Clinical trial NCT02389465
Conditions: Depression Inflammation
Keywords: Depression Geriatric Inflammation
Sponsor: University of Pennsylvania
Start date: 2014-08-01; Completion date: 2022-07-18
Enrollment: 119 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Over 18% of Americans aged 65 years and older have depression. Recent evidence suggests that there is a link between depression and inflammatory disease. This study investigates the relationship between inflammation in the brain and depression. Comparing biological and psychological differences in depressed and non-depressed people allows researchers to find better ways to treat and prevent depression. All participants will have: neuropsychological tests, an EKG, a spinal tap, a blood draw, and, if depressed, given either an antidepressant coupled with an anti-inflammatory medication or an anti-depressant coupled with a placebo for six weeks. The investigators are trying to correlate brain function with depression levels and biomarkers from the blood and spinal fluid.

Detailed description:

Arms: arm 1: This arm is for participants who are not depressed. arm 2: Depressed participants will receive an antidepressant (escitalopram) AND either a non-steroidal anti-inflammatory drug (celecoxib) OR placebo (sugar pill) for 6 weeks.
Interventions: intervention 1: Escitalopram + Celecoxib intervention 2: Escitalopram + Placebo
Intervention descriptions: intervention 1: Participants will receive celecoxib in addition to escitalopram intervention 2: Participants will receive a placebo in addition to escitalopram.

Protocol documents:
Prot_SAP_000.pdf: 
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STRESS AND INFLAMMATION IN THE PATHOPHYSIOLOGY MDD  
A Phase IV, randomized, double-blind, placebo-controlled, one-phase study of the effects of escitalopram and celecoxib 
on depression. 
 
Principal Investigator (1) 
Yvette Sheline, MD 
Center for Neuromodulation in Depression and Stress, 
Department of Psychiatry 
3700 Hamilton Walk, D307 
215-573-0082 
Sheline@pennmedicine.upenn.edu 
NIH Grant Number  
 
MH098260-03 
 
Study Drug Intervention: 
Escitalopram, celecoxib 
IRB Number: 
819654  
 
ClinicalTrials.gov Number  
 
NCT02389465 
 
Food and Drug 
Administration  
 
Exempt from IND regulations, letter dated 08/18/2015 
(attached in Appendix) 
 
Initial version 
4/23/15 Version 1.0; Revised August 6, 2015; Revised August 24, 2015 
Amended 
 11/10/15 Version 2.0 
Amended 
7/14/16 Version 3.0 


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Amended 
1/19/17 Version 4.0 
Amended            6/28/2017 Version 5.0;  
 
7/12/2017 Version 5.1 
 
8/_/2017 Version 5.2 
 
10/5/17 Version 5.3 
 
10/25/17 Version 5.4 
 
12/21/17 Version 5.5 
Amended 
1/19/18 Version 6.0 
Amended             10/5/18 Version 7.0 
Amended 
8/19/19 Version 8.0 
 
 


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Table of Contents 
 
Contents 
TABLE OF CONTENTS ............................................................................................................................... 3 
CO-INVESTIGATOR ................................................................................................................................... 8 
1   BACKGROUND AND STUDY RATIONALE .......................................................................................... 9 
1.1 
INTRODUCTION .............................................................................................................................. 9 
1.2 
BACKGROUND AND RELEVANT LITERATURE ................................................................................... 10 
1.3 
NAME AND DESCRIPTION OF THE STUDY DRUGS ........................................................................... 11 
2 
STUDY OBJECTIVES AND INVESTIGATIONAL PLAN .................................................................. 11 
2.1 
PRIMARY OUTCOME VARIABLE(S)* ................................................................................................. 12 
2.2 
STUDY DESIGN ............................................................................................................................ 12 
2.3 
STUDY DURATION ........................................................................................................................ 13 
2.4 
RESOURCES NECESSARY FOR HUMAN RESEARCH PROTECTION ...................................................... 13 
2.5 
TARGET POPULATION ................................................................................................................... 14 
2.6 
SUBJECTS ENROLLED AT PENN .................................................................................................... 14 
2.7 
ACCRUAL .................................................................................................................................... 14 
2.8 
KEY INCLUSION CRITERIA ............................................................................................................. 15 
2.9 
KEY EXCLUSION CRITERIA ............................................................................................................ 16 
2.10 
POPULATIONS VULNERABLE TO UNDUE INFLUENCE OR COERCION ................................................... 17 
3 
STUDY POPULATION ...................................................................................................................... 17 
3.1 
SUBJECT RECRUITMENT ............................................................................................................... 17 
3.2 
SUBJECT COMPENSATION ............................................................................................................. 19 
3.3 
SUICIDAL IDEATION AND BEHAVIOR ............................................................................................... 21 
4 
STUDY INTERVENTION (ESCITALOPRAM AND CELECOXIB.) ................................................... 22 
4.1 
DESCRIPTION ................................................................................................................................... 22 
4.2 
INTERVENTION REGIMEN ................................................................................................................... 22 
4.3 
RECEIPT .......................................................................................................................................... 22 
4.4 
STORAGE ......................................................................................................................................... 22 
4.5 
PREPARATION AND PACKAGING OF VERUM STUDY DRUG ............................................................... 22 
4.6 
BLINDING .................................................................................................................................... 24 
4.7 
ADMINISTRATION AND ACCOUNTABILITY ........................................................................................ 24 
4.8 
SUBJECT COMPLIANCE MONITORING ............................................................................................ 24 
4.9 
RETURN OR DESTRUCTION OF INVESTIGATIONAL PRODUCT ........................................................... 25 
5 
STUDY PROCEDURES .................................................................................................................... 25 
5.1 
INFORMED CONSENT PROCESS / HIPAA AUTHORIZATION ............................................................. 25 
5.2 
RECRUITMENT, SCREENING AND BASELINE ASSESSMENTS .............................................................. 26 
5.3 
ASSESSMENT MEASURES AND NEUROPSYCHIATRIC TESTS .............................................................. 28 
5.4 
BLOOD DRAWS ............................................................................................................................ 32 
5.5 
LUMBAR PUNCTURE ..................................................................... ERROR! BOOKMARK NOT DEFINED. 
5.6 
GASTROINTESTINAL SAFETY ............................................................................................................. 32 
5.7 
PROTOCOL NON-CONFORM DRUGS ..................................................................................................... 32 
5.8 
AMBULATORY BLOOD PRESSURE MONITORING (ABPM) ................................................................ 33 
5.9 
ACTIVITY DIARY ........................................................................................................................... 34 
5.10 
ACTIGRAPHY ............................................................................................................................... 34 


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5.11 
DRUG CONCENTRATIONS IN PLASMA ............................................................................................. 34 
5.12 
URINARY PROSTAGLANDIN METABOLITES ..................................................................................... 34 
5.13 
MICROBIOME ANALYSES .............................................................................................................. 34 
5.14 
DISTRIBUTION AND SHIPMENT OF HUMAN SPECIMENS ..................................................................... 35 
6 
ANALYSIS PLAN .............................................................................................................................. 35 
6.1 
DATA ANALYSIS AND PREDICTIONS ............................................................................................... 35 
6.2 
VARIABLES TO BE USED IN HYPOTHESIS TESTING ........................................................................... 36 
6.3 
ANALYSIS OF SPECIFIC AIMS ........................................................................................................ 37 
6.4 
EXPLORATORY AIMS .................................................................................................................... 38 
6.5 
FURTHER ANALYSES .................................................................................................................... 38 
7 
SAFETY AND ADVERSE EVENTS .................................................................................................. 38 
7.1 
DEFINITIONS ................................................................................................................................ 38 
7.1.1 
Adverse Event ..................................................................................................................... 38 
7.1.2 
Serious Adverse Event ....................................................................................................... 39 
7.2 
RECORDING OF ADVERSE EVENTS ............................................................................................... 39 
7.3 
RELATIONSHIP OF AE TO STUDY .................................................................................................. 40 
7.4 
REPORTING OF ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .............................................. 41 
7.4.1 
Follow-up report .................................................................................................................. 41 
7.4.2 
Investigator Reporting: Notifying the Penn IRB .............................................................. 41 
7.5 
UNBLINDING PROCEDURES .......................................................................................................... 41 
7.6 
MEDICAL MONITORING ................................................................................................................ 42 
7.6.1 
Data and Safety Monitoring Plan ....................................................................................... 42 
7.6.1.1 
Principal Investigator ..................................................................................................... 42 
7.6.1.2 
Medical monitor .............................................................................................................. 42 
7.6.1.3 
Data Safety and Monitoring Board (DSMB) .................................................................. 42 
7.7 
EXPEDITED FDA REPORTING REQUIREMENTS ............................................................................... 43 
7.8 
NIH/NIMH REPORTING REQUIREMENTS ....................................................................................... 43 
7.8.1 
Additional reporting requirements .................................................................................... 43 
7.8.2 
Reporting Process .............................................................................................................. 43 
8 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING .................................... 44 
8.1 
CONFIDENTIALITY ........................................................................................................................ 44 
8.2 
SUBJECT PRIVACY ...................................................................................................................... 44 
8.3 
DATA DISCLOSURE ...................................................................................................................... 45 
8.4 
DATA COLLECTION AND MANAGEMENT ........................................................................................ 45 
8.5 
RECORDS RETENTION ................................................................................................................. 46 
8.6 
TRIAL REGISTRATION .................................................................................................................. 46 
9 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 46 
9.1 
STUDY MONITORING PLAN ........................................................................................................... 46 
9.2 
AUDITING AND INSPECTING .......................................................................................................... 46 
10 
ETHICAL CONSIDERATIONS .......................................................................................................... 46 
10.1 
RISKS ......................................................................................................................................... 47 
10.1.1 
Risk of Breach of Confidentiality .................................................................................. 47 
10.1.2 
EKG .................................................................................................................................. 47 
10.1.3 
Blood draw ...................................................................................................................... 47 
10.1.4 
Lumbar Catheter ............................................................... Error! Bookmark not defined. 
10.1.5 
MRI scan .......................................................................................................................... 47 
10.1.6 
Escitalopram ................................................................................................................... 47 
10.1.7 
Celecoxib ......................................................................................................................... 47 
10.2 
MINIMIZING RISKS ........................................................................................................................ 48 
10.3 
BENEFITS .................................................................................................................................... 49 


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10.4 
RISK BENEFIT ASSESSMENT ........................................................................................................ 49 
10.5 
RISK / BENEFIT ASSESSMENT FOR CELECOXIB ............................................................................. 50 
10.5.1 
THROMBOTIC RISK AND CARDIOVASCULAR RISK PROFILE AT BASELINE ...................................... 50 
10.5.2 
BLOOD PRESSURE .................................................................................................................. 52 
10.5.3 
CO-ADMINISTRATION OF SSRIS AND CELECOXIB ...................................................................... 56 
10.5.1 
GASTROINTESTINAL BLEEDING RISK OF CELECOXIB ................................................................. 56 
11 
REFERENCES .................................................................................................................................. 56 
12 
APPENDIX ......................................................................................................................................... 60 
12.1 
STUDY FLOW-CHART ................................................................................................................... 60 
12.2 
DIARY RECALL FORM (EXAMPLE) ................................................................................................. 63 
12.3 
TEMPLATE MEDICAL MONITORING (EXAMPLE) ............................................................................... 65 
12.4 
DRUG PRESCRIBING INFORMATION ............................................................................................... 68 
12.5 
FOOD AND DRUG ADMINISTRATION-IND EXEMPT LETTER ............................................................. 69 
 
 
 


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Study Summary 
Title 
Stress and Inflammation in the Pathophysiology of Depression 
Short Title 
Stress and Inflammation 
IRB Number 
819654  
Phase 
Phase 4 
Methodology 
 Double-blinded study or open-label;  Randomized, placebo-controlled, one-
phase study 
Study Duration 
This study will last 6-12 weeks, dependent on whether the participant enters 
the open-label phase of the study. 
Study Center(s) 
Single-center. 
Objectives 
1: Characterize neuroanatomical and neuropsychological correlates of 
abnormal cytokines in MDD. 
2: Characterize the reversibility of brain dysfunction, including cognitive 
impairment, with treatment of depression and its association with 
inflammation. 
Number of Subjects 
100 depressed subjects, 50 control subjects 
Main Inclusion and 
Exclusion Criteria 
18-80, depressed, males and females, without psychosis or other 
concomitant psychiatric illnesses, or significant cardiac, liver, or GI disease.    
Drugs 
 
Escitalopram 10 mg/day for 3 days and then 20 mg/day for 39 day (taper 
down of 10 mg for 3 days) with placebo or Escitalopram 10 mg/day for 3 
days and then 20 mg/day for 39 day (taper down of 10 mg for 3 days) with 
celecoxib (400 mg/day)  


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Duration of 
administration  
6-12 weeks 
Statistical 
Methodology 
The design of this trial is simple repeated measures design. 
Safety Evaluations  
This is a low-risk study. Subject safety will be closely monitored. Subjects 
reporting of side effects will be used to evaluate individual safety of high 
doses of escitalopram and celecoxib. Additionally, heart rate monitoring will 
allow us to assess the safety of celecoxib for blood pressure risks.  
Data and Safety 
Monitoring Plan  
The sponsor is responsible for monitoring the data quality and the ongoing 
safety of subjects. The PI will be monitoring the data quality and the ongoing 
safety of subjects. 
 
 
 
 


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Co-Investigator 
 
Name: 
 
Title: 
Contact Information: 
Carsten Skarke 
MD 
8037 Maloney Bldg 
Hospital of the University of Pennsylvania 
3600 Spruce Street 
Philadelphia, PA 19104 
Phone: 215-746-8330 
Fax: 215-573-8996 
e-mail: cskarke@ upenn.edu  
 
 
 
 


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1   BACKGROUND AND STUDY RATIONALE 
This study will be conducted in full accordance with all applicable University of Pennsylvania 
Research Policies and Procedures and all applicable Federal and state laws and regulations 
including [as applicable include the following regulations as they apply 45 CFR 46, 21 CFR 
Parts 50, 54, 56, and 312, and Good Clinical Practice: Consolidated Guidelines approved by the 
International Conference on Harmonisation (ICH).] All episodes of noncompliance will be 
documented. 
1.1 
Introduction  
Major depression (MDD) is a cause of disability worldwide, but the etiology of MDD remains 
unclear. An emerging concept is that inflammation may have relevance, especially in MDD. We 
have data supporting increased inflammatory cytokines in MDD compared with controls that are 
associated with decreased hippocampus and amygdala volumes. MDD also had impairment in 
neuropsychological function in episodic memory, executive function, decreased hippocampus 
and amygdala resting state functional connectivity. Antidepressant treatment improved IL-6 
levels, neuropsychological testing and resting state connectivity.  
We will recruit patients with MDD (n = 100) and controls (n = 50) to characterize immune 
function, brain structure and connectivity and neuropsychological function. Using the Hospital 
of University of Pennsylvania’s Pepper Lab we will measure participants’ c-reactive protein 
(CRP) levels, and stratify participants according to CRP level (i.e. high (CRP ≥3) and low 
(CRP <3)). All participants with MDD (n=100),  will receive a selective serotonin reuptake 
inhibitor (SSRI) antidepressant and we will randomize them to SSRI plus placebo (n≤50) or 
SSRI + celecoxib (n≤50).  We will assess participants pre- and post-treatment with peripheral 
and central cytokine levels, neuropsychological tests and brain resting state functional 
connectivity.   
 
Hypothesis 1: a) Compared with matched controls, MDD will have abnormalities in peripheral 
and inflammatory cytokines, neuropsychological function, hippocampal, amygdala and 
prefrontal cortex (PFC) structure and functional connectivity; b) Peripheral/central inflammatory 
cytokine levels will be associated with volume loss in hippocampus and amygdala; and c) 
Cumulative duration of depression will correlate with volume loss in hippocampus, amygdala, 
and PFC. d) Across the lifespan there will be an age effect interaction with depression. 
Hypothesis 2: a) Once subjects have completed the antidepressant treatment, they will have 
greater normalization of IL-6 and IL-10, greater improvements in memory, executive function, 
and in resting state functional connectivity compared to their baseline measures; b) Improvement 
in clinical depressive scores will correlate with normalization of inflammatory cytokines; c) 
Those randomized to the addition of celecoxib (vs placebo) will have additive improvements in 
cytokines, resting state functional connectivity and depression scores. 


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1.2 
Background and Relevant Literature  
Depression is a common cause of morbidity, disability and mortality with an increasing 
worldwide prevalence.  A key distinguishing feature of MDD versus younger MDD is its 
association with comorbid medical illness, such as vascular diseases often resulting in decreased 
cognitive function. The etiological factors contributing to MDD are not entirely understood, but 
the vascular depression hypothesis posits that cerebrovascular disease contributes to the 
development and severity of depression in older adults by causing ischemic white matter lesions 
of subcortical limbic structure projections to the frontal cortex or in frontal cortical white matter 
tracts; these interruptions cause alterations in mood regulation and cognition. In addition, there is 
mounting evidence that patients with major depression (MDD), particularly those with MDD, 
have increased oxidative stress, resulting in part from increased peripheral blood inflammatory 
biomarkers.  Compared with nondepressed individuals, those with MDD have elevations of 
inflammatory cytokines and their soluble receptors in peripheral blood and CSF. Further, they 
have elevations in blood concentrations of acute phase reactants, including acute phase proteins, 
adhesion molecules, chemokines, and mediators of inflammation such as nitric oxide synthase 
(NOS) and prostaglandins.  Increased cytokines include interleukin (IL)-1, tumor necrosis factor 
(TNF) alpha, and IL-6, one of the most commonly and reliably elevated peripheral biomarkers in 
MDD.  In addition to an overall correlation with the depressed state, there are correlations 
between specific depressive symptoms and inflammatory markers.  These include associations of 
sleep impairment, fatigue and cognitive dysfunction with IL-6.  Evidence for an association with 
depression also includes the ability of proinflammatory factors to induce depressive symptoms, 
which were correlated with blood cytokine concentrations.  In the case of prolonged exposure to 
cytokines, there is a marked risk of becoming depressed, with approximately 25% of patients 
exposed to interferon (IFN)- experiencing symptoms of MDD. IL-6 has been shown to interfere 
with the production of serotonin from tryptophan by increasing breakdown of tryptophan, thus 
reducing serotonin levels (and increasing depression risk) and preferentially increasing the 
synthesis of kynurenine and its neurotoxic metabolites, 3-hydroxykynurenin and quinolinic acid. 
IL-6 drives this metabolic shunt and IL-10 partially counters it. 
 
Further, the inflammation hypothesis of aging proposes an age-related increase in cytokine 
production, resulting in a chronic proinflammatory state, which has a detrimental effect on 
cellular function.  Elevated plasma IL-6 is a common finding in older adults who are at greater 
risk of disease and disability.  Given the strong correlation between proinflammatory markers 
and illness, inflammation is particularly important in MDD.  Increased plasma IL-6 is a risk 
factor for many diseases of aging, including hypertension, atherosclerosis, cardiovascular 
ischemia and type 2 diabetes, all of which are more common in MDD.  IL-6 was called the 
gerontologists cytokine by William Ershler, who proposed that this cytokine regulates a key 
human aging pathway, given the consistent association between elevated plasma IL-6 and poor 
health outcomes.  In healthy older adults elevated plasma IL-6 has a linear inverse correlation 
with cognitive performance. A sizeable and growing number of older people are at risk for IL-6 
mediated cognitive effects. Chronically elevated IL-6 is associated with mild cognitive deficits, 


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even in apparently healthy community dwelling elders. Elevated IL-6 augments the risk of stroke 
and dementia and predicts future cognitive decline. Despite this evidence of a link between 
plasma IL-6 and CNS impairment the specific mechanisms remain largely unknown. We believe 
it is likely that with each repeated episode of depression and resultant exposure to elevated 
inflammatory cytokines in brain, there is progressive regional loss of inhibitory neurons in brain 
regions that are particularly sensitive to inflammatory damage, such as the hippocampal CA2-3 
region.  We hypothesize that this volumetric loss is critically associated with development of 
brain dysfunction and risk of repeated depressive episodes. 
A meta-analysis (1) that included 14 trials and 6262 participants was recently conducted to 
examine the use of non-steroidal anti-inflammatory drugs (NSAIDs) and cytokine inhibitors. The 
pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms 
compared with placebo. Subanalyses emphasized the antidepressant properties of celecoxib on 
remission and response, particularly in combination with antidepressant. Among the 6 studies 
that reported adverse events there was no evidence of an increased number of GI or 
cardiovascular events after 6 weeks or infections after 12 weeks.  
A meta-analysis of five (2) post-approval clinical trials associated lower depression scores with 
celecoxib treatment, 200 mg qd over 6 weeks, in patients with active osteoarthritis, n=607, 
compared to patients exposed to placebo (2). These clinical trials were highly protected against 
bias by following a multicenter, randomized, double-blinded, placebo-controlled, active-
comparator, parallel-group design (2). The authors write that a significant increase in systolic or 
diastolic blood pressure and heart rate was not evident after 6 weeks of celecoxib treatment (2). 
This supports a good safety profile for this celecoxib dosing regimen, in particular, when 
considering that 48% of patients (291/607) had hypertension at baseline, 20% (121/607) 
hyperlipidemia, and 17% (103/607) diabetes mellitus as baseline conditions. The high morbidity 
is also reflected in that 51% (310/607) of patients report at baseline to receive pharmacotherapy to 
treat cardiovascular disease (2). CRP levels have been shown to highly correlate with cytokine 
levels. Validation of commercially available methods of CRP has been conducted and shown that 
semi-quantative CRP strips can distinguish between normal and high levels of CRP within 
individuals very simply (3).   
 
1.3 
Name and Description of the Study Drugs  
Study drug intervention consists of escitalopram and celecoxib in doses approved for clinical 
use. Dose ranges for escitalopram are 10-20 mg/day. The dose of celecoxib is 400 mg/day.  
2 
Study Objectives and Investigational Plan 
Aim 1: Characterize neuroanatomical and neuropsychological correlates of abnormal cytokines 
in MDD. 


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Aim 2: Characterize the reversibility of brain dysfunction, including cognitive impairment, with 
treatment of depression and its association with inflammation. 
2.1 
Primary outcome variable(s)* 
1) Cytokine levels will be measured in blood:  Primary measure will be IL-6 pre- and post-
treatment. 
2) Hippocampus, including subvolume analyses and Amygdala volumes: Left and right 
volumes will be separately measured and standardized by brain volumes before being 
entered in analyses.  Prefrontal cortical thickness: L & R orbitofrontal, superior frontal 
and frontal pole. 
3) Antidepressant treatment response determined using the MADRS score following 
antidepressant treatment covaried on baseline MADRS score. 
4) Neuropsychological function as determined by factor scores from episodic memory and 
executive function. 
5) Resting state functional connectivity of the hippocampus and amygdala to anterior 
cingulate (AC) and dorsolateral prefrontal cortex (DLPFC). 
2.2 
Study Design 
100 depressed and 50 control subjects, age 18-80, male and female, will be recruited for this 
study. Depressed participants will be stratified based on their c-reactive protein (CRP) levels 
(i.e., “High” CRP≥3 and “Low” CRP<3).  All participants will be started on either 10 mg of 
escitalopram + placebo or 10 mg of escitalopram + celecoxib (400mg/day) daily for 3 days.  
Following this lead-in dose of the SSRI they will then take 20 mg daily thereafter for 39 days 
and have no changes in their dose of placebo or celcoxib. Follow-up visits for all depressed 
participants will occur at 1 week, 2-weeks, and 4-weeks, following the start of treatment. The 
study coordinator and PI will monitor side effects and vital signs, and the PI may adjust the 
medication dosage depending on the patient's response to treatment and/or the presence of side 
effects. Final dose (10 mg versus 20 mg, or a dose between 10 mg and 20 mg, e.g., 15 mg) will 
be determined by clinical response and side effects. This decision will be based on an ongoing 
discussion between the participant and the study doctor. Participants who remit will have their 
end of study visit with a blood draw, and neuropsych testing at 6 weeks. Participants will then 
taper off medication at 10 mg for 3 days (if taking 20 mg during study). Based on past studies, 
less than 10% of participants will be taking less than 20 mg/day of SSRI at the end of the study.  
 
Participants initially randomized to escitalopram + placebo, who do not remit will be 
treated with 6 weeks of escitalopram + celecoxib.  They will not repeat the baseline visit, but will 
re-complete medication visits at week 1,2, and 4,  After the 6 weeks of escitalopram + celecoxib 
they will undergo a 3rd MRI, neurocognitive session, and blood draw. Those who complete the 
study at this point will taper off medication at 10 mg for 3 days.  
 


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Participants will have total study participation of 6-12 weeks.  Participants may have 
unscheduled visits occur throughout the course of the study (screening-completion), if 
participants are unable to complete the required assessments within the allotted time period.  If 
this occurs participants will be compensated for the travel to these additional visits, but no 
changes will be made to their human subjects payment. Non-depressed, control group 
participants will not receive the study drug, and they will not attend the medication check visits 
at week 1, 2, and 4. Therefore, they will have 3-4 study visits: 1-2 screening visits, 1 baseline 
visit: blood draw , MRI, and neuropsych testing; Week 6 visit: blood draw, MRI scan, and 
neuropsych testing.   
 
