 
 
 
X 
X 
 
 
X 
 
Urine drug screen 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Other Procedures 
MRI scan (including 
fMRI tasks: EEfRT, 
Ad. MID, Gambles 
 
 
X 
X 
 
 
 
X 
 
Emotional Memory 
Assessment 
(Encoding & Recall) 
 
X 
 
 
 
X 
X 
 
 

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35
will be completed at pre-screening. The SCID, Bipolarity Index, ATRQ, and 
MMSE will be completed once during screening. The C-SSR and an adverse events 
assessment will be completed all study visits other than pre-screening, unless a 
subject completes a screening or study visit over multiple days or the assessment is 
deemed redundant due to administering of a SCID in which case the C-SSR may 
not be administered at the PI’s discretion. The SHAPS, FSS, MFI and MAP-SR 
will be completed at screening and at the 3, 7 and 14 day follow up visits. The IDS-
SR and PANAS-X will be completed at screening, on the infusion day and each 
follow up visit. A brief substance use assessment will be completed on the day of 
infusion and at each study visit following this visit. 
3. Volunteers (subjects) in this study who are in active psychiatric treatment during 
their involvement with this study will be asked to sign a release of information for 
the study PI to communicate important clinical changes, such as the development 
of suicidal ideation, to the primary clinician. Psychiatric follow-up following study 
completion will be with pre-existing primary physician for these subjects.  
4. All information gathered for this study and the medical records generated will be 
kept locked with appropriate protection to maintain confidentiality. Research 
records will only be released with the subject's written permission. The subject's 
name will not appear elsewhere in any form and if publications evolve from the 
study, names will in no way be associated with the reports. 
 
Reliability of Clinical Ratings:  
Training on the SCID and other clinician rated assessments will be provided for 
relevant study personnel and interrater reliability will be established and 
maintained. New staff joining the study team will go through an apprenticeship for 
the ratings and training for reliability prior to performing independent ratings. 
 
Safety Monitoring 
As noted in Figure 1, all infusions will be conducted at the ACTSI at Emory 
University Hospital or an infusion center at the Emory Clinic Building A. Subjects 
will be closely monitored during and after infusions for the development of any 
adverse reactions. Standard protocols are in place for treatment of any adverse 
reactions. In addition, all subjects will have access to the study 24 hour pager 
number through the Emory Clinic operator to report adverse events to a study 
physician by phone following each infusion and will be evaluated weekly (or bi-
weekly) in person thereafter. Finally, a designated physician member of the 
research team will be available 24 hours a day seven days a week by phone to study 
participants to address questions and evaluate potential adverse events. 
 
Discontinuation of Study Agent 
 
Study agent must be permanently discontinued if any of the following occur: 
• Subject is deemed ineligible according to the TB screening criteria: 
• A diagnosis of active TB is made. 
• A subject receiving treatment for latent TB discontinues this treatment prematurely 
or is noncompliant with the therapy. 

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36
• A subject has symptoms suggestive of active TB based on follow-up assessment 
questions and/or physical examination, or has had recent close contact with a person 
with active TB, and cannot or will not continue to undergo additional evaluation. 
• A subject undergoing continued screening has a chest radiograph with evidence of 
current active TB and/or a positive tuberculin skin test, unless active TB can be 
ruled out and appropriate treatment for latent TB can be initiated either prior to or 
simultaneously with the next administration of study agent and continued to 
completion. 
 
