Conditions: Depression
Keywords: Psychiatry
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 22
Healthy volunteers: no

Brief summary:
Increased inflammation has been implicated in the pathophysiology of a number of neuropsychiatric illnesses including mood disorders, which affect almost 30 million adults in the United States alone. One mechanism by which inflammation may alter behavior is through increasing brain glutamate, a neurotransmitter that in excess has been implicated in neuronal toxicity and resistance to conventional antidepressant therapy. The goal of the proposed research is to test the hypothesis that inflammation alters behavior through increasing glutamate in specific brain regions, ultimately leading to behavioral changes.

The proposed research is designed to determine the cause and effect relationship between inflammation and CNS glutamate as well as the relationship between CNS glutamate and specific symptoms. To accomplish these aims, investigators will administer a single infusion of either the tumor necrosis factor (TNF) antagonist infliximab or placebo (n=30 per group) to patients with high inflammation (CRP\>3mg/L). A CRP\>3mg/L was chosen because it is considered high inflammation according to guidelines by the American Heart Association. Moreover, a CRP\>3mg/L is associated with significantly increased basal ganglia glutamate and with a clinical response to infliximab. Inflammatory biomarkers, basal ganglia glutamate as measured by MRS, and motivation and psychomotor activity will be assessed at baseline and days 1 and 3 and weeks 1 and 2 following infliximab or placebo administration.

Detailed description:
This study aims to test the hypothesis that increased inflammation causes increased basal ganglia glutamate and consequently anhedonia and psychomotor retardation in patients with major depressive disorder (MDD). Excessive inflammation and glutamate excitotoxicity are two pathways that have received increasing attention regarding the pathophysiology of neuropsychiatric disease including mood disorders. Patients with depression exhibit increased peripheral and central nervous system (CNS) markers of inflammation as well as altered CNS glutamate as measured by magnetic resonance spectroscopy (MRS). In addition, drugs that block either inflammation or glutamate signaling can reverse depressive symptoms, especially in depressed patients with treatment resistance.

Inflammatory cytokines are known to inhibit glutamate reuptake and increase glutamate release from astrocytes, and glutamate antagonists have been shown to block inflammation-induced depressive-like behavior in mice. Moreover, using MRS, data has shown that administration of the inflammatory cytokine interferon (IFN)-alpha significantly increases glutamate in the basal ganglia in association with IFN-alpha-induced anhedonia and psychomotor slowing. In addition, increased inflammation as reflected by peripheral blood C-reactive protein (CRP) is correlated with increased basal ganglia glutamate in association with decreased motivation and psychomotor speed in patients with MDD. Nevertheless, the data to date has been correlational, and whether increased inflammation causes increased glutamate in the basal ganglia, which in turn contributes to behavioral changes in patients with depression has not been established.

To test this hypothesis, investigators plan to determine the cause and effect relationship between increased inflammation and increased CNS glutamate by blocking inflammation in depressed patients with high inflammation (CRP\>3mg/L) using the highly specific tumor necrosis factor (TNF) antagonist infliximab (n=30) versus placebo (n=30). In addition, the study team will examine whether changes in basal ganglia glutamate are linked to changes in behaviors related to the basal ganglia including anhedonia and psychomotor retardation.

Arms:
arm 1: Participants will be randomized to receive one intravenous (IV) infusion of infliximab. arm 2: Participants will be randomized to receive one intravenous (IV) infusion of placebo.

Interventions: intervention 1: Infliximab intervention 2: Placebo
Intervention descriptions: intervention 1: Infliximab will be administered intravenously (IV) as 5 mg/kg body weight over a 2 to 2.5 hour period. intervention 2: Saline solution will be administered intravenously over a 2 to 2.5 hour period.

Protocol document:
Prot_SAP_001.pdf: 
Study Protocol 
 
Title: Inflammation-Induced CNS Glutamate Changes in Depression 
 
NCT Number: NCT03004443 
 
Protocol Version Date: February 14, 2020 
 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
1 
Version: February 14th, 2020  
 
1. Title: Inflammation-Induced CNS Glutamate Changes in Depression (Infliximab Glutamate Study) 
 
Principle Investigator: Andrew H. Miller MD and Ebrahim Haroon MD 
Co-Investigator: Michael Treadway, PhD, Bobbi Woolwine, MSW 
 
Version: February 14th, 2020  
 
2. Précis/Abstract:  
The proposed research is designed to determine the cause and effect relationship between inflammation 
and CNS glutamate as well as the relationship between CNS glutamate and specific symptoms. To 
accomplish these aims, we will administer a single infusion of either the TNF antagonist infliximab or 
placebo (n=30 per group) to patients with high inflammation (CRP>3mg/L). A CRP>3mg/L was chosen 
because it is considered high inflammation according to guidelines by the American Heart Association.1 
Moreover, a CRP>3mg/L was associated with significantly increased basal ganglia glutamate and was 
associated with a clinical response to infliximab.2, 3 Inflammatory biomarkers, basal ganglia glutamate as 
measured by MRS, and motivation and psychomotor activity will be assessed at baseline and days 1 and 
3 and weeks 1 and 2 following infliximab or placebo administration.  Inflammation is rapidly reduced 
(within 6 hours) following infusion, and there is evidence of improved motivation within 2 weeks of the first 
infusion (see Preliminary Data).3, 4 Finally, as previously demonstrated, infliximab-treated depressed 
patients show a 4mg/L drop in plasma CRP within 1 week of infliximab infusion. 
3. Introduction and Background:  
Two emerging theories regarding the development of mood disorders involve excessive activation of 
inflammatory pathways and alterations in glutamate metabolism.5-8 For example, increased inflammatory 
markers have been reliably found in the peripheral blood and cerebrospinal fluid (CSF) of patients with 
unipolar and bipolar depression.5, 9, 10 Moreover, administration of inflammatory stimuli including interferon 
(IFN)-alpha, typhoid vaccination or endotoxin have all been shown to lead to behavioral changes that 
characterize depression including depressed mood, anhedonia, and psychomotor slowing.11-16 In addition, 
inflammatory cytokines interact with virtually every pathophysiologic domain known to be involved in the 
regulation of mood including neurotransmitter metabolism, synaptic plasticity, neuroendocrine function 
and relevant neurocircuitry.5, 17, 18 Finally, inhibition of inflammatory cytokines has been shown to lead to 
improvements in depressed mood, anhedonia, and psychomotor retardation in patients with increased 
inflammation associated with depression or medical illnesses such as autoimmune and inflammatory 
disorders as well as cancer.3, 19, 20 Alterations in glutamate metabolism have also been implicated in mood 
disorders.6 Indeed, a number of studies using magnetic resonance spectroscopy (MRS) have found 
alterations in glutamate and glutamate metabolite levels in multiple brain regions of depressed patients, 
with bipolar depressives showing relatively consistent elevations in CNS glutamate and unipolar 
depressed patients exhibiting more mixed results.21-27 In addition, loss of glial elements including 
astrocytes and oligodendrocytes as well as loss of the transporters for excitatory amino acids, which are 
responsible for the reuptake and recycling of glutamate, are some of the most reliable changes found in 
post mortem brain tissue from patients with mood disorders.6, 7, 28-30 Significant differences in methylation 
patterns specific for astrocytic dysfunction have also been associated with depressive psychopathology in 
postmortem brain samples.31 Probably the most dramatic evidence of the role of glutamate in 
psychopathology of mood disorders is derived from the profound and rapid response of treatment 
resistant depressed patients to ketamine, an antagonist of the glutamate N-methyl-d-aspartate 
(NMDA) receptor.32-34 Of note, data indicate that anhedonia may be an especially responsive symptom to 
ketamine administration.35 
Inflammation and Glutamate Pathology may be Linked Cytokines Can Alter Glutamate Metabolism 
Inflammatory cytokines have been shown to interact with glutamate pathways in several important ways 
that may contribute to altered glutamate metabolism. Inflammatory cytokines have been shown to 
decrease the expression of glutamate transporters (excitatory amino acid transporters – EAAT) on 
relevant glial elements (astrocytes and oligodendrocytes) and increase the release of glutamate from 
astrocytes via reverse efflux from the EAAT and increased secretion through the cysteine/glutamate 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
2 
Version: February 14th, 2020  
antiporter.36-39 Of note, glutamate released by astrocytes has preferential access to extrasynaptic NMDA 
receptors which have been shown to decrease brain derived neurotrophic factor (BDNF) and increase 
excitotoxicity.5, 40 Moreover, blockade of glutamate reuptake has been shown to lead to anhedonic-like 
behavior in rats.41  Glutamine synthetase which converts glutamate to glutamine, potentially leading to a 
build-up of intracellular and extracellular glutamate, along with cytokine induction of nitrogen and oxygen 
free radicals, can lead to astrocyte dysfunction and death.37, 42-44 Cytokines such as TNF can also reduce 
glutamate transporter expression on oligodendrocytes and in excess is directly toxic to these cells, further 
compromising glutamate reuptake.37, 42, 44 Finally, inflammatory cytokines can activate the kynurenine 
pathway leading to production of quinolinic acid by activated microglia. Quinolinic acid has been shown to 
act as an agonist at the glycine-binding site of the NMDA receptor, but also can stimulate synaptosomal 
glutamate release and decrease astrocytic glutamate reuptake both in vitro and in inflammatory pathways 
and alterations in glutamate metabolism.5-8 For example, increased inflammatory markers have been 
reliably found in the peripheral blood and cerebrospinal fluid (CSF) of patients with unipolar and bipolar 
depression.5, 9, 10 Moreover, administration of inflammatory stimuli including interferon (IFN)-alpha, typhoid 
vaccination or endotoxin have all been shown to lead to behavioral changes that characterize depression 
including depressed mood, anhedonia, and psychomotor slowing.11-16 In addition, inflammatory cytokines 
interact with virtually every pathophysiologic domain known to be involved in the regulation of mood 
including neurotransmitter metabolism, synaptic plasticity, neuroendocrine function and relevant 
neurocircuitry.5, 17, 18 Finally, inhibition of inflammatory cytokines has been shown to lead to improvements 
in depressed mood, anhedonia, and psychomotor retardation in patients with increased inflammation 
associated with depression or medical illnesses such as autoimmune and inflammatory disorders as well 
as cancer.3, 19, 20 Alterations in glutamate metabolism have also been implicated in mood disorders.6 
Indeed, a number of studies using magnetic resonance spectroscopy (MRS) have found alterations in 
glutamate and glutamate metabolite levels in multiple brain regions of depressed patients, with bipolar 
depressives showing relatively consistent elevations in CNS glutamate and unipolar depressed patients 
exhibiting more mixed results.21-27 In addition, loss of glial elements including astrocytes and 
oligodendrocytes as well as loss of the transporters for excitatory amino acids, which are responsible for 
the reuptake and recycling of glutamate, are some of the most reliable changes found in post mortem 
brain tissue from patients with mood disorders.6, 7, 28-30 Significant differences in methylation patterns 
specific for astrocytic dysfunction have also been associated with depressive psychopathology in 
postmortem brain samples.31 Probably the most dramatic evidence of the role of glutamate in 
psychopathology of mood disorders is derived from the profound and rapid response of treatment 
resistant depressed patients to ketamine, an antagonist of the glutamate N-methyl-d-aspartate 
(NMDA) receptor.32-34 Of note, data indicate that anhedonia may be an especially responsive symptom to 
ketamine administration.35 
Inflammation and Glutamate Pathology may be Linked 
Cytokines Can Alter Glutamate Metabolism 
Inflammatory cytokines have been shown to interact with glutamate pathways in several important ways 
that may contribute to altered glutamate metabolism. Inflammatory cytokines have been shown to 
decrease the expression of glutamate transporters (excitatory amino acid transporters – EAAT) on 
relevant glial elements (astrocytes and oligodendrocytes) and increase the release of glutamate from 
astrocytes via reverse efflux from the EAAT and increased secretion through the cysteine/glutamate 
antiporter.36-39 Of note, glutamate released by astrocytes has preferential access to extrasynaptic NMDA 
receptors which have been shown to decrease brain derived neurotrophic factor (BDNF) and increase 
excitotoxicity.5, 40 Moreover, blockade of glutamate reuptake has been shown to lead to anhedonic-like 
behavior in rats.41 Glutamine synthetase which converts glutamate to glutamine, potentially leading to a 
build-up of intracellular and extracellular glutamate, along with cytokine induction of nitrogen and oxygen 
free radicals, can lead to astrocyte dysfunction and death.37, 42-44 Cytokines such as TNF can also reduce 
glutamate transporter expression on oligodendrocytes and in excess is directly toxic to these cells, further 
compromising glutamate reuptake.37, 42, 44 Finally, inflammatory cytokines can activate the kynurenine 
pathway leading to production of quinolinic acid by activated microglia. Quinolinic acid has been shown to 
act as an agonist at the glycine-binding site of the NMDA receptor, but also can stimulate synaptosomal 
glutamate release and decrease astrocytic glutamate reuptake both in vitro and in vivo.45-47 Taken 
together, these effects of inflammatory cytokines on glutamate metabolism, reuptake and release by 
astrocytes and oligodendrocytes as well as the fundamental integrity (and survival) of these glial elements 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
3 
Version: February 14th, 2020  
provide an intriguing intersection of the inflammation and glutamate hypotheses of mood disorders 
including depression. Clinical data supporting the notion that inflammatory cytokines can alter CNS 
glutamate metabolism have recently been generated by our group in both patients treated with the 
inflammatory cytokine interferon (IFN)-alpha and in depressed patients with increased inflammation as 
reflected by elevated concentrations of plasma C-reactive protein (CRP). Indeed, administration of IFN-
alpha was found to increase glutamate as measured by the glutamate to creatine (Glu/Cr) ratio using 
MRS in the left basal ganglia and dorsal anterior cingulate cortex (dACC). The basal ganglia and dACC 
are brain regions that have been repeatedly implicated as targets of peripherally administered 
inflammatory stimuli including inflammatory cytokines as well as typhoid vaccination and endotoxin.11, 12, 
14-17 Of note, IFN-alpha-induced increases in glutamate in the basal ganglia in turn were correlated with 
IFN-alpha-induced depressive symptoms including anhedonia and psychomotor 
slowing.48, 49 In addition, IFN-alpha-induced increases in TNF were correlated with increased basal 
ganglia glutamate,48 suggesting a direct relationship between increased inflammatory cytokines and 
increased glutamate (as proposed in this application) and supporting the use of a TNF antagonist to 
reduce CNS glutamate as planned in Aims 1-3. Our recently published data  (MDD) also indicate that 
increased inflammation as reflected by plasma CRP is associated with increased basal ganglia glutamate 
in both a linear and stepwise fashion, with MDD patients with a CRP>3mg/L showing significantly higher 
basal ganglia glutamate than patients with a CRP<1mg/L(see Appendix 
http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2015206a.html).2 Interestingly, increased basal 
ganglia glutamate was also associated with anhedonia and psychomotor slowing in MDD patients. 
Finally, pretreatment with ketamine has been shown to block the development of depressive-like behavior 
in mice as a result of the administration of the inflammatory stimulus lipopolysaccharide.50 Surprisingly, 
ketamine had no effect on LPS-induced inflammatory activation in the brain. Taken together, these data 
provide convincing evidence across distinct experimental paradigms that increased inflammation may be 
linked to altered glutamate metabolism that is manifested as increased CNS glutamate as measured by 
MRS. Nevertheless, the data to date in humans is correlational in nature, and the opportunity exists to 
block inflammation in depressed patients with high inflammation and determine whether glutamate is 
decreased in a cause and effect manner. Relevant in this regard, is a recent study conducted by our 
group demonstrating that inhibition of TNF in depressed patients with high inflammation using a 
monoclonal antibody to TNF (infliximab) led to decreased anhedonia and psychomotor retardation, which 
are the two major symptoms that have been associated with increased basal ganglia glutamate in our 
previous studies.2, 48, 49 Whether this effect of the TNF antagonist was a result of effects on CNS 
glutamate will be tested in Aims 1 and 2 of this proposal. 
4. Objectives: (Primary and secondary aims) 
Specific Aims: To establish a cause and effect relationship between increased inflammation and basal 
ganglia glutamate, we propose to administer an anti-inflammatory challenge to depressed patients with 
high inflammation and determine whether basal ganglia glutamate is decreased in association with 
increased motivation and psychomotor speed. Recent data suggest that inflammation leads to increased 
CNS glutamate which may contribute to behavioral alterations in patients with neuropsychiatric disorders 
including depression. Consistent with this notion, data from our group has shown that administration of 
the inflammatory cytokine interferon (IFN)-alpha to otherwise non-depressed subjects leads to increased 
glutamate in the basal ganglia as measured by magnetic resonance spectroscopy (MRS). Increased 
basal ganglia glutamate was in turn associated with alterations in research domain criteria (RDoC) 
involving Positive and Negative Valence systems including anhedonia and psychomotor retardation. Our 
data in patients with major depression also suggest that increased inflammation as reflected by peripheral 
blood C-reactive protein (CRP) is correlated with increased basal ganglia glutamate in association with 
anhedonia and decreased psychomotor speed. Taken together, these data suggest that inflammation 
may increase basal ganglia glutamate, leading to the development of depressive symptoms relevant to 
motivation and motor activity. Nevertheless, the data to date has been correlational in nature. Our prior 
data demonstrate that administration of the anti-inflammatory agent infliximab, a highly specific 
monoclonal antibody to TNF, powerfully reduces inflammation (e.g. CRP) and decreases symptoms of 
anhedonia and psychomotor retardation in depressed patients with high inflammation. Therefore, through 
the use of state-of-the-art MRS techniques and a biologic agent that can block inflammation (TNF 
antagonist) with limited off-target effects, the proposed research will test the hypothesis that increased 
inflammation leads to increased basal ganglia glutamate, which in turn is associated with changes in 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
4 
Version: February 14th, 2020  
behavior related to motivation and psychomotor performance. Accordingly, the following specific aims are 
proposed: 
Aim 1) To determine whether inhibition of inflammation reduces basal ganglia glutamate following 
acute administration of the anti-inflammatory agent infliximab versus placebo in depressed 
patients with high inflammation. 60 medication-free depressed patients ages 21-65 with high 
inflammation (CRP >3mg/L) will be enrolled. Single-voxel MRS assessments of absolute glutamate in the 
basal ganglia and other regions of relevance including the dorsal anterior cingulate cortex (dACC) as well 
as the left medial parietal cortex (as a control region) will be assessed at baseline and on day 3 and week 
2 after a single infusion of the 
TNF antagonist infliximab or placebo. For exploratory analyses, additional metabolites will also be 
examined, and multivoxel chemical shift imaging (CSI) will be performed. Hypothesis 1: Compared to 
placebo, infliximab treated patients will exhibit decreased absolute glutamate in the basal ganglia on day 
3 and week 2. 
Aim 2) To determine the relationship between basal ganglia glutamate and anhedonia and 
psychomotor retardation following acute administration of the anti-inflammatory agent infliximab 
versus placebo in depressed patients with high inflammation. Objective and clinical measures of 
anhedonia and psychomotor retardation will be obtained in the subjects in Aim 1 at baseline and day 3 
and week 2 after administration of infliximab or placebo. Hypothesis 2: Decreased basal ganglia 
glutamate concentrations will precede and ultimately be associated with improved objective and clinical 
measures of anhedonia and psychomotor retardation. 
Aim 3) To determine the relationship between inflammatory markers and basal ganglia glutamate 
following acute administration of the anti-inflammatory agent infliximab versus placebo in 
depressed patients with high inflammation. Peripheral blood protein and gene expression markers of 
inflammation will be assessed at baseline and on post-infusion days 1 and 3 and weeks 1 and 2 along 
with central (cerebrospinal fluid) measures of protein inflammatory markers at week 2 in subjects 
recruited in Aim 1. 
Hypothesis 3: Decreased peripheral and central markers of inflammation will precede and predict 
decreases in basal ganglia glutamate. Determination of dynamic, temporal relationships among 
inflammation, CNS glutamate and behavior will provide the foundation for biomarker-driven, intelligently-
designed studies of novel therapeutic agents that target inflammation and/or glutamate for the treatment 
of alterations in motivation and motor activity in patients with depression and other neuropsychiatric 
disorders with increased inflammation. 
5. Study design and methods: Two hundred male and female participants ages 21-65 will be enrolled in 
the study to obtain 60 qualified subjects. Written informed consent will be obtained from all patients 
before protocol-specified procedures are conducted. Subjects will be drawn from an ambulatory sample 
of patients with MDD. 
Participant Selection 
Inclusion Criteria:  
a. willing and able to give written informed consent;  
b. men or women, 21-65 years of age;  
c. a primary diagnosis of DSM-V MDD, current, or Bipolar, depressed type as diagnosed by the SCID-V; 
d. score of ≥14 on the Quick Inventory of Depressive Symptomatology (QIDS)-SR-16*51 or score ≥ 15 on 
the Patient Health Questionnaire 9 item (PHQ-9) 
e. absence of significant suicidal ideation defined using the Columbia Suicide Severity Rating Scale – 
Screen Version (CSSRS) as follows: 
 
*PI discretion or 
d/w BW, AHM or 
EH, ** = refer for 
Rx. 
 