Participants will be recontacted six months post-study completion to assess efficacy and 
longevity of the treatment.  At the six-month follow-up, participants will be asked to complete a 
series of questionnaires regarding their medical and psychiatric history.  This follow-up 
appointment is optional.  
2.3 
 Study duration 
The study will be ongoing until recruitment is completed. The goal is to complete recruitment in 
four years. Individuals will participate in the study for approximately 6-12 weeks (from 
screening through to the last assessment, dependent on whether or not they enter the open-label 
phase of the study).  
2.4 
Resources necessary for human research protection 
To reduce risks to participants, only physicians and scientists with extensive training and 
experience will supervise and perform procedures.. Additionally, participants will be provided 
with phone numbers of research personnel whom the participants may call if they are 
experiencing any discomfort so that the research personnel can coordinate appropriate response 
and care. Medication will be packaged by UPenn's Investigational Drug Service (IDS) and will 
be dispensed to the research team who will pick up the medication on the day it is to be given to 
the participant. If there is a gap between picking up the medication and dispensing it, the pills 
will be kept in locked cabinets behind locked doors until the appointment. While taking the 
medication, participants will be closely monitored for any side effects from taking escitalopram 
or celecoxib. Several safeguards will be put into place for protecting the confidentiality of 
research material. Staff members will also be trained to understand the importance of 
confidentiality. Information gathered about individual participants is maintained in secured 
storage areas at each site. All phone screenings during the recruitment process will be conducted 
in a private office area, and after asking the potential participant if they are in an environment 
where they feel comfortable answering questions related to their eligibility to participate. All 
aspects of the informed consent process will be conducted in a private consultation room. Study 
procedures will occur in a private room by personnel trained in following procedures whereby 
the privacy of the participant is maintained. All psychological assessments will be conducted by 
experienced and highly trained researchers or clinicians. All assessments will be conducted in 


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private rooms to ensure privacy and the maintenance of confidentiality. Only information 
necessary for the completion of this study will be collected.   All computer data obtained from 
the laboratory and from research interviews will be identified by a code number. All data will be 
kept in locked file cabinets and only made available to qualified research personnel. Only code 
numbers will appear on any data and documents used for evaluation or statistical analysis for this 
study. Publications emanating from this research will not identify individual patients. HIPAA 
compliance will be enforced as per University of Pennsylvania policy. Reports from patients' 
clinical records concerning research observations will not be available to outside medical 
facilities without the written consent of the participant.  It is not anticipated that additional 
medical or psychological services will be necessary as a consequence of this research; however, 
should that event occur, participants will be referred to the appropriate service provider and the 
study coordinator and PI will follow-up to ensure that services were received if necessary. 
2.5 
Target population 
One-hundred depressed subjects, aged 18-80, right handed, male and female (50 with high-CRP 
levels (CRP ≥3) and 50 with low-CRP levels (CRP<3). In addition, 50 non-depressed controls, 
matched on demographic and vascular risk factors. 
2.6 
Subjects Enrolled at Penn 
N=150 
2.7 
Accrual 
One hundred depressed participants will be recruited from the community, from outpatient 
psychiatry clinics at the University of Pennsylvania (General Outpatient Psychiatry, Family 
Medicine, Geriatric Psychiatry, the Treatment Resistant Depression Clinic, the HUP consult 
liaison services), and from the Veterans' Administration Medical Center to complete this study 
with usable data.  Fifty non-depressed control participants will also be recruited from the 
community and the aforementioned sources to complete this study with usable data.   
Careful consideration was provided to the determination of sample size requirements. The 
following section breaks down the statistical methods and theoretical justification for our sample 
size of 150 participants: 100 depressed (High and Low CRP groups) and 50 control. 
Aim 1: Characterize neuroanatomical and neuropsychological effects of abnormal cytokines in 
MDD. Hypothesis 1a: Inflammatory cytokines will be elevated centrally and peripherally relative 
to matched controls; neuropsychological performance will be poorer in MDD; hippocampus, 
amygdala and PFC volumes will be decreased in MDD; and connectivity of hippocampus and 
amygdala to rostral AC and DLPFC will be decreased in MDD. The power for the IL-6 mean 
differences was based on our preliminary IL-6 data where the mean (SD) difference is 2.1 (3.6), 
with 80% power, two-tailed t-test at 5% significance level. A t-test was used to estimate the 
power to compare the mean difference of regional correlations (functional connectivity) and 
neuropsychometric function between controls and depressed subjects. To achieve 80% power 


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with a two-tailed test and 5% significance level, an effect size (mean difference/SD) of at least 
.49 can be detected for a sample of 150 subjects, where 50 are controls. Based on our preliminary 
data, the group difference of the mean (SD) Fisher-z of the amygdala-subgenual AC is 0.23 
(0.17), and of hippocampus-DLPFC is -0.24 (0.12). The preliminary neuropsychometric data 
supports this power analysis and requires a group difference of the mean (SD) for episiodic 
memory of -1.44 (2.96) and for executive function of -1.64 (3.35). 
Hypothesis 1b: Cytokine levels will be correlated with hippocampal and amygdala volumes and 
PFC thickness; To examine correlational hypothesis 1b, we used a Fisher's r-to-Z transformation 
test for a correlation between IL-6 and volumetric measures. To achieve 80% power with a two-
tailed Z test and 5% significance level, a correlation of |.23| can be detected for a sample of 150 
subjects. Based on our preliminary data for IL-6 and for left CA2-3 we have a correlation of .33. 
Aim 2: Characterize the effects of treatment on depression and the association with 
inflammation. Hypothesis 2a: Subjects randomized to treatment will have greater normalization 
of IL-6 and functional connectivity compared to those randomized initially to placebo. To 
achieve 80% power with a two-tailed t-test and 5% significance level, a mean difference of 2.1 
can be detected with a standard deviation of 3.6 for a sample of 50 medicated and 50 
nonmedicated subjects. Based on our preliminary data for IL-6, the mean (SD) difference, 
between the nonmedicated and medicated group for IL-6 is 2.7 (3.6). We will test Hypothesis 2a 
for improvement in functional connectivity with repeated measures ANOVA with the treatment 
group x time interaction result testing whether improvement in the outcome variables (increase 
in hippocampus and amygdala connectivity to DLPFC and AC) is greater in the treatment group 
than the placebo group, over and above non-specific changes over time (e.g., practice effects, 
naturalistic changes) that would be seen also in the control group. Our sample size of 100 with 
50 in each group provides 80% power to detect a moderate effect size of .38 with .7 intraclass 
correlation on the group x time interaction, based on a two-tailed F-test with 5% significance 
level and assuming 10% attrition. 
2.8 
Key inclusion criteria 
Inclusion Criteria for all Participants: 
1) Age 18-80, right-handed male or female, any race;  
2) Absence of clinical dementia  
3) English speaking  
4) Blood pressure not exceeding 150/90 mmHg, treated or untreated 
5) Normal result on liver-function test  
6) No history of ulcer disease or GI bleeding 
7) No renal insufficiency  
8) Weight greater than 110 lbs 
Additional Inclusion Criteria for Depressed Participants: 


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1) DSM-IV criteria for MDD 
2) PHQ-8 Score equal to or greater than 10 
2.9 
Key exclusion criteria 
Stress and Inflammation exclusions:   
1) Known history of relevant severe drug allergy or hypersensitivity (e.g. to Citalopram or 
Escitalopram, and/or to celecoxib, aspirin, or other NSAIDs; known demonstration of 
allergic-type reactions to sulfonamides);  
2) Does not speak English;  
3) Cannot give informed consent;  
4) MRI contraindications (e.g., foreign metallic implants, pacemaker);  
5) Known primary neurological disorders, such as Parkinson's disease, Alzheimer's disease, 
traumatic brain injury, cognitive impairment or dementia,  
6) Known severe inflammatory disease such as systemic lupus erythematosis, known 
autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis; 
7) Clinical Dementia Rating Scale score greater than 0;  
8) Diagnosis of a chronic psychiatric illness other than MDD at the discretion of the study 
doctor;  
9) Significant handicaps (e.g. uncorrected hearing or visual impairment, mental retardation) 
that would interfere with testing;  
10) Bleeding diathesis;  
11) Severe Medical problem, which in the opinion of the investigator would pose a safety 
risk to the subject;  
12) Clinically significant cardiovascular disease that will be assessed on a case-by-case basis. 
Clinically significant cardiovascular disease usually includes one or more of the 
following: cardiac surgery or myocardial infarction within the last 4 weeks; unstable 
angina; acute decompensated congestive heart failure or class IV heart failure; current 
significant cardiac arrhythmia or conduction disturbance, particularly those resulting in 
ventricular fibrillation, or causing syncope or near syncope; uncontrolled high blood 
pressure; QTc greater than 450msec (by history for subjects with cardiac disease); 
documented prior stroke;  
13) Clinically significant abnormalities on EKG. Primary AV block or Right bundle branch 
block are not necessarily exclusionary;  
14) Current diagnosis of cancer 
15) Current  diagnosis of HIV, active Hepatitis B and/or Hepatitis C 
16) Use of an Investigational medicine within the past 30 days;  
17) Use of Coumadin, Warfarin within the past 2 months;  
18) Current treatment with psychotropic drugs or drugs that affect the CNS such as beta-
blockers, mood stabilizers, antipsychotics, steroids or non-steroidal anti-inflammatory 
medications or other antidepressants. No subjects will be included in the study unless 


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they have been off all psychotropics for at least 3 weeks, except in the case of fluoxetine, 
where 5 weeks off treatment will be required;  
19) Current alcohol or substance abuse disorder, schizophrenia or other psychotic disorder, 
bipolar disorder,  or current OCD;  
20) Abnormal liver-function test  
21) Current diagnosis of ulcer disease, Chron’s disease, GI bleeding or anemia 
22) Weight less than 110 lbs 
23) Renal insufficiency  
24) Any other factor that in the investigator's judgment may affect patient safety or 
compliance (e.g. distance greater than 100 miles from this facility);  
Additional Exclusion Criteria for Depressed Subjects:   
1) Active suicidality or current suicidal risk as determined by the investigator 
2.10 Populations vulnerable to undue influence or coercion 
During the consent process, all potential participants are made aware and reminded that their 
participation is completely voluntary and that they may choose to not participate or withdraw 
from participation at any time. All researchers are made aware of the importance of the voluntary 
participation and the need to convey this fact to all potential participants throughout the consent 
process and during participation. The voluntary nature of participation is reviewed with the 
potential participant as is the ability to withdraw at any time should a participant choose to do so. 
3 
Study Population 
3.1 
Subject recruitment 
In addition to recruiting participants from the community, several physicians and collaborators 
have expressed interest and willingness to provide referrals and contacts to facilitate recruitment 
for this study. We will use the Penn Data Store to identify potentially eligible participants. We 
will be incorporating Penn Data Store (part of DAC) as a recruitment resource. We will send the 
DAC a list of basic inclusion criteria for a report every 2 weeks. Due to the sensitive nature of 
the diagnosis (depression) we are seeking, we will first be contacting potential participant's 
diagnosing provider requesting to contact his/her patient; we will attempt to contact the provider 
2 times via Epic and we will seek expressed approval for permission to contact each patient (we 
will not attempt to contact any patients for which we had not received written approval from 
their diagnosing provider). We will attempt (up to 2 times) to contact the patient/potential 
participant. If these individuals have an email on file, we will first attempt to contact via email; 
otherwise we will use the phone number provided in EPIC. Please find scripts attached for the 
1st provider contact, 2nd provider contact, participant email, and phone script (participant). 
  Flyers and brochures will be distributed throughout the greater Philadelphia area with a heavy 
concentration in medical facilities such as HUP, Perelman Center, and Penn Radnor.  We also 


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will run advertisements in locally circulated newspapers and paper publications as well as radio 
stations.  We also will advertise on electronic platforms such as the iConnect portal at the 
University of Pennsylvania, Craigslist, and social media sites.  
      We will utilize a social media campaign ran by Splash Clinical, a research study marketing 
company, which will advertise on Facebook, Craigslist, Google, and Instagram. Splash Clinical 
will create the social media page on each platform to advertise this study, with the exception of 
Facebook. Splash Clinical will utilize our current Facebook page for the Center for 
Neuromodulation in Depression and Stress. Splash Clinical creates the advertisements we will 
post for the campaign, monitors the traffic, and provides us with diagnostics of this campaign. 
Interested participants will click on an advertisement that will populate in their newsfeed/Google 
search, and be directed to a landing page that provides a brief description of our study and a link 
to the RedCap Self-Screener, which previously has received IRB-approval.  We will also run a 
social media campaign internally.  We will utilize the Center for Neuromodulation in Depression 
and Stress Facebook page to post these advertisements. We also would like to utilize the “boost” 
post or “boost” page feature to allow us to target a specific population when we are advertising 
our study. 
    The PennBioBank will also act as a recruitment resource. We will provide the Penn BioBank 
with a list of ICD-10 codes that we would like included or excluded in a participant's medical 
record and they will provide us with a report of eligible participants for whom they have a tissue 
sample for (namely plasma or serum).  We will then reach out to these potential participants as 
they have signed an agreement when they donated the sample to be contacted for research 
studies in the future.  We will call them at the phone number they had previously provided the 
BioBank, state that we attained their information from the Biobank and that they had previously 
consented to being contacted by Penn researchers, and then we will continue with our normal 
phone script. 
 
University of Pennylvania’s iConnect, a database of clinical research studies at the 
University of Pennsylvania added a feature that allows individuals with certain conditions, to 
sign up as part of a volunteer registry.  We will utilize this registry to find older individuals who 
are suffering from depression and inflammation. They also have a feature to utilize a pre-
screener form for individuals who find our study on their website, which we will be 
implementing to help lower the rate of false positives. 
   Additionally, we will be using the IRB-approved protocol #826348, A Feasibility Study: 
Department of Psychiatry Research Initiative (PI: Yvette Sheline, MD). Protocol #826348 is a 
pilot study the will continue through August 2017; the study collects basic contact and 
psychiatric intake information from Penn Behavioral Health Corporate Services & 
Departmentally. Only individuals who meet the basic criteria for this study will be contacted. 
Please see details of 826348 for further information, if necessary. 


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3.2 
Subject compensation 
Total compensation for completion of the entire study is $215 for the experimental group, $310 
for experimental group that also completes the open label phase, and $120 for the control group 
(non-depressed) participants. If a participant takes part in a portion of the study, but does not 
complete the entire study, he/she will be paid incrementally in proportion to the degree of 
participation. If a potential participant passes the phone screen, he/she will be given an 
appointment to conduct the baseline informed consent. Once consented, the patient will undergo 
a more thorough diagnostic screening interview, EKG and blood draw. If the patient is found to 
be ineligible, it will be explained that he/she will not participate in the study and he/she will be 
excused. If the participant completes the blood draw at this screening visit but has been 
determined, ineligible they will be given $10.00 compensation for the blood draw. Following the 
screen, those who are eligible for participation will receive the full informed consent form and 
they will continue with the full baseline assessment battery. Unscheduled visits may occur if 
participants cannot complete the assessments required within the allotted time.  If this does occur 
participants will receive travel compensation, but no changes will be made to their human 
subjects payment. Furthermore, participants in the depressed group will be paid an additional 
$10 for the second blood draw as well as additional funds in $5 increments for interim follow up 
visits occurring in week 1, 2, and 4. Control group participants do not have weekly follow up 
visits, thus they will not receive these interim payments. Subjects will be compensated through 
University of Pennsylvania supported Greenphire ClinCard. This is a reloadable prepaid card 
(similar to a debit/credit card) which allows funds to be available immediately. Study staff will 
provide participants with a ClinCard Cardholder FAQ: US document. 
 
Subjects will receive compensation at the end of their study completion. If subjects do not fully 
complete the study, they will receive compensation for the parts of the study they did complete, 
based on the following outline:  
Payment regimen for Depressed Group: 
Baseline assessment & full study consent process = $20;  
Baseline MRI = $20; 
Baseline Blood Draw = $10  
Week 1 assessment = $5;  
Week 2 assessment = $5;  
Week 4 assessment = $5;  
Week 6 MRI = $25;  
Week 6 Blood Draw = $10  
Week 6 Neuropsychological Testing = $25; 
Optional additional blood collection = $50 
Optional saliva samples = $20 
Optional 6-month follow-up = $20 


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Those who complete all study visits, participate in the optional additional blood collection, 
provide the optional saliva samples, and participate in the 6 month follow-up, will be paid a total 
of $215. 
 
Those who complete the open-label phase of the study will receive an additional $95 (including 
optional saliva collection) broken down below.  These participants will receive $310 total 
including the optional saliva sample collection  
Week 1 assessment- $5 
Week 2 assessment- $5 
Week 4 assessment- $5 
Final Neuropsychological assessment- $25 
Final MRI- $25 
Final Blood Draw- $$10 
Optional Saliva Collection - $20 
Optional 6 month follow-up (same as above)- $20 
 
Payment regimen for Control Group: 
Baseline assessment & consent process = $20;  
Baseline MRI = $20;  
Baseline Blood Draw = $10  
Final MRI and Blood Draw = $35;  
Final Neuropsychlogical Testing = $25; 
Control participants will be paid a total of $120for full study completion (Including screening 
visit blood draw= $10). 
 
Subjects who do not feel comfortable with the Greenphire ClinCard may be compensated 
by a check, in lieu of the ClinCard. We are not stating this option in the ICF, as we would prefer 
all participants to use the ClinCard for consistency; however, we acknowledge that not all 
individuals will feel comfortable with this method and therefore, if during the consenting process 
or at any time during the study, a participant expresses discomfort, we will then verbally offer 
them the option of being paid with a check.  
 
Transportation 
We will provide participants who drive to study visits (including screening visit), a parking 
voucher for free parking at the Perelman Center parking ramps.  Participants will also receive 
compensation for travel for any unscheduled visits that occur. 
Participants who take public transportation to study visits (including screening visit) will be 
provided up to $5.00 cash for the cost of taking public transportation with proof of transportation 
(e.g., SEPTA regional rail ticket, Uber or taxi receipt, etc.) on their Greenphire ClinCard. 
 


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3.3 
Suicidal Ideation and Behavior 
Plan for assessing suicidal ideation and behavior:  The drug, escitalopram, will be administered 
to a portion of the participants in this study. Escitalopram does interact with the central nervous 
system as an antidepressant. Because it is an antidepressant, it is not expected to cause or 
contribute to the development of suicidal ideation or behavior. However, to monitor for a 
potential increase in risk of suicidal thinking and behavior, a safety protocol has been developed 
and plans are in place to evaluate all participants for clinical worsening and suicidality 
throughout participation in this study. 
Safety Protocol to address potential risk of clinical worsening and suicidality: 
As part of this study protocol, depressed patients will be enrolled and will be receiving anti-
depressant medication, escitalopram. Current suicidality at the time of consent deems potential 
participants as ineligible to participate, thus suicidal patients will be screened out of the study. 
However, it is recognized the patients could possibly experience clinical worsening and 
potentially become suicidal.  This possibility is unlikely for those who are receiving escitalopram 
since this medication is an anti-depressant and it is prescribed for the specific purpose of treating 
depressed mood.  
To address the risk of suicidality, all patients will be closely monitored and they will receive 
psychiatric evaluations at baseline, weeks 1, 2, 4, and 6, as well as during all of these time points 
during the open label phase. The Montgomery-Asberg Depression Rating Scale will be 
administered at each follow-up visit to evaluate the presence of depressive symptoms. 
Additionally, participants will be provided with phone numbers of research staff and they will be 
instructed to contact the staff if clinical worsening occurs. If research staff become aware of 
clinical worsening or suicidality, they will immediately intervene and activate safety procedures. 
Safety procedures will include informing the principle investigator who will then meet with the 
participant to assess the situation. If the participant is in imminent danger to her/himself, s/he 
will be escorted to the emergency room for immediate care. If the patient is reluctant or 
unwilling to be escorted to the emergency room the principle investigator will call 911. If the 
patient expresses no immediate desire to hurt her/himself, but is still considered to be a potential 
risk, the principle investigator will provide emergency numbers such as suicide hotline phone 
numbers and the principle investigator will also provide referral phone numbers for psychiatric 
care, facilitating the scheduling of an appointment. The principle investigator will engage the 
participant in a contract whereby the participant will agree to utilize the suicide hotline phone 
number if necessary and s/he will follow through with the psychiatric appointment. 
If it is believed that the clinical worsening is deemed related to participation in the study, the 
principle investigator will evaluate whether the medication regimen should be modified or if the 
participant should be withdrawn from participation. 


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All evaluations and decisions regarding a participant's clinical worsening and or suicidality will 
be documented and the appropriate regulatory authorities will be notified. 
4 
Study Intervention (Escitalopram and Celecoxib.) 
The PI will utilize the services offered by IDS to obtain escitalopram and celecoxib, and placebo 
for celecoxib, repackaged so that the research team is blind. The drug and placebo will be picked 
up from IDS as needed and then stored at the Center for the Neuromodulation of Depression and 
Stress (CNDS) in locked cabinets behind locked doors until the appointment. Only research 
personnel will have keys and access to the medications. The drugs and placebo will be dispensed 
by the principle investigator or designee to each participant at each appointment. The medication 
regimen will be thoroughly reviewed with the patient (i.e., dosage and duration) and written 
instructions will be provided. Additionally, all participants will have contact information for 
research personnel should they have any questions about the medication or concerns about 
reactions to the medication. 
 
4.1 
Description 
Escitalopram and celecoxib are FDA approved drugs. Escitalopram will be administered in a 
tablet. Celecoxib will be administered in a capsule to hide whether it is active drug or placebo.   
4.2 
Intervention Regimen 
 Participants will take escitalopram (10 mg/day for 3 days and 20 mg/day for 39 days ) plus 
celecoxib (400 mg/day) or escitalopram (10 mg/day for 3 days and 20 mg/day for 39 days ) plus 
placebo for 6 weeks. Participants will be lowered to a smaller dose of the study drug, if they are 
unable to handle the higher dose (as determined by side effects or subjects expressing concerns 
about side-effects). All participants will receive a taper dose of escitalopram at 10 mg for 3 days 
at the completion of the study.   
4.3 
Receipt  
IDS will package and deliver the drugs or study coordinators will pick them up as needed for 
participants. Drug accountability will be maintained by IDS and study coordinators. Before study 
drugs are dispensed to enrolled study participants, pill count will be conducted by the attending 
nurse, study coordinator or investigator.  Study participants are encouraged to personally check 
that they received the right number of pills.  
4.4 
Storage 
Room temperature, protect from light, protect from moisture.  
4.5 
Preparation and Packaging of Verum Study Drug 
The Investigational Drug Service will purchase CELECOXIB 200mg capsules from Pfizer, Inc.  
These capsules will be over-encapsulated into opaque Size 1 pharmaceutical-grade, BSE-free 


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certified, gelatin capsule shells and then backfilled with lactose monohydrate NF as described 
below. 
Capsules:   
– 
Size 1 Green 
– 
Source:  Fagron, Inc, 2400 Pilot Knob Rd, St. Paul, MN 55120 
– 
Item # 800710 
Lactose Monohydrate, NF 
– 
Source:  Fagron, Inc, 2400 Pilot Knob Rd, St. Paul, MN 55120 
– 
Item # 801787 
The capsules will be prepared using a GMP-grade machine capable of loading and filling 300 
capsules at a time (Profill-324™ Machine, Serial # 3FB.49).  All surfaces in contact with the 
capsule or filler, are type-316 surgical stainless steel. 
Capsules are filled in an enclosed pharmaceutical compounding area which is not accessible to 
general traffic and in which food items are not allowed.  All persons working with the capsules 
have been previously trained in the capsule loading and filling procedure and all items used in the 
preparation are verified by two persons before the start of the session and again at the end of the 
session.  Only one type of product is made at one time; the product is completed, all containers 
sealed and product moved away from the machine, then the machine is then disassembled and 
cleaned and the work area cleaned, before a second product may be prepared on the machine.   
Persons working with the machine first enter through an anteroom in which hands are washed 
thoroughly and a hair net, gown or scrubs, and gloves are worn, before entering the compounding 
area.  The area where the capsules are prepared is cleaned with 70% isopropyl alcohol prior to the 
start of the procedure.   The removable top and bottom plates from the capsule filling machine are 
washed in a laboratory-equipment washer (LabConCo FlaskScrubber™), with a high-heat drying 
cycle, between uses. 
The capsules are loaded into a filling tray by placing empty gelatin shells into the hopper of the 
capsule loader tray, which orients and drops the shells into precut holes in the capsule filler tray.  
The capsule halves are separated and the filled tray is then removed from the loader and placed 
into the filling machine, where the shells are then separated, leaving the bottom half to be filled, 
while the top half of each shell is held in a tray which is set aside.  A stainless-steel frame is placed 
over the filler apparatus containing the bottom halves of the capsules; this frame prevents powder 
from being lost during the filling process. 
Once the capsules are separated, a total of 300 CELECOXIB capsules are first counted and 
verified, then the operator places one whole tablet into each capsule.  A second person then verifies 
visually and signs the batch worksheet to document that each capsule shell contained one tablet 
and that no shells were empty.  Once this process is complete, lactose monohydrate is backfilled 
over the capsules until flush with the rim of the capsule shell. 
At this point the stainless-steel frame is removed and the tray containing the lids for each capsule 
is placed back over the capsule bottoms.  The capsules are rejoined, removed from the machine, 
then placed in a Type 2 HDPE plastic container with a tightly sealing lid. 
The container is sealed and labeled clearly with the contents (drug, strength, quantity), an internal 
lot number and use-by date which are assigned at the time of preparation.  The use-by date will be  
either 12 months or the remaining expiration of any component, whichever is less), the name of 
the study for which the capsules have been prepared, and the statement "Caution: Drug Limited 
by Federal Law to Investigational Use" 


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Finished capsules will be dispensed in blister packs pursuant to an individual prescription for each 
study participant, provided by the investigator/prescriber.  A prescription label will be affixed, 
including directions, study name, medication name (blinded description) and quantity, investigator 
name, subject ID number and the statement ‘Caution: new drug limited by Federal (USA) law to 
investigational use only”. 
 
Caution: New Drug Limited by Federal 
(USA) Law to Investigational Use Only 
University of Pennsylvania – Investigational Drug Service 
3600 Spruce St – Ground Maloney – Philadelphia PA 19104    215-349-8817   
AH4429177 
 
RX # XXXXXXXXX                           Dr. _________________ 
 
Patient: XXXXXX (######)               Date: ________ 
 
TAKE ONE (1) CAPSULE BY MOUTH TWICE EACH DAY AS DIRECTED. 
 
 
IND# ######     Study Period: ____     
 
 
CELECOXIB 200MG OR PLACEBO CAPSULES #10 
Study: IRB#819654         Refills: 2      
INVESTIGATIONAL DRUG 
[BARCODE HERE] 
Rx# XXXXXXXXX 
4.6 
Blinding 
The PI and all but one member of the study team will be blinded. The unblinded member will perform the 
randomization and will enter the group into a password protected excel sheet. This team member will be 
able to break the blind in an emergency.     
4.7 
Administration and Accountability    
Study drug will be delivered by the UPENN Investigational Drug Service. Escitalopram will be 
administered once daily, in the morning or evening, with or without food. Single doses of celecoxib 
can be given without regard to timing of meals. 
The Investigator will maintain adequate records showing the receipt, dispensing, return, or other 
disposition of the investigational product, including the date, quantity, batch or code number, and 
identification of subjects (subject number and initials) who received the investigational product. 
Investigational Product may not be relabeled or reassigned for use by other subjects. 
 
4.8 
Subject Compliance Monitoring 
Participants will be asked to bring back their empty pill bottles/packs for pill counts to assess 
compliance. If pills have not been taken, the participant will be engaged in discussing issues of 
compliance and how these can be addressed by the study team. If compliance remains poor he PI 
will discuss with study participants the possibility of discontinuation/withdrawal.  
Post study, compliance can be objectively assessed by measuring drug levels in plasma samples 
and possibly in CSF as well. 