Adverse Event Reporting and Follow-Up  
An adverse event is any unfavorable and unintended sign, symptom, or disease 
(including an abnormal laboratory finding), temporally associated with the use of a study 
agent(s), whether or not related to the study agent(s), occurring at any time during the study 
(i.e., any time after informed consent is obtained). Should there be an adverse event, PI Dr. 
Treadway or Co-I Dr. Miller shall inform the IRB within the stipulated time frame. 
Recording should be done in a concise manner using standard, acceptable medical terms.  
The adverse event recorded should not be a procedure or a clinical measurement (i.e., a 
laboratory value or vital sign) but should reflect the reason for the procedure or the 
diagnosis based on the abnormal measurement.  Preexisting conditions identified during 
screening that worsen in severity or frequency during the study will be reported to the IRB 
within the stipulated time frame (a preexisting condition that does not worsen is not an 
adverse event).  Further, a procedure or surgery is not an adverse event; rather, the event 
leading to the procedure or surgery is considered an adverse event and will be reported to 
the IRB within the stipulated time frame. 
If, in the investigator’s judgment, a clinically significant worsening from baseline 
is observed in any laboratory or other test parameter (e.g., electrocardiogram, angiogram), 
physical exam finding, or vital sign, a corresponding clinical adverse event will be reported 
to the IRB within the stipulated time frame.  If a specific medical diagnosis has been made, 
that diagnosis will be recorded. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not “elevated liver 
function tests” will be recorded. If the cause is not known, the abnormal test or finding 
should be recorded as an adverse event, using appropriate medical terminology (e.g., 
thrombocytopenia, peripheral edema, QT prolongation).  The actual numeric value of a test 
result will not be recorded. 
 
A serious adverse event is any adverse event occurring at any dose that: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity (i.e., a substantial disruption 
in a person’s ability to conduct normal activities of daily living) 
• Is a congenital anomaly/birth defect 
• In addition, an important medical event that may not result in death, be life-
threatening, or require/prolong hospitalization may be considered a serious adverse 
event when, based on appropriate medical judgment, it may jeopardize the subject 

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and/or may require medical or surgical intervention to prevent one of the outcomes 
listed above. 
 
An unexpected adverse event is any adverse event, the specificity or severity of which is 
not consistent with the current Investigator Brochure. 
 
A reasonably related adverse event is one that is, in the opinion of the investigator, 
possibly, probably or definitely related to study agent. 
 
Any serious adverse event, regardless of relationship to the study agent, must be 
reported immediately.  A serious adverse event must be reported if it occurs during a 
subject’s participation in the study (whether receiving study agent or not) or within [30 
days or 5-half lives of study agent – choose whichever is longer; if 5-half lives is chosen, 
put in the number of days that it represents, followed parenthetically by “5-half lives”] of 
receiving the last dose of study agent, whichever is longer.  
 
Investigators are also advised that active TB is considered a reportable disease in 
most countries. 
 
Any serious adverse event that is ongoing when a subject completes his/her participation 
in the trial must be followed until any of the following occurs: 
• The event resolves or stabilizes; 
• The event returns to baseline condition or value (if a baseline value is available); 
• The event can be attributed to agent(s) other than the study agent, or to factors 
unrelated to study conduct. 
 
Warnings and Precautions 
REMICADE® (infliximab) 
 
Serious infections, including sepsis and pneumonia, have been reported in subjects 
receiving TNF-blocking agents. Some of these infections have been fatal. Many of the 
serious infections in subjects treated with REMICADE have occurred in subjects on 
concomitant immunosuppressive therapy that, in addition to their underlying disease, could 
predispose them to infections. REMICADE should not be given to subjects with a clinically 
important, active infection. Caution should be exercised when considering the use of 
REMICADE in subjects with a chronic infection or a history of recurrent infection. 
Subjects should be monitored for signs and symptoms of infection while on or after 
treatment with REMICADE. New infections should be closely monitored. If a subject 
develops a serious infection, REMICADE therapy should be discontinued. Cases of 
tuberculosis, histoplasmosis, coccidioidomycosis, listeriosis, pneumocystosis, other 
bacterial, mycobacterial and fungal infections have been observed in subjects receiving 
REMICADE. For subjects who have resided in regions where histoplasmosis or 
coccidioidomycosis is endemic, the benefits and risks of REMICADE treatment should be 
carefully considered before initiation of REMICADE therapy.  
 
