Clinical trial NCT02238977
Conditions: Major Depression End Stage Renal Disease
Keywords: depression ESRD hemodialysis
Sponsor: University of Arkansas
Start date: 2016-03-31; Completion date: 2018-03-01
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The proposed study will evaluate the response and remission rates for major depressive disorder (MDD) in end-stage renal disease (ESRD) patients undergoing maintenance hemodialysis (HD) treated with bupropion or fluoxetine for 12 weeks. In addition, the study will document the relative tolerability and safety, and longitudinally contrast the effects of bupropion and fluoxetine on measures of cognitive function, fatigue, inflammation, and tryptophan (TRP) and TRP catabolites in blood. It is hypothesized that both drugs will significantly reduce MDD symptoms from baseline, and be tolerable and safe, but bupropion will be associated with greater reduction in pro-inflammatory cytokines, cognitive impairment, and fatigue compared with fluoxetine.

The Specific Aims of this study are:

Aim 1: Determine the efficacy of bupropion and fluoxetine in treatment of MDD in ESRD/HD patients.

Aim 2: Determine whether longitudinal change in MDD symptoms, cognitive dysfunction, and fatigue differ between bupropion and fluoxetine.

Aim 3: Determine whether longitudinal change in MDD symptoms, cognitive dysfunction, and fatigue correlate with change in inflammation, measures of TRP availability to brain, or neurotoxic TRP metabolites.

Hypotheses:

1. Bupropion and fluoxetine will both show efficacy in treating MDD;
2. Bupropion will lead to greater improvement in cognitive dysfunction and fatigue than fluoxetine; and
3. Change in cognition and fatigue over time will correlate with change in c-reactive protein (CRP) and quinolinic acid and change in overall depression score will correlate with measures of TRP availability.

Detailed description:

Arms: arm 1: Fluoxetine up to 20 mg orally daily for 12 weeks. Flexible dosing between a minimum of 10 mg daily and 20 mg daily as tolerated. arm 2: Bupropion sustained release (SR) 150 mg orally twice per week
Interventions: intervention 1: Fluoxetine intervention 2: Bupropion
Intervention descriptions: intervention 1: Antidepressant intervention 2: Antidepressant

Protocol documents:
Prot_SAP_000.pdf: 
Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 1 
 
 
 
Study Title: 
Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
 
Principal Investigator:  Pedro L. Delgado, M.D.  
 
 
 
University of Arkansas for Medical Sciences 
 
 
 
4301 W. Markham Street, Slot # 554 
 
 
 
Little Rock, AR 72205 
 
 
 
Telephone:  501-526-8140 
 
 
 
Email: pldelgado@uams.edu 
 
 
Sub-Investigator (s): 
Ricardo Caceda, M.D., PhD  
Michelle Krause, M.D. 
 
 
 
Jeffrey Clothier, M.D. 
 
 
 
Andrew James, Ph.D. 
 
 
 
Melissa G. Efurd, Ed.D., RDH 
 
 
Claire Tucker, MEd, RDH 
 
 
 
Study location: 
UAMS Outpatient Renal Dialysis Unit 
 
 
 
1910 John Barrow Road 
 
 
 
Little Rock, AR 72205 
 
 
 
 
Psychiatric Research Institute 
 
 
 
UAMS 
 
 
 
 
 
 
 
 
 
 
 
 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 2 
1. Purpose and Objectives 
The proposed study will evaluate the response and remission rates for major depressive disorder (MDD) 
in chronic kidney disease (CKD) patients treated with bupropion or fluoxetine for 12 weeks. In addition, 
the study will document the relative tolerability and safety, and longitudinally contrast the effects of 
bupropion and fluoxetine on measures of cognitive function, fatigue, inflammation, and tryptophan (TRP) 
and TRP catabolites in blood. It is hypothesized that both drugs will significantly reduce MDD symptoms 
from baseline, and be tolerable and safe, but bupropion will be associated with greater reduction in pro-
inflammatory cytokines, cognitive impairment, and fatigue compared with fluoxetine. 
 
The Specific Aims of this study are: 
Aim 1: Determine the efficacy of bupropion and fluoxetine in treatment of MDD in CKD patients. 
Aim 2: Determine whether longitudinal change in MDD symptoms, cognitive dysfunction, and fatigue 
differ between bupropion and fluoxetine. 
Aim 3: Determine whether longitudinal change in MDD symptoms, cognitive dysfunction, and fatigue 
correlate with change in inflammation, measures of TRP availability to brain, or neurotoxic TRP 
metabolites. 
 
Hypotheses:  
1) Bupropion and fluoxetine will both show efficacy in treating MDD;  
2) Bupropion will lead to greater improvement in cognitive dysfunction and fatigue than fluoxetine; and  
3) Change in cognition and fatigue over time will correlate with change in C-reactive protein (CRP) and 
quinolinic acid and change in overall depression score will correlate with measures of TRP availability. 
 
2. Background 
Depressive symptoms, major depressive disorder (MDD), fatigue, and cognitive dysfunction are among 
the most common symptoms in patients with chronic kidney disease (CKD). In one study, 71% of 
ESRD/HD patients had MDD [1], although lower rates were reported when structured diagnostic 
interviews were used to diagnose [2].  Even when the full criteria for MDD are not met, most ESRD/HD 
patients suffer from moderate to severe depressive symptoms.  ESRD/HD patients also show high rates 
of cognitive dysfunction, with up to 87% showing some cognitive impairment and 37% showing severe 
impairment [3]. 
 
There have been few controlled trials for treating MDD in CKD patients [18], although uncontrolled studies 
are encouraging.  The relative safety of selective serotonin reuptake inhibitor (SSRI) drugs such as 
fluoxetine led to its use in several positive open label studies [19-26]; however the one placebo-controlled 
trial failed [27].  While SSRIs are efficacious in treating MDD in patients with chronic general medical 
conditions, symptoms of fatigue and cognitive dysfunction are often unresponsive [28, 29].  Bupropion is 
a unique antidepressant, being a selective norepinephrine (NE) and dopamine (DA) reuptake inhibitor. 
These properties may underlie its relative advantage to SSRIs in improving fatigue and cognition.  
Bupropion is efficacious in MDD [30], attention deficit disorder [31], and improves cognitive dysfunction in 
MDD patients [30].  Bupropion’s selectivity for NE/DA, and the modulation of prefrontal cortex 
attention/cognition and limbic reward circuits by NE/DA may underlie its favorable profile on cognition, 
fatigue, energy, weight, and sexual function. 
 
MDD is not a single disease, but a genetically complex syndrome with many causal pathways [4].  While 
early research focused exclusively on monoamines, pro-inflammatory pathways are now known to play a 
role, being capable of inducing depressed mood, fatigue, and cognitive impairment [5-7].  This line of 
research has been complicated in part by the variate sources of inflammation for a given individual, (e.g. 
age, gender, weight health status, allergies, environment, medications, mental health, substance, etc). 
For instance the most common cause of inflammation is presence of dental disease. Tryptophan (TRP) 
depletion, pro-inflammatory cytokines, and neurotoxic TRP metabolites affect the brain circuits involved in 
depression and cognitive function [8].  Experimental depletion of the essential amino acid TRP can induce 
depressive symptoms, anorexia, fatigue, and cognitive dysfunction in humans [4, 9] due to reductions in 
brain serotonin (5-HT) [10] while administration of lipopolysaccharide (LPS) induces depressive 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 3 
symptoms, fatigue, and cognitive impairment through direct effects of pro-inflammatory cytokines on brain 
circuits.  Many of these effects can be blocked by antidepressants [6]. 
Elevated levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β 
(IL-1β), and IL-6 are prominent features of HD [11, 12]. Reduction in total plasma TRP is also a well 
documented abnormality in CKD patients [11], with plasma levels of total TRP as low as those that are 
associated with depressive reactions induced by experimental TRP depletion in humans [8].  Elevated 
TNF-α and IL6 have direct effects on the central nervous system and increase peripheral conversion of 
TRP to the neurotoxic catabolites kynurenine (KYN) and quinolinic acid [13] [14]; in part by inducing an 
increase in the activity of the enzyme indoleamine 2,3-dioxygenase (IDO). While total TRP is low, free 
TRP levels can increase in blood between dialysis treatments [15], further driving its metabolic conversion 
to KYN and quinolinic acid.  KYN and quinolinic acid levels are known to be markedly increased in 
ESRD/HD patients [16], plausibly contributing to the depressive symptoms, fatigue, and cognitive 
impairment [17]. 
 
Independent of its effects on cognition and fatigue through NE/DA mechanisms, bupropion may have 
anti-inflammatory actions that could further enhance its efficacy in reducing cognitive dysfunction and 
fatigue secondary to inflammation.  This is suggested by its ability to reduce TNF-α in mice challenged 
with LPS [33] and to reduce inflammation and improve mood in patients with atopic dermatitis [34].  
Bupropion also reduced TNF-α in patients with Crohn’s disease and chronic hepatitis B virus infection [35, 
36].  While there are no trials of bupropion in ESRD/HD patients with MDD, a retrospective review 
suggested bupropion might be beneficial [37].  This proposal will obtain preliminary data needed to fully 
justify and design a definitive trial of bupropion in ESRD/HD patients with MDD. 
 
Lastly, it is well known that depression has a mutually enhancing relationship with pain. As chronic pain is 
associated with depression and other psychiatric syndromes, and in turn depressed patients endorse 
somatic symptoms, mainly pain. This is particularly relevant to our study population, since approximately 
half of the patients with chronic kidney disease suffer from chronic pain, and frequently increased 
inflammation is the main suspected mechanism. 
 
Choices of bupropion and fluoxetine for the treatment:  
Bupropion is unique amongst antidepressants because it selectively blocks reuptake of NE and DA 
without having appreciable affinity for postsynaptic receptors including histamine, α- or β-adrenergic, 5-
HT, or acetylcholine [30, 88].  This confers a favorable side effect and safety profile [89], absence of 
weight gain [90] or somnolence [91]; side effects frequently reported by HD patients with other 
antidepressants [92-95]. Bupropion has no clinically significant effects on the cardiovascular system (e.g., 
heart rate, blood pressure, QTc interval) in patients with MDD [96]. It can increase the incidence of 
seizures [97] in a dose-dependent (>450 mg/day) [30] fashion in patients with a history of seizures; 
therefore it is contraindicated in these patients. Bupropion may preferentially reduce a subset of 
symptoms of MDD common in medically ill patients, including fatigue, drowsiness, cognitive dysfunction, 
anhedonia, and mental concentration [98, 99].  In healthy humans, after oral administration, bupropion is 
rapidly and ~100% absorbed by the intestine, metabolized in the liver, and excreted via kidney. The 
hepatic cytochrome P450 (CYP) 2B6 catalyzes bupropion to a primary active metabolite, hydroxyl-
bupropion. Several studies [62, 100, 101] have provided guidelines and recommendations about 
antidepressant agents in patients with ESRD/HD. One study [80] determined the PK of bupropion and its 
active metabolites in HD patients following a single 150-mg oral dose and found comparable PK profile to 
individuals with normal renal function. Compared with controls, hydroxyl-bupropion demonstrated a >2-
fold greater AUC and substantially increased t½, indicating reduced clearance. Based on these data, the 
authors [80] suggested an oral dose of 150 mg bupropion every 3 days in HD patients. 
 
