Conditions: Depression
Keywords: Neuroscience Behavioral Social
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 42
Healthy volunteers: no

Brief summary:
The main purpose of this study is to examine the effects of infliximab on measures related to depression symptoms. Infliximab is also known by its brand name Remicade. Infliximab, or Remicade, is given to by an intravenous (IV) needle and is currently used to treat rheumatoid arthritis and Crohn's disease. Infliximab is thought to help these conditions because it reduces inflammation in the body. Infliximab (Remicade) reduces inflammation by blocking a chemical in the body called tumor necrosis factor (TNF)-alpha. This chemical produces inflammation. Inflammatory chemicals in the body like TNF-alpha appear to be increased in some people with major depression. Researchers believe that a drug like infliximab, which blocks TNF-alpha, may be helpful in treating depression.

This is a double-blind, placebo-controlled study in which participants will be randomized to receive one infusion of infliximab or placebo. The study will assess neuroimaging measures of corticostriatal circuitry before and after a placebo-controlled pharmacologic blockade of inflammation in 80 depressed patients.

Detailed description:
The main purpose of this study is to examine the effects of infliximab on measures related to depression symptoms. Infliximab is also known by its brand name Remicade. Infliximab, or Remicade, is given by an intravenous (IV) needle and is currently used to treat rheumatoid arthritis and Crohn's disease. Infliximab is thought to help these conditions because it reduces inflammation in the body. Infliximab (Remicade) reduces inflammation by blocking a chemical in the body called tumor necrosis factor (TNF)-alpha. This chemical produces inflammation. Inflammatory chemicals in the body like TNF-alpha appear to be increased in some people with major depression. Researchers believe that a drug like infliximab, which blocks TNF-alpha, may be helpful in treating depression.

This is a double-blind, placebo-controlled study in which participants will be randomized to receive one infusion of infliximab or placebo. This 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 (CRP \> 3mg/L).

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 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.

Arms:
arm 1: Participants randomized to the infliximab group will receive one infusion of infliximab at 5mg/kg body weight. arm 2: Participants randomized to the placebo group will receive one placebo infusion.

Interventions: intervention 1: Infliximab intervention 2: Placebo
Intervention descriptions: intervention 1: One infusion of Infliximab (Remicade) will be administered intravenously (IV) at 5 mg/kg body weight over a two hour period. intervention 2: One infusion of placebo treatment will be administered intravenously (IV) over a two hour period.

Protocol document:
Prot_SAP_000.pdf: 
Version: 07062020 
1
 
 
 
 
 
 
 
 
 
 
 
Dynamics of Inflammation and its Blockade on Motivational 
Circuitry in Depression 
 
 
NCT03006393 
 
Date: July 6th, 2020 
 
IRB00087941 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version: 07062020 
2
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 


Version: 07062020 
3
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 


Version: 07062020 
4
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 


Version: 07062020 
5
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 


Version: 07062020 
6
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:  


Version: 07062020 
7
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 


Version: 07062020 
8
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 


Version: 07062020 
9
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.    
  


Version: 07062020 
10
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, 


Version: 07062020 
11
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 


Version: 07062020 
12
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 


Version: 07062020 
13
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—


Version: 07062020 
14
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 


Version: 07062020 
15
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. 
 


Version: 07062020 
16
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 


Version: 07062020 
17
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 


Version: 07062020 
18
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). 


Version: 07062020 
19
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 


Version: 07062020 
20
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 


Version: 07062020 
21
 
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 


Version: 07062020 
22
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 


Version: 07062020 
23
 
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 


Version: 07062020 
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  


Version: 07062020 
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 


Version: 07062020 
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 


Version: 07062020 
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.  


Version: 07062020 
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 
 
 


Version: 07062020 
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. 


Version: 07062020 
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 


Version: 07062020 
37
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 


Version: 07062020 
38
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 


Version: 07062020 
39
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  
 


Version: 07062020 
40
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 


Version: 07062020 
41
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 


Version: 07062020 
42
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.  


Version: 07062020 
43
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 


Version: 07062020 
44
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 


Version: 07062020 
45
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 


Version: 07062020 
46
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.”  


Version: 07062020 
47
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.  
Literature Cited 
 
1. 
Schultz W. Multiple dopamine functions at different time courses. Annu Rev 
Neurosci. 2007;30:259-288. 
2. 
Schultz W, Dickinson A. Neuronal coding of prediction errors. Annu Rev Neurosci. 
2000;23:473-500. 
3. 
Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. 
Science. 1997;275(5306):1593-1599. 
4. 
Schultz W. Neuronal reward and decision signals: from theories to data. Physiol 
Rev. 2015;95(3):853-951. 
5. 
Choi EY, Yeo BT, Buckner RL. The organization of the human striatum estimated 
by intrinsic functional connectivity. J Neurophysiol. 2012;108(8):2242-2263. 
6. 
Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from 
translational neuroscience. Neurosci Biobehav Rev. 2011;35(3):537-555. 
7. 
Treadway MT, Zald DH. Parsing Anhedonia Translational Models of Reward-
Processing Deficits in Psychopathology. Current Directions in Psychological 
Science. 2013;22(3):244-249. 
8. 
Pizzagalli DA, Holmes AJ, Dillon DG, Goetz EL, Birk JL, Bogdan R, Dougherty 
DD, Iosifescu DV, Rauch SL, Fava M. Reduced caudate and nucleus accumbens 
response to rewards in unmedicated individuals with major depressive disorder. Am 
J Psychiatry. 2009;166(6):702-710. 
9. 
Kumar P, Waiter G, Ahearn T, Milders M, Reid I, Steele JD. Abnormal temporal 
difference reward-learning signals in major depression. Brain. 2008;131(Pt 
8):2084-2093. 
10. 
Juckel G, Schlagenhauf F, Koslowski M, Wustenberg T, Villringer A, Knutson B, 
Wrase J, Heinz A. Dysfunction of ventral striatal reward prediction in 
schizophrenia. Neuroimage. 2006;29(2):409-416. 
11. 
Gradin VB, Kumar P, Waiter G, Ahearn T, Stickle C, Milders M, Reid I, Hall J, 
Steele JD. Expected value and prediction error abnormalities in depression and 
schizophrenia. Brain. 2011;134(Pt 6):1751-1764. 
12. 
Morris RW, Vercammen A, Lenroot R, Moore L, Langton JM, Short B, Kulkarni 
J, Curtis J, O'Donnell M, Weickert CS. Disambiguating ventral striatum fMRI-
related bold signal during reward prediction in schizophrenia. Mol Psychiatry. 
2011;17(3):280-289. 
13. 
Felger JC, Mun J, Kimmel HL, Nye JA, Drake DF, Hernandez CR, Freeman AA, 
Rye DB, Goodman MM, Howell LL. Chronic Interferon-Œ± Decreases Dopamine 
2 Receptor Binding and Striatal Dopamine Release in Association with Anhedonia-
Like Behavior in Nonhuman Primates. Neuropsychopharmacology. 2013. 
14. 
Capuron L, Pagnoni G, Drake DF, Woolwine BJ, Spivey JR, Crowe RJ, Votaw JR, 
Goodman MM, Miller AH. Dopaminergic mechanisms of reduced Basal Ganglia 


Version: 07062020 
48
responses to hedonic reward during interferon alfa administration. Arch Gen 
Psychiatry. 2012;69(10):1044-1053. 
15. 
Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR. 
Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to 
reward. Biol Psychiatry. 2010;68(8):748-754. 
16. 
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of 
cytokines in the pathophysiology of major depression. Biol Psychiatry. 
2009;65(9):732-741. 
17. 
Dantzer R, Meagher MW, Cleeland CS. Translational approaches to treatment-
induced symptoms in cancer patients. Nat Rev Clin Oncol. 2012;9(7):414-426. 
18. 
Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A, McCorkle R, 
Seligman DA, Schmidt K. The relationship of depression and stressors to 
immunological 
assays: 
a 
meta-analytic 
review. 
Brain 
Behav 
Immun. 
2001;15(3):199-226. 
19. 
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL. A 
meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446-
457. 
20. 
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon 
E, Miller AH. A Randomized Controlled Trial of the Tumor Necrosis Factor 
Antagonist Infliximab for Treatment-Resistant DepressionThe Role of Baseline 
Inflammatory BiomarkersInfliximab for Treatment-Resistant Depression. JAMA 
Psychiatry. 2013;70(1):31-41. 
21. 
Treadway MT, Buckholtz JW, Schwartzman AN, Lambert WE, Zald DH. Worth 
the 'EEfRT'? The effort expenditure for rewards task as an objective measure of 
motivation and anhedonia. PLoS ONE. 2009;4(8):e6598. 
22. 
Knutson B, Fong GW, Adams CM, Varner JL, Hommer D. Dissociation of reward 
anticipation 
and 
outcome 
with 
event-related 
fMRI. 
Neuroreport. 
2001;12(17):3683-3687. 
23. 
Pessiglione M, Seymour B, Flandin G, Dolan RJ, Frith CD. Dopamine-dependent 
prediction errors underpin reward-seeking behaviour in humans. Nature. 
2006;442(7106):1042-1045. 
24. 
Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, 
Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ. 
Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 
2006;354(12):1243-1252. 
25. 
Gold JM WJ, Prentice KJ, Morris SE, Heerey EA. Reward processing in 
schizophrenia: a deficit in the representation of value. Schizophr Bull. 
2008;34(5):835-847. 
26. 
Nutt D, Demyttenaere K, Janka Z, Aarre T, Bourin M, Canonico PL, Carrasco JL, 
Stahl S. The other face of depression, reduced positive affect: the role of 
catecholamines in causation and cure. J Psychopharmacol. 2007;21(5):461-471. 
27. 
Shelton RC, Tomarken AJ. Can recovery from depression be achieved? Psychiatr 
Serv. 2001;52(11):1469-1478. 
28. 
Salamone JD, Correa M, Farrar A, Mingote SM. Effort-related functions of nucleus 
accumbens dopamine and associated forebrain circuits. Psychopharmacology 
(Berl). 2007;191(3):461-482. 