 
 
 
 
 
Yes on: 
Q6 (<30d) 
Q6 (>30d/lifetime) 
Q6 (no) 
Q3 (- Intent/- Plan) 
Exclude** 
Include* 
Include 
Q4 (+ Intent/- plan) 
Exclude** 
Exclude** 
Include 
Q5 (+ Intent/+ Plan) 
Exclude** 
Exclude** 
Exclude** 
Q6 (s/p SIB) 
Exclude** 
N/A 
N/A 
Q6 (>30d/lifetime)  
(Lifetime SIB) 
N/A 
Include 
Include 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
5 
Version: February 14th, 2020  
f. off all antidepressant or other psychotropic therapy (e.g. mood stabilizers, antipsychotics, anxiolytics, 
and sedative hypnotics) for at least 4 weeks prior to the baseline visit (8 weeks for fluoxetine)*. No 
patients will be removed from their psychotropic medications for the sole purpose of participating in the 
study. 
g. sexually active participants are required to agree to abstain from sexual intercourse 14 days prior to 
study infusion and are required to use medically approved birth control methods as defined in the Birth 
Control Method Form below for the duration of the study and advised to delay conception for 6 months 
post infusion. 
 
 
  
 
BIRTH CONTROL METHOD 
 
Participant name  
 
Sex 
Male___Female___ 
DOB 
(___/___/___) 
 
Sexually active participants of childbearing potential must agree to use contraception or abstain from sexual activity as defined below.   
Please initial all that apply below: 
 
□ 
 
□ 
 
Female participants practice abstinence from sexual activity 14 days prior to date of study infusion. 
 
Male and female participants agree to use a medically approved birth control method as defined below for at least 60 days post study infusion. Participants 
are advised to delay conception for 6 months post-infusion. 
 
□ 
□ 
□ 
 
 
Female (patient or partner) not of reproductive potential 
  
Removal of ovaries and/or uterus (when: _____ ) 
Post-menopausal for at least 2 years (when: _____ )            
 
□ 
Medically approved contraception methods (participant or partner)  
(Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception) 
□ 
Abstinence from sexual activity that could result on pregnancy 
□ 
Sterilization surgery  
Males: vasectomy (when: _____ ) 
Females: Bilateral tubal ligation (when: _____ ) 
□ 
Condoms (male or female) with spermicide 
□ 
Diaphragm or cervical cap with spermicide 
□ 
Intrauterine device (IUD) (when: _____ ) 
□ 
Hormone-based therapy, e.g. birth control pills, Norplant, or Dep-Provera 
 
□ I have been informed of and fully understand the potential risks of the study drug (infliximab/inflectra) with pregnancy.   
 
Participant signature 
 
Date 
 
PI/NP/designee signature 
 
Date 
  
 
10/23/2019 BW                                                                                                                           __________________________________________________________________   Page 1 of 1 
 
 
Exclusion Criteria: a. any active or history of autoimmune disorder (as confirmed by laboratory testing); 
b. history of tuberculosis (by history or as discovered by chest X-ray, skin testing or blood testing) or high 
risk of tuberculosis exposure; c. hepatitis B or C infection or human immunodeficiency virus infection (as 
established by laboratory testing); d. history of fungal infection; e. history of recurrent viral or bacterial 
infections, including dental, gum, and ear infections; f. history of any type of cancer; g. unstable 
cardiovascular, endocrinologic, hematologic, hepatic, renal, or neurologic disease (as determined by 
physical examination and laboratory testing); h. history of any (non-mood-related) psychotic disorder; 
active psychotic symptoms of any type; antisocial personality disorder as determined by a clinician; 
substance abuse/dependence within 6 months of study entry (as determined by SCID)*; i. active suicidal 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
6 
Version: February 14th, 2020  
plan as determined by a score >3 on item #3 on the HAM-D; j. an active eating disorder, unless limited to 
binge eating in the context of a mood disorder and in absence of purging; k. a history of a cognitive 
disorder or < 28 on the Mini-Mental State Exam*;52 l. pregnancy or lactation; m. women of child bearing 
potential who are not using a medically accepted means of contraception; n. heterosexual males and their 
partners who do not agree to practice appropriate birth control; o. known allergy to murine products or 
other biologic therapies; p. chronic use of non-steroidal anti-inflammatory agents (NSAIDS), 
glucocorticoid containing medications or statins*; q. use of NSAIDS, glucocorticoids, or statins at any time 
during the study*; r. contraindication to MRI (see Human Subjects), s. previous organ transplant, and t. 
history of CNS trauma or active seizure disorder.* Due to the high co-morbidity between anxiety disorders 
and depression, we plan to include patients with anxiety disorders  as long as depression is the primary 
diagnosis. Patients with stable medical conditions and on medications for those conditions will not be 
excluded. Finally, highly treatment resistant depressed patients who score >5 on the MGH Antidepressant 
Treatment Response Questionnaire (ATRQ) for current episode will be excluded, because these 
individuals may represent an extreme subgroup with a qualitatively distinct biology.53 *unless otherwise 
approved by the PI. 
Description of Study Procedures 
Screening: Subjects potentially qualified for enrollment will undergo a screening evaluation after written 
informed consent. Screening will involve subject interview and evaluation, as well as obtaining collateral 
history and data from other relevant sources (i.e. medical records, referring physician). Screening will 
include the following assessments: (1) Assessment of past psychiatric history and current symptom 
severity using the Structured Clinical Interview for DSM-V (SCID-V), 24-item HDRS, QIDS-16 SR or PHQ-
9, and a DSM V-based interview to rule out antisocial personality disorder (2) Assessment of past and 
current psychiatric treatment history using the ATRQ supplemented by information from medical records 
and referring physicians when available, (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 infliximab dose for patients randomized to the infliximab 
arm of the study), and (7) plasma CRP. The PI may request to perform a rapid CRP test at screening 
using the Diazyme hsCRP POC Test Kit. This kit produces rapid results using a finger prick method to 
collect 20μl of blood and is intended for the in vitro quantitative determination of C-reactive protein. 
Screening laboratory evaluations may be repeated at PI’s or PI designee’s discretion. Additional 
assessments will be conducted if more than 4 weeks from screening, unless otherwise approved by the 
PI, study physician or PI’s designee. 
Baseline: Baseline will occur over 2 days, including MRS, blood sampling and behavioral and 
neurocognitive assessments on Day 1 (Visit 1), and randomization to infliximab versus placebo on Day 2 
(Visit 2). Vital signs, safety labs, urine toxicology and adverse events will be collected as indicated in 
Table 1. 
 
Table 1A: Schedule of Study Procedures and Assessments 
Assessments 
Intake 
Screening 
Baseline* 
Day 1 
Day 3 
Week 1 
Week 2 
30 Day  
F/U  
Phone Call  
Visit 1 
Visit 2 
Visit 1 
Visit 2 
(Optional) 
Intake forms and assessments: Consent, HIPPA tracking, 
Release of Information**, Consent of Means of 
Communication**, Participant Payment Form**, MRI 
Screening Form**, Clinician-Assisted QIDS-16 SR** or  
Patient Health Questionnaire PHQ-9**, Medication 
Avoidance List**, Lumbar Puncture Information Guide, 
Schedule Quick Guide 
X 
 
 
 
 
 
 
 
 
 
Psychiatric screening: WRAT-3**, MMSE**,  HAM-D**, 
ATRQ, SCID V**, CSSRS, Clinical Interview Review [to be 
done in place of imported psych assessments from prior 
study] 
 
X 
 
 
 
 
 
 
 
 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
7 
Version: February 14th, 2020  
*Baseline will occur over 2 visits: Visit 1: MRS, blood and Symptom Domain Assessments; Visit 2: Infusion; see below for abbreviations, **Unless prior documentation 
available from previous study, ⁰Screening (or Baseline 1) and Week 2 only, [ ] indicates option to complete assessment, *** PCL-5 (with LEC) at Baseline 1 only, and PCL-5 
(without LEC) at Day 3 and Week 2 
 
 
 
Table 1B: Participants in the combination study will complete the above schedule in 
addition to the adapted version below: 
 
OPTIONAL: Combination Study   
 
Infliximab Administration: The dosing protocol and scheduling of the infliximab infusions for this proposal 
was derived from the standard intravenous regimen for the treatment of inflammatory bowel disease.54 
Independent pharmacists will dispense either infliximab or placebo in a 250ml saline bag according to a 
computer-generated randomization list provided by the study statistician. The placebo will be matched to 
Laboratory Screening: Anti-nuclear AB**, C-reactive 
protein, TSH, Hepatitis B surface antigen**, Hepatitis C 
antibody**, HIV antigen/antibody**, QuantiFERON-TB Gold 
or TB Gold Plus,  Hemoglobin A1c, Diazyme hsCRP POC 
Test Kit [if necessary to verify CRP], EKG, CXR 
 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test 
 
X 
 
X 
 
 
 
X 
 
 
Medical History and Physical Examination or medical 
update 
 
X 
X 
X 
[X] 
X 
[X] 
X 
[X] 
X 
Adverse events, Concomitant medications [Con. Med. not 
completed at 30 day F/U phone call only] 
 
X 
X 
X 
[X] 
X 
[X] 
X 
[X] 
X 
Vital Signs, weight, height [screen only], waist-hip ratio 
[screen only] 
 
X 
X 
X 
[X] 
X 
[X] 
X 
[X] 
 
Routine Labs: CBC with differential, urinalysis w/ micro, 
comprehensive metabolic panel⁰   
 
X 
 
X 
 
 
[X] 
X 
[X] 
 
Urine toxicology 
 
X 
X 
X 
[X] 
X 
[X] 
X 
[X] 
 
Psychiatric baseline: Demographic data**, Childhood 
Trauma**,  Bipolarity Index** 
 
 
X 
 
 
 
 
 
 
 
Infusion (Infliximab or placebo) 
 
 
 
X 
 
 
 
 
 
 
Estrogen/progesterone 
 
 
 
X 
 
 
 
 
 
 
Urine pregnancy test kit 
 
 
X 
 
 
X 
X 
X 
 
 
Research blood: Cytokine Multiplex, mRNA, Plasma CRP 
 
 
X 
X 
[X] 
X 
[X] 
X 
 
 
Clinician-Administered: SHAPS-C, CSSRS⁰, SRRS⁰, HAM-
A⁰ 
 
 
X 
 
 
X 
 
X 
 
 
Self-Report: MFI, MAP, IDS-SR, BAI, PCL-5***, STAI-State 
 
 
X 
 
 
X 
 
X 
 
 
Neurocognitive Tests: FTT, RTT, DSST, Trails A 
 
 
X 
 
 
X 
 
X 
 
 
Computer Assessments: Gamble, Go No-Go, RLT, SLT 
 
 
X 
 
 
 
 
X 
 
 
MRS 
 
 
X 
 
 
X 
 
X 
 
 
PT, PTT 
 
 
 
 
 
 
 
[X] 
 
 
Lumbar Puncture (Optional) 
 
 
 
 
 
 
 
 
[X] 
 
Assessments 
Intake 
Screening 
Baseline* 
Day 1 
Day 3 
Week 1 
Week 2 
30 Day  
F/U  
Phone Call  
Self-Report: PANAS-X,  IDS-SR  
 
 
X 
 
[X] 
X 
[X] 
[X] 
 
 
Behavioral Computer Task: behEEfRT (in place of 
Gamble task) 
 
 
X 
 
 
X 
[X] 
[X] 
 
 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
8 
Version: February 14th, 2020  
infliximab on the basis of color and consistency when dissolved in saline. Several factors contributed to 
the decision to use infliximab in this study. First, we have data using infliximab that demonstrates that 
patients with high inflammation administered this drug exhibit a decrease in both plasma and PBMC 
protein and gene expression of inflammatory markers as well as certain depressive symptoms.3, 4 
Second, unlike etanercept and anakinra, which require daily or several times a week dosing done at 
home, infliximab provides significant and long-lasting anti-inflammatory activity after a single infusion. 
Third, the administration of infusions at our site under our supervision guarantees that all subjects will 
receive identical medication exposure, thus eliminating adherence issues. Finally, 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.3 
Infliximab Infusion Protocol: Double-blinded infusions of infliximab or saline will be administered in the 
research outpatient unit of the Atlanta Clinical and Translational Science Institute- Clinical Research 
Network (ACTSI-CRN). Infusions will be performed following guidelines in place for patients who receive 
infliximab at the ACTSI-CRN. Specifically, intravenous access will be obtained in a sterile manner and 
infliximab (5 mg/kg body weight) or saline will be administered over a 2 to 2½ hour period while subjects 
rest quietly in an infusion chair solely used for infusions. Subjects will be monitored during the infusion 
and for 30 minutes after completion for the possible development of anaphylaxis, which occur in less than 
1% of patients receiving an initial dose of infliximab. All aspects of the infusion will be overseen by 
infliximab-trained nurses and the standard protocol for acute adverse reactions will be initiated if subjects 
develop anaphylaxis during infusion. 
Randomization: A randomly generated sequence of assignments to infliximab or saline will be created 
and maintained by the study pharmacist. Subjects will be stratified on the basis of sex to obviate any 
confounding effect of gender on the outcome variables. Subjects will be randomized in blocks of 4. 
Allocation to infliximab or saline will occur when a patient is eligible for the study and the consent for 
randomization has been obtained. If a subject drops out prior to receiving the infusion, he/she will not be 
included in data analyses and his/her randomization assignment will “roll over” to the next recruited 
subject until 60 subjects have received an infusion and at least one post infusion assessment. 
Blinding/Saline Preparation: An unblinded pharmacist will be responsible for preparing the infusion bag 
with either infliximab or normal saline based on the pre-determined order of the randomization list 
supplied by the study statistician. 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. Such adverse reactions are indicated in section on Human Subjects Protection. 
Unblinded subjects will be discontinued from the protocol. An unblinded physician not associated with the 
study will contact the study pharmacist in cases where medical intervention requiring knowledge of group 
assignment is clinically warranted. 
Lumbar Puncture (LP): On Week 2-Visit 2 (within 2 weeks, or at the discretion of the PI) of the Week 2-
Visit 1 procedures (blood sampling, neuropsychiatric assessments and MRS), all subjects will receive ~1 
liter of normal saline through an indwelling catheter to reduce incidence of post-LP headache and 
standardize hydration levels. Before the procedure, subjects will be offered pre-LP sedation (e.g. Versed) 
through IV. An anesthesiologist will review the results of the PT and PTT coagulation tests collected 1-14 
days prior. The anesthesiologist will perform the LP using standard sterile technique and local anesthesia 
with patients in the lateral decubitus position. ~10 cc of CSF will be withdrawn. After discarding the initial 
1 ml (to avoid blood contamination), remaining CSF will be collected into chilled tubes and aliquoted on 
ice in 1ml Eppendorf tubes, which will be immediately frozen at –80 C for later batched analyses. Upon 
LP completion, subjects will lay flat for ~1 hour and will be observed and treated for any side effects (e.g. 
headache or local irritation at LP site). The nurse practitioner or designee will also make a follow-up call 
1, 3, 7, and 14 days following the LP to check if patients are experiencing any other study emergent side 
effects including chronic pain. If any patient expresses persisting pain or any other study emergent 
adverse event, then the information will be forwarded to the study MD for further management. 
30 Day (Post-Infusion) Follow-Up Call: The research team will call subjects 30 days post-infusion to 
assess for any adverse events that may have occurred after study completion.      
 
 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
9 
Version: February 14th, 2020  
Optional Combination Study: Department of Psychology Task-Based fMRI Scan Visits: 
Study participants may choose to complete 2 additional scan visits as an optional extension of this study. 
These visits are a part of a Task-Based Functional MRI (fMRI) study under the Department of 
Psychology, Dynamics of Inflammation and its Blockade on Motivational Circuitry in Depression, 
IRB#00087941 (see Table 1B). The purpose of the study is to see how the brain processes different 
types of information, and the way this affects behavior. Both study visits, the Baseline: fMRI Scan Visit 
and 14 Day: fMRI Scan Visit will take place at the Emory Department of Psychology on campus. The 
combined protocol scan visits will be consistently scheduled in the following order: Baseline Visits (fMRI 
scan → MRS Scan) and 14 Day Visits (MRS Scan→ fMRI scan). All scans should be within 3 days of 
either the infusion visit or week 2. Participants will complete behavioral tasks, self-report questionnaires, 
fMRI scans, urine drug tests and urine pregnancy tests (if applicable) at each visit. Subjects will sign a 
separate consent form to participate in the combination study. Participants completing the additional 2 
day study option will be paid up to $800 in addition to the compensation received for the main study.  
 
Table 1C:  
Baseline: Task- 
Based fMRI  
scan  
** 
 
 
Baseline 
(MRS Scan) 
 
Infusion 
1 Day 
 
 
3 Day 
(MRS Scan) 
 
7 Day 
 
 
14 Day 
(MRS Scan) 
 
14 Day: 
Task- Based 
fMRI scan 
** 
LP 
Optional 
IGLU Study 
IGLU Study 
IGLU Study 
IGLU Study 
IGLU Study 
IGLU Study 
Optional 
IGLU Study 
 
Subjects participating in the combination I-Glu/Infliximab studies will complete the Additional Measures 
below as part of participation in the IGLU study schedule: 
Self-Report Measures 
The below self-report measures will be collected at the Baseline, 24-Hr, 3-Day, and 7-Day Visits.  
PANAS-X: The Positive Affect/Negative Affect Scale (PANAS) is a widely used measure of in-the-moment 
aspects of positive and negative affectivity, and will be used as an additional measure of self-reported 
changes in anhedonic symptoms following inflammation blockade.  
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.  
Optional Combination Study (con’t): 
Behavioral Computer Tasks 
The below task will replace the Gambling task administered at Baseline, 3-Day, and 7-Day visits. 
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. 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 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
10 
Version: February 14th, 2020  
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.  
 
Criteria for Study Discontinuation (“Stopping Rules”):  
Individual: 
Subjects will be closely evaluated for worsening of psychiatric symptoms during the study. Subjects will 
be evaluated at baseline and at post-infusion Day 3 and weeks 1 and 2. Subjects will be discontinued at 
any point after screening for any of the following: 1) significant suicidal ideation as determined by 
spontaneous subject report or as clinically warranted based on the Columbia Suicide Severity Rating 
Scale – Screen Version (CSSRS),55 2) psychotic or catatonic symptoms and 3) serious complications of 
TNF antagonism (e.g. serious infection). Meeting discontinuation criteria prior to baseline will result in a 
subject not undergoing infusion. Subjects who meet discontinuation criteria following infusion will be 
discontinued. Subjects requiring discontinuation will be evaluated for danger to self or others and will 
receive emergency referral if required. In non-emergent cases, the referring clinician will be contacted 
immediately and a plan for appropriate psychiatric or medical care will be established and implemented.  
Study: 
1) If more than two individuals experience a reportable serious adverse event related to study procedures 
within a six month period, the study will be stopped and reviewed by the DSMB. 
 