While it has been suggested that antidepressants may in general reduce inflammation, research data 
suggests that SSRIs and tricyclic antidepressants may not.  Other hand, there has been considerable 
recent interest in the anti-inflammatory effects of bupropion, although more research is needed [102]. 
Brustolim et al. [33] demonstrated that bupropion significantly reduced the levels of TNF-α in mice 
challenged with lipopolysaccharide and suggested that this effect might have important clinical 
consequences. In case reports, Kast and Altschuler [35, 36] proposed the potential anti-inflammatory 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 4 
function of bupropion against TNF-α in patients with Crohn’s disease and chronic hepatitis B virus 
infection. Bupropion has been found to be effective at both reducing inflammation and improving mood in 
patients with atopic dermatitis [34]. While Eller et al [103] found no effect of bupropion on TNF-α when it 
was added to ongoing escitalopram treatment, this study was in medically healthy MDD patients whose 
TNF-α levels were not much elevated, suggesting a possible “floor” effect.  TNF-α is considered as a 
“master regulator” of the cytokine cascade in HD [48].  Given the well-established TNF-α elevation in HD, 
bupropion may be a uniquely well-suited antidepressant for these patients. 
 
Fluoxetine is first SSRI approved by the Food and Drug Administration for treatment of MDD in the US.  It 
is the most studied antidepressant in ESRD/HD patients [18, 20, 23, 27, 60-62] and has been found to be 
safe, tolerable, and to have some suggestive evidence of being efficacious.  It may not reduce 
inflammation, [60, 104] and therefore will serve as a good comparator for bupropion. 
 
Current Practice 
The Food and Drug Administration has approved both drugs proposed in this study (fluoxetine and 
bupropion) as standard therapy for MDD. The unfortunate reality is that most ESRD/HD patients that 
develop MDD are never treated.  When antidepressants are prescribed for MDD in any patient with 
another co-occurring condition, they are selected based on the individual prior treatment history and 
contraindications for the patient.  While neither of the medications being studied is contraindicated in 
ESRD/HD patients, dose adjustments are made due to differences in excretion rates. 
 
3. Study Design 
The current study proposes to randomly assign 40 CKD patients with MDD to 12 weeks of open label, 
flexible dose treatment with either bupropion (N=20) or fluoxetine (N=20).  
 
[NOTE: We are requesting to enroll up to 50 subjects/with 40 completers.  One of the outcome measures 
will be the number of weeks of treatment that a person completes.  This is a preliminary feasibility and 
pilot study, so establishing an estimate of drop out rate will be important for when we design the 
"definitive" study in the future.] 
 
4. Study population is defined as CKD patients with chronic kidney disease with MDD. 
Inclusion Criteria 
• age 30-70 yrs;  
• meet the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for MDD;  
• have a Ham-D score > 17 
• if receiving any of these medications, on a stable or maintenance dose of iron or erythropoietin-
stimulating agents, statins, angiotension receptor blockers and/or angiotension converting enzyme 
inhibitors, phosphate binders and vitamin D receptor analogs as these agents may influence 
cytokines proposed in the study;  
• serum albumin of ≥ 3.2 g/dl, serum phosphate of <6.5 mg/dl, and serum hemoglobin of ≥9 mg/dl in 
two consecutive  blood tests [subjects failing screening due to these blood tests will be allowed to be 
re-screened in 30 days]; 
For patients not on HD or Peritoneal Dialysis 
• Estimated glomerular filtration rate below 59 mL/min per 1.73 m2. 
For patients on HD 
• have patent and non-infected arteriovenous fistula or graft;  
• are receiving maintenance HD 2-3 times per week; 
For patients on Peritoneal Dialysis 
• compliance with outpatient visits for the past two months; 
 
Exclusion Criteria 
• meet DSM-IV criteria for Bipolar Disorder or other psychotic disorder in the month prior to screening; 
• are taking antidepressants, anti-anxiety medications, or hypnotics (including Zyban for smoking 
cessation); 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 5 
• failure to respond to or tolerate bupropion or fluoxetine in the past 
• allergic to fluoxetine or bupropion 
• known history of HIV/AIDS; No testing will be conducted for screening purposes 
• known history of alcohol or drug abuse or dependence within the month prior to screening based on 
clinical records;  
• history of myocardial infarction or heart failure within one month of screening or a history of seizures 
or stroke at any point; 
• history of chronic liver disease and diagnosis of hepatic encephalopathy based on clinical records;  
• currently diagnosed with cancer or receiving any cancer treatment;  
• history of any infection within the last 2 weeks ; 
• currently taking any antibiotics, anti-inflammatory (low dose aspirin is acceptable), and immune-
modulator agents;  
• recorded noncompliance with dialysis schedules; and  
• currently participating in clinical or behavioral intervention studies. 
 
Recruitment Process—Identifying Potential Subjects 
Subjects will be recruited from the UAMS Kidney Center, other outpatient UAMS clinics, UAMS 
Hemodialysis Center and other local dialysis centers using flyers, electronic dissemination of the flyer to 
UAMS physicians and/or newspaper ads.  Referring physicians will be invited to provide the information 
to patients who they feel are appropriate for the study and, if the patient expresses an interest in 
participation or obtaining more information, the physician will provide the contact information of the study 
staff to the patient, who will voluntarily choose whether to contact the study staff for screening.  Release 
of information/consent documents will be obtained prior to accessing patient clinical information.  Prior to 
beginning the protocol and after obtaining patient’s consent, study physicians will discuss the merits of a 
patient’s participation in the study with the patient’s hemodialysis physician. 
 
Patients seeking information about the study will initiate phone contact with study staff for initial screening 
regarding inclusion and exclusion criteria. A partial HIPAA waiver will be requested from the IRB for 
phone screening purposes only. Subsequent access to clinical information will require written release of 
information/consent by the patient. 
 
Each potential subject will contact the study staff by phone for initial screening regarding inclusion and 
exclusion criteria.  Patients, who appear to meet inclusion and exclusion criteria and indicate agreement 
for the study team to contact their treating physician, will be scheduled to come in for a face-to-face 
meeting, be provided with study information, sign informed consent/HIPAA Authorization and undergo 
initial evaluation.  After consent/authorization is signed by the subject, the research staff will contact the 
treating physician to discuss the subject’s participation, provide medical records release, and obtain 
medical information from the treating physician. 
 
5. Consent Process 
Patients, who contact the research staff, appear to meet inclusion and exclusion criteria and indicate 
during this contact that they will agree to allow the study team to contact their treating physician, will be 
scheduled for a face-to-face meeting for informed consent and initial evaluation either at the UAMS 
Psychiatric Research Institute (PRI; 4th floor) or their dialysis site.  Consent will be obtained prior to any 
research procedures taking place. The potential subject will be encouraged to bring a family member with 
them for this appointment.  During this meeting, a member of the research staff will describe the study 
and review the IRB-approved consent form using lay terms with special emphasis on the risks and 
benefits, in an objective way. The team member will make attempts to answer & clarify or address any 
questions or concerns the subject (and family member) may have during this process. Ample time will be 
given to the subject to make a voluntary decision. The study information, inclusion and exclusion criteria, 
and consent documents will be reviewed.  The study team member conducting the consent process will 
sign and date the consent form. The subject will be given a business card of the study team so that 
he/she can discuss any further questions or concerns that may arise in the future. A copy of the signed 
and dated consent form will be given to the subject for his/her record.   


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 6 
 
Subjects will be encouraged to take the consent form at home to read, understand, and discuss with his/ 
her family members and or primary care physician. In this situation, subject will be contacted after one 
week to learn his/her decision to participate in the study and a subsequent meeting scheduled to sign the 
documents. An interested subject must sign the consent form in presence of the study personnel. 
Patients will be scheduled for consent/initial evaluation appointments during the initial phone screening.  
This appointment will take place between 1-14 days, giving subjects ample time to make a voluntary 
decision. There is no specific waiting time limit. 
 
Participation of an eligible subject in this clinical trial is a voluntary process. Subjects will not be coerced 
or influenced by the study personnel.  In order to participate, subjects will have to voluntarily initiate a 
phone screening and subsequently come to a face-to-face consent/initial evaluation meeting.  A research 
staff member or study investigator will conduct the consent process in order to minimize the possibility of 
undue influence from the treating physician on their hemodialysis team.  Subjects will be informed that 
participation is voluntary and not participating will not affect the delivery of the routine health care.  They 
and their treating physicians will be informed that the medications being used in the current study are 
routinely available and relatively inexpensive to obtain.  They do not have to participate in this study to 
receive any of the treatment options. 
 
Subjects are randomly assigned to open label treatment with one of two medications.  Therefore, there 
are two groups: 
• Bupropion group:  
o 
For patient not on hemodialysis, oral administration of bupropion SR tablet at a dose of 
150 mg daily. Bupropion SR doses will be adjusted upward or downward based on 
tolerability and response. 
o 
For patient on hemodialysis or peritoneal dialysis, oral administration of bupropion SR 
tablet at a dose of 150 mg on the 1st and the 3rd dialysis day of each week. Bupropion 
SR doses will be adjusted upward or downward based on tolerability and response. 
 
• Fluoxetine group: Oral administration of fluoxetine tablet will be started at a dose of 10 mg/day for the 
first week and then increased, as tolerated to 20 mg/day for weeks 2–4. After this, doses will be 
adjusted based on clinical response and side effects up to a maximum dose of 60 mg/daily by week 
10. 
 
Although non-English speaking participants are not anticipated, there is an unlikely possibility that we 
may recruit a Spanish-speaking individual. If this occurs we will submit the translated materials and 
certification of translation to the IRB for approval prior to enrolling the subject. The principal investigator is 
fluent in Spanish (reading, writing, speaking) and will obtain consent from any Spanish speaking subjects. 
Study staff will assess each subject’s understanding of the study procedures, including risks and benefits, 
during the initial evaluation process.  A Spanish-speaking physician will interview Spanish-speaking 
subjects during the initial evaluation to determine their understanding of the materials, and subjects will 
be given the option of having study materials in their preferred language. Since the possibility of 
recruitment of a non-English speaking participant is unlikely in this small population, we will not submit 
translated materials for approval unless necessary. 
 
6. Research Plan 
The current study proposes to recruit up to 50 participants in order to have 40 completers. Eligible CKD 
patients with MDD will be randomly assigned to 12 weeks of open label, flexible dose treatment with 
either Bupropion SR (N=20) or Fluoxetine (N=20). Patients will be recruited from the UAMS dialysis 
center or other local dialysis centers via flyers, referral by their treating physician and/or newspaper ads. 
Written consent will be obtained before any study procedures. Subjects are randomly assigned to open 
label treatment with one of the following: 
• Bupropion group:  


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 7 
o 
For patient not on hemodialysis or peritoneal, oral administration of bupropion SR tablet 
at a dose of 150 mg daily. Bupropion SR doses will be adjusted upward or downward 
based on tolerability and response. 
o 
For patient on hemodialysis or peritoneal dialysis, oral administration of bupropion SR 
tablet at a dose of 150 mg on the 1st and the 3rd dialysis day of each week. Bupropion 
SR doses will be adjusted upward or downward based on tolerability and response. 
• Fluoxetine group: Oral administration of fluoxetine tablet will be started at a dose of 10 mg/day for the 
first week and then increased, as tolerated to 20 mg/day for weeks 2–4. After this, doses will be 
adjusted based on clinical response and side effects up to a maximum dose of 60 mg/daily by week 
10. 
 