Version: 07062020 
49
29. 
Walton ME, Kennerley SW, Bannerman DM, Phillips PE, Rushworth MF. 
Weighing up the benefits of work: behavioral and neural analyses of effort-related 
decision making. Neural Netw. 2006;19(8):1302-1314. 
30. 
Floresco SB, Ghods-Sharifi S. Amygdala-prefrontal cortical circuitry regulates 
effort-based decision making. Cereb Cortex. 2007;17(2):251-260. 
31. 
Berridge KC, Robinson TE. Parsing reward. Trends Neurosci. 2003;26(9):507-513. 
32. 
Berridge KC. The debate over dopamine's role in reward: the case for incentive 
salience. Psychopharmacology (Berl). 2007;191(3):391-431. 
33. 
Schultz W DP, Montague PR. A neural substrate of prediction and reward. Science. 
1997;275(5306):1593-1599. 
34. 
Schott BH, Minuzzi L, Krebs RM, Elmenhorst D, Lang M, Winz OH, Seidenbecher 
CI, Coenen HH, Heinze HJ, Zilles K, Duzel E, Bauer A. Mesolimbic functional 
magnetic resonance imaging activations during reward anticipation correlate with 
reward-related ventral striatal dopamine release. J Neurosci. 2008;28(52):14311-
14319. 
35. 
D'Ardenne K MS, Nystrom LE, Cohen JD. BOLD responses reflecting 
dopaminergic signals in the human ventral tegmental area. Science. 
2008;5867(319):1264-1267. 
36. 
Frank MJ, O'Reilly RC. A mechanistic account of striatal dopamine function in 
human cognition: psychopharmacological studies with cabergoline and 
haloperidol. Behav Neurosci. 2006;120(3):497. 
37. 
Frank MJ, Seeberger LC, O'Reilly RC. By carrot or by stick: cognitive 
reinforcement learning in parkinsonism. Science. 2004;306(5703):1940-1943. 
38. 
Kravitz AV, Tye LD, Kreitzer AC. Distinct roles for direct and indirect pathway 
striatal neurons in reinforcement. Nat Neurosci. 2012;15(6):816-818. 
39. 
Salamone JD, Correa M. The mysterious motivational functions of mesolimbic 
dopamine. Neuron. 2012;76(3):470-485. 
40. 
Bardgett ME, Depenbrock M, Downs N, Points M, Green L. Dopamine modulates 
effort-based decision making in rats. Behav Neurosci. 2009;123(2):242-251. 
41. 
Floresco SB, Tse MT, Ghods-Sharifi S. Dopaminergic and glutamatergic regulation 
of effort- and delay-based decision making. Neuropsychopharmacology. 
2008;33(8):1966-1979. 
42. 
Venugopalan VV, Casey KF, O'Hara C, O'Loughlin J, Benkelfat C, Fellows LK, 
Leyton M. Acute Phenylalanine/Tyrosine Depletion Reduces Motivation to Smoke 
Cigarettes Across Stages of Addiction. Neuropsychopharmacology. 2011. 
43. 
Wardle MC, Treadway MT, Mayo LM, Zald DH, de Wit H. Amping Up Effort: 
Effects of d-Amphetamine on Human Effort-Based Decision-Making. J Neurosci. 
2011;31(46):16597-16602. 
44. 
Rushworth MF, Noonan MP, Boorman ED, Walton ME, Behrens TE. Frontal 
cortex 
and 
reward-guided 
learning 
and 
decision-making. 
Neuron. 
2011;70(6):1054-1069. 
45. 
Hunt LT, Kolling N, Soltani A, Woolrich MW, Rushworth MFS, Behrens TEJ. 
Mechanisms underlying cortical activity during value-guided choice. Nat Neurosci. 
2012;15(3):470-476. 


Version: 07062020 
50
46. 
Hare TA, O'Doherty J, Camerer CF, Schultz W, Rangel A. Dissociating the role of 
the orbitofrontal cortex and the striatum in the computation of goal values and 
prediction errors. J Neurosci. 2008;28(22):5623-5630. 
47. 
Rangel A, Camerer C, Montague PR. A framework for studying the neurobiology 
of value-based decision making. Nat Rev Neurosci. 2008;9(7):545-556. 
48. 
Hauber W, Sommer S. Prefrontostriatal Circuitry Regulates Effort-Related 
Decision Making. Cereb Cortex. 2009. 
49. 
Pizzagalli DA, Iosifescu D, Hallett LA, Ratner KG, Fava M. Reduced hedonic 
capacity in major depressive disorder: evidence from a probabilistic reward task. J 
Psychiatr Res. 2008;43(1):76-87. 
50. 
Treadway MT, Bossaller NA, Shelton RC, Zald DH. Effort-based decision-making 
in major depressive disorder: a translational model of motivational anhedonia. J 
Abnorm Psychol. 2012;121(3):553. 
51. 
Yang X-h, Huang J, Zhu C-y, Wang Y-f, Cheung EFC, Chan RCK, Xie G-r. 
Motivational deficits in effort-based decision making in individuals with 
subsyndromal depression, first-episode and remitted depression patients. 
Psychiatry Res. 2014;220(3):874-882. 
52. 
Barch DM, Treadway MT, Schoen N. Effort, anhedonia, and function in 
schizophrenia: Reduced effort allocation predicts amotivation and functional 
impairment. J Abnorm Psychol. 2014;123(2):387. 
53. 
Treadway MT, Peterman JS, Zald DH, Park S. Impaired effort allocation in patients 
with schizophrenia. Schizophr Res. 2014. 
54. 
Fervaha G, Graff-Guerrero A, Zakzanis KK, Foussias G, Agid O, Remington G. 
Incentive motivation deficits in schizophrenia reflect effort computation 
impairments 
during 
cost-benefit 
decision-making. 
J 
Psychiatr 
Res. 
2013;47(11):1590-1596. 
55. 
Felger JC, Mun J, Kimmel HL, Nye JA, Drake DF, Hernandez CR, Freeman AA, 
Rye DB, Goodman MM, Howell LL. Chronic interferon-α decreases dopamine 2 
receptor binding and striatal dopamine release in association with anhedonia-like 
behavior in nonhuman primates. Neuropsychopharmacology. 2013;38(11):2179-
2187. 
56. 
Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong JS, Knapp DJ, Crews FT. 
Systemic 
LPS 
causes 
chronic 
neuroinflammation 
and 
progressive 
neurodegeneration. Glia. 2007;55(5):453-462. 
57. 
Felger JC, Alagbe O, Hu F, Mook D, Freeman AA, Sanchez MM, Kalin NH, Ratti 
E, Nemeroff CB, Miller AH. Effects of interferon-alpha on rhesus monkeys: a 
nonhuman primate model of cytokine-induced depression. Biol Psychiatry. 
2007;62(11):1324-1333. 
58. 
Gentile A, Fresegna D, Federici M, Musella A, Rizzo FR, Sepman H, Bullitta S, 
De Vito F, Haji N, Rossi S. Dopaminergic dysfunction is associated with IL-1β-
dependent mood alterations in experimental autoimmune encephalomyelitis. 
Neurobiol Dis. 2015;74:347-358. 
59. 
Sarkar C, Basu B, Chakroborty D, Dasgupta PS, Basu S. The immunoregulatory 
role of dopamine: an update. Brain, behavior, and immunity. 2010;24(4):525-528. 


Version: 07062020 
51
60. 
Yan Y, Jiang W, Liu L, Wang X, Ding C, Tian Z, Zhou R. Dopamine Controls 
Systemic Inflammation through Inhibition of NLRP3 Inflammasome. Cell. 
2015;160(1):62-73. 
61. 
Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD. 
Inflammation causes mood changes through alterations in subgenual cingulate 
activity and mesolimbic connectivity. Biol Psychiatry. 2009;66(5):407-414. 
62. 
Vichaya EG, Hunt SC, Dantzer R. Lipopolysaccharide Reduces Incentive 
Motivation 
While 
Boosting 
Preference 
for 
High 
Reward 
in 
Mice. 
Neuropsychopharmacology. 2014. 
63. 
Nunes EJ, Randall PA, Estrada A, Epling B, Hart EE, Lee CA, Baqi Y, Mueller 
CE, Correa M, Salamone JD. Effort-related motivational effects of the pro-
inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 
5/chow feeding choice task. Psychopharmacology (Berl). 2013:1-10. 
64. 
Felger JC, Miller AH. Cytokine effects on the basal ganglia and dopamine function: 
the subcortical source of inflammatory malaise. Front Neuroendocrinol. 2014. 
65. 
Couch Y, Anthony DC, Dolgov O, Revischin A, Festoff B, Santos AI, Steinbusch 
HW, Strekalova T. Microglial activation, increased TNF and SERT expression in 
the prefrontal cortex define stress-altered behaviour in mice susceptible to 
anhedonia. Brain, behavior, and immunity.29:136-146. 
66. 
Thorne R, Hanson L, Ross T, Tung D, Frey Ii W. Delivery of interferon-Œ≤ to the 
monkey nervous system following intranasal administration. Neuroscience. 
2008;152(3):785-797. 
67. 
Capuron L, Ravaud A, Miller AH, Dantzer R. Baseline mood and psychosocial 
characteristics of patients developing depressive symptoms during interleukin-2 
and/or interferon-alpha cancer therapy. Brain Behav Immun. 2004;18(3):205-213. 
68. 
Capuron 
L, 
Miller 
AH. 
Immune 
system 
to 
brain 
signaling: 
neuropsychopharmacological implications. Pharmacol Ther. 2011;130(2):226-
238. 
69. 
Berridge KC. 'Liking' and 'wanting' food rewards: brain substrates and roles in 
eating disorders. Physiol Behav. 2009;97(5):537-550. 
70. 
Pecina S, Smith KS, Berridge KC. Hedonic hot spots in the brain. Neuroscientist. 
2006;12(6):500-511. 
71. 
Cannon 
CM, 
Palmiter RD. 
Reward 
without 
dopamine. 
J 
Neurosci. 
2003;23(34):10827-10831. 
72. 
Hnasko TS, Sotak BN, Palmiter RD. Morphine reward in dopamine-deficient mice. 
Nature. 2005;438(7069):854-857. 
73. 
Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of 
cytokines in the pathophysiology of major depression. Biol Psychiatry. 
2009;65(9):732-741. 
74. 
Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive 
protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71(2):171-186. 
75. 
Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL. A 
meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67(5):446-
457. 
76. 
Pincus T, Griffith J, Pearce S, Isenberg D. Prevalence of self-reported depression 
in patients with rheumatoid arthritis. Br J Rheumatol. 1996;35(9):879-883. 


Version: 07062020 
52
77. 
Dickens C, Creed F. The burden of depression in patients with rheumatoid arthritis. 
Rheumatology. 2001;40(12):1327-1330. 
78. 
Blume J, Douglas SD, Evans DL. Immune suppression and immune activation in 
depression. Brain Behav Immun. 2011;25(2):221-229. 
79. 
Raison CL, Miller AH. Is depression an inflammatory disorder? Curr Psychiatry 
Rep. 2011;13(6):467-475. 
80. 
Mehta D, Raison CL, Woolwine BJ, Haroon E, Binder EB, Miller AH, Felger JC. 
Transcriptional signatures related to glucose and lipid metabolism predict treatment 
response to the tumor necrosis factor antagonist infliximab in patients with 
treatment-resistant depression. Brain, behavior, and immunity. 2013;31:205-215. 
81. 
Hyman SE. Neuroscience, genetics, and the future of psychiatric diagnosis. 
Psychopathology. 2002;35(2-3):139-144. 
82. 
Hyman SE. The diagnosis of mental disorders: the problem of reification. Annu Rev 
Clin Psychol. 2010;6:155-179. 
83. 
Treadway MT, Buckholtz JW, Cowan RL, Woodward ND, Li R, Ansari MS, 
Baldwin RM, Schwartzman AN, Kessler RM, Zald DH. Dopaminergic 
mechanisms of individual differences in human effort-based decision-making. J 
Neurosci. 2012;32(18):6170-6176. 
84. 
Treadway MT, Buckholtz JW, Zald DH. Perceived stress predicts altered reward 
and loss feedback processing in medial prefrontal cortex. Front Hum Neurosci. 
2013;7:180. 
85. 
Treadway MT, Grant MM, Ding Z, Hollon SD, Gore JC, Shelton RC. Early adverse 
events, HPA activity and rostral anterior cingulate volume in MDD. PLoS ONE. 
2009;4(3):e4887. 
86. 
Treadway MT, Waskom ML, Dillon DG, Holmes AJ, Park MTM, Chakravarty 
MM, Dutra SJ, Polli FE, Iosifescu DV, Fava M. Illness Progression, Recent Stress, 
and Morphometry of Hippocampal Subfields and Medial Prefrontal Cortex in 
Major Depression. Biol Psychiatry. 2014. 
87. 
Raison CL, Borisov AS, Majer M, Drake DF, Pagnoni G, Woolwine BJ, Vogt GJ, 
Massung B, Miller AH. Activation of central nervous system inflammatory 
pathways by interferon-alpha: relationship to monoamines and depression. Biol 
Psychiatry. 2009;65(4):296-303. 
88. 
Rushworth MFS, Kolling N, Sallet J, Mars RB. Valuation and decision-making in 
frontal cortex: one or many serial or parallel systems? Curr Opin Neurobiol. 
2012;22(6):946-955. 
89. 
Hartmann MN, Hager OM, Tobler PN, Kaiser S. Parabolic discounting of monetary 
rewards by physical effort. Behav Processes. 2013;100:192-196. 
90. 
Buckholtz JW, Treadway MT, Cowan RL, Woodward ND, Benning SD, Li R, 
Ansari MS, Baldwin RM, Schwartzman AN, Shelby ES, Smith CE, Cole D, Kessler 
RM, Zald DH. Mesolimbic dopamine reward system hypersensitivity in individuals 
with psychopathic traits. Nat Neurosci. 2010;13(4):419-421. 
91. 
Wu CC, Samanez-Larkin GR, Katovich K, Knutson B. Affective traits link to 
reliable neural markers of incentive anticipation. Neuroimage. 2014;84:279-289. 
92. 
Reader BF, Jarrett BL, McKim DB, Wohleb ES, Godbout JP, Sheridan JF. 
Peripheral and central effects of repeated social defeat stress: Monocyte trafficking, 
microglial activation, and anxiety. Neuroscience. 2015. 