Malignancies 

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In the controlled portions of clinical trials of some TNF-blocking agents including 
REMICADE, more malignancies have been observed in patients receiving those TNF-
blockers compared with control patients. Caution should be exercised in considering 
REMICADE treatment in patients with a history of malignancy or in continuing treatment 
in patients who develop malignancy while receiving REMICADE. 
Rare postmarketing cases of hepatosplenic t-cell lymphomas have been reported in 
adolescent and young adult patients with Crohn’s disease treated with infliximab. All of 
these reports have occurred in patients on concomitant treatment with azathioprine or 6-
mercaptopurine. The clinical course of this disease is very aggressive with a fatal outcome 
in most patients within 2 years of diagnosis. The causal relationship of hepatosplenic t-cell 
lymphoma to infliximab therapy remains unclear. 
In a clinical trial exploring the use of REMICADE in patients with moderate to 
severe chronic obstructive pulmonary disease (COPD), more malignancies, the majority of 
lung or head and neck origin, were reported in REMICADE-treated patients compared with 
control patients. All patients had a history of heavy smoking (see ADVERSE 
REACTIONS, Malignancies). Prescribers should exercise caution when considering the 
use of REMICADE in patients with moderate to severe COPD. 
 
Malignancies, including non-Hodgkin’s lymphoma and Hodgkin’s disease, have 
also been reported in patients receiving REMICADE during post-approval use. 
 
Hepatotoxicity  
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and 
cholestasis have been reported rarely in postmarketing data in patients receiving 
REMICADE. Autoimmune hepatitis has been diagnosed in some of these cases. Severe 
hepatic reactions occurred between two weeks to more than a year after initiation of 
REMICADE; elevations in hepatic aminotransferase levels were not noted prior to 
discovery of the liver injury in many of these cases. Some of these cases were fatal or 
necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction 
should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme 
elevations (e.g., ≥5 times the upper limit of normal) develops, REMICADE should be 
discontinued, and a thorough investigation of the abnormality should be undertaken. As 
with other immunosuppressive drugs, use of REMICADE has been associated with 
reactivation of hepatitis B in patients who are chronic carriers of this virus (i.e., surface 
antigen positive). Chronic carriers of hepatitis B should be appropriately evaluated and 
monitored prior to the initiation of and during treatment with REMICADE. In clinical 
trials, mild or moderate elevations of ALT and AST have been observed in patients 
receiving REMICADE without progression to severe hepatic injury.  
 
Patients with Heart Failure   
REMICADE has been associated with adverse outcomes in patients with heart 
failure, and should be used in patients with heart failure only after consideration of other 
treatment options. The results of a randomized study evaluating the use of REMICADE in 
patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in 
patients who received 10 mg/kg REMICADE, and higher rates of cardiovascular adverse 
events at doses of 5 mg/kg and 10 mg/kg. There have been post-marketing reports of 

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worsening heart failure, with and without identifiable precipitating factors, in patients 
taking REMICADE. There have also been rare post-marketing reports of new onset heart 
failure, including heart failure in patients without known pre-existing cardiovascular 
disease. Some of these patients have been under 50 years of age. If a decision is made to 
administer REMICADE to patients with heart failure, they should be closely monitored 
during therapy, and REMICADE should be discontinued if new or worsening symptoms 
of heart failure appear.  
 
Hematologic Events  
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with 
a fatal outcome, have been reported in patients receiving REMICADE. The causal 
relationship to REMICADE therapy remains unclear. Although no high-risk group(s) has 
been identified, caution should be exercised in patients being treated with REMICADE 
who have ongoing or a history of significant hematologic abnormalities. All patients should 
be advised to seek immediate medical attention if they develop signs and symptoms 
suggestive of blood dyscrasias or infection (e.g., persistent fever) while on REMICADE. 
Discontinuation of REMICADE therapy should be considered in patients who develop 
significant hematologic abnormalities. 
 
