Clinical trial NCT03993457
Conditions: Depression
Keywords: depression mental health mood disorders major depressive episode major depressive disorder antidepressants escitalopram bupropion depression treatment
Sponsor: University of Texas Southwestern Medical Center
Start date: 2019-07-23; Completion date: 2022-03-25
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
PRECISE-D is a single site, randomized, open label 8-week clinical trial that will enroll 70 participants to evaluate if the level of inflammation in our body can predict how we will respond to antidepressants. C-reactive protein (CRP) is a substance in the body that is associated with inflammation. Previous research has suggested that people with high CRP (i.e., high inflammation levels) tend to have greater improvement of depressive symptoms with an antidepressant called bupropion, while individuals with low CRP (i.e., low inflammation levels) appear to have more benefit from selective serotonin reuptake inhibitors antidepressants (SSRI), such as escitalopram. However, it is not completely clear if CRP can predict your response to these two antidepressants.

Participants will undergo a screening visit that includes a physical exam, overall health evaluation, assessment of mental health history, and a toxicology and pregnancy test. Once screening is complete, participants will be randomized to one of two groups that will determine whether their CRP levels will be used to select which antidepressant they will receive. Participants will then complete 4 follow up visits at weeks 2, 4, 6, and 8. A follow-up phone call from the study team will occur at week 12.

Detailed description:
PRECISE-D is a single site, randomized, open label 8-week clinical trial that will enroll 70 participants. Participants will be asked to attend approximately 5 visits with the researchers or study staff.

The screening process will take approximately 2 hours, and will include a physical examination, toxicology and pregnancy test, as well as the completion of assessments. We will ask participants a series of questions regarding their general health, mental health history, and any medications they are currently taking. Additionally, some self-report questionnaires will be used as part of this process. The results of the screening exams, tests, and/or procedures will be reviewed to determine whether a participant will be allowed to continue in the study. In the event that there are questions about a participant's eligibility or screening procedures are remaining, the screening visit may be conducted over 2 visits.

Once eligibility is determined, the baseline visit (Week 0) will be completed. This visit will last approximately 1 hour and 15 minutes and will include the following:

* Bloodwork: We will obtain levels of CRP and other inflammatory substances. We will also examine electrolytes, kidney function, thyroid function, lipid panel, blood cell count, and other tests of general health.
* Self-Report Questionnaires: Participants will complete 8 questionnaires. These include questions about mental health and mood. The questionnaires range from 5 to 20+ items.
* Cognitive tests: We will examine the participant's attention, memory, and cognition using a series of computerized assessments.

Participants will be assigned to a study group based on their CRP level: CRP less than 1 (low CRP), or CRP greater than or equal to 1 (high CRP). Within this group assignment, participants will then be randomized, or assigned by chance (like flipping a coin), to one of 2 study groups:

• CRP consistent antidepressant selection (medication will be prescribed based on participant's CRP level).

If CRP less than 1, participant will be prescribed escitalopram. If CRP greater than or equal to 1, participant will be prescribed bupropion XL.

• CRP inconsistent antidepressant selection (medication will be prescribed in contradiction to participant's CRP level) If CRP less than 1, participant will be prescribed bupropion XL. If CRP greater than or equal to 1, participant will be prescribed escitalopram.

In each group participants will receive either escitalopram or bupropion XL.

* 1 tablet of 150 mg of bupropion-XL per day (initial dose). The dose will be increased to 300mg per day after the first week, and may be increased up to 450 mg/per day if deemed necessary by the clinician.
* 1 tablet of 5 mg of escitalopram per day (initial dose). The dose will be increased to 10 mg per day after the first week, followed by an additional increase to 20 mg/day if deemed necessary by clinician.

Participants and study doctors will know which medication is being used, but not which group the participant is in; that is, participants and study doctors will not know the participant's CRP levels nor whether the medication assignment is consistent with CRP levels. The dose of the medication may be adjusted up or down during the study to improve effects of the medication or reduce possible side effects. Dose changes will be made based on how the participant is feeling and any side effects.

Participants will then complete a clinical visit at Week 2, 4, and 6. These visits will last approximately 1 hour and 15 minutes, and will include the following:

* Clinical Evaluation: a psychiatrist will check the participant's vital signs and assess their overall wellbeing. Symptom changes, side effects, and adherence to treatment will be evaluated. Medication dosage adjustments will be made as necessary.
* Self-Report Questionnaires

The final clinical visit will occur at week 8. This visit will be the last in person visit and will last approximately 1 hour and 45 minutes. The following will be completed

* Clinical Evaluation
* Self-Report Questionnaires
* Cognitive tests
* Bloodwork
* Pregnancy test (if you are a female able to become pregnant)

After study completion, participants who wish to remain on treatment will be given a four week supply of study drug while they transition care.

Additionally, a remote follow up assessment will be done at Week 12. Participants will be contacted via phone to complete a series of questionnaires. Additionally, they will receive a series of self reports via email. Paper forms will be also available at the Center for Depression Research and Clinical Care if the participant prefers to answer them on paper or don't have access to an email.

The self-report questionnaires, study evaluations, and assessment of CRP levels and additional inflammatory substances in this study are designed for research, not for medical purposes. Even though the researchers are not specifically looking at blood to find a medical problem, participants will be notified if any abnormal results are identified.

Participants will also have the option to participate in a Finger Prick Blood CRP substudy that will compare CRP results based on the blood source: venous blood obtained via venipuncture and capillary blood obtained via finger prick. A few drops of capillary blood will be collected via finger prick once during the study at week 0 (screening/baseline). We will compare the finger prick results to the results obtained from venipuncture at the same visit.

Arms: arm 1: Participants with CRP\<1 will be prescribed escitalopram arm 2: Participants with CRP\> or equal to 1 will be prescribed bupropion XL arm 3: Participants with CRP\< 1 will be prescribed bupropion XL arm 4: Participants with CRP\> or equal to 1 will be prescribed escitalopram
Interventions: intervention 1: Escitalopram intervention 2: Bupropion
Intervention descriptions: intervention 1: Escitalopram will be started at 5 mg/day during the first week of treatment. The dose will then be increased to 10mg/day, and can be increased to 20 mg/day. Dose can be decreased to 5 mg by clinician discretion such as to increase tolerability or better manage side-effects. 5 mg will be the lowest dose allowed in the study. intervention 2: Bupropion-XL will be started at 150 mg/day and increased to 300 mg/day after one week. This dose can be increased to 450 mg/day (divided in 2 doses) at Week 2 or later. Clinicians may opt to titrate bupropion-XL in a slower fashion in cases that might increase tolerability or better manage side-effects. 150 mg will be the lowest dose allowed in the study.