Version: 07062020 
53
93. 
Rutgeerts P, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, 
Rachmilewitz D, Wolf DC, Olson A, Bao W, Hanauer SB. Comparison of 
scheduled and episodic treatment strategies of infliximab in Crohn's disease. 
Gastroenterology. 2004;126(2):402-413. 
94. 
Trivedi MH, Rush AJ, Ibrahim HM, Carmody TJ, Biggs MM, Suppes T, Crismon 
ML, Shores-Wilson K, Toprac MG, Dennehy EB, Witte B, Kashner TM. The 
Inventory of Depressive Symptomatology, Clinician Rating (IDS-C) and Self-
Report (IDS-SR), and the Quick Inventory of Depressive Symptomatology, 
Clinician Rating (QIDS-C) and Self-Report (QIDS-SR) in public sector patients 
with mood disorders: a psychometric evaluation. Psychol Med. 2004;34(1):73-82. 
95. 
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method 
for grading the cognitive state of patients for the clinician. J Psychiatr Res. 
1975;12(3):189-198. 
96. 
First MB, Spitzer RL, Gibbon M, Williams JB. Structured Clinical Interview for 
DSM-IV. Washington DC: American Psychiatric Press; 1997. 
97. 
Chandler GM, Iosifescu DV, Pollack MH, Targum SD, Fava M. RESEARCH: 
Validation of the Massachusetts General Hospital Antidepressant Treatment 
History Questionnaire (ATRQ). CNS Neurosci Ther. 2010;16(5):322-325. 
98. 
Fava M. Diagnosis and definition of treatment-resistant depression. Biol 
Psychiatry. 2003;53(8):649-659. 
99. 
Sachs GS. Strategies for improving treatment of bipolar disorder: integration of 
measurement and management. Acta Psychiatr Scand. 2004;110(s422):7-17. 
100. 
Knutson B, Bhanji JP, Cooney RE, Atlas LY, Gotlib IH. Neural responses to 
monetary incentives in major depression. Biol Psychiatry. 2008;63(7):686-692. 
101. 
Knutson B, Cooper JC. Functional magnetic resonance imaging of reward 
prediction. Curr Opin Neurol. 2005;18(4):411-417. 
102. 
Knutson B, Fong GW, Bennett SM, Adams CM, Hommer D. A region of mesial 
prefrontal cortex tracks monetarily rewarding outcomes: characterization with 
rapid event-related fMRI. Neuroimage. 2003;18(2):263-272. 
103. 
Samanez-Larkin GR, Gibbs SE, Khanna K, Nielsen L, Carstensen LL, Knutson B. 
Anticipation of monetary gain but not loss in healthy older adults. Nat Neurosci. 
2007;10(6):787-791. 
104. 
Sutton RS, Barto AG. Reinforcement Learning: An Introduction. Cambridge, MA: 
MIT Press; 1998. 
105. 
Luce RD. Individual choice behavior: a theoretical analysis. New York, NY: 
Wiley; 1959. 
106. 
Palminteri S, Justo D, Jauffret C, Pavlicek B, Dauta A, Delmaire C, Czernecki V, 
Karachi C, Capelle L, Durr A, Pessiglione M. Critical roles for anterior insula and 
dorsal striatum in punishment-based avoidance learning. Neuron. 2012;76(5):998-
1009. 
107. 
Chase HW, Fournier JC, Greenberg T, Almeida JR, Stiffler R, Zevallos CR, Aslam 
H, Cooper C, Deckersbach T, Weyandt S. Accounting for Dynamic Fluctuations 
across Time when Examining fMRI Test-Retest Reliability: Analysis of a Reward 
Paradigm in the EMBARC Study. 2015. 


Version: 07062020 
54
108. 
Wardle MC, Treadway MT, de Wit H. Caffeine increases psychomotor 
performance on the effort expenditure for rewards task. Pharmacol Biochem Behav. 
2012;102(4):526-531. 
109. 
Frank MJ, Moustafa AA, Haughey HM, Curran T, Hutchison KE. Genetic triple 
dissociation reveals multiple roles for dopamine in reinforcement learning. 
Proceedings of the National Academy of Sciences. 2007;104(41):16311-16316. 
110. 
Frank MJ, Samanta J, Moustafa AA, Sherman SJ. Hold your horses: impulsivity, 
deep 
brain 
stimulation, 
and 
medication 
in 
parkinsonism. 
Science. 
2007;318(5854):1309-1312. 
111. 
Turi Z, Mittner M, Opitz A, Popkes M, Paulus W, Antal A. Transcranial direct 
current stimulation over the left prefrontal cortex increases randomness of choice 
in instrumental learning. Cortex. 2015;63:145-154. 
112. 
Spreen O, Strauss, E. A Compendium of Neuropsychological Tests. New York: 
Oxford University Press; 1991. 
113. 
Aparicio P, Diedrichsen J, Ivry RB. Effects of focal basal ganglia lesions on timing 
and force control. Brain Cogn. 2005;58(1):62-74. 
114. 
Majer M, Welberg LA, Capuron L, Pagnoni G, Raison CL, Miller AH. IFN-alpha-
induced motor slowing is associated with increased depression and fatigue in 
patients with chronic hepatitis C. Brain Behav Immun. 2008;22(6):870-880. 
115. 
Joy S, Fein D, Kaplan E. Decoding digit symbol: speed, memory, and visual 
scanning. Assessment. 2003;10(1):56-65. 
116. 
Bermel RA, Bakshi R, Tjoa C, Puli SR, Jacobs L. Bicaudate ratio as a magnetic 
resonance imaging marker of brain atrophy in multiple sclerosis. Arch Neurol. 
2002;59(2):275-280. 
117. 
Starkstein SE, Brandt J, Folstein S, Strauss M, Berthier ML, Pearlson GD, Wong 
D, McDonnell A, Folstein M. Neuropsychological and neuroradiological correlates 
in Huntington's disease. J Neurol Neurosurg Psychiatry. 1988;51(10):1259-1263. 
118. 
Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of 
Depressive Symptomatology (IDS): psychometric properties. Psychol Med. 
1996;26(3):477-486. 
119. 
Wildocher D, Ghozlan, A. The measurement of retardation in depression. In: 
Hindmarch I, Stonier, P.D., ed. Human Psychopharmacology. Vol 2. New York: 
John Wiley and Sons; 1989:1-22. 
120. 
Bonin-Guillaume S, Sautel L, Demattei C, Jouve E, Blin O. Validation of the 
Retardation Rating Scale for detecting depression in geriatric inpatients. Int J 
Geriatr Psychiatry. 2007;22(1):68-76. 
121. 
Smith RS, Maes M. The macrophage-T-lymphocyte theory of schizophrenia: 
additional evidence. Medical Hypotheses. 1995;45(2):135-141. 
122. 
Leventhal AM, Chasson GS, Tapia E, Miller EK, Pettit JW. Measuring hedonic 
capacity in depression: a psychometric analysis of three anhedonia scales. J Clin 
Psychol. 2006;62(12):1545-1558. 
123. 
Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue 
Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J 
Psychosom Res. 1995;39(3):315-325. 
124. 
Capuron L, Pagnoni G, Drake DF, Woolwine BJ, Spivey JR, Crowe RJ, Votaw JR, 
Goodman MM, Miller AH. Dopaminergic mechanisms of reduced basal ganglia 


Version: 07062020 
55
responses to hedonic reward during interferon alfa administration. Arch Gen 
Psychiatry. 2012;69(10):1044-1053. 
125. 
Llerena K, Park SG, McCarthy JM, Couture SM, Bennett ME, Blanchard JJ. The 
Motivation and Pleasure Scale–Self-Report (MAP-SR): Reliability and validity of 
a self-report measure of negative symptoms. Compr Psychiatry. 2013;54(5):568-
574. 
126. 
Watson D, Clark LA, Tellegen A. Development and validation of brief measures 
of positive and negative affect: the PANAS scales. J Pers Soc Psychol. 
1988;54(6):1063-1070. 
127. 
Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. 
Application to patients with multiple sclerosis and systemic lupus erythematosus. 
Arch Neurol. 1989;46(10):1121-1123. 
128. 
Dittner AJ, Wessely SC, Brown RG. The assessment of fatigue: a practical guide 
for clinicians and researchers. J Psychosom Res. 2004;56(2):157-170. 
129. 
Brydon L, Harrison NA, Walker C, Steptoe A, Critchley HD. Peripheral 
inflammation is associated with altered substantia nigra activity and psychomotor 
slowing in humans. Biol Psychiatry. 2008;63(11):1022-1029. 
130. 
Huber W, von Heydebreck A, Sultmann H, Poustka A, Vingron M. Variance 
stabilization applied to microarray data calibration and to the quantification of 
differential expression. Bioinformatics. 2002;18 Suppl 1:S96-104. 
131. 
Johnson WE, Li C, Rabinovic A. Adjusting batch effects in microarray expression 
data using empirical Bayes methods. Biostatistics. 2007;8(1):118-127. 
132. 
Potter DM. A permutation test for inference in logistic regression with small- and 
moderate-sized data sets. Stat Med. 2005;24(5):693-708. 
133. 
Felger JC, Li Z, Haroon E, Woolwine B, Jung MY, Hu X, Miller AH. Inflammation 
is associated with decreased functional connectivity within corticostriatal reward 
circuitry. Mol Psychiatry. in press. 
134. 
Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M. Cumulative meta-
analysis of interleukins 6 and 1 b, tumour necrosis factor a and C-reactive protein 
in patients with major depressive disorder. Brain Behav Immun. 2015;49:20. 
135. 
Friston KJ, Buechel C, Fink GR, Morris J, Rolls E, Dolan RJ. Psychophysiological 
and modulatory interactions in neuroimaging. Neuroimage. 1997;6(3):218-229. 
136. 
Cole SW, Yan W, Galic Z, Arevalo J, Zack JA. Expression-based monitoring of 
transcription factor activity: the TELiS database. Bioinformatics. 2005;21(6):803-
810. 
137. 
Cole SW, Hawkley LC, Arevalo JM, Cacioppo JT. Transcript origin analysis 
identifies antigen-presenting cells as primary targets of socially regulated gene 
expression in leukocytes. Proc Natl Acad Sci U S A. 2011;108(7):3080-3085. 
138. 
Felger JC, Cole SW, Pace TW, Hu F, Woolwine BJ, Doho GH, Raison CL, Miller 
AH. Molecular signatures of peripheral blood mononuclear cells during chronic 
interferon-alpha treatment: relationship with depression and fatigue. Psychol Med. 
2011:1-13. 
139. 
Preacher KJ, Hayes AF. Asymptotic and resampling strategies for assessing and 
comparing indirect effects in multiple mediator models. Behav Res Methods. 
2008;40(3):879-891. 