Hypersensitivity  
REMICADE has been associated with hypersensitivity reactions that vary in their 
time of onset and required hospitalization in some cases. Most hypersensitivity reactions, 
which include urticaria, dyspnea, and/or hypotension, have occurred during or within 2 
hours of REMICADE infusion. However, in some cases, serum sickness-like reactions 
have been observed in Crohn’s disease patients 3 to 12 days after REMICADE therapy was 
reinstituted following an extended period without REMICADE treatment. Symptoms 
associated with these reactions include fever, rash, headache, sore throat, myalgias, 
polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated 
with marked increase in antibodies to infliximab, loss of detectable serum concentrations 
of infliximab, and possible loss of drug efficacy. REMICADE should be discontinued for 
severe reactions. Medications for the treatment of hypersensitivity reactions (e.g., 
acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for 
immediate use in the event of a reaction.  
 
Neurologic Events 
REMICADE and other agents that inhibit TNF have been associated in rare cases 
with optic neuritis, seizure and new onset or exacerbation of clinical symptoms and/or 
radiographic evidence of central nervous system demyelinating disorders, including 
multiple sclerosis, and CNS manifestation of systemic vasculitis. Prescribers should 
exercise caution in considering the use of REMICADE in patients with pre-existing or 
recent onset of central nervous system demyelinating or seizure disorders. Discontinuation 
of REMICADE should be considered in patients who develop significant central nervous 
system adverse reactions.  
 
PRECAUTIONS  
 

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Autoimmunity  
Treatment with REMICADE may result in the formation of autoantibodies and, rarely, in 
the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a 
lupus-like syndrome following treatment with REMICADE, treatment should be 
discontinued. 
 
Vaccinations  
No data are available on the response to vaccination with live vaccines or on the secondary 
transmission of infection by live vaccines in patients receiving anti-TNF therapy. It is 
recommended that live vaccines not be given concurrently.  
 
Pregnancy Category B  
Since infliximab does not cross-react with TNFα in species other than humans and 
chimpanzees, animal reproduction studies have not been conducted with REMICADE. No 
evidence of maternal toxicity, embryotoxicity or teratogenicity was observed in a 
developmental toxicity study conducted in mice using an analogous antibody that 
selectively inhibits the functional activity of mouse TNFα. Doses of 10 to 15 mg/kg in 
pharmacodynamic animal models with the anti-TNF analogous antibody produced 
maximal pharmacologic effectiveness. Doses up to 40 mg/kg were shown to produce no 
adverse effects in animal reproduction studies. It is not known whether REMICADE can 
cause fetal harm when administered to a pregnant woman or can affect reproduction 
capacity. REMICADE should be given to a pregnant woman only if clearly needed. 
 
Nursing Mothers 
It is not known whether REMICADE is excreted in human milk or absorbed systemically 
after ingestion. Because many drugs and immunoglobulins are excreted in human milk, 
and because of the potential for adverse reactions in nursing infants from REMICADE, a 
decision should be made whether to discontinue nursing or to discontinue the drug, taking 
into account the importance of the drug to the mother. 
Please see the latest version of the REMICADE package insert and investigator brochure 
for further information on adverse reactions, warnings, and precautions. 
 
Data Analysis Plan 
 
For all three aims, analyses will focus on a priori inflammatory markers CRP and IL-6. 
These two inflammatory markers were chosen based on their role in sample selection, 
response to infliximab and association with reward pathways in our preliminary data as 
well as published papers by our group
133 and meta-analyses of elevated inflammatory 
makers in depression.
134 We did not include plasma measures of TNF in this analysis 
because measurement of plasma TNF is confounded by infliximab, which binds to TNF 
and leads to arbitrarily high concentrations of TNF on ELISA. Instead, the role of TNF 
will be investigated using gene expression data examining TNF signaling pathways (See 
Aim 2 below).  
Aim 1: Determine the relationship between inflammation and corticostriatal circuit 
function in patients with major depression and high inflammation before and after an 