Protocol documents:
Prot_000.pdf: 
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Protocol 
 
 
 
 
Promoting Enhanced Pharmacotherapy Choice 
through Immunomarkers Evaluation in 
Depression: PRECISE-D 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: Madhukar H. Trivedi, MD 
 
Study Sponsor: UT Southwestern Medical Center  
 
September 11, 2020 
 
Version 1.2 


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TABLE OF CONTENTS 
1. Background and Significance  
1.1. Burden of Major Depressive Disorder and the Decisional Dilemma….……………………………………………..3 
1.2. Current Practice Guidelines for Antidepressant Prescription and the Critical Evidence Gap………….…3 
1.3. Filling the Critical Evidence Gap……………………………………………………………………………………………………….4 
1.4. Inflammatory Biomarkers can Reduce Decisional Uncertainty…………………………………………………………4 
2. Introduction and Purpose  
2.1. Study Overview…………………………………………………………………………….……………………………………………….…5 
2.2. Study Aims………………………………………………………………………………………………………………………..……..…..….5 
3. Study Design 
3.1. Overview………………………………………………………………………………………………………………………………………....6 
3.2. Methods…………………………………………………………………………………………………………………………………………..6 
3.3. Study Population………………………………………………………………………………………………………………………………6 
3.4. Subject Eligibility………………………………………………………………………………………………………………………………7 
4. Study Procedures 
4.1. Overview………………………………………………………………………………………………………………………………………....8 
4.2. Screening and Baseline Visit……………………………………………………………………………………………………………..9 
4.3. Randomization………………………………………………………………………………………………………………………………..10 
4.4. Study Visits…………..…………………………………………………………………………………………………………………………10 
4.5. Laboratory and Diagnostic Procedures……………………………………………………………………………………………11 
4.6. Optional Finger Prick………………………………………………………………………………………………………………….……12 
4.7. Optional EEG…………………………………………………………………………………………………………………………….....…12 
5. Treatment 
5.1. Overview…………………………………………………………………………………………………………………………………………12 
5.2. Mechanism of Action………………………………………………………………………………………………………………………13 
5.3. Dosing Schedule……………………………………………………………………………………………………………………………..13 
5.4. Concomitant Therapy……………………………………………………………………………………………………………………..14 
6. Sources of Research Material  
6.1. Outcome Measures…………………………………………………………………………………………………………………………14 
6.2. Demographic Forms………………………………………………………………………………………………………………………..14 
6.3. Clinical, General Health, and Medical History Surveys…………………………………………………………………….14 
6.4. Depression Severity Measurement Tools………………………………………………………………………………………..15 
6.5. Anxiety Symptoms…………………………………………………………………………………………………………………………..16 
6.6. Side Effects and Adherence…………………………………………………………………………………………………………….16 
6.7. Neurocognitive and Behavioral Phenotyping Tasks…………………………………………………………………………16 
7. Patient Recruitment and Consenting Process  
7.1. IRB Review……………………………………………………………………………………………………………………………………..17 
7.2. Recruitment…………………………………………………………………………………………………………………………………..17 
7.3. Informed Consent………………………………………………………………………………………………………………………….17 
8. Potential Risks……………………………………………………………………………………………………………………………………………..18 
9. Subject Safety and Data Monitoring 
9.1. Safety Measures………………………………………………………………………………………………………………………….…18 
9.2. Suicide Monitoring………………………………………………………………………………………………………………….……..18 
9.3. Reasons for Early Termination…………………………………………………………………………………………….…………19 
9.4. Evaluation of Adverse Events…………………………………………………………………………………………….…………..19 
10. Procedures to Maintain Confidentiality…………………………………………………………………………………………….…………20 
11. Potential Benefits to Study Participants and Others…………………………………………………………………….………………21 
12. References…………………………………………………………………………………………………………………………………………………..22 
 
 


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1. Background and Introduction 
 
1.1. 
Burden of Major Depressive Disorder and the Decisional Dilemma 
Major Depressive Disorder (MDD) affects approximately 10% of the adult population in the United States,1 
and according to the World Health Organization, MDD is now the leading cause of disability worldwide.2 
The chronic course of the illness, which is characterized either by unremitting symptoms and dysfunction 
or repeated depressive episodes interspersed with periods of remission,3,4 significantly contributes to the 
personal and public health costs of the disease, which total over $210 billion per year in the US alone.5 
The relative effectiveness of medications for the treatment of MDD are comparable to those for other 
chronic medical conditions.6-8 However, outcomes in clinical practice continue to be poor.9 This is related 
in part to the decisional dilemma faced by clinicians and patients in determining which antidepressant is 
right for which patient.10 Although extensive data indicate that there are no meaningful differences among 
second generation antidepressants (see below), large community trials such as the Sequenced Treatment 
Alternatives to Relieve Depression (STAR*D) trial clearly indicate that only a minority of patients respond 
to the initial antidepressant, and most patients require several trials of medications to achieve 
response.6,11,12 Thus, while antidepressants are equally effective on average,  response for a given patient 
is very antidepressant specific, leaving clinicians and patients guessing as to which drug is the best choice. 
This decisional dilemma results in a trial and error process of antidepressant selection, which can 
undermine the patient’s confidence in the decision-making process, and ultimately contribute to multiple 
treatment trials, ineffective medications taken too long, treatments switched too early, or patients simply 
dropping out of care. This process also may inadvertently lead to patients being labeled treatment 
resistant, even when effective treatments may exist for them. Hence, reducing the decisional dilemma 
regarding antidepressant choice in primary care will increase the effectiveness of currently available 
antidepressant medications. 
 
1.2. 
Current Practice Guidelines for Antidepressant Prescription and the Critical Evidence 
Gap 
Based on an Executive Summary by the Effective Health Care Program of the Agency for Healthcare 
Research and Quality, which performed a comparative effectiveness review of second generation 
antidepressants, “no substantial differences in efficacy exist among second generation antidepressants for 
the treatment of MDD”. 13 Accordingly, the most recent practice guidelines from the American Psychiatric 
Association recommend: “Because the effectiveness of antidepressant medications is generally 
comparable between classes and within classes of medications, the initial selection of an antidepressant 
medication will largely be based on the anticipated side effects, the safety or tolerability of these side 
effects for the individual patient, pharmacological properties of the medication (e.g., half-life, actions on 
cytochrome P450 enzymes, other drug interactions), and additional factors such as medication response 
in prior episodes, cost, and patient preference.”10  However, there is no empirical evidence that any of 
these or other clinical variables (such as baseline symptom severity, age of onset, presence of insomnia, 
chronicity, atypical or melancholic features) can meaningfully guide selection of one antidepressant 
medication over another.14-19 As a consequence, a critical evidence gap exists regarding how to decide 
which antidepressant will be most effective for a given patient.  Because of this evidence gap, patients 
and providers face a decisional uncertainty that can undermine treatment effectiveness and patient 
engagement in the treatment process.  
 
 
 


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1.3. 
Filling the Critical Evidence Gap: Inflammation as a Predictor of Antidepressant 
Treatment Response  
Data indicate that inflammation plays an important role in the response to antidepressants.20-24 A 
significant percentage of depressed patients exhibit increased inflammation,25 and studies have shown 
that increased biomarkers of inflammation including c-reactive protein (CRP) can predict response to 
antidepressant treatment, including the prediction of differential response to different types of 
antidepressants.21-24,26 Relevant to the mechanisms by which inflammation can affect antidepressant 
response, inflammatory cytokines and their signaling pathways have been shown to increase the 
expression and function of the transporters for serotonin,27 thereby potentially undermining the effects 
of selective serotonin reuptake inhibitors (SSRIs), which act in large part by blocking these transporters.28 
Moreover, data from both laboratory animals and humans have demonstrated that inflammatory 
cytokines reduce dopamine neurotransmission and inhibit dopamine-mediated reward circuits in the 
brain that are associated with anhedonia, a core symptom of depression.29 Interestingly, administration 
of medications that increase dopamine signaling have been shown to reverse anhedonic symptoms in 
laboratory animals exposed to inflammatory cytokines.30 Taken together, these translational studies 
strongly suggest that patients with increased inflammation are less likely respond to SSRIs and are more 
likely respond to drugs that augment dopamine. 
 