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4.9 
Return or Destruction of Investigational Product 
Any extra drug returned will be given to IDS.  
5 
Study Procedures 
5.1 
Informed Consent Process / HIPAA Authorization  
100 depressed participants will be recruited from the community, from outpatient psychiatry 
clinics at the University of Pennsylvania (General Outpatient Psychiatry, Family Medicine, 
Geriatric Psychiatry, the Treatment Resistant Depression Clinic, the HUP consult liaison 
services), and from the Veterans' Administration Medical Center.  Fifty non-depressed control 
participants will also be recruited from the community and the aforementioned sources. These 
participants initially will be contacted by research staff via telephone to conduct a phone screen 
interview and also to explain the study, including the time commitment required for participation 
and the basic procedures to be completed. This information is required to determine eligibility 
and is directly related to our inclusion/exclusion criteria. The information obtained through the 
phone screen is our way of ruling out specific and obvious things that will determine if a person 
meets preliminary inclusion/exclusion criteria without having to make a trip to this facility. We 
are requesting a waiver of documentation of informed consent for this procedure; verbal 
informed consent will be obtained from all subjects. Individuals who are patients in the Penn 
system will be asked for verbal consent during the pre-screening to release their PennChart 
electronic medical record. Data from the PennChart electronic medical record will be viewed 
only. The information will not be downloaded or stored. Individuals without a PennChart 
electronic medical record will have one created for them in order to participate in full screening 
study procedures (i.e. blood draw and EKG).  Individuals who are not in the Penn system will be 
asked to complete an medical record release authorization form at the screening visit after their 
have signed the informed consent. Upon receipt of their medical records, personal health 
information and identitifiers will be redacted to mitigate the risk of lost of confidentiality and 
privacy.   For those who pass the initial phone screening, an appointment will be scheduled for 
an in-person visit to complete the informed consent process and to conduct a diagnostic screen, 
blood draw to determine CRP levels, the presence of HIV, Hepatitis B and C, autoimmune 
disease, and rheumatoid factor, and EKG to further assess eligibility. There will be time between 
the phone screen and the in person visit so that participants can consider participation and 
discuss the study with family and friends. Following the diagnostic assessment and EKG, if a 
participant continues to be eligible for participation, s/he will receive a second consent that 
addresses the expectations for participation in the entire study. Additionally, participants will be 
provided a copy of the consent to keep for their files which will contain all research staffs' 
contact information. Prior to participation, the research staff will thoroughly review the consent 
form, answering any and all questions. The participant will be made aware that participation is 
entirely voluntary and he/she may stop at any time during the study, including after signing the 
consent form.  As mentioned previously, unscheduled visits may occur if assessments required 
are not completed within the allotted time. 


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5.2 
Recruitment, screening and baseline assessments 
Brief Summary of Procedures (also see attached schedule of procedures and assessments): 
Potential participants will be recruited from the community or they may be approached by 
collaborating clinicians or research team members (see recruitment plans) to explore potential 
participant's interest in taking part in a research study. Those who are interested will receive a 
telephone call from research staff to conduct a telephone screen. Those who pass the phone 
screen will receive an appointment to come to the research location to review and sign the 
informed consent form for screening purposes and to complete baseline diagnostic assessment 
screen, blood draw to test for CRP level, Hepatitis B and C, HIV, and rheumatoid arthritis, and 
will also complete an EKG to determine eligibility. Those who are eligible will return for a 
baseline visit and will review and sign another informed consent form for participation in the full 
protocol. Once fully consented, participants will undergo a series of visits to conduct multiple 
assessments which will include: 
(1) Psychological and Neuropsychological Tests at baseline and week 6; Open Label at week 6;   
(2) Medical Examination;   
 (4) 3-4 Blood Collections (blood draw at screening, blood draw at baseline, blood draw at week 
2 for liver function and hematocrit assessment, and one at Week 6) for those who enter the open-
label phase they will receive an additional 2 blood draws (one at Open Label Week 2 to assess 
for liver function and hematocrit levels, and one at Open Label Week 6). All participants will be 
asked if willing to participate in additional blood collection for immune profiling. 
(5)2-3 MRIs, one at baseline, one at week 6, and one at open-label week 6; the baseline scan will 
occur before treatment begins;   
(6) 2-3 fMRI (one at baseline which will occur during the same baseline MRI session, one at 
Week 6, and one at open-label week 6); 
(7) Optional Nutrition Assessment. Participants will be asked to do a 24-hour dietary recall. The 
food recall will also be collected using the Nutrition Data System for Research (NDSR). 
Participants are guided through a multiphase interview where they are guided to recall all the 
food they ate in the preceding 24 hours.  
(8) Participants will be closely monitored for problems resulting from participation. They will be 
provided with contact information for research personnel should any problems or questions arise, 
and they will be contacted by research personnel during their participation to ascertain the 
presence of any problem.  
Treatment Design: 


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All subjects will have an initial telephone screening. Screened participants will have an 
appointment to come to the research facility to conduct informed consent for the diagnostic 
screen and blood test to measure CRP levels and test for HIV, Hepatitis B and C, autoimmune 
diseases and rheumatoid factor. This visit is expected to last approximately 90 minutes. Informed 
consent will be obtained, and then participants will undergo a blood draw to assess c-reactive 
protein level, as they will be stratified depending on the current level. Subjects will participate in 
a structured clinical interview, EKG, and a review of medical history with the research staff. All 
participants will be given the screener for Structured Clinical Interview for DSM-IV (SCID-1) to 
ascertain the presence or absence of Major Depressive Disorder (MDD) and to rule out other 
psychiatric disorders. They will also be given the Hamilton Rating Scale for (HAMD) and 
Montgomery-Asberg Depression Rating Scale (MADRS). Those with MDD may be enrolled in 
the experimental condition. Potential Controls may be enrolled in the control condition if they 
have no psychiatric disorders and their HAMD score is less than or equal to 7. Participants will 
receive an EKG to screen for any abnormalities or conditions that would suggest they should not 
receive medication thus be deemed ineligible at this point.  Participants will be asked medical 
screening questions (e.g., from the Framingham Scale to determine a vascular risk factor), and 
they will be assessed with the Clinical Dementia Rating (CDR) scale to determine whether there 
is any cognitive impairment. At the screening, the participants will be asked to fill out the 
Perceived Stress Scale (PSS) and Life Events Stress (LES). A trained study team member will 
then perform a neuropsychiatric test on the participants that include questions about the 
participants' memory, attention, spatial abilities, general abilities, motor control, and problem 
solving.   
At this point, all participants who remain eligible will undergo a second informed consent to 
address the next steps in participation. Following the acquisition of the second consent, an 
appointment will be scheduled for the participant to conduct the baseline assessments.  At these 
baseline assessments participants will receive their actigraph which will monitor their physical 
activity throughout the course of the study. These baseline assessments include 
neuropsychological tests, which will take approximately 1 hour to complete. Also at baseline, 
participants will receive anMRI (detailed further below).Following completion of all baseline 
assessments, the experimental group participants will receive the drug. Participants will take 10 
mg of the antidepressant + placebo or 10 mg of the antidepressant + celecoxib for 3 days, and 
then they will increase the antidepressant to 20 mg for the remaining 39 days of the study. Final 
dose (10 mg versus 20 mg) will be determined by clinical response and side effects. This 
decision will be based on an ongoing discussion between the participant and the study doctor. 
Participants will be closely monitored for side effects via phone calls from research staff and in 
person inquiries during the follow-up visits. They will be provided with contact information 
(phone numbers) for research personnel should any problems or questions arise, and they will 
also be instructed to contact research personnel with any problems, questions, or concerns. 
Participants in the experimental group will have scheduled appointments at weeks 0, 1, 2, 4, and 


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6. At the end of the 6 weeks participants will have their final physical and psychological 
assessment.  Individuals remitting will be given an additional 2 weeks of escitalopram at this 
time; this is done so that individuals have enough time to schedule a visit with a provider of their 
choice, if they wish to remain on the medication. At the end of the study, all depressed 
participants will be transitioned into follow-up care with their own doctor or given a referral. For 
those who do not remit and had received escitalopram + placebo initially, they will be eligible 
for the open-label phase of the study.  During this phase they will be given escitalopram + 
celecoxib.  They will follow the same study procedures as the initial phase of the study 
(Medication visits Week 1, Week 2, Week 4, 3rd and Final MRI, neurocognitive testing, and 
blood draw).    
5.3 
Assessment measures and neuropsychiatric tests 
The following assessment measures and neuropsychiatric tests will be used: 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I - Abbreviated version). The 
Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) is a semi-structured 
interview for making Axis-I diagnoses according to the DSM-IV, and usually takes 60-90 
minutes to administer. We will perform only the overview portion;   
Montgomery-Asberg Depression Rating Scale (MADRS). The ten-item MADRS will be used to 
determine the presence of and severity of current depressive symptoms, and will be the primary 
outcome measure of depression severity in this study. The MADRS is included as it was used in 
our previous studies and will allow for comparison;   
Hamilton Rating Scale for Depression (HAMD). All patients and controls will also be assessed 
using the HAMD, 17-item version, to determine the presence of any current depressive 
symptoms. The HAMD is included as it is more widely used in the US than the MADRS;   
Montreal Cognitive Assessment (MOCA): This short test of visual and verbal functioning and 
delayed recall gives an indication of cognitive decline and dementia..  
Framingham scale. For each subject we will rate a vascular risk factor (VRF) total score using 
the approach of the Framingham Study (Wolf et al., 1991), which gives a validated number 
based on the presence and severity of VRFs, weighted according to their predictive power for 
stroke;    
Cumulative Illness Rating Scale-Geriatric (CIRS-G).  A history of major illnesses and treatments 
will be taken, and the Cumulative Illness Rating Scale-Geriatric (CIRS-G) will be completed by 
the evaluating physician at the start of the trial (Miller et al., 1992). The CIRS-G covers all major 
systems (cardiovascular, pulmonary, renal, genitourinary, etc), and provides scores for current 
and past medical illnesses, including a global composite score that will be used as a measure of 
medical morbidity;   


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The following Self-Report Questionnaires will be distributed:   
Perceived Stress Scale (PSS).  We will use the PSS score, a validated measure of subjective life 
stress to characterize the relationship between inflammatory cytokine levels, subjective stress, 
depression severity and treatment response.  It is the most widely used measure of subjective 
stress;   
Life Events Stress (LES) Scale. Each event is assigned a weight for the severity of the stressor, 
e.g. death of spouse vs. friction at work.  Scores for all relevant events are summed to yield a 
total life events stress score.  This scale will be used to determine the cumulative amount of 
stress experienced by each participant;   
Maltreatment and Abuse Chronology of Exposure (MACE) Scale There is reason to believe that 
childhood maltreatment can affect the trajectory of brain development and enhance the risk of 
medical and psychiatric disorders.  We will use this scale to further test this theory. The 
‘Maltreatment and Abuse Chronology of Exposure’ (MACE) scale (1) can be used to assess not 
only the type and severity of abuse exposure but also the timing of the exposure.  There is 
increasing interest in childhood maltreatment as a potent stimulus that may alter trajectories of 
brain development and enhance the risk for medical and psychiatric disorders.  Although a 
number of other scales exist for retrospective assessment they fail to provide detailed 
information on the timing of the exposure, critical for delineation of sensitive periods. Using the 
MACE (2) both dose dependent and timing effects were demonstrated for some disorders, 
whereas overall amount of adverse experiences was the critical.  In our current study the 
variables obtained from the MACE will be included in predictive models to help understand 
which brain circuits are affected in particular symptom clusters and disorders.  This will help us 
improve our predictive models, given the strong relationships obtained using the MACE. 
Answers to the MACE will be anonymized and entered into the database. As with all procedures, 
participation is voluntary and it will be explained to participants that the interview might be 
uncomfortable or upsetting. In the event that a participant becomes upset they will be asked if 
they would like to stop the questions. Participants will be asked if they would like counseling 
and referred for care if appropriate. 
 
The following comprises the Complete Neuropsychological Battery. This will be performed at 
the beginning and end (weeks 0 and 6):   
Controlled Oral Word Association (COWA)/Verbal Fluency:  In these tests, which are widely 
validated tests of frontal lobe function (Cohen, 1993), subjects are given 60 seconds to generate 
as many words as possible that begin with a specific letter of the alphabet or to name as many 
examples in a particular category (such as animals), respectively.  Subjects receive one point for 
every correct word.  For the COWA, a standardized set of letters (CFL) with established norms 


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will be used.  The animal category is the easiest of the verbal fluency categories (Monsch, 1992) 
and has been shown to discriminate Alzheimers Disease from depression, whereas letter fluency 
did not (Hart, 1988);   
Trail Making Test A&B:  In this test subjects are required to sequentially connect on a page of 
paper dots that are marked with either letters or numbers (Part A).  They are then instructed to 
connect dots by alternating between numbers and letters sequentially (e.g. 1-A-2-B-3-C-4-) (Part 
B).  In each part, performance is timed.  This test is sensitive to deficits in visuomotor tracking, 
speed, and attention (Lezak, 1995), and performance is correlated with frontal activation 
(Segalowitz, 1992).  Studies show depressed patients to be significantly slower on Part B (King, 
1993).  Normative studies show increased performance times with age;   
Mini-Mental Status Exam: This is a short 5 minute test used to assess orientation, memory, and 
recall. It measures cognitive decline and dementia. Participants must score a 26 or above to 
participate in the study. 
Word List Memory Test:  In this test a 10-word list is presented to subjects three times and 
immediate free recall of the list is tested after each presentation.  Then following a 30-minute 
delay, free recall is again tested.  Subjects are then asked to recognize the learned words from a 
list of 20 words.  This test measures immediate and long-term memory and allows for an 
assessment of both memory acquisition and retrieval;   
Digits Forward:  This simple test of memory and concentration subjects are presented orally with 
a list of digits and are required to recite them back to the examiner.  The digit list becomes 
progressively longer.  Subjects are scored based on the number of correct trials;   
Digits Backward:  This simple test of memory and concentration subjects are presented orally 
with a list of digits and are required to recite them in reverse order.  The digit list becomes 
progressively longer.  Subjects are scored based on the number of correct trials;   
Digits Ascending:  This simple test of memory and concentration subjects are presented orally 
with a list of digits and are required to recite them in ascending order.  The digit list becomes 
progressively longer.  Subjects are scored based on the number of correct trials;   
Logical Memory (Immediate and Delayed Recall):  This subtest of the Wechsler Memory Scale 
tests immediate recall.  In this task a short story is read to the subject and they are required to 
recall the story immediately following the presentation.  They are scored based on the number of 
correct elements recalled from the story.  After a 30 minute delay the subject will be asked to 
recall each story again;     
Digit Symbol:  In this task, subjects are given a key in which symbols are assigned a digital 
value from 1-9.  Subjects are then required to use the key to translate a list of symbols into digits;    


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Benton Visual Retention Test: This task has the participants look at 10 cards, one at a time, for 
10 seconds, the card is removed and they are to draw what they saw on the card;    
Shipley Vocabulary Test: The subject is given a word along with 4 choices and asked to circle 
the word that means the same thing as the given word;     
Boston Naming: The subject is shown cards and asked to name the picture that appears on the 
card;     
Stroop Color and Word Test:  This task has participants read a series words that spell out 
different colors in a color not the same as the word itself. This is a measure of selective attention 
and processing speed. 
MRI procedures:  At baseline, all participants will be taken to University of Pennsylvania 
imaging facilities for neuroimaging whereby MRI and a fMRI will be conducted.  At baseline, 
we will acquire anatomical MR images as well as functional MR images while doing the resting 
state connectivity task. We will also acquire functional MR images at the end of the study (end 
of week 6). 
Image Acquisition: Structural and functional scans will be obtained in a single session on a 
clinically-approved 3 Tesla Siemens Trio (Erlangen, Germany) scanner, equipped with 40mT/m 
gradients and 200 mT/m/s slew-rates. RF transmission will use a quadrature body-coil, and 
reception will use a Siemens receive-only 64-channel head coil. The total time in the scanner will 
be approximately 1 hour. Based on our experience, this is well within patients ability to tolerate 
the scanning procedures without discomfort and without excessive motion. We will acquire 
structural images, perfusion images, and functional images as follows; all MRI imaging be 
reviewed and approved by CAMRIS. High-resolution Anatomical Images: A 5 min. 
magnetization prepared, rapid acquisition gradient echo (MPRAGE) image is acquired, which 
includes an inversion recovery preparation period to produce T1-weighted contrast, and has a 
1x1x1mm voxel size. The MPRAGE is used to screen for gross anatomical abnormalities, to 
facilitate registration of lower resolution functional images into a standardized space, and to 
allow identification of between-group or inter-individual variation in volume of regions that 
could affect interpretation of functional results. 
Resting Perfusion Images: A ~5 min. pulsed arterial spin labeled (ASL) perfusion MRI and ~1.5 
min. reference scan are acquired to directly measure resting cerebral blood flow, using 
magnetically-labeled blood as an endogenous non-invasive tracer. Functional Images: Functional 
scans lasting ~15 minutes. fMRI will be acquired with blood oxygenation level dependent 
imaging (BOLD) using a whole-brain, single-shot gradient-echo (GE) echo-planar (EPI) 
sequence. The BOLD sequences include on-line geometric correction for spatial distortions due 
to magnetic field inhomogeneity using a magnetic field map acquired with a 2 min reference 
scan.  


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5.4 
Blood draws 
During the screening visit, all participants will have a blood draw to test for CRP levels to 
stratify the participants accordingly in High CRP and Low CRP groups.  Participants will also 
have a blood sample drawn at the end of the screening visit to test immediately for Hepatitis B 
and C, HIV, autoimmune diseases (double-stranded DNA test), and rheumatoid factor; as well as 
to use in later analyses of inflammatory markers.  Participants will have a blood sample drawn 
(approximately 16.5mL) at the screening visit, approximately 40 mL at the baseline visit, 
approximately 40 mL at the end of the study, 40 mL at the end of the open label phase. Blood 
samples will be used for doing tests for inflammatory markers and for measuring levels of 
Interleukin-6, Interleukin-10, TNF-alpha, and C-reactive protein. We will look at immunological 
markers by two methods; luminex and flow cytometry. The Luminex assay measures soluble 
proteins in the sera. Molecules such as IL-6 and TNF-alpha, MIP1-alpha, IFN-alpha, CRP will 
be assessed. We will include or alter molecules in the luminex assay based on the most recent 
literature as we near the end of sample collection. Flow cytometry will also be utilized. Flow 
cytometry will be used to measure the status of T cells which are important in suppressing such 
conditions as infectious disease and cancer. We will develop a series of markers that define the 
memory and naive phenotype of T cells along with their activation status and functionality. We 
will also assess additional cell subsets such as NK and macrophages. Molecules that will be 
assessed include but are not limited to; CD3, CD4, CD8, CD45RO, CD27, CCR7, CD69, CD33, 
CD68, CD56,CD16, CD38 and HLADR and CD11c -monocytes. Some blood will be retained 
and banked for future research. Additional blood is being collected for ex vivo isolation of 
human peripheral blood mononuclear cells (PMBC), which is another assessment of 
inflammation levels. This additional blood draw will be optional and offered to all depressed 
participants.  
Participants will give blood for a liver-function test and for hematocrit levels to test for GI 
bleeding. Participants may also have 24-hour ambulatory blood-pressure monitoring. Participants 
may wear a cuff for 24 hours that is set to automatically take blood pressure every 15 minutes 
during the day and every 30 minutes during the night.  
5.5 
Gastrointestinal Safety 
At the beginning of the study, GI/bleeding risks will be examined. Hematocrit levels will be 
tested in blood samples to assess this risk at baseline, and at week 2.    
5.6 
Protocol Non-Conform Drugs 
Urine may be used to assess intake of protocol non-conform drugs by means of the Rapid Detect 
10 Panel Test Dip Card, Rapid Detect, Inc., 804 South Broadway, Poteau, OK (or similar). The 
drug screen includes for example Amphetamines (AMP), cocaine (COC), Tetrahydrocannabinol 
(THC), methamphetamine (mAMP), opiates (OPI), Phencyclidine (PCP), benzodiazepines 
(BZO), tricyclic antidepressants (TCA), barbiturates (BAR), and methadone (MTD).  This can be 
done both prospectively and retrospectively. 


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5.7 
Ambulatory Blood Pressure Monitoring (ABPM) 
Ambulatory blood pressure monitors (ABPM) are readily available to the investigators to assess 
ABP in this study protocol. The 90207 ABP monitors are compact and lightweight to optimize 
subject comfort and a choice of four cuff sizes further aids comfort while also maximizing 
accuracy.  
ABPM will be guided by the AHA Scientific Statement, Council on High Blood Pressure (4). 
Recommendations relevant to the present study are: 
• Select ABP cuff size according to Table 1, 
• Select the non-dominant upper arm for ABPM measurements, 
• Instruct the patient to hold the arm still by their side while the device is taking a reading. 
 
Table 1 Cuff Sizes for ABPM 
Cuff Size* 
Arm circumference 
[cm] 
Arm circumference 
[inches] 
Small Adult  
17-26 
 
7-10 
 
Adult 
24-32 
 
9-13 
 
Large Adult  
32-42 
 
13-17 
 
Extra Large Adult  
38-50 
 
15-20 
 
* The bladder of the cuff should encircle at least 80% of the arm circumference (4). 
 
The monitors for the 24-hr ambulatory blood pressure measurements will be preset to assess BP 
every 20 minutes in the daytime, defined as 0600h to 2200h, and every 30 minutes during the 
nighttime, defined as 2200h-0600h (Error! Reference source not found.). Preset ranges for 
acceptable BP measurements are 60–250 mmHg systolic, 30-200 mmHg diastolic, 40-230 
mmHg for mean arterial values, and 200 b/min for heart rate. ABP readings should cover ≥ 80% 
of the expected readings with interruptions of less than 1 hour. Awake and asleep times will be 
determined by patient diaries. This protocol is well established (5, 6). 
Blood pressure cuff is usually mounted on the non-dominant arm of the patient connected 
through a hose with the recorder, which initializes the blood pressure measurements following 
the preset paradigm. 
Experience in the field, however, informed us that the 24-hr ambulatory blood pressure 
measurements are tolerated by the patients only in varying degrees. Therefore, we will adapt the 
ABP settings to achieve tolerability. The minimum frequency of 2 measurements per hour during 


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the day and 1 measurement per hour during the night will be observed as well as a minimum 
time of observation of 15 hours (e.g. 16:00 until 07:00 the following day).  
5.8 
 Activity Diary 
Patients will be asked to fill out an activity diary during each of the 24 hour ABPM session. An 
example of the diary form is provided in the appendix. 
5.9 
Actigraphy  
Actigraphy will noninvasively assess and log the sleep, wake and activity patterns for each 
patient. In detail, data capture entails 24 hour sleep/wake measurements including total sleep 
time (TST), sleep latency, wake after sleep onset (WASO), sleep efficiency, energy expenditure, 
metabolic rates, steps taken, physical activity intensity, subject position, and ambient light levels.  
This device will be applied as a wrist watch which facilitates incorporation into the clinical study 
setting. Actigraphy devices will be sources from e.g. ActiGraph, Pensacola, FL, 
http://www.actigraphcorp.com/company/ or similar suppliers. 
Participants will be asked to wear this device for the course of the study 6 weeks in total.  
5.10 Drug concentrations in plasma 
Escitalopram and Celecoxib drug concentration will be determined in plasma and CSF (optional) 
using standard mass spectrometric methods. 
5.11 Urinary Prostaglandin Metabolites 
If urine samples are available, drug effects of celecoxib are easily quantified by measuring 
prostaglandin metabolites in the spot urine collections.  Spot urine collections will be stored at -
80◦C until analysis. The urinary prostacyclin metabolite, 2,3-dinor-6-keto-PGF1α (PGI-M), the 
thromboxane metabolite, 11-dehydro-thromboxane B2 (TxB-M), possibly also including 2,3-
dinor-TxB-M and the prostaglandin metabolites 7a-hydroxy-5,11-diketotetranorprostane-1,16-
dioic acid (PGE-M) and 11β-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid 
(PGD-M) will be quantified by LC/MS/MS. These assays are routinely performed in the Institute 
for Translational Medicine and Therapeutics' mass spectrometry laboratories with inter- and intra-
assay variabilities of 4-8%. 
5.12 Microbiome Analyses 
Microbiome can be analyzed through an optional stool sample or optional mouth swab (inside of 
both cheeks) and saliva collection. DNA from will be extracted from each sample; PCR 
amplified using 16S primers, and subjected to 454/Roche pyrosequencing.  At least 1000 
sequence reads will be used to characterize each community.  The 16S sequence reads are then 
aligned using the NAST and GreenGenes servers and inserted into a well characterized 
phylogenetic trees of 16S sequences, allowing phylogenetic placement of each sequence read. As 
a first step in analyzing the global effects of each treament, we will compare microbial 
communities using UniFrac, which quantifies the similarities among microbial communities 


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based on phylogenetic distances.  To compare two communities, sequences from both 
communities are placed on a common phylogenetic tree generated using ARB.  The fraction of 
the branch length on the tree unique to each community is then measured.  This provides a 
objective measure of community similarity based on the amount of shared evolutionary 
history.  To compare multiple communities, distances between all pairs of communities are 
computed to generate a distance matrix and Principal Coordinate Analysis is used to plot 
communities in a scatter plot along orthogonal axes of maximal variance.  Such scatter plots can 
be generated taking into account the abundance as well as the presence of each taxa (weighted 
UniFrac), or using only presence/absence information (unweighted UniFrac).  The two methods 
thus address different questions--weighted analysis allows differences in proportional 
representation of community members to be assessed, while unweighted analysis discloses 
changes in community composition.  Measures of alpha diversity such as the Chao1 and 
Shannon Indices will also be used to characterize communities.  Saliva swab samples will be 
obtained for future unplanned analysis including DNA analyses specifically looking at the APOE 
genotype as it may affect treatment response.  
5.13 Distribution and shipment of human specimens 
The human specimens collected for this study will be de-identified and will not contain any 
Protected Health Information (PHI) prior to in-house sample distribution or shipment to external 
collaborators. 
 