Neuropsychiatric Assessments 
Structured Clinical Interview for DSM-V Axis I Disorders (SCID-V) is a semi-structured clinical 
interview that provides a wide range of DSM-V diagnoses.56 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 psychiatric predictors of treatment response, including number of past major 
depressive episodes, length of the current episode and presence of co-morbid anxiety disorders and/or 
dysthymia. The Mood Disorders and Alcohol/Substance Abuse Modules will be administered at all study 
assessments to evaluate whether subjects continue to meet criteria for major depression and to evaluate 
whether subjects have developed substance abuse symptoms (also confirmed by urine toxicology screen 
at each assessment). 
The MGH Antidepressant Treatment Response Questionnaire (ATRQ):57 The ATRQ provides specific 
criteria for adequate dose and adequate length of a trial for it to be considered a failure, thus allowing 
clinicians to systematically collect data aimed at assessing degree of treatment-resistance of the MD 
episode. The data obtained can then be used to calculate a score using the MGH Staging Method (MGH-
S) to classify degree of treatment resistance.58 Degree of resistance will be used as a covariate in 
relevant statistical analyses and to exclude severely treatment resistant subjects.53 
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 < 28, which is a standard cutoff for clinically significant cognitive 
impairment.52 
Dependent Variables 
MRS acquisition: 
The scanner hardware and the scanning sequences described in this section are similar to those 
described previously,2 but modified for the PRISMA platform. All images will be acquired using a Siemens 
3 Prisma 3T scanner (Siemens Medical Solutions, Malvern, PA, USA) equipped with a maximum gradient 
strength of 80 mT/m and a rise time of 200 μs, which will provide nearly double the signal-to-noise ratio 
enabling high-resolution structural imaging data. The new digital RF system equipped with 64-channel RF 
head-and-neck coil and the two-channel RF excitation coils will provide better spectral resolution with 
improved signal-to-noise ratio while at the same time providing more uniform excitation pulses. For image 
guidance and MRS volume of interest prescription, anatomic images will be obtained using a T1-weighted 
MPRAGE sequence with the following parameters: TR/TI/TE =2300/900/3.02 msec; flip angle=8°; FOV 
read=256 mm; matrix=256; slice thickness=1mm; GRAPPA factor of 0; total scan time=6 minutes. 
Single Voxel MRS Acquisition: 
Single Voxel Spectroscopy (SVS) will be used to quantitate of neurometabolites of interest in specific 
brain regions with a focus on the basal ganglia (see Figure 5 for sample basal ganglia spectrum). SVS 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
11 
Version: February 14th, 2020  
will be acquired using ChemicalShift Selective (CHESS)-based MRS sequence using settings of TR/TE = 
3000/30 ms, sampling size=128 averages, bandwidth=1024Hz. Two voxels with sizes of 17 x 30 x 17 
mm3 located in the left and right basal ganglia (encompassing parts of the caudate, putamen and 
pallidum and the associated intervening white matter),one voxel in dACC (BA 24) with a size of 20 x 30 x 
10mm3, and one “control” voxel located in the left medial parietal regions of 20x20x20 mm3 (to explore 
regional specificity of the findings) will be used for SVS (see Figure 6). Spatial localization will be 
implemented using PRESS technique.59 Numerically optimized Shinnar-Le Roux (SLR) radio frequency 
pulses will be used for PRESS (90°, 180°, 180°) and CHESS (90°, 90°, 90°).60 Four unsuppressed water 
FIDs (free induction decay) will also be acquired for eddy current suppression and phase correction66 
and to compute metabolite/water ratios if needed (LC-Model). The FWHM of the unsuppressed water 
peak will be optimized to <14 Hz by shimming. Of note, to facilitate spectral acquisition in deeper regions, 
previously phantom optimized 20-channel coil will be used. The spectral data will not be apodized  
Chemical Shift Imaging (CSI): The application of a single voxel to a specific region makes it difficult to 
evaluate diffuse or global cortical and subcortical glutamate abnormalities that may occur in association 
with inflammation and have been proposed to occur in unipolar depression.61 The setting will be similar to 
those reported in our recent publication. CSI will be acquired for exploratory analyses using 2D Point 
Resolved Spectroscopy (PRESS)-based MRSI sequence using settings of TR=1590 ms, TE=30 ms, 
averages= 7, matrix=16×16, voxel size=11. 3×11.3×15 mm3, slice thickness=15mm. The raw files will be 
processed using LC-Model.62 
Post Processing: 
Metabolite Spectral Fitting: The LC-Model62 is an operator-independent commercial software package 
that fits in vivo metabolite spectra using model resonances acquired from multiple compounds in standard 
phantom solutions. The water suppressed time-domain data will be analyzed between 0.4 ppm and 4.0 
ppm without T1 and T2 correction. The basis set provided by the vendor of the LC Model62 will be used 
and then scaled to account for receiver gain differences. While the entire 18 metabolite basis set would 
be entered during metabolite fitting, the analysis will only include metabolite variances (Cramer Rao 
Lower Bounds or CRLB) <20. Use of a high field strength (Prisma 3T) scanner and short TE (=30 msec) 
sequence has enabled us to calculate metabolites at very low metabolite variance (CRLB <10) in our 
previously published MRS studies. 
Water scaling and relaxometry: The post processing pipeline will be developed to yield absolute 
metabolite quantitation as well as metabolite/water and metabolite/creatine values. LC model provides 
automated water scaling settings which will be used (DOWS). All data (water signal and water 
suppressed data) will be phased followed by quantification of water relaxometry data. The relaxometry 
data will then be fitted to obtain water reference data and in the case of gray matter following 
segregation of the CSF and tissue water constituent. Finally, water signal will be scaled to that of 
resulting value obtained in previous steps.  
Tissue correction and segmentation: T1-weighted images will be segmented into gray matter (GM), 
white matter (WM), and cerebrospinal fluid (CSF) compartments using FreeSurfer 
(https://surfer.nmr.mgh.harvard.edu/fswiki) on the whole brain T1 images. A volume of interest (VOI) will 
be generated on the T1 images, matching the location and size of MRS voxels indicated above. 
Volumes of GM, WM and CSF segments in this volume-of-interest will then be generated using 
FreeSurfer. The absolute metabolite concentrations generated by the LC-Model will then be corrected 
for CSF using the formula metabolite C = Co x 1/(1-fCSF), where C is corrected metabolite 
concentrations, Co is metabolite concentrations generated by LC-Model output and fCSF is fraction of 
CSF volume.63, 64 The final output of the absolute metabolite quantitation 
will be provided in units of molality. CSI data will be assessed using metabolite values normalized to 
creatine to minimize methodological constraints published elsewhere65 after ensuring that raw 
uncorrected concentrations of creatine (Cr) and phosphocreatine (PCr) are not significantly different 
among the different study groups in the prescribed regions of interest. 
Macromolecular separation: To address over-interpretation of MR spectra with respect to 
quantification of glutamate in the presence of overlapping glutamine and macromolecules (MM), we will 
conduct a substudy involving 10 healthy control subjects using the approach proposed by Cudalbu and 
Gottschalk et al. in all three regions.66, 67 This experimentally acquired prior-knowledge will represent 
both MM and lipids. This manual metabolite quantitation may have better accuracy than the LC-Model 
vendor-provided synthetic prior-knowledge, and if so, can be used to statistically correct metabolite 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
12 
Version: February 14th, 2020  
quantitation using LC-Model and assist in interpretation of the data. We will also conduct the analysis 
using the individual values of Glu, Glx (glutamate+glutamine) and Gln (glutamine); while setting the 
Crammer-Rao lower bound (CRLB) value for Gln at high (<30%) with LC-Model processing. An 
exploratory analysis of the impact of inflammation on other metabolites of interest including 
choline (Cho), myoinositol (mI) and n-acetyl aspartate (NAA) will also be conducted. 
Neurocognitive Assessments 
In accordance with the recent RDoC proposals by NIMH,68 for our primary dependent behavioral 
variables, we have chosen to examine specific symptom domains that are relevant to the function of the 
basal ganglia and their role in moderating positive and negative valence systems (e.g. anhedonia and 
psychomotor retardation). The entire assessment will take up to approximately 120 minutes (with breaks 
as needed). The examiner will code the reliability of each test score, any alteration of standard procedure, 
and the reason (e.g., frequently repeating instructions due to difficulty with attention). Only trained 
research personnel will perform neurocognitive ratings. 
 
Positive Valence Domain (Motivation) 
Objective 
Neurocognitive Assessments 
Gamble Task: 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, 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 have demonstrated that this technique can be used to establish a relationship between 
task earnings and happiness. This task takes between 10-20 minutes per session. 
  
Go No-Go Variant Task: 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. 
 
Reinforcement Learning Task: Trials for this task involve a 1-3s cue presentation during which subjects 
choose between two abstract stimuli, 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) model 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. This task will include between 80-120 trials and will take approximately 10-15 minutes in 
length. 
 
Subjective Value Task: In this task, subjects will be asked to repeatedly choose between two options to 
obtain a monetary reward. Each option will consist of a horizontal bar (representing reward magnitude) 
with a percentage written underneath it (representing reward probability). A subset of trials in this task will 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
13 
Version: February 14th, 2020  
feature one option where both the magnitude and probability are higher than the alternative option (‘catch’ 
trials). Options will be presented, during which time subjects must wait to indicate their choice. Next, a 
question mark will appear, to prompt participants to press a button to indicate their choice. Choices will be 
confirmed by a frame around the chosen option, which will remain on the screen until the outcome is 
revealed. The outcome (reward or no reward) will be indicated by the bars turning green or red, 
respectively. Outcomes are then followed by an intertrial interval (ITI).  A “prize bar” will be displayed 
between the options and will grow by the width of the reward bar when a subject options a reward. The 
subject’s goal will be to move the prize bar across a target line to win a certain amount of money. Once 
this goal is achieved, the prize bar will be reset and the subject will begin again. This task will last a 
maximum of 20 minutes.  
 
Negative Valence Domain (Psychomotor Retardation) 
Objective 
Neurocognitive Assessments 
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 
nonpreferred 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.73 The 
FTT is designed to assess subtle motor impairment and is altered in subjects with basal ganglia disorders 
and lesions.74 Variables: Mean and total number of taps in 90 sec. for both dominant and non-dominant 
hands 
Reaction Time Task (RTT)(CANTAB): The RTT measures simple and choice movement and reaction 
time 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.75 Variables: Simple and Choice Reaction Time and Movement 
time 
Digit Symbol Substitution Task (DSST): The Digit Symbol Substitution Task is a subtest of the 
Wechsler Adult Intelligence Scale (WAIS) and consists of rows of blank squares, each printed with a 
randomly assigned number. The test involves graphimotor speed, visual scanning and memory, with 
about half of the variance being accounted for by graphimotor speed, a third by visual scanning and 4-5% 
by memory.76 Performance on the DSST has been found to correlate with subcortical atrophy in disorders 
involving basal ganglia including Huntington’s disease and multiple sclerosis.77, 78 Variables: # Correct 
responses within 2 minutes 
Trails Making Test A:79, 80 The scale measures cognitive processing speed using a series of non-
sequentially arranged numbers where the participant is asked to sequentially track the numbers occurring 
to numerical order as quickly as possible. Variables: Completion time 
 
Clinician-Administered and Self-Report Instruments 
Snaith-Hamilton Pleasure Scale (SHAPS-C): The SHAPS-C is a 14-item clinician-administered scale 
that assesses hedonic tone.69, 70 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. In a 
previous study examining hedonic capacity, confirmatory factor analysis revealed a Hedonic Capacity 
factor that was largely defined by the SHAPS.69, 71 
Motivation and Pleasure Scale (MAP): The motivation and pleasure questionnaire is an 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.72 This scale will be used to assess self-reported changes in 
symptoms of anhedonia before and after inflammation blockade. 
Retardation Rating Scale: The RRS is a 14-item, clinician-administered scale used to assess 
psychomotor retardation.81 The items of the scale are either related to motility or mental activity. In factor 
analyses, items 1-8 have been specifically associated with motor retardation in elderly depressed 
patients.82 
Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to measure 
motivation and fatigue, covering the dimensions General Fatigue (GF), Physical Fatigue (PF), Mental 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
14 
Version: February 14th, 2020  
Fatigue (MF), Reduced Motivation (RM) and Reduced Activity (RA).83 Separate scores for each of these 
five dimensions are generated from the MFI. This instrument has reasonable internal consistency 
(Cronbach’s alpha between 0.53 and 0.93) and construct validity. The Reduced Motivation score from the 
MFI has been shown to highly correlate with reduced neural activation in the ventral striatum to a hedonic 
reward task during IFN-alpha administration as determined by fMRI.12 
Assessments of Depression Severity, Suicidality and Bipolarity 
Inventory of Depressive Symptoms-Clinician Rating (IDS-SR) (Item 20) 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.51, 84 
Columbia-Suicide Severity Scale: The Columbia-Suicide Severity Rating Scale (C-SSRS) is a fully-
structured, clinical interview designed to systematically query patients regarding past and current suicidal 
ideation and behavior (SIB)55. The psychometric characteristics of the patient- reported C-SSRS have 
been assessed in multiple contexts. It has well validated to elicit suicidal ideas in depressed subjects and 
will be consequently used to identify individuals experience acute severe depressive symptoms and refer 
them for immediate treatment. 
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.85 To quantify the 
bipolarity risk, the STEP-BD computed bipolarity index scores by rating the patient’s profile relative to five 
traits believed to be most characteristic of Bipolar I disorder. 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. The dimensions include: episode 
characteristics, age of onset, course of illness/associated features, response to treatment and family 
history. A theoretical case with the traits most convincing for bipolar disorder on every dimension would 
score 100 points and most Bipolar I patients score above 60. Most unipolar depressed patients score 
much lower. 
Assessments of Anxiety and PTSD Severity 
Hamilton Anxiety Rating Scale (HAM-A):86 The HAM-A is a 14-item clinician-administered scale that 
assesses the severity of symptoms of anxiety.  
Beck Anxiety Inventory (BAI):87 The BAI is a 21-item self-report measure of anxiety symptoms, rated on 
a 4-point Likert scale modified to be based on the patient's experience in the past week.  
State-Trait Anxiety Inventory (STAI) State Scale:88 This 20-item self-report scale is used to measure 
current anxiety symptoms. 
PTSD Checklist for DSM-5 (PCL-5):89 The PCL-5 is a 20-item self-report measure that assesses the 20 
DSM-5 symptoms of PTSD, rated on a 5-point Likert scale modified to be based on the patient's 
experience in the past week. The accompanying Life Events Checklist (LEC) and Criterion A assessment 
measures trauma exposure. 
 
Safety and Tolerability 
Adverse Event Recording: All adverse events will be coded in standard MeDRA terms (Version 14.1), 
and whether events are expected and study-related will be determined by the study PI or designee. In 
addition, severity and start and end dates will be recorded as well as any evidence of unanticipated 
problems. This information will be provided to the Department of Psychiatry and Behavioral Sciences 
DSMB and IRB annually as described in the Human Subjects Section. 
Laboratory and Biological Variables: 
Blood collection: At Baseline Visits 1 and 2, and post-treatment Days 1 and 3 and Weeks 1 and 2, study 
bloods will be collected under fasting conditions between 8am-10am by venipuncture into two 6mL and 
one 10mL EDTA-containing vacutainer tubes using standard sterile technique. 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. 
Plasma and CSF cytokines and soluble cytokine receptors: Fluorokine MAP Multiplex Human 
Biomarker Panels (R&D Systems, Minneapolis, MN) will be used to measure plasma and CSF TNF-
alpha, sTNFR2, IL-1ra, IL-6, sIL-6R, IL-10, and monocyte chemoattractant protein (MCP)-1. These 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
15 
Version: February 14th, 2020  
cytokines and their receptors have all been found to be altered in depression,5 and TNF and sTNFR2 
have been found to predict response to infliximab and to correlate with basal ganglia glutamate.3, 48, 49 
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 and CSF CRP will be assessed with a high sensitivity turbidimetric 
assay based within the Emory University Hospital. 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. 
Estrogen and Progesterone: Serum estrogen and progesterone will be collected at the ACTSI CRN on 
the day of the subject’s infusion and sent to the EUH laboratory for analysis. Processed in the Emory 
Medical Laboratory. 
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.90 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 analyses. To 
correct for confounding due to batch effects, expression profiles will be normalized using ComBat, an 
empirical Bayes method for batch correction.91 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).92 
6. Participant selection: 
Recruitment and Informed Consent Process 
Male and female subjects with depression will be recruited from local (inter-Departmental) referrals, 
medical record queries and/or social media recruitment campaign(s). Subjects in this study may also be 
referred from our Behavioral Immunology Program “Recruitment Clinic” protocol, Psychiatric Research 
Screening Clinic: IRB0000075162, which uses the screening strategy for this protocol to recruit and 
screen patients with depression for our active studies through IRB approved social media campaigns. An 
overview of the study will initially be provided in person or over the phone by study clinicians or trained 
study staff.  A telephone prescreening interview will be conducted on candidates providing verbal 
consent. If a subject shows interest in the study, research staff members will describe the general 
procedures involved and will answer relevant questions. If a subject remains interested in participation, 
the detailed nature, purpose, procedures, benefits, risks of, and alternatives to this research study will be 
explained to each subject, and written informed consent will be obtained by a study clinician, in a private 
office space, who provides this information. To ensure comprehension of the informed consent 
information, the clinician will allow time for questioning and administer a WRAT-3 brief screening level of 
reading to determine if participant is at least evaluated at an 8th grade reading level in order to understand 
the consent language. Informed consent will be documented on the Institutional Review Board-approved 
form. A copy of the signed consent form will be given to the participant and the original document filed in 
a central study consent binder. The consent binder(s) and subject casebooks containing information 
gathered as part of the study will be kept in a locked office and/or cabinet. 
Telephone Prescreen Interview 
A telephone prescreen interview will be conducted with study referrals following verbal consent. 
Candidates eligible to proceed with the study process will be scheduled for an appointment to see a study 
clinician 
Onsite visit (s): Trained personnel will obtain written informed consent from candidates prior to initiating 
study procedures. Screening information will be collected by interview and evaluation, as well as 
obtaining collateral history and data from other relevant sources (e. g. medical records, referring 
physician). Screening will include the following assessments: (1) History of medical and psychiatric 
conditions (2) screening laboratory evaluations, (3) subject height and weight measurements and waist 
circumference obtained by staff 4) Concomitant Medications 5) Adverse Events 6) MRI Safety Form 7) 
Demographics and 8) assessments below: 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
16 
Version: February 14th, 2020  
Clinician-Assisted Quick Inventory of Depressive Symptomology (QIDS-16 SR)- A 16-item self-report 
instrument that includes assessment of nine diagnostic symptom domains used to characterize a major 
depressive episode. 
Patient Health Questionnaire (PHQ-9) is a nine-item measurement used to assess depressive symptoms 
and suicidal ideation.    
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 <28 (unless otherwise approved by the PI), which is evidence of mild 
cognitive impairment.83  
WRAT-3 is a very brief screening measure for reading level. Participants evaluated at less than an 8th 
grade reading level may not participate unless otherwise approved by the PI.  
Child Trauma Questionnaire (CTQ) is a standardized, retrospective 28-item self-report inventory that 
measures the severity of different types of childhood trauma. Participants will not be excluded for history 
of childhood trauma.  
 