1.4. 
Inflammatory Biomarkers Can Reduce Decisional Uncertainty and Fill the Critical 
Evidence Gap 
In the absence of data demonstrating differential efficacy among antidepressants coupled with lack of 
predictive power of clinical variables, there is a critical evidence gap regarding the initial choice of 
currently available antidepressants.31-33  Consistent with the translational studies described above, 
biomarkers of inflammation may fill this gap, given that they have been shown to be effective in predicting 
differential response to antidepressant subtypes in MDD.34-37 Indeed, CRP, a clinically available and 
inexpensive biomarker of systemic inflammation, has been shown to predict differential response to 
currently available antidepressants in post hoc analyses of two large community studies of over 300 
patients. For example, in a study conducted by our group, MDD patients with high CRP (≥1mg/L) were 
found to respond better to the dopamine reuptake inhibitor bupropion in combination with escitalopram 
compared to patients treated with escitalopram alone, who responded better when CRP concentrations 
were low (<1mg/L ).22 While systematic reviews and meta-analyses have failed to find significant 
differences in treatment outcomes in head-to-head comparisons of SSRIs and bupropion,38,39 the above-
mentioned differential treatment response to an SSRI versus bupropion based on CRP level clearly 
demonstrates a heterogeneity in treatment effects (HTE). Hence, superiority of antidepressant selection 
informed by point-of-care (POC) CRP testing over the current practice of using clinical variables can reduce 
the decisional uncertainty of choosing the right antidepressant compared to the currently used “trial and 
error” process, ultimately closing the evidence gap and increasing the effectiveness of currently available 
antidepressant medications. 
 
 
 
 
 
 
 


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2. Introduction and Purpose  
 
2.1. 
Study Overview  
Despite the large socioeconomic impact of major depressive disorder (MDD), our ability to provide 
optimal antidepressant treatment is significantly limited. The lack of consistent clinical or laboratory 
predictors of response to antidepressants remains a major challenge. Currently, no biomarker is used in 
clinical care to aid in the selection of treatment, and finding the right medication for people suffering from 
MDD still relies on a “trial-and-error” method. There is an urgent need to better predict differential 
response to antidepressants.  
 
The main objective of the proposed study is to evaluate the use of POC CRP as a predictor of differential 
antidepressant response (escitalopram versus bupropion extended-release [XL]) in individuals with MDD. 
Additionally, two optional sub-studies will be available for participants to enroll in.  
 
The first sub-study will evaluate if capillary blood obtained via finger prick can be used for the POC CRP 
test instead of venous blood. Hence, our proposed study results have the potential to markedly impact 
antidepressant selection in routine clinical practice and allow treatment providers and patients to choose 
an antidepressant that is more likely to result in favorable treatment outcomes. If favorable, this study 
would also support personalized selection of antidepressant medications to individual MDD patients using 
a readily-available inexpensive blood test. Additionally, results from the sub-study could validate the use 
of finger prick blood for the CRP test, providing an easier and faster alternative for busy clinical practice.   
 
The second sub-study will investigate if pre- and post-treatment connectomic profiles obtained from 
resting electroencephalography (EEG) are able to predict differential antidepressant treatment response. 
EEG also offers clinical utility as a cost-effective and rapid means of assessing neurological activity. EEG 
biomarkers have demonstrated ability to predict response to different interventions in depression 65, 66. 
Further development of this capability has potential to rapidly advance personalized medicine. 
 
To facilitate the understanding of the protocol, we define two commonly used terms in this protocol: 
 
CRP-consistent antidepressant selection: participants with a baseline venous CRP level greater than or 
equal to 1 will be prescribed bupropion XL and participants with a baseline venous CRP level less than 1 
will be prescribed escitalopram.  
 
CRP-inconsistent antidepressant selection: participants with a baseline venous CRP level greater than or 
equal to 1 will be prescribed escitalopram and participants with a venous baseline CRP level less than 1 
will be prescribed bupropion XL.   
 
2.2. 
Study Aims 
• 
Primary Aim 1: To compare the efficacy of CRP-consistent antidepressant selection versus CRP-
inconsistent antidepressant selection on remission rates in patients with MDD.  
 
• 
Primary Aim 2: To compare the efficacy of CRP-consistent antidepressant selection versus CRP-
inconsistent antidepressant selection on improving social and occupational functioning.  
 
• 
Primary Aim 3: To compare CRP-consistent antidepressant selection versus CRP-inconsistent 
antidepressant selection on adverse antidepressant treatment effects.  


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o Sub-Study Aim 1: To investigate if capillary blood provides a valid and reliable CRP measurement by 
comparing the levels of POC CRP obtained by capillary blood (finger prick) with those obtained by 
venous blood (blood draw). 
 
o Sub-Study Aim 2: To evaluate the ability of various measures of functional network connectivity 
obtained from resting EEG to predict treatment response. 
 
 
3. Study Design 
 
3.1. 
Overview 
The current study is single site, randomized, open label 8-week clinical trial comparing the efficacy of CRP-
consistent antidepressant selection vs CRP-inconsistent antidepressant selection. Venous levels of CRP 
will be measured by an FDA cleared Point of Care Smart analyzer (Diazyme Laboratories) and/or Quest 
Diagnostics, which provides the CRP concentration within few minutes. The study will use a stratified 
randomization (i.e. separate randomization schemes for patients with POC CRP ≥ 1 and POC CRP < 1). This 
will assure that the four study groups have similar sample sizes: 1) escitalopram with CRP < 1, 2) 
bupropion-XL with CRP < 1, 3) escitalopram with CRP ≥ 1, 4) bupropion-XL with CRP ≥ 1. We anticipate 
that participants with higher inflammation (CRP ≥ 1) will have higher remission rates with bupropion-XL 
than escitalopram, while individuals with low levels of systemic inflammation (CRP < 1) will remit more 
frequently with escitalopram when compared to those treated with bupropion XL. A sub-study will 
compare POC CRP levels based on the blood source: venous blood obtained by venipuncture vs capillary 
blood obtained via fingerstick.  
 
3.2. 
Methods 
70 eligible subjects will be assigned to one of two groups based on their baseline venous CRP level: CRP< 
1 or CRP≥1. Participants in both groups will then be randomly assigned in a 1:1 fashion to one of two 
treatment arms: a) CRP consistent antidepressant selection or b) CRP inconsistent antidepressant 
selection.  All subjects will be followed for 56 (+/- 3) days (8 weeks) to examine the efficacy of the study 
treatments. The treatment phase is followed by a remote follow-up call and electronic self-report 
questionnaires at 12 weeks.  
 
3.3. 
 Study Population 
 
Number of Subjects 
 
70 subjects will enter the open-label treatment phase of this single site study at the Center for Depression 
Research and Clinical Care. This trial will be conducted according to the U.S. FDA guidelines and the 
Declaration of Helsinki. IRB-approved written informed consent will be obtained from all patients before 
any protocol-specified procedures are carried out. The subjects will be drawn from an outpatient sample 
of patients with MDD, diagnosed with the use of the Mini International Neuropsychiatric Interview (MINI).  
 
 
 
 
 


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3.4. 
 Subject Eligibility  
 
Inclusion Criteria 
 
A subject will be eligible for inclusion only if all of the following criteria are met: 
• 
Women and men ages 18-65 
• 
Diagnosis of Major Depressive Disorder according to Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) criteria confirmed by the Mini International Neuropsychiatric 
Interview (MINI).  
• 
Have a score of 14 or higher on the Hamilton Scale for Depressive Symptomatology as assessed 
by trained clinicians.  
 