Version: 07062020 
56
140. 
Gitelman DR PW, Ashburner J, Friston KJ. Modeling regional and 
psychophysiologic interactions in fMRI: the importance of hemodynamic 
deconvolution. Neuroimage. 2003;19(1):200-207. 
141. 
Braver TS, Cole MW, Yarkoni T. Vive les differences! Individual variation in 
neural mechanisms of executive control. Curr Opin Neurobiol. 2010;20(2):242-
250. 
142. 
Liu G, Liang K-Y. Sample size calculations for studies with correlated 
observations. Biometrics. 1997:937-947. 
143.     Gross, R., Matthews, I., Cohn, J., Kanade, T., & Baker, S. (2010). Multi-PIE. 
Image and Vision Computing, 28, 807-813. 
144.     Hamilton, M. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 
56-62 (1960). 
145.  Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as 
an outcome measure for insomnia research. Sleep Med. 2001;2:297–307 
 
 
 
 

ICF_001.pdf: 
Dynamics of Inflammation and its Blockade on Motivational Circuitry 
in Depression
Date: 11/26/2019
NCT03006393
IRB00087941


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 1 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
You Are Being Asked to Be in a Research Study
What Is a Research Study?
The main purpose of research studies is to gain knowledge. This knowledge may be used to 
help others. Research studies are not intended to benefit you directly, though some might.  
Do I Have to Do This?
No. Being in this study is entirely your choice.  If you decide to join this study, you can 
change your mind later on and withdraw from the research study.
Taking part in a study is separate from medical care. The decision to join or not join the 
research study will not affect your status as a patient.  
What Is This Document? 
This form is an informed consent document. It will describe the study risks, procedures, and 
any costs to you.
This form is also a HIPAA Authorization document. It will describe how your health information 
will be used and by whom.
Signing this form indicates you are willing to take part in the study and allow your health 
information to be used.
What Should I Do Next?
1. Read this form, or have it read to you.
2. Make sure the study doctor or study staff explains the study to you.
3. Ask questions (e.g., time commitment, unfamiliar words, specific procedures, etc.)
4. If there will be medical treatment, know which parts are research and which are
standard care.
5. Take time to consider this, and talk about it with your family and friends.
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 2 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
Emory University
Consent to be a Research Subject / HIPAA Authorization 
Title: Infliximab
Principal Investigator: Michael Treadway, PhD
Sponsor: National Institute of Mental Health (NIMH)
Introduction
You are being asked to be in a medical research study. This form is designed to tell you everything you need to think 
about before you decide if you want to be a part of the study.  It is entirely your choice.  If you decide to take part, you 
can change your mind later on and withdraw from the research study. The decision to join or not join the research 
study will not cause you to lose any medical benefits.  If you decide not to take part in this study, your doctor will 
continue to treat you.
Before making your decision:
•
Please carefully read this form or have it read to you
•
Please listen to the study doctor or study staff explain the study to you
•
Please ask questions about anything that is not clear
You can take a copy of this consent form, to keep. Feel free to take your time thinking about whether you would like to 
participate. You may wish to discuss your decision with family or friends. Do not sign this consent form unless you have 
had a chance to ask questions and get answers that make sense to you.  By signing this form you will not give up any 
legal rights.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This Web site 
will not include information that can identify you. At most the Web site will include a summary of the results. You can 
search this Web site at any time.
What is the purpose of this study?
You are being asked to volunteer for a research study because you have been diagnosed with major depression or 
because you are participating as a healthy volunteer. The main purpose of this study is to examine the effects of a 
medicine called infliximab on measures related to depression symptoms. Infliximab is also known by its brand name 
Remicade. Infliximab, or Remicade, is given to people by an IV needle. It is currently used to treat two illnesses: 
rheumatoid arthritis and Crohn’s disease. Infliximab is thought to help these conditions because it reduces inflammation 
in the body. Infliximab (Remicade) reduces inflammation by blocking a chemical in the body called tumor necrosis factor 
(TNF)-alpha. This chemical produces inflammation. Inflammatory chemicals in the body like TNF-alpha appear to be 
increased in some people with major depression. Researchers think that a drug like infliximab, which blocks TNF-alpha, 
may be helpful in treating depression. The Food and Drug Administration has not approved infliximab for treating 
depression.  We plan to enroll up to 140 participants for this study.
Note: In some cases we will use a medicine similar to Infliximab in its place. This medicine, Inflectra, is an Infliximab 
biosimilar. This means that Inflectra is very similar to Infliximab but is not identical. While there may be some small 
differences between Inflectra and Infliximab, there are no clinically important differences in terms of safety and purity of 
the medicine. Inflectra is approved by the FDA for the same conditions as Infliximab. Please note each time you see 
Infliximab mentioned in this form, that Inflectra may be used instead.
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 3 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
What will I be asked to do? 
All procedures that you will be involved with in this study are experimental, except for the drawing of blood for routine 
laboratory tests to make sure you are not having a bad reaction to the study medicine. 
Before you can participate in this study, you will need to come in for screening to see if you are able to enter the study. 
The investigator and/or the investigator’s staff will ask you questions and run tests to determine if you are able to enter 
the study. These tests are described below. It is important that you answer all of the questions honestly and completely. 
If your condition or situation changes during the study, you must tell the investigator.
To be in this study, you must be off all antidepressant treatments for at least 8 weeks before the baseline visit. You 
cannot enroll in this study if you have had an antidepressant more recently than this period. If you are doing well on 
antidepressant medicine, you will not be able to be in this study. It would not be in your best interest to stop medicine 
that is helping you. If you have any questions or concerns about this, please speak with your physician or the study 
doctor. 
You will not be able to enter the study if you are chronically taking a benzodiazepine at a dosage that is more than the 
equivalent of 2 milligrams a day of lorazepam. 
If you plan to take any medicine or receive any medical treatment other than taking the study infusion given to you, 
please tell the study staff before starting the medicine or treatment. This includes medicines given to you or suggested 
by any other doctor. It also includes over-the-counter drugs. For example, cough treatments, cold treatments, pain 
medicines such as aspirin or ibuprofen, investigational drugs/procedures and sleeping medicines. If you plan to undergo 
elective surgery or a diagnostic procedure, you must tell the study staff before the procedure is performed. 
You will be asked not to take the following medicines during the study: 
•
Aspirin
•
Non-steroidal anti-inflammatory agents (such as ibuprofen or naproxen)
•
COX-2 inhibitors (such as Celebrex or Bextra) during the study.
Use of these medicines may affect study findings. It is ok to use Tylenol during the study. However, please remember to 
tell the study staff if you’ve used this or any other medicines during the study. Please ask a study staff member if you are 
unsure if a medication you take falls in to one of the categories described above.  You will receive a take-home 
instruction sheet that will remind you which medicines you should avoid while you are in this study. If you take one of 
these medications, whether on accident, out of necessity, or for any other reason, please contact the study team right 
away. The information sheet has contact information you can use to reach a member of the study staff. If you cannot 
reach the study team or need assistance after hours or on weekends/holidays, please call the Emory Clinic Operator at 
404-778-5000 and ask them to page Bobbi Woolwine, LCSW at PIC# 15375. If you feel it is a medical emergency, please 
go to the nearest emergency room.  
Although it is recommended that you do not drink alcoholic drinks during your participation in the study,
you may drink alcohol on occasion (at most 1 glass of wine or equivalent per day). Use of illegal drugs during your 
participation in the study is not allowed. You will be drug-tested at each study visit for illegal drugs as part of this study. 
If the study investigators (Dr. Treadway, Dr. Miller or their designees) decide that your depression has gotten worse at 
any time during the study, you may be asked to leave the study. 
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 4 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
During this study you will interact with study investigators and doctors. You will also interact with research clinicians 
trained to administer psychiatric questionnaires and nurses trained to infuse drugs like infliximab. You will also interact 
with research coordinators who will help arrange your schedule during the study. A table of study events is provided 
below:
Schedule of Visits 
Visit
Visit Overview
Pre-Screening Visit
•
Self-report questionnaires
•
Blood work and/or finger stick
Screening Visit(s)
•
Clinical interview
•
Self-report questionnaires
•
Behavioral tasks
•
Chest X-Ray
•
EKG
•
Laboratory testing
•
Blood work
•
Urine test
•
Urine pregnancy test (if applicable)
•
Urine drug test
*Note that assessments completed during one Screening Visit will not be repeated at
another. However, assessments will be repeated if deemed necessary under PI and/or
study physician advisement.
*Note that healthy controls will undergo all pre-screening and screening procedures as
subjects, except that they will not receive a Chest X-Ray, EKG, or Quantiferon Gold TB
Test
Optional Scan Visit