After consent, subjects will be interviewed by a study staff for eligibility, including a review of medical 
records (if available), clinical interview, physical examination, routine blood tests, and EKG, if not already 
available (within one month).  Psychiatric diagnosis will be established after interview using the Mini 
International Neuropsychiatric Interview (MINI) [75], depressive symptoms will be assessed with the 
Hamilton Depression (HAM-D) Scale [76], and cognitive status will be assessed using the n-back and 
MSIT tasks [77] and the Modified Mini Mental Status (3MS) Examination [78]. Pain will be characterized 
with the Physical and Psychological Pain Scale [142].  Pressure pain threshold will be measured with an 
Algometer [143]. Thermal pain sensitivity will be characterized with Quantitative Sensory Testing (QST). 
Delay discounting, MSIT and n-back will be the primary measures of cognitive function and the 3MS will 
be used for comparison to other studies.  History of prior antidepressant treatment and response will be 
obtained using the Antidepressant Treatment Response Questionnaire (ATRQ) [79].  Given the under-
recognized role of dental and gum disease in systemic inflammation a basic noninvasive dental 
evaluation will be performed by Dr. Melissa Efurd at UAMS Dental Hygiene Clinic. Dialysis dose, pre- and 
post-dialysis body weight and blood pressure, serum urea nitrogen, albumin, serum phosphate 
hemoglobin, calcium, parathyroid hormone, vitamin D and lipid profile will be extracted. Measures of 
dialysis adequacy (kt/V) will also be extracted. 
 
Participants will receive the study medication during the baseline assessment and instructed to begin the 
medication on day 1 (1st dialysis day) of week 1 of the study.  For patient on hemodialysis or peritoneal 
dialysis, generic bupropion SR will be dosed at 150 mg on the 1st and the 3rd dialysis day of each week 
with doses adjusted upward or downward based on tolerability. The initial dose of bupropion-SR is based 
on the findings of Worrall et al [80], who measured plasma bupropion levels in a pharmacokinetic study of 
bupropion in HD patients.  For patient not on hemodialysis or peritoneal dialysis, generic bupropion SR 
tablet will be dosed at 150 mg daily.  Bupropion SR doses will be adjusted upward or downward based on 
tolerability and response.  Fluoxetine will be started at 10 mg/day for the first week and then increased, as 
tolerated to 20 mg/day for weeks 2–4.  After this, doses will be adjusted based on clinical response and 
side effects up to a maximum dose of 60 mg/daily by week 10 [62]. At the week 12 visit, the participants 
will stop the medication or may undergo a 1-2 week taper (depending on maintenance dose) if they are 
on a dose of fluoxetine that is higher than 20 mg. 
 
Subjects will be seen during weeks 1, 2, 3, 4, 6, 8, 10, and 12 in face-to-face meetings by a rater blind to 
study medication and a study physician for Ham-D ratings, CGI, medication accountability, and 
measurement of adverse events.  On weeks 5, 7, 9 and 11, subjects will come in to return the previous 
week’s pill bottles and pick up the current week’s medication.  Table 1 shows study procedures. 
Medication will be prepared by UAMS Research Pharmacy, labeled with the directions for use and 
contact information, and given to participants by study staff on a weekly basis. Compliance will be 
monitored using the MAFV at each scheduled encounter and by analysis of antidepressant blood levels. 
Results of a second EKG done during week 4 will be reviewed to ensure QTc interval is less than 500 
msec. 
 
In order to control for the potential confound of chronic pain we will characterize it with the physical and 
psychological pain scale and with two objective measures, i.e. the pressure pain threshold and the 
Quantitative Sensory Test (QST). 
 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 8 
Given that dental disease (gum disease and caries) is the main source of increased inflammation in the 
general population we aim to control for this confound for our Specific Aim 3 by having a baseline and 
end of study dental assessment.  
 
Biochemical Measurements:  
Plasma for inflammatory markers, TRP, and TRP metabolites will be obtained at mid-week prior to 
dialysis on weeks 1, 4, and 12.  Blood fluoxetine and hydroxyl-bupropion levels will be obtained at weeks 
4, and 12. When possible, samples will be taken from pre-filtered blood at the dialysis site and sent to a 
research laboratory core at UAMS and/or UT San Antonio for analysis. Twenty ml of venous blood will be 
collected as described in Table 1.  Blood for free- and total-TRP and large neutral amino acids (LNAA) 
will be assayed by high performance liquid chromatography with coulometric detection (HPLC) [105] and 
expressed in µM.  Plasma KYN concentrations will be determined by HPLC [106]. Quinolinic acid will be 
quantified by electron capture negative chemical ionization gas chromatography/mass spectrometry with 
[180] QUIN as internal standard [107].  Determinations of plasma concentrations of CRP, IL-1β, IL-6, and 
TNF-α will be performed by ELISA with the use of Quantikine High Sensitivity kits (intra-assay coefficient 
of variation for these cytokines 2.0 to 8.6%; interassay coefficient of variation 3.9 to 7.0%; R&D Systems, 
Minneapolis, MN) following established guidelines [108].  Bupropion and its active metabolites 
hydroxybupropion and fluoxetine and norfluoxetine will be analyzed using HPLC and mass spectrometry 
(MS) [109] [110]. 
 
The following tools will be utilized: 
a) The Mini International Neuropsychiatric Interview (MINI) [75]. Psychiatric diagnosis will be assessed 
with the MINI, a widely used semi-structured interview for DSM-IV diagnoses. It has high reliability, for 
MDD and depressive subtypes. (Time - 30 min). 
b) The Hamilton Depression (HAM-D) Scale [76].  Depressive symptoms in all phases of this study will 
be measured with the 25-item version of the HAM-D.  (Time – 5 minutes). 
c) The Profile of Mood States (POMS) [81, 82].  The POMS is one of the most validated measures for 
measuring a wide range of clinical and subclinical changes in mood.  It has been studied extensively in 
various clinical samples including psychiatric patients as well as in cancer, drug abuse and addictions, 
and the broad domain of exercise, fitness, sports psychology, and sports medicine.  (Time – 10 min). 
d) The Brief Fatigue Inventory (BFI) [83]: It is used to assess the severity of fatigue and the interference 
of fatigue with daily functioning. The interference items include general activity, mood, walking ability, 
normal work (includes both work outside the home and housework), relations with other people, and 
enjoyment of life. The interference items are measured on a 0–10 scale, with 0 being “does not interfere” 
and 10 being “completely interferes.” (Time – 5 minutes). 
e) The Modified Mini Mental Status (3MS) Examination [78]: The 3MS Examination is a validated 
screening tool to evaluate global cognitive function with components for orientation to time and place, 
attention, language, immediate recall, short-term verbal memory, calculation, construct ability, and 
memory. [84]. (Time – 8 minutes). 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 9 
f) 
Delay discounting task. It 
is a decision making 
task. Subjects will be 
presented a series of 
trials in which they will 
choose between a set of 
hypothetical rewards or 
losses to be received in 
variable time spans. 
Smaller sooner (SS) 
hypothetical reward/loss 
($X) received today or a 
larger later reward/loss 
(LL) ($1000) received at 
a future delay (1wk, 
1mo, 6mo, 1yr). The 
value of the SS award 
will be titrated with 
participant responses so 
that an equal number of 
SS and LL choices are 
selected for each delay. 
Time - 5 minutes [144]. 
g) Multi-Source 
Interference Test 
(MSIT): MSIT is a non-
verbal test of attentional 
conflict which combines 
elements of the Stroop, 
Flanker, and Simon effects. Although designed as a standardized fMRI task for studying attention, 
MSIT has robust behavioral effects [77]. This task is selected because Dr. James has used it to study 
cognition in a large normative sample. 
h)  N-back task. The n-back task is a non-verbal test of working memory, a cognitive process that 
generally facilitates other cognitions [77]. Dr. James has previously shown this task to have strong 
construct validity with clinical measures of working memory. 
i) 
Antidepressant Treatment Response Questionnaire (ATRQ;[79]): A scale to determine treatment 
resistance.  It provides criteria for adequate dose duration of a trial for it to be considered a failure. 
i) 
Clinical Global Impressions - Severity and Improvement (CGI-S, CGI-I;[85]) (Time 3-5 minutes): 
These two instruments are scored 1-7 by the clinician based on assessment of the patient's clinical 
status. They measure: a) depression severity (CGI-S), and, b) clinical improvement (CGI-I) 
k) Systematic Assessment For Treatment Emergent Events (SAFTEE) [86, 87] (Time-5 - 15 minutes)- 
This measures treatment-emergent events, using both the general and a modified specific inquiry that 
asks about each symptom found problematic. To this list will be added any item elicited from that 
patient in response to previous general inquiries and any additional adverse events elicited in at least 
10% of the first 50 patients. For each symptom the patient is then asked about onset, intensity, off-set 
and counteractive measures, and the clinician judges the likelihood it is medication-related. 
l) 
Medication Accountability Record (Time 2-3 minutes).  Used to record medication adherence.  
Pharmacy staff will record number of pills missing from previous week’s bottle after each study visit. 
m) Physical and Psychological Pain Scale, self-report has 7 items and takes 2-3 minutes to complete. It 
characterizes psychological pain in comparison with physical pain [142]. 
Table 1. Study Procedures 
Measures 
Week of Study 
 
B 
1 
2 
3 
4 
6 
8 
10 
12 
ATRQ 
X 
 
 
 
 
 
 
 
 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MINI 
X 
 
 
 
 
 
 
 
 
Dental evaluation 
X 
 
 
 
 
 
 
X 
 
Ham-D 
X 
X 
X 
X 
X 
X 
X 
X 
X 
POMS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BFI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood (20 ml) 
X 
X 
 
 
X 
 
 
 
X 
EKG 
 
 
 
 
X 
 
 
 
 
CGI 
 
X 
X 
X 
X 
X 
X 
X 
X 
SAFTEE 
 
X 
X 
X 
X 
X 
X 
X 
X 
MAFV 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical and 
Psychological Pain 
Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pain threshold 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quantitative Sensory 
Test (QST) 
X 
 
 
 
 
X 
 
 
X 
Delay discounting task 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cognition (MSIT, n-
back& 3MS) 
X 
 
 
 
X 
 
 
 
X 
MINI: Mini International Neuropsychiatric Interview; HAM-D, Hamilton 
Depression (HAM-D) Scale;  ATRQ: Antidepressant Treatment 
Response Questionnaire; POMS: Profile of Mood States; BFI: Brief 
Fatigue Inventory; CGI: Clinical Global Impressions;  SAFTEE: 
Systematic Assessment For Treatment Emergent Events;  MAFV: 
Medication Accountability Form;; 3MS:  Modified Mini Mental Status 
Examination 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 10 
n) Pressure Pain Test Patients will be placed supine. A point five inches below the patella in the medial 
border of the tibia will be identified in both sides. Pressure will be applied using a digital force gauge 
with a 1-cm2 rubber tip (J-Tech Medical, Commander Algometer or equivalent) alternately to the left 
and the right tibia for a total of three times each. Participants are instructed to verbally report when 
their sensations change from pressure to pain. A mean tender point threshold (kg) is calculated from 
the six measurements [143]. To prevent any possible tissue damage, stimulation will only be applied 
to a maximum of 20 Lb. 
o) Quantitative Sensory Testing (QST) on untreated skin will be performed using cutaneous hot and cold 
stimuli via a thermal stimulator (Q-Sense) thermode on the Medoc Pathway System (Medoc Ltd 
Advanced Medical Systems, Ramat Yishai, Israel). It will be performed via method of limits testing on 
the right thenar eminence with a program designed to randomly order 5 hot and 5 cold stimuli with 
random durations (5–35 seconds) between each trial. The Q-Sense thermode will begin at 32°C and 
increase or decrease by 0.5°C per second. Participants will be instructed to press a button to signify 3 
different measures: 1) sensory threshold, or the temperature at which the stimulus becomes 
noticeable; 2) pain threshold, or the temperature at which the stimulus becomes painful; and 3) pain 
tolerance, or the temperature at which the stimulus becomes unbearable. The device will be set to 
stop heating at 51.5°C and stop cooling at 0°C to avoid tissue damage. 
 