6 
Analysis Plan 
6.1 
Data Analysis and Predictions  
At a basic level, the design of this trial is simple repeated measures design with a) two replicates 
(time points) b) baseline covariates and outcomes, and c) a single between-person factor (initial 
case-control depression status).  The data collected at two time points to be included in analysis 
(pre- and post-treatment) will be the depression severity, inflammatory markers, resting state 
functional connectivity and neuropsychometric data.  There have been no published studies to 
date examining adjuvant celecoxib and SSRI treatment in patients who simultaneously received 
assessment of inflammatory biomarkers. However, based on our own small pilot sample we will 
have greater than 85% power to detect differences in changes in IL-6 between SSRI responders 
and SSRI + celecoxib responders. Volumetric data and confounders to be included in the 
analysis will be collected at baseline.  Classic models of change scores can be used where the 
baseline level can be controlled giving the so-called residual change score.  Use of residualized 
change scores has several analytic advantages: (1) control for variance (the best predictor of 
today's value is yesterday's value), (2) statistically each subject is started at the same point.  
Thus, our estimation model will be extended from the classic model of change scores to a 
repeated measures ANOVA (analysis of variance) or mixed model repeated measures design.  A 
joint modeling approach with mixed models for repeated measures data can be used to address 
within-subject variation and between-subject variation of the repeated measurements of multiple 


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variables such as neuropsychological measures and inflammatory markers. Generalized linear 
models (GLM) will be used for the baseline data.  We are aware that numerous other 
confounders exist (such as age, race, education, statin use and gender).  When a variable is 
identified to be related to the outcome and covariate of interest, i.e. confounder, we will adjust 
for it in the model of choice.  A sensitivity analysis of statin and/or ARB use will be performed 
via analysis by statin and ARB use to determine if it is necessary to adjust or stratify by statin 
and ARB use. Models consider inclusion of the list of known covariates and their interaction. 
The importance of these models will be assessed through inspection of the change in the 
parameter of interest, as well as the parameter (and p-value) for the covariate. Point estimates, p-
values, and confidence intervals to test the covariate of interest will be computed. Mixed model 
diagnostics and GLM diagnostics will be evaluated.  For the continuous outcomes, we will assess 
if transformations exist that can bring about near normality.  In addition, the impact of skew on 
the stability of estimates can be assessed using bootstrap methodology.  For all models involving 
skewed predictors, we will assess the impact of the significant outliers using bootstrap and will 
check the linearity assumption. Other diagnostic procedures will be used to check for the validity 
of the GLM assumptions such as normality of the residuals and linearity assumption.  Missing 
data problems are ubiquitous in aging research.  Missing values can arise from several sources, 
(1) subjects are lost to follow-up, (2) missing CRFs, or (3) particular items of a CRF are skipped.  
We will employ multiple imputation. In this design, we have numerous indicators of outcome 
and predictors.  The concern is that the possibility of a Type-I error is increased if a series of 
univariate tests is employed.  Several solutions are possible in the context of this design: 1) use 
of Bonferroni Corrections or the less conservative extension to Bonferroni corrections 2) use of 
data reduction techniques like Principal Component Analysis (PCA) , and 3) use of multivariate 
mixed models. Based on the  estimated numbers of remitters vs non-remitters we expect to enter 
approximately 53 subjects in Phase II. Using the estimates from Abbasi et al. (7) for serum IL-6 
comparing SSRI+celecoxib to SSRI+placebo, we will have greater than 95% power by 
randomizing the 53 subjects between the two groups. 
6.2 
Variables to be used in hypothesis testing 
1) 
For measure of cytokine levels we will measure these in CSF and blood:  Primary 
measure IL-6 pre- and post-treatment. 
2) 
Hippocampus, including subvolume analyses and Amygdala volumes: Left and right 
volumes will be separately measured and standardized by cortical volumes before 
being entered in analyses.  Prefrontal cortical thickness: L & R orbitofrontal, superior 
frontal and frontal pole. 
3) 
Antidepressant treatment response determined using the MADRS score following 
antidepressant treatment covaried on baseline MADRS score. 
4) 
Neuropsychological function as determined by factor scores from episodic memory 
and executive function. 


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5) 
Resting state functional connectivity of the hippocampus and amygdala to anterior 
cingulate (AC) and dorsolateral prefrontal cortex (DLPFC). 
6.3 
Analysis of Specific Aims 
Aim 1: Characterize neuroanatomical and neuropsychological effects of abnormal cytokines in 
MDD.  Hypothesis 1a: Inflammatory cytokines will be elevated centrally and peripherally 
relative to matched controls; neuropsychological performance will be poorer in MDD;  
hippocampus and amygdala volumes and PFC thickness will be decreased in MDD; and 
connectivity of hippocampus and amygdala will be decreased in MDD (hippocampus to DLPFC 
and AC; amygdala to subgenual AC).  For an unadjusted analysis, a t-test can be utilized to 
assess depression group differences among the various outcomes. Linear regression will be used 
to assess whether various outcomes differ between depression status adjusting for confounders 
(such as age, race, education, statin use, and gender).   Baseline inflammatory cytokines, 
neuropsychological measures, functional connectivity, and volumetric data will be treated as 
outcomes in the linear regression model with depression status as a covariate as well as possible 
other confounders as covariates.  
Hypothesis 1b:  Cytokine levels will be correlated with hippocampal and amygdala volumes and 
PFC thickness; we predict that higher IL-6 and lower IL-10 will be correlated with decreased 
hippocampal and amygdalar volumes and decreased PFC thickness.  The Pearson moment-
product correlation coefficient (or Spearmans rank correlation coefficient when normality 
assumptions are violated) will be used to assess relationships between cytokines and ROI 
measures for an unadjusted analysis.  Linear regression will be used to assess whether the ROI 
data are related to the inflammatory markers, while adjusting for depression status and 
confounders.  In addition, we will confirm whether an interaction term between the inflammatory 
markers and depression is necessary. 
Hypothesis 1c: There will be a correlation between cumulative duration of depression and 
volume loss in hippocampus and amygdala, particularly hippocampus CA2-3.  We will correlate 
the lifetime history of depression with hippocampal and amygdala volumes and predict a 
significant correlation using the Pearson product-moment correlation coefficient or Spearman 
rank correlation coefficient depending on normality assumptions.  
Aim 2: Characterize the reversibility of brain dysfunction, including cognitive impairment with 
treatment of depression and its association with inflammation. Hypothesis 2a: Subjects 
randomized to treatment will have greater normalization of IL-6 and IL-10, greater 
improvements in memory, executive function and improvements in resting state functional 
connectivity compared to those randomized to placebo.  For an unadjusted analysis, a paired t-
test can be used to determine if there is a difference in the pre-treatment and post-treatment 
inflammatory cytokines.  Mixed models will be utilized to assess if the inflammatory markers 
change over time adjusting for confounders.  A mediator analysis will be utilized to determine 
whether MADRS has an effect independent of treatment on the inflammatory levels. The first 


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approach would be to test for an interaction effect between baseline MADRS and treatment in a 
mixed model with inflammatory markers as the outcome adjusting for MADRS, treatment, and 
an interaction between MADRS and treatment. If the interaction term is not significant we will 
determine if MADRS independently of treatment or additively with treatment is related to 
inflammatory markers. Structural equation models can be an alternative approach for the 
mediator analysis.  
Hypothesis 2b: Improvement in clinical depressive scores post treatment will be correlated with 
changes in cytokine levels. Change score models or joint mixed models will be utilized to assess 
the relationship between depression scores (outcome) and inflammatory markers, while adjusting 
for confounders in the depressed subjects.   
6.4 
Exploratory Aims 
Hypothesis 1E:  Normalization of cytokine levels will be correlated with increased functional 
connectivity of the hippocampus and amygdala and with improvements in memory and executive 
function. 
Hypothesis 2E: Peripheral blood cytokine levels are sufficiently sensitive to substitute for CSF 
levels. 
Hypothesis 3E: MDD participants will have CSF abnormalities in tryptophan, kynurenine, YKL-
40, and increased protein sulfenne and methionine sulfoxide conversion, specific for tissue 
hydrogen peroxide and superoxide, respectively. 
6.5 
Further Analyses 
 At the completion of the study, we will have a rich database with which to conduct exploratory 
analyses.  Such analysis will include relationships between volumetric measures, CSF and serum 
inflammatory markers, stressful life events and perceived stress.  While extreme deviations from 
normality provides some analytic challenges and linearity is assumed, the model is flexible in 
allowing covariates. Importantly, Abbasi et al. (7) provides some preliminary estimates for 
serum IL-6 concentrations for the conditions SSRI+celecoxib versus SSRI+placebo (7). 
7 
Safety and Adverse Events 
In brief, both the PI and sponsor assess and evaluate all AEs. SAEs need to be reported to the sponsor 
within 48 hours. AEs will be reported in aggregates. 
7.1 
Definitions 
7.1.1 
Adverse Event 
Expected adverse events include all adverse events listed in the escitalopram and celecoxib 
prescription information (see appendix). It is further expected that the incidences of these 
adverse events are higher in the particular age group under study.  


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An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study.  Intercurrent illnesses or injuries should be regarded as 
adverse events.  Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
7.1.2 
Serious Adverse Event 
Serious Adverse Event  
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that, 
in the view of either the investigator or the sponsor, is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of 
major clinical significance.   They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above.  For example, drug overdose or abuse, a 
seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm in 
an emergency department would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-
serious adverse events.  
 
7.2 
Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events will 
be recorded immediately in the source document, and also in the appropriate adverse event module 
of the case report form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic 
procedures results should recorded in the source document, though should be grouped under one 
diagnosis. 
 
All adverse events occurring during the study period will be recorded.  The clinical course of each 
event will be followed until resolution, stabilization, or until it has been determined that the study 
intervention or participation is not the cause.  Serious adverse events that are still ongoing at the 
end of the study period will be followed up to determine the final outcome.  Any serious adverse 
event that occurs after the study period and is considered to be possibly related to the study 
intervention or study participation will be recorded and reported immediately. 
 


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The Investigator will monitor and/or ask about or evaluate AEs using non-leading questions at 
each visit or evaluation. The occurrence of all AEs will be documented in the CRF with the 
following information, where appropriate: 
• AE name or term 
• When the AE first occurred (start date) 
• When the AE stopped (stop date), (Or an indication of “ongoing”) 
• How long the AE persisted  
• Intensity of the AE 
• Seriousness  
• Actions taken 
• Outcome 
• Investigator opinion regarding the relationship of AE to the investigational product(s).  
7.3 
Relationship of AE to Study  
The relationship of each adverse event to the study procedures will be characterized by the PI. The 
categories for classifying the Investigator’s opinion regarding the relationship of an AE to 
investigational product(s) are listed below.  
Definitely related: 
An AE occurring in a plausible time relationship to study drug 
administration, and which cannot be explained by a concurrent 
disease or other drugs or events. The response to withdrawal of the 
drug (dechallenge) is clinically reasonable.  
Probably related: 
An AE with a reasonable time sequence to administration of the 
study drug and which is unlikely to be attributed to concurrent 
disease or other drugs or events. The response to withdrawal of the 
drug (dechallenge) is clinically reasonable. 
Possibly related: 
An AE with a reasonable time sequence to administration of the 
study drug, but which could also be explained by concurrent disease 
or other drugs or events. Information on drug withdrawal may be 
lacking or unclear.  
Unlikely: 
A clinical event, including laboratory test abnormality, with a 
temporal relationship to study drug administration which makes a 
causal relationship improbable, and in which other drugs, events or 
underlying disease provide plausible explanations.  
Unrelated: 
An AE with sufficient evidence to accept that there is no causal 
relationship to study drug administration (e.g., no temporal 
relationship to drug administration, because the drug was 
administered after onset of event; investigation shows that the drug 
was not administered; another cause was proven; etc.).  


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Unassessable 
(Unclassifiable): 
A report suggesting an adverse reaction, which cannot be judged 
because information is insufficient or contradictory, and which 
cannot be supplemented or verified.  
 
7.4 
Reporting of Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, 
formats and requirements of the various entities to which they are responsible. The UPenn IRB 
Reportable events policy will be accessed at http://www.upenn.edu/IRB/mission-institutional-
review-board-irb/reportable-events to concur to the latest requirements. 
 
If the report is supplied as a narrative, the minimum necessary information to be provided at the 
time of the initial report includes: 
• Study identifier 
• Study Center 
• Subject number 
• A description of the event 
• Date of onset 
• Current status 
• Whether study intervention was discontinued 
• The reason why the event is classified as 
serious 
• Investigator assessment of the association 
between the event and study intervention 
 
Additionally all other events (unanticipated problems, adverse reactions, and subject complaints  
will be recorded and reported with respect to institutional and federal policies as described in the 
Penn Manual and below.  
 
7.4.1 
Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes 
the investigator’s assessment of the event, a follow-up report including all relevant new or 
reassessed information (e.g., concomitant medication, medical history) should be submitted to the 
IRB. The investigator is responsible for ensuring that all SAE are followed until either resolved or 
stable.  
 
7.4.2 
Investigator Reporting: Notifying the Penn IRB  
Reportable events will be reported to the UPenn IRB observing applicable timelines as detailed at 
http://www.upenn.edu/IRB/mission-institutional-review-board-irb/reportable-events.  
7.5 
Unblinding Procedures 
While the safety of the subject always comes first, it is still important to seriously consider if 
unblinding the study therapy is necessary to ensure a subject’s safety.  Authorization for unblinding 
must be given by the principal investigator or sponsor.  
To break the code, contact the 24 hour emergency number at the Investigational Drug Service 
at the University of Pennsylvania School of Medicine, Institute for Translational Medicine and 
Therapeutics: 
1-800-670-3151 


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Unblinding will be recorded in print in the source documents and reported to the UPenn IRB. 
7.6 
Medical Monitoring 
7.6.1 
Data and Safety Monitoring Plan 
7.6.1.1 
Principal Investigator  
The principal investigator or a designee for this clinical study, blinded to the treatment allocation, 
will continuously monitor efficacy and safety of the study participants. 
7.6.1.2 
Medical monitor  
The sponsor or a designee for this clinical study, blinded to the treatment allocation, will be 
reviewing subjects’ safety labs, SAE/AE reporting and subjects' overall study course to monitor 
for missed AEs/SAEs. A template similar to the one provided in the appendix will be used. 
7.6.1.3 
Data Safety and Monitoring Board (DSMB) 
Both principal investigator and sponsor will be supported in their safety assessments by an 
independent Data Safety and Monitoring Board comprised of three (3) members who have 
expertise in psychiatry, pharmacology and biostatistics.  
Meetings 
The DSMB will convene as often as necessary, but at least once annually, to examine the 
accumulated safety and enrollment data, review study progress, and discuss other factors (internal 
or external to the study) that might impact continuation of the study as designed. A DSMB meeting 
may be requested by DSMB members, IRB, study sponsor, or study Principal Investigator at any 
time to discuss safety concerns. Meetings may be held by conference calls or videoconferences or 
as face-to-face meetings, information can be shared electronically per e-mail.  
Reporting 
The DSMB will issue a written report that identifies topics discussed by the DSMB and describes 
their individual findings, overall safety assessment and recommendations. The rationale for 
recommendations will be included when appropriate. This report will be circulated to the IRB and 
study investigators. 
Conflict of Interest 
No member of the DSMB should have direct involvement in the conduct of the study. Furthermore, 
no member should have financial, proprietary, professional, or other interests that may affect 
impartial, independent decision-making by the DSMB. 
Responsibility 
The DSMB will review cumulative data for evidence of escitalopram- and celecoxib-related 
adverse events. Safety data will comprise results from the laboratory blood chemistry, in-office 
blood pressure and ambulatory blood pressure monitoring data collected. The study Principal 


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Investigator, study sponsor-investigator, DSMB members and the IRB can request additional data 
to assess the study safety of celecoxib. 
7.7 
Expedited FDA Reporting Requirements  
The study sponsor is required to report certain study events in an expedited fashion to the FDA.  
These written notifications of adverse events are referred to as IND safety reports.  
 
The following describes the IND safety reporting requirements by timeline for reporting and 
associated type of event: 
 
• Within 7 calendar days 
Any study event that is all: 
– associated with the use of celecoxib, and 
– unexpected, and  
– fatal or life-threatening, 
 
• Within 15 calendar days 
Any study event that is: 
– associated with the use of celecoxib, and 
– unexpected, and 
– serious, but not fatal or life-threatening 
-or- 
– a previous adverse event that was not initially deemed reportable but is later found to fit 
the criteria for reporting (reporting within 15 calendar days from when event was 
deemed reportable). 
 
7.8 
NIH/NIMH Reporting Requirements  
Reporting to NIH/NIMH will follow the time frame as outlined above in “Expedited FDA 
Reporting Requirements”. 
7.8.1 
Additional reporting requirements 
Sponsors are also required to identify in IND safety reports all previous reports concerning 
similar adverse events and to analyze the significance of the current event in light of the previous 
reports. 
7.8.2 
Reporting Process 
Applicable events can be reported to the FDA using Form FDA3500A or in narrative format. 
The report must be sent to the correct division. Specific information that must be included in the 
reports can be found in 21 CFR 312.32. 


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8 
Study Administration, Data Handling and Record Keeping 
8.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
 
Several safeguards will be put into place for protecting the confidentiality of research material. 
Staff members will be trained to understand the importance of confidentiality. Information 
gathered about individual participants is maintained in secured storage areas at the site. All 
phone screenings done during the recruitment process will be done from a private office area, 
and after asking the potential participants if they are in an environment where they feel 
comfortable answering questions related to their eligibility to participate. All aspects of the 
informed consent process are done in a private consultation room. Study procedures will occur in 
a private room by personnel trained in following procedures in a manner in which the privacy of 
the participant is maintained. Only information, images, and biological samples necessary for the 
completion of this study will be collected. All computer data obtained from the laboratory and 
from research interviews will be de-identified and then only identified by a code number. All 
data will be kept in locked file cabinets behind locked doors and only made available to qualified 
research personnel. All data will be de-identified and only code numbers will appear on any data 
and documents used for evaluation or statistical analysis for this study. Publications emanating 
from this research will not identify individual patients. HIPAA compliance will be enforced as 
per University of Pennsylvania policy. Reports from patients clinical records concerning research 
observations will not be available to outside medical facilities without the written consent of the 
participant. 
8.2 
Subject Privacy 
Several safeguards will be put into place for protecting the privacy of participants and the 
confidentiality of research material. Staff members will be trained to understand the  importance 
of privacy and confidentiality. Information gathered about individual participants is maintained 
in secured storage areas at the site. All phone screenings done during the recruitment process will 
be done from a private office area, and after asking the potential participants if they are in an 
environment where they feel comfortable answering questions related to their eligibility to 


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participate. All aspects of the informed consent process are done in a private consultation room. 
Study procedures will occur in a private room by personnel trained in following procedures in a 
manner in which the privacy of the participant is maintained. Only information,  images, and 
biological samples necessary for the completion of this study will be collected. All computer 
data obtained from the laboratory and from research interviews will be de-identified and then 
only identified by a code number. All data will be kept in locked file cabinets behind locked 
doors and only made available to qualified research personnel. All data will be de-identified and 
only code numbers will appear on any data and documents used for evaluation or statistical 
analysis for this study. Publications emanating from this research will not identify individual 
patients. HIPAA compliance will be enforced as per University of Pennsylvania policy. Reports 
from patients clinical records concerning research observations will not be available to outside 
medical facilities without the written consent of the participant. 
An exception to confidentiality is if a subject reports child abuse or neglect or if a subject reports current 
suicidal or homicidal ideation of concern to the research team. Any information about child abuse or 
imminent intent to harm one’s self or others will be reported to authorities, as required by law. 
8.3 
Data Disclosure 
The following entities may have access to the data if requested: 1) Government representatives, 
(including the funding  sponsor (NIH) and the Office for Human Research Protections) to 
complete federal or state responsibilities 2) The U.S. Food and Drug Administration 3) Hospital 
or University representatives, to complete Hospital or University responsibilities 4) University of 
Pennsylvania's Institutional Review Board, 5) future collaborators for the advancement of 
scientific knowledge. 
8.4 
Data Collection and Management  
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and 
date it. 
The UPenn-based data management software REDCap (http://project-redcap.org/) will be 
deployed to collect and store study data. REDCap (Research Electronic Data Capture) is a secure 
web application for building and managing online surveys and databases. Using REDCap's 
stream-lined process for rapidly developing projects, one may create and design projects using 1) 
the online method from your web browser using the Online Designer; and/or 2) the offline 
method by constructing a 'data dictionary' template file in Microsoft Excel, which can be later 


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uploaded into REDCap. Both surveys and databases (or a mixture of the two) can be built using 
these methods. REDCap provides audit trails for tracking data manipulation and user activity, as 
well as automated export procedures for seamless data downloads to Excel, PDF, and common 
statistical packages (SPSS, SAS, Stata, R). Also included are a built-in project calendar, a 
scheduling module, ad hoc reporting tools, and advanced features, such as branching logic, file 
uploading, and calculated fields. 
8.5 
Records Retention  
Study essential documents will be retained for 7 years after completion of research. 
8.6 
Trial Registration 
This study is registered in ClinicalTrials.gov - NCT02389465.  
9 
Study Monitoring, Auditing, and Inspecting 
9.1 
Study Monitoring Plan 
Reporting unanticipated problems involving risks to participants or others: The PI or authorized 
designee will monitor the study for any unanticipated problems including adverse and serious 
adverse events. All unanticipated problems will be reported to the IRB and collaborators within 
10 working days with the following exception: If the adverse event involved a death and 
indicates that participants or others are at increased risk of harm, investigators are required to 
submit a report to the IRBs within 3 work days. 
9.2 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
10 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and 
international standards of Good Clinical Practice, and applicable institutional research policies and 
procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent Ethics 
Committee (EC) or Institutional Review Board (IRB), in agreement with local legal prescriptions, 
for formal approval of the study conduct.  The decision of the EC/IRB concerning the conduct of 
the study will be made in writing to the investigator and a copy of this decision will be provided 
to the sponsor before commencement of this study.  


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10.1 Risks 
There are some potential risks associated with study participation and these have been carefully 
considered to substantially reduce occurrence and minimize such risks. Potential risks include: 
Clinical interview and assessments: Some discomfort may be associated with the clinical 
assessments conducted in this study.  Some participants may experience emotional discomfort 
when answering some questions in the questionnaires or talking about their personal situation.  
Participants may choose not to answer any question. 
 
10.1.1 Risk of Breach of Confidentiality 
Breaches in confidentiality could impact future insurability and/or employability. 
10.1.2 EKG 
Participants may experience some discomfort that is similar to removing an adhesive bandage 
when the EKG technician must remove the electrodes that have been placed on the participant's 
chest in order to conduct the test. 
10.1.3 Blood draw 
Participants may experience discomfort, bruising and or bleeding at the site of needle insertion 
when blood is drawn.  Also, some people experience dizziness or feel faint. There is a slight risk 
of infection. 
10.1.4 MRI scan 
There are no known risk factors associated with MRI scans for healthy subjects except that 
participants may experience discomfort as they will be required to lie still in a confined area. 
Participants may experience claustrophobia (fear of enclosed spaces and/or anxious feelings 
accompanied by fast heart rate or shortness of breath) within the MRI scanner. In addition, the 
scanner produces a loud repetitive knocking noise during the study that some people find 
bothersome.  
10.1.5 Escitalopram 
Side effects of escitalopram include nausea, sleepiness, headache, dizziness, tremor, diarrhea, 
nervousness, dry mouth, increased sweating, and insomnia or ejaculation failure. Less common 
side effects include: rash, agitation, decreased sex drive, fatigue. Rare or uncommon side effects 
include: constipation, loss of appetite, vomiting, stomach upset, and vision abnormalities 
10.1.6 Celecoxib 
Celecoxib has been associated with an increased risk of cardiovascular events in people with 
cardiovascular disease (Celecoxib package insert). Side effects include nausea, diarrhea, gas, 
cold symptoms, sore throat, lack of energy, loss of appetite, fever, rash, back pain, and flu-like 
symptoms, among others. Participants would be instructed to contact study members if severe, 


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serious, or persisting side effects occur. There is a rare risk of stroke or heart attack; however 
these very serious side effects are greatest risk for those with current clinically significant cardiac 
disease, and we are excluding these people (clinically significant cardiovascular disease usually 
includes one or more of the following: cardiac surgery or myocardial infarction within the last 4 
weeks; unstable angina; acute decompensated congestive heart failure or class IV heart failure; 
current significant cardiac arrhythmia or conduction disturbance, particularly those resulting in 
ventricular fibrillation, or causing syncope or near syncope; uncontrolled high blood pressure; 
QTc greater than 450msec (by history for subjects with cardiac disease); documented prior 
stroke; clinically significant abnormalities on EKG.)  Celecoxib also has increased risk for 
gastrointestinal bleeding and hepatic impairment. We will exclude those with current ulcer 
disease or GI bleeding as well as those with liver function impairment (as determined by a liver 
function test prior to entry into the study). We are excluding clinically significant cardiovascular 
disease for the past 6 months.  
10.2 Minimizing risks 
The following considerations have been made in order to minimize risk as much as possible:   
Informed Consent: All consenting procedures will be HIPAA compliant. Participants will be 
given a full description of all study procedures and the risks involved, and any questions the 
participant may have will be answered prior to consenting to the study. The consent process will 
be done in a private exam room. 
Clinical interview and assessment: All clinical assessors have extensive experience in clinical 
psychiatric assessment and will make every effort to implement protocol procedures in a 
sensitive and supportive manner. Other measures to minimize risks include the careful 
assessment of each subject before the study, and close clinical scrutiny during all aspects of the 
study. There are no physical risks of diagnostic procedures or ratings. 
Blood draw: To reduce the risks to subjects from the drawing of blood, only trained personnel 
will perform these procedures, and immediate medical assistance and facilities will be available 
at all times.  
MRI scan: The potential risks related to MRI will be minimized in the following manner: 
Subjects are screened for exclusions such as foreign metallic implants and pacemakers to MRI 
participation prior to enrollment; claustrophobia from MRI will be reduced by explaining the 
nature of the magnetic resonance scanner in detail to all participants prior to their enrollment. 
Subjects who have a history of claustrophobia will not be enrolled into the study. If the subject 
complains of feeling claustrophobic, the study will be terminated; to lessen the noise of the 
scanner, earplugs will be provided. 
Treatment with Escitalopram: Participants receiving treatment with escitalopram will be 
monitored closely for any adverse side effects. Two-week follow-up visits will be scheduled to 


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evaluate response to treatment and participants will be withdrawn from the study if their 
depressive symptoms worsen or they have intolerable side effects to escitalopram. These patients 
will be referred for follow-up care. 
Confidentiality: The risk of violating confidentiality will be minimized by the following: all 
computer data obtained from the laboratory and from research interviews will be identified by a 
code number; all data will be kept in locked file cabinets and only made available to qualified 
research personnel; participants will be asked to provide only the contact numbers or e-mail 
addresses which they want us to use for study related contact. HIPAA compliance will be 
enforced as per 
University of Pennsylvania policy and approval; reports from patients clinical records 
concerning research observations will not be available to outside medical facilities without the 
written consent of the subject; all participant interaction with the PI will occur in private exam 
rooms or in the PIs private office; only essential, engaged study members will interact with 
participants during all research activities. 
Others: Any unanticipated findings of potential medical significance discovered during the 
course of this study, such as an abnormality in the MRI scan or significant deficit during 
neuropsychological testing, will be reported to the PI. The participant will be informed and 
referred to their private physician. 
10.3 Benefits 
There is no promise of benefit to subjects in this study. Depressed subjects may benefit from 
treatment with escitalopram and may derive additional anti-depressant benefit from the 
combination of escitalopram and celecoxib. There is no benefit to receiving the MRI scans or to 
the clinical assessments.  The scans and the clinical assessments are performed only for research, 
and the results are not routinely shared with participants. However, in the event that clinically 
significant MRI or EKG abnormalities are discovered, subjects will be informed of the finding 
and referred to their physician. An indirect benefit is contributing to scientific knowledge. This 
study has the potential to greatly increase our knowledge of inflammation in people with 
depression and may lead to new treatments. 
10.4 Risk Benefit Assessment 
There are risks associated with participation in this study, but they are minimal and even rare and 
it is believed that the benefits of conducting the study outweigh the minimal risk.  
Celecoxib has been associated with an increased risk of cardiovascular events in people with 
cardiovascular disease. To mitigate this risk we will enforce our stringent exclusion criteria for 
people with cardiac risk factors, monitor blood pressure, assess gastrointestinal safety, appoint an 
independent data safety monitoring board (DSMB) and conduct this study under an FDA-IND 
for the use of celecoxib. A separate risk/benefit analysis for the use of celecoxib follows below. 