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anti-inflammatory challenge. Hypothesis 1a: Mixed-effects models for repeated measures 
(MMRM) will first be employed to examine effects of group (infliximab vs. placebo), 
time and their interaction on neuroimaging data using an a Region-of- Interest (ROI) 
approach. For ROI analysis, as described above, first-level GLMs will be created in 
normalized space for each time-point for each task, and a priori functional ROI in the 
striatum and vmPFC will be defined for both main effects using the baseline scan. 
Anatomically-defined ROIs will also be examined. Parameter estimates will be extracted 
from these ROI for each time-point. Relevant covariates, including age, sex, race 
(white/non-white) and body mass index (BMI) as well as number of depressive episodes, 
length of current depressive episode (in months), treatment responsiveness (ATRQ), age 
of onset, bipolarity index score and family history of depression (yes/no) will be 
sequentially tested in the models for goodness of fit (Akaike Information Criterion) and 
included as appropriate. To examine possible neural markers of inflammation change 
outside of our a priori ROIs, an exploratory voxel-wise approach will also be used. For 
this analysis, pre-post change in two primary inflammatory markers (CRP and IL-6) will 
be regressed against whole-brain corrected maps (pFWE < 0.05) for primary contrasts as 
described above. Hypothesis 1b: A Psychophysiological Interaction Analysis
135 
implemented through the gPPI toolbox (http://brainmap.wisc.edu/PPI) will be used to 
investigate connectivity between vmPFC and ventral striatum during effort-based 
decisions. Seed-regions will be based on two striatal ROIs corresponding to ventral and 
dorsomedial striatum that have been previously shown to exhibit robust resting state 
connectivity with aspects of vmPFC. These ROIs are drawn from a 17-network 
parcellation of corticostrial connectivity performed in a large (n = 1,000) sample
5. After 
single-subject connectivity maps have been generated for each time point, difference 
maps will be generated reflecting the change connectivity strength before and after 
infliximab or placebo treatment. A paired t-test as implemented through SPM12 will be 
used to compare pre-post change in corticostriatal connectivity (whole-brain corrected, 
pFWE < 0.05).  
Aim 2: Determine the temporal dynamics of change in inflammation and change in 
behavioral and clinical measures of motivational anhedonia in depressed patients before 
and after an anti- inflammatory challenge. Hypothesis 2: As above, initial analyses will 
focus on plasma CRP and IL-6. Random intercept linear mixed models will be used to 
assess whether change in these markers predicts change in self-reported anhedonic 
symptoms, effort expenditure (BehEEfRT) or reinforcement learning (PST) when 
controlling for relevant covariates as appropriate (see above). For each of these two 
inflammatory markers, four separate models will be employed to assess the association 
between each inflammatory marker at each time point and 1) composite self-report data, 
2) behEEfRT performance (proportion of high effort choices) 3) Go learning 
performance (PST) and 4) No-Go learning performance. To control for multiple 
comparisons across these 8 models, alpha significance will be set to a Bonferroni-
corrected p<0.00625. Given the rapid changes that will likely occur in inflammatory 
markers prior to changes in behavioral measures, the models described above will be 
repeated using a “lagged regressor” that will test the associations between gene-
expression at time t against inflammation, symptom and behavioral measures at time t+1. 
Exploratory analyses will be used to test for any incremental predictive power of 