Behavioral tasks

MRI Scan

Blood work

Urine drug test

Urine pregnancy test (if applicable)
Infusion Visit
•
Clinical interview
•
Self-report questionnaires
•
Medical follow-up (F/U) assessment
•
Medical history
•
Laboratory testing
•
Behavioral tasks
•
Blood work
•
Urine test
•
Urine drug test
•
MRI scan (if not performed previously)
•
Infliximab or Placebo (salt water) Infusion
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 5 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
Schedule of Visits (continued)
Optional 24 Hour Visit
•
Clinical interview
•
Self-report questionnaires
•
Medical F/U assessment
•
Blood work
•
Vital signs
•
Urine drug test
•
Urine pregnancy test (if applicable)
3 Day Visit
•
Clinical interview
•
Self-report questionnaires
•
Medical F/U assessment
•
Behavioral tasks
•
Blood work
•
Vital signs
•
Urine drug test
•
Urine pregnancy test (if applicable)
Optional 7 Day Visit
•
Clinical interview
•
Self-report questionnaires
•
Medical F/U assessment
•
Behavioral tasks
•
Blood work
•
Vital signs
•
Urine drug test
•
Urine pregnancy test (if applicable) 
14 Day Visit
•
Clinical interview
•
Self-report questionnaires
•
Medical F/U assessment
•
Laboratory testing
•
Behavioral tasks
•
Blood work
•
Vital signs
•
Urine drug test
•
Urine pregnancy test (if applicable)
•
MRI scan
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 6 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
Abbreviations: EKG – electrocardiogram, CXR – chest x-ray, MRI scan – magnetic resonance imaging scan
If you agree to be in the study, this is what will happen.
To be in this study, you will have to complete up to three screening visits for the study staff to review and verify your 
eligibility. At the first screening visit, we will ask you to complete a short questionnaire. We will also draw some of your 
blood to measure a marker of inflammation called C-reactive protein. This could also be done using a finger stick.  
Over all of the study visits, we will draw about 67 teaspoons of blood. 
The following procedures will happen at additional screening visits, depending on your schedule and study staff 
availability. A study clinician or trained study staff member will ask you some questions about your mental health and 
psychiatric treatment history. A study doctor or nurse will review your medical history with you and will also conduct a 
physical examination. You will receive an electrocardiogram (EKG) and a chest x-ray to make sure you have no heart 
abnormalities. Also, some of your blood will be drawn to check for any abnormalities that would exclude you for study 
participation. This includes testing for the human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C 
virus (HCV). You will be excluded from the study and referred to your primary care physician should you test positive for 
any of these abnormalities. At the screening visits, you will also complete some questionnaires and behavioral 
assessments. 
Note: If you have previously participated in another research study from our group, you may not have to complete some 
of the procedures in this study described under “Pre-Screening” and “Screening” if the results are still valid from the 
previous study. For your safety, however, some of these procedures may need to be re-done.
A marker of inflammation called C-reactive protein will also be measured in your blood. You will also have a tuberculosis 
blood test. This test requires a small blood draw. If this test is positive for tuberculosis you will not be able to enter the 
study. The study investigator will recommend that you contact your primary care doctor for a referral to a TB specialist. 
You will be excluded from the study if you have TB and need INH treatment. You will also receive a pregnancy blood test 
at your first screening visit if you are a female. At following visits, you will receive a urine pregnancy test. You will be 
excluded from the study if you are pregnant.  We will ask you, regardless of if you are a man or a woman, to complete a 
form about the birth control you and your partner will use during the study period.  The screening process will take in 
total about 7-8 hours spread out over two-three visits. It will occur at the Emory Clinic Building A and/or B, 1327 Clifton 
Rd, the Emory Department of Psychology, and/or the Atlanta Clinical Translational Science Institute (ACTSI) in the Emory 
University Hospital. You are strongly encouraged to ask the study investigator or a member of the study staff questions 
about the results of your lab tests and other diagnostic procedures.
If you qualify for the study and choose to enroll you will participate in 6-8 visits across about 2 weeks (depending on 
scheduling and other factors). All study visits will take place at one or more of the following places at Emory: Emory 
Clinic Building A and B, 1327 Clifton Road, the Emory Department of Psychology, and/or the ACTSI in the Emory 
University Hospital. At all visits a study clinician will ask you questions about symptoms of depression using a 
standardized interview. You will also fill out several self-report questionnaires. These will ask about depressive 
symptoms and about the quality of your life. We will analyze your blood to see whether a decrease in depression after 
30 Day Phone Call
•
Clinical interview
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 7 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
the infliximab infusion is linked to a decrease in inflammation chemicals. On the day of the infusion and the follow-up at 
14 days, you will start your visit either at the Emory Department of Psychology or Emory Clinic Building A or Building B. 
On these days you may also go to the outpatient area in the ACTSI. The infusion may occur at either the ACTSI in the 
Emory University Hospital, or an infusion center in Emory Clinic Building A.  For screening and all other follow-up visits, 
you will begin your study visit either at the Emory Department of Psychology or Emory Clinic Building A or B. On these 
days you may also go with the study coordinator to other places in the Emory Clinic or Emory University Hospital, like 
Cardiology, if certain tests and procedures are scheduled for that visit.  The infusion study visit (including MRI scan) will 
take about 7-8 hours If you complete the MRI scan and infusion at separate visits, those visits will be about 2-3 hours 
and 5-6 hours respectively. The study visits at 24 hours (optional), 3 days, and 7 days (optional) after infusion will take 
about 3 hours. The study visit at 14 days after infusion will take about 5 hours. At each of these visits your blood will be 
drawn to do routine laboratory checks and also for research purposes.
Please note: You may be asked to complete a blood draw at each visit. The study investigators, including the study 
physicians, may decide it is in your best interest—and in the interest of safety—to repeat a test or collect a new test.
At screening and other visits, you will be asked to supply about 10 tablespoons of urine in a special cup. We may use the 
urine sample you provide to do a test to look for the presence of drugs of abuse, such as marijuana, cocaine or heroin. A 
positive test for any of these drugs at screening will prevent you from being in the study. We will also use the urine 
sample from this cup to test for the presence of a urinary tract infection (UTI). A positive urine test for drugs or a UTI at 
any visit may be a reason for withdrawing you from this study. 
After the urine sample is collected, we may send the sample to a partner laboratory at Emory to conduct some further 
tests. If the sample collected at screening is not sufficient or a sample cannot be collected at that visit, we may ask you 
for another sample at a following visit. The researchers in this partner lab may take the cells from your urine to create 
something called induced pluripotent stem cells (iPSC). Using certain techniques, researchers can “reprogram” adult 
cells from urine and other sources to act like embryonic stem cells. These cells can then be directed to develop into 
specific types of cells in the body, like those found in the brain. For more information on how the cells from your urine 
sample may be used for this purpose, please see the section “How samples and/or data might be used”.
If the urine or blood sample we collect is not sufficient for the further testing we may conduct or if we do not ask you to 
provide a urine or blood sample at your visit, we may ask you if you are willing to return to the lab to provide a sample. 
Our study team will measure your vital signs, including pulse and blood pressure. These will be recorded lying down 
and/or standing at most visits. Your height, weight, and waist circumference (girth) will be measured during screening 
and your infusion visits. Further, head circumference and size as well as eye prescription strength may be recorded in 
order to prepare for the MRI scan.
Given constraints of time and study staff availability, we may complete the MRI scan portion of the infusion visit one day 
before the scheduled infusion. This will also depend, when possible, on your preference for scheduling the visits.
At or after your screening visit(s), a study staff member may ask you if you are interested in completing further 
assessments for the study through a mobile application. If you are interested, we may ask you to download the mobile 
app and complete brief questionnaires and/or behavioral tasks. We may ask you to complete assessments 1-5 times per 
day after your screening visit through up to 2 weeks after your final follow-up visit. Your compensation for this 
component of the study will depend on how many assessments you complete and your choices and performance in the 
behavioral tasks through the app. 
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 8 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
At the study visit on the day of the infusion, you will be randomly assigned (similar to a flip of a coin) to receive either 
infliximab or placebo (an inactive compound). As part of the study you will receive one infusion. The placebo will be salt 
water. You have a one in two chance of receiving infliximab and a one in two chance of receiving placebo. If you receive 
infliximab, your dose will be 5 milligrams for every kilogram of your body weight. The infusion will occur after your 
Screening visits and will take place at either an infusion center at Emory Clinic Building A or the ACTSI. You will sit in a 
special chair and a trained nurse will place an intravenous (iv) needle in a vein in your arm.  Some of your blood will be 
drawn through the IV for routine labs and for research purposes before you receive the infusion, as described above.
Neither you nor the study investigator will know whether you receive infliximab or placebo. This is because all subjects 
will receive their infusions from identical looking bags that have been specially prepared for the study.  However, if a 
medical emergency occurs, the information about whether you received infliximab or placebo is available to the study 
investigator. The IV bags with either infliximab or placebo will be prepared in a separate room. The bag will be 
connected to the IV in your arm. It will take about 2 hours for the infusion to be completed. You will be monitored for 
any type of bad reaction, such as an allergic response, during the infusion and for about 10-20 minutes afterwards. The 
nurse at the center you receive the infusion or one of the nurses or doctors on the study team may ask you to stay 
longer if they think it is best for your safety.
During the infusion visit, a study nurse or doctor will review your medical history with you and also complete follow-up 
assessment. For example, the nurse or doctor may ask you if there has been any change in the medications you take. A 
trained study staff member will complete a clinical interview with you and ask you about any bad reactions to a study 
procedure. Your height, weight, and vital signs will be recorded again at this visit. You will be asked to supply about 4 
tablespoons of urine in a special cup. This will test for the presence of drugs of abuse, such as marijuana, cocaine or 
heroin. A positive test for any of these drugs at screening will prevent you from participating in the study. A positive test 
at any other visits may be a reason for withdrawing you from this study. Also, you will be asked to supply about 4 
tablespoons of urine in the same or a different cup that will be used to test for the presence of a urinary tract infection. 
You will also complete some questionnaires and behavioral tasks on a computer if there is time. 
Before you receive the infusion, a nurse or doctor from the study team or infusion center may ask you to take a 
medicine that could help prevent a bad reaction from the study drug. The medicine(s) you may be asked to take would 
be Tylenol, Benadryl, and/or Pepcid. 
If you have a bad reaction to the study drug, the nurses at the site you receive the infusion are trained to help you. The 
nurse would follow a special protocol that includes steps for stopping the infusion, giving you some oxygen, and giving 
you some medicine (Benadryl, Pepcid, and/or adrenaline). 
Please ask the study nurse or doctor if you have any questions or concerns about the medicines you may be asked to 
take before or after the infusion. Any medicine you would be asked to take would be to help prevent or make better any 
symptoms you were having from the infusion. 
At the infusion and 14-day visits, we will also do an MRI scan.  The scanning session may include several different types 
of scans: structural, diffusion tensor imaging, MR spectroscopy (MRS), and functional scans. For this part of the visit, a 
study staff member will escort you to or meet you at the Facility for Education and Research in Neuroscience (FERN) on 
the Emory main campus. The MRI scan will last for about 90 minutes. Before the MRI scan, we will ask you some 
questions to make sure it is safe for you to have an MRI.
Note: Based on scheduling and your preference, the first MRI scan may be completed the day before the infusion visit.  
To be scanned, you will be asked to remove all jewelry and other metal-containing objects (including credit cards). You 
will enter a large room where a powerful magnet is located. You will be asked to lie down on a narrow table and then 
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 9 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
you will be put in a small tunnel about 6 feet long and 2 feet in diameter. You will then be asked to lie as still as possible 
during the scan. You will be wearing headphones and a small mirror will be positioned above your head so you will be 
able to see out the end of the scanner. During scanning, you will hear a loud banging noise as the MRI machine takes 
pictures of your brain. This is normal. You will be given earplugs to make you more comfortable. If you feel 
uncomfortable at any point, the MRI scanner has a microphone and you can ask us to stop the scanning procedure 
without penalty.
You will be getting a scan for research purposes only.  The research does not require health professionals to read the 
scan. The researchers are not qualified to interpret the images for healthcare purposes. Do not rely on the scan for 
clinical or diagnostic purposes.  However, if the researchers have a question about something they see on the scan they 
will tell you, and ask you if you want the scan sent to a qualified health professional for review and any further medical 
treatment.   You or your insurance company may have to pay for the review and any such treatment.
During the scan, we may ask you to rate certain things by pressing buttons on a box.  For example, we may ask you to 
rate how you are feeling at the moment. We may also ask you to do one or more computer tasks while in the MRI 
scanner. 
You will be able to hear and speak to the research staff at all times during the scan.  If you become uncomfortable or 
want to stop the scan for any reason, just tell us. We will stop the scanning process immediately. 
Visits at 24 hours (Optional), 3 days, 7 days (Optional), and 14 days post-infusion will involve completing questionnaires 
asking about symptoms and side effects. A nurse practitioner or trained study staff member may also ask you questions 
about your symptoms and any changes you may have experienced during the study. A nurse practitioner may also 
complete a physical examination with you. Each of these visits will require about 2-3 hours of your time. At each of these 
visits some of your blood will be drawn to do routine laboratory checks and also for research purposes.
At your study visit on the day of screening, infusion and at 3, 7 (Optional), and 14 days post infusion, you will also be 
asked to complete a series of decision-making tasks. On the infusion day and 14-day visits, you may complete some of 
these tasks while in the MRI scanner. The tasks will require you to select different options using different buttons. Some 
tasks will require you to make your responses very rapidly. 
Around one month after the infusion, you will receive a follow-up phone call from a study staff member. He or she will 
ask you questions to make sure you have not had a bad reaction to anything that happened in the study.
Participants recruited as healthy controls will undergo a shortened version of the study protocol consisting of pre-screening 
and screening visits, as well as a scan visit. Healthy controls will go through a pre-screen and screening process that will 
consist of psychiatric evaluations, research and safety labs, and baseline assessments (clinician-rated assessments, self-
reports, behavioral tasks).  The pre-screening and screening procedures will be identical to those a subject goes through, 
except that a healthy control will not receive a Chest X-Ray, EKG, or Quantiferon Gold TB Test. Healthy controls will 
undergo a scan visit as well. It is important to note, however, that healthy controls will not receive any drug or any infusion.
How will the study medicine be provided? 
The study medicine that you will take will be dispensed by the pharmacy and delivered to the principal investigator or 
study team member.  The principal investigator or health care providers on his/her research team will provide the 
medicine to you.  If you have questions about the medicine, you should ask one of the study doctors or either of the 
study nurses. If you have an urgent question or concern related to the study medicine after normal business hours, 
please contact the Emory Clinic operator 
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 10 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
The Food and Drug Administration (FDA) issued a Black Box Warning for this medicine because patients in treatment 
with this product are at increased risk of infections. This includes a worsening of symptoms that may lead to 
hospitalization or death. Please read the possible side effects in the table on the next page.
Who owns my study information and samples?
If you join this study, you will be donating your samples and study information.  You will not receive any compensation if 
your samples or information are used to make a new product. If you withdraw from the study, data and samples that 
were already collected may be still be used for this study. Urine samples will be safely disposed of immediately after 
each drug or pregnancy test is completed. Dr. Michael Treadway, the primary investigator, will own the research blood 
samples drawn in this study. Any study samples collected at ACTSI or the Emory Medical Lab (EML) will be managed by 
that facility.
What are the possible risks and discomforts?
This study is designed to test the effects of a medicine called infliximab on measures related to depression symptoms. 
The use of infliximab to treat major depression has not been approved by the Food and Drug Administration. There is no 
information regarding side effects or serious reactions to infliximab in medically healthy patients who receive infliximab. 
Some side effects and more serious reactions to infliximab have been reported in patients receiving the medication 
medicine for the treatment of rheumatoid arthritis or Crohn’s disease. 
Possible Side Effects of Infliximab
Other Important Risk Information to Consider
•
Most of the possible rare side effects described in the table occurred in patients who were taking other
medicines that suppress the immune system while they were taking infliximab. If you choose to enter this study 
Rare Side Effects (less than 1% of 
patients)
Occasional Side effects (1-10% of 
patients)
Frequent (10-50% of patients)
Severe immediate allergic reaction
Shortness of breath
Mild allergic reaction
Delayed allergic response to medicine
Itchy skin
Stomach pain
Serious bacterial infection
Chest pain
Nausea 
Tuberculosis
An abscess
Diarrhea
Fungal infection
Insomnia
Heartburn
Death
Depression
Upper respiratory tract infection
Oral thrush 
Sore throat
Sinusitis (sinus infection)
Coughing
Runny nose
Rash
Fatigue
Fever
Headache
Joint pain
Back pain
Urinary tract infection
Hypertension
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 11 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
you will be tested for tuberculosis using the Quantiferon Gold blood test. If this test is positive you will not be 
able to participate in the study. 
•
At screening you will be asked if you have any symptoms of infection or if you have a history of any chronic or 
serious infections. If you do, you will be excluded from the study. 
•
An increased risk of infection has been noted in patients taking drugs like infliximab who are also taking a drug 
called anakinra. If your doctor has prescribed anakinra for you, you will not be eligible for this study. 
Possible Allergic/Delayed Reactions to Infliximab
Symptoms of severe immediate 
allergic reaction
Symptoms of serious delayed reaction
Hives (red, raised, itchy patches of 
skin)
Fever 
Difficulty breathing
Rash
Chest pain
Headache
High or low blood pressure
Muscle or joint pain
Symptoms of severe immediate allergic reaction to infliximab can include hives (red, raised, itchy patches of skin), 
difficulty breathing, chest pain and high or low blood pressure. Symptoms of serious delayed reaction may include fever, 
rash, headache, and muscle or joint pain. If allergic symptoms occur during or immediately after the infusion you will be 
evaluated by a study physician who is expert at treating these symptoms. There is a standard procedure in place for 
treating allergic reactions at either of the locations you might receive the infusion. If you develop symptoms of a delayed 
reaction at home, or if you develop any of the negative health events listed above, you should contact the study clinician 
immediately. To do this, call the Emory Clinic operator (available 24 hours a day) at 
 