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Because of these precautions, the addition of Celecoxib is not a greater than minimal risk to 
participants. We will perform the EKG and cardiac risk assessment following the completion of 
the initial phase of the study before entering into the celecoxib phase in case their cardiac profile 
has changed. Our exclusion criteria related to cardiac risk include:   lifetime history of cardiac 
surgery or myocardial infarction; unstable angina; acute decompensated congestive heart failure 
or class IV heart failure; current significant cardiac arrhythmia or conduction disturbance, 
particularly those resulting in ventricular fibrillation, or causing syncope or near syncope; 
uncontrolled high blood pressure; QTc greater than 450msec (by history for subjects with cardiac 
disease); documented prior stroke; Clinically significant abnormalities on EKG.  
Additionally, subjects will have blood pressure monitoring at each visit, as it may be a surrogate 
for celecoxib thrombotic risk. There is also a risk of boredom and/or fatigue from study visits. 
There is also a rare risk of breach of confidentiality. We have developed procedures for 
Protection Against or Minimizing Risks for the participant. To reduce risks to participants, only 
physicians and scientists with extensive training and experience will supervise and perform 
procedures. Participants will be closely monitored for any side effects from taking escitalopram. 
There are significant benefits to the research. This study has the potential to greatly increase our 
knowledge in the treatment and prevention of Depression. No direct benefits are expected to the 
participant aside from the satisfaction of participating in a study that addresses an important 
health issue. 
10.5 Risk / Benefit Assessment for Celecoxib  
Celecoxib is a purposefully designed non-steroidal anti-inflammatory drug, or pdNSAID, which 
inhibits the enzyme prostaglandin-endoperoxide synthase 2, also known as cyclooxygenase-2, or 
COX-2. The cardiovascular hazard of NSAIDs is a direct consequence of their intended 
mechanism of action, inhibition of COX-2 (8, 9). Seven placebo-controlled trials of structurally 
distinct NSAIDs specific for inhibition of COX-2 have revealed the increase in cardiovascular 
complications on these drugs (8).  Inhibition of the COX enzymes by NSAIDs causes 
suppression of prostaglandin (PG) production. PGs play important roles in pain, inflammation 
and pyresis, but also in platelet function, vascular integrity and the regulation of renal blood 
flow, volume control and vascular tone 
 
This study exposes patients in the age group of 50-80 years diagnosed with depression to 6 
weeks of oral celecoxib 200 mg bid. The factors to consider for the risk assessment are i) 
thrombotic risk, ii) cardiovascular risk profile at baseline, iii) blood pressure response, iv) co-
administration of SSRI & COX-2 inhibitor. 
 
10.5.1 Thrombotic risk and cardiovascular risk profile at baseline 
Reports on the cardiovascular safety outcomes are available from the Adenoma Prevention With 
Celecoxib (APC) clinical trial which used similar dosing, 200 mg celecoxib bid, as in the present 
protocol as well as double the dose, 400 mg bid (10). The hazard ratio for the pre-specified 
composite safety end point “cardiovascular death, nonfatal myocardial infarction, nonfatal 
stroke, or heart failure” was 2.6 (95% confidence interval [CI], 1.1 to 6.1) in patients taking 200 


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mg celecoxib bid, and 3.4 (95% CI, 1.5 to 7.9) for 400 mg celecoxib bid. Though these risk 
estimates are derived from studies not designed to test for cardiovascular safety but in the case of 
APC powered to test the efficacy and safety of celecoxib versus placebo in reducing colorectal 
adenoma recurrence after polypectomy, the data underscores the dose-dependent increase in 
cardiovascular risk observed for COX-2 selective inhibitors. Hence, to mitigate the 
cardiovascular risk for the participants of this protocol, celecoxib will be administered in 
the lower dose of 200 mg bid.  
 
The presence of cardiovascular events in the past medical history elevates the hazard ratio to 
8.3% in patients exposed to celecoxib compared to 1.9% for the patients on celecoxib without 
such a history (10). The difference in hazard ratios observed in users and non-users of low-dose 
aspirin may convey a similar message: patients taking cardioprotective aspirin indicating a past 
history of CVD show a higher hazard ratio (4.4%) than patients not on aspirin (2.3%) (10). 
Therefore, to mitigate the cardiovascular risk for the participants of this protocol, patients 
with a past history of cardiovascular disease will be excluded. 
 
A difference in the cardiovascular risk (and upper gastrointestinal complications) at baseline 
impacts the risk for major vascular (and gastrointestinal) events during treatment with a selective 
COX-2 inhibitor (11). As these data estimate the per annum risk, we reached out to the senior 
author, Dr. Colin Baigent FRCP FFPH, (11) with the question of the adverse event profile in 
patients during 0-2 months of exposure to celecoxib in patients > 60 years of age. Of note is, that 
this overview analysis from individual patient data (11) report on the safety of high doses of 
celecoxib, i.e. 800 mg per day.  Dr. Baigent pointed out the following: 
• In this meta-analysis, there were only 5 trials involving a randomized comparison of 
celecoxib vs placebo in which at least 1 major vascular event occurred and only 2 trials in 
which at least 1 symptomatic upper GI event occurred (see (11), Webfigures 15 and 20 
from the supplementary material that was published alongside the 2013 Lancet paper 
(11)). 
• In the 5 trials in which a major vascular event (MVE) occurred, at least one MVE 
occurred for 30 out of 1158 patients randomized to celecoxib 800 mg (during a total of 
1819 person-years) compared with 8 out of 1079 patients randomized to placebo (during 
a total of 1750 person-years), yielding an average event rate ratio of 2.96 (99% CI 1.21 to 
7.25) ((11), Webfigure 15). Most of the information comes from the APC trial (23 versus 
6 MVEs). 
• In the 2 trials in which a symptomatic upper GI event, the respective counts were 16 out 
of 872 randomized to celecoxib 800 mg versus 11 out of 778 randomized to placebo (RR 
1.32, 99% CI 0.45 to 3.86) ((11), Webfigure 20). Again, this mostly derived from the 
APC trial (13 versus 11). 
• Given the very small numbers involved, Dr. Colin Baigent does not advise to try and 
subdivide these events further by age or duration of follow-up. But, it is worth noting that 
the effects of any coxib by duration of follow-up/baseline age were also published in the 
webmaterial ((11), Webfigures 2, 7, 12 and 13). 
 
In conclusion, absolute numbers of patients in which a cardiovascular (or gastrointestinal) event 
occurred are too small to estimate the risk for the short-term exposure of 8 weeks in this 
protocol. The strategy here to mitigate cardiovascular risk is i) to include patients below a 


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Framingham 10-year risk score of 13 (15% 10-year risk), taking into consideration that the 
10-year cardiovascular risk in our elderly age group (age 60-80) is estimated at 13.5% in 
the general population and 15% in patients with cerebrovascular risk factors, and ii) to 
reduce the upper age for inclusion to 80 years of age.. The feasibility of this approach is 
drawn from our pilot data in a sample (n=217) of late life depression and controls where we 
determined the Framingham score in both patients with MDD (who had higher vascular risk 
scores) and age matched controls: Age 60-65 mean score MDD: 9.0 (10-year stroke risk of 8% 
vs 7% for general population). Age 65-74 mean score: 12.2 (10-year risk of 13.5% vs average 
risk = 11%); 75-84 mean score: 16.2 (10-year risk of 23% vs average risk of 20%).  
 
To explore retrospectively how adverse events relate to differences in drug effects, i.e. 
inhibition of prostaglandin synthesis, urine spot samples will be collected for prostaglandin 
metabolite analysis at select time points optionally.   
 
10.5.2 Blood pressure 
The risk of NSAIDs to induce hypertension (12, 13), sodium retention (13) and edema (13) is 
well recognized (14-17), but it remains unclear why some patients develop such complications 
and others do not. Factors associated with this risk are age, co-morbidity, preexisting 
hypertension and elements of drug exposure to selective COX-2 inhibitors. Latter includes dose, 
attained plasma concentrations, duration of action and dosing and the degree of selectivity for 
COX-2. 
 
Retrospective analyses of blood pressure responses have been performed in most NSAID trials 
of large populations and/or those involving extended drug exposure, although these are usually 
not based on rigorous (or, in some cases, not even pre-specified) blood pressure measurements. 
In some studies, the incidence of hypertension has been recorded merely as reported adverse 
events or by retrospectively defined changes from baseline. Based on these assessments, all 
NSAIDs have increased blood pressure or induced hypertension within diverse study 
populations, although this appears to relate to COX-2 selectivity (confounded with drug 
exposure; (9)). Perhaps unsurprisingly, the rates in blood pressure increase were highly variable 
across studies and conditioned by the specific characteristics of the study population and by 
recording methods. However, the lack of information from rigorously designed and sufficiently 
sized trials limit any conclusions about the relative likelihood of hypertension on specific 
inhibitors or in subpopulations.  
 
Only a small number of clinical trials – some of which were not powered to detect small changes 
– have assessed prospectively the effects of COX inhibition on blood pressure control. Of note is 
that young, healthy individuals are unlikely to experience an increase in blood pressure in 
response to traditional (t)NSAIDs, such as naproxen or ibuprofen or purposefully-designed, 
selective COX-2 inhibitors, like rofecoxib or celecoxib based on these studies. Older, 
normotensive subjects and patients with controlled, stable hypertension can be expected to have 
average increases of 3-5 mmHg in systolic blood pressure (18-22) with an incidence of above 
average responses (as defined by an increase of 20 mmHg in systolic blood pressure and a 
systolic blood pressure above 140 mmHg) ranging from 7-17 %. As one would expect, 


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hypertensive responses to COX-2 selective inhibitors were reported to be more likely in patients 
with elevated blood pressure as a pre-existing condition (23).  
 
A number of retrospective studies, RCTs, and database studies, as recently reviewed (24), 
suggest that SSRIs including escitalopram have an overall neutral impact on the cardiovascular 
system including blood pressure.  In a randomized clinical trial using fixed-dose escitalopram, 10 
mg/d, over a period of 8 months, hypertension was the reason for discontinuation in only n=2 out 
of n=274 (0.7%) escitalopram-treated patient (25). 
 
Age has an physiological effect on the glomerular filtration rate (GFR), quantified as a decline in 
GFR by 0.4 ml/min/year (26). COX-2 inhibitors’ renal effects are a decline in the GFR (27) and 
an alteration of the feedback mechanism which controls renin release (28). Thus, the noted 
increase in aldosterone concentrations after escitalopram administration - 261±36 pmol/liter at 
baseline, 269±38 pmol/liter at 2 weeks, and 282±40 pmol/liter at 6 weeks (p=0.04) (29), by itself 
functionally not associated with changes in blood pressure in this study of normotensive males 
with depression (29) - might sensitize the reno-vascular system for hypertensive responses under 
conditions of celecoxib co-administration.    
 
Taking the consideration outlined above into account, our initial strategy to mitigate this risk 
was to identify the patients responding to celecoxib administration with an above average 
increase in blood pressure. The paradigm to detect such an above average signal was the 
use of continuous 24-hour ambulatory blood pressure monitoring (ABPM) before the start 
of their enrollment to establish a baseline, and under steady state conditions of celecoxib 
plasma drug concentrations, i.e. one to two weeks after start of the study; ABPM at the end 
of the study was planned to collect further safety and interventional data. Patients 
demonstrating an elevation of 10 mmHg in mean daytime and nighttime systolic blood 
pressure at 1-2 weeks after the start of the study compared to the mean daytime and 
nighttime systolic blood pressure at baseline and the mean daytime (that is out of bed 
times) systolic blood pressure is ≥150 mmHg were instructed to discontinue trial 
medication and excluded from the study and instructed to see their primary care physician 
for further evaluation and follow up.  
 
However, using this initial strategy we were only able to enroll n=2 patients during the past 
2 years, concluding that the in-/exclusion criteria and protocol procedures, in particular the 
24-hour ambulatory blood pressure measurements, are too demanding for the patient 
cohort under study. Patient screening interviews conducted by the clinical study 
coordinators reflected this notion among the majority of patients potentially eligible for 
study inclusion.   
 
Therefore, to increase enrollment, we amend the protocol to make optional the 24-hour 
ambulatory blood pressure monitoring, thus focusing on the weekly in-office blood 
pressure measurements as described below to screen primarily for the risk of blood 
pressure elevation. 
 
A similar approach to risk detection was taken in the largest prospectively randomized clinical 
study on NSAIDs (Nissen SE et al. N Engl J Med. 2016 Dec 29;375(26):2519-29. 


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Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. PMID: 27959716) 
where patients with osteoarthritis or rheumatoid arthritis and with elevated cardiovascular risk or 
established cardiovascular disease received either a high dose of ibuprofen or naproxen or a low 
to medium dose of celecoxib. Data on blood pressure suggests that less than 0.1% of patients 
exposed to NSAIDs experience hypertensive urgencies or emergencies at 45 days into dosing, 
which is the planned duration of celecoxib exposure for the current study. The incidence of blood 
pressure related events did not exceed 0.6% after 30 months of NSAID treatment.    
 
 
Time to first hospitalization for hypertension in PRECISION (Ruschitzka F et al. Differential 
blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: the 
PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety 
Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) Trial. Eur Heart J. 
2017 Nov 21;38(44):3282-3292. PMID: 29020251) 
 
Regression lines were added manually per visual inspection to extrapolate the NSAID-
exposure-related event risk at 45 days of administration. 
 
In the case that patients opt in for the 24hr APBM, patients’ activity patterns during the 24 
hour ABPM sessions, in particular in- and out-of-bed times to differentiate the diurnal 
profile of blood pressure changes during day- and nighttime, will be recorded by two 
different methods, paper and pencil logs and body actigraphy. 
 


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In-office blood pressure measurements (in triplicates 5 minutes apart after a 5 minute 
resting period) will continue at weekly intervals throughout the study. In the case that all 
systolic blood pressures taken on ≥2 separate office visits are ≥150 mmHg systolic blood 
pressure or ≥90 mmHg diastolic blood pressure, a follow up 24-hour ABPM will be 
scheduled within one to two weeks. Here, the same criteria for study exclusion, as outlined 
above, will be applied.  
 
The reference systolic and diastolic blood pressure of 150/90 mmHg in people aged 60 years 
and older has recently been recommended in the “JNC8 evidence-based guideline for the 
management of high blood pressure in adults 2014” (30).  
 
In the case that patients opt in for the 24hr APBM, the benefit to patients is the extensive 
phenotyping of their blood pressure response to celecoxib. Patients exhibiting an above 
average blood pressure response to celecoxib will be advised to be cautionary in particular 
when taking over-the-counter or prescription NSAIDs for longer periods of time. In 
addition, the primary care physician will be advised to monitor blood pressure in such 
patients.   
 
A challenge will be the high prevalence of hypertension in this age group, estimated at 
approximately 65% of men and 75% of women by age 70 years (31). Study enrollment can be 
offered to this patient cohort provided that blood pressure is adequately controlled with life style 
changes and/or anti-hypertensive pharmacotherapy. This option will also be offered to patients 
initially excluded from the study or excluded from the study due to elevated blood pressure. 
Here, the benefit to patients is that their blood pressure is monitored over periods of 24 
hours on multiple occasions, a diagnostic tool less common in the primary care setting. This 
is expected to actively engage patients in the control of their blood pressure, which is 
beneficial across all ages (32). 
 
High salt diet and dehydration are two conditions known to induce COX-2 expression in renal 
medullary interstitial cells (33-36), which play an important role in adaptive regulation of arterial 
pressure. Resultant vasodilator COX-2 products contribute to the regulation of medullary blood 
flow (MBF), which drives pressure natriuresis and diuresis. In mice, COX-2 inhibition and 
nonselective COX-inhibition (37), reduces acutely MBF, sodium excretion and urine volume 
(38). Coincident challenge of the renal autoregulatory mechanisms by vasopressors, excessive 
salt intake or volume depletion results in a rise in systemic arterial pressure (38, 39). This is 
consistent with clinical observations in young and healthy populations in which both 
nonselective COX inhibition and selective COX-2 inhibition have no effects on arterial pressure 
despite transient changes in GFR and sodium handling on initiation of dosing, while elderly 
volunteers show a depression of MBF and in an increase in blood pressure (40). To mitigate the 
risk for a diet-drug interaction on blood pressure, patients will be screened for dietary salt 
intake per 24-hour dietary recall administered by the CTRC bionutrition core. If the daily 
salt intake exceeds 1.5 g (http://www.cdc.gov/salt/), the patient will receive dietary 
recommendations to follow a sodium-deplete diet for the duration of exposure to the COX-
2 inhibitor in Phase 2. Furthermore, patients will be instructed how to prevent 
dehydration. This will be achieved by having the patients log their intake of fluids (type, 
volume) which will be reviewed and, where required, adjusted to meet the Institute of 


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Medicine’s recommended 13 cups (3 liters) of total beverages a day for men or 9 cups (2.2 
liters) of total beverages a day for women 
(http://www.iom.edu/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx).  
 
10.5.3 Co-administration of SSRIs and Celecoxib 
Safety data from co-administration of a SSRI and celecoxib is available from a handful of studies 
(7, 41-43) using various dose regimens over period of times similar to the present study. All of 
these studies support a cardiovascular and gastrointestinal profile not different to the placebo 
treatments, but significant limitations arise from i) the small sample sizes, up to n=20 per group, 
ii) the patients selected for the study, these belong to different groups at risk, i.e. age, e.g. 24-46 
years of age (41), and gender, i.e. only premenopausal women (43), and iii) the method of 
assessing cardiovascular and gastrointestinal adverse events, e.g. “checklist administered by a 
resident” as stated in (41).  
 
Both escitalopram and celecoxib are weak inhibitors of CYP2D4. Increases in the area 
under plasma drug concentration over time curve (AUC) can be expected between ≥ 1.25 
but < 2-fold (44). Drug clearance may decrease by 20-50% (44). To retrospectively attribute 
adverse events to differences in drug exposure, plasma samples will be collected for 
pharmacokinetic analysis at select time points.   
 
10.5.1 Gastrointestinal Bleeding Risk of Celecoxib 
NSAIDs, including Celecoxib, cause an increased risk of gastrointestinal adverse events 
including bleeding, ulceration, and perforation of the stomach or intestines. These events can be 
fatal. Patients with a current diagnosis of peptic ulcer disease and/or gastrointestinal bleeding 
will therefore be excluded. GI/bleeding risk will be screened for in medical history & physical 
examination. In weekly intervals, each patient will be monitored for GI pain and GI bleeds. In 
addition, hepatic function panel and hematocrit blood testing before entering the study, during 
week 1 or 2, and at the end of the study will screen for the presence of blood in stool and loss of 
excessive blood.  
 
11 
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Harris, R. C., M. Z. Zhang, and H. F. Cheng. 2004. Cyclooxygenase-2 and the renal renin-
angiotensin system. Acta Physiol Scand 181: 543-547. 
34. 
Hao, C. M., F. Yull, T. Blackwell, M. Komhoff, L. S. Davis, and M. D. Breyer. 2000. Dehydration 
activates an NF-kappaB-driven, COX2-dependent survival mechanism in renal medullary interstitial cells. 
J Clin Invest 106: 973-982. 
35. 
Yang, T., J. B. Schnermann, and J. P. Briggs. 1999. Regulation of cyclooxygenase-2 expression in 
renal medulla by tonicity in vivo and in vitro. Am J Physiol 277: F1-9. 
36. 
Hao, C. M., M. Komhoff, Y. Guan, R. Redha, and M. D. Breyer. 1999. Selective targeting of 
cyclooxygenase-2 reveals its role in renal medullary interstitial cell survival. Am J Physiol 277: F352-359. 
37. 
Terragno, N. A., K. U. Malik, A. Nasjletti, D. A. Terragno, and J. C. McGiff. 1976. Renal 
prostaglandins. Adv Prostaglandin Thromboxane Res 2: 561-571. 


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38. 
Qi, Z., C. M. Hao, R. I. Langenbach, R. M. Breyer, R. Redha, J. D. Morrow, and M. D. Breyer. 2002. 
Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II. J Clin 
Invest 110: 61-69. 
39. 
Zewde, T., and D. L. Mattson. 2004. Inhibition of cyclooxygenase-2 in the rat renal medulla leads 
to sodium-sensitive hypertension. Hypertension 44: 424-428. 
40. 
Dilger, K., C. Herrlinger, J. Peters, H. W. Seyberth, H. Schweer, and U. Klotz. 2002. Effects of 
celecoxib and diclofenac on blood pressure, renal function, and vasoactive prostanoids in young and 
elderly subjects. J Clin Pharmacol 42: 985-994. 
41. 
Akhondzadeh, S., S. Jafari, F. Raisi, A. A. Nasehi, A. Ghoreishi, B. Salehi, S. Mohebbi-Rasa, M. 
Raznahan, and A. Kamalipour. 2009. Clinical trial of adjunctive celecoxib treatment in patients with 
major depression: a double blind and placebo controlled trial. Depress Anxiety 26: 607-611. 
42. 
Muller, N., M. J. Schwarz, S. Dehning, A. Douhe, A. Cerovecki, B. Goldstein-Muller, I. Spellmann, 
G. Hetzel, K. Maino, N. Kleindienst, H. J. Moller, V. Arolt, and M. Riedel. 2006. The cyclooxygenase-2 
inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, 
placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11: 680-684. 
43. 
Majd, M., F. Hashemian, S. M. Hosseini, M. V. Shariatpanahi, and A. Sharifi. A Randomized, 
Double-blind, Placebo-controlled Trial of Celecoxib Augmentation of Sertraline in Treatment of Drug-
naive Depressed Women: A Pilot Study. Iranian Journal of Pharmaceutical Research Articles in Press, 
Accepted Manuscript , Available Online from 29 September 2014   
44. 
FDA. accessed 2/4/2015. Drug Development and Drug Interactions: Table of Substrates, 
Inhibitors and Inducers. 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabe
ling/ucm093664.htm#inVivo. 
 
 
 
 
 


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12 Appendix 
12.1 Study Flow-Chart 
Procedures conducted with all participants 
Procedure 
Phone Screen 
In-person Screen 
Baseline  
Week 6 
Informed Consent 
 
X (Initial screening 
consent) 
X (Full study 
consent) 
X  
Verbal Consent 
X 
 
 
 
Screen, History (include GI/bleeding risks) 
X 
 
 
X  
Screen, History, SCID, MADRS, HAMD, CGI, MOCA 
 
X 
 
 
EKG 
 
X 
 
X  
PE , Laboratory tests, including IL-6, IL-10, CBC with diff;  
 
X 
X 
X  
MRI; structural and functional  
 
 
X 
X 
Lifetime depression, PSS, LES score 
 
 
X 
 
Framingham VRF, CIRS-G, QOL 
 
X 
 
X 
Neuropsychological tests (COWA, Trails A & B, WLMT, Digits 
Forward, Digits Backward, Digits Ascending, MMSE, Logical 
Memory, Digit Symbol, Benton Visual Retention, Shipley 
Vocabulary, Boston Naming, CogState) 
 
 
X 
X 
*.  
 