 
Exclusion Criteria 
 
A potential participant will NOT be eligible for participation in this study if any of the following criteria are 
met: 
• 
Any antidepressant use within the last 8 weeks  
• 
Active infection or uncontrolled autoimmune disease 
• 
Currently on oral corticosteroids or active immune suppressive therapy (methotrexate, 
cyclosporine, anti-cytokines medications, etc. Note that nonsteroidal anti-inflammatory drugs - 
NSAIDs - will be allowed). 
• 
Current diagnosis of uncontrolled HIV, hepatitis C or significant immunodeficiency 
• 
Subject has a history of moderate or severe substance or alcohol use disorder according to  
DSM-5 criteria, except nicotine or caffeine, within 3 months before signing informed consent 
form.  
• 
Positive urine drug test for illicit substances or substances used out of the context of prescription 
• 
Cognitively unable to give informed consent 
• 
Pregnant or breastfeeding women, women of childbearing potential who are not using an 
accepted means of birth control, or women with a positive urine pregnancy test 
• 
History of seizure disorder 
• 
Previous significant adverse reaction to escitalopram or bupropion 
• 
History of non-response to adequate doses of escitalopram or bupropion XL 
• 
Current use of concomitant psychotropic agents (anticonvulsants, benzodiazepines, hypnotics, 
opiates, triiodothyronine (T3), modafinil, psychostimulants, buspirone, melatonin, folate, l-
methylfolate, s-adenosyl methionine, lithium) not on the same dose for at least four weeks prior 
to study entry or who do not agree to continue at the same dose during the acute phase of the 
study. 
• 
Lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder or other psychotic 
disorder except for Major Depressive Disorder with psychotic features in prior episode. 
• 
Current anorexia nervosa or bulimia nervosa per Mini International Neuropsychiatric Interview 
(MINI). 
• 
Suicidal ideation of the degree that, in the opinion of the evaluating clinician, participation in the 
study would place them at significantly increased risk of suicide 
• 
Unstable medical issues of such degree that, in the opinion of the evaluating clinician, 
participation in the study would place them at significant risk of a serious adverse event 
 


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Rationale for the Inclusion/Exclusion Criteria 
 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects 
and to ensure that the results of the study are meaningful in support of the research hypotheses. It is 
imperative that subjects fully meet all eligibility criteria. 
 
4. Study procedures  
 
4.1. 
Overview  
Subjects will be screened for eligibility as detailed above. Study participants will be consented prior to the 
administration of any procedure. Following the screening assessment and confirmation that all criteria for 
entry into the study are met, eligible subjects will be assigned to 2 different groups based on their baseline 
venous CRP level: CRP≥ 1 and CRP<1. Participants within each group will then be randomized in a 1:1 
fashion to one of the two treatment arms: a) CRP-consistent antidepressant selection or b) CRP-
inconsistent antidepressant selection.    
 
Table 1. 
Visit Week 
Week 0* 
Week
2+ 
Week
4+ 
Week 
6+ 
Week 
8 
Week 
12+ 
Screening 
Baseline 
Visit Day Window 
0 
14 
(+/-3) 
28 
(+/-3) 
42 
(+/-3) 
56 
(+/-3) 
84 
(+/-3) 
Informed Consent and Eligibility Screening 
Informed Consent 
X 
 
 
 
 
 
 
Eligibility Screening 
X 
 
 
 
 
 
 
The Demographics Form 
X 
 
 
 
 
 
 
Clinical, General Health, and Medical History Surveys 
The Self-Administered Comorbidity Questionnaire 
(SCQ) 
X 
 
 
 
 
 
 
Prior  and Concomitant Medication and 
Treatment and Adverse Events  
X 
X 
X 
X 
X 
X 
X 
Antidepressant Treatment Response 
Questionnaire (ATRQ) 
X 
 
 
 
 
 
 
Fagerstrom Test of Nicotine Dependence 
X 
 
 
 
 
 
 
Depression Severity Measurement Tools 
M.I.N.I. (7.0) Structured Diagnostic Interview 
X 
 
 
 
 
 
 
Hamilton Depression Rating Scale  
X 
 
 
 
 
X 
X 
Inventory of Depressive Symptomatology (IDS) 
 
X 
X 
X 
X 
X 
X 
Concise Health Risk Tracking Scale (CHRT) 
 
X 
X 
X 
X 
X 
X 
Work and Social Adjustment Scale (WSAS) 
 
X 
X 
X 
X 
X 
X 
The Temporal Experience of Pleasure Scale (TEPS) 
 
X 
X 
X 
X 
X 
X 
Behavioral Inhibition System/ Behavioral 
Approach System (BIS/BAS) Scale 
 
X 
X 
X 
X 
X 
X 
 
(TABLE 1 continued on next page) 
 


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Anxiety Symptoms 
Generalized Anxiety Disorder 7-item (GAD-7) 
 
X 
X 
X 
X 
X 
X 
State Trait Anxiety Inventory (STAI) 
 
X 
X 
X 
X 
X 
X 
Side Effects and Adherence 
Patient Adherence to Antidepressant Medication 
Questionnaire (PAQ) 
 
 
X 
X 
X 
X 
X 
Frequency, Intensity, and Burden of Side Effects 
 
 
X 
X 
X 
X 
X 
Cognition and Behavioral 
Flanker Test 
 
X 
 
 
 
X 
 
Digit Symbol Substitution Test 
 
X 
 
 
 
X 
 
Behavioral Phenotyping - 24 Hours Substance 
Use 
 
X 
 
 
 
X 
 
Physical Examination and Collection of Biospecimens 
Physical Examination  
X 
 
 
 
 
 
 
Vital Signs (BP, HR, RR, Temperature, Pain) 
X 
X* 
X** 
X** 
X** 
X** 
 
HT/WT/BMI, Waist/ Hip Circumference 
X 
X* 
X** 
X** 
X** 
X 
 
Blood Collection: CBC, BMP, TSH, Lipid Panel, 
Hemoglobin A1c, CRP 
 
X 
 
 
 
X++ 
 
Urine Toxicology Screen 
X 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
 
 
 
 
 
 
Blood Based Immunomarkers 
Optional Venous Blood Draw for Biobanking 
 
X 
 
 
 
X 
 
Optional Finger Prick 
 
X 
 
 
 
 
 
Electroencephalogram (EEG) 
Optional EEG: Resting State 
 
X 
 
 
 
X 
 
*Screening and baseline will take place on the same visit. If not possible, baseline will be completed within 2 weeks after 
screening. Vital signs, BMI, and Waist:Hip ratio will be updated.  
** Obtained during in office visits only. 
+  Weeks 2, 4, 6, and 12 visits may be performed remotely when necessary. 
++ CRP and HbA1C only  
 
4.2. 
 Screening and Baseline Visit  
 
Screening  
Duration: 2 hours  
 
The screening phase will start with the informed consent procedures. Once patients agree to participate 
in the study by signing the informed consent document, a medical and psychiatric history will be taken 
and a physical examination will be performed, as outlined in Table 1.  The purpose is to ensure that only 
appropriate patients are entered into the study. The investigator will determine that the patients meet 
eligibility criteria and will collect the demographic and medical data permitting full characterization of the 
patients. Patients found to be in potential need of hospitalization due to their degree of suicidal ideation 
at screening will be referred to the nearest emergency room. 
 
If the participant meets all of the inclusion criteria and none of the exclusion criteria, he/she will proceed 
to the baseline portion of the visit.  


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Baseline – Week 0  
Duration: 1 hour 15min OR up to 2 hours    
 
1. Self-Report Questionnaires (30 min) 
2. Clinician/Assessor Rated Assessments (HAM-D, M.I.N.I and  ATRQ) (45min) 
3. Neurocognitive and behavioral phenotyping tasks (30 minutes).  
o Including optional EEG (30 minutes)  
4. Blood Draw (15 minutes)  
 
4.3. 
Randomization 
 
Patients will be assigned to one of two groups based on their baseline CRP level as measured by a venous 
blood sample: CRP≥1 or CRP<1. Participants from both groups will then be randomized in a 1:1 fashion to 
one of the two treatment arms: CRP consistent antidepressant selection or CRP inconsistent 
antidepressant selection.  
 