Laboratory Variables 
Research bloods will be collected by venipuncture into EDTA-containing vacutainer tubes using standard 
sterile technique. Plasma and buffy coat for the evaluation of 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 and buffy coat will be removed separately, aliquoted into siliconized polypropylene tubes, 
and stored at -80°C until batch assay. Bloods will also be collected by venipuncture into Tempus mRNA 
tubes and directly placed in freezer storage at -20°C. In order to further assess immune cell profiles, we 
will additionally collect 10 ml of whole blood in EDTA at room temperature for immune cell extraction. 
Tempus tubes and buffy coats will be sent to the Emory Integrated Genomics Core for RNA extraction, 
gene expression, mRNA profiling, epigenetic evaluation and measurement of gene polymorphisms. Some 
samples may be sent to other labs for additional analysis. 
Plasma cytokines and soluble cytokine receptors: Customized high sensitivity Fluorokine MAP 
Multiplex Human Biomarker Panels (R&D Systems, Minneapolis, MN) will be used to measure plasma 
TNF-alpha, sTNFR1 and 2, IL-1ra, IL-6 and sIL-6R. 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 is 0.18 mg/L, range of measure is 0.2 to 80 mg/L, and functional sensitivity (at 20% CV) is 0.2 
mg/ L. 
Tryptophan and Kynurenine: Free tryptophan and kynurenine plasma concentrations will be determined 
by high-performance liquid chromatography in the laboratory of Dr. Dietmar Fuchs or other laboratories 
with equivalent expertise at the PI’s discretion. 
Gene expression and epigenetics: As indicated above, blood will be obtained for analysis of 
inflammatory mediators and signaling pathways. 
7. Management of MRS Incidental Findings 
The purpose of these scans is not to make a clinical determination of patients’ brain health.  However, if 
any incidental finding is noticed during the scan, the information will be provided to patients or their 
medical provider-of-record for further management.  Incidental findings are those abnormalities seen in 
patients’ brain images during the scanning process, which may or may not be of clinical importance.  
Follow-up of the scan findings will be the responsibility of the patients’ Emory Healthcare provider-of-
record.  
8. Sources of Materials: Research material will be derived from clinician-administered and self-report 
questionnaires, blood, urine, cerebrospinal fluid and MRS scans. Material for evaluating baseline medical 
status and subject safety prior to infusion will be obtained from blood and urine. Data to be recorded from 
subjects will include standardized ratings of emotional, cognitive and physical symptoms, as well as 
clinical information derived from medical records when available, interviews with the subject, referring 
physicians and family members when relevant. Data on cardiac functioning will be obtained from EKG. 
Data will be obtained from peripheral blood, including complete metabolic panel, CBC with differential, 
serum pregnancy test, anti-nuclear antibodies, rheumatoid factor, serum concentrations of estrogen and 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
17 
Version: February 14th, 2020  
progesterone, blood tests for fungal infection (aspergillus antibody, blastomyces antibody, coccidioides 
antibody, histoplasma antibody) plasma concentrations of TNF-alpha, sTNFR 2, IL-1 beta, IL-1ra,IL-6, 
sIL-6R, IL-10, MCP-1, and CRP. CSF will be used to measure concentrations of TNF-alpha, sTNFR 2, IL-
1 beta, IL-1ra, IL-6, sIL-6R, IL-10, MCP-1, and CRP. Blood for mRNA expression analyses will also be 
collected. Data obtained from urine will include urinalysis and toxicology screen. Clinical data that will be 
used to assess eligibility and safety will be collected via interview and documented by study clinicians. 
Standardized clinician administered and self-report questionnaires will be administered and collected by 
study physicians or study coordinator. Blood and urine samples at screening will be obtained by the study 
coordinator and nursing staff at the Emory Clinical Research Network (CRN). Blood and urine for the 
baseline assessment (Visits 1 and 2) and subsequent assessments on days 1 and 3 and weeks 1 and 2 
for study bloods and weeks 1 and 2 for safety labs will also be obtained by CRN nursing staff. All data, 
including questionnaires and blood and urine samples will be coded by unique identifying numbers. 
Subjects’ names will not appear elsewhere in any form that would link them specifically to data. Subject 
name and identifying number will be kept on separate forms in a locked office separate from data files. 
Only the study coordinator and study physicians will have access to subject identities. Research 
personnel analyzing blood data or entering data into the database will not be provided information from 
which they could identify subjects by name. Only the identifying number will be used during MRS 
 scanning and post processing. All information will be obtained solely to determine eligibility for study 
participation or for research purposes or to monitor subject safety following the infusion. Nevertheless, 
any abnormalities uncovered will be reported to the subject and his/her treating physician for follow-up or 
will be used by study clinicians to determine appropriate medical care in the case of adverse events 
related to the infusion. 
9. Data Collection and Management: The data management team will use REDCap.93 REDCap allows 
database construction, an interface for collecting data, data validation, and automated export procedures 
for data downloads to statistical packages (SPSS, SAS, Stata, R). Dr. Miller is currently using REDCap 
for 3 of his currently funded projects, and he and his staff have extensive experience with its usage. 
Caveats and Considerations 
It should be noted that in this study we are using peripheral blood CRP as a proxy measure for CNS 
inflammation. Our previous data in two published reports have demonstrated that plasma 
CRP is associated not only with basal ganglia glutamate, but also connectivity between ventral striatum 
and ventral medial prefrontal cortex, both of which were correlated with anhedonia.2, 94 In addition, plasma 
CRP was a robust predictor of the clinical response to infliximab.3 Finally, peripheral CRP highly 
correlates with CSF CRP (see Figure 7), and CSF CRP not only correlated with left basal ganglia 
glutamate using CSI in our recently published work,2 but also significantly correlates with CSF IL-6, CSF 
sTNFR2 and CSF MCP-1 (all p<0.05). Therefore, for the purposes of identifying patients that are likely to 
exhibit increased inflammation and its consequences in the CNS, we believe plasma CRP is an excellent 
proxy measure for CNS inflammation. Another caveat is that infliximab does not cross an intact blood 
brain barrier (BBB). Nevertheless, previous studies have shown that blockade of peripheral inflammation 
through the use of monoclonal antibodies like infliximab can abrogate stress-induced depressive-like 
behavior in rodents.95 These data suggest that peripheral inflammation may drive central inflammatory 
responses and their effects on behavior, and blocking peripheral inflammation may reduce central 
inflammation and its effects on the brain.8 This possibility will be examined for the first time in Aim 3 by 
sampling CSF inflammatory markers after inhibition of peripheral inflammation by infliximab. Finally, we 
should note that the MRS glutamate signal is a proxy measure for glutamate concentrations in the brain 
including both intracellular and extracellular compartments. Moreover, the modeling which determines 
glutamate concentrations in the brain provides an approximation of several confluent spectral peaks 
including glutamate, glutamine, GABA and glutathione, with glutamate representing the primary 
component. As indicated above, however, various strategies are proposed to address this issue. 
10. Statistical Analyses 
Aim 1: To determine whether inhibition of inflammation reduces basal ganglia glutamate. 
Hypothesis 1. Compared to placebo, infliximab-treated patients will exhibit decreased absolute 
glutamate in the basal ganglia on day 3 and week 2. Mixed-effects models for repeated measures 
(MMRM) will be employed to examine effects of group, time and their interaction on left and right basal 
ganglia glutamate controlling for baseline glutamate concentrations. Relevant covariates including age, 
sex, race (white/non-white), menstrual status (estrogen/progesterone) and body mass index (BMI) as well 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
18 
Version: February 14th, 2020  
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 teste tested in the conducted for the dACC and medial parietal voxels. 
Aim 2. To determine the relationship between basal ganglia glutamate and anhedonia and 
psychomotor retardation. 
Hypothesis 2. Decreased basal ganglia glutamate concentrations will be associated with improved 
objective and clinical measures of anhedonia and psychomotor retardation. Random intercept 
linear mixed models will be used to assess whether change in left or right basal ganglia glutamate predict 
change in motivation and psychomotor activity. Models will be adjusted for relevant clinical covariates as 
indicated above. Separate analyses will be run for each behavioral outcome of motivation (Gamble Task, 
Go No-Go, RLT, PRT SHAPS-C, MAP) and psychomotor speed (FTT, RTT, DSST, Trails, RRS, MFI) as 
well as total depression severity scores using the IDS-SR. Type I errors as a result of multiple testing will 
be controlled by using a step down Bonferroni procedure.96 Given that changes in basal ganglia glutamate 
may occur prior to changes in behavior, lagged regressor models will also be explored to determine 
whether early changes in basal ganglia glutamate predict subsequent changes in motivation and motor 
activity in separate analyses. Finally, exploratory analyses will be conducted to examine the impact of 
basal ganglia glutamate on suicidality (STS), given that the relationship between inflammation and 
suicidality may be mediated by glutamate. This possibility is supported by the impact of the glutamate 
antagonist ketamine on suicidality as well as the relationship between gene expression of glutamate 
signaling pathways and suicide in postmortem brain tissue.97, 98 
Aim 3: To determine the relationship between inflammatory markers and basal ganglia glutamate. 
Hypothesis 3. Decreased peripheral and central markers of inflammation will precede and predict 
decreases in basal ganglia glutamate. Random intercept linear mixed models will be used to assess 
whether change in inflammatory variables predict change in left or right basal ganglia glutamate 
controlling for relevant covariates as appropriate (see above). In the first model, only the effect of CRP 
will be tested.  Subsequent models will include the cytokines and their receptors in both blood and CSF. 
In the case of collinearity among inflammatory measures, principal component analyses will be used for 
the purposes of data reduction. Given the rapid changes that will likely occur in inflammatory markers 
prior to changes in basal ganglia glutamate, lagged regressor models will also be explored to determine 
whether early changes in inflammatory variables predict subsequent changes in basal ganglia glutamate. 
For analysis of mRNA expression, separate delta values between baseline and day 3 and baseline and 
week 2 will be calculated for both mRNA expression and basal ganglia glutamate. Regression analyses 
will then be performed on delta values to identify mRNA transcripts that are significantly correlated with 
delta glutamate (FDR<0.05). RNA transcripts found to significantly predict changes in basal ganglia 
glutamate will be entered into pathway analyses using a number of tools including the WebGestalt 
WikiPathways tool and Bibliosphere™ 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).99 Transcript origin analysis will also be used.100 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 groups.100, 101 Exploratory 
analyses will be conducted using the strategies indicated above for CSI measurements of glutamate and 
other metabolites normalized to creatine. 
11. Power Analysis: A power analysis was conducted using our preliminary data examining a cohort of 
50 unmedicated patients with major depression. The sample size was powered on the basis of Aim 1, 
which represents the primary hypothesis of the study that decreasing inflammation will decrease basal 
ganglia glutamate. The effect size (d) of the differences in glutamate concentrations between high 
(>3mg/L) and low (<1mg/L) CRP was 1.15 using absolute tissue-corrected glutamate concentrations. 
Using a beta/alpha error ratio of 4, the proposed sample size of 60 patients (30 infliximab and 30 placebo) 
will yield a power of 0.99 with an alpha error probability of 0.001 and beta error probability of 0.005 
(computed using G*power). Linear analysis-based power calculations using r=0.43 and d=0.95 (from our 
preliminary data) with the proposed sample size of 60 and 5 predictors (age, sex, race, BMI, CRP) will 
have a power of 0.93, with alpha error of 0.01 and beta error of 0.07. Given our anticipated attrition rate of 
10%, we will still have ample power for the proposed analyses. 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
19 
Version: February 14th, 2020  
12. Potential Study Risks: There are 7 major areas of potential risk in the proposed study stemming 
from 1) neuropsychiatric assessments, 2) blood drawing, 3) lumbar puncture, 4) MRS scanning, 5) 
infusion of infliximab, 6) placebo treatment, and 7) loss of confidentiality. Neuropsychiatric assessments 
may uncover strong and potentially disturbing feelings about the subject’s past or present emotional state. 
The risks of blood drawing include discomfort, bruising, infection, bleeding, and fainting. Undergoing MRS 
scan poses no more risk than undergoing a routine MRI scan. Physical discomfort due to lying in the 
scanner, occasional headaches due to scanner sounds and previously unrecognized claustrophobic 
attacks are the prominent adverse effects of the procedure. Some patients experience some lower back 
pain after a lumbar puncture. This is usually felt in and around the area where the needle was inserted. In 
most cases, the pain will ease after a few days and it can be treated with analgesics, such as 
acetaminophen, if necessary. Headache and lower back pain are the most common side effects of a 
lumbar puncture, usually developing within 24 to 48 hours of the procedure. There is a small risk of a 
lumbar puncture leading to intracerebral bleeding, although this is very rare. The likelihood of a lumbar 
puncture causing an infection in the spine is also very small. 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. Very rarely (less than 1%), more serious adverse events have been reported, including 
severe anaphylactic reaction to 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.102 Nevertheless, 
more recent data in RA patients (including analysis of more than 40,000 patients and 150,000 patient-
years exposure) indicate that TNF inhibitors are not clearly associated with increased malignancy in RA 
excluding skin cancer.103 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). 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. Finally, there is a risk of loss of confidentiality. Confidentiality of all subjects will be protected per 
institutional and NIH and other federal requirements, and as described in greater detail below. 
Alternatives include not participating in the proposed study. An array of demonstrated effective treatments 
for depression exists and include, but are not limited to: selective serotonergic antidepressants (i.e. 
fluoxetine, paroxetine, etc.), serotonin-norepinephrine reuptake inhibitors (i.e. venlafaxine, duloxetine), 
atypical antidepressants (i.e. bupropion, mirtazapine, nefazodone), tricyclic antidepressants, monoamine 
oxidase inhibitors, electroconvulsive therapy (ECT) and psychotherapy (i.e. interpersonal and cognitive 
behavioral therapies). Risks and side effects of these agents vary in type and severity depending on 
class, but include sexual dysfunction, gastrointestinal distress, anxiety, anticholinergic symptoms, 
induction of mania, suicidal ideation and potential lethality in overdose. Common risks of ECT include 
short term memory loss, head and body aches and risks related to anesthesia. Benefits of 
antidepressants and ECT include documented efficacy in the treatment of depression. In addition to 
approved modalities, trials of novel treatments for more severe depressions are ongoing and include the 
use of vagal nerve stimulation and deep brain stimulation. Benefits of these modalities may include 
efficacy for patients who have failed traditional agents. Risks include the possibility that these modalities 
are not effective. There are also surgery-related risks of infection and anesthesia involved with these 
modalities. At screening, study clinicians’ will discuss benefits and side effects of these alternative 
treatments with subjects compared to the risks and potential benefits of study participation. 
13. Adequacy of Protection Against Risks:  
Recruitment and Informed Consent: 
Subjects with major depression will be recruited from outpatient evaluation clinics within the Department 
of Psychiatry and Behavioral Sciences, Emory University School of Medicine and from advertising in 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
20 
Version: February 14th, 2020  
radio, television, internet and print media. The Emory outpatient clinics evaluate potential subjects for 
appropriateness for participation in several on-going trials of various modalities for MD. 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 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 a 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 
case-book containing relevant demographic data for the subject. Of note, because this case-book will 
contain personal identifiers (i.e. name), it will be kept separate from any data 
gathered as part of the study, and will be kept in a locked office. Protection Against Risk: Every effort will 
be taken to prevent injury or distress that may result from this study. 
Neuropsychiatric Assessments: 
Care will be taken to avoid bringing about undue psychological distress during the neuropsychiatric 
interviews. This will be accomplished by using trained raters (clinicians) for all neuropsychiatric 
assessments. In the event that a subject becomes unduly distressed, Drs. Miller or Haroon will be 
immediately contacted, and an appropriate clinical intervention plan will be developed. Drs. Miller and 
Haroon are Board Certified psychiatrists, consultation-liaison, inpatient and outpatient psychiatry. In 
cases where patients need extra time to collect their thoughts and emotions, mental health clinicians will 
be available for emotional support after all interviews. 
Blood Draws: Standard sterile procedure for blood withdrawal will be used. Blood draws will be 
conducted by clinicians with significant experience in the technique. In addition, the volume of blood 
withdrawn for this study will not exceed 200 ml over a maximum 4-week period (from screening to study 
completion). 
MRS scans: To minimize discomfort during the MRS scanning, patients will be provided with a head 
cushion and ear plugs. Patients will also be informed about the progress of the procedure through a 
remote microphone. In the case of patients developing acute anxiety or panic the scanning session will be 
terminated and patient provided enough support to cope with the feelings induced by the scanner. 
Lumbar Puncture: On day of the Emory outpatient CRN admission, subjects will receive approximately 
~1 liter of fluid iv as a result of a KVO (keep vein open) flow of normal saline through the indwelling 
catheter. This administration of iv fluids has been found in our experience to markedly reduce the 
incidence of post-LP headache. It will also help standardize hydration levels between subjects. An 
anesthesiologist will review the results of the PT and PTT coagulation tests collected 1-7 days prior. The 
anesthesiologist will perform the LP, using standard sterile technique and local anesthesia with patients in 
the lateral decubitus position. Approximately 10 cc of CSF will be withdrawn. After discarding the initial 1 
ml (to avoid blood contamination), the remaining CSF will be collected into chilled tubes and aliquoted on 
ice in 1 ml Eppendorf tubes, which will be immediately frozen at –80 C for later batched analyses. Upon 
completion of the LP, subjects will lie flat for approximately one hour and subsequently discharged. Some 
patients experience some lower back pain after a lumbar puncture. This is usually felt in and around the 
area where the needle was inserted. In most cases the pain will ease after a few days and it can be 
treated with analgesics, such as acetaminophen, if necessary. A headache is a common side effect of a 
lumbar puncture, usually developing within 24 to 48 hours of the procedure. Most people describe a dull 
or throbbing pain at the front of their head and this can sometimes spread to the neck and shoulders. The 
pain is usually worse while standing or sitting up and is usually relieved by lying down. The headache can 
usually be treated with simple painkillers such as acetaminophen. Some people have also reported that 
drinks containing caffeine, such as coffee, tea and or cola, have helped reduce the discomfort. If post-
lumbar puncture headaches persist, are particularly severe, or are accompanied by sickness and 
vomiting, the patient will be advised to call the study physician to be triaged appropriately. For intractable 
post LP headaches, the current standard-of-care is to apply an epidural blood patch. At Emory, 
anesthesiologists conduct this procedure, which can be performed 24 hours a day for emergencies. 
There is a small risk of a lumbar puncture leading to intracerebral bleeding, although this is very rare. The 
likelihood of a lumbar puncture causing an infection in the spine is also very small. However, patients will 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
21 
Version: February 14th, 2020  
be asked to call the study physician, if the patient develops a temperature or sensitivity to bright lights, or 
if the lumbar puncture site becomes painful and swollen. 
Infliximab: Several procedures will be put in place to reduce the risks associated with receiving 
infliximab. At screening, subjects will be carefully evaluated for the presence of any medical conditions 
that might increase the risk of an adverse reaction to the medication. For example, because anaphylactic 
reactions are more common after subsequent dosages of infliximab, all subjects will be naïve to the 
medication so that they will be receiving their first dose of infliximab in this protocol. It should be noted 
that the medical exclusion criteria for the protocol are very conservative and address all areas of potential 
concern, including outcomes such as cancer (including skin cancer), which has been linked to the use of 
infliximab in some studies. Moreover, to reduce the risk of inducing autoimmunity, subjects will be 
excluded for a history of autoimmune conditions such as RA and Inflammatory Bowel Disease (IBD), for 
which infliximab has FDA approval and has been established as safe enough to warrant widespread use. 
Subjects will be excluded for presence of autoantibodies to nuclear antigens and the presence of 
rheumatoid factor. A full list of all exclusionary criteria is presented in the text of the proposal (see 
Research Strategy). To further reduce risks associated with infliximab, all infusions will be conducted in 
the research outpatient unit of the Atlanta Clinical and Translational Science Institute- Clinical Research 
Network. All infusions will be conducted by specially-trained infliximab infusion nurses who will follow the 
standard protocol for acute adverse reactions if necessary. Subjects will be evaluated by medical 
personnel 1 and 2 weeks post-infusion and will be available 24/7 if problems arise. Safety labs will be 
drawn prior to and up to 2 weeks after the infusion to screen for adverse responses to the medication. 
Prior to the infusion, a study clinician will review potential adverse events and will explain symptoms to 
look for (i.e. signs of infection or sickness, rash, fatigue, etc.) and report. The ACTSI-CRN has standard 
protocols in place for the treatment of acute allergic reactions to the infliximab infusion as follows: 
FOR MILD REACTIONS: Headache, chills, itching, hives, rash, chest tightness, low grade fever: 
A. Stop infliximab infusion 
B. Monitor patient closely for further side effects (monitor vital signs q 5 minutes x 15-30 minutes) 
C. May give acetaminophen 325-1000 mg po 
D. May give diphenhydramine 25-50 mg IV or po 
E. Restart infliximab infusion at reduced rate (10 cc/hour x 15 minutes and increase by 5 cc/hour @ 15 
minute intervals once symptoms subside and patient is reassured by physician 
FOR SEVERE REACTIONS: Hypotension, bronchospasm, wheezing, shortness of breath, throat 
tightening, swelling, body temperature >101 F. 
A. Stop infusion of infliximab immediately 
B. Call M.D. Administer 02 
C. Call 911 if patient acutely unstable 
D. 0.9 normal saline IV fluid per physician order 
E. Monitor patient closely for airway, breathing, circulation. Monitor vital signs q 5 minutes 
F. Give diphenhydramine 25-50 mg IV push (may repeat in 2-3 hours) 
G. Give solucortef 250 mg IV push per M.D. 
H. Give epinephrine 1 mg in 1:1000 concentrate IV push (may repeat q 2-5 minutes as needed for blood 
pressure/heart rate support) per M.D. 
I. Place oral airway, lay flat, start CPR if needed. STAY WITH PATIENT. Call 911. 
Placebo: 
To reduce the risks associated with not receiving an active treatment, only subjects judged to have no 
active suicidal plan or intent will be recruited. Between signing consent and completing the screening 
assessment, a period of no more than 2 weeks will pass until baseline, and during this period a study 
clinician will evaluate each depressed subject every 7 days to ensure that symptoms haven’t worsened 
appreciably or that suicidal ideation has not developed. In the case of either of these eventualities, 
subjects will be discontinued from the study immediately and appropriate psychiatric referral will be made. 
Specific indications for discontinuation (Stopping Rules) between screening and study endpoint for any 
subject will include any of the following: 1) the development of significant suicidal ideation, plan or intent 
as determined by spontaneous subject report or as determined by the Columbia Suicide Severity Rating 
Scale – Screen Version (CSSRS), 2) the development of psychotic or catatonic symptoms, 3) the 
development of serious complications of cytokine antagonism (e.g. serious infection), and 4) a 25% 
increase from baseline of IDS-SR score. Other criteria for discontinuation between screening and the 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
22 
Version: February 14th, 2020  
baseline visit include: hospitalization for any reason or a clinical judgment that a subject is an imminent 
threat to self or others. Subjects will be evaluated for the appropriate level of care, including emergency 
hospitalization if indicated. Subjects with non-emergent symptoms but who disqualify for further 
participation and who are in active treatment will be referred back to their primary psychiatric physician. 
Appropriate follow-up care will be arranged for subjects not in active psychiatric treatment. An 
individualized plan will be crafted for each subject to ensure psychiatric back-up should emergency 
psychiatric care be required after hours or on weekends. Upon completion of the study protocol, all 
depressed subjects without a current psychiatrist will be offered an appropriate referral. 
 