 
 
 
 
 


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Additional procedures conducted with depressed participants initially randomized to celecoxib: 
Procedure 
Study Visits 
Baseline  
Wk 1 
Wk 2 
Wk 4 
Wk 6 
Concomitant Medications 
X 
X 
X 
X 
X 
Drug Dispensed Escitalopram + celecoxib or escitalopram 
+ placebo (weeks 0-6) 
X 
X 
X 
X 
X 
Psychiatrist evaluation, depression scales,  Vital Signs 
(including optional urine samples at baseline, week 1 or 2, 
and 6; triplicate in-office BP weekly and monitor GI-
pain/bleeding for safety ),AEs, SAEs 
X 
X 
X 
X 
X 
PE (Lab tests including IL-6, IL-10, CBC with diff) 
X 
X 
X 
X 
X 
Liver function test & GI/bleeding risks  
X 
 
X 
 
 
Actigraphy (1 consecutive day minimum, optional longer),  
 
X 
X 
X 
 
Optional Stool Sample 
X 
 
X 
 
X 
Optional Saliva samples 
X 
X 
X 
X 
X 
Safety (ABPM, FOBT and/or hematocrit levels) 
X 
 
X 
 
 
Safety (24-hour dietary recall, optional counseling on 
sodium-deplete diet) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Concomitant Medications 
X 
 
 
 
 
 
 
 
 
Drug Dispensed Escitalopram + celecoxib or escitalopram 
+ placebo (weeks 0-6) (Open label- Escitalopram + 
celecoxib) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Psychiatric evaluation, depression scales,  Vital Signs 
(including optional urine samples at baseline, week 1 or 2, 
and 6; triplicate in-office BP weekly and monitor GI-
pain/bleeding for safety ),AEs, SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver function test & GI/bleeding risks  
X 
 
X 
 
 
 
X 
 
 
Actigraphy   
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optional Saliva samples 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety (ABPM, FOBT and/or hematocrit levels) 
X 
 
X 
 
 
 
X 
 
 
Safety (24-hour dietary recall, optional counseling on 
sodium-deplete diet) 
X 
X 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional procedures conducted with depressed participants initially randomized to placebo: 
Procedure 
Phase 1 
Open Label Phase 
 
Baselin
e  
Wk 1 
Wk 2 
Wk 4 
Wk 6 
Wk 1 
Wk 2 
Wk 4 
Wk 6 


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12.2 Diary Recall Form (example) 
 


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12.3 Template Medical Monitoring (example) 
 
Subject Binder: ID ___    ___    ___   (Initials ___    ___    ___ ) 
 
Medical Monitoring 
 
Lab Work 
 
Please specify which labs are being reviewed 
Screening 
 Close-out visit 
  Both 
 
 
1. Are all out-of-range values accounted for and reviewed by the investigator?  
Yes 
 No 
 
If “No”, Please Explain: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________ 
__________________________________________________________________ 
__________________________________________________________________ 
 
2. Are the ratings “Not Clinically Significant (NCS)” and “Clinically Significant 
(CS)”, when indicated, appropriate for the out-of-range values? 
Yes 
 No 
 
If “No”, Please Explain: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________ 
__________________________________________________________________ 
__________________________________________________________________ 
 
Adverse Events (AE) 
 
1. Are all Adverse Events accounted for and reviewed by the investigator? 
Yes 
 No 
   
N/A 
 (No AE occurred) 
If “No”, Please Explain: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________ 
__________________________________________________________________ 
__________________________________________________________________ 
__________________________________________________________________ 


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Subject Binder: ID ___    ___    ___   (Initials ___    ___    ___ ) 
 
2. Do all Adverse Events have a corresponding completed adverse event form? 
Yes 
 No 
   
N/A 
 (No AE occurred) 
If “No”, Please Explain: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________ 
 
3. Has the overall study course for the subject for Adverse Events been reviewed? 
Yes 
 No 
   
N/A 
 (No AE occurred) 
If “No”, Please Explain: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________ 
 
4. Have Adverse Events been identified, investigated, reported, and all necessary 
follow-ups performed? 
Yes 
 No 
   
N/A 
 (No AE occurred) 
If “No”, Please Explain: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________ 
 
Serious Adverse Events (SAE) 
 
 
Please describe the serious adverse event and the action taken following event: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
N/A 
 (No SAE occurred) 
 
1. Are all Serious Adverse Events accounted for and reviewed by the investigator? 
Yes 
 No 
   
N/A 
 (No SAE occurred) 
If “No”, Please Explain: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________ 
__________________________________________________________________ 
__________________________________________________________________ 


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Subject Binder: ID ___    ___    ___   (Initials ___    ___    ___ ) 
 
2. Do all Serious Adverse Events have a corresponding completed Serious Adverse 
Events Form? 
Yes 
 No 
   
N/A 
 (No SAE occurred) 
If “No”, Please Explain: 
__________________________________________________________________
__________________________________________________________________ 
 
3. Has the IRB been notified within 5 calendar days of the SAE? 
Yes 
 No 
   
N/A 
 (No SAE occurred) 
If “No”, Please Explain: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________ 
 
4. Has the overall study course for the subject for Serious Adverse Events been 
reviewed? 
Yes 
 No 
   
N/A 
 (No SAE occurred) 
If “No”, Please Explain: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________ 
 
5. Have Serious Adverse Events been identified, investigated, reported, and all 
necessary follow-ups performed? 
Yes 
 No 
   
N/A 
 (No SAE occurred) 
If “No”, Please Explain: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________ 
 
Medical Monitor’s Name (print):  ___________________________ 
 
Medical Monitor’s Signature:  
___________________________ 
 
Date:  
 
 
 
___________________________ 
 
 


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12.4 Drug Prescribing Information 
 
Escitalopram/Lexapro included in pdf version of protocol. 
Celecoxib/Celebrex included in pdf version of protocol. 
 
 


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12.5 Food and Drug Administration-IND Exempt Letter  
 
 
 
 


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ICF_001.pdf: 
Official Title: Stress and Inflammation in the Pathophysiology of Late Life Depression 
NCT Number: NCT02389465 
Protocol Document Date: 06/04/2020 


Sheline: Stress and Inflammation – Initial Consent 
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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT 
INFORMED CONSENT - 
INITIAL ASSESSMENT 
 
Protocol Title: 
Stress and Inflammation in the Pathophysiology of 
Depression 
 
Principal Investigator: 
 
 
 
 
 
Center for 
Neuroscience of 
Depression and Stress: 
Yvette Sheline, M.D. 
Department of Psychiatry 
University of Pennsylvania 
3700 Hamilton Walk 
Philadelphia, PA 19104-4283 
Email: sheline@mail.med.upenn.edu 
 
 
Tommaso Girelli 
Email: Tommaso.girelli@pennmedicine.upenn.edu 
Office Phone: 215-573-0083 (Scheduling/general questions) 
 
 
Emergency Contact: 
If you have a study related medical emergency, please 
contact the study staff or call 911 
 
 
 
 
Why am I being asked to volunteer? 
You are being invited to participate in a research study. We are contacting 
you because you expressed a potential interest in participating. Your 
participation is voluntary, which means you can choose whether or not you 
want to participate. If you choose not to participate, there will be no loss of 
benefits to which you are otherwise entitled. We will be recruiting about 100 
subjects with depression and 50 subjects with no depression who are 18- 
80 years old to participate. 
 
This consent form describes what this visit is about. You will be asked to 
complete a psychological assessment in order to determine your eligibility 
to participate in the research study. If you are eligible, you will be given the 
option of participating in the research study, and you will be asked to sign a 
second consent form. If you are not eligible, you will not lose any benefits 


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to which you are entitled. The research team will explain the study and 
answer any questions you may have. If you decide to participate, you will 
be asked to sign this form. If you have any questions, please ask the 
researcher. You will be given a copy of this form for your records. 
 
The National Institutes of Health (NIH) is funding this research study. 
 
What is the purpose of this research study? 
The purpose of the initial assessment is to determine whether you are 
eligible to participate in this research study. 
 
The purpose of this entire research study is to see if depression over a 
person’s lifetime is related to the amount of inflammation in the brain and 
whether the amount of inflammation affects treatment response. We also 
want to determine whether taking an antidepressant affects the level of 
inflammatory proteins in the body. This information may help us find better 
ways to prevent episodes of depression. 
 
How long will I be in the study? 
The screening assessment will take approximately 90 minutes of your time. 
The electrocardiogram (EKG) will take about 10 minutes. Your participation 
in this phase (the screen) will take approximately 80 minutes. If you are 
eligible to participate in the entire study, your participation will last 
approximately 6 weeks. Overall, about 100 depressed participants and 50 
non-depressed participants will be enrolled over a period of 4 years. 
 
What am I being asked to do? 
You will be asked to complete an assessment that consists of a psychiatric 
evaluation and some brief surveys. We will also measure your vitals 
(temperature, respiration rate, heart rate, and blood pressure) as well as 
record your height and weight at this visit. 
 
We will also administer a blood draw to test for c-reactive protein (an 
inflammatory protein used to measure levels of inflammation), HIV, 
Hepatitis B, Hepatitis C, rheumatoid factor, and autoimmune diseases. We 
will perform an electrocardiogram (EKG) to assess your cardiovascular 
health. An EKG is a test that allows physicians to assess the heart’s 
function. During the procedure, you will be asked to remove your shirt and 


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lie on a table. A technician will put electrode patches on chest to measure 
your heartbeat. 
 
 
 
Continuation of the study for eligible participants: 
If you are eligible to continue in the study, additional information will be 
provided to you about the procedures involved and you will be asked to 
sign a second consent form. The procedures of the study include receiving 
1-3 blood draws, two MRIs, and additional neuropsychological testing. You 
may be asked to take either escitalopram with celecoxib, a non-steroid anti- 
inflammatory, or escitalopram and placebo for 6 weeks. The total duration 
of this study will be about 6 weeks long. 
 
What are the possible risks or discomforts? 
Clinical assessment: Common side effects of participating in this 
evaluation may include discomfort associated with disclosing personal 
information. 
Electrocardiogram (EKG): You may feel some discomfort similar to 
pulling off an adhesive bandage when the technician removes the 
electrodes placed on your chest during the procedure. 
Blood draw: 
Likely/Common: 
ï There is a slight risk of bruising and infection at the site of the blood 
draw, as well as some discomfort during the blood draw. 
 
Risk of Breach of Confidentiality: There is a rare risk of breach of 
confidentiality. Breaches in confidentiality could impact future insurability 
and/or employability. 
Future Use of Data and/or Specimens 
Your information and samples will be de-identified. De-identified means 
that all identifiers have been removed. The information [and samples] could 
be stored and shared for future research in this de-identified fashion. It 
would not be possible for future researchers to identify you as we would not 
share any identifiable information about you with future researchers. This 
can be done without again seeking your consent in the future, as permitted 
by law. The future use of your information and samples only applies to the 
information and samples collected on this study. 


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What if new information becomes available about the study? 
During the course of this study, we may find more information that could be 
important to you. This includes information that, once learned, might cause 
you to change your mind about being in the study. We will notify you as 
soon as possible if such information becomes available. 
 
What are the possible benefits of the study? 
In the event that EKG clinically significant abnormalities are discovered, we 
will inform you of the finding and refer you to your physician. You are not 
expected to gain any other benefits from this portion of the study. 
In the event that we discover any abnormalities in your blood work, we 
will let you know of this. We request permission to contact your primary 
care provider to share the results of your blood work for further 
interpretation and to have follow up procedures to determine the accuracy 
of these findings. Should we receive abnormal results from your blood 
work, we will not include you in the study until we can verify the accuracy 
these results through follow up testing and discussions with your primary 
care provider. The study will not pay for the cost of this follow blood work 
or provider visit. 
 
What other choices do I have if I do not participate? 
You may choose to participate in the assessment or you may choose not to 
participate in the assessment. Your participation is voluntary. There is no 
penalty if you choose not to participate in the evaluation. 
 
Will I be paid for being in this study? 
There is compensation for this portion of the study if you complete the visit 
up to and including the blood draw at the end of the appointment. This 
compensation will be $10 and it is strictly for completing the blood draw. If 
you are eligible to continue with the study, you will be compensated further 
for subsequent participation. 


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If you drive, we will provide you a parking voucher to make the parking free. 
We cannot reimburse for the cost of gas. If you take public transportation, 
we can provide you $5 on your Greenphire ClinCard for your travel with 
proof of transportation (SEPTA ticket, Uber/taxi receipt, etc.). 
 
Will I have to pay for anything? 
There will be no cost to you associated with participation in the 
assessment. 
 
What happens if I am injured from being in the study? 
We will offer you the care needed to treat injuries that are a direct result of 
taking part in this research. We may bill your insurance company or other 
third parties, if appropriate, for the costs of the care you get for the injury, 
but you may also be responsible for some of them. 
 
There are no plans for the University of Pennsylvania to pay you or give 
you other compensation for the injury. You do not give up your legal rights 
by signing this form. 
 
If you think you have been injured as a result of taking part in this research 
study, tell the person in charge of the research study as soon as possible. 
The researcher’s name and phone number are listed in the consent form. 
 
When is the Study over? Can I leave the Study before it 
ends? 
The assessment will take approximately 90 minutes of your time. You have 
the right to discontinue your participation in the assessment at any time 
during the evaluation. You can discontinue your participation by telling the 
researcher that you do not want to participate any longer. There is no 
penalty or loss of benefits if you decide to do so. Withdrawal will not 
interfere with your future care. 
 
Who can see or use my information? How will my personal 
information be protected? 
We will do our best to make sure that the personal information obtained 
during the course of this research study will be kept private. However, we 
cannot guarantee total privacy. Your personal information may be given 
out if required by law. If information from this study is published or 
presented at scientific meetings, your name and other personal information 


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will not be used. If this study is being overseen by the Food and Drug 
Administration (FDA), they may review your research records. 
 
We will keep your participation in this research study confidential to the 
extent permitted by law. However, it is possible that other people such as 
those indicated below may become aware of your participation in this study 
and may inspect and copy records pertaining to this research. Some of 
these records could contain information that personally identifies you. 
 
ï Government representatives, (including the funding sponsor (NIH) 
and the Office for Human Research Protections) to complete federal 
or state responsibilities 
ï The U.S. Food and Drug Administration 
ï Hospital or University representatives, to complete Hospital or 
University responsibilities 
ï University Pennsylvania’s Institutional Review Board (a committee 
that oversees the conduct of research involving human participants.) 
The Institutional Review Board has reviewed and approved this 
study. 
 
To help protect your confidentiality, your data will only be transported by 
qualified study team members, and only during actual subject participation. 
Once all hard copy records are collected, they will be kept in a double- 
locked environment. Data collected during the study will be entered and 
stored in a password-protected database, accessible only to engaged study 
members. Electronic records will not be transported via external drives or 
any other means. If we write a report or article about this study or share the 
study data set with others, we will do so in such a way that you cannot be 
directly identified. 
 
Protected Health Information (PHI) is health information that identifies you. 
PHI is protected by federal law under HIPAA (the Health Insurance 
Portability and Accountability Act). To take part in this research, you must 
give the research team permission to use and disclose (share) your PHI for 
the study as explained in this consent form. The research team will follow 
state and federal laws and may share your health information with the 
agencies and people listed under the previous section titled, “How will you 
keep my information confidential?” 


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Once your health information is shared with someone outside of the 
research team, it may no longer be protected by HIPAA. 
 
The research team will only use and share your information as talked about 
in this form. When possible, the research team will make sure information 
cannot be linked to you (de-identified). Once information is de-identified, it 
may be used and shared for other purposes not discussed in this consent 
form. 
 
What information about me may be collected, used or shared 
with others? 
In order to enroll you into the study, schedule appointments, contact you for 
follow-up, we will ask you for your name, address, telephone number, 
alternate telephone number, date of birth, and social security number. This 
information will be used only for contact and payment (if you proceed 
through the screen and agree to participate in the full study) and will not be 
linked to any of your medical data or the information you provide during the 
assessments. All research data will be de-identified and assigned a 
randomly generated research identification number. All information obtained 
will be kept completely confidential and will be in locked files behind locked 
doors. Electronic data will be encrypted and password protected. 
 
During your participation, you will be asked to answer questions about your 
medical history including questions about your physical and mental health. 
Information from your medical charts will be reviewed and documented for 
research purposes. Results from physical exams and assessments will be 
part of the research record. All research data will be de-identified and 
assigned a randomly generated research identification number. All 
information obtained will be kept completely confidential and will be in 
locked files behind locked doors. Electronic data will be encrypted and 
password protected. 
 
What may happen to my information and samples collected 
on this study? 
The data/sample was collected knowing the identity of the subject, but 
identifiers were removed. All samples will only be identified by the 
participants’ randomly generated study ID number, and the date and time 
of the sample collection. If we write a report or article about this study or 


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share the study data set with others, we will do so in such a way that you 
cannot be directly identified 
 
Your samples may be used to create products, including some that may be 
sold and/or make money for others. If this happens, there are no plans to 
tell you, or to pay you, or to give any compensation to you or your family. 
 
Whole genome sequencing will not be conducted on your samples. Whole 
genome sequencing involves analyzing your entire personal genetic code. 
 
Why is my information being used? 
Your information is used by the research team to contact you during the 
study. Your information and results of tests and procedures are used to: 
ï Do the research 
ï Oversee the research 
ï To see if the research was done right. 
 
Will I receive the results of research testing? 
Most tests done in research studies are only for research and have no clear 
meaning for health care. Research results will not be returned to you 
because they would not be relevant to your health care. 
 
Who may use and share information about me? 
We will do our best to make sure that the personal information obtained 
during the course of this research study will be kept private. However, we 
cannot guarantee total privacy. Your personal information may be given 
out if required by law. If information from this study is published or 
presented at scientific meetings, your name and other personal information 
will not be used. If this study is being overseen by the Food and Drug 
Administration (FDA), they may review your research records. 
 
An exception to confidentiality is if you report child abuse or neglect or if you report current 
suicidal or homicidal ideation of concern to the research team. Any information about child 
abuse or imminent intent to harm yourself or others will be reported to authorities, as required by 
law. 


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If you test positive for hepatitis or human immunodeficiency virus (HIV), by 
law we have to report the positive test results to the City of Philadelphia 
Health Department and/or the PA Department of Health. Personal 
identifiers such as name, sex, date of birth, address, and phone number 
will be reported. For more information about the requirements reporting 
infectious diseases to the City of Philadelphia Health Department, please 
visit https://hip.phila.gov/ReportDisease. For more information about the 
requirements reporting infectious diseases to the PA Health Department, 
please visit http://www.health.pa.gov/Your-Department-of- 
Health/Offices%20and%20Bureaus/epidemiology/Pages/Reportable- 
Diseases.aspx#.V620aZ3D9eU. 
 
 
Once your personal health information is disclosed to others outside the 
School of Medicine, it may no longer be covered by federal privacy 
protection regulations. 
The Principal Investigator or study staff will inform you if there are any 
additions to the list above during your active participation in the trial. Any 
additions will be subject to University of Pennsylvania procedures 
developed to protect your privacy. 
 
How long may the School of Medicine use or disclose my 
personal health information? 
Your authorization for use of your personal health information for this 
specific study does not expire. 
 
Your information may be held in a research database. However, the 
School of Medicine may not re-use or re-disclose information collected in 
this study for a purpose other than this study unless: 
ï You have given written authorization 
ï The University of Pennsylvania’s Institutional Review Board grants 
permission 
ï As permitted by law 
Can I change my mind about giving permission for use of my 
information? 
Yes. You may withdraw or take away your permission to use and disclose 
your health information at any time. You do this by sending written notice 


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to the investigator for the study. 
If you withdraw your permission, you will 
not be able to stay in this study. 
 
What if I decide not to give permission to use and give out 
my health information? 
Then you will not be able to be in this research study. 
 
You will be given a copy of this Research Subject HIPAA Authorization 
describing your confidentiality and privacy rights for this study. 
 
By signing this document you are permitting the School of Medicine to use 
and disclose personal health information collected about you for research 
purposes as described above. 
 
If you decide not to sign this form, it will not affect 
ï Your treatment or the care given by your health provider. 
ï Your insurance payment or enrollment in any health plans. 
ï Any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
ï You authorize the use of your PHI for this research 
ï Your signature and this form will not expire as long as you wish to 
participate. 
ï You may later change your mind and not let the research team use or 
share your information 
 
If you revoke your authorization: 
ï The research team may only use and share information already 
collected for the study. 
ï Your information may still be used and shared if necessary for safety 
reasons. 
ï You will not be allowed to continue to participate in the study. 
Can we contact you by email? 
We would like to contact you by email for the purposes listed below. Some 
of these emails may contain health information that identifies you. 
 
ï 
Setting or verifying your appointment 


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Only the research team will have access to your email communications. 
We will only communicate by email to send you the information listed 
above. For scheduling concerns and questions about participation, please 
call Tommaso Girelli at 215-573-0083. If you have a medical emergency, 
please call 911. 
 
What is an Electronic Medical Record? 
An Electronic Medical Record (EMR) is an electronic version of the record 
of your care within a health system. An EMR is simply a computerized 
version of a paper medical record. 
 
If you are receiving care or have received care within the University of 
Pennsylvania Health System (UPHS) (outpatient or inpatient) and are 
participating in a University of Pennsylvania research study, results of 
research-related procedures (i.e. laboratory tests, imaging studies and 
clinical procedures) may be placed in your existing EMR maintained by 
UPHS. 
 
If you have never received care within UPHS and are participating in a 
University of Pennsylvania research study that uses UPHS services, an 
EMR will be created for you for the purpose of maintaining any results of 
procedures performed as part of this research study. The creation of this 
EMR is required for your participation in this study. In order to create your 
EMR, the study team will need to obtain basic information about you that 
would be similar to the information you would provide the first time you visit 
a hospital or medical facility (i.e. your name, the name of your primary 
doctor, the type of insurance you have). Results of research procedures 
performed as part of your participation in the study (i.e. laboratory tests, 
imaging studies and clinical procedures) may be placed in this EMR. 
 
Once placed in your EMR, these results are accessible to appropriate 
UPHS workforce members that are not part of the research team. 
Information within your EMR may also be shared with others who are 
determined by UPHS to be appropriate to have access to your EMR (e.g. 
health insurance company, disability provider, etc). 


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Who can I call with questions, complaints or if I’m concerned 
about my rights as a research subject? 
For general questions or for scheduling, please call Tommaso Girelli at 
215-573-0083. If you have concerns or complaints regarding your 
participation in this research study or if you have any questions about your 
rights as a research subject, please call Janet Stock at 215-746-5703. If a 
member of the research team cannot be reached or you want to talk to 
someone other than those working on the study, you may contact the 
Office of Regulatory Affairs with any question, concerns or complaints at 
the University of Pennsylvania by calling (215) 898-2614. 
 
Do you agree to be contacted for future studies by the Center for 
Neuromodulation of Depression and Stress? 
 
Yes 
No 
 
 
Initials 
Date 
 
 
 
 
 
 
 
Name of Subject (Please Print) 
 
 
 
 
Signature of Subject 
Date 
When you sign this form, you are agreeing to take part in this 
research study. This means that you have read the consent form, 
your questions have been answered, and you have decided to 
volunteer. Your signature also means that you are permitting the 
University of Pennsylvania to use your personal health information 
collected about you for research purposes within our institution. You 
are also allowing the University of Pennsylvania to disclose that 
personal health information to outside organizations or people 
involved with the operations of this study. 


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Name of Person Obtaining Consent (Please Print) 
 
 
 
 
Signature 
Date 


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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT 
INFORMED CONSENT FORM AND HIPAA 
AUTHORIZATION FORM 
- 
CONTROL CONSENT 
 
Protocol Title: 
Stress and Inflammation in the Pathophysiology of 
Depression 
 
Principal 
Investigator: 
 
 
 
 
 
Center for 
Neuroscience of 
Depression and 
Stress: 
Yvette Sheline, M.D. 
Department of Psychiatry 
University of Pennsylvania 
3700 Hamilton Walk 
Philadelphia, PA 19104-4283 
Email: sheline@pennmedicine.upenn.edu 
 
 
Tommaso Girelli 
Email:Tommaso.girelli@pennmedicine.upenn.edu 
Office Phone: 215-573-0083 (Scheduling/general questions) 
 
Emergency Contact: 
If you have a study related medical emergency, please contact 
the study staff or call 911 
 
 
 
 
 
Why am I being asked to volunteer? 
You are being invited to participate in a research study. We are 
contacting you because you may have an interest in participating. 
Your participation is voluntary, which means you can choose whether 
or not you want to participate. If you choose not to participate, there 
will be no loss of benefits to which you are otherwise entitled. We will 
be recruiting about 100 subjects with depression and 50 subjects with 
no depression who are 18-80 years old to participate. You are being 


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asked to volunteer as a participant in the control group (those with no 
depression). 
 
This consent form describes what this study is about, the possible 
risks and benefits of being in this study, and what we will ask you to 
do. The research team will explain the study and answer any 
questions you may have. You may also discuss it with your family, 
friends, or doctor. You may find some of the medical language 
difficult to understand, so please ask the research team about 
anything you would like to know. If you decide to participate, you will 
be asked to sign this form. 
The National Institute for Health (NIH) is funding this research study. 
 
What is the purpose of this research study? 
 
The purpose of this entire research study is to see if depression over 
a person’s lifetime is related to the amount of inflammation in the 
brain and whether the amount of inflammation affects treatment 
response. We also want to determine whether taking an 
antidepressant alone or with an anti-inflammatory affects the level of 
inflammatory proteins in the body. This information may help us find 
better ways to prevent episodes of depression. 
 
We are asking about 100 depressed and 50 non-depressed people 
aged 18-80 to participate in this study. We would like to investigate 
the effect of taking a certain type of antidepressant medication, 
Selective Serotonin Reuptake Inhibitors (SSRIs), and a non-steroid 
anti-inflammatory on the levels of cytokines, which are inflammatory 
proteins in the body. The specific SSRI used in this study is 
escitalopram. We will ask you not to take any anti-depressant drugs 
or celecoxib, a non-steroid anti-inflammatory drug while you are 
participating in this study. You may use other types of anti 
inflammatory drugs, such as aspirin or ibuprofen, on a per need basis 
only, while you are participating in this study. 
 
We want to compare the brain structure and blood of people without 
depression to those who have depression. 
 
We will ask to take pictures of your brain using a magnetic resonance 
imaging scanner (MRI). MRI scans are commonly used by doctors to 


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look at structures in the body and are generally considered safe (see 
risks and discomforts section below). 
 
You will also be asked to complete two blood draws (in addition to the 
blood draw you had completed at your screening visit) A portion of 
your blood will be saved and banked for use in future data analysis. 
 
How long will I be in the study? 
If you agree to take part in this study, your involvement will include 
several visits over about 6 weeks. Your participation will involve: 
 
o A series of questions about your history and 
neuropsychological tests. This initial visit will last up to 2 
hours. 
o At-home actigraphy, which will not take anytime, you will be 
asked to simply wear an actigraph, which is a watch-like 
device for the course of the study 
o Completing one initial and one final MRI. For both the initial 
and the final MRI you will be in the scanner approximately 1 
hour. 
o Optional saliva swab sample, which will be used for future 
analysis, including DNA analysis 
o Two blood draws, which should take about 5 minutes each 
o A final assessment visit, which involves a physical and 
neuropsychological assessment. This visit will last 
approximately 4 hours. 
 
Stress and Inflammation in the Pathophysiology of Late-Life Depression – 
Schedule of Assessments 
Procedures conducted with all participants 
Procedure 
In-person 
Screen 
Baseline (Wk 
0) 
Wk 6 
Informed Consent 
X 
 
 
Screen, History 
X 
 
 
Blood Draw 
X 
X 
X 
EKG 
X 
 
 
MRI 
 
X 
X 
Psychiatric evaluation 
X 
 
X 


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Neuropsychological tests 
 
X 
X 
At-home actigraphy 
 
X 
X 
Optional Saliva Collection 
 
X 
X 
 
 
What am I being asked to do? 
Neuropsychological testing, Clinical interviewing 
We will conduct neuropsychological tests to assess your attention, 
concentration and memory. We will also ask you questions about 
your medical and psychological history. Some of these questions are 
of a sensitive nature as they inquire about past traumas including 
those of a sexual nature. If you believe you would like counseling 
services in reference to the events inquired about in these surveys 
please contact a member of the research team whose contact 
information is noted on the cover of this document. 
 