• 
CRP-consistent antidepressant selection 
If venous blood CRP<1, then prescribe escitalopram. 
If venous blood CRP≥1, then prescribe bupropion XL 
 
• 
CRP-inconsistent antidepressant selection 
If venous blood CRP≥1, then prescribe escitalopram 
If venous blood CRP<1, then prescribe bupropion XL 
 
4.4. 
Study Visits  
 
Week 2, 4, and 6 
Duration: 1 hour  
 
1. Self-Report Questionnaires (30 min) 
2. Prior and Concomitant Medication and Treatment, Adverse Events (5-10 min) 
3. Clinician General Interview (15min) 
4. Assessment of vital signs and weight (10 minutes). 
 
Week 8 (Exit Phase)  
Duration: 2 hours OR up to 2 hours and 35 minutes 
 
1. Self-Report Questionnaires (30 min) 
2. Prior and Concomitant Medication and Treatment (5-10 min) 
2. Clinician General Interview and Hamilton Depression Rating Scale (25 min) 
4. Assessment of vital signs and weight (15 min) 
5. Neurocognitive and behavioral phenotyping tasks (30 minutes). 
o Including optional EEG (30 minutes) 
6. Blood draw (15 min) 
 
 


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Post Study Follow Up 
 
Week 12  
Duration: 1 hour  
 
Consists of a phone call and self-administered questionnaires. The phone call will last approximately 20 
minutes and will include a clinician rated Hamilton Depression Rating Scale.  A series of self-report 
questionnaires will be sent electronically and will take approximately 40 minutes.  
 
 
4.4.1.  Participant Compensation  
Essential to the study is appropriate support for participants’ time and effort contributing to the study. 
Participants will receive monetary remuneration for participation in the study to compensate for time 
burden and travel arrangements and will be paid for each eligible visit using UT Southwestern ClinCard, 
per IRB regulations. Compensation for study procedures will be made each time a complete study is 
performed throughout the study duration. Bus passes or other help with transportation and/or parking 
expenses may also be available, if needed. 
Participants completing a screening and baseline visit inclusive of data collection and biospecimens will 
be compensated ($25). Participants will be paid ($10) for completed visits at week 2, 4, 6, and 8. 
Participants who complete the follow up visit via telephone at week 12 will be compensated for 
completed assessments ($10) and self-report questionnaires ($10).  
 
4.4.2. Costs 
Participants or insurance providers will not be charged for events related to this study (i.e., screening 
procedures, laboratory procedures). Study medications (i.e. escitalopram or bupropion-XL) will also be 
provided at no cost. UT Southwestern Medical Center will not pay for doctor visits, other treatments, or 
tests that are NOT part of this study. Compensation for an injury resulting from the participation in this 
research is not available from the University of Texas Southwestern Medical Center at Dallas. If a situation 
arises in which a participant is unable to collect their prescription at the designated study pharmacy, they 
will be reimbursed for the cost of their medication pick-up, using the receipt of the transaction as proof 
of purchase. 
 
4.5. 
Laboratory/Diagnostic Procedures 
Blood samples will be collected from participants by trained phlebotomists, who will draw the sample 
using standard venipuncture procedures, through a single venipuncture using a small gauge needle. 
Universal precautions will be observed by the phlebotomists during all draws. Each tube will be labeled 
and packaged for processing and storage.   
 
Screening Phase - Week 0 
Once the patient has signed the informed consent document, the urine drug screen and pregnancy test 
will be performed (if applicable) 
 
Baseline Phase - Week 0 
About 30 ml (~2 tablespoons) of venous blood will be collected and the following tests will be completed: 
Complete Blood Count, Basic Metabolic Panel, Lipid Panel, Hemoglobin A1c, TSH levels, and CRP levels. 
Later analysis of other immunomarkers (eg. IL-1, IL-6, TNF alpha), metabolism (eg. lipids, glucose 


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tolerance, amino acids, kyni), neurological function (eg. brain-derived neurotrophic factor, monoamine 
receptors, etc) and genetic testing will also be performed. The rest of the blood samples will be stored 
indefinitely until the sample runs out or it is destroyed. 
 
Week 8 - Exit Phase  
About 25 ml (~2 tablespoons) of venous blood will be collected and used for CRP and later analysis of 
other immunomarkers level measurements (eg. IL-1, IL-6, TNF), metabolism (eg. lipids, glucose tolerance, 
amino acids, etc), neurological function (eg. brain-derived neurotrophic factor, monoamine receptors, 
etc) and genetic testing will also be performed. The rest of the blood samples will be stored indefinitely 
until the sample runs out or it is destroyed.  
 
4.6 
Optional Finger Prick   
Participants will have the option to participate in a sub-study that will compare venous blood CRP levels 
with capillary blood CRP levels.  The purpose of this sub-study is to examine if the latter is accurate and 
can be used in future studies and clinical practice. During the baseline visit, 2-5 drops of capillary blood 
will be collected using a finger prick. The CRP levels on the capillary blood will be analyzed and compared 
to those obtained using venous blood obtained via venipuncture.  
 
4.7 
Optional Electroencephalogram (EEG) 
Participants will have the option to participate in a sub-study that will acquire 10 minutes of resting state 
EEG at baseline and Week 8 to provide measures of functional network connectivity. The purpose of this 
sub-study is to determine the predictive utility of EEG-derived measures in treatment response to 
escitalopram and bupropion.  
 
 
4.7.1 Electroencephalogram (EEG) Procedures 
 
Participants will undergo EEG recordings at baseline and at Week 8. EEG is performed by placing an elastic 
cap containing electrodes on the participant’s scalp. These electrodes are previously soaked in a 
potassium chloride saline solution (similar to salt water) in order to better conduct electrical signals at the 
scalp. The technician ensures correct alignment of the cap and the quality of measured signals. This 
process takes approximately 10-15 minutes. The participant’s brain activity is then recorded for 5 minutes 
as they sit quietly with their eyes open, generally fixating a marked point in front of them. This procedure 
is repeated for 5 minutes but with the participant’s eyes closed as the rest quietly but awake. The cap is 
then removed and the participant can pat dry their hair with a provided towel. The total time estimate for 
completion of the EEG collection at each visit is approximately 30 minutes. The EEG workgroup will ensure 
that adequate training, standardization of measures, and validation of equipment is maintained for data 
consistencies and quality control purposes. 
 
5. Treatment 
 
5.1. 
Overview  
The current study will use two FDA-approved medication for MDD: escitalopram and bupropion-XL. 
Systematic reviews and meta-analyses have failed to find significant differences in treatment outcomes 
in head-to-head comparisons of SSRIs and bupropion. In this context, the treatment provided in this 
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Escitalopram is a widely-used SSRI, which is FDA-approved for MDD in people aged 12 or older.40 The 
efficacy is similar to other SSRIs but escitalopram is known for fewer side-effects and fewer 
pharmacological interactions making it well-tolerated and commonly used in clinical practice.41 The 
medication is commercially available in the generic form or under the brand name Lexapro. The generic 
medication will be provided in this study. The compound will be obtained from a commercial pharmacy. 
Since this is study is open-label, the medication will be dispensed to the participants in its usual 
commercial form. We will provide escitalopram in tablets of 5 mg, 10 mg, 15 mg and 20 mg.  
Bupropion is a commonly used norepinephrine-dopamine reuptake inhibitor that is FDA-approved for 
MDD.41 Its antidepressant effects are comparable to SSRIs and other antidepressants.42-44 Bupropion has 
good overall tolerability.45 Bupropion is commercially available in the generic form as well as under the 
brand names Wellbutrin, Zyban and Aplenzin. The medication comes in three formulations: regular 
bupropion, bupropion sustained-release (SR) and bupropion extended-release (XL). Bupropion-XL will be 
provided in this study (tablets of 150 mg and 300 mg). This formulation has the advantage of being used 
just once a day, while the other formulations need to be taken twice or three times a day. In addition to 
a better dosing schedule, bupropion-XL has theoretically fewer side-effects.44 
5.2. 
Mechanisms of action 
Escitalopram exerts its antidepressant actions through blockage of the serotonin reuptake pump leading 
to synaptic changes that result on increased serotoninergic transmission.41 It is a “clean” SSRI - i.e. no 
significant secondary pharmacological actions and no known immunological effect.23 Escitalopram usually 
starts working in 2 to 4 weeks. 
 