Confidentiality and Data Management: 
Loss of confidentiality is a risk of research participation. Every effort will be made to maintain subject 
confidentiality throughout the study. All project personnel, including those involved in data entry, have 
completed an on-line course in human subjects’ protection for patient-related research with annual 
recertification. Each subject will be assigned a unique ID number that will be used in all data files and on 
all measures in place of personal identifiers. Data entry forms will be developed using the REDcap 
database system developed at the Vanderbilt Institute for Clinical and Translational Research (CTSA). 
REDCap (Research Electronic Data Capture) is an Oracle-based, secure, password-protected, HIPAA-
compliant, web-based application designed to support data capture for research studies. REDCap 
provides: 1) an intuitive interface for data entry (with intrinsic data validation); 2) audit trails for tracking 
data manipulation and export procedures; 3) automated export procedures for seamless data downloads 
to common statistical packages (SPSS, SAS, Stata, R); 4) procedures for importing data from external 
sources; 5) Real-time data cleaning and validation; 6) Automatic field computation; 7) Data dropdowns for 
choice lists (including condition selections based on earlier responses); 8) Data entry warnings for out of 
range or missing values; and 9) Electronic scheduling. Data entry can be performed anywhere using the 
internet and provides 128-bit SSL security. All electronic and hard entry forms will include unique patient 
identifiers to maintain patient confidentiality and will not relate to the patient in any way. Any protected 
personal health information will be encrypted and stored separately. The only link between identifying 
information (e.g.name, contact information) and project data will be in a key stored on a password-
protected computer accessible only to the PIs and to the project coordinators, who will be making 
appointments and assigning research personnel to meet with the participant. Paper forms will be stored in 
locked file cabinets accessible only to study personnel. 
 
Appointment Scheduling & Reminders: 
All participants will be given the opportunity to receive appointment reminders and scheduling information 
via text message on their mobile phones. If the subject consents to this form of communication, study 
staff 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 404-727-9828 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. 
 
Compensation to Participants: 
 
Participants will receive up to $560-$2225 for completion of the study. Participants will be 
compensated using ClinCard. The ClinCard is a web based, reloadable, debit card that automates 
reimbursements for clinical research participants. An additional $25 will be provided to cover travel 
expenses for participants that travel equal to or greater than 50 miles to Atlanta. 
Visit 
Total Amount  
Amount put on Clincard 
immediately after visit  
Amount put on 
Clincard at the end of 
study participation 
Intake 
$25 
$25 
 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
23 
Version: February 14th, 2020  
(Visit Total) 
$25 
 
 
Screening  
 
 
 
Psychiatric evaluation, history 
and physical, EKG, chest x-ray 
and lab work  
$50* 
$50* 
 
(Visit Total) 
$50 
 
 
Baseline Visit 1 
 
 
 
Medical and psychiatric 
assessments, lab work 
research blood, 
neurocognitive tests, and self-
report surveys 
$50 
$50 
 
Computer Motivation Tasks 
(depending on choice made 
on the computer) 
$5-$100 
 
$5-$100 
Complete Scan 
$300 
 
$300 
Incomplete Scan 
$25** 
$25** 
 
Extended break 
$50*** 
$50*** 
 
(Visit Total) 
$80-$500 
 
 
Baseline Visit 2 
 
 
 
Infusion (Infliximab or 
placebo) and all scheduled 
assessments  
$150 
$50 
$100 
(Visit Total) 
$150 
 
 
Post-Treatment Day 1 
(Optional) 
 
 
 
Medical assessment, lab work, 
research blood 
$50 
$50 
 
(Visit Total) 
$50 
 
 
Post-Treatment Day 3 
 
 
 
Medical assessment, lab work, 
research blood, 
neurocognitive tests, and self-
report surveys 
$50 
$50 
 
Complete Scan 
$300 
 
$300 
Incomplete Scan 
$25** 
$25** 
 
Extended break 
$50*** 
$50*** 
 
(Visit Total) 
$75-$400 
 
 
Post-Treatment Week 
1 (Optional) 
 
 
 
Medical assessment, lab work, 
research blood 
$50 
$50 
 
(Visit Total) 
$50 
 
 
Post-Treatment Week 
2  
 
 
 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
24 
Version: February 14th, 2020  
Medical assessment, lab work 
research blood, 
neurocognitive tests, and self-
report surveys 
$50 
$50 
 
Computer Motivation Tasks 
$5-$100 
 
$5-$100 
Complete Scan 
$300 
 
$300 
Incomplete Scan 
$25** 
$25** 
 
Extended break 
$50*** 
$50*** 
 
(Visit Total) 
$80-$500 
 
 
Post-Treatment Week 
2-Visit 2 (Optional) 
 
 
 
Spinal Tap (Lumbar Puncture)  
$500 
 
$500 
(Visit Total) 
$500 
 
 
Total Study 
Compensation 
$560-$2225 
 
*=Screening visit may be divided across 2 visits and paid $25 per visit  
**= Unable to complete scan leading to termination from the study 
***=Subject can leave and return to complete visit if break is a minimum of 2 hours 
 
 
 
POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECTS AND OTHERS 
The direct benefits of study participation will include receiving a psychiatric and medical evaluation, 
including standard blood and urine-based laboratory tests, EKG and MRI scan – done prior to MRS scan 
to enable voxel placement. In addition, subjects will have a 50% chance of receiving a medication that 
may have efficacy for the treatment of their symptoms (infliximab). In addition, placebo interventions are 
effective in reducing or remitting depressive symptoms in some patients and hence may be of benefit to 
some study subjects. Subjects will also have the chance to contribute to a scientific investigation, which 
may be of benefit to future patients. Benefits to others may include gaining significant knowledge 
regarding the role of inflammatory activation in the pathophysiology and treatment of severe depressions. 
As a result of this knowledge, this study may contribute to novel therapeutic strategies for patients with 
major depression. The side effect burden of infliximab is mild and most frequently manifests as minor 
infusion reaction symptoms such as headache and low grade fever. In our pilot study, no differences in 
side effects between infliximab and placebo were found at any point during the study, and neither 
subjects nor staff were able to discern group assignment. These findings suggest that some of the 
reported reactions to infliximab in patients with autoimmune or inflammatory disorders may represent an 
interaction between the drug and their disease. Rates of serious adverse events, such as severe 
anaphylactic reaction or development of serious infection, are rare (less than 1%). In comparison, 
subjects who will be administered infliximab in this study will meet criteria for major depression, a 
condition characterized by severe symptoms, a chronic course and a profound decrement in quality of life 
and social and occupational functioning. Given data that TNF antagonists improve emotional functioning 
in patients with RA and IBD, it is reasonable to expect that subjects who receive infliximab may derive a 
benefit that outweighs the risks involved, especially given evidence that effects from a single infusion of 
infliximab can last for several months. Study subjects who receive a saline infusion will be exposed to the 
risk of venipuncture and of exposure to a pharmacologically inactive treatment. However, subjects 
receiving placebo frequently demonstrate symptomatic improvement. Given the low risk involved with the 
saline infusion and the likelihood that many patients will obtain at least some symptomatic benefit, we feel 
that the risks of the study are reasonable in relationship to the benefits for subjects receiving placebo. 
IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
Successful treatment modalities both arise from, and contribute to, our understanding of disease 
pathophysiology. Mounting data indicate that depression is associated with evidence of 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
25 
Version: February 14th, 2020  
immune/inflammatory activation, and that patients with major depression may be especially likely to 
demonstrate increased proinflammatory cytokine production/release. Furthermore, alterations in the 
functioning and/or metabolic recycling of glutamate and neurotransmission have been demonstrated 
extensively in bipolar depressions and some unipolar depressions as well as anxiety disorders. 
Nevertheless, studies conducted to date have not explored the connection between inflammation and 
glutamate, leaving unanswered questions about the direct relevance of inflammation to the 
phenomenology and/or treatment of major depression as it relates to alterations in CNS glutamate. In 
addition, just as evidence for a conclusive role for monoamines in depression first arose 
from studies of medications that affected the bio-availability of these neurotransmitters, agents that block 
proinflammatory cytokine activity may represent a novel and important strategy for evaluating whether 
inflammation contributes to alterations of glutamate systems that are believed to be directly involved in 
the genesis of depression and responsiveness to treatment. Understanding the mechanisms by which 
inflammatory changes alter glutamate will provide key insights into the association between glutamate 
changes and treatment of depression. Given the current evidence that medications that block NMDA 
glutamate receptor have antidepressant efficacy, this study will reveal mechanisms underlying glutamate 
alterations in depression. Because a wide range of inflammatory indices are being examined, data from 
the proposed study may also shed light on novel biomarkers of inflammation that may help identify 
patients with increased CNS glutamate and may be most likely to respond to therapies targeting the 
immune system and/or glutamate metabolism. For these reasons, we feel that risks to subjects are 
reasonable in relationship to the value of the knowledge (both theoretical and practical) to be gained. 
Investigational Drug Status 
Infliximab has FDA approval for the treatment of RA and IBD. The current proposal represents the use of 
infliximab as an experimental tool to dissect the role of inflammatory processes leading to changes in 
glutamate turnover and changes in specific symptom domains. The proposed study meets the 
requirements for an IND waiver for the following reasons: 
1) Results from the proposed study are not intended to be reported to the FDA in support of a new 
indication for use or to support any other significant change in the labeling for infliximab. 
2) Results from this study are not intended to support a significant change in the advertising for the 
product. 
3) The design of the study does not call for any new route of administration or dosage level (we will use a 
standard dose). There is no evidence that the subject population of the study (medically healthy 
individuals with treatment resistant depression) are at any greater risk than FDA-approved populations 
with RA or IBD. Indeed, our population should be at less risk, given that many patients with RA or IBD are 
also on other immunosuppressive agents. Co-administration of infliximab with other immunosuppressive 
agents (i.e. methotrexate) appears to increase the risk of serious infection with infliximab. There are no 
other factors in our design that significantly increase the risk (or decreases the acceptability of the risks) 
associated with infliximab.Data suggest that depression is associated with greater disability than RA, and 
we are selecting a patient population with a tremendous clinical need. 
4) The proposed study will be conducted in compliance with the requirements for IRB review and 
informed consent [21 CFR parts 56 and 50, respectively]. 
5) The study will be conducted in compliance with the requirements concerning the promotion and sale of 
drugs [21 CFR 312.7]. 
6) The study will not involve a waiver of informed consent in an emergency room setting. 
14. Data and Safety Monitoring Plan (DSMP) 
The DSMB for this study will consist of Larry Tune, M.D. Chairman, Boadie Dunlop, M.D., Tanja Mletzko, 
M.S. and Marian Evatt, M.D. Each of these clinical researchers has agreed to serve as the external 
DSMB for investigator-initiated clinical trials conducted by Emory researchers in the Department of 
Psychiatry & Behavioral Sciences. If the DSMB requires additional specialized expertise to evaluate 
safety issues related to the performance of this study, a relevant specialist will be consulted by the 
DSMB. The frequency of the Department of Psychiatry and Behavioral Sciences DSMB review for this 
protocol will be once every year based on IRB recommendations consistent with the assessed risk status 
of the study. 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 Emory DSMB 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
26 
Version: February 14th, 2020  
At least four weeks prior to each DSMB meeting, the data manager/research coordinator will prepare a 
report to be reviewed during that meeting. The report will include the number of participants who signed 
consent for the study and were randomized, the number of post-randomization dropouts, reasons for 
these dropouts, and any safety concerns, adverse events, etc. An up-to-date consent form may  be 
provided, as well as a summary of measures taken to protect confidentiality (e.g., data storage, use of 
coded ID numbers, etc.) The PIs will also prepare a report summarizing any new data/evidence that might 
alter the risk/benefit ratio for participating in the study (e.g., newly published studies, etc.). Data will be 
presented to the DSMB in such a way as to maintain patient confidentiality. 
Based on the information provided to the Department of Psychiatry and Behavioral Sciences DSMB, once 
every year the DSMB will issue a letter to the PI to be included in the annual Emory IRB Continuing 
Review submission. The letter will inform the Emory IRB that the study is approved to proceed or state 
any safety related concerns expressed by the committee.  Reports will not specifically disclose the 
treatment arm of the study for relevant subjects unless this disclosure is required for safety reasons.  
 
PI and designated trained study personnel will review all pertinent aspects of study conduct including 
patient safety, compliance with protocol, data collection and efficacy. Periodic chart monitoring will be 
conducted by study personnel to validate integrity of the data. 
 
Adverse Event Reporting 
Note that any adverse event or serious adverse event (SAE) meeting Emory IRB criteria for on 
Unanticipated Problem will be reported to the Emory IRB and the study DSMB according to standard 
regulations. The IRB defines a serious adverse event as: “any adverse experiences occurring that result 
in any of the following outcomes: death, a life-threatening adverse experience, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. For the purposes of this policy, death is never expected.” According to the Emory 
IRB, an AE meets criteria for an Unanticipated Problem (UP) if all of the following criteria are met: 1) The 
AE is unexpected 1) the AE is related or possibly related to participation in the research 3) the AE 
suggests that the research places subjects or others at a greater risk of harm that was previously know.  
 