MRI scans 
We will ask you to complete 2 MRI scans of your brain. For the MRI, 
you will be asked to lie still on a padded table in the scanner while 
images of your brain are obtained. 
 
Blood Draw 
There will be 2 blood draws. During each blood draw, we will take 
about 2 tablespoons of blood from your arm via a needle. 
 
In the event that we discover any abnormalities in your blood work, 
we will let you know of this. We request permission to contact your 
primary care provider to share the results of your blood work for 
further interpretation and to have follow up procedures to determine 
the accuracy of these findings. Should we receive abnormal results 
from your blood work, we will not include you in the study until we can 
verify the accuracy these results through follow up testing and 
discussions with your primary care provider. The study will not pay 
for the cost of this follow-up blood work or provider visit. 
 
After the blood draw, we will ask you to rest for a little while to ensure 
you are not dizzy. After you have rested, we will discharge you. The 
second blood draw will occur during the same visit as the second MRI 
scan. 


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Cheek swab/saliva sample 
 
We can obtain information about bacteria and health from a saliva 
sample. Your samples may be retained for future analyses that we 
have not yet planned, including DNA analyses. The results of these 
analyses will not be given to you. This is optional. 
 
The cheek swab saliva sample will be stored for future analyses, 
including DNA analysis. This is optional 
 
Vitals 
 
We will record your blood pressure, heart rate, respiration rate, 
and temperature at each study visit. 
 
Actigraphy 
You will be asked to wear an actigraph, a watch-like device that 
monitors your activity. This is optional, and will occur for the duration 
of the study. 
 
What are the possible risks or discomforts? 
You may experience one or more of the risks indicated below from 
being in this study. In addition to these, there may be other unknown 
risks, or risks that we did not anticipate, associated with being in this 
study. If you are injured, you should inform your treating physician 
that you are participating in this study. 
 
Clinical interview and assessment: Some discomfort may be 
associated with the clinical assessments conducted in this study. 
Participants may experience emotional discomfort when answering 
some questions in the questionnaires or when talking about personal 
information. As noted above, some of these questions may be of past 
traumas including those of a sexual nature, therefore, if you feel you 
are in need of counseling services regarding these events, please 
notify a member of the research staff team, and they will provide you 
with information on counseling services. Participants may choose not 
to answer any of the questions. 


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MRI scan: 
Likely/Common: You may experience claustrophobia (fear of 
enclosed spaces and/or anxious feelings accompanied by fast heart 
rate or shortness of breath) within the MRI scanner. In addition, the 
scanner produces a loud repetitive knocking noise during the study 
that some people find bothersome. If you have a problem with feeling 
uncomfortable while inside the scanner you may stop this study. To 
lessen the noise, earplugs will be provided. The picture below 
provides an example of a standard 64-channel head coil that will be 
placed on your head during the MRI scan. This coil is made for you to 
be able to look at the screen while being inside the MRI scanner. 
 
Picture by Siemens Healthcare GmbH ©2020 
 
 
Rare: 
ï Implanted medical devices and metallic foreign fragments 
inside your body may pose a risk if you were to enter the MRI 
magnet room. Devices such as Pacemakers, Internal Cardiac 
Defibrillators, Insulin Pumps, and other medical devices may 
also prevent you from safely having the MRI. Therefore, 
questions regarding medical and work history will be asked 
prior to your exam. Patients who have metallic devices in their 
bodies will not be permitted to be scanned using MRI. There 
are no known risk factors associated with MRI scans for healthy 
subjects. 
 


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ï It is possible that during the course of the research study, the 
research staff may notice an unexpected finding(s). Should this 
occur, the finding(s) will be considered by the appropriate 
personnel and the PI will inform you if necessary. These 
possible finding(s) may or may not be significant and may lead 
to anxiety about your condition and to further work-up by your 
physician. 
ï Although there are no known risks related to MRI on pregnant 
women or a fetus, there is a possibility of yet undiscovered 
pregnancy related risks. Since there is no possible benefit from 
participating in this protocol for a pregnant woman, we will 
exclude pregnant women. A negative pregnancy test will be 
required before a woman of child-bearing potential can 
participate in this study. 
 
Blood draw: 
Likely/Common: 
ï There is a slight risk of bruising and infection at the site of the 
blood draw, as well as some discomfort during the blood draw. 
 
Actigraphy 
There are no known risks of wearing an activity monitor. 
 
Optional Saliva Collection and Saliva Cheek Swab Collection 
Saliva collection is one way in which we can collect DNA. Your 
samples may be retained for future analyses that we have not yet 
planned, including DNA analyses. The results of these analyses will 
not be given to you. We do not anticipate risks due to the saliva 
collection. 
 
Risk of Breach of Confidentiality: There is a rare risk of breach of 
confidentiality. Breaches in confidentiality could impact future 
insurability and/or employability. 
 
Future Use of Data and/or Specimens 
Your information and samples will be de-identified. De-identified 
means that all identifiers have been removed. The information and 
samples could be stored and shared for future research in this de- 


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identified fashion. It would not be possible for future researchers to 
identify you as we would not share any identifiable information about 
you with future researchers. This can be done without again seeking 
your consent in the future, as permitted by law. The future use of your 
information and samples only applies to the information and samples 
collected on this study. 
 
What if new information becomes available about the 
study? 
During the course of this study, we may find more information that 
could be important to you. This includes information that, once 
learned, might cause you to change your mind about being in the 
study. We will notify you as soon as possible if such information 
becomes available. 
 
What are the possible benefits of the study? 
You are not expected to get any benefit from being in this research 
study. We hope that in the future, other people might benefit from this 
study because it has the potential to greatly increase our knowledge 
in the treatment and prevention of depression. 
What other choices do I have if I do not participate? 
This is a voluntary study. You are not being treated for any condition; 
therefore, you do not need to seek alternate treatment if you choose 
not to participate. 
 
Will I be paid for being in this study? 
You will receive a total payment of $120 throughout the course of the 
entire study(including the $10 for the screening visit blood draw). If 
you choose to withdraw before the end, you will be paid incrementally 
in proportion to the degree of your participation and according to this 
schedule: 
 
Initial assessment & consent process = $20; 
Baseline MRI = $20; 


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Baseline Blood Draw = $10; 
Final MRI and Blood Draw = $35; 
Final psychological assessment = $25; 
 
Optional Saliva Sample Collection = $10 (Total payment becomes 
$130 if you complete this portion) 
 
Your payments will be given to you in the form of a Greenphire 
ClinCard at the end of your study participation. This is a reloadable 
prepaid card (similar to a debit/credit card) which allows funds to be 
available immediately. You can use it for in-store or online purchases 
by selecting the “Credit” option at check-out, or it can be cashed out 
by presenting to a teller at any MasterCard member bank (look for a 
MC logo on the bank window). Study staff will provide you with a 
“ClinCard Cardholder FAQ: US” document to help answer any 
questions you may have. 
 
Please note: In order to be compensated for your participation in this 
study, you must provide your Social Security Number. Additionally, 
please note that the University of Pennsylvania is required to report to 
the IRS any cumulative payments for participation in research studies 
that exceed a total of $600 in a calendar year. 
 
If you drive, we will provide you a parking voucher to make the 
parking free. We cannot reimburse for the cost of gas. If you take 
public transportation (i.e. SEPTA Regional Rail or Norristown High 
Speed Line), we can provide up to $5 on your ClinCard per visit. If 
your transportation cost is greater than $5, we will still reimburse you 
up to $10, but we require a receipt. 
 
Will I have to pay for anything? 
You will not have any costs for participating in this research study. 
The administration of all procedures will be covered by the study. The 
scans, 2 blood draws, and any associated costs will be covered by 
the study. 
What happens if I am injured from being in the study? 


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We will offer you the care needed to treat injuries directly resulting 
from taking part in this research. We may bill your insurance 
company or other third parties, if appropriate, for the costs of the care 
you get for the injury, but you may also be responsible for some of 
them. 
 
There are no plans for the University of Pennsylvania to pay you or 
give you other compensation for the injury. You do not give up your 
legal rights by signing this form. 
 
This research may involve risks that are currently unforeseeable. 
University of Pennsylvania investigators and staff will try to reduce, 
control, and treat any complications from this research. If you feel you 
are injured because of the study, please contact the investigator, Dr. 
Yvette Sheline at 215-573-0085. 
 
When is the Study over? Can I leave the Study before it 
ends? 
 
This study is expected to end after all participants have completed all 
visits, and all information has been collected. However, your 
personal participation in the study will probably last approximately 6 
weeks. This study may be stopped by you or your physician at any 
time. It may also be stopped by the Principal Investigator, the study 
Sponsor, or the Food and Drug Administration (FDA) without your 
consent if: 
ï The Principal Investigator feels it is necessary for your health or 
safety. Such an action would not require your consent, but 
you will be informed if such a decision is made and the reason 
for this decision. 
ï You have not followed study instructions. 
ï The Sponsor, the study Principal Investigator has decided to 
stop the study. 
If you decide to participate, you are free to leave the study at any 
time. There are no medical risks involved in the early termination of 
this study. Withdrawal will not interfere with your future care. 


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Who can see or use my information? How will my 
personal information be protected? 
 
We will do our best to make sure that the personal information 
obtained during the course of this research study will be kept private. 
However, we cannot guarantee total privacy. 
 
An exception to confidentiality is if you report child abuse or neglect or if you 
report current suicidal or homicidal ideation of concern to the research team. Any 
information about child abuse or imminent intent to harm yourself or others will 
be reported to authorities, as required by law. 
 
We will keep your participation in this research study confidential to 
the extent permitted by law. However, it is possible that other people 
such as those indicated below may become aware of your 
participation in this study and may inspect and copy records 
pertaining to this research. Some of these records could contain 
information that personally identifies you. 
ï Government representatives, (including the funding sponsor 
(NIH) and the Office for Human Research Protections) to 
complete federal or state responsibilities 
ï The U.S. Food and Drug Administration 
ï Hospital or University representatives, to complete Hospital 
or University responsibilities 
ï University Pennsylvania’s Institutional Review Board (a 
committee that oversees the conduct of research involving 
human participants.) The Institutional Review Board has 
reviewed and approved this study. 
ï Representatives from collaborating institutions 
 
To help protect your confidentiality, your data will only be transported 
by qualified study team members, and only during actual subject 
participation. Once all hard copy records are collected, they will be 
kept in a double-locked environment. Data collected during the study 
will be entered and stored in a password-protected database, 
accessible only to engaged study members. Electronic records will 
not be transported via external drives or any other means. All 
biological samples will be transported by trained members of the 
research team directly to the appropriate facility where processing 


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and analysis of the samples will take place. All samples will only be 
identified by the participants’ randomly generated study ID number, 
and the date and time of the sample collection. If we write a report or 
article about this study or share the study data set with others, we will 
do so in such a way that you cannot be directly identified. 
 
Protected Health Information (PHI) is health information that identifies 
you. PHI is protected by federal law under HIPAA (the Health 
Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and 
disclose (share) your PHI for the study as explained in this consent 
form. 
Once your health information is shared with someone outside of the 
research team, it may no longer be protected by HIPAA. 
 
The research team will only use and share your information as talked 
about in this form. When possible, the research team will make sure 
information cannot be linked to you (de-identified). Once information 
is de-identified, it may be used and shared for other purposes not 
discussed in this consent form. 
 
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 information about me may be collected, used or 
shared with others? 
During your participation, you will be asked to provide your name, 
address, telephone number, email address, and your social security 
number (so that we may issue you a check to compensate you for 
participation). We will also obtain or create a medical record number 
(in the event that we need to order procedures and to access your 
medical records to collect information about your medical history). 
This identifiable information will be held in strict confidence and will 
be kept in password protected files behind locked doors. Your 
personally identifying information will not be linked to any of the data 
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reported. You will also be asked to answer questions about your 
medical history including questions about your physical and mental 
health. Information from your medical charts will be reviewed and 
documented for research purposes. Results from physical exams and 
cognitive assessments will be part of the research record. All 
research data will be de-identified and assigned a randomly 
generated research identification number. All information obtained will 
be kept completely confidential and will be in locked files behind 
locked doors. Electronic data will be encrypted and password 
protected. 
 
What may happen to my information and samples 
collected on this study? 
The data/sample was collected knowing the identity of the subject, 
but identifiers were removed. All samples will only be identified by the 
participants’ randomly generated study ID number, and the date and 
time of the sample collection. If we write a report or article about this 
study or share the study data set with others, we will do so in such a 
way that you cannot be directly identified 
 
Your samples may be used to create products, including some that 
may be sold and/or make money for others. If this happens, there are 
no plans to tell you, or to pay you, or to give any compensation to you 
or your family. 
 
Whole genome sequencing will not be conducted on your samples. 
Whole genome sequencing involves analyzing your entire personal 
genetic code. 
 
 
 
Why is my information being used? 
 
Your information is used by the research team to contact you during 
the study. Your information and results of tests and procedures are 
used to: 
ï Do the research 
ï Oversee the research 
ï To see if the research was done right. 


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Will I receive the results of research testing? 
Most tests done in research studies are only for research and have 
no clear meaning for health care. Research results will not be 
returned to you because they would not be relevant to your health 
care. 
 
How long may the School of Medicine use or disclose 
my personal health information? 
 
Your authorization for use of your personal health information for this 
specific study does not expire. 
 
Your information may be held in a research database. However, the 
School of Medicine may not re-use or re-disclose information 
collected in this study for a purpose other than this study unless: 
ï You have given written authorization 
ï The University of Pennsylvania’s Institutional Review Board 
grants permission 
ï As permitted by law 
Can I change my mind about giving permission for use 
of my information? 
 
Yes. You may withdraw or take away your permission to use and 
disclose your health information at any time. You do this by sending 
written notice to the investigator for the study. If you withdraw your 
permission, you will not be able to stay in this study. 
 
What if I decide not to give permission to use and give 
out my health information? 
Then you will not be able to be in this research study. 
You will be given a copy of this Research Subject HIPAA 
Authorization describing your confidentiality and privacy rights for this 
study. 


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By signing this document you are permitting the School of Medicine 
to use and disclose personal health information collected about you 
for research purposes as described above. 
 
If you decide not to sign this form, it will not affect 
ï Your treatment or the care given by your health provider. 
ï Your insurance payment or enrollment in any health plans. 
ï Any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
ï You authorize the use of your PHI for this research 
ï Your signature and this form will not expire as long as you wish 
to participate. 
ï You may later change your mind and not let the research team 
use or share your information 
 
If you revoke your authorization: 
ï The research team may only use and share information already 
collected for the study. 
ï Your information may still be used and shared if necessary for 
safety reasons. 
ï You will not be allowed to continue to participate in the study. 
Can we contact you by email? 
 
We would like to contact you by email for the purposes listed below. 
Some of these emails may contain information that identifies you. 
 
ï Setting or verifying your appointment 
 
Only the research team will have access to your email 
communications. We will only communicate by email to send you the 
information listed above. 
 
What is an Electronic Medical Record? 


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An Electronic Medical Record (EMR) is an electronic version of the 
record of your care within a health system. An EMR is simply a 
computerized version of a paper medical record. 
 
If you are receiving care or have received care within the University of 
Pennsylvania Health System (UPHS) (outpatient or inpatient) and are 
participating in a University of Pennsylvania research study, results 
of research-related procedures (i.e. laboratory tests, imaging studies 
and clinical procedures) may be placed in your existing EMR 
maintained by UPHS. 
 
If you have never received care within UPHS and are participating in 
a University of Pennsylvania research study that uses UPHS 
services, an EMR will be created for you for the purpose of 
maintaining any results of procedures performed as part of this 
research study. The creation of this EMR is required for your 
participation in this study. In order to create your EMR, the study 
team will need to obtain basic information about you that would be 
similar to the information you would provide the first time you visit a 
hospital or medical facility (i.e. your name, the name of your primary 
doctor, the type of insurance you have). 
Once placed in your EMR, these results are accessible to appropriate 
UPHS workforce members that are not part of the research team. 
Information within your EMR may also be shared with others who are 
determined by UPHS to be appropriate to have access to your EMR 
(e.g. health insurance company, disability provider, etc). 
 
Who can I call with questions, complaints or if I’m 
concerned about my rights as a research subject? 
 
For general questions or for scheduling, please call Tommaso Girelli 
at 215-573-0083. If you have concerns or complaints regarding your 
participation in this research study or if you have any questions about 
your rights as a research subject, please call Janet Stock at 215-746- 
5703. If a member of the research team cannot be reached or you 
want to talk to someone other than those working on the study, you 
may contact the Office of Regulatory Affairs with any question, 
concerns or complaints at the University of Pennsylvania by calling 
(215) 898-2614. 


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Do you agree to additional blood being collected (~4 tablespoons) 
for additional inflammatory analysis? 
You may still participate in the study if you refuse to submit additional 
blood. 
 
 
Yes 
No 
 
 
 
 
Initials 
Date 
 
 
 
 
Do you agree to submit a saliva cheek swab sample as a part of 
this study? 
You may still participate in the study if you refuse to submit a saliva 
cheek swab sample. 
 
 
Yes 
No 
 
 
 
 
Initials 
Date 
 
 
Do you agree to submit saliva samples at each study visit as a 
part of this study? 
You may still participate in the study if you refuse to submit saliva 
samples. 
 
 
Yes 
No 


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Initials 
Date 
 
 
 
 
 
 
A copy of this consent form will be given to you. 
 
 
 
 
 
Name of Subject (Please Print) 
 
 
 
 
 
Signature of Subject 
Date 
 
 
 
 
 
Name of Person Obtaining Consent (Please Print) 
 
 
 
 
 
 
Signature 
Date 
When you sign this form, you are agreeing to take part in this 
research study. This means that you have read the consent form, 
your questions have been answered, and you have decided to 
volunteer. Your signature also means that you are permitting the 
University of Pennsylvania to use your personal health information 
collected about you for research purposes within our institution. You 
are also allowing the University of Pennsylvania to disclose that 
personal health information to outside organizations or people 
involved with the operations of this study. 


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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT 
INFORMED CONSENT FORM AND HIPAA 
AUTHORIZATION FORM 
– 
STUDY GROUP 
 
Protocol Title: 
Stress and Inflammation in the Pathophysiology of 
Late-Life Depression 
 
Principal 
Investigator: 
 
 
 
 
 
Center for 
Neuroscience of 
Depression and 
Stress: 
Emergency 
Contact: 
Yvette Sheline, M.D. 
Department of Psychiatry 
University of Pennsylvania 
3535 Market St., Suite 676 
Philadelphia, PA 19104-4283 
Email: sheline@pennmedicine.upenn.edu 
 
 
Tommaso Girelli 
Email: Tommaso.girelli@pennmedicine.upenn.eduOffice Phone: 
215-573-0083 (Scheduling/general questions) 
 
If you have a study related medical emergency, please contact the 
study staff or call 911 
 
 
 
 
Why am I being asked to volunteer? 
You are being invited to participate in a research study. We are 
contacting you because you may have an interest in participating. 
Your participation is voluntary, which means you can choose whether 
or not you want to participate. If you choose not to participate, there 
will be no loss of benefits to which you are otherwise entitled. We will 
be recruiting about 100 subjects with depression and 50 subjects 
without depression who are 18-80 years old to participate. 


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This consent form describes what this study is about, the possible 
risks and benefits of being in this study, and what we will ask you to 
do. The research team will explain the study and answer any 
questions you may have. You may also discuss it with your family, 
friends, or doctor. You may find some of the medical language 
difficult to understand, so please ask the research team about 
anything you would like to know. If you decide to participate, you will 
be asked to sign this form. You are being asked to participate as a 
person with depression. 
 
The National Institute for Health (NIH) is funding this research study. 
 
What is the purpose of this research study? 
 
The purpose of this entire research study is to see if depression over 
a person’s lifetime is related to the amount of inflammation in the 
brain and whether the amount of inflammation affects treatment 
response. We also want to determine whether taking an 
antidepressant affects the level of inflammatory proteins in the body. 
This information may help us find better ways to prevent episodes of 
depression. 
 
We are asking about 100 depressed and 50 non-depressed people 
aged 18-80 to participate in this study. We would like to investigate 
the effect of taking a certain type of antidepressant medication, 
Selective Serotonin Reuptake Inhibitors (SSRIs), in combination with 
a non-steroidal anti-inflammatory on the levels of cytokines, which are 
inflammatory proteins in the body and the number of people who stop 
being depressed. The SSRI used in this study is escitalopram, which 
is commonly used in the treatment of depression. This drug is 
approved by the U.S. Food and Drug Administration (FDA) to be 
given to people who meet criteria for major depression. We will ask 
participants to take a dosage of escitalopram over a period of about 6 
weeks. During these 6 weeks you will come in for the same biweekly 
visits to receive the medication. We will also ask participants to take a 
dosage of Celecoxib, which can be used to treat inflammatory illness 
and has been shown to help treat depression when coupled with an 
anti-depressant. This drug is approved by the U.S. FDA to be given to 
people for inflammatory disease. Celecoxib is not used for the 
treatment of depression. Our study is hoping to show that anti- 


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depressant in combination with an anti-inflammatory helps people 
with depression more than an anti-depressant alone. We will ask 
participants to take a dosage of escitalopram + celecoxib over a 
period of about 6 weeks. Another group of participants will receive a 
placebo pill for about 6 weeks. A placebo is a harmless substance 
that does not contain treatment. Following the initial 6 weeks we will 
check to see if you were receiving escitalopram or placebo. If you 
were on placebo and you are still depressed you will offered 
treatment with 6 weeks of escitalopram + celecoxib. 
We will ask to take pictures of your brain using a magnetic resonance 
imaging scanner (MRI). MRI scans are commonly used by doctors to 
look at structures in the body and are generally considered safe (see 
risks and discomforts section below). 
 
You will also be asked to complete three-five blood draws A portion of 
your blood and spinal fluid will be saved and banked for use in future 
data analysis. 
 
How long will I be in the study? 
 
If you agree to take part in this study, your involvement will include 
several visits over about 6-12 weeks. Your participation will involve: 
o A series of questions about your history and 
neuropsychological tests. This initial visit will last up to 1 
hour. 
o Completing one initial, one final MRI at 6 weeks, and an 
additional MRI at Open Label Week 6. For all MRI sessions 
you will be in the scanner approximately 1 hour. 
o Completing 3-5 blood draws (2 of which to assess 
hematocrit levels). Individuals will have the option to provide 
an additional amount of blood for additional inflammatory 
state analyses. 
o You may complete a nutrition assessment at baseline. A 
researcher will help you to recall all of the foods you have 
eaten in the past 24 hours. 
o Optional saliva samples at baseline, week 1, 2, 4, and 6 both 
initially and during open label phase if applicable 


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o At-home actigraphy, which will not take any time, you will be 
asked to simply wear an actigraph, which is a watch-like 
device for the course of the study 
o Optional saliva swab sample, which will be used for future 
analysis, including DNA analysis 
o Taking a daily dose of the antidepressant escitalopram for 
about 6-12 weeks dependent upon which group you are 
initially randomized to. 
o Follow-up visits to check your progress while taking 
escitalopram. There will be 3 follow-up visits over 6 weeks or 
6 follow-up visits over the course of 12 weeks. These visits 
involve a psychological assessment and vitals assessment 
These visits last about 30 minutes each. 
o A final follow-up phone call check-in will be conducted 6 
months after study completion. 
 
Stress and Inflammation in the Pathophysiology of Late-Life Depression – 
Schedule of Assessments 
 
Procedures conducted with all participants 
 
Procedure 
In- 
person 
Screen 
Baseline 
(Wk 0) 
Wk 1 
Wk 2 
Wk 4 
Wk 6 
Optional 6 
month 
follow-up 
Informed Consent 
X 
X 
 
 
 
 
 
Screen, History 
X 
 
 
 
 
X 
Cardiac screening 
and history, EKG, 
nutrition screen 
X 
 
 
 
 
 
Blood Draw 
X 
X 
 
X 
 
X 
 
MRI 
 
X 
 
 
 
X 
 
Neuropsychological 
tests 
 
X 
 
 
 
X 
 
Procedures at weekly visits: 
 
Drug Dispensed 
(Escitalopram + 
celecoxib or 
escitalopram + 
placebo) 
 
X 
X 
X 
X 
X 
 
Psychiatric 
Evaluation 
X 
X 
X 
X 
X 
X 
X 
Vital Signs & 
Physical 
Assessment 
X 
X 
X 
X 
X 
X 
X 


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Blood pressure 
monitoring 
(optional) 
X 
X 
 
 
X 
 
Hematocrit & liver 
function blood test 
 
X 
 
X 
 
 
 
Saliva samples 
(optional) 
 
X 
X 
X 
X 
X 
 
At-home actigraphy  
X 
X 
X 
X 
X 
 
If you complete the study, your depression has not remitted, and you were 
on the escitalopram + placebo, we can offer you six weeks of escitalopram + 
celecoxib, and end your participation or we can keep you enrolled in the study 
and dispense escitalopram + celecoxib in the same way, where you return every 
one-two weeks for more and complete the appropriate assessments for which 
you will be compensated. 
 
 
What am I being asked to do? 
Neuropsychological testing, Clinical interviewing 
 
We will conduct neuropsychological tests to assess your attention, 
concentration and memory. We will also ask you questions about 
your medical and psychological history. Some of these questions are 
of a sensitive nature as they inquire about past traumas including 
those of a sexual nature. If you believe you would like counseling 
services in reference to the events inquired about in these surveys 
please contact a member of the research team whose contact 
information is noted on the cover of this document. 
 
 
MRI scans 
We will ask you to complete 2-3 MRI scans of your brain. For the 
MRI, you will be asked to lie still on a padded table in the scanner 
while images of your brain are obtained. 
 
 
Saliva Sample 
You will provide saliva samples for microbiome analysis. This is 
optional. 
 
Blood Draw 


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We will take about 2 tablespoons of blood from your arm via a 
needle. 
 
If you have a CRP level 2: 3.0mg/L you may be eligible to provide 
additional blood for analyses. The purpose of this additional blood 
collection would be to evaluate an individual’s inflammatory state. 
This additional analyses would require taking an additional ~4 
tablespoons of blood. 
 
After the blood draw, we will ask you to rest for a little while to ensure 
you are not dizzy. After you have rested, we will discharge you. 
 