Bupropion XL is a commonly used norepinephrine-dopamine reuptake inhibitor. As a result, this 
medication is believed to increase norepinephrine and dopamine neurotransmission. Evidence from in 
vitro and pre-clinical studies suggest that bupropion has an additional anti-inflammatory action.46-48 
Therefore, this antidepressant would be particularly useful for MDD with underlying systemic 
inflammation. Bupropion antidepressant effects usually start in 2 to 4 weeks after its initiation. 
5.3. 
Dosing Schedule 
Escitalopram will be started at 5 mg/day during the first week of treatment. The dose will then be 
increased to 10mg/day, and can be increased to 20 mg/day if side-effects allow and QIDS-C is higher than 
5. Dose can be decreased to 5 mg by clinician discretion such as to increase tolerability or better manage 
side-effects. 5 mg will be the lowest dose allowed in the study. 
Bupropion-XL will be started at 150 mg/day and increased to 300 mg/day after one week. This dose can 
be increased to 450 mg/day (divided in 2 doses) at Week 2 or later if side-effects allow and QIDS-C is 
higher than 5. Clinicians may opt to titrate bupropion-XL in a slower fashion in cases that might increase 
tolerability or better manage side-effects. 150 mg will be the lowest dose allowed in the study.  
After study completion at week 8, participants who wish to remain on treatment will be given a four-week 
supply of study drug while they transition care.  
The medications schedule described above is based on previous trials.49,50  
 
 


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5.4. 
Concomitant Therapy 
All concomitant medications taken during the study will be recorded in the Concomitant Medication Log 
for each patient, along with dosage information and start and stop dates. Allowed concomitant 
medications include any prescription or over-the-counter medication not specifically excluded by the 
protocol. Patients requiring excluded drugs will be discontinued from the study. 
 
6. Sources of Research material  
 
6.1. 
Outcome Measures  
The primary study endpoint will be remission rates based on the 16-item Quick Inventory of Depressive 
Symptomatology, Self-Report (QIDS-SR), which will be extracted from the 30-item Inventory of Depressive 
Symptomatology (IDS-SR). QIDS-SR measures MDD severity; a score of 5 or less is considered remission. The 
secondary study endpoints will be: a) improvement in social and occupational function according to the 5-
item self-administered Work and Social Adjustment Scale and b) side effect measures using the 3-item 
Frequency, Intensity, and Burden of Side Effects Rating (FIBSER) scale. 
 
6.2. 
Demographics Forms  
 
Demographics Form: The demographics form will be administered to all participants during the screening 
phase. The form consists of basic demographic information (e.g., gender, race/ethnicity, education). 
 
6.3. 
Clinical, General Health, and Medical History Surveys 
 
Self-Administered Comorbidity Questionnaire (SCQ): The SCQ  assesses the presence of medical problems, 
whether treatment is received for the condition, and whether or not the condition limits functioning. Each 
question is answered on a yes/no basis. Each affirmative response to the three items per medical 
condition is coded as a 1, with the total score being the sum of all positive responses. The medical 
conditions specified on the SCQ include: heart disease, high blood pressure, lung disease, diabetes, ulcer 
or stomach disease, kidney disease, liver disease, anemia or other blood disease, cancer, depression, 
arthritis, thyroid disease and back pain.  
 
Prior and Concomitant Medications: The Prior and Concomitant Medications form assesses prescribed 
and certain over-the-counter medications taken by the participant. The Prior and Concomitant 
Medications form will be administered at the baseline visit and at each visit thereafter, if the participant 
endorses a change in medication status. 
 
Antidepressant Treatment Response Questionnaire (ATRQ): clinician-rated scale used to determine 
treatment resistance in MDD. The MGH ATRQ defines 6 weeks on an adequate dose of antidepressant 
medication as an adequate duration of treatment. It also provides specific operational criteria for 
adequate dosage for each of the most commonly used antidepressants.52 
 
Fagerstrom Test of Nicotine Dependence: The Fagerstrom Test of Nicotine Dependence consists of six 
items that test for dependence to nicotine. Sample items include “How soon after you awake do you 
smoke your first cigarette?” with answers including “within 5 minutes”, “6-30 minutes”, “31-60 minutes” 
and “after 60 minutes”. A scoring algorithm has been created for all items in order to denote ranges of 
severity of dependence, including “very low dependence,” “low”, “moderate”, “high”, and “very high” 
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6.4. 
Depression Severity Measurement Tools  
 
Mini-International Neuropsychiatric Interview: The MINI, Version 7.0. is a structured diagnostic interview 
designed to screen for Axis I psychiatric disorders in the Diagnostic and Statistical Manual of Mental 
Disorders (DSM-5). Clinicians complete this structured interview to assess for the presence of various 
forms of psychopathology, including mood and anxiety disorders; psychotic disorders; anxiety disorders; 
substance use disorders; eating disorders; and antisocial personality disorders. Our study also adds in 
specific questions to gauge various specifiers of a major depressive episode, including with anxious 
distress, atypical or melancholic features. Permission to use this measure has been granted by the 
measure’s lead author, David Sheehan.54 
 
Hamilton Depression Rating Scale: a 17-item clinician-administered scale that has been widely used to 
determine cut-offs for clinical trials and also to determine changes overtime. The items are anchored from 
0 to 4 or from 0 to 2 where higher scores indicate worse severity. There are well established cut-offs for 
this scale: 0-7 = normal; 8-13 = mild depression; 14-18 = moderate depression; 19-22 = severe depression 
and ≥ 23 very severe depression. The current trial will use moderate depression (i.e., total score of at least 
14) as severity cut-off for eligibility.55 
 
Inventory of Depressive Symptomatology:  Self Report (IDS-SR):  a 30-item rating scale designed to assess 
the severity of depressive symptoms over the past week. The questionnaire assesses the core symptoms 
of depression such as depressed mood and anhedonia, alongside additional items that measure, for 
example, anxiety, irritability, insomnia/hypersomnia, somatic complaints and other physical symptoms, 
panic, and reactivity to interpersonal rejection.56 
 
Concise Health Risk Tracking - Self Report: The CHRT-SR is a 16-item participant self-report assessment of 
suicidality and related thoughts and behaviors. The scale is designed to quickly and easily track suicidality 
in a manner consistent with the Columbia Classification Algorithm of Suicide Assessment (C-CASA). Items 
are rated on a fully anchored 5-point Likert scale with responses ranging from 1 (strongly disagree) to 
5 (strongly agree), with total scores ranging from 13 to 65. The first 13 items detail suicide propensity and 
include items measuring passive suicidal ideation and lack of social support. The final 3 items include 
suicide risk items and measure active suicidal ideation and planning. The CHRT-SR has good internal 
consistency (Cronbach’s alpha of 0.78).57 
 
Work and Social Adjustment Scale: consists of 5 items, each on a 0 (“No impairment at all”) to 8 (“very 
severe impairment”) scale, that inquiries about the impact of one’s current feelings on one’s employment 
and psychosocial functioning. Sample items include “Because of the way I feel, my ability to work is 
impaired” and “because of the way I feel, my ability to form and maintain close relationships with others, 
including those I live with, is impaired”. Internal reliability was at appropriate levels, ranging from 
Cronbach’s alpha = .70 and .94.58 
 