Concomitant Clinical Management and Study Termination 
Patients will continue to be managed by their treating physician during the study.  Acute events 
that may require hospitalization are expected in this population. These events and possible interruptions 
of study drugs will be recorded, and if necessary, patients may be discontinued from the study. Patients 
expressing suicidal ideation or plans will be brought to the attention of the treating physician and 
treatment options discussed. The PI will be available for consultation on such cases. Depending on the 
severity and/or wishes of the treating physician and patient, a number of options are available, including 
transportation to a nearby emergency department, referral to the Psychiatry outpatient clinic, or medical 
intervention at the dialysis center. 
Subjects may terminate the study at any time for any reason.  Reasons for early discontinuation 
will be ascertained by research staff as best possible and recorded in the following categories: 1) 
unspecified patient request or failure to return, 2) patient request or physician decision due to clinical 
worsening without meeting relapse criteria: 3) adverse event, 4) protocol violation.  Subjects that 
discontinue prematurely will be given referral options and advice, if possible.   
Non-responders to treatment will meet with a physician to review options, including referral to a 
community clinic or the Psychiatry Department.  Subjects that complete the study with no relapse will be 
given the option to be referred to a physician in the Psychiatry Outpatient Clinic or have their medication 
managed by their current general physician.   
 
End of study Follow-up Phone call 
Participants will be contacted by phone at week 14 (two weeks after concluding the trial) to determine if 
the participant is experiencing any post-treatment adverse events related to the cessation of study 
medications. Participants experiencing distress will be referred to the UAMS Walker Family Clinic for 
further psychiatric care. 
 
Limitations and Alternative Design  
The use of peripheral measures rather than measurement of cytokines or biochemical markers in the 
cerebrospinal fluid (CSF) is a limitation, however, the risks and discomfort involved in CSF measurements 
is not warranted without stronger justification. The central action of proinflammatory cytokines on the 
hypothalamic-pituitary-adrenal (HPA) axis has been suggested to be a risk factor for MDD [111]. 
However, data suggest that the HPA axis function is not markedly altered in HD patients [112, 113]. 
TNF-α antagonists [114] could be used to test the hypothesis that TNF-α contributes to depressive and 
cognitive symptoms.  However, these compounds are expensive, difficult to administer, and have 
potentially serious adverse effects [115]. 
 
Data Analysis, Statistical Considerations, and Testing of Hypotheses: 
Determination of Sample Size: Hypothesis 1 concerns within-treatment group improvement of 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 11 
depression. With four post-baseline measures, calculation of power requires an estimate of the matrix of 
correlations among the repeated measures. We specified a medium effect size averaged across the post-
baseline measures (Cohen’s d=0.5 SD, 1988), unadjusted alpha of 0.05. We specified compound 
symmetry among the measures with r=0.50 because the measurements are relatively close in time. With 
these specifications, it is possible to calculate the standard error of the difference between baseline and 
the average of the post-baseline measures. With N=20, IBM SamplePower3’s (IBM SPSS, 2000) module 
for the t-test for paired observations indicates power=0.78 with N=20. We confirmed this result with a 
simulation with 1000 datasets with the structure described, performing mixed effects analyses as 
described below. The simulation yielded an empirical power estimate of 0.79 for Hypothesis 1. We also 
evaluated a banded covariance structure in which the correlations fell off from .50 to .32 over time, and 
found that yielded power=0.75. Hypothesis 2 concerns between group differences. Power was 
calculated using Hedeker’s RMASS2 software for mixed models with longitudinal data. Specifications 
were as above but the effect size was adjusted for the use of a baseline covariate and the design involves 
two groups of N=20 each assessed at four occasions. In this case, power is 0.80 to detect a standardized 
mean difference (Cohen’s d) of 0.6. This is slightly larger than the conventional medium effect size of 
d=0.50. The analyses for Hypothesis 3 involves using the TRP/LNAA ratio as a covariate in mixed 
effects regression models with the same design structure and analytic plan as the between-groups 
models for Hypothesis 2. Converting Cohen’s d to the correlation coefficient equivalent, d=.6 is roughly 
equal to r=.30, Cohen’s convention for a medium correlation. Evidence that these assumptions about 
effect sizes are probably quite conservative can be found in previously described effects of bupropion [68, 
70, 90, 116-120] and fluoxetine [28, 60, 104, 116, 121] on symptoms of major depression, cognition, and 
inflammation. 
 
General Methods: Given that a primary goal of the current study is to obtain data to justify and support the 
feasibility of a future definitive trial, a variety of data necessary for this, including data on tolerability and 
safety (see below), will be obtained. For example, subject disposition will be summarized with a table 
indicating the number of subjects screened, the number of screen failures by reason, the number 
enrolled, the number who dropped out (by reason), and the number completing the study. Random 
double-blind assignment of patients to fluoxetine or bupropion is expected to yield similar distributions of 
measured and unmeasured variables of interest. This design provides a strong basis for making 
inferences about causal relationships between variables by controlling a priori for a wide range of patient 
and situational factors, thereby increasing the validity of estimates and inferential tests. In between-
groups analyses, variables that are related to outcome which differ between groups will be included as 
predictors in a logit model predicting group assignment, and the predicted values of this model will be 
incorporated as a covariate in all subsequent analyses. This includes factors that could influence 
treatment response [125-127], including number of prior episodes (>2 or not), treatment response vs. 
remission during treatment, and sex [128]. Continuously distributed outcomes will be summarized with the 
sample size, mean, standard deviation, median, minimum and maximum and categorical or binary 
outcomes with counts and percentages. Distributions will be examined to identify potentially influential 
observations (outliers) and suggest transforms (e.g., log) to normalize. The final report containing 
formatted tables and embedded graphics will be produced in Microsoft Word directly from the database 
using the SAS Output Delivery System. Analyses will use all subjects with usable data. All statistical 
testing will be two-sided with a significance level of 5%. The Holm-Bonferroni step down method will be 
applied as necessary to correct for multiple testing. SAS Version 9.2 for Windows (SAS Institute, Cary, 
North Carolina) will be used throughout. 
  
Tolerability and Safety: We will determine incidence rates for all adverse events and treatment emergent 
adverse events will be determined using the SAFTEE. Treatment emergent adverse events will be 
defined as those that were not present before the first administration of drug, but occurred after the first 
administration, or that were present before the first administration but increased in severity or frequency 
after the first administration. Incidence rates for all adverse event and treatment emergent adverse events 
will be compared between medication groups using chi-square for frequencies with any events or Poisson 
regression for counts of numbers of events adjusting for time at risk using log time as an offset variable. 
The numbers of subjects withdrawing from the study for each reason will also be compared across 
groups using survival analysis on time to study discontinuation. 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 12 
Testing Hypothesis 1. Both antidepressants will be efficacious based on change in Ham-D scores over 
time. The primary analyses will be mixed effects regression models with repeated measures (baseline, 1, 
4, 8, 12 weeks) performed separately in the medication groups. The fixed effect is time, and the 
hypothesis test is an a priori contrast comparing the baseline value with the average of the four post-
baseline values. In secondary analyses, patients will be categorized as responders and remitters, with 
response defined as a 50% or greater improvement in Ham-D score with total score ≤ 15 at the 12 weeks 
compared with baseline and remission [129] as having had a treatment response plus a final Ham-D 
score ≤7.  
Testing Hypothesis 2. Changes in cognition, fatigue, and depression will be evaluated between and 
within treatment groups. Changes in BFI and cognition should be greater in bupropion SR-treated 
patients [30, 32, 89, 130-140]. These analyses will use mixed effects regression models with repeated 
measures. Treatment group, time and their interaction are the fixed independent variables. Change in 
Ham-D, BFI and cognitive dysfunction (3MS, MSIT, and n-back performance) are the time-varying 
dependent variables. All subscales of the BFI will be summarized by time point.  
Testing Hypothesis 3. These analyses will measure the association between CRP, TRP availability, and 
quinolinic acid to Ham-D score, BFI, and cognitive measures over time. Because the effects of TRP on 
brain 5-HT is best estimated by the ratio of free TRP to LNAA, this ratio will be calculated and used as the 
primary measure of possible brain 5-HT depletion. The analyses will use mixed effects regression with 
time, the TRP/LNAA ratio, and their interaction as independent variables and measures of depressive 
symptoms (HAMD) and cognitive dysfunction (3MS, n-back accuracy, and MSIT reaction time) serving as 
dependent variables. Supplemental analyses will be done using the presence of residual depressive 
symptoms (yes: HAM-D>15; no: HAM-D<=15) and presence of cognitive impairment (yes: 3MS <80, no: 
3MS ≥80), presence of dental disease (yes/ no) over time (1, 4, 8 and 12 weeks) using the generalized 
linear model (GEE) with the same fixed effects and binomial error.  
Exploratory Analyses: Additional analyses will explore age, sex, baseline depressive symptoms 
(HAMD), baseline dental disease and interactions of these covariates with the fixed effects in the models 
described above. McNemar’s test will be used to compare the proportion of subjects meeting criteria for 
cognitive dysfunction at baseline compared with study end, and chi-square tests to compare these 
proportions with population rates. Pearson correlations will be used to assess the strength of associations 
between variables at each assessment. Correlations between the measures of depression, cognitive 
function, and fatigue will be tabled and summarized with scatter plots across all time points and by time 
point. Exploratory analyses will also substitute individual cytokines and the ratio of pro- to anti-
inflammatory cytokines for inflammation in relevant analyses and also seek to define whether there is a 
threshold for individual cytokines or the pro/anti-inflammatory ratio before depressive symptoms (HAM-
D>8) or cognitive dysfunction occur. The threshold analysis will utilize traditional receiver-operator 
characteristics (ROC) analyses. Both buproprion SR and Fluoxetine are local standard practice. 
 
Source of Funds 
This study is funded by UAMS Department of Psychiatry.  
 
Probable Duration 
The study will be completed in 1 year. 
 
Risks and Benefits: 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 13 
Study Intervention #1 Benefits 
Bupropion SR Group 
Bupropion SR Group 
Possible improvement in depression status 
Reasonably foreseeable risks: 
 
Not serious 
Serious  
Likely 
These risks are expected to occur 
in more than 10 out of 100 
subjects. 
• 
Dizziness 
• 
Agitation 
• 
Blurred vision  
• 
Tremor 
• 
Sweating 
• 
Headache/migraine 
• 
Inability to get adequate sleep 
• 
Increased heart beat 
• 
Dry mouth 
• 
Constipation 
• 
Decreased appetite 
• 
Nausea, vomiting 
• 
Weight gain 
• 
None 
 
Not serious 
Serious 
Less likely  
These risks are expected to occur 
in 2-9 subjects or less out of 100 
subjects. 
• 
High blood pressure (Hypertension) 
• 
Low blood pressure (Hypotension) 
• 
Skin rash and itching 
• 
Impotence 
• 
Urinary frequency 
• 
Arthritis   
• 
Slowness in movement (bradykinesia)  
• 
Upper respiratory complaints 
• 
Fatigue 
• 
Anxiety 
• 
Decreased sexual desire (libido) 
• 
Abnormal heart rhythm 
 
 
  
Serious 
Rare These risks are expected to 
occur in less than 1 subject in 100. 
 
 
• 
Urinary retention 
 
1) Suicidal ideation 
2) Suicide 
3) Faint (syncope) 
4) Seizures.  In doses over 400mg 
per day, bupropion SR can be 
associated 
with 
seizures. 
The 
incidence of seizure with bupropion 
SR at the usual daily dose of 300 mg 
is approximately 0.1%, (or 1 out of 
every 
1000 
patients), 
which 
increases to approximately 0.4% at 
the maximum dose of 400 mg/day.  
The dose of 150 mg twice per week 
used in this study was previously 
shown to lead to blood levels in 
hemodialysis patients comparable 
to those obtained during routine 
treatment 
of 
non-hemodialysis 
patients treated with 300 mg daily. 
 