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additional collected cytokines and their receptors. For gene-expression analysis, an 
identical set of models will be run using gene-expression within the previously identified 
transcripts in TNF signaling pathways as described in Preliminary Study 9. In addition to 
these a priori transcripts, an exploratory gene expression analysis will be performed. 
Based on change in reported symptoms at week 2, participants will be divided into 
“responders” and “non-responders”. Individuals who cannot easily be assigned to one 
group or the other will be excluded from the analysis. A list of differentially expressed 
genes (based on a 1.2 fold difference and a false discovery rate of p<0.01) will be 
generated between infliximab “responders” versus “non responders” in self-report 
measures. To compare differences in gene expression at baseline between responders 
versus non-responders within groups, we will use logistic regression, correcting for 
relevant covariates as described above and including differential expression of white 
blood cells as determined by the white blood cell count. In addition, we will use a 
transcript origin analysis (see below). For differentially expressed genes in responders 
versus non-responders as a function of group (infliximab vs. placebo), pathway analysis 
will be done using a number of tools including the WebGestalt WikiPathways tool and 
BibliosphereTM data mining software from Genomatix. Overrepresentation of specific 
transcription binding factors such as NF-kB in the promoters of the associated transcripts 
will be tested using the cREMaG interface (http://149.156.177.116/cremag/), TRAP 
(http://trap.molgen.mpg.de) and the TELIS database. (http://www.telis.ucla.edu).
136 
Transcript origin analysis will also be used.
137 This analysis examines specific patterns of 
gene expression that are associated with immune cell subtypes and generates a cell origin 
diagnosticity score, which provides information on which cell types are contributing to 
changes in gene expression observed between responders and non-responders within 
groups.
137, 138 Expression levels within transcripts identified by the exploratory analysis 
will be additionally employed as predictors of change in EEfRT and PST performance, as 
described above. Finally, to test whether changes in gene-expression may serve as an 
“early indicator” of infliximab response, lagged regressor models will also be explored to 
determine whether early changes in these inflammatory variables predict subsequent 
changes in task performance.  
Aim 3: Explore the inter-relationship among inflammation, corticostriatal circuit function 
and reward motivation using path analysis. Hypothesis 3: A final aim of the study is to 
explore multi-level path modeling between measures of inflammation, corticostriatal 
circuitry, and motivational anhedonia. Using a bootstrapped estimation procedure, we 
will test whether change in VS signal and vmPFC-VS connectivity mediate the 
relationship between change in CRP and/or IL-6 and change in motivational anhedonic 
symptoms. Bootstrapping will be used to provide an empirical estimate of the sampling 
distribution for indirect effects and will be used to generate confidence intervals for the 
purpose of inferential testing.
139 We will additionally test a model of moderated-
mediation to assess whether mediation pathways are influenced by the presence of high 
vs. low baseline inflammation. Path analysis will be implemented using macros 
developed by Preacher and Hayes (http://quantpsy.org/medn.htm), which enable 
inclusion of covariates as well as possible moderators.  

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Power Analysis: For neuroimaging measures in Aim 1, the MID, fMRI-EEfRT and RL 
tasks have excellent power for generating main effect contrasts140 and our sample is well 
above the minimum n=50 recommended for individual differences analysis in fMRI 
studies.141 For the within (pre-post treatment) by between (infliximab vs. placebo) 
interaction, we have excellent power (99%) to detect a medium effect size of f = 0.25, 
and good power (84%) for smaller effect sizes (f = 0.15). For Aim 2, because data at 
multiple time-points are clustered within subject, effect sizes that ignore clustering may 
be inflated (i.e., design effects).142 Consequently, power analysis is based on a 
conservative effect size estimate of slope = 0.3, for which we have adequate power 
(80%). Finally, for Aim 3, the use of bootstrapping to adjust for low sample sizes has 
received wide-acceptance in the literature139, and will provide adequate power for partial 
mediation in the current sample.  
 
Safety Issues and Safety Analyses: We recognize that a single-dose of infliximab is a 
potent anti-inflammatory challenge with the potential to result in immunosuppression. 
Nevertheless, in our previous study, we found no differences in adverse events in 
infliximab versus placebo- treated patients for up to 6 months after 3 infusions (published 
and unpublished data). Moreover, in more recent studies (derived from large pre- and 
post-marketing databases) infliximab and other TNF antagonists have not been clearly 
associated with increased risk of cancer, serious adverse cardiovascular events or adverse 
de novo neurologic adverse events. Given that all adverse event data is largely derived 
from patients who have received months to years of treatment with these drugs, we 
believe a single infusion of an anti-inflammatory challenge poses limited risk under the 
conditions of careful patient selection and monitoring. Adverse events (AEs) will be 
recorded and reported using standard Medra categories, and suicidality will be assessed at 
each visit using the C-SSR. Dropout rates by category (e.g., adverse events, SAE’s, non-
adherence, etc.) will be reported and compared using Fisher Exact Tests.  
GENERAL RISKS AND DISCOMFORTS 
 
There are 7 major areas of potential risk in the study, as outlined below.  
 