Administration of escitalopram and celecoxib or escitalopram 
and placebo 
 
Patients will be randomized into one of two groups, those taking 
escitalopram and celecoxib and those taking escitalopram and a 
placebo. Random assignment and chance procedures means that we 
might use methods like flipping a coin to assign participants to a 
particular group. You will be asked to take the assigned medication 
for 6 weeks. The pills are taken orally. The researchers will not know 
if you are receiving the drug or the placebo. 
 
o In one group, participants will take up to 20mg daily dose of 
escitalopram, a commonly used anti-depressant, along with 
celecoxib, a non-steroidal anti-inflammatory, at 400 mg/day for 
6 weeks. 
 
o In the other group, participants will take up to 20 mg daily dose 
of escitalopram, a commonly used anti-depressant, along with a 
placebo. A placebo is a harmless, inactive substance that looks 
like the anti-depressant drug but contains no actual medicine. 
 
You have a 50/50 chance of being assigned to either group. The 
experimenters will dispense the escitalopram or placebo pills to you 
at each visit. You will also receive a paper with instructions on how 
much to take and you will receive phone calls from research staff to 
make sure that you understand the procedures and the dosing 
schedule, as well as to evaluate whether or not any drug related side 


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effects are occurring. The physician may adjust the dosage you 
receive. 
 
When you have completed the study, the researchers will determine 
which group you were assigned to and they will share this information 
with you. Those receiving escitalopram + placebo who are still 
depressed at the end of the initial phase will be offered treatment with 
escitalopram + celecoxib following the same dosing schedule as 
participants who received escitalopram + celecoxib initially (200 mg in 
AM, 200 mg in PM). These participants will not re-complete the 
baseline visits, but will be asked to return for drug visits again (weeks 
1, 2, and 4) as well as final visits (LP/blood draw and 
MRI/neurocognitive testing). 
 
Blood Pressure Monitoring 
You may be asked to participate in continuous 24-hour ambulatory 
blood pressure monitoring (ABPM) before the start of the study to 
establish a baseline, one to two weeks after the start of the study; 
and at the end of the study. This will involve taking home a blood 
pressure monitoring device for 24 hours. During a 24-hour period you 
will wear a blood-pressure monitoring cuff around your non-dominant 
arm connected to a recorder, please see picture below, which will be 
for example attached to your belt. The cuff will self-inflate and take 
your blood pressure and heart rate every 20 minutes during the day 
(6 am-10 pm) and every 30 minutes at night (10 pm-6 am). 
 
We will ask you to keep a diary of your activities during this time, 
most importantly we need to know the times when you fall asleep and 
when you wake up. 
 
Urine Samples 


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Urine spot samples may be collected at biweekly visits. We will look 
in these samples for breakdown products of fats associated with the 
drug effects of celecoxib. This is optional. 
 
Liver Function Test (LFT) 
Celecoxib has been associated with increased risk for people with 
hepatic (liver) impairment. At the baseline visit of the study, we will 
draw blood to perform a liver function test. If your liver is found to be 
impaired, you will no longer be able to participate in this study. 
 
Hematocrit Blood Test 
Celecoxib has been associated with an increased risk for bleeding in 
the stomach and/or small or large intestine. At the baseline/screening 
for the study, one or two weeks into the study, and at the end of this 
phase, we will test if your hematocrit levels are decreased in a blood 
sample. This test are important to look for possible bleeding in your 
digestive system. We will explain how this test works and what kind of 
foods, red meat or radish for example, not to eat before the test. If 
hematocrit levels are abnormal, you may not be able to participate in 
the study or if this occurs during the study we have to consider 
discontinuing your participation. 
 
Cheek swab/saliva sample 
 
We can obtain information about bacteria and health from a saliva 
sample. Your samples may be retained for future analyses that we 
have not yet planned, including DNA analyses. The results of these 
analyses will not be given to you. This is optional. 
 
The cheek swab saliva sample will be stored for future analyses, 
including DNA analysis. This is optional 
 
Actigraphy 
You will be asked to wear an actigraph, a watch-like device that 
monitors your activity. This will occur for the duration of the study. 
 
Vitals 
 
We will record your blood pressure, heart rate, respiration rate, 
and temperature at each study visit. 


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What are the possible risks or discomforts? 
You may experience one or more of the risks indicated below from 
being in this study. In addition to these, there may be other unknown 
risks, or risks that we did not anticipate, associated with being in this 
study. If you are injured, you should inform your treating physician 
that you are participating in this study. 
 
Clinical interview and assessment: Some discomfort may be 
associated with the clinical assessments conducted in this study. 
Participants may experience emotional discomfort when answering 
some questions in the questionnaires or when talking about personal 
information. As noted above, some of these questions may be of 
past traumas including those of a sexual nature, therefore, if you feel 
you are in need of counseling services regarding these events, 
please notify a member of the research staff team, and they will 
provide you with information on counseling services. Participants 
may choose not to answer any of the questions. 
 
MRI scan: 
Likely/Common: You may experience claustrophobia (fear of 
enclosed spaces and/or anxious feelings accompanied by fast heart 
rate or shortness of breath) within the MRI scanner. In addition, the 
scanner produces a loud repetitive knocking noise during the study 
that some people find bothersome. If you have a problem with feeling 
uncomfortable while inside the scanner you may stop this study. To 
lessen the noise, earplugs will be provided. The picture below 
provides an example of a standard 64-channel head coil that will be 
placed on your head during the MRI scan. This coil is made for you to 
be able to look at the screen while being inside the MRI scanner. 


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Picture by Siemens Healthcare GmbH ©2020 
 
 
Rare: 
ï Implanted medical devices and metallic foreign fragments 
inside your body may pose a risk if you were to enter the MRI 
magnet room. Devices such as Pacemakers, Internal Cardiac 
Defibrillators, Insulin Pumps, and other medical devices may 
also prevent you from safely having the MRI. Therefore, 
questions regarding medical and work history will be asked 
prior to your exam. Patients who have metallic devices in their 
bodies will not be permitted to be scanned using MRI. There 
are no known risk factors associated with MRI scans for healthy 
subjects. 
ï It is possible that during the course of the research study, the 
research staff may notice an unexpected finding(s). Should this 
occur, the finding(s) will be considered by the appropriate 
personnel and the PI will inform you if necessary. These 
possible finding(s) may or may not be significant and may lead 
to anxiety about your condition and to further work-up by your 
physician. 
ï Although there are no known risks related to MRI on pregnant 
women or a fetus, there is a possibility of yet undiscovered 
pregnancy related risks. Since there is no possible benefit from 
participating in this protocol for a pregnant woman, we will 
exclude pregnant women. A negative pregnancy test will be 


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required before a woman of child-bearing potential can 
participate in this study. 
ï A MRI scan requires you to be in a partially enclosed space 
inside the scanner. Some people may find this to be 
uncomfortable and claustrophobic. You need to inform the 
doctor ordering the scan, or the study staff, if you suffer from 
claustrophobia. The MRI scanner produces different types of 
noises during a scan. Since the noise level can be loud, you 
may be given special earplugs to reduce the noise. The MRI 
scanner has an intercom which allows the technologist to talk to 
you and to hear you during the scan. You will be able to hear 
the technologist talking to you during the scan even if you wear 
earplugs. 
 
ï A MRI scanner has a strong magnet which attracts certain 
metals. If anyone has these types of metal in their body, the 
MRI’s strong magnetic field can cause them to move which may 
cause injury. The MRI will not be performed on anyone having 
these types of metal in their body. To prevent an injury, you will 
be asked questions or given a form requesting information 
about any metal in your body and if you work with metals. 
Some dyes in tattoos and permanent eyeliner contain metals 
which may move during the MRI scan causing the area with the 
tattoo to become irritated and swollen. 
 
ï No metal objects are allowed to be brought into the MRI scan 
room at any time, because the MRI magnet will quickly and 
strongly pull those items into the scanner. To prevent any 
injury to patients and staff and any damage to the MRI scanner, 
you will be asked to remove all jewelry and clothing containing 
metal before you enter the MRI scan room. Also, since the MRI 
magnet will erase credit cards, they must not be taken into the 
scan room. Once you are positioned in the scanner, the door to 
the room will be closed to prevent anyone with any metal object 
entering the scan room. 
 
ï Before you are scanned, you must tell the MRI technologist if 
there is any chance that you may be pregnant. Your pregnancy 
status needs to be determined. If you are pregnant, then 
consultation with your physician is required before having an 


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MRI scan. You should provide your physician with a copy of this 
research protocol. 
 
 
 
Blood draw: 
Likely/Common: 
ï There is a slight risk of bruising and infection at the ite of the 
blood draw, as well as some discomfort during the blood draw. 
 
Risk of Breach of Confidentiality: There is a rare risk of breach of 
confidentiality. Breaches in confidentiality could impact future 
insurability and/or employability. 
 
Escitalopram: 
Likely/ Common: 
Nausea, sleepiness, headache, dizziness, tremor, diarrhea, 
nervousness, dry mouth, increased sweating, insomnia, and 
ejaculation failure. 
 
Less common: 
Rash, agitation, decreased sex drive, vomiting, stomach upset, and 
fatigue. 
 
Rare: 
Constipation, loss of appetite, and vision abnormalities, which may 
include blurred vision and sensitivity to light. 
 
Abrupt cessation of taking Escitalopram may cause withdrawal 
symptoms such as dysphoric mood, irritability, agitation, dizziness, 
anxiety, confusion, headache, and lethargy. To prevent this, a 
tapered dose will be provided following the final LP. 
 
Celecoxib: 
Celecoxib has been associated with an increased risk of 
cardiovascular events in people with cardiovascular disease. To 
minimize this risk we are excluding anyone with significant 
cardiovascular risk factors. We have included a consultant on the 
study who is an expert in the use of celecoxib. 


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Celecoxib has also been associated with increased risk for 
gastrointestinal bleeding and liver failure. For this reason, you must 
tell us if you have a history of ulcers or GI bleeding. We will ask you 
not to participate if you have impaired liver function. 
 
Likely/Common: upset stomach, diarrhea, bloating, gas, dizziness, 
nervousness, headache, runny or stuffy nose, sore throat, mild skin 
rash. 
 
Less common: Chest pain, weakness, shortness of breath, slurred 
speech, vision or balance problems, discolored stools, coughing up 
blood, vomit, unusual weight gain, decrease in urination frequency, 
jaundice, loss of appetite, discolored urine, severe skin reaction. 
 
Rare: Heart attack, intestinal obstruction or perforation, 
gastrointestinal bleeding, liver or kidney failure. 
 
Actigraphy 
There are no known risks of wearing an activity monitor. 
 
Optional Saliva Collection 
We do not anticipate risks due to the saliva collection. 
 
Future Use of Data and/or Specimens 
Your information and samples will be de-identified. De-identified 
means that all identifiers have been removed. The information [and 
samples] could be stored and shared for future research in this de- 
identified fashion. It would not be possible for future researchers to 
identify you as we would not share any identifiable information about 
you with future researchers. This can be done without again seeking 
your consent in the future, as permitted by law. The future use of your 
information and samples only applies to the information and samples 
collected on this study. 
 
What if new information becomes available about the 
study? 


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During the course of this study, we may find more information that 
could be important to you. This includes information that, once 
learned, might cause you to change your mind about being in the 
study. We will notify you as soon as possible if such information 
becomes available. 
 
What are the possible benefits of the study? 
Participants who receive escitalopram during the course of the study 
may experience mental health benefits such as alleviation from 
depression. However, not all depressed participants are expected to 
experience benefits from being in this research study. Participants 
receiving celecoxib may experience additional alleviation from 
depression as well as a decrease in inflammatory disease. 
 
In the future, other people might benefit from this study because it 
has the potential to greatly increase our knowledge in the treatment 
and prevention of depression. 
What other choices do I have if I do not participate? 
This is a voluntary study. If you choose not to participate, you may 
seek information about other alternatives and treatments available by 
discussing options with your personal physician. 
 
Will I be paid for being in this study? 
Yes, the amount you are compensated will depend on whether or not 
you complete all study visits. If you complete all visits without the 
optional 6-month follow-up, additional blood, or saliva samples you 
will be paid $125 in total (including the $10 received after completion 
of the blood draw at the screening visit). If you choose to withdraw 
before the end, you will be paid incrementally in proportion to the 
degree of your participation and according to this schedule: 
 
 
Initial assessment & full study consent process = $20 
Baseline MRI = $20 
Baseline Blood Draw = $10; Drug visits = $5 each 


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Final MRI = $25; 
Week 6 Blood Draw = $10; 
Final cognitive & psychological assessments = $25; 
Optional additional blood collection = $50 (with saliva payment 
becomes $195; without saliva = $175) 
Optional saliva samples ($20) (without optional blood collection 
payment becomes $145 with this option) 
Optional 6-month follow up- $20 (upon completion of follow-up) 
If you initially receive escitalopram and placebo and do not remit, you 
will be eligible to participate in the open-label phase of the study. If 
you complete all study visits you will receive an additional $95. In this 
phase you will receive the escitalopram and celecoxib and be 
compensated according to this schedule: 
Drug Visits- $5 each 
Final cognitive and psychological assessments- $25 
Final MRI- $25 
Blood Draw- $10 
Optional Saliva Collection- $20 
 
 
Your payments will be given to you in the form of a Greenphire 
ClinCard at the end of your study participation. This is a reloadable 
prepaid card (similar to a debit/credit card) which allows funds to be 
available immediately. You can use it for in-store or online purchases 
by selecting the “Credit” option at check-out, or it can be cashed out 
by presenting to a teller at any MasterCard member bank (look for a 
MC logo on the bank window). Study staff will provide you with a 
“ClinCard Cardholder FAQ: US” document to help answer any 
questions you may have. 
 
 
Please note: In order to be compensated for your participation in this 
study, you must provide your Social Security Number. Additionally, 
please note that the University of Pennsylvania is required to report to 


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the IRS any cumulative payments for participation in research studies 
that exceed a total of $600 in a calendar year. 
 
If you drive, we will provide you a parking voucher to make the 
parking free. We cannot reimburse for the cost of gas. If you take 
public transportation (i.e. SEPTA Regional Rail or Norristown High 
Speed Line), we can provide up to $5 on the ClinCard per visit. If your 
transportation cost is greater than $5, we will still reimburse you up to 
$10, but we require a receipt. 
 
Will I have to pay for anything? 
You will not have any costs for participating in this research study. 
The administration of all procedures will be covered by the study. The 
scans, blood draws, and any associated costs will be covered by the 
study. 
What happens if I am injured from being in the study? 
We will offer you the care needed to treat injuries directly resulting 
from taking part in this research. We may bill your insurance 
company or other third parties, if appropriate, for the costs of the care 
you get for the injury, but you may also be responsible for some of 
them. 
 
There are no plans for the University of Pennsylvania to pay you or 
give you other compensation for the injury. You do not give up your 
legal rights by signing this form. 
 
This research may involve risks that are currently unforeseeable. 
University of Pennsylvania investigators and staff will try to reduce, 
control, and treat any complications from this research. If you feel you 
are injured because of the study, please contact the investigator, Dr. 
Yvette Sheline at 215-573-0083. 
 
When is the Study over? Can I leave the Study before it 
ends? 


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This study is expected to end after all participants have completed all 
visits, and all information has been collected. However, your 
personal participation in the study will probably last approximately 6- 
12 weeks dependent on whether you receive escitalopram + placebo 
initially. This study may be stopped by you or your physician at any 
time. It may also be stopped by the Principal Investigator, the study 
Sponsor, or the Food and Drug Administration (FDA) without your 
consent if: 
ï The Principal Investigator feels it is necessary for your health 
or safety. Such an action would not require your consent, but 
you will be informed if such a decision is made and the reason 
for this decision. 
ï You have not followed study instructions. 
ï The Sponsor, the study Principal Investigator has decided to 
stop the study. 
If you decide to participate, you are free to leave the study at any 
time. There are no medical risks involved in the early termination of 
this study. Withdrawal will not interfere with your future care. 
 
Who can see or use my information? How will my 
personal information be protected? 
We will do our best to make sure that the personal information 
obtained during the course of this research study will be kept private. 
However, we cannot guarantee total privacy. 
 
An exception to confidentiality is if you report child abuse or neglect or if you 
report current suicidal or homicidal ideation of concern to the research team. Any 
information about child abuse or imminent intent to harm yourself or others will 
be reported to authorities, as required by law. 
 
 
 
We will keep your participation in this research study confidential to 
the extent permitted by law. However, it is possible that other people 
such as those indicated below may become aware of your 
participation in this study and may inspect and copy records 
pertaining to this research. Some of these records could contain 
information that personally identifies you. 


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ï Government representatives, (including the funding sponsor 
(NIH) and the Office for Human Research Protections) to 
complete federal or state responsibilities 
ï The U.S. Food and Drug Administration 
ï Hospital or University representatives, to complete Hospital or 
University responsibilities 
ï University Pennsylvania’s Institutional Review Board (a 
committee that oversees the conduct of research involving 
human participants.) The Institutional Review Board has 
reviewed and approved this study. 
ï Representatives from collaborating institutions 
 
To help protect your confidentiality, your data will only be transported 
by qualified study team members, and only during actual subject 
participation. Once all hard copy records are collected, they will be 
kept in a double-locked environment. Data collected during the study 
will be entered and stored in a password-protected database, 
accessible only to engaged study members. Electronic records will 
not be transported via external drives or any other means. All 
biological samples will be transported by trained members of the 
research team directly to the appropriate facility where processing 
and analysis of the samples will take place. All samples will only be 
identified by the participants’ randomly generated study ID number, 
and the date and time of the sample collection. If we write a report or 
article about this study or share the study data set with others, we will 
do so in such a way that you cannot be directly identified. 
 
Protected Health Information (PHI) is health information that identifies 
you. PHI is protected by federal law under HIPAA (the Health 
Insurance Portability and Accountability Act). To take part in this 
research, you must give the research team permission to use and 
disclose (share) your PHI for the study as explained in this consent 
form. 
Once your health information is shared with someone outside of the 
research team, it may no longer be protected by HIPAA. 
 
The research team will only use and share your information as talked 
about in this form. When possible, the research team will make sure 
information cannot be linked to you (de-identified). Once information 


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is de-identified, it may be used and shared for other purposes not 
discussed in this consent form. 
 
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 information about me may be collected, used or 
shared with others? 
During your participation, you will be asked to provide your name, 
address, telephone number, email address, and your social security 
number (so that we may issue you a check to compensate you for 
participation). We will also obtain or create a medical record number 
(in the event that we need to order procedures and to access your 
medical records to collect information about your medical history). 
This identifiable information will be held in strict confidence and will 
be kept in password protected files behind locked doors. Your 
personally identifying information will not be linked to any of the data 
that is analyzed and reported. All data will be de-identified when 
reported. You will also be asked to answer questions about your 
medical history including questions about your physical and mental 
health. Information from your medical charts will be reviewed and 
documented for research purposes. Results from physical exams and 
cognitive assessments will be part of the research record. All 
research data will be de-identified and assigned a randomly 
generated research identification number. All information obtained will 
be kept completely confidential and will be in locked files behind 
locked doors. Electronic data will be encrypted and password 
protected. 
 
What may happen to my information and samples 
collected on this study? 
The data/sample was collected knowing the identity of the subject, 
but identifiers were removed. All samples will only be identified by the 
participants’ randomly generated study ID number, and the date and 
time of the sample collection. If we write a report or article about this 


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study or share the study data set with others, we will do so in such a 
way that you cannot be directly identified 
 
Your samples may be used to create products, including some that 
may be sold and/or make money for others. If this happens, there are 
no plans to tell you, or to pay you, or to give any compensation to you 
or your family. 
 
Whole genome sequencing will not be conducted on your samples. 
Whole genome sequencing involves analyzing your entire personal 
genetic code. 
 
Why is my information being used? 
Your information is used by the research team to contact you during 
the study. Your information and results of tests and procedures are 
used to: 
ï Do the research 
ï Oversee the research 
ï To see if the research was done right. 
Will I receive the results of research testing? 
Most tests done in research studies are only for research and have 
no clear meaning for health care. Research results will not be 
returned to you because they would not be relevant to your health 
care. 
 
How long may the School of Medicine use or disclose 
my personal health information? 
Your authorization for use of your personal health information for this 
specific study does not expire. 
 
Your information may be held in a research database. However, the 
School of Medicine may not re-use or re-disclose information 
collected in this study for a purpose other than this study unless: 
ï You have given written authorization 


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ï The University of Pennsylvania’s Institutional Review Board 
grants permission 
ï As permitted by law 
Can I change my mind about giving permission for use 
of my information? 
Yes. You may withdraw or take away your permission to use and 
disclose your health information at any time. You do this by sending 
written notice to the investigator for the study. If you withdraw your 
permission, you will not be able to stay in this study. 
 
What if I decide not to give permission to use and give 
out my health information? 
Then you will not be able to be in this research study. 
You will be given a copy of this Research Subject HIPAA 
Authorization describing your confidentiality and privacy rights for this 
study. 
 
By signing this document you are permitting the School of Medicine 
to use and disclose personal health information collected about you 
for research purposes as described above. 
 
If you decide not to sign this form, it will not affect 
ï Your treatment or the care given by your health provider. 
ï Your insurance payment or enrollment in any health plans. 
ï Any benefits to which you are entitled. 
However, it will not be possible for you to take part in the study. 
 
If you sign this form: 
ï You authorize the use of your PHI for this research 
ï Your signature and this form will not expire as long as you wish 
to participate. 
ï You may later change your mind and not let the research team 
use or share your information 
 
If you revoke your authorization: 


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ï The research team may only use and share information already 
collected for the study. 
ï Your information may still be used and shared if necessary for 
safety reasons. 
ï You will not be allowed to continue to participate in the study. 
Can we contact you by email? 
We would like to contact you by email for the purposes listed below. 
Some of these emails may contain information that identifies you. 
 
ï 
Setting or verifying your appointment 
 
Only the research team will have access to your email 
communications. We will only communicate by email to send you the 
information listed above. 
 
What is an Electronic Medical Record? 
An Electronic Medical Record (EMR) is an electronic version of the 
record of your care within a health system. An EMR is simply a 
computerized version of a paper medical record. 
 
If you are receiving care or have received care within the University of 
Pennsylvania Health System (UPHS) (outpatient or inpatient) and are 
participating in a University of Pennsylvania research study, results 
of research-related procedures (i.e. laboratory tests, imaging studies 
and clinical procedures) may be placed in your existing EMR 
maintained by UPHS. 
 
If you have never received care within UPHS and are participating in 
a University of Pennsylvania research study that uses UPHS 
services, an EMR will be created for you for the purpose of 
maintaining any results of procedures performed as part of this 
research study. The creation of this EMR is required for your 
participation in this study. In order to create your EMR, the study 
team will need to obtain basic information about you that would be 
similar to the information you would provide the first time you visit a 
hospital or medical facility (i.e. your name, the name of your primary 
doctor, the type of insurance you have). 


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Once placed in your EMR, these results are accessible to appropriate 
UPHS workforce members that are not part of the research 
team. Information within your EMR may also be shared with others 
who are determined by UPHS to be appropriate to have access to 
your EMR (e.g. health insurance company, disability provider, etc). 
 
Who can I call with questions, complaints or if I’m 
concerned about my rights as a research subject? 
For general questions or for scheduling, please call Tommaso Girelli 
at 215-573-0083. If you have concerns or complaints regarding your 
participation in this research study or if you have any questions about 
your rights as a research subject, please call Janet Stock at 215-746- 
5703 If a member of the research team cannot be reached or you 
want to talk to someone other than those working on the study, you 
may contact the Office of Regulatory Affairs with any question, 
concerns or complaints at the University of Pennsylvania by calling 
(215) 898-2614. 
 
 
 
 
Do you agree to submit a saliva cheek swab sample as a part of 
this study? 
You may still participate in the study if you refuse to submit a saliva 
cheek swab sample. 
 
 
Yes 
No 
 
 
 
 
Initials 
Date 
 
 
Do you agree to submit saliva samples at each study visit as a 
part of this study? 
You may still participate in the study if you refuse to submit saliva 
samples. 


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Yes 
No 
 
 
 
 
Initials 
Date 
 
Do you agree to participate in the 6-month follow-up visit ? 
You may still participate in the study if you refuse to participate 
in the 6 month follow-up visit. 
 
 
Yes 
No 
 
 
 
 
Initials 
Date 
If eligible, do you agree to provide the additional blood needed to 
conduct additional inflammatory state analyses? 
You may still participate in the study if you refuse to participate 
in the additional blood collection. 
 
 
 
Yes 
No 
 
 
 
 
Initials 
Date 
 
 
 
 
 
When you sign this form, you are agreeing to take part in this 
research study. This means that you have read the consent form, 
your questions have been answered, and you have decided to 
volunteer. Your signature also means that you are permitting the 


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A copy of this consent form will be given to you. 
 
 
Name of Subject (Please Print) 
 
 
 
 
Signature of Subject 
Date 
 
 
 
 
Name of Person Obtaining Consent (Please Print) 
 
 
 
 
Signature 
Date 
University of Pennsylvania to use your personal health information 
collected about you for research purposes within our institution. 
You are also allowing the University of Pennsylvania to disclose 
that personal health information to outside organizations or people 
involved with the operations of this study. 


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UNIVERSITY OF PENNSYLVANIA 
RESEARCH SUBJECT 
INFORMED CONSENT FORM AND HIPAA 
AUTHORIZATION FORM 
- 
CONTROL CONSENT 
 
Protocol Title: 
Stress and Inflammation in the Pathophysiology of 
Depression 
 
Principal 
Investigator: 
 
 
 
 
 
Center for 
Neuroscience of 
Depression and 
Stress: 
Yvette Sheline, M.D. 
Department of Psychiatry 
University of Pennsylvania 
3700 Hamilton Walk 
Philadelphia, PA 19104-4283 
Email: sheline@pennmedicine.upenn.edu 
 
 
Tommaso Girelli 
Email:Tommaso.girelli@pennmedicine.upenn.edu 
Office Phone: 215-573-0083 (Scheduling/general questions) 
 
Emergency Contact: 
If you have a study related medical emergency, please contact 
the study staff or call 911 
 
 
 
 
 
Why am I being asked to volunteer? 
You are being invited to participate in a research study. We are 
contacting you because you may have an interest in participating. 
Your participation is voluntary, which means you can choose whether 
or not you want to participate. If you choose not to participate, there 
will be no loss of benefits to which you are otherwise entitled. We will 
be recruiting about 100 subjects with depression and 50 subjects with 
no depression who are 18-80 years old to participate. You are being 
 
 
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