. The study coordinator will give you an emergency information contact card to keep 
in your wallet.
Congestive heart disease
•
Infliximab has been reported to worsen a condition called congestive heart disease and to lead to increased 
deaths in patients with this condition. You will be asked about any history of heart disease. 
•
In addition, you will receive an electrocardiogram (EKG) at the Emory Clinic or ACTSI. This test checks if your 
heart is working normally. 
•
To be enrolled in this study, you will need to have a normal EKG and no history of heart disease. 
•
No known risks are connected to the EKG screening test. However, it is possible the gel or tape, used in the 
procedure, may cause skin irritation at the site of the electrode(s).
Decrease in white and red blood cells
•
Infliximab has been rarely connected to a decrease in white and red blood cells, as well as platelets. 
•
There have been reports of death from these blood cell abnormalities in patients taking infliximab. However, it 
has not been proven that infliximab directly caused these abnormalities. 
•
You will have your blood cells examined before and after the infusion during the study. This test will occur at 
each assessment visit. If your red or white blood cells or platelets are abnormal before the infusion you will be 
excluded from the study. 
Central nervous system conditions
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 12 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
•
In rare cases, Infliximab has been connected to a variety of central nervous system conditions. These include
inflammation of the nerves of the eye, seizures or a condition like multiple sclerosis.
•
The study investigator will ask you about any history of central nervous system disorders, such as multiple
sclerosis or seizures. If you have a history of a central nervous system illness such as multiple sclerosis, Guillain-
Barre syndrome or seizures, or have tingling or numbness in any part of your body, you will be excluded from
study participation.
Allergic reaction to handling rodents and/or taking medicines made from mouse chemicals
•
You will be asked if you have ever had an allergic reaction from being around, or handling rodents. If you have
had such an allergic reaction you will not be able to be in this study. 
•
You will also be asked if you have ever had an allergic reaction to medicines made from mouse chemicals. These
medicines include basiliximab (Simulect), daclizumab (Zenapax), gemtuzumab ozogamicin (Mylotarg), rituximab 
(Rituxan) and trastuzumab (Herceptin). These medicines are used for cancer and to stop transplanted organs 
from being rejected from the body. If you have ever had an allergic reaction to any of these medicines you will 
not be able to be in this study. 
Autoimmune conditions
•
Infliximab may increase the risk of developing an autoimmune condition like systemic lupus erythematosis or
multiple sclerosis. But, this has not been proven. 
•
At screening you will be asked whether you have a history of any autoimmune related disorders, including lupus
and multiple sclerosis. This also includes other conditions such as Crohn’s disease, ulcerative colitis, rheumatoid 
arthritis, ankylosing spondilitis, scleroderma, thyroid or parathyroid disease or sarcoid. 
•
If you have a history of any autoimmune condition you will not be eligible for this study.
Live virus vaccines
•
It is not known whether receiving infliximab would increase the risks involved in receiving a modified live virus
vaccine. For this reason you will be asked about whether you have received a vaccine within four weeks of study 
entry. 
•
You will also be asked if you plan to receive a vaccine during the study or for a month afterwards. It is very
important that you not receive any modified live virus vaccines for a month before the study, during the study 
and for at least one month after you have finished the study. 
•
You will not be able to be in this study if you have or will receive a vaccine during this time. Examples of
common modified live virus vaccines include vaccines for smallpox (vaccinia), measles, mumps, rubella (MMR), 
varicella (chicken pox and shingles), yellow fever and the oral vaccines for: influnza (flu), typhoid, and polio 
vaccines. The injectable forms of influenza (flu), typhoid, and polio are killed (inactive) vaccines. 
Cancer
•
People who have been treated with Infliximab for rheumatoid arthritis or Crohn’s disease for a long time tend to
be more prone to a type of blood cancer called lymphoma.
•
There have been some patients that while taking infliximab developed other types of cancer. But, the number of
people taking infliximab that developed cancer does not seem to be much different from what you would expect
to see in people who are not taking infliximab.
•
It is not known whether brief treatment with infliximab is a risk for cancer in medically healthy subjects, such as
in this study.
•
If you have ever had any type of cancer in the past, including skin cancer, you will not be able to be in this study.
In addition to risks related to taking infliximab there are other risks linked to participating in this study. 
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 13 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
Other Risks
Drawing Blood and Finger Stick
•
The risks of inserting and drawing blood from a finger stick, venous catheter or a syringe are minimal. The risks
include swelling, tenderness, discomfort, bruising, infection, bleeding and fainting.
•
To minimize these risks, the procedure will be done in a sterile manner by trained research or clinical staff while
you are comfortably seated. 
•
Venous catheter placement and blood withdrawal will be done by nurses or trained phlebotomists with
extensive experience with blood drawing. 
•
The amount of blood that we will draw over the course of the study is in compliance with the American Red
Cross safety guidelines.
Psychiatric/Psychological Assessments
•
The assessment of psychiatric and psychological issues may be connected to disturbing memories or feelings.
•
To minimize this, you will be given ample opportunity during the assessment to discuss any disturbing memories
or feelings you may experience.
•
Research staff will be careful to avoid causing undue psychological distress during any part of the psychiatric
assessment.
Computer Tasks/Cognitive Testing
•
No known risks are linked to the computerized cognitive testing or computer tasks you will do.
•
Some of the computerized tasks may be boring, but otherwise pose no risk.
Mobile App
•
You may be distracted in your daily life by phone notifications and/or email notifications to complete
assessments. 
MRI
•
The MRI machine is as loud as riding in a loud train – you will be given earplugs and headphones to
lessen the noise.
•
You may experience some muscle discomfort while lying in the scanner.
•
You may also become too hot or too cold, in which case you may ask for an adjustment of room
temperature or a blanket.
•
Some people become nervous or claustrophobic (anxious or afraid of closed spaces) in the scanner. If
this happens to you, you may ask to be withdrawn immediately. You may also experience a sense of
dizziness in the magnet. This is due to the strong magnetic field, and if it disturbs you, you may ask to be
withdrawn.
•
The magnetic field will affect any metallic object. You should not participate if you have any type of
metallic implant in your body, including pacemakers, aneurysm clips, shrapnel, metal fragments,
orthopedic pins, screws, or plates, non-MR safe IUD’s (if you are unsure, you should discuss with study
staff and/or your doctor), or piercings that you cannot remove. If you have any of these items in your
body, there is a risk that the magnetic field could cause them to move or heat up. It is important that
you inform the study staff if you have any implants.
•
This type of brain scan is not designed to detect problems of the brain. You will be getting a scan for
research purposes only.  The research does not require health professionals to read the scan. The
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 14 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
researchers are not qualified to interpret the images for healthcare purposes. Do not rely on the scan 
for clinical or diagnostic purposes.  However, if the researchers have a question about something they 
see on the scan they will tell you, and ask you if you want the scan sent to a qualified health professional 
for review and any further medical treatment.   You or your insurance company may have to pay for the 
review and any such treatment.
Treatment for Depression
•
Participation in this study will delay the delivery of active treatment for your depression.
•
The risks connected to the delay of treatment for depression include continued symptoms of depression with
the accompanying distress and difficulty in functioning, the possibility of worsening of the depressive symptoms,
including the risk of suicidality.
The risk of suicide is always possible with depression. Please call the Emory Clinic operator at (404) 778-5000 and ask 
for Bobbi Woolwine, LCSW to be paged at #15375, immediately if you experience thoughts of suicide. If you feel that 
you are at risk of harming yourself, please go to the nearest emergency room.
Risks with Pregnancy
•
The study medicine (infliximab or placebo) may involve currently unforeseeable risks to pregnant women, the
embryo or fetus, or to children of nursing women. 
•
If you are a woman who is pregnant, breast feeding, or planning to become pregnant within the period of the
study, you must not participate in the study. Also, all women of childbearing potential are required to undergo 
pregnancy testing before entering the study and at each study visit.  A woman of childbearing potential is 
defined as one who is biologically capable of becoming pregnant.
•
All women of child bearing potential must use a medically acceptable contraceptive throughout the study. This
includes oral (birth control pills), double-barrier method, injectable or implantable, or mechanical contraception. 
It also includes women whose sexual partners have had a vasectomy or have received or are using mechanical 
contraceptive devices. Condoms should be used in addition to other contraceptive methods to provide 
protection against sexually transmitted diseases and to provide added protection against pregnancy. 
•
All women of child bearing potential will be asked to abstain from sexual activity for 14 days prior to the study
infusion visit.
•
If you miss a period or think you might be pregnant during the study, you must tell the investigator immediately
so that you can be withdrawn from the study.
•
For women of childbearing potential, if you (a) plan to become pregnant, (b) become pregnant, (c) think you
may have become pregnant, or (d) plan to discontinue contraception, you must tell the study investigator 
immediately.
If you are a woman: to protect against possible side effects of the study drug, women who are pregnant or nursing a 
child may not take part in this study. If you become pregnant, there may be risks to you, the embryo, or fetus. 
If you are a man: the effect of the study drug on sperm is not known. You and the study doctor should agree on a 
method of birth control to use throughout the study. Men who are participating in this research study need to 
understand the possible danger of taking a drug that’s effects on a fetus are unknown. 
Study Drug
The study drug taken in this study may also have unknown risks.
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 15 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
New Information
It is possible that the researchers will learn something new during the study about the risks of being in it.  If this 
happens, they will tell you about it. Then you can decide if you want to continue to be in this study or not.  You may be 
asked to sign a new consent form that includes the new information if you decide to stay in the study.
Will I benefit directly from the study? 
This is not a treatment study. Taking part in this research study may not benefit you personally, but researchers may 
learn new things about that treatment of depression that will help others. You will receive a single dose of the study 
drug as a part of this study. The study medicine may have no beneficial effect for you.  Your depression may continue or 
worsen. You may benefit from this experimental research if the study medicine or placebo reduces your depressive 
symptoms. However, it is unlikely that you will benefit long-term from a single dose of the study drug, Infliximab. If you 
do benefit from a single dose of the study drug, it is unlikely that you will be able to continue to receive the drug outside 
of this study. Results from this study may also provide new understandings of the chemicals that are believed to be 
involved in major depression.
Will I be compensated for my time and effort?
To compensate for time required for participation, inconvenience and travel expenses, you will receive $100, $60, and 
$200 for the outpatient study visits at 24 hours (Optional), 3 days, and 7 days (Optional) after your infusion respectively. 
You will receive $100 for the pre-screening visit (which may be done prior to consent through the Behavioral 
Immunology Program), and $100 for screening visit procedures. You will receive $410 for the infusion visit, and $310 for 
the study visit at 14 days (because you will receive an MRI scan at this visit). During the visits where you receive an MRI 
scan (on the day of infusion and at 14 days after infusion), you will have the opportunity to earn an additional $150 per 
visit based on your choices and performance in a series of computer tasks. You may have the option of completing the 
MRI scan portion of the infusion visit one day before infusion. At visits on days 3 and 7 after infusion, you will have the 
opportunity to earn an additional $50 per visit based on your task choices and performance. As a result, you will be 
compensated $880 for this study but could earn up to $1,580 total across all study visits. You will also receive a physical 
examination, EKG and laboratory evaluations free of charge as a result of participating in this study.
If you participate in the daily assessment part of this study, and complete all assigned days of assessment with the 
mobile app, you will receive an additional $2-10 dollars for each day of mobile assessments you complete. The exact 
compensation you receive will be based on your choices and performance in the task(s) on the mobile app. If you 
complete 3 days of assessments, you could receive between $6 and $30. If you complete 7 days of assessments, you 
could receive between $14 and $70, and so on. You may earn up to $150 for completing the mobile assessments. This 
would make your maximum amount of compensation across all visits $1,730. 
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 16 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
You may be paid by check or prepaid card. You will be asked to fill out a tax form, including your Social Security or 
Taxpayer Identification Number. If you elect payment via check, the check will be mailed to your house, which may be 
seen by others in your household. Depending on processing time, the compensation check may take up to about 4-6 
weeks to arrive and will not be paid until after completion of the study. All payment for performance on tasks will be 
issued after completion of the study (regardless of payment method). The payment card is a prepaid debit card. It can be 
used exactly like a Mastercard. We load money onto your card electronically every time you 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 your card, we need to give Greenphire some of your personal information. Banks and other financial institutions 
can access this information if they need to verify your identity when you use your card. Emory University is required by 
law to report any payments we make to the IRS. To do this, Emory University Department of Finance needs to keep your 
Social Security Number on file. We are asking you to allow us to communicate your name, address, date of birth, 
Visit
Total Amount Earned
PRE-SCREENING (May be completed and compensated 
through Behavioral Immunology Screening Clinic)
$100
Visit Total
$100
SCREENING VISIT(S)
Visit A
$50
Visit B
$50
Visit Total
$100
INFUSION VISIT(S)
fMRI (May be completed one day before infusion day)
$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
$1,830
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 17 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
research study name and Social Security Number to Greenphire and Emory University Department of Finance. If you 
want to receive e-mail or text alerts when payments are made to you, we will ask you to provide your e-mail or phone 
number as well. 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 your card are included when/if 
we issue it. Please ask if you have any questions or concerns about the card scheme or the use of your personal 
information.
What are my other options if I want treatment now?
Participation in this study does not include treatment. If you decide not to enter this study, there is care available to you 
outside of this research study.  
Some medicines as well as other talking or behavioral therapies, which may be evaluated to treat your condition include, 
but are not limited to:
•
Antidepressants (such as Paxil or Zoloft),
•
Tricyclic antidepressants (including clomipramine),
•
Monoamine Oxidase Inhibitors (such as phenelzine),
•
Electroconvulsive shock therapy (ECT)
•
Talking therapy (formal psychotherapy, and/or cognitive-behavioral therapy)
Participation in this study is not a substitute for your usual medical care by your regular doctor or specialist. At your 
request, we will give you copies of the results to review with your regular doctor or specialist. 
The study investigator will discuss potential benefits and side effects of these treatments with you. You may choose to 
be treated with one or more of these treatments rather than participate in the study. Their effectiveness and side 
effects can vary according to their suitability for an individual patient. Some side effects include but are not limited to 
headache, sleepiness, diarrhea, insomnia, and sexual dysfunction. You do not have to participate in this research study 
to be treated for your condition.
Taking part in this study, however, may make you unable to participate in some other research studies, if they exclude 
people who have taken certain treatments.  You should discuss this with the researchers if you have concerns. You may 
wish to research other study options at websites like clinicaltrials.gov and ResearchMatch.org.
How will you protect my private information that you collect in this study?