 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 14 
Study Intervention #2 Benefits 
Fluoxetine Group 
 
Fluoxetine group 
Possible improvement in depression status 
Reasonably foreseeable risks: 
 
Not serious 
Serious  
Likely 
These risks are expected to occur 
in more than 10 out of 100 
subjects. 
• Decreased appetite 
• Anxiety 
• Nervousness  
• Inability to obtain adequate 
sleep (insomnia) 
• 
None 
 
Not serious 
Serious 
Less likely  
These risks are expected to occur 
in 2-9 subjects or less out of 100 
subjects. 
• 
Impaired thinking 
• Alteration in blood glucose 
• Abnormal bleeding 
• Weight loss 
 
 
Serious 
Rare  
These risks are expected to occur 
in less than 2 subjects out of 100  
 
• Suicidal ideation 
• Suicide 
• Serotonin syndrome symptoms (mental status 
changes [agitation], increased heart beat, 
change in blood pressure, dizziness, tremor, 
seizures, and/or nausea, vomiting, diarrhea) 
• Allergic reactions (Anaphylactoid reactions - 
including bronchospasm, angioedema, 
laryngospasm, and urticarial) and skin rash 
 
Risks associated with stopping the study medication. To our knowledge, there are no known risks to 
stopping bupropion abruptly. In addition, although abrupt termination of selective serotonin reuptake 
inhibitors (SSRIs) have been associated with a SSRI discontinuation syndrome (consisting of symptoms 
described as "head shocks," dizziness, electric shock-like sensations, sweating, nausea, insomnia, 
tremor, confusion, nightmares, and vertigo), fluoxetine has been associated with only mild dizziness and 
vertigo in patients maintained on fluoxetine at 20 mg/day that was abruptly terminated in a randomized 
double blind trial (141). 
 
Procedures to Minimize Risks 
 All side effects will be closely monitored; 
 Physical examination and blood test results will be performed reviewed to help detect an increased 
risk of developing side effects; 
 Aseptic precautions to minimize risks associated with blood draw;  
 Subjects will be educated to share any unusual event or change in their health with the study staff; 
 Study staff will ask questions to elicit any new event or change in their health during each encounter; 
 The study procedures to be performed on subjects are consistent with sound research design. 
 Participants maintained on fluoxetine at doses higher than 20 mg/day will undergo a 1-2 weeks taper 
depending on the maintenance dose. 
 The researchers have taken steps to minimize the known or expected risks.  However, appropriate 
medical treatment will be provided for any adverse event (anticipated or un-anticipated) as per 
standard medical practice and guidelines. In addition, the event will be documented for proper 
notification. In addition, following measures will be implemented: 
o 
All patients will continue to be managed by their treating physician during the study. Acute events 
that may require hospitalization for reasons unrelated to the study are possible in this population. 
These events and possible interruptions of study drugs will be recorded, and if necessary, 
patients may be discontinued from the study. Patients expressing suicidal ideation or plans will be 
brought to the attention of the treating physician and treatment options discussed. The PI will be 
available for consultation on such cases. Depending on the severity and/or wishes of the treating 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 15 
physician and patient, a number of options are available, including transportation to an 
emergency department medical facility, referral to Psychiatry outpatient clinic, or medical 
intervention at a nearby dialysis center. 
 
Minimize Risks From Loss of Privacy:   
All participant information (clinical and research information) will be maintained in a research file separate 
from hospital medical records. In addition to current measures, the present study will comply with the 
Health Insurance Portability and Accountability Act of 2003. No biological result or data are released to 
subjects or third parties under any circumstances. 
 
Data at each visit will be recorded using a standardized clinician assessment forms, a set of patient rating 
scales and/or computer-delivered tasks. To protect participants’ confidentiality, minimal identifying 
information will be collected, and any information collected will be stored securely.  Paper-based and 
electronic records will be stored in a locked cabinet located in an office at the Psychiatric Research 
Institute at UAMS, Little Rock, AR 72205 and a secure server, respectively. Only the PI, Co-PI and the 
study coordinator will have access to the locked cabinet. Only the Principal Investigator and research staff 
will have access to these files.  Electronic records will be encrypted and stored on password-protected 
computers accessible only to members of the research team. All data will be double entered and 
compared using automated comparison programs.  Inconsistent data entry will be resolved against the 
raw data and comparisons will continue until all inconsistency is removed. Edited and corrected data will 
be added to a database that is ready to be used as input to statistical software. All data will be kept in 
password-protected files separate from the data for analyses or stored in locked file cabinets. No 
identifiers other than study patient number assignment will be included in the dataset.  In the reporting of 
results, only aggregate group information will be presented. No unique personal identifiers that could 
disclose the identity of the research participants will be presented or published   Clinical and research 
information will be maintained in a research file separate from hospital medical records.  
 
Data will be kept in accordance with FDA, UAMS, and NIH guidelines.  When the study is complete, data 
will be stored at a secure long-term storage facility managed and operated by UAMS.  Only limited staff 
will have access to the stored data.  Where policies overlap, the longest retention policy will be followed, 
and then the most stringent destruction policy will be followed.   
 
Biological materials for will be identified by bar code or study ID rather than by name. Any records (either 
hard copies or removable electronic files) with identifiable patient information are kept in a locked file in 
the Department of Psychiatry and can only be accessed by the investigators and study staff. Biological 
specimens will be analyzed as per Protocol. Specimens collected during this study, if any are remaining, 
will be destroyed by the end of the study. 
 
Payment.   
A subject will receive a small reimbursement for time/travel for being in this study. S/he will be 
compensated with a check for $25.00 for every study visit completed that involves assessments.  
Subjects can earn up to a total of $250.00 upon completing 10 study visits that involve assessment.  
Subjects will not be compensated for visit that involve only picking up meds.  However, subjects can be 
provided taxi rides for the visits to pick up meds.  If a subject does not finish all the study visits, he/she will 
be paid only for the visits completed. 
 
Costs to Subjects.     
The Investigator will provide the study drug free of charge during this study. In addition, all tests, 
examinations, and medical care required in this study are provided to a participant at no cost.  There will 
be no costs for the subject participation          
 
The researchers will take steps to minimize the known or expected risks.  However, the subject may still 
experience problems or side effects, even though the researchers are careful to avoid them.  If the 
subject believes that he/she has been harmed, she/he will be instructed to notify the researchers as soon 


Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
PI:  Pedro L. Delgado  
 
Version #: 17, IRB #203076 
Date:  03.10.2017  
Page 16 
as possible. In the event of a research-related injury or if the subject experiences an adverse reaction, 
he/she will be instructed to immediately contact the study doctor.  
 
If the subject is injured as a result of the research procedures, the injury will be treated. 
   
The subject/insurance company will be responsible for any charges.  We have no plans to give the 
subject money if he/she is injured. 
Subjects are informed that they do not give up any of legal rights by signing the Consent Form.  
Data and Safety Monitoring Plan. 
The current study is a Clinical Trial and includes procedures that could pose a risk to subjects. A data and 
safety monitoring plan has been developed.  
 
Data Acquisition, Collection, Transmission, and Entry: 
Procedures in Place to Ensure the Validity and Integrity of the Data 
 
Written standard operating procedures will be used to protect data from error, negligence, misconduct, 
conflict of interest, malicious acts, and catastrophe. The principal investigator will maintain all research 
records. They will not be mingled with or co-located with medical records. To insure an adequate archive, 
data will be collected on paper forms and stored in folders unique to each participant. Calculations of test 
scores will be made by the test administrator and independently verified by the principal investigator. The 
test administrator will enter data into a dedicated computer database within one week of collection. The 
principal investigator will independently verify accuracy of data entry. Computer files will be backed up 
daily. The principal investigator and test administrator will verify data integrity weekly. To safeguard 
patient anonymity and the confidentiality of research records, all data collection forms and computer 
databases will identify patients by subject identification number only. Computers and computer databases 
will be password protected with independent passwords known only to the principal investigator and test 
administrator. Computers used for data storage and analysis will be not be networked to public access 
servers. Original paper files and backup disks will be archived in locked file cabinets in a locked room in a 
secure building. Access to combinations/keys will be limited to the principal investigator and test 
administrator. The UAMS Institutional Review Board (IRB) will monitor the conduct and progress of the 
study at least annually and may audit data collection and management procedures without notice. 
 
The entire study team is responsible for collecting study data including safety data during each encounter 
(e.g., scheduled clinic visit, telephone contact, subject’s reporting). Data will be entered in the Source 
Document as a narrative. PI and the Sub-Investigators will review the data and additional information will 
be collected or verified through medical records, electronic medical data sources, further subject interview 
etc.  The CRF (or the electronic data capturing) will be updated as per verified Source Document. All data 
will be maintained and kept confidential in a locked cabinet (or electronic devise) with authorized access. 
 
The research assistants will have at least a bachelor's level education (or relevant experience) and 
previous experience in clinical rating and/or interviewing. One of the investigators or designee will give a 
training session on the background of the particular scale and how it is to be completed. Then the staff 
member will observe completion of the assessment by an experienced rater on at least three occasions. 
Afterward, the staff member will complete the assessment in the presence of an experienced rater on at 
least three occasions, with feedback given each time, until the trainer is confident that the person 
understands the assessment and completes it properly. Thereafter, assessments will be checked on a 
continuous basis for appropriate completion, and constructive criticism will be given as necessary. Staff 
members will also undergo a refresher on assessments every 4 months. 
 
Each research staff member will be instructed on the timing of assessments for each individual. 
Checklists will be used to ensure that assessments are obtained at the time indicated. The PI or designee 
also will review assessments. For the computerized assessments, the research assistants will create 
each subject’s template. The computer data will be backed up on a secure server and checked by the PI 


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or designee, for missing data. The computer(s) used to collect data will be kept in a locked office when 
not in use and will not be networked. 
 
For paper assessments, the research assistants will review the assessments for missing/out-of-range 
values. If any missing or inaccurate values are found, the participant will be asked to complete those 
again. Paper data will be entered into the computer by trained research staff within one week of the 
assessment. 
 
Prior to statistical analyses, the Data Manager will check the data for mislabeling, missing data, out-of-
range data, etc., and will change/correct as appropriate based on source data. The Data Manager will 
also assign study condition per study ID for analysis purposes. A master data set will be created with at 
least two backups. One of these backup disks will be given to the statistician, with a data assessment 
dictionary, for analysis. 
 
Collection and Reporting of Adverse Events (AEs), Serious Adverse Events (SAEs) and Unanticipated 
Problems involving Risks to Subjects or Others (UPIRTSOs) 
 
Any adverse event (AE) or serious adverse event (SAE) or unanticipated problem involving risk to 
subjects or others (UPIRSO) or any change in health from the baseline including injuries, accidents or 
hospitalizations will be reported. Safety data or events will be captured by interviewing the study 
participants with specific questions asking any changes in health and functionality since the previous visit 
and/or by reviewing the following in the participant’s medical chart (if available): physical examinations, 
vital sign measurements, 12-lead electrocardiograms, clinical laboratory measurements, and concomitant 
medications. 
 
All adverse events (AEs) occurring during the course of the study must be collected, documented, and 
reported to the PI. The occurrence of AEs will be assessed in an ongoing way. Each week the PI and 
study personnel will review and discuss the AEs from the previous week for events that were reported as 
new or continuing and discuss appropriate measure to address each event – such as notification to the 
proper authority, prevention and treatment of the event, notification to the study subjects, suspension of 
enrollment, and termination or suspension of the study. The study team will follow all AEs to the point of 
satisfactory resolution.  
 