The Temporal Experience of Pleasure Scale: this instrument is a self-reported 18-item scale that 
investigates the two main components anhedonia: 1) anticipatory anhedonia, and 2) consummatory 
anhedonia. Anticipatory anhedonia (assessed by 10 items) is related to low motivation and impaired goal-
directed behavior. Consummatory anhedonia (evaluated by 8 items) is associated with lack of pleasure or 
inability to satiate a desire. The two components of anhedonia are specific and distinct constructs (Gard 
et al., 2006). Each item follows a 6-point Likert format where 1 = very false for me and 6 = very true for 
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Behavioral Inhibition System/Behavioral Approach System Scale: this scale consists of 24 self-reported 
items that assesses two motivational systems: 1) avoidance/inhibition where the objective is to avoid a 
situation or stimuli, and 2) drive/appetite to move towards a goal, and (Carver and White, 2013).  Each 
item follows a 4-point Likert format. Each construct (inhibition and activation) had subscales that further 
explore their components.60 
 
6.5. 
Anxiety Symptoms  
 
The Generalized Anxiety Disorder 7-item Scale (GAD-7): assesses common symptoms of anxiety and serves 
as an anxiety-severity scale. Participants respond on a 0 to 3 scale, from “not at all” to “nearly every day”, 
the number of days over the past two weeks that they have been affected by problems including 
“worrying too much about different things” and “trouble relaxing”. The total score of this scale ranges 
from 0-21, with scores from 5-9 indicating mild anxiety, scores from 10-14 indicating moderate anxiety, 
and scores 15 or higher indicating severe anxiety.61 
 
State-Trait Anxiety Inventory: The 40-item State-Trait Anxiety Inventory includes 20 items indicative of 
state – or current levels of anxiety – and 20 items of trait – or enduring – anxiety. Items are scored on a 
four-point scale, ranging from “almost never” to “almost always”, with higher scores indicating higher 
levels of anxiety. Sample state anxiety items are “I am worried” and “I feel calm” while sample trait anxiety 
items include “I worry too much over something that doesn’t really matter.” The psychometrics of this 
measure have been well-established.62 
 
6.6. 
Side Effects and Adherence  
 
The Patient Adherence Questionnaire (PAQ): two-item inventory that assesses for adherence to 
antidepressant medication. The first item asks how often participants have taken their medication, with 
responses ranging from “I have taken my medications every day without missing a day” to “I have stopped 
taking my medications.” The second item asks about adjustments made to medication, and answer 
choices include various options about why individuals might have reduced or increased their dosage, or 
whether medication has always been taken as prescribed. The measure is scored by adding up items that 
encode if individuals have missed taking their medication two or more days or have reduced or increased 
their dosage, with any positive response classifying the patient as being “non-adherent” to medication.63 
 
The Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER):  used to rate side effects from 
antidepressant medication. The measure consists of three items, each scored on a 0 to 6 scale, that inquire 
about the frequency of side effects over the past week (from “no side effects” to “present all the time”); 
the intensity of such side effects (from “no side effects” to “intolerable”), and the interference on day-to-
day functioning due to medication side effects (from “no impairment” to “unable to function”).64 
 
6.7. 
Neurocognitive and Behavioral Phenotyping Tasks 
 
Flanker Test:  series of response inhibition tests used to assess the ability of suppress responses that are 
inappropriate in a particular context. The target is flanked by non-target stimuli which correspond either 
to the same directional response as the target (congruent flankers), to the opposite response 
(incongruent flankers), or to neither (neutral flankers).  
 


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Digit Symbol Substitution Test: timed standardized neuropsychological test that assess processing speed.  
 
7. Patient Recruitment and Consenting Process  
 
7.1. 
IRB Review 
Before study initiation, the Investigator must have written and dated approval/favorable opinion from the 
IRB for the protocol, consent form, patient recruitment materials/process (e.g., advertisements), and any 
other written information to be provided to patients. 
 
7.2. 
Recruitment  
Individuals are going to be recruited from the well-established network developed by the Center for 
Depression Research and Clinical Care (CDRC) and which includes the Mood Disorders Network, and 
current CDRC studies such as the Dallas 2K Study (D2K) and the Resilience in Adolescent Development 
(RAD). The Mood Disorders Network (MDN) consists of primary care practices, psychiatric care practices, 
charity clinics, community, schools, who are interested in collaborating with CDRC on activities and 
projects geared toward improving care for those suffering from depression. Many MDN clinical sites use 
the Vital Sign 6 (VS6) software, an application that allows screening and management of depression, using 
the principles of Measurement-Based Care (MBC). Using VS6 application, participants are systematically 
assessed for depression and treatment outcomes are monitored utilizing multi-step evidence-based 
treatment algorithms.  
 
The D2K is an observational long-term study conducted by the CDRC researching the biological 
mechanisms of depression and antidepressant treatment response. The D2K study is comprised of 2,000 
participants, over 10 years of age, with a lifetime or current diagnosis of a mood disorder. A significant 
part of the individuals in this study are not taking antidepressants. RAD is a 10-year study of 1,500 
participants (ages 10-24) that will help uncover the factors that contribute to resilience among children, 
adolescents, and young adults at risk for mood and anxiety disorders. In addition to these observational 
studies, the CDRC conducts clinical trials for which there are standard recruitment processes. Previous 
participants in research at the CDRC who have provided consent for future contact will be invited to 
participate in this study. Participants recruited from the CDRC will already be registered under a research 
protocol and not a part of the principal investigator’s clinical practice.  
 
Participants will also be recruited from registries such as the UT Southwestern Research Volunteer 
Registry, UTSW Family Medicine Clinic, the UTSW General Internal Medicine Clinic and the UTSW 
Employee Assistance Program. The PI and study psychiatrist will meet with MDs and clinic managers at 
these sites to explain the study goals, inclusion and exclusion criteria, and study process prior to 
recruitment.  We will provide the MDs with written information about the study and the characteristics 
desired in referrals. Finally, PRECISE-D will recruit from self- and clinician-referral, and IRB-approved study 
advertisements. 
 
7.3. 
Informed Consent 
All subjects will receive the consent form for the study as well as the Human Subject’s Bill of Rights. First, 
patients interested in the study will be given a copy of the informed consent form so they can carefully 
read the document and discuss the research with their family, friends and/or physician and develop 
questions to ask at their next meeting with the research staff.  If they continue to be interested, they will 
visit the clinic and the investigator will meet with the potential subject to review and to discuss the details 
of the research study using the informed consent document as a guide. This discussion should include all 


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of the required elements of informed consent, e.g., the purpose of the research, the procedures to be 
followed, the risks and discomforts as well as potential benefits associated with participation, and 
alternative procedures or treatments, if any, to the study procedures or treatments. Subjects will always 
be given the opportunity to ask questions and have them answered by the investigator and, whenever 
possible, to consult with friends/family and/or their physicians. Once they have read the consent 
document and their questions are answered, if they agree to participate in the research, they sign and 
date the informed consent document.  Patients will sign informed consent and only then will any study-
related procedures be conducted. In order to remove any undue pressure on patients referred to the 
study from a study investigator who happens to be their personal clinician, such interested patients will 
first have an opportunity to inquire about the study from a research assistant, and obtain a copy of the 
consent form in advance.  In addition, when presenting for screening, they can only be screened and 
followed during the study (if eligible) from an investigator who is different than their personal clinician. 
 
8. Potential Risks 
Human subject risk related to administration of antidepressant medication is minimal as the medications 
planned for use in this study, escitalopram and bupropion, are approved by the Food and Drug 
administration and are frequently prescribed in routine practice and for time-periods that are consistent 
with recommended treatment practices. Additionally, the routine assessment of side effects with 
measures such as the FIBSER will enable quick detection of adverse effects if they are present.  
 