Whenever possible, a study number, rather than your name, will be used on study records.  Your name and other 
identifying information will not appear when we present or publish the study results.
There is a Certificate of Confidentiality from the National Institutes of Health for this Study.  The Certificate of 
Confidentiality helps us to keep others from learning that you participated in this study.  Emory will rely on the Certificate 
of Confidentiality to refuse to give out study information that identifies you.  For example, if Emory received a subpoena 
for study records, it would not give out information that identifies you.
The Certificate of Confidentiality does not stop you or someone else, like a member of your family, from giving out 
information about your participation in this study.  For example, if you let your insurance company know that you are in 
this study, and you agree to give the insurance company research information, then the investigator cannot use the 
Certificate to withhold this information. This means you and your family also need to protect your own privacy.
The Certificate does not stop Emory from making the following disclosures about you:
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 18 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
•
Giving state public health officials information about certain infectious diseases,
•
Giving law officials information about abuse of a child, elderly person or disabled person.
•
Giving out information to prevent harm to you or others.
•
Giving the study sponsor or funders information about the study, including information for an audit or evaluation.
Storage and release of samples, genomic data, and health information
Portions of your samples, genomic data, and health information will be stored and shared with other researchers. The 
samples and information will be available for any research question, such as research to understand what causes certain 
diseases (for example heart disease, cancer, or psychiatric disorders), development of new scientific methods, or the 
study of where different groups of people may have come from.
How samples and/or data might be used:
We will use your samples and data only for research. We will not sell them. However, the results of this research might 
someday lead to the development of products (such as a commercial cell line, a medical or genetic test, a drug, or other 
commercial product) that could be sold by a company. You will not receive money from the sale of any such product. For 
more information on how your data may be shared with other researchers, please see the section called “National 
Institute of Mental Health Data Archive”.
For this study, your samples and data will be used for purposes like making sure you are eligible to complete certain 
parts of the study like the MRI scans.
Your urine samples may be used to create a living tissue sample (called a “cell line”) that can be grown in the laboratory.  
This allows researchers to have an unlimited supply of your cells in the future without asking for more samples from 
you.
We may use the cells taken from your urine to create a type of cell known as a pluripotent cell.  This type of cell can be 
used to create different types of tissue, including cells found in the brain called neurons.  Your cells might be used in 
research involving genetic alteration of the cells.
Your cells may be mixed with other human cells, mixed with animal cells, or grown in lab animals like mice.
What you should know about the cell lines that will be derived in the course of this study:
•
The cell lines created will be similar or identical to you genetically.
•
The cell lines may be kept indefinitely.
•
There is the possibility that your cells or the created cell lines might be used in research that will involve genetic
manipulation of the cells or the mixing of human and non-human cells in the animal models.
•
The cell lines may be shared with researchers both inside and outside of Emory University, including commercial
partners.
•
The cell lines may be used to develop treatments for a variety of diseases and conditions.
National Institute of Mental Health Data Archive
Data from this study may be submitted to the National Institute of Mental Health Data Archive (NDA).  NDA is a data 
repository run by the National Institute of Mental Health (NIMH) that allows researchers studying mental illness to 
collect and share deidentified information with each other.  A data repository is a large database where information 
from many studies is stored and managed.  Deidentified information means that all personal information about research 
participants such as name, address, and phone number is removed and replaced with a code number.  With an easier 
way to share, researchers hope to learn new and important things about mental illnesses more quickly than before.
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 19 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
During and after the study, the researchers will send deidentified information about your health and behavior and in 
some cases, your genetic information, to NDA. Other researchers nationwide can then file an application with the NIMH 
to obtain access to your deidentified study data for research purposes.  Experts at the NIMH who know how to protect 
health and science information will look at every request carefully to minimize risks to your privacy.
You may not benefit directly from allowing your information to be shared with NDA.  The information provided to NDA 
may help researchers around the world treat future children and adults with mental illnesses so that they have better 
outcomes.  NIMH will also report to Congress and on its web site about the different studies that researchers are 
conducting using NDA data. However, you will not be contacted directly about the data you contributed to NDA. 
You may decide now or later that you do not want to share your information using NDA.  If so, contact the researchers 
who conducted this study, and they will tell NDA, which can stop sharing the research information.  However, NDA 
cannot take back information that was shared before you changed your mind.  If you would like more information about 
NDA, this is available on-line at http://data-archive.nimh.gov.
How is my Genetic Information Protected? What are the Risks?
The Genetic Information Nondiscrimination Act (GINA) is a federal law that generally makes it illegal for health insurance 
companies, group health plans, and most employers to discriminate against you based on your genetic information. This 
law generally will protect you in the following ways: 
•
Health insurance companies and group health plans may not request your genetic information that we get from
this research.
•
Health insurance companies and group health plans may not use your genetic information when making
decisions regarding your eligibility or premiums. 
•
Employers with 15 or more employees may not use your genetic information that we get from this research
when making a decision to hire, promote, or fire you or when setting the terms of your employment.
Be aware that GINA does not protect you against genetic discrimination by companies that sell life insurance, disability 
insurance, or long-term care insurance, and does not apply to employers with less than 15 employees.
In addition to GINA, the State of Georgia has laws that prohibit insurers from using genetic testing information for any 
non-treatment purpose.  However, like GINA, this state law protection has exclusions: life insurance policies, disability 
income policies, accidental death or dismemberment policies, medicare supplement policies, long-term care insurance 
policies, credit insurance policies, specified disease policies, hospital indemnity policies, blanket accident and sickness 
policies, franchise policies issued on an insurance policy written as a part of workers’ compensation equivalent coverage, 
or other similar limited accident and sickness policies.
Privilege 
In the State of Georgia, your genetic information has special legal protections called “privilege,” which means that the 
information cannot be used as evidence in a court.  By signing this form and allowing us to use and disclose your genetic 
information for the purposes described in this consent, you waive any privilege with regard to that genetic information, 
meaning that the information loses this legal protection.  
What will happen to samples and/or data following a change in participation status:
If you decide to withdraw from the study, become ineligible to continue in the study, or have some other change in 
status that might affect your willingness to participate we might continue to use your stored samples and/or genomic 
data. 
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 20 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
What will happen to samples and/or data if the repository closes:
Your samples and/or genomic data will be transferred or destroyed if the repository closes.
Medical Record
We will take reasonable steps to keep copies of this form out of Emory Healthcare’s medical records system.  If we 
aren’t successful in keeping these forms out, despite our efforts, we will take steps to remove them.  If they cannot be 
removed, we will take steps to limit access to them. 
Emory Healthcare may create study information about you that can help with your care.  For example, the results of 
study tests or procedures.  These study results will be put in your Emory Healthcare medical record. Anyone who has 
access to your medical records will be able to have access to all the study information placed there.  The confidentiality 
of the study information in your medical record will be protected by laws like the HIPAA privacy rule.  State and federal 
laws may not protect the research information from disclosure. 
The results of some study tests and procedures will be used only for research purposes and will not be placed in your 
medical record.  For this study, those items include: the urine drug and urine and blood pregnancy tests, the research 
blood work, and the MRI scans.
Tests and procedures done at non-Emory places may not become part of your Emory medical record. Also, if you decide 
to be in this study, it is up to you to let your other health providers know. 
In Case of Injury
If you get ill or injured from being in the study, Emory will help you get medical treatment.   Emory and the sponsor have 
not, however, set aside any money to pay you or to pay for this medical treatment. The only exception is if it is proven 
that your injury or illness is directly caused by the negligence of an Emory or sponsor employee.  “Negligence” is the 
failure to follow a standard duty of care. 
If you become ill or injured from being in this study, your insurer will be billed for your treatment costs.  If you do not 
have insurance, or if your insurer does not pay, then you will have to pay these costs.  
If you believe you have become ill or injured from this research, you should contact Dr. Michael Treadway at telephone 
number 
. You should also let any health care provider who treats you know that you are in a research 
study. 
Costs
There will be no costs to you for participating in this study, other than basic expenses like transportation. You will not be 
charged for any of the research activities. 
Withdrawal from the Study
You have the right to leave a study at any time without penalty.  
For your safety, if you leave the study before the final planned study visit, the researchers may ask you to have some of 
the final follow-up steps done.  
The researchers also have the right to stop your participation in this study without your consent for any reason, especially if 
they believe it is in your best interest or if you were to object to any future changes that may be made in the study plan.
Authorization to Use and Disclose Protected Health Information
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 21 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
The privacy of your health information is important to us.  We call your health information that identifies you, your 
“protected health information” or “PHI.”  To protect your PHI, we will follow federal and state privacy laws, including the 
Health Insurance Portability and Accountability Act and regulations (HIPAA).  We refer to all of these laws as the “Privacy 
Rules.”  Here we let you know how we will use and disclose your PHI for the study.
PHI that Will be Used/Disclosed:  
The PHI that we will use or share for the main research study includes:
•
Medical information about you including your medical history and present/past medicines.
•
Results of exams, procedures and tests you have before and during the study.
•
Laboratory test results.
•
Biological samples.
•
Genetic information.
•
Clinical records.
Purposes for Which Your PHI Will be Used/Disclosed:
We will use and share your PHI for the conduct and oversight of the research study.  We will use and share your 
PHI to provide you with study related treatment and for payment for such treatment.  We will also use and 
share your PHI to conduct normal business operations.  We may share your PHI with other people and places 
that help us conduct or carry out the study, such as laboratories, data management centers, data monitors, 
contract research organizations, Institutional Review Boards (IRBs) and other study sites. If you leave the study, 
we may use your PHI to determine your health, vital status or contact information. 
Use and Disclosure of Your Information That is Required by Law:  
We will use and disclose your PHI when we are required to do so by law. This includes laws that require us to 
report child abuse or abuse of elderly or disabled adults. 
Authorization to Use PHI is Required to Participate:
By signing this form, you give us permission to use and share your PHI as described in this document. You do not 
have to sign this form to authorize the use and disclosure of your PHI.  If you do not sign this form, then you may 
not participate in the research study or receive research-related treatment.  You may still receive non-research 
related treatment.  
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 22 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
People Who will Use/Disclose Your PHI:
The following people and groups will use and disclose your PHI in connection with the research study:
Other: Sometimes a Principal Investigator or other researcher moves to a different institution. If this happens, 
your PHI may be shared with that new institution and their oversight offices. PHI will be shared securely and 
under a legal agreement to ensure it continues to be used under the terms of this consent and HIPAA 
authorization.
Expiration of Your Authorization
The Researchers will continue to use your PHI until the time at which the study is closed and the period for which any 
records relating to the study must be retained. After this, your Authorization to use your PHI will end and all identifiers 
will be removed from your information making it impossible to link you to the study.
Other Items You Should Know about Your Privacy
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care providers, health care 
payers, and health care clearinghouses.  If we disclose your information to people who are not covered by the Privacy 
Rules, including HIPAA, then your information won’t be protected by the Privacy Rules.  People who do not have to 
follow the Privacy rules can use or disclose your information with others without your permission if they are allowed to 
do so by the laws that cover them. 
Person/Entity 
Purpose
Researchers
To conduct the study entitled, “Dynamics of Inflammation and its Blockade 
on Motivational Circuitry in Depression", the purpose of which is to establish 
the validity of an inflammation-dependent path towards the development of 
motivational anhedonia.
Governmental Agencies with 
oversight over the research 
being conducted, including the 
Food and Drug Administration 
(FDA), the Office for Human 
Research Protections (OHRP), 
and National Institute of 
Mental Health (NIMH).
To monitor safety, efficacy and compliance with applicable laws and 
regulations.
University personnel, 
committees and departments 
charged with oversight of 
research, including the 
Institutional Review Board 
(IRB).
To monitor safety and compliance with applicable laws, regulations and 
University policies and procedures, and to run normal business operations.
Statisticians hired by the study 
sponsor.
To perform data analysis.
Emory University laboratories 
hired by the researchers
To analyze specimens.
MOD001-IRB00087941
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 23 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
To maintain the integrity of this research study, you generally will not have access to your PHI related to this research 
until the study is complete.  When the study ends, and at your request, you generally will have access to your PHI that 
we maintain in a designated record set.  A designated record set is data that includes medical information or billing 
records that your health care providers use to make decisions about you. 
If it is necessary for your health care, your health information will be provided to your doctor. In general, we will not give 
you any individual results from the study of the samples you give us. If we find something of urgent medical importance 
to you, we will inform you, although we expect that this will be a very rare occurrence.
We may remove identifying information from your PHI.  Once we do this, the remaining information will not be subject 
to the Privacy Rules.  Information without identifiers may be used or disclosed with other people or organizations for 
purposes besides this study.  
Other Items You Should Know 
Dr. Treadway is a co-inventor of the EEfRT task software, which is used in this study. Emory University and Vanderbilt 
University licensed this software to BlackThorn Therapeutics. Under the IP Policies of both universities, Dr. Treadway 
receives licensing fees and royalties from BlackThorn Therapeutics. Additionally, Dr. Treadway has a paid consulting 
relationship with BlackThorn. The terms of this arrangement have been reviewed and approved by Emory University in 
accordance with its conflict of interest policies.
Contact Information
Contact Bobbi Woolwine, LCSW at 
:
•
if you experience thoughts of suicide or feel you are at risk of harming yourself, or 
•
if you feel you have had a research-related injury or a bad reaction to the study drug
Contact Dr. Michael Treadway at
:
•
if you have any questions about this study or your part in it,  or
•
if you have questions, concerns or complaints about the research
Contact the Emory Institutional Review Board at
 