Neuropsychiatric assessments: Neuropsychiatric assessments may uncover strong and 
potentially disturbing feelings about the subject’s past or present emotional state. 
 
Blood draws: The risks of blood drawing include discomfort, bruising, infection, bleeding, 
and fainting. 
 
Infliximab infusion: Use of infliximab has been associated with a number of short and 
long term risks (in 10%-50% of subjects), including mild allergic reaction to the 
medication, stomach pain, nausea, diarrhea, heartburn, upper respiratory tract infections, 
sore throat, sinusitis, coughing, runny nose, rash, fatigue, fever, headache, joint pain, back 
pain, urinary tract infection and hypertension. It should be noted however that in our 
previous study of infliximab, there were no differences in the number or severity of adverse 
events in the infliximab group compared to placebo over the 12 weeks of the study and up 
to 6 months post study completion.1(unpublished observations) Very rarely (less than 1%), 
more serious adverse events have been reported, including severe anaphylactic reaction to 

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the infusion, development of serum sickness following infusion, reactivation of 
tuberculosis, development of serious and occasionally life threatening infections, induction 
of autoimmunity, worsening of congestive heart failure, bone marrow suppression, optic 
neuritis, seizures, cerebral demyelination and development of lymphoma or other cancers 
including skin cancer. Of note, early data from pooled randomized clinical trials revealed 
increased malignancy including lymphoma with TNF inhibitors in rheumatoid arthritis 
(RA) leading to the current FDA black box warning.2 Nevertheless, more recent data in 
RA patients (including analysis of more than 40,000 patients and 150,000 patient-years 
exposure) as well as patients with inflammatory bowel disease indicate that TNF 
inhibitors are not clearly associated with increased malignancy.3,4 In addition, data from 
pooled databases of over 100,000 patients and post-marketing data reported to the FDA 
indicate that TNF-inhibitors are also not clearly associated with major adverse 
cardiovascular events or de novo neurologic events.5,6 Finally, although there is a 
possibility of drug-drug interactions with infliximab, according to MicroMedex, an 
evidence-based drug information resource (used by Emory Healthcare), there are few 
drug-drug interactions with infliximab excluding other immunosuppressants, other 
monoclonal antibodies, and “moderate” interactions with the following psychotropic 
agents: phenytoin, thioridizine and pimozide (all of which are exclusionary – patients will 
be free of psychotropic medications). 
 
Placebo treatment: Subjects in this study also have a 50% chance of receiving a placebo 
infusion. Risks of placebo include lack of efficacy relative to active antidepressant 
treatments that might lead to a worsening of depressive symptoms, including the 
development of suicidal ideation. 
 
MRI scan: Undergoing fMRI scans 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 fMRI procedure. 
 
Suicidality: Given the fact that patients are not on any standard antidepressant 
medications, it is possible that they may experience worsening of their symptoms over 
the course of the study including the experiencing of suicidal ideation. Appropriate 
measures will be taken if patients exhibit significant suicidal risk. 
 
Confidentiality: Confidentiality of all subjects will be protected per institutional and NIH 
and other federal requirements, and as described in greater detail below. At screening, 
study clinicians’ will discuss benefits and risks of participation as well as alternative 
options. 
 
A number of procedures will be in place to prevent a breach of confidentiality from 
taking place. All potential subjects will be fully informed of their rights pertaining to 
disclosure of PHI in accordance with HIPAA regulations. Confidentiality will be 
maintained by assigning participants a study number and numerically coding all data. 
One hard copy file linking the code number with identifying information will be kept in 
separate locked file with direct access available to the PI only. All records and research 

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data will be kept in locked filing cabinets or computers.  Only summaries of group data 
will be reported in any publications or presentations, with no identification of individuals. 
These precautions should serve to minimize legal risks to participants.  
 