The PI and sub-Investigators will determine whether an event meets the criteria of a serious adverse 
event (SAE) and/or an unanticipated problem involving risks to subjects or others (UPIRTSO). The PI will 
report AEs and SAEs on an annual basis and UPIRTSOs to the IRB in a timely fashion 
 
The study investigators will follow all AEs to the point of a satisfactory resolution. A study participant may 
be withdrawn from the study if the study physician determines it is the best decision in order to protect the 
safety of the participant. In the event that a participant either withdraws from the study or the investigator 
decides to discontinue a patient due to an SAE, the participant will have appropriate follow-up medical 
monitoring. Monitoring will continue until the problem requiring hospitalization has resolved or stabilized 
with no further change expected, is clearly unrelated to study interventions, or results in death. 
 
The IRB communicates recommendations and decisions to the PI in a timely manner. The decision to 
terminate the study early for suspected or actual benefit or risk will be made by the principal investigator 
in consultation with the Chair of the IRB. 
 
DSM Plan 
 
The PI will be ultimately responsible for monitoring the safety and efficacy of the trial, executing the DSM 
plan, and complying with reporting requirements. Any adverse events that occur will be monitored in an 
ongoing way, as well as being formally reviewed by investigators after 50% and 100% of participants 
have been enrolled. Whether risks of participation remain acceptable under the present protocol or 
modifications to the protocol are necessary while still maintaining scientific integrity of the project will be 


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determined. Any data accrued will be summarized and reviewed by the study investigators after 50% and 
100% of participants have been enrolled. In addition, the PI will submit a report of recruitment and 
retention, protocol deviations, adverse events (summary), serious adverse events (individually), and 
reasons for study discontinuation to the IRB on at least an annual basis. Interim analyses will not be 
performed unless clinically indicated. All SAEs, such as death, hospitalization, and unexpected toxicity, 
will be reported to the IRB under expedited reporting, as appropriate. The procedures for this reporting 
include written documentation using the clinical notes related to the adverse event and specific forms 
detailing the event with a sign-off by all appropriate supervisory personnel. According to SF 424 
guidelines, a Data and Safety Monitoring Board is required only for multi-site clinical trials; thus, there is 
no current plan to form a DSMB for this trial. 
 
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Title:  Bupropion for Depression in Chronic Kidney Disease (CKD) Patients  
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141. Zajecka J1, Fawcett J, Amsterdam J, Quitkin F, Reimherr F, Rosenbaum J, Michelson D, Beasley C. 
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ICF_001.pdf: 
Bupropion for Depression in Chronic Kidney Disease Patients  
Informed Consent form for Protocol #203076 
University of Arkansas for Medical Sciences 
P.I.: Pedro Delgado, M.D. 
   
Version 12 
03.10.2017 
Page 1 of 15 
DESCRIPTION OF RESEARCH BY INVESTIGATOR  
 
You may be eligible to take part in a research study. This form gives you important information 
about the study.  You will be asked to sign in more than one place in this document. 
 
Please take time to review this information carefully.  You should talk to the researchers about 
the study and ask them any questions you have.  You may also wish to talk to others (for 
example, your friends, family, or a doctor) about your participation in this study.  If you decide to 
take part in the study, you will be asked to sign this form.  Before you sign this form, be sure you 
understand what the study is about, including the risks and possible benefits to you. 
 
Please tell the researchers or study staff if you are taking part in another research study. 
 
Voluntary Participation - You do not have to participate if you don't want to. You may also leave 
the study at any time. If you leave the study before it is finished, there will be no penalty to you, 
and you will not lose any benefits to which you are entitled. 
 
Principal Investigator: The Principal Investigator (PI) is the researcher directing this study; the 
PI is responsible for protecting your rights, safety and welfare as a participant in the research. 
The PI for this study is Pedro L. Delgado, MD, Marie Wilson Howells Professor and Chair of the 
Department of Psychiatry in the UAMS College of Medicine and Director of the UAMS 
Psychiatric Research Institute (PRI). 
 
Study Sponsor: This study is being funded by UAMS department of Psychiatry internal funds. 
 
 
SECTION I. THE PURPOSE OF THE STUDY AND HOW LONG IT WILL LAST.  
 
You are being asked to be a participant in this study because you have chronic chronic kidney 
disease and you have been diagnosed with major depressive disorder (MDD). This study will 
enroll approximately 50 men and women between 30 and 70 years of age. If you join the study, 
your participation would last about 14 weeks. 
 
MDD, depressive symptoms, and impaired thinking, reasoning, or remembering (cognitive 
functioning) are the most common mental health (psychological) problems in patients with 
chronic kidney disease receiving hemodialysis. MDD can lead to poor quality of life, increased 
hospitalizations, failure to take medications as directed, dialysis withdrawal, premature death, 
and other health problems in chronic kidney disease patients. MDD is often under-diagnosed 
and/or underrated. If we can diagnose MDD early and treat MDD appropriately in patients with 
chronic kidney disease, these patients may see an improvement in overall quality of life.  
This study involves the use of two drugs: Fluoxetine (Prozac) and sustained release 
Bupropion (Wellbutrin SR). These two drugs are different from each other with regard to 
chemical structures, mechanisms of actions, and other characteristics. The U.S. Food & Drug 


Bupropion for Depression in Chronic Kidney Disease Patients  
Informed Consent form for Protocol #203076 
University of Arkansas for Medical Sciences 
P.I.: Pedro Delgado, M.D. 
   
Version 12 
03.10.2017 
Page 2 of 15 
Administration (FDA) has approved both drugs for treating MDD. This study will compare the 
effects, good and/or bad, of Bupropion versus Fluoxetine on chronic kidney disease patients 
with MDD. The safety of these drugs in humans has been tested in prior research studies; 
however, some side effects may not yet be known, especially in chronic kidney disease 
patients on hemodialysis. 
 
 
SECTION II. DESCRIPTION OF THE STUDY INCLUDING PROCEDURES TO BE USED.  
 
If you decide to take part, you will be asked to sign this consent form. 
While you are taking part in this study, you will be asked to complete assessments and study 
procedures at 10 visits including a screening visit with the researchers or study staff over the 
period of about 14 weeks. Screening visit is followed by Baseline visit (Week 0) and then visits 
to complete assessments are scheduled at Weeks 1, 2, 3, 4, 6, 8, 10, and 12. For weeks 5, 7, 
9 and 11, you will only be required to come in and pick up your medication for those weeks 
and return the medication bottle from the previous week. Most visits will occur on the 4th floor 
of the Psychiatric Research Institute (PRI) at the University of Arkansas for Medical Sciences 
before or after your regularly scheduled dialysis treatments. Depending on your dialysis site, 
visits may occur during regularly scheduled dialysis treatments. Extra visits may occur on non-
dialysis days, if needed. If your visits need to occur at PRI, we will discuss with you options for 
traveling to/from PRI and your dialysis site, including providing taxi service, if needed. 
 
Screening: 
After you sign this consent to participate, exams, tests, and/or procedures may be done as 
described below to find out if you are eligible to continue in the study. We may be able to use 
the results of exams, tests, and/or procedures you completed before enrolling in this study. You 
will have to give us permission to access these tests and/or exams to your medical records.  If 
we are not able to access them, we may need to redo these tests in order to determine your 
eligibility to participate.  You will be told which results we will obtain and which procedures will 
not have to be repeated. 
 
Screening Procedures – The following procedures will be performed on you by the study team 
OR the information taken from your medical record in order to evaluate whether you qualify to be 
in this study. 
 
 Demographics, medical history, and medications: We will review your medical history and 
demographic (date of birth, sex, race, ethnicity) information. You will be asked to report 
any medications you are taking (including all prescribed medications and any over-the-
counter or herbal medications).  
 Physical examination: You will have a physical exam and an assessment of vital signs 
(heart rate, blood pressure, temperature, weight and height) and a basic dental 
evaluation. Most of this examination will occur at PRI on the same floor where you 
received this form. The dental examination will occur on the first floor of UAMS hospital at 


Bupropion for Depression in Chronic Kidney Disease Patients  
Informed Consent form for Protocol #203076 
University of Arkansas for Medical Sciences 
P.I.: Pedro Delgado, M.D. 
   
Version 12 
03.10.2017 
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the Dental Hygiene Clinic, attached to PRI (5 minute walk). 
 Blood: 20 ml blood (about four teaspoons) will be collected at screening if no current lab 
results can be extracted from your medical record. 
 Electrocardiogram (EKG): An EKG (a painless test that provides a recording of your heart 
rhythm) will be performed on you.  
 The Hamilton Depression (HAM-D) Scale: You will complete a 25-item questionnaire to 
assess depression.  
 Clinical Interview: A psychiatrist, a member of the study team, will conduct a structured 
clinical interview to evaluate your depression. 
We will have you sign a release of information so that we can request information from your 
medical record such as dialysis dose, pre- and post-dialysis body weight and blood pressure. 
Although this information will not be necessary for enrollment, we will obtain it to confirm dialysis 
adequacy (kt/V). 
 
The procedures listed above may take approximately 90 minutes. 
 
The results of the screening exams, tests, and/or procedures will be reviewed to determine 
whether you will be allowed to continue in the study. If you are not allowed to continue in the 
study, the researcher will discuss the reasons and other possible options with you. 
 
Assignment to Study Groups - When it is determined that you are eligible for the study, you 
will be assigned randomly (by chance-like flipping a coin) to one of 2 study groups: Bupropion 
SR or Fluoxetine. You have equal probability of being assigned to either group. Both of these 
drugs are taken by mouth. We may change your dose later on, depending on how you do on 
the medication. Your study doctor will know which drug you are taking, but you and the study 
raters will not know.  
 
Study Procedures: As a participant, you will undergo the following procedures: 
 
 
Treatment Phase – Baseline visit (Week 0): 
 
After randomization, you will have the following procedures completed and/or the information 
will be obtained from your medical record:  
 
 Assessment of any changes in prior/current medical conditions, symptoms, and 
complaints, including any changes in other medications you may be taking.  
 Assessment of vital signs: heart rate, temperature, pre- and post-dialysis body weight, and 
pre- and post-dialysis blood pressure. 
 Blood: 20 ml blood (about four teaspoons) will be collected at the middle of the week 
(either Wednesday or Thursday depending on your dialysis regimen) pre-dialysis to be 
tested for several biomarkers related to the breakdown of a substance called tryptophan 
and inflammatory markers. Whenever possible, blood will be drawn from your pre-dialysis 
intravenous line rather than doing a separate needle stick.  
 Pregnancy test: For female patients capable of becoming pregnant, a pregnancy test in 


Bupropion for Depression in Chronic Kidney Disease Patients  
Informed Consent form for Protocol #203076 
University of Arkansas for Medical Sciences 
P.I.: Pedro Delgado, M.D. 
   
Version 12 
03.10.2017 
Page 4 of 15 
blood will be done before you receive study treatment.  If you are pregnant you will not 
be allowed to continue in the study. 
 Interview and questionnaires: we will do several interview and questionnaire tools with you, 
typically at the middle of the week (either Wednesday or Thursday). You will be asked to 
participate in interviews, fill out questionnaires, and complete computer tasks that are 
designed to measure your mood, depression symptoms, treatment response, fatigue, 
cognitive ability, medication side effects, and medication adherence. 
We will measure your pain sensitivity by gently placing a pressure indicator on the skin of both 
legs for approximately 5 seconds until you report any sensation of discomfort or mild pain. We 
will also measure your pain sensitivity with  a thermal (warm and cold) sensor in your right 
hand with approximately 5 series of questions about your temperature perception (some will 
ask for pain recognition and other for how much pain you can take) for approximately 45 
seconds each. You will then receive study medication bottles with instructions on when to start 
the study medication as well as timing and dose. 
 