Human Subjects Bibliography 
1. Keystone EC. Does anti-tumor necrosis factor-alpha therapy affect risk of serious infection and cancer 
in patients with rheumatoid arthritis: a review of longterm data. The Journal of rheumatology. 
2011;38(8):1552-62. 
2.Mariette X, Matucci-Cerinic M, Pavelka K, Taylor P, van Vollenhoven R, Heatley R, Walsh C, Lawson R, 
Reynolds A, Emery P. Malignancies associated with tumour necrosis factor inhibitors in registries and 
prospective observational studies: a systematic review and meta-analysis. Ann Rheum Dis. 
2011;70(11):1895-904. 
Bibliography and References Cited 
1. 
Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and 
prevention. Circulation. 2003;107(3):363-9. Epub 2003/01/29. PubMed PMID: 12551853. 
2. 
Haroon E, Fleischer CC, Felger JC, Chen X, Woolwine BJ, Patel T, Hu XP, Miller AH. Conceptual 
convergence: increased inflammation is associated with increased basal ganglia glutamate in patients 
with major depression. Mol Psychiatry. 2016;21(10):1351-7. Epub 2016/01/13. doi: 10.1038/mp.2015.206. 
PubMed PMID: 26754953; PMCID: PMC4940313. 
3. 
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 
depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70(1):31-41. Epub 
2012/09/05. doi: 10.1001/2013.jamapsychiatry.4. PubMed PMID: 22945416; PMCID: PMC4015348. 
4. 
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 Behav Immun. 2013;31:205-
15. Epub 2013/04/30. doi: 10.1016/j.bbi.2013.04.004. PubMed PMID: 23624296; PMCID: PMC3673885. 
5. 
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):732-41. Epub 2009/01/20. doi: 
10.1016/j.biopsych.2008.11.029. PubMed PMID: 19150053; PMCID: PMC2680424. 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
27 
Version: February 14th, 2020  
6. 
Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging 
frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012;62(1):63-77. Epub 
2011/08/11. doi: 10.1016/j.neuropharm.2011.07.036. PubMed PMID: 21827775; PMCID: PMC3205453. 
7. 
Sanacora G, Banasr M. From pathophysiology to novel antidepressant drugs: glial contributions 
to the pathology and treatment of mood disorders. Biol Psychiatry. 2013;73(12):1172-9. Epub 2013/06/04. 
doi: 10.1016/j.biopsych.2013.03.032. PubMed PMID: 23726152; PMCID: PMC3688253. 
8. 
Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to 
modern treatment target. Nat Rev Immunol. 2016;16(1):22-34. Epub 2015/12/30. doi: 10.1038/nri.2015.5. 
PubMed PMID: 26711676; PMCID: PMC5542678. 
9. 
Stertz L, Magalhaes PV, Kapczinski F. Is bipolar disorder an inflammatory condition? The 
relevance of microglial activation. Curr Opin Psychiatry. 2013;26(1):19-26. Epub 2012/12/01. doi: 
10.1097/YCO.0b013e32835aa4b4. PubMed PMID: 23196997. 
10. 
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):446-57. Epub 2009/12/18. doi: 
10.1016/j.biopsych.2009.09.033. PubMed PMID: 20015486. 
11. 
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):1022-9. Epub 2008/02/05. doi: 10.1016/j.biopsych.2007.12.007. PubMed PMID: 18242584; 
PMCID: PMC2885493. 
12. 
Capuron L, Pagnoni G, Drake DF, Woolwine BJ, Spivey JR, Crowe RJ, Votaw JR, Goodman MM, 
Miller AH. Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during 
interferon alfa administration. Arch Gen Psychiatry. 2012;69(10):1044-53. Epub 2012/10/03. doi: 
10.1001/archgenpsychiatry.2011.2094. PubMed PMID: 23026954; PMCID: PMC3640298. 
13. 
Raison CL, Borisov AS, Woolwine BJ, Massung B, Vogt G, Miller AH. Interferon-alpha effects on 
diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and 
behavior. Mol Psychiatry. 2010;15(5):535-47. Epub 2008/06/04. doi: 10.1038/mp.2008.58. PubMed 
PMID: 18521089; PMCID: PMC3403676. 
14. 
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):748-54. Epub 2010/08/20. doi: 10.1016/j.biopsych.2010.06.010. PubMed PMID: 20719303; 
PMCID: PMC3025604. 
15. 
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):407-14. Epub 2009/05/09. doi: 10.1016/j.biopsych.2009.03.015. PubMed PMID: 19423079; 
PMCID: PMC2885494. 
16. 
Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Dolan RJ, Critchley HD. Neural origins of 
human sickness in interoceptive responses to inflammation. Biol Psychiatry. 2009;66(5):415-22. Epub 
2009/05/05. doi: 10.1016/j.biopsych.2009.03.007. PubMed PMID: 19409533; PMCID: PMC2885492. 
17. 
Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on 
neurotransmitters and neurocircuits. Depress Anxiety. 2013;30(4):297-306. Epub 2013/03/08. doi: 
10.1002/da.22084. PubMed PMID: 23468190; PMCID: PMC4141874. 
18. 
Haroon E, Raison CL, Miller AH. Psychoneuroimmunology meets neuropsychopharmacology: 
translational implications of the impact of inflammation on behavior. Neuropsychopharmacology. 
2012;37(1):137-62. Epub 2011/09/16. doi: 10.1038/npp.2011.205. PubMed PMID: 21918508; PMCID: 
PMC3238082. 
19. 
Tyring S, Gottlieb A, Papp K, Gordon K, Leonardi C, Wang A, Lalla D, Woolley M, Jahreis A, 
Zitnik R, Cella D, Krishnan R. Etanercept and clinical outcomes, fatigue, and depression in psoriasis: 
double-blind placebo-controlled randomised phase III trial. Lancet. 2006;367(9504):29-35. Epub 
2006/01/10. doi: 10.1016/S0140-6736(05)67763-X. PubMed PMID: 16399150. 
20. 
Monk JP, Phillips G, Waite R, Kuhn J, Schaaf LJ, Otterson GA, Guttridge D, Rhoades C, Shah M, 
Criswell T, Caligiuri MA, Villalona-Calero MA. Assessment of tumor necrosis factor alpha blockade as an 
intervention to improve tolerability of dose-intensive chemotherapy in cancer patients. J Clin Oncol. 
2006;24(12):1852-9. Epub 2006/04/20. doi: 10.1200/JCO.2005.04.2838. PubMed PMID: 16622259. 
21. 
Frye MA, Watzl J, Banakar S, O'Neill J, Mintz J, Davanzo P, Fischer J, Chirichigno JW, Ventura 
J, Elman S, Tsuang J, Walot I, Thomas MA. Increased anterior cingulate/medial prefrontal cortical 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
28 
Version: February 14th, 2020  
glutamate and creatine in bipolar depression. Neuropsychopharmacology. 2007;32(12):2490-9. Epub 
2007/04/13. doi: 10.1038/sj.npp.1301387. PubMed PMID: 17429412. 
22. 
Xu J, Dydak U, Harezlak J, Nixon J, Dzemidzic M, Gunn AD, Karne HS, Anand A. Neurochemical 
abnormalities in unmedicated bipolar depression and mania: a 2D 1H MRS investigation. Psychiatry Res. 
2013;213(3):235-41. Epub 2013/07/03. doi: 10.1016/j.pscychresns.2013.02.008. PubMed PMID: 
23810639; PMCID: PMC3729606. 
23. 
Yoon SJ, Lyoo IK, Haws C, Kim TS, Cohen BM, Renshaw PF. Decreased glutamate/glutamine 
levels may mediate cytidine's efficacy in treating bipolar depression: a longitudinal proton magnetic 
resonance spectroscopy study. Neuropsychopharmacology. 2009;34(7):1810-8. Epub 2009/02/06. doi: 
10.1038/npp.2009.2. PubMed PMID: 19194376. 
24. 
Yuksel C, Ongur D. Magnetic resonance spectroscopy studies of glutamate-related abnormalities 
in mood disorders. Biol Psychiatry. 2010;68(9):785-94. Epub 2010/08/24. doi: 
10.1016/j.biopsych.2010.06.016. PubMed PMID: 20728076; PMCID: PMC2955841. 
25. 
Zwanzger P, Zavorotnyy M, Gencheva E, Diemer J, Kugel H, Heindel W, Ruland T, Ohrmann P, 
Arolt V, Domschke K, Pfleiderer B. Acute shift in glutamate concentrations following experimentally 
induced panic with cholecystokinin tetrapeptide--a 3T-MRS study in healthy subjects. 
Neuropsychopharmacology. 2013;38(9):1648-54. Epub 2013/03/07. doi: 10.1038/npp.2013.61. PubMed 
PMID: 23463151; PMCID: PMC3717541. 
26. 
Castillo M, Kwock L, Courvoisie H, Hooper SR. Proton MR spectroscopy in children with bipolar 
affective disorder: preliminary observations. AJNR Am J Neuroradiol. 2000;21(5):832-8. Epub 
2000/05/18. PubMed PMID: 10815657. 
27. 
Hashimoto K, Sawa A, Iyo M. Increased levels of glutamate in brains from patients with mood 
disorders. Biol Psychiatry. 2007;62(11):1310-6. Epub 2007/06/19. doi: 10.1016/j.biopsych.2007.03.017. 
PubMed PMID: 17574216. 
28. 
Rajkowska G, Miguel-Hidalgo JJ. Gliogenesis and glial pathology in depression. CNS Neurol 
Disord Drug Targets. 2007;6(3):219-33. Epub 2007/05/22. PubMed PMID: 17511618; PMCID: 
PMC2918806. 
29. 
Hamidi M, Drevets WC, Price JL. Glial reduction in amygdala in major depressive disorder is due 
to oligodendrocytes. Biol Psychiatry. 2004;55(6):563-9. Epub 2004/03/12. doi: 
10.1016/j.biopsych.2003.11.006. PubMed PMID: 15013824. 
30. 
Ongur D, Drevets WC, Price JL. Glial reduction in the subgenual prefrontal cortex in mood 
disorders. Proc Natl Acad Sci U S A. 1998;95(22):13290-5. Epub 1998/10/28. PubMed PMID: 9789081; 
PMCID: PMC23786. 
31. 
Nagy C, Suderman M, Yang J, Szyf M, Mechawar N, Ernst C, Turecki G. Astrocytic abnormalities 
and global DNA methylation patterns in depression and suicide. Mol Psychiatry. 2015;20(3):320-8. Epub 
2014/03/26. doi: 10.1038/mp.2014.21. PubMed PMID: 24662927; PMCID: PMC5293540. 
32. 
aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ. Safety 
and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 
2010;67(2):139-45. Epub 2009/11/10. doi: 10.1016/j.biopsych.2009.08.038. PubMed PMID: 19897179. 
33. 
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. 
Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-4. Epub 
2000/02/25. PubMed PMID: 10686270. 
34. 
Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid 
antidepressant actions of ketamine. Neuropharmacology. 2012;62(1):35-41. Epub 2011/09/13. doi: 
10.1016/j.neuropharm.2011.08.044. PubMed PMID: 21907221; PMCID: PMC3195863. 
35. 
Lally N, Nugent AC, Luckenbaugh DA, Ameli R, Roiser JP, Zarate CA. Anti-anhedonic effect of 
ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry. 
2014;4:e469. Epub 2014/10/15. doi: 10.1038/tp.2014.105. PubMed PMID: 25313512; PMCID: 
PMC4350513. 
36. 
Ida T, Hara M, Nakamura Y, Kozaki S, Tsunoda S, Ihara H. Cytokine-induced enhancement of 
calcium-dependent glutamate release from astrocytes mediated by nitric oxide. Neurosci Lett. 
2008;432(3):232-6. Epub 2008/02/08. doi: 10.1016/j.neulet.2007.12.047. PubMed PMID: 18255223. 
37. 
Matute C, Domercq M, Sanchez-Gomez MV. Glutamate-mediated glial injury: mechanisms and 
clinical importance. Glia. 2006;53(2):212-24. Epub 2005/10/06. doi: 10.1002/glia.20275. PubMed PMID: 
16206168. 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
29 
Version: February 14th, 2020  
38. 
Tilleux S, Hermans E. Neuroinflammation and regulation of glial glutamate uptake in neurological 
disorders. J Neurosci Res. 2007;85(10):2059-70. Epub 2007/05/15. doi: 10.1002/jnr.21325. PubMed 
PMID: 17497670. 
39. 
Dantzer R, Walker AK. Is there a role for glutamate-mediated excitotoxicity in inflammation-
induced depression? J Neural Transm (Vienna). 2014;121(8):925-32. Epub 2014/03/19. doi: 
10.1007/s00702-014-1187-1. PubMed PMID: 24633997; PMCID: PMC4134384. 
40. 
Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications 
for neurodegenerative disorders. Nat Rev Neurosci. 2010;11(10):682-96. Epub 2010/09/16. doi: 
10.1038/nrn2911. PubMed PMID: 20842175; PMCID: PMC2948541. 
41. 
Bechtholt-Gompf AJ, Walther HV, Adams MA, Carlezon WA, Jr., Ongur D, Cohen BM. Blockade 
of astrocytic glutamate uptake in rats induces signs of anhedonia and impaired spatial memory. 
Neuropsychopharmacology. 2010;35(10):2049-59. Epub 2010/06/10. doi: 10.1038/npp.2010.74. PubMed 
PMID: 20531459; PMCID: PMC3055299. 
42. 
Buntinx M, Moreels M, Vandenabeele F, Lambrichts I, Raus J, Steels P, Stinissen P, Ameloot M. 
Cytokine-induced cell death in human oligodendroglial cell lines: I. Synergistic effects of IFN-gamma and 
TNF-alpha on apoptosis. J Neurosci Res. 2004;76(6):834-45. Epub 2004/05/26. doi: 10.1002/jnr.20118. 
PubMed PMID: 15160395. 
43. 
Kazazoglou T, Fleischer-Lambropoulos E, Geladopoulos T, Kentroti S, Stefanis C, Vernadakis A. 
Differential responsiveness of late passage C-6 glial cells and advanced passages of astrocytes derived 
from aged mouse cerebral hemispheres to cytokines and growth factors: glutamine synthetase activity. 
Neurochem Res. 1996;21(5):609-14. Epub 1996/05/01. PubMed PMID: 8726970. 
44. 
Li J, Ramenaden ER, Peng J, Koito H, Volpe JJ, Rosenberg PA. Tumor necrosis factor alpha 
mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes 
are present. J Neurosci. 2008;28(20):5321-30. Epub 2008/05/16. doi: 10.1523/JNEUROSCI.3995-
07.2008. PubMed PMID: 18480288; PMCID: PMC2677805. 
45. 
Schwarcz R. The kynurenine pathway of tryptophan degradation as a drug target. Curr Opin 
Pharmacol. 2004;4(1):12-7. Epub 2004/03/17. doi: 10.1016/j.coph.2003.10.006. PubMed PMID: 
15018833. 
46. 
Tavares RG, Schmidt AP, Abud J, Tasca CI, Souza DO. In vivo quinolinic acid increases 
synaptosomal glutamate release in rats: reversal by guanosine. Neurochem Res. 2005;30(4):439-44. 
Epub 2005/08/04. PubMed PMID: 16076013. 
47. 
Tavares RG, Tasca CI, Santos CE, Alves LB, Porciuncula LO, Emanuelli T, Souza DO. Quinolinic 
acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. 
Neurochem Int. 2002;40(7):621-7. Epub 2002/03/20. PubMed PMID: 11900857. 
48. 
Haroon E, Felger JC, Woolwine BJ, Chen X, Parekh S, Spivey JR, Hu XP, Miller AH. Age-related 
increases in basal ganglia glutamate are associated with TNF, reduced motivation and decreased 
psychomotor speed during IFN-alpha treatment: Preliminary findings. Brain Behav Immun. 2015;46:17-
22. Epub 2014/12/17. doi: 10.1016/j.bbi.2014.12.004. PubMed PMID: 25500218; PMCID: PMC4414678. 
49. 
Haroon E, Woolwine BJ, Chen X, Pace TW, Parekh S, Spivey JR, Hu XP, Miller AH. IFN-alpha-
induced cortical and subcortical glutamate changes assessed by magnetic resonance spectroscopy. 
Neuropsychopharmacology. 2014;39(7):1777-85. Epub 2014/02/01. doi: 10.1038/npp.2014.25. PubMed 
PMID: 24481242; PMCID: PMC4023151. 
50. 
Walker AK, Budac DP, Bisulco S, Lee AW, Smith RA, Beenders B, Kelley KW, Dantzer R. NMDA 
receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in 
C57BL/6J mice. Neuropsychopharmacology. 2013;38(9):1609-16. Epub 2013/03/21. doi: 
10.1038/npp.2013.71. PubMed PMID: 23511700; PMCID: PMC3717543. 
51. 
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. Epub 2004/02/20. PubMed 
PMID: 14971628. 
52. 
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):189-98. Epub 1975/11/01. 
PubMed PMID: 1202204. 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
30 
Version: February 14th, 2020  
53. 
Petersen T, Papakostas GI, Posternak MA, Kant A, Guyker WM, Iosifescu DV, Yeung AS, 
Nierenberg AA, Fava M. Empirical testing of two models for staging antidepressant treatment resistance. 
J Clin Psychopharmacol. 2005;25(4):336-41. Epub 2005/07/14. PubMed PMID: 16012276. 
54. 
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):402-13. Epub 2004/02/06. PubMed PMID: 
14762776. 
55. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, 
Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal 
consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168(12):1266-77. Epub 2011/12/24. doi: 10.1176/appi.ajp.2011.10111704. PubMed PMID: 
22193671; PMCID: PMC3893686. 
56. 
First M, Spitzer R, Gibbon M, Williams J. Structured Clinical Interview for DSM-IV. Washington, 
DC: American Psychiatric Press; 1997. 
57. 
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):322-5. Epub 2009/09/23. doi: 10.1111/j.1755-5949.2009.00102.x. PubMed PMID: 
19769599. 
58. 
Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 
2003;53(8):649-59. Epub 2003/04/23. PubMed PMID: 12706951. 
59. 
Bottomley PA. Spatial localization in NMR spectroscopy in vivo. Ann N Y Acad Sci. 
1987;508:333-48. Epub 1987/01/01. PubMed PMID: 3326459. 
60. 
Haase A, Frahm J, Hanicke W, Matthaei D. 1H NMR chemical shift selective (CHESS) imaging. 
Phys Med Biol. 1985;30(4):341-4. Epub 1985/04/01. PubMed PMID: 4001160. 
61. 
Nikolaus S, Larisch R, Beu M, Vosberg H, Muller-Gartner HW. Diffuse cortical reduction of 
neuronal activity in unipolar major depression: a retrospective analysis of 337 patients and 321 controls. 
Nucl Med Commun. 2000;21(12):1119-25. Epub 2001/02/24. PubMed PMID: 11200016. 
62. 
Provencher SW. Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR 
Biomed. 2001;14(4):260-4. Epub 2001/06/19. PubMed PMID: 11410943. 
63. 
Gussew A, Erdtel M, Hiepe P, Rzanny R, Reichenbach JR. Absolute quantitation of brain 
metabolites with respect to heterogeneous tissue compositions in (1)H-MR spectroscopic volumes. 
MAGMA. 2012;25(5):321-33. Epub 2012/03/01. doi: 10.1007/s10334-012-0305-z. PubMed PMID: 
22366889. 
64. 
Crook JM, O'Callaghan CJ, Duncan G, Dearnaley DP, Higano CS, Horwitz EM, Frymire E, 
Malone S, Chin J, Nabid A, Warde P, Corbett T, Angyalfi S, Goldenberg SL, Gospodarowicz MK, Saad F, 
Logue JP, Hall E, Schellhammer PF, Ding K, Klotz L. Intermittent androgen suppression for rising PSA 
level after radiotherapy. N Engl J Med. 2012;367(10):895-903. Epub 2012/08/31. doi: 
10.1056/NEJMoa1201546. PubMed PMID: 22931259; PMCID: PMC3521033. 
65. 
Posse S, Otazo R, Dager SR, Alger J. MR spectroscopic imaging: principles and recent 
advances. J Magn Reson Imaging. 2013;37(6):1301-25. Epub 2012/11/29. doi: 10.1002/jmri.23945. 
PubMed PMID: 23188775. 
66. 
Cudalbu C, Bucur A, Graveron-Demilly D, Beuf O, Cavassila S. Comparison of two strategies of 
background-accommodation: influence on the metabolite concentration estimation from in vivo Magnetic 
Resonance Spectroscopy data. Conf Proc IEEE Eng Med Biol Soc. 2007;2007:2077-80. Epub 
2007/11/16. doi: 10.1109/IEMBS.2007.4352730. PubMed PMID: 18002396. 
67. 
Gottschalk M, Lamalle L, Segebarth C. Short-TE localised 1H MRS of the human brain at 3 T: 
quantification of the metabolite signals using two approaches to account for macromolecular signal 
contributions. NMR Biomed. 2008;21(5):507-17. Epub 2007/10/24. doi: 10.1002/nbm.1219. PubMed 
PMID: 17955570. 
68. 
Insel TR. The NIMH Research Domain Criteria (RDoC) Project: precision medicine for psychiatry. 
Am J Psychiatry. 2014;171(4):395-7. Epub 2014/04/02. doi: 10.1176/appi.ajp.2014.14020138. PubMed 
PMID: 24687194. 
69. 
Ameli R, Luckenbaugh DA, Gould NF, Holmes MK, Lally N, Ballard ED, Zarate CA, Jr. SHAPS-C: 
the Snaith-Hamilton pleasure scale modified for clinician administration. PeerJ. 2014;2:e429. Epub 
2014/07/16. doi: 10.7717/peerj.429. PubMed PMID: 25024906; PMCID: PMC4081294. 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
31 
Version: February 14th, 2020  
70. 
Snaith RP, Hamilton M, Morley S, Humayan A, Hargreaves D, Trigwell P. A scale for the 
assessment of hedonic tone the Snaith-Hamilton Pleasure Scale. Br J Psychiatry. 1995;167(1):99-103. 
Epub 1995/07/01. PubMed PMID: 7551619. 
71. 
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):1545-58. 
Epub 2006/10/05. doi: 10.1002/jclp.20327. PubMed PMID: 17019674. 
72. 
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):568-74. Epub 2013/01/29. doi: 
10.1016/j.comppsych.2012.12.001. PubMed PMID: 23351831; PMCID: PMC4762003. 
73. 
Spreen O, Strauss E. A Compendium of Neuropsychological Tests. New York: Oxford University 
Press; 1991. 
74. 
Aparicio P, Diedrichsen J, Ivry RB. Effects of focal basal ganglia lesions on timing and force 
control. Brain Cogn. 2005;58(1):62-74. Epub 2005/05/10. doi: 10.1016/j.bandc.2004.09.009. PubMed 
PMID: 15878727. 
75. 
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):870-80. Epub 2008/02/09. doi: 10.1016/j.bbi.2007.12.009. PubMed PMID: 
18258414; PMCID: PMC2497339. 
76. 
Joy S, Fein D, Kaplan E. Decoding digit symbol: speed, memory, and visual scanning. 
Assessment. 2003;10(1):56-65. Epub 2003/04/05. doi: 10.1177/0095399702250335. PubMed PMID: 
12675384. 
77. 
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):275-80. Epub 2002/02/15. 
PubMed PMID: 11843699. 
78. 
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):1259-63. Epub 1988/10/01. PubMed PMID: 2976080; PMCID: 
PMC1032911. 
79. 
Reitan RM. The relation of the trail making test to organic brain damage. J Consult Psychol. 
1955;19(5):393-4. Epub 1955/10/01. PubMed PMID: 13263471. 
80. 
Reitan RM, Tarshes EL. Differential effects of lateralized brain lesions on the trail making test. J 
Nerv Ment Dis. 1959;129:257-62. Epub 1959/09/01. PubMed PMID: 14437233. 
81. 
Wildocher D, Ghozlan A. The measurement of retardation in depression. In: Hindmarch I, Stonier 
P, editors. Human psychopharmacology. New York: John Wiley and Sons; 1989. p. 1-22. 
82. 
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. Epub 
2006/09/22. doi: 10.1002/gps.1657. PubMed PMID: 16988949. 
83. 
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):315-25. Epub 
1995/04/01. PubMed PMID: 7636775. 
84. 
Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of Depressive 
Symptomatology (IDS): psychometric properties. Psychol Med. 1996;26(3):477-86. Epub 1996/05/01. 
PubMed PMID: 8733206. 
85. 
Aiken CB, Weisler RH, Sachs GS. The Bipolarity Index: a clinician-rated measure of diagnostic 
confidence. J Affect Disord. 2015;177:59-64. Epub 2015/03/10. doi: 10.1016/j.jad.2015.02.004. PubMed 
PMID: 25745836. 
86. 
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50-5. 
Epub 1959/01/01. PubMed PMID: 13638508. 
87. 
Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: 
psychometric properties. J Consult Clin Psychol. 1988;56(6):893-7. Epub 1988/12/01. PubMed PMID: 
3204199. 
88. 
Spielberger C, Gorsuch R, Lushene R, Vagg P, Jacobs G. Manual for the State-Trait Anxiety 
Inventory. Palo Alto, CA: Consulting Psychologists Press; 1983. 


Emory IRB#00090667 
PI: AH Miller  
Sponsor: NIMH 
32 
Version: February 14th, 2020  
89. 
Blevins CA, Weathers FW, Davis MT, Witte TK, Domino JL. The Posttraumatic Stress Disorder 
Checklist for DSM-5 (PCL-5): Development and Initial Psychometric Evaluation. J Trauma Stress. 
2015;28(6):489-98. Epub 2015/11/26. doi: 10.1002/jts.22059. PubMed PMID: 26606250. 
90. 
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. Epub 2002/08/10. PubMed PMID: 12169536. 
91. 
Johnson WE, Li C, Rabinovic A. Adjusting batch effects in microarray expression data using 
empirical Bayes methods. Biostatistics. 2007;8(1):118-27. Epub 2006/04/25. doi: 
10.1093/biostatistics/kxj037. PubMed PMID: 16632515. 
92. 
Potter DM. A permutation test for inference in logistic regression with small- and moderate-sized 
data sets. Stat Med. 2005;24(5):693-708. Epub 2004/10/30. doi: 10.1002/sim.1931. PubMed PMID: 
15515134. 
93. 
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data 
capture (REDCap)--a metadata-driven methodology and workflow process for providing translational 
research informatics support. J Biomed Inform. 2009;42(2):377-81. Epub 2008/10/22. doi: 
10.1016/j.jbi.2008.08.010. PubMed PMID: 18929686; PMCID: PMC2700030. 
94. 
Felger JC, Li Z, Haroon E, Woolwine BJ, Jung MY, Hu X, Miller AH. Inflammation is associated 
with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. 
2016;21(10):1358-65. Epub 2015/11/11. doi: 10.1038/mp.2015.168. PubMed PMID: 26552591; PMCID: 
PMC4862934. 
95. 
Krugel U, Fischer J, Radicke S, Sack U, Himmerich H. Antidepressant effects of TNF-alpha 
blockade in an animal model of depression. J Psychiatr Res. 2013;47(5):611-6. Epub 2013/02/12. doi: 
10.1016/j.jpsychires.2013.01.007. PubMed PMID: 23394815. 
96. 
Hochberg Y, Benjamini Y. More powerful procedures for multiple significance testing. Stat Med. 
1990;9(7):811-8. Epub 1990/07/01. PubMed PMID: 2218183. 
97. 
Larkin GL, Beautrais AL. A preliminary naturalistic study of low-dose ketamine for depression and 
suicide ideation in the emergency department. Int J Neuropsychopharmacol. 2011;14(8):1127-31. Epub 
2011/05/12. doi: 10.1017/S1461145711000629. PubMed PMID: 21557878. 
98. 
Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V, Rehal S, Klempan T, Gratton 
A, Benkelfat C, Rouleau GA, Mechawar N, Turecki G. Global brain gene expression analysis links 
glutamatergic and GABAergic alterations to suicide and major depression. PLoS One. 2009;4(8):e6585. 
Epub 2009/08/12. doi: 10.1371/journal.pone.0006585. PubMed PMID: 19668376; PMCID: PMC2719799. 
99. 
Cole SW, Yan W, Galic Z, Arevalo J, Zack JA. Expression-based monitoring of transcription 
factor activity: the TELiS database. Bioinformatics. 2005;21(6):803-10. Epub 2004/09/18. doi: 
10.1093/bioinformatics/bti038. PubMed PMID: 15374858. 
100. 
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):3080-5. Epub 2011/02/09. doi: 10.1073/pnas.1014218108. PubMed PMID: 
21300872; PMCID: PMC3041107. 
101. 
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. 2012;42(8):1591-603. Epub 2011/12/14. doi: 
10.1017/S0033291711002868. PubMed PMID: 22152193; PMCID: PMC3433045. 
102. 
Keystone EC. Does anti-tumor necrosis factor-alpha therapy affect risk of serious infection and 
cancer in patients with rheumatoid arthritis?: a review of longterm data. The Journal of rheumatology. 
2011;38(8):1552-62. Epub 2011/05/17. doi: 10.3899/jrheum.100995. PubMed PMID: 21572154. 
103. 
Mariette X, Matucci-Cerinic M, Pavelka K, Taylor P, van Vollenhoven R, Heatley R, Walsh C, 
Lawson R, Reynolds A, Emery P. Malignancies associated with tumour necrosis factor inhibitors in 
registries and prospective observational studies: a systematic review and meta-analysis. Ann Rheum Dis. 
2011;70(11):1895-904. Epub 2011/09/03. doi: 10.1136/ard.2010.149419. PubMed PMID: 21885875. 
 