At the completion of the study, all MDD patients will be provided with a comprehensive 
list of treatment options for depression and related mental health issues. A copy of this 
information has been included as a separate attachment in our resubmission (please see 
“MDD_PostStudy_Treatment_Resource_List.doc”). 
 
The key investigators will meet quarterly to discuss any potential adverse event and side 
effects. We will involve the IRB for consultation if any additional potential risks arise. 
Adverse events and unanticipated problems involving risks to subjects or others will be 
reported to the IRB in accordance with reporting guidelines. 
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 will only 
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-
7541 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. 
 
Adverse Event Reporting 
 
Enrolled participants will be monitored closely by study clinicians for any adverse 
events. If any overt study-related adverse events occur, a decision will be made about study 
continuation. Additionally, a record of adverse events for study participants will be 
reported to the DSMB on a regular basis (see below). Subjects will be closely monitored 
during the course of the study for development of any serious or unexpected adverse 
reactions. Those events meeting Emory IRB criteria for a reportable event will be reported 
to the IRB or DSMB according to standard regulations and procedures.  The Emory 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.” 
 
Data and Safety Monitoring Plan (DSMP) 
 
This study utilizes an anti-inflammatory pharmacological challenge paradigm to 
explore the relationship among inflammation, corticostriatal circuit function and 
motivational anhedonia in patients with MD. Because study subjects will be receiving an 
active pharmacologic medication that has rare potentially serious side effects, we have 
elected to utilize a Data and Safety Monitoring Board as part of our data and safety-
monitoring plan. The DSMB is described in detail below. In addition, study clinicians 
will be available by pager 24 hrs/7 days a week during the period between screening and 
completion of study assessments. Should a subject’s depressive symptoms appreciably 

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worsen or should active suicidal ideation develop, either Dr. Treadway, Dr. Miller or 
their designee will be immediately notified. Dr. Treadway is a licensed clinical 
psychologist and Dr. Miller a board-certified psychiatrist. Both have extensive experience 
in the treatment of psychiatric emergencies. If the assessment in question was done by a 
clinician other than either of them, one of them will immediately contact the subject and 
will evaluate the need for further psychiatric treatment and will arrange psychiatric 
follow-up. They will evaluate each case individually to make a determination regarding 
whether the subject can remain in the study or whether the subject should be terminated 
in addition to receiving a mental health referral.  
 
Composition of the Data Safety Monitoring Board (DSMB) 
 
The DSMB for this study will consist of Larry Tune, M.D. Chairman, Boadie Dunlop, 
M.D., Tanja Mletzko, M.S. and Marian Evatt, M.D. Each of these clinical researchers has 
agreed to serve as the external DSMB for investigator-initiated clinical trials conducted 
by Emory researchers in the Department of Psychiatry and Behavioral Sciences. If the 
DSMB requires additional specialized expertise to evaluate safety issues related to the 
performance of this study, a relevant specialist will be consulted by the DSMB. The 
frequency of Emory DSMB review for this protocol will be once every six months based 
on IRB recommendations consistent with the assessed risk status of the study. Of note, 
based on a random internal audit (not for cause) of the previous infliximab trial, 
accolades were given for regulatory compliance and documentation of all adverse events 
as well as timely reporting and processing with the Emory DSMB and IRB.  
Procedures and Responsibilities of the DSMB 
 
At least four weeks prior to each DSMB meeting, the data manager/research coordinators 
will prepare a report to be reviewed during that meeting. The report will include the 
number of participants who signed consent for the study, the number of screening failures 
and dropouts, reasons for these screening failures or 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 PI 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 six 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. 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.”  

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The PI will take responsibility for reporting any serious and unexpected adverse events in 
a timely fashion directly to the Emory DSMB. The PI will also report serious and 
unexpected adverse events or other unanticipated study problems or variances to the 
Emory. Actions taken by the IRB in response to adverse event reports will be 
immediately reported to the Emory DSMB. Statistical analysis of adverse event data will 
be provided by the study biostatistician.  
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