This visit will take approximately 2 hours. 
 
Treatment Phase – Week 1 - 12 [Week 12 will be the final study visit.]:  
During weeks 1,2,3,4,6,8,10, and 12 you will have the following procedures completed 
at the middle of the week (typically either Wednesday or Thursday) and/or the 
information will be taken from your medical record. 
 Assessment of any changes in prior/current medical conditions, symptoms, and 
complaints including changes in other medications you may be taking.  
 Assessment of vital signs: heart rate, temperature, pre- and post-dialysis body 
weight, and pre- and post-dialysis blood pressure.  
 Blood: On weeks 1, 4 and 12, 20 ml blood (about 4 teaspoons) will be collected pre-
dialysis to be tested for tryptophan (TRP) and TRP metabolites, and inflammatory 
markers. Blood levels of study medication metabolites will also be measured.  
 EKG (week 4) 
 Mood and cognitive assessments: We will ask you to participate in interviews, fill 
out questionnaires, and complete computer tasks that are designed to measure 
your mood, depression symptoms, treatment response, fatigue, cognitive ability, 
medication side effects, and medication adherence.  
 Measure of pain sensitivity. 
 
Either Bupropion SR or Fluoxetine will be given in bottle to take at home at weekly intervals 
during the study. During weeks 5, 7, 9, and 11 you will only come in to pick up your medication 
for the week and to return the pill bottle from the previous week. 
For Week 12 (End of Study Visit) either the medication will be stopped or you will be given 
instructions to taper off the study medication over 1-2 weeks. If you decide that it would be 
beneficial for you to continue the medication once you are no longer a research participant, you 
can sign a release of information for one of the study physicians to inform your primary care 
provider about the medication and dose you had been taking. You can then follow up with your 


Bupropion for Depression in Chronic Kidney Disease Patients  
Informed Consent form for Protocol #203076 
University of Arkansas for Medical Sciences 
P.I.: Pedro Delgado, M.D. 
   
Version 12 
03.10.2017 
Page 5 of 15 
own physician to be prescribed the medication once your participation has ended. 
 
These visits will take approximately 30-60 minutes. 
 
Could your participation end early? There are several reasons why the researchers may 
end your participation in the study at any time (early withdrawal).  Some reasons are: 
 The researcher believes that it is not in your best interest to stay in the study. 
 You become ineligible to participate. 
 Your condition changes and you need treatment that is not allowed while you are taking 
part in the study. 
 You do not follow instructions from the researchers. 
 The study is stopped prematurely. 
 The investigator can end your participation at any time for any reason. 
 
The researchers will discuss your options for medical care when your participation in this study 
ends. You always have the option of withdrawing your consent at any time during the study and 
not have any further study procedures. 
 
What happens after treatment?  12 weeks of treatment with either antidepressant typically 
leads to improvement in depressed mood state. However, not all people respond to 
medications the same way. Two weeks after you finish the study, we will call you to see how 
you are doing and how well you are tolerating the stoppage of study medications. If you 
experience any distress related to stoppage of medication, please contact Dr. Delgado at the 
phone numbers given below. 
 
SECTION III. DESCRIPTION OF ANY PROCEDURES THAT MAY RESULT IN 
DISCOMFORT OR INCONVENIENCE.  
 
There are procedures that may result in discomfort or inconvenience during your participation 
in this study. These include:  
1. You may be bored during the study visits.  
2. You may find that filling out forms and doing computerized tasks tedious, redundant, 
stressful, or boring.  
3. It may be inconvenient for you to attend the study visits.  
4. You will briefly experience pain in the form of pressure, cold or heat from the pain 
sensitivity measures. 
 
 
SECTION IV. EXPECTED RISKS OF STUDY.  
 
The investigators have designed this study to learn how effective Bupropion SR is versus 
Fluoxetine for MDD in chronic kidney disease patients. There is a risk that the effectiveness 
and/or safety of Bupropion SR and/or Fluoxetine may not be as good as it is for patients with 


Bupropion for Depression in Chronic Kidney Disease Patients  
Informed Consent form for Protocol #203076 
University of Arkansas for Medical Sciences 
P.I.: Pedro Delgado, M.D. 
   
Version 12 
03.10.2017 
Page 6 of 15 
MDD who do not have chronic kidney disease. Bupropion SR or Fluoxetine may not help treat 
your MDD and continuing to be depressed may make your condition or disease worse. 
 
Collecting the blood samples. You will have approximately 20mL (about 4 teaspoons) of blood 
drawn during screening, baseline (week 0), week 1, week 4, and week 12. This is a small 
quantity of blood and should have minimal if any effect on your total blood volume. Blood 
drawing may result in pain and bruising at the site and/or feeling faint, especially if we need to 
do an extra needle stick rather than draw the blood from the IV line during dialysis. 
 
Risks from the specific research procedures. There are risks to taking part in this research study.  
One risk is that you may experience side effects related to Bupropion SR or Fluoxetine while on 
the study.  Everyone taking part in the study will be watched carefully for any side effects.  
However, the study doctors don’t know all the side effects that may happen.  Be sure to tell your 
study doctor immediately, about any side effect that you have while taking part in the study. 
 
Side effects can range from mild to serious.  Serious side effects are those that may require 
hospitalization, are life threatening or fatal (could cause death). The frequency that people 
experience a certain side effect can range from many (likely), few (less likely) or only one or two 
(rarely). 
 
The following sections describe the risks related to each drug and procedure that is part of this 
research study. These are these most commonly reported side effects; there may be additional 
side effects that we do not know. You should talk to your study doctor about any side effects or 
other problems that you have while taking part in the study. 
 
Risks and side effects related to Bupropion SR include those that are:  
 
Likely 
(10 or more subjects out of 100) 
Not Serious 
Potentially Serious 
 
Dizziness 
 
Agitation 
 
Blurred vision 
 
Tremor 
 
Sweating 
 
Headache/migraine 
 
Inability to get adequate sleep 
 
Increased heart beat 
 
Dry mouth 
 
Constipation 
 
Decreased appetite 
 
Nausea, vomiting 
 
Weight gain 
 
None 
Less Likely 
(Between 2-9 subjects out of 100) 


Bupropion for Depression in Chronic Kidney Disease Patients  
Informed Consent form for Protocol #203076 
University of Arkansas for Medical Sciences 
P.I.: Pedro Delgado, M.D. 
   
Version 12 
03.10.2017 
Page 7 of 15 
Not Serious 
Serious 
 
High blood pressure (Hypertension) 
 
Low blood pressure (Hypotension) 
 
Skin rash and itching 
 
Impotence 
 
Urinary frequency 
 
Arthritis 
 
Slowness in movement (bradykinesia) 
 
Upper respiratory complaints 
 
Fatigue 
 
Anxiety 
 
Decreased sexual desire (libido) 
 
Abnormal heart rhythm 
Rare 
(Less than 1 subject out of 100) 
Not Serious 
Serious 
 
Urinary retention 
 
 
 
 Suicidal ideation 
 Suicide 
 Faint (syncope) 
 Seizures.  At doses similar to the initial dose 
used in this study, the chance of a seizure is 
approximately 1 in about 1,000 patients. At 
doses higher than the initial dose, the chance 
of a seizure can increase at least 4 out of 
every 1,000 patients.  
 
 
 
Risks and side effects that have been observed with Fluoxetine include those which are: 
 
 
Likely 
(10 or more subjects out of 100) 
Not Serious 
Potentially Serious 
 Decreased appetite 
 Anxiety 
 Nervousness 
 Inability to obtain adequate sleep (insomnia) 
 
None 
Less Likely 
(Between 2-9 subjects out of 100) 
Not Serious 
Serious 
 Impaired thinking 
 Alteration in blood glucose 
 Abnormal bleeding 
 Weight loss 
Rare 
(Less than 2 subjects out of 100) 


Bupropion for Depression in Chronic Kidney Disease Patients  
Informed Consent form for Protocol #203076 
University of Arkansas for Medical Sciences 
P.I.: Pedro Delgado, M.D. 
   
Version 12 
03.10.2017 
Page 8 of 15 
Not Serious 
Serious 
 
 
 
 
 
 
Suicidal ideation 
 
Suicide 
 
Serotonin syndrome symptoms (mental status 
changes  [agitation], increased heartbeat, 
change in blood pressure, dizziness, tremor, 
seizures, and/or nausea, vomiting, diarrhea) 
  Allergic reactions (including difficulty breathing 
(bronchospasm), swelling under the skin 
(angioedema), involuntary muscle contraction 
of the vocal cords resulting in difficulty 
breathing (laryngospasm), hives (urticaria) 
and skin rash 
 
Risks associated with abruptly stopping the study medication: To our knowledge, abruptly 
stopping the bupropion will not result in side effects due to the abrupt discontinuation. Fluoxetine 
at doses up to 20 mg/day may result in mild dizziness or vertigo when the medication is abruptly 
stopped. If you are maintained on fluoxetine at a higher dose than 20 mg/day, you will be 
instructed to taper off the medication over a 1-2 week period to help prevent side effects. 
 
When you complete the 12-week study, you may experience withdrawal from the study 
medication. These drugs are standard treatments for depression and may be obtained from your 
regular doctor as part of routine care. 
 
Risks and side effects related to the Blood Collection include those that are: 
 
Likely and not serious (more than 20 out of 100) 
 Pain 
 Bruising (black and blue marks) 
 Bleeding from the puncture site 
 Discomfort 
 
Rare but Serious (less than 5 out of 100) 
 Infection 
 Formation of a blood clot or swelling of the vein and surrounding tissue 
 
Risks and side effects related to the Electrocardiogram or EKG: There are no known risks 
associated with this test. However, removal of small adhesive patches may cause minor irritation 
to skin. 
 
There are no known risks associated with any of the following assessment tools – Mini 
International Psychiatric Interview (MINI), Hamilton Depression (HAM-D) Scale, Profile of Mood 
States (POMS), Brief Fatigue Inventory (BFI), Modified Mini Mental Status (3MS) Examination, 
cognitive tasks, Antidepressant Treatment Response Questionnaire (ATRQ), Clinical Global 


Bupropion for Depression in Chronic Kidney Disease Patients  
Informed Consent form for Protocol #203076 
University of Arkansas for Medical Sciences 
P.I.: Pedro Delgado, M.D. 
   
Version 12 
03.10.2017 
Page 9 of 15 
Impressions - Severity and Improvement (CGI-S, CGI-I), Systematic Assessment For Treatment 
Emergent Events (SAFTEE), Medication Accountability Record. 
 
For more information about risks and side effects, ask one of the researchers or study staff. 
 
We will tell you about any significant new findings which develop during the course of this 
research which may relate to your willingness to continue taking part. 
 
Risks related to withdrawing from the study. If you decide to withdraw from this study early, 
please discuss your decision with the principal investigator, Dr. Pedro Delgado. The 
researchers may ask you to complete study withdrawal procedures at a final study visit. This visit 
includes the procedures listed for the Week 12 visit described earlier in this document. 
Depending on the study medication and dose you are on, you may be asked to taper off the 
medication. 
 
Risks to privacy.  
There is a risk that other people may become aware that you are participating in this study. To 
avoid this risk, we will protect your privacy by assigning you a subject ID code. Identifiable 
health information gathered from you (such as your name, date of birth, blood samples, test 
results, etc.) will be linked to your subject ID code rather than your name.   
 