•
if you have questions about your rights as a research participant.
•
if you have questions, concerns or complaints about the research.
•
You may also let the IRB know about your experience as a research participant through our Research Participant 
Survey at http://www.surveymonkey.com/s/6ZDMW75.
Consent 
TO BE FILLED OUT BY SUBJECT ONLY
Please print your name, sign, and date below if you agree to be in the study. By signing this consent and authorization 
form, you will not give up any of your legal rights. We will give you a copy of the signed form to keep.
Name of Subject 
Signature of Subject (18 or older and able to consent)
Date              Time
IRB Approved
7/16/2020


Study No.: «ID»
Emory University IRB
IRB use only
Document Approved On: «ApproveDate»
Page 24 of 24
Version Date: 11262019_Mod20
IRB Form 04152016
TO BE FILLED OUT BY STUDY TEAM ONLY
__________________________________________________________
Name of Person Conducting Informed Consent Discussion
Signature of Person Conducting Informed Consent Discussion
Date        
TO BE FILLED OUT BY SUBJECT ONLY – CONSENT TO BE CONTACTED VIA TEXT MESSAGE
If you are interested, we may send appointment reminders and scheduling information via text message to your mobile 
phone. All standard data rates would apply.
Please indicate below (with your initials) if you are interested in being contacted via text message.  
_______  I am interested in receiving appointment reminders and scheduling information via text message.
_______  I am NOT interested in receiving appointment reminders and scheduling information via text message. 
TO BE FILLED OUT BY SUBJECT ONLY – CONSENT FOR PARTICIPATION IN MOBILE APPLICATION ASSESSMENTS
If you are interested, we may ask you to download a mobile application and complete brief questionnaires and/or 
behavioral tasks over the course of the study. The mobile app is currently only available for iOS devices.
Please indicate below (with your initials) if you are interested in participating in this component of the study.  
_______  I am interested in completing the mobile app component of this study and have an iOS device.
_______  I am NOT interested in completing the mobile app component of this study and/or do not have an iOS device. 
TO BE FILLED OUT BY SUBJECT ONLY – CONSENT FOR RECONTACT FOR ADDITIONAL SAMPLES
If the urine or blood sample we collect is not sufficient for the further testing we may conduct or if we do not ask you to 
provide a urine or blood sample one of your study visits, we may ask you if you are willing to return to the lab to provide 
a sample.
Please indicate below (with your initials) if you consent to be re-contacted for this purpose. 
_______  I agree to be re-contacted for an additional blood or urine sample in the future.
_______  I do NOT agree to be re-contacted for an additional blood or urine sample in the future. 
MOD001-IRB00087941
IRB Approved
7/16/2020