ICF_000.pdf: 
 
 
 
 
Informed Consent Form 
 
 
 
Title: Inflammation-Induced CNS Glutamate Changes in Depression 
 
NCT Number:  NCT03004443 
 
Version Date:  October 23, 2019 
 
 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 1 of 21 
 
Version Date: 10/23/2019 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 2 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
 
Emory University 
Consent to be a Research Subject / HIPAA Authorization  
 
 
Title: Inflammation-Induced CNS Glutamate Changes in Depression 
 
Principal Investigator:  Andrew H. Miller MD and Ebrahim Haroon MD 
 
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.  The purpose of this study is to understand how increased inflammation, a process called immune 
activation, causes a change to our normal brain chemistry to fuel symptoms of depression. Also, this study will 
determine whether a medicine called infliximab will improve symptoms of depression by decreasing 
inflammation.  Infliximab is also known by its brand name Remicade. Infliximab (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. For this reason, researchers 
think that a drug like infliximab, which reduces inflammation, may be helpful in treating symptoms of 
depression in people with high inflammation. Still, it is important to point out that the Food and Drug 
Administration has not approved infliximab for treating depression. 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. 
 
Before you agree to take part in this study, please read this consent form and ask as many questions as you 
need to be sure you understand the possible risks and benefits. You may talk to family and friends about your 
decision. Please take your time to make your decision. Should you decide to participate in this study, you are 
free to change your mind at any time without penalty or loss of any benefit.  


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 3 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
 
This consent form contains important facts to help you decide if it is in your best interest to take part in this study. 
If you have any questions that are not answered in this consent form, one of the research staff will be happy to 
give you further information. 
 
Two hundred male and female participants with depression, between the ages of 21-65 years, will be enrolled 
into the study. Sixty participants will be randomized to study medication or placebo. Your participation, should 
you decide to enter the study, will last about a month, including your screening visit(s).  
 
Before you can participate in this study, you will need to come in for a screening visit to see if you are eligible 
to enter the study.  The investigator and/or the investigator’s staff will ask you questions and run tests that are 
described below to determine if you are eligible to enter the study. It is important that you answer all of the 
questions honestly and completely. If your condition or circumstances change during the study, you must tell 
the investigator. 
 
If you are currently doing well on antidepressant medication, you will not be eligible to participate in this study. 
It would not be in your best interest to discontinue medication that is helping you. On the other hand, you may 
enter this study if you are not currently taking an antidepressant, mood stabilizer or any other psychotropic 
medication.  
 
If you plan to take any medication or undergo any medical treatment other than taking the study infusion given 
to you, please notify the study team before starting the medication or treatment. This includes medications given 
to you or recommended by any other doctor, and over-the-counter drugs such as cough treatments, cold 
treatments, pain medications such as aspirin or ibuprofen, investigational drugs/procedures and sleeping 
medications. If elective surgery or a diagnostic procedure is planned the investigator has to be notified before 
the procedure is performed.  
 
Medications to Avoid: 
 
You will be excluded from the study if you take any of the following medications on a regular basis or if they are 
prescribed by a physician: psychiatric medication (for example: antidepressants, mood stabilizers, etc.) aspirin 
or aspirin-like compounds, ibuprofen or naproxen (for example: Advil, Aleve, Motrin IB), cholesterol medications 
(for example: simvastatin, Lipitor, Pravachol), antibiotics, topical steroids (i.e. hydrocortisone), vaccinations, 
herbal medications and omega-3 supplements. Please contact us if your doctor prescribes any new medication 
while participating in the study.  Please also contact us if you plan on starting any new over-the-counter 
medications between study visits. Please do not stop taking any prescribed medications. If you take above 
medications on an as-needed (prn) basis, we will determine your eligibility to participate in the study based on 
frequency and necessity of intake and may need to discuss this with the prescribing physician before arriving at 
this decision 
 
Although it is recommended that you do not drink alcoholic beverages 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 and you will be drug-tested for illegal drugs as part of this study.  
 
 
If the study doctor (Dr. Miller or his designee) determines that your depression has gotten worse at any time 
during the study, you may be discontinued from the study.  When you have completed or been discontinued from 
the study, the study doctor will discuss how to best continue your treatment for depression.  In addition, the study 
team will try to find a physician for follow up care if you do not have one. 
 
During this study you will interact with study doctors, research clinicians and nurses trained to infuse infliximab. 
You will also interact with a research coordinator and other staff who will help arrange your schedule during the 
study. 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 4 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
Study Procedures: 
 
If you agree to participate, this is what will happen during the study. You will be screened first to see if you are a 
good match for the study. If you qualify, the study visits will be spread across ~ 4 weeks. 
 
Table 1. Schedule of Study Procedures and Assessments 
Assessments 
Intake 
Screening 
Baseline*      Day 1 
 
Day 3 
Week 1 
Week 2 
30 Day 
F/U 
Phone 
Call 
Visit 
1 
Visi
t 2 
Visit 1 
Visit 2 
 
Intake forms and assessments: Consent, 
HIPPA tracking, Release of Information**, 
Consent of Means of Communication**, 
Participant Payment Form**, MRI Screening 
Form**,  Patient Health Questionnaire (PHQ-
9)** or  Clinician-Assisted QIDS-16 SR **, 
Medication Avoidance List**, Lumbar Puncture 
Information Guide, Schedule Quick Guide 
X 
 
 
 
 
 
 
 
 
 
Psychiatric screening: WRAT-3**, MMSE**,  
HAM-D**, ATRQ, SCID V**,  CSSRS, Clinical 
Interview Review [to be done in place of imported 
psych assessments from prior study] 
 
X 
 
 
 
 
 
 
 
 
Laboratory Screening: Anti-nuclear AB**, C-
reactive protein, TSH, Hepatitis B surface 
antigen**, Hepatitis C antibody**, HIV 
antigen/antibody**, QuantiFERON-TB Gold or 
TB Gold Plus,  Rapid CRP Finger Prick [if 
necessary to verify CRP], EKG, CXR 
 
X 
 
 
 
 
 
 
 
 
Serum pregnancy test 
 
X 
 
X 
 
      
 
X 
 
 
Medical History and Physical Examination or 
medical update 
 
X 
X 
 
[X] 
X 
[X] 
X 
[X] 
 
Adverse events, Concomitant medications 
[Con. Med. not completed at 30 day F/U phone call 
only]  
 
X 
X 
X 
[X] 
X 
[X] 
X 
[X] 
X 
Vital Signs, weight, height [screen only], waist-
hip ratio [screen only] 
 
X 
X 
X 
[X] 
X 
[X] 
X 
[X] 
 
Routine Labs: CBC with differential, urinalysis 
w/ micro, comprehensive metabolic panel⁰ 
 
X 
 
X 
 
 
[X] 
X 
[X] 
 
Urine toxicology 
 
X 
X 
X 
[X] 
X 
[X] 
X 
[X] 
 
Psychiatric baseline: Demographic Data**, 
CTQ**, Bipolarity Index** 
 
 
X 
 
 
 
 
 
 
 
Infusion (Infliximab or placebo) 
 
 
 
X 
 
 
 
 
 
 
Estrogen/progesterone 
 
 
 
X 
 
 
 
 
 
 
Urine pregnancy test 
 
 
X 
 
 
X 
X 
X 
 
 
Research blood: Cytokine Multiplex, mRNA, 
Plasma CRP 
 
 
X 
X 
[X] 
X 
[X] 
X 
 
 
Clinician-Administered: SHAPS-C, CSSRS⁰, 
SRRS⁰, HAM-A⁰ 
 
 
X 
 
 
X 
 
X 
 
 
Self-Report Forms 
 
 
X 
 
 
X 
 
X 
 
 
Neurocognitive Tests 
 
 
X 
 
 
X 
 
X 
 
 
Computer Assessments  
 
 
X 
 
 
 
 
X 
 
 
MRI Scan 
 
 
X 
 
 
X 
 
X 
 
 
Blood test_PT, PTT 
 
 
 
 
 
 
 
[X] 
 
 
Lumbar Puncture (Optional) 
 
 
 
 
 
 
 
 
[X] 
 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 5 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
*Baseline will occur over 2 visits: Visit 1: MRS, blood and Symptom Domain Assessments; Visit 2: Infusion; see below for abbreviations, **Unless 
prior documentation available from previous study, ⁰Screening (or Baseline 1) and Week 2 only, [ ] indicates option to complete assessment, *** 
PCL-5 (with LEC) at Baseline 1 only, and PCL-5 (without LEC) at Day 3 and Week 2 
 
Types of Assessments will include:  
 
a. Psychiatric assessments 
b. Self report forms (to assess severity of depression, early life trauma) 
c. Neurocognitive testing 
d. Medical history and physical exam 
e. Blood sampling  
f. 
MRS scans-completed on 3 of your visits   
g. Lumbar puncture (optional) 
 
 
Screening Visit(s): (Duration: approximately 7-8 hours and may be spread across more than one visit if 
needed). 
 
Participation in this study requires a screening visit at which time your eligibility will be reviewed and verified. 
After you sign the consent form, a study clinican will ask you about your medical condition and mental health. 
The doctor or nurse practitioner will also conduct a physical examination. You will receive an electrocardiogram 
(EKG) to make sure you have no heart abnormalities and a chest x-ray to screen for tuberculosis. Approximately 
5 teaspoons of your blood will be drawn to check for any abnormalities that would disqualify 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 viruses. 
  
Your blood will also be evaluated for a marker of inflammation called C-reactive protein and other tests to assess 
your general medical status including tests to assess your blood, kidney, thyroid and liver status. You may have 
one or two drops of blood collected by trained research staff from a finger prick to measure inflammation level. 
You will also have a tuberculosis blood test. This test requires a small blood draw. If the test is positive for 
tuberculosis you will not be able to enter the study and the study doctor 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 test if you are a female. You will be disqualified from the study 
if you are pregnant. If you are a woman of childbearing age we will ask you for documentation of adequate birth 
control during the study period. The screening process will take in total approximately 7-8 hours, but can be 
spread out over at least two visits if needed, and will occur either at the Emory Clinic Building B, 1365B Clifton 
Rd, or the Atlanta Clinical Translational Science Institute (ACTSI) in the Emory University Hospital. You are 
strongly encouraged to ask the study doctor or a member of the study staff if you have 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 7-9 visits (including screening visits) across 
~ 4 weeks. All study visits will take place either at Emory Clinic Building B or the Atlanta Clinical Translational 
Science Institute (ACTSI) outpatient research unit in the Emory University Hospital on the main Emory campus. 
At all visits you will fill out several self-report questionnaires that will ask about depressive symptoms and about 
the quality of your life. In terms of research, your blood will be looked at to see whether a decrease in depression 
following the infliximab infusion is associated with a decrease in inflammation chemicals. At each of these visits 
approximately eight teaspoons of your blood will be withdrawn to do routine laboratory checks and also for 
research purposes. Study visits will range in 4-8 hours of your time.  
 
At screening and each visit, you will be asked to supply approximately 4 tablespoons of urine in a special cup 
that 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 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 6 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
be a reason for withdrawing you from this study. Additionally, you will be asked to supply approximately 4 
tablespoons of urine in a different cup that will be used to test for the presence of an infection. 
 
Vital signs, including pulse and blood pressure, as well as weight will be measured at every visit. Height and 
waist circumference will be measured at screening. You may be asked to come in for additional screening visits 
to repeat any lab work or assessments. 
 
 
 
Baseline Visits 1 & 2 
 
Baseline 1: (Duration approximately 8.5 hours)  
 
You will arrive to Emory Clinic Building B in the morning of your Baseline 1 visit. You will be asked to avoid 
Benadryl, alcohol, cigarettes, and foods high in MSG (for example, Chinese fast food, frozen dinners, or other 
processed foods) 24 hours prior to this visit. You will be asked not to eat or drink anything but water after 
midnight the night before your visit, planning for blood to be drawn first thing in the morning. You will be asked 
to give a small sample of blood, about 5 teaspoons collected from a vein in your arm by an Emory Healthcare 
professional, to measure your inflammation level and to look at your genes related to inflammation and 
metabolism. You will also give a urine sample in order to test for any signs of infection and drugs of abuse. 
After the blood draw, you will be able to eat and drink as normal until two hours before your scan, when you 
will be asked to not eat or drink anything but water. You will undergo a study medical evaluation with a doctor 
or nurse practitioner and will have your vital signs checked. You will be asked questions about how you are 
feeling and fill out questionnaires intended to measure the current level of emotional distress and other 
symptoms pertaining to mental health. The fasting research and safety lab tests, medical evaluation, and self-
report behavioral assessments will take about 60-90 minutes. 
You will then have a ~ 30 minute break following which you will complete paper and pencil and computerized 
neuropsychological tests. You will complete a series of computer-based tests intended to measure your 
cognitive abilities including attention, concentration, memory and reaction time. You will also complete a series 
of computerized decision-making tasks that will require you to select different options using different buttons. 
These tasks measure your level of motivation. Some tasks will require you to make your responses very 
rapidly. On these tasks, you will have the opportunity to earn additional payment based on your task choices 
and performance. You will receive this payment by check in the mail. The assessments and tests will take 
about ~ 90 minutes.  
You will then be escorted to the scan room where you will undergo MRI scans for 2.5 hours (maximum). The 
MRS scan is being done to identify brain changes resulting from high inflammation in the body. You will be 
walked by study staff to the Emory University Imaging Facility and enter a large room where the MRI scanner 
is located. This scanner uses a very strong magnet to take pictures of your brain. MRI scans are painless and 
contain no radiation. You will be asked to remove all jewelry and other metal-containing objects. You will then 
be placed on a narrow table, which will slide into the MRI scanner. The scanner is a large closed box with a 
tube in the middle. You will lie in the tube while the scan is being done. The tube is about 6 feet long and 25 
inches wide. You will then be asked to lie still during the scan for about 90 minutes.  
As part of the scanning process, you will be fit with a head coil, which resembles a larger frame football helmet 
for the entire duration of the scanning period. You will be able to communicate with the scanning personnel 
using a microphone and speaker in the scanner bore. You will hear some loud noises as the scanner takes 
pictures of your head. You will be offered earplugs to wear while you are being scanned to decrease how loud 
the noise seems to you. Occasionally, people have an extreme fear reaction (claustrophobia) to being in the 
scanner. If this occurs you will be removed from the scanner and the experiment will be stopped. You will be 
given a short break (lasting for 15 minutes) an hour into the scan.  After the scan you may eat and drink as 
normal. The scans will take approximately 120-150 minutes total. You will repeat the MRI scanning procedure 
on Visit Day 3 and Week 2.   
Your total time commitment for this visit will be approximately 8.5 hours with breaks.  


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 7 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
If there is a considerable break between study visit procedures (i.e. a lapse of at least 2 hours outside of the 
total time commitment), you may leave and then return to complete the visit, and will be compensated an 
additional study visit’s compensation. 
 
Baseline 2 (Infusion): (Between 1-7 days after Baseline 1; duration approximately 4-5 hours)  
 
You will be escorted to ACTSI-CRN where you will complete routine lab work checking for signs of infection. 
There you will be randomly assigned (similar to a flip of a coin) to receive either infliximab or placebo             
(an inactive compound). 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 placebo will be salt water. Neither you nor the study doctor will know whether you receive 
infliximab or placebo because all subjects will receive their infusions from identical appearing 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 your study doctor.  
During the infusion visit, a study nurse or doctor will review your medical history with you and also complete a 
physical examination. 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 a different cup that will be 
used to test for the presence of any infections or drugs of abuse. 
For the infusion, 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. 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 where 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. 
Your total time commitment will be approximately 4-5 hours.  
 
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. 
 
 
Post-Infusion Visits: Day 1, Day 3, Week 1, Week 2 (spread across 2 visits) 
 
Optional - Day 1 & Week 1: (Duration approximately 2-3 hours)  
 
Study visits Day 1 and Week 1 are optional. If you choose to participate in either one or both of the visits, you 
will come to the Emory Behavioral Immunology Program in the Emory Clinic, Building B in the morning. You 
will also be asked not to eat or drink anything but water the night before, in preparation for a fasting research 
blood sample draw. You will also give a urine sample in order to test for signs of infection and any drugs of 
abuse. You will undergo a short medical evaluation, in which a nurse practitioner or trained study staff member 
will take your vital signs, pulse, blood pressure, and weight, and ask you how you have been feeling since your 
infusion visit. 
Your total time commitment for each visit will be approximately 2-3 hours.  
 
Day 3 & Week 2-Visit 1: (Duration approximately 7.5 hours)  
 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 8 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
Just like the Baseline 1 Visit, you will arrive to the Emory Behavioral Immunology Program in the Emory Clinic, 
Building B in the morning. You will be asked to avoid Benadryl, alcohol, cigarettes, and foods high in MSG (for 
example, Chinese fast food, frozen dinners, or other processed foods) 24 hours prior to these visits. You will 
also be asked not to eat or drink anything but water the night before, planning for blood to be drawn first thing 
in the morning. You will give a urine sample in order to test for signs of infection and any drugs of abuse. After 
the blood draw, you will be able to eat and drink as normal until two hours before your scan, when you will be 
asked to not eat or drink anything but water. You will undergo a short medical evaluation with a nurse 
practitioner or trained study staff member, who will take your vital signs and ask you how you have been 
feeling since your previous visit. You will be asked questions about how you are feeling and fill out 
questionnaires intended to measure the current of level of emotional distress and other symptoms pertaining to 
mental health. The study medical evaluation, fasting research and safety lab tests and self-report behavioral 
assessments will take ~ 60-90 minutes. 
You will then have a ~ 30 minute break following which you will complete the same paper and pencil 
neuropsychological tests you did at Baseline Visit 1, but only complete the computerized assessments at Week 
2, Visit 1. You will receive payment for these tasks by check in the mail. The assessments and tests will take 
about ~ 60-90 minutes.  
You will then undergo MRI scans for 2.5 hours (maximum). You will be walked by study staff to the Emory 
University Imaging Facility and enter a large room where the MRI scanner is located. You will be asked to 
remove all jewelry and other metal-containing objects. You will then be placed on a narrow table, which will 
slide into the MRI scanner. You will be asked to lie still in the tube while the scan is being done for about 90 
minutes. After the scan, you may eat and drink as normal. The scans will take approximately 120-150 minutes.  
Your total time commitment for each visit will be approximately 7.5 hours with breaks.  
If there is a considerable break between study visit procedures (i.e. a lapse of at least 2 hours outside of the 
total time commitment), you may leave and then return to complete the visit, and will be compensated an 
additional study visit’s compensation. 
 
Optional - Week 2-Visit 2 (Lumbar Puncture): (Within 2 weeks of Week 2-Visit 1; Duration approximately 6 
hours) 
 
You may be asked to come in for an additional visit, which will consist of a lumbar puncture. This portion of the 
study is optional. If you choose to participate in this portion of the study, you will arrive at ACTSI-CRN 
(Research Unit inside Emory University Hospital). You will have a fasting research blood sample drawn 
following which you will be given a bag of saline through an IV in your arm. After 2-4 hours, you will have a 
spinal tap (Lumbar puncture or LP) in addition to the blood draw. The LP procedure allows us to collect a 
sample of your spinal fluid for the purpose of measuring inflammatory markers. An anesthesiologist from 
Emory University with considerable experience in performing spinal taps will conduct the procedure. Before the 
procedure, you will be offered pre-LP sedation with Versed through IV. The procedure will involve inserting a 
special long bore needle into the spine to obtain about 10ml (two teaspoons full) of fluid. This is a safe 
procedure and is often used to identify and treat brain diseases. It is possible that multiple attempts could be 
made to obtain the fluid. However, you have the ability to stop at any time. The procedure would be carried at a 
research unit dedicated to aid in such procedures by personnel who are well trained in conducting these 
procedures. Following the LP you will be instructed to rest till the research nurse determines that it is safe for 
discharge. You will be carefully observed for any side effects prior to discharge. A family member or friend will 
need to drive you home from the hospital after discharge. The nurse practitioner or designee will also make a 
follow-up call 1, 3, 7, and 14 days following the LP to check if you are experiencing any other study emergent 
side effects including chronic pain. 
 
Your total time commitment will be approximately 6 hours.  
 
30-Day Phone Call - Around one month after the infusion, you will receive a follow-up phone call from the 
coordinator or 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. 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 9 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
 
 
 
Optional-Emory Department of Psychology 2-Visit (Functional MRI) fMRI Study 
 
Study participants may choose to complete 2 additional study visits as an optional extension of this 
study. These visits are a part of a Task-Based Functional MRI (fMRI) study under the Department of 
Psychology, Dynamics of Inflammation and its Blockade on Motivational Circuitry in Depression, 
IRB#00087941 (see Table 1B). The purpose of the study is to see how the brain processes different 
types of information, and the way this affects behavior.  
 