Reproductive Risks. 
Concerns for sexually active women.   All pregnancies have a background risk of birth defects, 
loss, or other adverse outcome regardless of drug exposure. Information about risk of the study 
drugs (Bupropion SR and Fluoxetine) in pregnancy is incomplete. Therefore, you should not 
become pregnant while taking part in this study.  It is important that you talk to your study 
doctor about avoiding pregnancy during this study. If you think you might have become 
pregnant while you are in this study, you must tell one of the study doctors right away so that 
management of the pregnancy and the possibility of stopping the study can be discussed. 
 
Risks to babies who are being breastfed. Like many other drugs, both Bupropion SR and 
Fluoxetine may be present in breast milk. The effects of these drugs on breastfed babies are not 
known. If you are planning to breastfed your baby, please consult with the Principal Investigator 
Dr. Pedro Delgado. 
 
Risks if you also participate in other research studies.  
Being in more than one research study at the same time may increase the risk to you, especially 
when enrolled in multiple drug treatment studies. It may also affect the results of the studies.  
You should not take part in more than one study without approval from the researchers. 
 
Risk from not knowing which medication you are taking. 
In case of an emergency, a physician outside of the study may need to know which medication 
(Bupropion or Fluoxetine) you are taking. Dr. Pedro Delgado can also be contacted at his office 
(501-526-8140) or cell (501-313-6724) at any time to provide this information. 
 
SECTION V. EXPECTED BENEFITS OF STUDY.  


Bupropion for Depression in Chronic Kidney Disease Patients  
Informed Consent form for Protocol #203076 
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P.I.: Pedro Delgado, M.D. 
   
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You may benefit directly from your study participation. Your MDD may improve as a result of 
treatment with one of the study drugs. Your mental and physical health will also be closely 
monitored during the study. Treatment of depression with antidepressants can improve 
symptoms of depression, including depressed mood, loss of energy and interest, impaired 
concentration, guilt feelings, impaired sleep or appetite, and others.  When these symptoms 
improve, people can often become more functional in their lives and have the motivation and 
energy needed to face difficult situations more effectively.  There is no guarantee that you will 
benefit from participation or that the effects of the treatment will outweigh the risks of study 
participation. 
 
We hope the information learned from this study will benefit other people with similar conditions 
in the future. 
SECTION VI. ALTERNATIVE THERAPY OR DIAGNOSTIC TEST.  
 
There are other options available to you. 
 
You do not have to be in this study to get help for your MDD.  If you choose not to participate in 
this study, you may consider other treatment such as psychotherapy for MDD.  Also, both 
Bupropion SR and fluoxetine are FDA approved drugs and are available for the treatment of 
MDD off study. You may also seek other FDA approved drugs for treatment of MDD. 
 
You should discuss your alternatives to participating in this research with the study doctor or 
study staff. In addition, you may discuss your options with your regular health care provider. 
 
SECTION VII. USE OF RESEARCH RESULTS.  
 
If results of this study are reported in medical journals or meetings, you will not be identified by 
name or by any other means without your specific consent. As described above, all research 
information acquired from you (including blood samples) will be linked to a study code instead 
of your name. Your medical records will be maintained according to this medical center's 
requirements.  
 
If suicidal intent or other major clinical findings are observed during clinical or research 
assessments, the study physician will be notified immediately. If you are suicidal, 911 will be 
called and an ambulance will take you to an emergency department where you will be further 
evaluated. You may be hospitalized against your will.  
 
By participating in this study, you also consent that representatives of the Institutional Review 
Board, other UAMS institutional oversight offices, the Office of Human Research Protection, 
and/or National Institutes of Health may review your complete research records, including 
information that identifies you. All such record reviews will be conducted on the premises of the 
University of Arkansas for Medical Sciences. Your consent to such reviews includes knowing 


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that any medical record information related to disorders such as drug abuse, HIV infection, 
alcoholism and/or sickle cell anemia would thereby be disclosed to the representative.  
 
Information we learn about you in this study will be handled in a confidential manner, within the 
limits of the law.  By law, we must release information to the appropriate authorities if at any 
time during the study there is a concern that child abuse or elder abuse has possibly occurred 
or if you disclose a desire to harm yourself or others. 
 
More information concerning confidentiality is described in the “Authorization to Use and 
Disclose Protected Health Information as part of a Research Study” located later in this form.
 
SECTION VIII. SPECIAL CIRCUMSTANCES.  
 
You will receive a small reimbursement for your time in this study. You will be compensated 
with a check for $25.00 for every study visit that includes completing assessments up to a total 
of $250.00 upon completing all 10 study visits involving assessments.  If you do not finish all 
the assessment visits, you will receive checks of $25 each only for the visits you have 
completed. For your information, if you earn more than $600.00 during your participation in this 
study combined with any other UAMS funded research study during the calendar year (that is, 
between January 1 and December 31), the amount will be reported to the Internal Revenue 
Service.  
 
The study will provide you the study drugs, either Bupropion SR or Fluoxetine, free of charge 
during this study. In addition, all tests, examinations, and medical care required solely for 
purposes of this study will be provided at no cost to you. There will be no additional costs to you 
for your participation. You/your insurance company will continue to be responsible for the costs 
of your standard of care treatment for chronic kidney disease. 
 
In the event you are hurt by being in this research, treatment will be available. This treatment 
may include:  
First aid,  
Emergency treatment and/or  
Follow-up care  
This treatment may be billed to you, or your insurance company, in the normal manner. 
Normally, no other form of compensation is available.  
If you have questions now, feel free to ask us. If you have additional questions, concerns, 
comments or complaints later, you feel you have been hurt by this research or you wish to 
report a problem that may be related to this study please contact Pedro L. Delgado, MD during 
and after normal work hours at 501-526-8140 (office) or 501-313-6724 (cell). 
You have not waived your legal rights by signing this consent form. If you have any questions 
about your rights as a research subject or concerning a research related injury, you can call 
the UAMS Institutional Review Board representative at phone number (501) 686-5667. The 


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Institutional Review Board of the University of Arkansas for Medical Sciences reviews research 
projects independently based upon the principle that human participants will be adequately 
protected.  
 
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.  
RESEARCH SUBJECTS' RIGHTS  
The purpose and voluntary nature of this study, as well as the potential benefits and risks that 
are involved have been explained to me. I have been able to ask questions and express 
concerns, which have been satisfactorily responded to by the study team. I have been told that 
I will be given a copy of this consent form.  
 
 
___________________________     _______________________________         ___________ 
Printed Name of Subject 
Signature of Subject 
      Date 
 
 
 
___________________________     _______________________________         ___________ 
Printed Name of Person 
Signature of Person                                 Date  
Obtaining Consent 
Obtaining Consent 
 
 
 
 
 
 


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Authorization to Use and Disclose 
Protected Health Information as part of a Research Study 
 
This section describes the use of your health information. If you agree to allow the researcher 
to use your private information, you will be asked to sign at the end of this section. 
 
Research policies require that private information about you be protected. This is especially 
true for your health information. 
 
However, the law sometimes allows or requires others to see your information.  The 
information given below describes how your privacy and the confidentiality of your research 
records will be protected in this study. 
 
What is Protected Health Information (PHI)? 
Protected Health Information is information about a person’s health that includes information that 
would make it possible to figure out whose it is. According to the law, you have the right to 
decide who can see your protected health information.  If you choose to take part in this study, 
you will be giving your permission to the investigators and the research study staff (individuals 
carrying out the study) to see and use your health information for this research study.  In carrying 
out this research, the health information we will see and use about you will include: your medical 
history and blood work, information that we get from your medical record, information you give 
us during your participation in the study, results of blood tests, demographic information like your 
age, gender, race/ethnicity, etc. 
 
We will get this information by asking you, asking your doctor, by reviewing your medical records 
and charts. 
 
How will your PHI be shared? 
Because this is a research study, we will be unable keep your PHI completely confidential. We 
may share your health information with people and groups involved in overseeing this research 
study including: 
 The research study staff and the staff at dialysis centers from where study subjects will be 
recruited 
 The committee that checks the study data on an ongoing basis, to determine if the study 
should be stopped for any reason 
 The members of the local research team 
 The Institutional Review Board and the Compliance Office of the UAMS, and other groups 
that oversee how research studies are carried out 
 The Research offices at the UAMS and the University Health System 
 The Food and Drug Administration (FDA) 
 
How will your PHI be protected? 
In an effort to protect your privacy, the study staff will use code numbers instead of your name, 
to identify your health information.  Code numbers will be used on any study-related records or 
materials (such as blood samples) that are sent outside of the UAMS for review or testing. 


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Blood samples will be sent to the University of Texas Health Sciences Center at San Antonio 
for analyses; these samples with be coded using your subject ID code. If the results of this 
study are reported in medical journals or at meetings, you will not be identified. 
 
Do you have to allow the use of your health information? 
You do not have to allow (authorize) the researchers and other groups to see and share your 
health information. If you choose not to let the researchers and other groups use your health 
information, there will be no penalties but you will not be allowed to participate in the study. 
 
After you enroll in this study, you may ask the researchers to stop using your health information 
at any time. However, you need to say this in writing and send your letter to Pedro L. Delgado, 
M.D.; Department of Psychiatry, University of Arkansas for Medical Sciences; 4301 W. 
Markham, #554; Little Rock, AR 72205.  If you tell the researchers to stop using your health 
information, your participation in the study will end and the study staff will stop collecting new 
health information from you and about you for this study.  However, the study staff will continue 
to use the health information collected up to the time they receive your letter asking them to 
stop.  
 
The groups receiving your health information may not be obligated to keep it private. They may 
pass information on to other groups or individuals not named here. 
 
If you decide to participate in this study, you will be giving your permission for the groups named 
above, to collect, use and share your health information. If you choose not to let these groups 
collect, use and share your health information as explained above, you will not be able to 
participate in the research study. 
 
Can you ask to see the PHI that is collected about you for this study? 
The federal rules say that you can see the health information that we collect about you and use 
in this study. Contact the study staff if you have a need to review your PHI collected for this 
study. During the course of the study, you may be denied access temporarily to certain medical 
information about you that is study related. However, the Principal Investigator and staff will not 
automatically deny a request, but will consider whether it is appropriate under the circumstances 
to allow access. If access is denied during the study, once the study is completed, you will be 
able to request access to the information again. At that time, you have the right to see and copy 
the medical information we collect about you during the study, for as long as that information is 
kept by the study staff and other groups involved. 
 
How long will your PHI be used? 
If you sign this form, you are giving us permission to create, collect, use and share your health 
information as described in this form. You do not have to sign this form. However, if you decide 
not to sign this form, you cannot be in the research study. You need to sign this form and the 
research consent form if you want to be in the research study. You agree to let us use and 
disclose your health information for purposes of the study until the end of the study.  This 
permission to use your personal health information expires when the research ends and all 
required study monitoring is over. 
 


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If you sign this form but decide later that you no longer want us to collect or share your health 
information, you must send a letter to the person and the address listed by “Principal 
Investigator” on the first page of this form. The letter needs to be signed by you, should list the 
“Study Title” listed on this form, and should state that you have changed your mind and that you 
are revoking your “HIPAA Research Authorization”. You will need to leave the research study if 
we cannot collect and share any more health information. However, in order to maintain the 
reliability of the research, we may still use and share your information that was collected before 
the Principal Investigator received your letter withdrawing the permissions granted under this 
authorization.  
 
If you decide not to sign this form or change your mind later, this will not affect your current or 
future medical care at the University of Arkansas for Medical Sciences.  
 
SIGNATURE, DATE, AND IDENTITY OF PERSON SIGNING  
 
The health information about ___________________________ can be collected and used by 
the researchers and staff for the research study described in this form and the research consent 
form.  
 
Signature:________________________________________ Date:_____________  
 
Print name:_______________________________________  
 
The researcher will give you a signed copy of this form.