The risks involved in drawing blood from a vein may include, but are not limited to, momentary discomfort 
at the site of the blood draw, possible bruising, redness, and swelling around the site, bleeding at the site, 
feeling of lightheadedness when the blood is drawn, and rarely, an infection at the site of the blood draw.  
 
The risks of finger stick for the point of care (POC) C-reactive protein (CRP) testing include excessive 
bleeding, bruising/discoloration, infection, dizziness, fainting and pain. These risks are comparable to 
routine clinical practice where venous blood work and finger stick tests are routinely used for 
management of chronic medical conditions.  
 
The risk of EEG includes discomfort from wearing a close-fitting elastic cap and the use of an electrolyte 
solution (KCl, similar to salt water). 
 
The risk of loss of privacy is judged to be low. However, patients will be asked to provide personal 
identifying information, and there is a very rare risk of breach of confidentiality.  
 
 
9.  Subject Safety and Data Monitoring  
 
9.1. 
Safety Measures 
Minimal risk is expected from the medications as FDA approved low doses will be administered initially, 
side-effects to these doses monitored and dosage adjustments made according to guidelines. If physical 
adverse effects are intolerable at the lowest therapeutic dose, subjects may leave the study and will be 
offered an alternative treatment in consultation with their provider. Minimal risk is also expected from 
venipuncture and finger stick for POC CRP testing. These will be further minimized by having laboratory 
work performed only by trained and certified staff, following aseptic procedures, and ascertaining that 
patient does not have and active infection or taking immunosuppressive treatment (as part of eligibility 
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All research personnel are trained in safety precautions in the event the patient needs immediate clinical 
management or an imminent clinical issue is identified.  
 
9.2. 
 Suicide Monitoring  
Participants who report risk of self-harm at any point of contact will be thoroughly evaluated by the study 
personnel for intent, plan and means for suicide. If the participant is in the clinic, the study clinician will 
be immediately notified to further assess the participant. If the participant is deemed an acute risk for 
suicide, the physician will direct the measures necessary to get the participant to safety, using clinic 
specific crisis management procedures. If study personnel learn that a participant may be at acute risk 
during a phone assessment, a complete evaluation of the situation will become necessary. For example, 
if the participant indicates thoughts of suicide/death several times a day on the CHRT scale, the study 
team will obtain information about the participant’s intent, plan, and means at hand for suicide, as well 
as determine the location of the participant and whether anyone else is with the participant. Measures to 
keep the participant safe, including the option of calling 911 for police assistance will be implemented. 
Specifically: 
• 
In the event that a participant contacts the study and indicates suicidal ideation with intent  
• 
Study personnel will determine if participant is alone or has supportive family or friends with him. 
• 
Personnel will contact family members/significant friends using the contact information provided by 
participant at study entry. 
• 
If family is contacted, they will be alerted to the urgency and need to limit the participant’s access to 
the means of suicide. Personnel will review plan with family should participant need urgent care to 
prevent a suicide attempt. 
Whether the participant presents in clinic or calls in expressing active suicidality, the clinician or study 
personnel will instruct the participant to go to the nearest emergency room. If family or friends are not 
available to take the participant to the emergency room, or if the participant refuses, the clinician/study 
personnel may call 911 and have the participant escorted involuntarily. In situations where participants 
have made initial contact with the study personnel and not the study clinician, the study personnel will 
notify the licensed treating clinician of the event. Following resolution of the acute suicidal status, the 
participant will be evaluated for continuation in the study. This will be based on the current need for best 
clinical care. 
 
9.3. 
Reasons for Early Termination 
Acceptable reasons for early termination from the randomized clinical trial include the following: 1) 
request of patient, 2) decision of physician, 3) serious adverse event and 4) protocol violation.  Patients 
will be assessed for suicidal ideation at every visit.  Subjects who, in the opinion of the assessing clinician 
have a worsening of suicidal ideation that renders them at increased risk for study participation will be 
removed from the study and given an appropriate clinical referral.  
 
9.4. 
Evaluation of Adverse Events (AEs) 
An adverse event is any untoward medical occurrence in a study subject.  The reporting period begins 
when a study subject signs consent and ends at Week 12 or earlier for patients who prematurely 
discontinue the study.    
 


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Adverse events will be recorded using the appropriate form. Patients shall be allowed to contact the 
investigator or a member of his staff at any time between visits concerning adverse events or worsening 
of symptoms. 
 
Unanticipated problems involving risks to subjects, including adverse events, will be reported to the 
overall study PI and to the site IRB. 
 
Serious adverse events, including those spontaneously reported to the site-investigator from the time a 
signed and dated ICF is obtained until within 30 days after the last dose of study drug must be reported 
using the Serious Adverse Event Form.  
 
Pregnancy 
 
If a subject (or subject’s partner) becomes pregnant during the study, it must be reported within 24 
business hours of the time the investigator becomes aware of the event to study PI and site IRB. Pregnancy 
in itself is not regarded as an AE unless there is a clinical suspicion that a study drug may have interfered 
with the effectiveness of a contraceptive medication. Any pregnancy that occurs from the first day of 
treatment to 30 days following the last treatment given will be followed for gestational outcome. 
 
Disease Progression or Worsening Depression 
 
The development of worsening depression should be considered as disease progression and not an AE. 
Events, which are unequivocally due to disease progression, should not be reported as an AE during the 
study.  
 
Serious Adverse Events (SAEs) 
 
The following criteria define an SAE: a) death, b) life-threatening event, c) hospitalization or prolongation 
of hospitalization, d) persistent or significant disability/incapacity, or e) congenital anomaly/birth defect.  
The study PI are in charge of determining if an adverse event represents an SAE.   
 
10. Procedures to Maintain Confidentiality  
All investigators are required to prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the investigation on each individual treated in the 
investigation.  
 
All research staff will receive training through the Collaborative Institutional Training Initiative. Required 
courses will include: HIPAA, Good Clinical Practice, and Human Subject Protection. Staff will only have 
access to identifying information as needed for their role in the study. No information about or provided 
by the subjects will be disclosed to others without written permission. Electronic health records will be 
stored on password-protected, secure networks or devices. 
 
Potential risks to data confidentiality will be mitigated by requirements for the de-identification of all data 
and by security protocols for all data capture systems. As with all research data, information gathered by 
the study will be used only for aggregate analysis. It will not be released with any information that 
identifies research participants. Uses and risks related to data collection will be outlined in the informed 
consent and reviewed with the subjects.  


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11. Potential Benefits to Study Participants and Others 
Study participants will have the opportunity to directly benefit from the antidepressant medications 
escitalopram and bupropion. It is expected that a subset of patients in both treatment arms will show 
either improvement in or remission of their disorder. The population of depressed patients as a whole has 
an opportunity to benefit from the study, as the results may be valuable in prescribing appropriate 
personalized treatment strategies in the long-term treatment of depression. 
 
If we find that CRP-consistent antidepressant selection is superior to CRP-inconsistent antidepressant 
selection, it will reduce the decisional uncertainty associated with antidepressant selection in routine 
clinical practice and allow treatment providers and patients to choose an antidepressant that is more 
likely to result in favorable treatment outcomes. If favorable, this study would also support personalized 
selection of antidepressant medications to individual MDD patients using a readily-available inexpensive 
blood test. Additionally, if the secondary analysis demonstrates that finger stick blood can be used for the 
CRP test instead of venous blood, then this will represent a direct point-of-care option.  
 
The study will also evaluate EEG connectivity measures’ ability to predict differential treatment response 
to escitalopram and bupropion. These results have the potential to significantly impact clinical practice as 
EEG is an economical, rapid, and easy to administer method of obtaining treatment-guiding 
neurophysiological measures. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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