If you decide to participate, you will review and sign a separate consent form. If you complete the optional 2 
visit study, you will be compensated approximately $800 (in addition to the amount of compensation you 
receive for the main study). Both visits will take place on campus at the Emory Department of Psychology. 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. You will also be asked to complete some computer tasks and undergo a functional MRI 
scan which means you will be doing tasks while lying in the scanner.  At each visit, they will collect a urine 
sample to test for drugs that may be present in your body and complete a pregnancy test if applicable. 
 
 
Study Visit Schedule (including the optional 2-visits): 
 
Extra 
Visit 1 
** 
Baseline 
Infusion 
1-Day 
3-Day 
7-Day 
14-Day 
Extra 
Visit 2 
** 
LP 
 
 
 What are the possible risks and discomforts? 
 
 The most common risks and discomforts expected in this study are: 
 
   There may be risks, discomforts or side effects that are not yet known. 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 are being treated for major depression. 
A number of side effects and more serious reactions to infliximab have been reported in patients receiving the 
medication for the treatment of rheumatoid arthritis or Crohn’s disease. The Food and Drug Administration (FDA) 
issued a Black Box Warning for this medication because patients in treatment with this product are at increased 
risk of infections, including worsening of symptoms that may lead to hospitalization or death. Please read the list 
of possible side effects below. 
 
From studies of infliximab, 10-50% of patients on infliximab had the following frequent negative health events: 
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.  
 
The following negative health events were reported occasionally (in 1-10% of patients receiving infliximab): 
shortness of breath, itchy skin, chest pain, an abscess, insomnia, depression and oral thrush.  
 
Rare negative health events occurring in less than 1% of patients receiving infliximab included severe immediate 
allergic reaction to the medication, delayed allergic response to the medication, serious bacterial infections, 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 10 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
tuberculosis, fungus infections and death. Most of these infections occurred in patients who were taking other 
medicines that suppress the immune system while they were taking infliximab. If you elect to enter this study you 
will be tested for tuberculosis using the blood test. If this test is positive, you will be excluded from study 
participation. 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. Because taking infliximab could 
make you more vulnerable to getting a fungal infection we will take a small amount of blood at week 10 and sent 
it to Emory University Hospital lab to test for fungal infection. 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.  
 
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 at the Infliximab Infusion Center for treating allergic reactions. 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 doctor immediately by calling the Emory Clinic operator (available 24 hours a day ) at 
404-778-5000 and page Bobbi Woolwine, MSW at pager ID#15375. The study coordinator will give you an 
emergency information contact card to keep in your wallet. 
 
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 Mood and Anxiety Disorders Program offices or the Emory Clinic. 
This test examines whether your heart is functioning 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 associated with 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). 
 
Infliximab has been rarely associated with reductions 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 established that infliximab directly caused these abnormalities. You will have your blood cells examined 
prior to receiving the single infusion and repeated at each study visit after the infusion. If your white blood cells, 
platelets or red blood cells are abnormal prior to the infusion you will be excluded from the study. If you have a 
drop in any of your blood cells after the first infusion you will be assessed for medical follow-up when appropriate 
as determined by the study physician(s)   
 
Infliximab has been associated in rare cases with a variety of central nervous system conditions, including 
inflammation of the nerves of the eye, seizures or a demyelinating condition that resembles multiple sclerosis. 
The study doctor 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. 
 
 
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 participate 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 medications 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 medications you will not be able to participate 
in this study.  
 
Infliximab may increase the risk of developing an autoimmune condition such as systemic lupus erythematosis 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 11 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
or multiple sclerosis, but this has not been established. At screening you will be asked whether you have a history 
of any autoimmune related disorders, including lupus and multiple sclerosis, but also 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. 
  
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 prior to 
study entry or whether you are scheduled 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 be ineligible to participate in this 
study if you have or will receive a vaccine during this period. 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: influenza (flu), typhoid, and polio vaccines. The injectable forms of 
influenza (flu), typhoid, and polio are killed (inactive) vaccines.  
 
People who have been treated 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 eligible to participate in this study. 
 
In addition to risks related to taking infliximab there are other risks associated with participating in this trial.  
 
Blood Draws:  Collecting blood from a vein in someone's arm is a standard medical procedure, although 
sometimes there may be some minor pain or bruising. Fainting and infection at the site of the blood draw are 
also known risks. Because we will be looking at biochemical information in your blood, there may also be other 
risks that we currently don't recognize or expect. Results that are considered important for your safety such as 
signs of infection, changes in blood glucose or electrolyte concentrations will be provided to you or your primary 
care provider, after obtaining a consent from you by obtaining your signature on the form for release of 
information. The research information that is learned from studies of your samples may be used scientifically 
and may be used by the sponsor in other research. The results of the analysis of your samples WILL NOT be 
made available to you or to your referring health care professional. A research lab, not by an Emory Healthcare 
lab, will do the testing. Some samples may be sent to other labs for additional analysis. The results of the 
biochemical analysis will not be recorded in your medical record, nor will they be provided to third parties. As for 
the blood drawing, standard sterile procedure for blood withdrawal will be used. In addition, the volume of blood 
withdrawn for this study will not exceed 200 ml (about 13 tablespoons).  
 
Chest X-Ray: You will be exposed to radiation from x-rays. These procedures are not necessary for your medical 
care and will occur because you participate in this study. The estimated radiation dose that you will receive is 
equal to or less than the natural environmental radiation the average person receives in the United States 
annually. The principal risk associated with a radiation dose is the possibility of developing a radiation-induced 
cancer later in life. The risk for radiation-induced cancer from this study is negligible.  
 
Psychiatric Assessments: The psychiatric assessments may involve detailed questioning regarding 
memories or feelings. Discussing mental symptoms may bring up emotions that distress some people. To 
minimize this, you will be able to discuss any disturbing memories or feelings you may experience with the 
study staff. Research personnel will be careful not to cause psychological distress during any part of the 
psychiatric assessment. There is a possible social risk involved if sensitive information related to previous 
mental health treatment is accidentally released. To guard against this risk, we will use a number and not your 
name to identify personal information. All documents will be kept in a locked area, and only the researchers will 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 12 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
have a key. The study has been designated as sensitivity study and the information will not be included in your 
regular Emory Healthcare Chart.  
 
Computer Testing: There are no known risks for the tests of your thinking ability. 
 
MRI: The MRI scanner contains a very strong magnet. Therefore, you may not be able to have the MRI if you 
have any type of metal implanted in your body, for example, any pacing device (such as a heart pacer), any 
metal in your eyes, or certain types of heart valves or brain aneurysm clips. Someone will ask you questions 
about this before you have the MRI. If you are a woman of childbearing potential, there may be unknown risks 
to the fetus. Therefore, you will not be allowed to participate in the study if you are pregnant. 
 
Because the MRI is performed in an enclosed narrow space, some people may experience extreme fear, 
shortness of breath, rapid heartbeat or claustrophobia. If this happens to you, you may ask to stop the scan 
immediately. Metallic objects implanted in the body may move or heat due to force from the magnet in the 
scanner. Therefore, you will be carefully screened for any type of metal objects in your body prior to receiving 
the scan. If you have metal objects/implants in your body that are considered risky by Federal Government 
MRI safety guidelines, you will not receive the scan. No other known risks are associated with receiving the 
MRI/MRS scan.  
 
Lumbar puncture: Some of the side effects of this procedure include bruising at the site of needle insertion, 
infection, bleeding and headache (post-LP headache). To reduce risks associated with receiving an LP, an 
experienced physician will conduct the procedure under standard sterile conditions. Subjects will receive two 
liters of normal saline prior to the procedure.  This has been found to reduce the incidence of post-LP headache. 
Subjects will lie flat for two hours after the procedure and will be observed in the outpatient research unit for the 
emergence of any significant adverse effects until the research nurse deems it safe for you to be discharged. If 
subjects develop a headache they will be treated with pain medication or application of blood patch. Very rarely, 
some individuals develop neurological symptoms following the procedure, in which they would be evaluated by 
the Emory Emergency Room Physicians and treated accordingly. The Department of Anesthesiology at Emory 
University has 24 hour coverage of the ACTSI-CIN if more emergent side effects develop following LP. In 
addition, the entire procedure will be conducted in the Emory research unit at ACTSI-CIN, which has immediate 
access to EKG monitoring, cardiac resuscitation equipment and is located in close proximity to the Emory 
University Hospital Emergency room. You will be encouraged to call your study doctor right away if you have 
any of these side effects: 
• 
you feel faint, or unsteady on your feet, when you stand up after you have been sitting or lying down 
• 
you have lost power or sensation of one or both your lower limbs 
• 
you have a headache that is not relieved by several doses of painkillers 
• 
you feel confused 
• 
your neck feels sore and stiff 
• 
you develop nausea or vomiting 
 
Risks with Pregnancy 
The study medication (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. In addition, 
all women of childbearing potential are required to undergo pregnancy testing before entering the study.  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; 
women whose sexual partners have had a vasectomy or have received or are using mechanical contraceptive 
devices. Condoms plus spermicide should be used in addition to other contraceptive methods to provide 
protection against sexually transmitted diseases and to provide additional protection against pregnancy. Men 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 13 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
who are participating in this research study need to understand the possible danger of taking a drug whose 
effects on the fetus are unknown. 
 
 
If you miss a period or think you might be pregnant during the study, you must notify the investigator 
immediately so that you can be withdrawn from the study. If you become pregnant during the study or within 15 
days after your last dose of study medication and your pregnancy is carried to term, the study doctor will ask to 
follow the course of the pregnancy and delivery, as well as the condition of the newborn. 
 
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 are required to notify the study 
doctor immediately. 
 
The study medication taken in this study may also have unknown risks. 
 
Will I benefit directly from the study?  
This study is not designed to benefit you directly.  Your depression may improve while you are in this study but 
it may not, and it may even get worse. This study is designed to learn more about how the study drug 
infliximab may decrease inflammation and treat symptoms of depression. The study results may be used to 
help others in the future. 
Will I be compensated for my time and effort? 
Our preferred method of compensation will be the use of Clincards.  All payments are made using a personal 
payment card. We issue this to you for free. 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. Research payments in cash 
or cash equivalents that exceed $600.00 per calendar year must be reported to the Internal Revenue Service 
(IRS) by the University. The level of reimbursement for this study is at a level that the potential exists for the 
federal tax reporting to the IRS for your participation in this study. 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, 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 we issue it. Please ask if you have any 
questions or concerns about the card scheme. 
 
Each of your visits will be prorated according to the table below. An additional $25 will be provided to cover 
travel expenses for participants that travel equal to or greater than 50 miles one way to Atlanta. Please let us 
know if you have any questions regarding the compensation schedule.  
 
Table 2: Compensation Schedule 
Visit 
Total Amount  
Amount put on Clincard 
immediately after visit  
Amount put on 
Clincard at the end of 
study participation 
Intake 
$25 
$25 
 
(Visit Total) 
$25 
 
 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 14 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
Screening  
 
 
 
Psychiatric evaluation, 
history and physical, EKG, 
chest x-ray and lab work  
$50* 
$50* 
 
(Visit Total) 
$50 
 
 
Baseline Visit 1 
 
 
 
Medical and psychiatric 
assessments, lab work 
research blood, 
neurocognitive tests, and 
self-report surveys 
$50 
$50 
 
Computer Motivation Tasks 
(depending on choice made 
on the computer) 
$5-$100 
 
$5-$100 
Complete Scan 
$300 
 
$300 
Incomplete Scan 
$25** 
$25** 
 
Extended break 
$50*** 
$50*** 
 
(Visit Total) 
$80-$500 
 
 
Baseline Visit 2 
 
 
 
Infusion (Infliximab or 
placebo) and all scheduled 
assessments  
$150 
$50 
$100 
(Visit Total) 
$150 
 
 
Post-Treatment 
Day 1 (Optional) 
 
 
 
Medical assessment, lab 
work, research blood 
$50 
$50 
 
(Visit Total) 
$50 
 
 
Post-Treatment 
Day 3 
 
 
 
Medical assessment, lab 
work, research blood, 
neurocognitive tests, and 
self-report surveys 
$50 
$50 
 
Complete Scan 
$300 
 
$300 
Incomplete Scan 
$25** 
$25** 
 
Extended break 
$50*** 
$50*** 
 
(Visit Total) 
$75-$400 
 
 
Post-Treatment 
Week 1 (Optional) 
 
 
 
Medical assessment, lab 
work, research blood 
$50 
$50 
 
(Visit Total) 
$50 
 
 
Post-Treatment 
Week 2  
 
 
 
Medical assessment, lab 
work research blood, 
neurocognitive tests, and 
self-report surveys 
$50 
$50 
 
Computer Motivation Tasks 
$5-$100 
 
$5-$100 
Complete Scan 
$300 
 
$300 
Incomplete Scan 
$25** 
$25** 
 
Extended break 
$50*** 
$50*** 
 
(Visit Total) 
$80-$500 
 
 
Post-Treatment 
Week 2-Visit 2 
(Optional) 
 
 
 
Spinal Tap (Lumbar 
Puncture)  
$500 
 
$500 
(Visit Total) 
$500 
 
 
Total Study 
Compensation 
$560-$2225 
Department of 
Psychology 2-Day 
Study (Optional) 
$800 Maximum 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 15 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
*=Screening visit may be divided across 2 visits and paid $25 per visit 
**= Unable to complete scan leading to termination from the study 
***=Subject can leave and return to complete visit if break is a minimum of 2 hours 
 
 
 
What are my other options? 
If you decide not to enter this study, there is care available to you outside of this research study. The study 
clinician will discuss these options with you.  You do not have to be in this study to be treated for depression. 
 
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. 
 
Study records can be opened by court order. 
 
Certificate of Confidentiality 
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: 
 
• 
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. 
 
Storing and Sharing your Information 
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. You will not be able 
to request destruction of these samples in this study. 
 
How is my Genetic Information Protected? What are the Risks? 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 16 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
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.   
 
Medical Record 
If you have been an Emory Healthcare patient before, then you already have an Emory Healthcare medical 
record.  If you have never been an Emory Healthcare patient, you do not have one.   An Emory Healthcare 
medical record will be made for you if an Emory provider or facility gives you any services or procedures for 
this study.   
 
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: Cognitive testing results, self-report forms, clinician 
administered evaluations, History and Physical, MRI/MRS scans and biological samples (blood and CSF 
samples) collected for research purposes. 
 
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.  
 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 17 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
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. Andrew H. Miller at 
telephone number 404-727-8260. 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. If the study procedures result in any medical 
complications that would not fall under “injury” as discussed above, the cost of treatment for those 
complications may be charged to you or your insurance.   
 
Withdrawal from the Study 
You have the right to leave a study at any time without penalty.   
 
For your safety, however, you should consider the study doctor’s advice about how to go off the study 
treatment.  If you leave the study before the final planned study visit, the researchers may ask you to have 
some of the final 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. 
 
30 Day Off-Study Policy 
There may be situations based on your schedule or ours that require more than 30 days to occur between 
study visits. If this is the case, for the purposes of your care and safety, a research assistant will inform you of 
the delay and temporarily remove you from the study. In the meantime, you should feel free to start or resume 
any form of treatment. When you return for your next study visit, you will be reevaluated for study eligibility and 
re-consented by a study clinician or coordinator. Based on your status, we will continue the study where you 
left off and will use as much previously collected data as possible. However you may be asked to repeat some 
bloodwork or assessments to evaluate any changes in your status.  
 
 
Authorization to Use and Disclose Protected Health Information 
 
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 main 
study and for any optional studies in which you may choose to participate. 
 
Main Study 
 
PHI that Will be Used/Disclosed:   


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 18 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
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 medications. 
• 
Results of exams, procedures and tests you have before and during the study. 
• 
Laboratory test results. 
 
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. We will use and disclose your PHI for the administration and payment of 
any costs relating to subject injury from the study 
 
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. We will also comply with legal 
requests or orders that require us to disclose your PHI.  
 
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.   
 
People Who will Use/Disclose Your PHI: 
The following people and groups will use and disclose your PHI in connection with the research study: 
 
• 
The Principal Investigator and the research staff will use and disclose your PHI to conduct the 
study and give you study related treatment. 
• 
Emory may use and disclose your PHI to get payment for study related treatment and to run 
normal business operations.  
• 
The Principal Investigator and research staff will share your PHI with other people and groups to 
help conduct the study or to provide oversight for the study. 
• 
 National Institute of Mental Health (NIMH) is the Sponsor of the study.  The Sponsor may use 
and disclose your PHI to make sure the research is done correctly and to collect and analyze 
the results of the research.  The Sponsor may disclose your PHI to other people and groups like 
study monitors to help conduct the study or to provide oversight for the study.   
• 
The research team and the Sponsor may use and disclose your PHI, including disclosure to 
insurance carriers to administer payment for subject injury.  
• 
The following people and groups will use your PHI to make sure the research is done correctly 
and safely: 
o Emory offices that are part of the Human Research Participant Protection Program and 
those that are involved in study administration and billing.  These include the Emory IRB, 
the Emory Research and Healthcare Compliance Offices, and the Emory Office for 
Clinical Research.  
o Government agencies that regulate the research including:  Office for Human Research 
Protections; Food and Drug Administration. 
o Public health agencies. 
o Research monitors and reviewer. 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 19 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
o Accreditation agencies. 
• 
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 
Your PHI will be used until this research study ends. 
 
Revoking Your Authorization 
If you sign this form, at any time later you may revoke (take back) your permission to use your information.  If 
you want to do this, you must contact the study team at: 
 
At that point, the researchers would not collect any more of your PHI.  But they may use or disclose the 
information you already gave them so they can follow the law, protect your safety, or make sure that the study 
was done properly, and the data is correct.  If you revoke your authorization you will not be able to stay in the 
main 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.  The Sponsor, and people and 
companies working with the Sponsor on this study are not covered by the Privacy Rules.  They will only use 
and disclose your information as described in this Consent and Authorization.  
 
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.  
 
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.   
 
If you decide to sign consent for enrollment into this study, there are a couple of items that you may opt to 
check on the signature pages. You do not have to check these items in order to be in the study. They are 
optional. The first item is whether or not you are willing to participate in the lumbar puncture procedure. If you 
are not willing to participate in the lumbar puncture procedure you may still participate in the study. The second 
item is agreeing to allow the results of your screening assessments and any data collected from you during the 
study to be shared with other research studies of your choosing. If you decide not to check this item you may 
still participate in the study. 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 20 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
Contact Information 
Contact Bobbi Woolwine, LCSW at 404-712-9620: 
• 
if you have any questions about this study or your part in it,   
• 
if you feel you have had a research-related injury or a bad reaction to the study drug, or 
• 
if you have questions, concerns or complaints about the research 
 
Contact the Emory Institutional Review Board at 404-712-0720 or 877-503-9797 or irb@emory.edu: 
• 
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 and Authorization 
 
You are also free to agree or disagree to the option below: 
 
In the box below, please put your initials under “Yes” if you agree to the statement, or “No” if you do not agree 
and then sign on the appropriate line below: 
 
 
 
 
 
 
 
                            
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
TO BE FILLED OUT BY SUBJECT ONLY 
Please print your name, sign, and date below if you agree to be in the main 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. 
 
Yes        No   
     
 
I DO agree to abstain from sexual intercourse 14 days prior to study 
infusion and to use a medically approved birth control method for the 
duration of the study. If I am a woman, I HAVE been advised to delay 
conception for 6 months post-infusion.  
Yes        No   
     
 
I AM willing to participate in the LP procedure, as described on page 8 of 
this consent form. 
 
 
 
 
 
 
 
 
 
Yes        No   
     
 
I AM interested in participating in the 2-Visit Study with the Emory 
Department of Psychology, IRB#87941, as an optional extension of this 
study. 
 
 
Yes        No   
     
I DO agree, if I consent to participate in any additional studies, that the 
results of my screening tests (laboratory, medical, and psychiatric) and any 
data collected during my study visits for this project may be shared with the 
study team of the project for which I gave consent. I also authorize the use 
of my PHI for this purpose.  
 
 
Yes        No   
     
  
 
 
May we contact you in the future regarding participation in future research  
studies? You may then decide if you are willing to participate. 
 


Study No.: IRB00090667 
Emory University IRB 
IRB use only 
Document Approved On: «ApproveDate» 
 
 
Page 21 of 21 
 
Version Date: 10/23/2019 
IRB Form 04152016 
 
 
Name of Subject  
 
 
 
 
 
  
Signature of Subject (18 or older and able to consent) 
Date              Time 
 
TO BE FILLED OUT BY STUDY TEAM ONLY 
 
__________________________________________________________ 
Name of Person Conducting Informed Consent Discussion 
 
 
 
 
 
Signature of Person Conducting Informed Consent Discussion 
Date              Time