Clinical trial NCT01479829
Conditions: Bipolar Depression
Keywords: Bipolar depression Celecoxib Escitalopram Inflammation
Sponsor: Loyola University
Start date: 2011-03-23; Completion date: 2018-01-24
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This project will attempt to enhance and augment the antidepressant efficacy of a commonly used antidepressant in poorly responding bipolar depressed patients.

Detailed description:
This is a placebo-controlled study of patients with bipolar I disorder (BPD) utilizing a well-known antidepressant, escitalopram (ESC), in combination with the anti-inflammatory agent, celecoxib (CBX). The investigators hypothesize that combination treatment will lead to a qualitatively and quantitatively augmented response and will result in greater numbers of remitters compared to ESC monotherapy.

Arms: arm 1: Participants assigned to the intervention cohort receive 10mg escitalopram twice daily plus 200mg celecoxib twice daily. arm 2: Participants assigned to the control cohort receive 10mg escitalopram twice daily plus placebo administered twice daily.
Interventions: intervention 1: Escitalopram intervention 2: Celecoxib intervention 3: Placebo
Intervention descriptions: intervention 1: Escitalopram is a Selective Serotonin Reuptake Inhibitor (SSRI) intervention 2: Celecoxib is a nonsteroidal anti-inflammatory drug intervention 3: Placebo is a manufactured capsule with no active ingredient

Protocol documents:
Prot_SAP_000.pdf: 
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Cyclooxygenase-2-Inhibitor Combination Treatment for Bipolar Depression: Role of Inflammation and 
Kynurenine Pathway Biomarkers 
 
 
ABSTRACT  
 
A chronic sub-threshold pro-inflammatory status may interfere with the ability of an antidepressant to exert its 
full therapeutic action in bipolar disorder (BPD) patients whose depression has failed to respond or remit. 
Additionally, a pathological shunt in the kynurenine pathway may be involved in these delayed or diminished 
responses to antidepressant monotherapy.  
 
We propose a placebo-controlled study to treat bipolar depressed patients not responsive to antidepressant 
monotherapy with the well-known antidepressant escitalopram in combination with the anti-inflammatory agent 
celecoxib. We hypothesize that combination treatment will result in augmented treatment responses. We also 
expect to see greater numbers of remitters in response to escitalopram + celecoxib combination therapy 
compared to escitalopram monotherapy. 
 
 
BACKGROUND 
 
Burden of Bipolar Depression 
In bipolar disorder I and II, the depressive phase dominates over manic or hypomanic symptoms and most 
adversely affects the quality of life. In the natural course of bipolar I disorder (BPD), depressive symptoms 
occur in 31.9% of the weeks, and hypomanic/manic symptoms occur in 8.9% of the weeks the patient 
experiences symptoms (Judd et al, 2002). In bipolar II disorder, depressive symptoms occur in 50.3% of the 
weeks and hypomanic/manic symptoms in 1.3% of the weeks (Judd et al, 2003). Amongst 258 bipolar patients 
admitted from 1996 to 1999 to the Stanley Foundation Bipolar Network, 25% were ill with depressive 
symptoms averaging 214 days/year and 40% were ill with depressive symptoms averaging 120 days/year (Post 
et al, 2003a). Despite comprehensive pharmacologic treatment, mean time depressed was 3-fold higher than 
manic time. 62.8% of patients had 4 or more episodes per year. It was concluded that in bipolar patients’ 
depressive symptoms pose a greater burden for treatment than mania (Post et al, 2003b). The suicide rate is 
highest in patients with bipolar disorder. It occurs most frequently after severe and recurrent depressive 
episodes (Tondo et al, 2003). Regarding response to antidepressant treatment, bipolar depressed patients 
generally respond more poorly than patients with major depression. In a study comparing response to 
antidepressant treatment of bipolar depressed patients versus that of patients with major depression, the non-
response rate was 1.6 times higher in bipolar depressed patients. In another study, failure to respond to anti-
depressant therapy was reported to be 3.4 times more common in bipolar depressed patients (Ghaemi et al, 
2004). The reasons for the above observations are not clear. However, prompt diagnosis and specific therapeutic 
strategies are critical for the successful management of bipolar disorder.  
 
Role of Inflammation 
For decades our understanding of the pathophysiology of affective disorders and the development of 
antidepressant medications have been almost solely guided by the Monoamine Theory of Depression. While 
monoamine-based antidepressants have proven suitable as a mainstay treatment for most cases, their prolonged 
intervals to achieve symptom control, and the high percentage of non-remitters in both unipolar and bipolar 
depression have remained insurmountable attributes of these medications. New and innovative treatment 
strategies are therefore needed. Meanwhile, there has been an impressive accumulation of knowledge about pro-
inflammatory compounds (e.g., cytokines, chemokines, C-reactive protein) contributing to the pathophysiology 


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of depression. This has led to the formulation of the Cytokine Theory of Depression (Ur et al, 1992; Dantzer et 
al 2008; Leonard and Song, 1996; Miller et al, 2009).  There are numerous reports (Drexhage et al; Drexhage et 
al; Kim et al, 2007; Kim et al, 2002; Maes et al, 1995; Rapaport et al, 1999; Su et al, 2002; Tsai et al, 1999; Tsai 
et al, 2001) linking the immune system, in particular cytokines and C-reactive protein (CRP), to bipolar 
disorder.  There is additional evidence that the persistent pro-inflammatory status found in depression may 
delay, diminish, and even thwart antidepressant response. Furthermore, a persistent pro-inflammatory status is 
likely increases the risk for depressed patients to develop serious and potentially life-threatening complications 
such cardiovascular and cerebrovascular disease.   
 
There is an interaction between cytokines and serotonergic transmission involving the metabolism of tryptophan 
and modulation by the NMDA receptor. This interaction in the CNS occurs in part through the enzyme 
indoleamine 2,3-dioxygenase (IDO). IDO catabolizes tryptophan to kynurenine. Kynurenine metabolism has 
been implicated in the pathophysiology of depression, especially the chronicity of the disorder (Myint and Kim, 
2003). The involvement of the NMDA receptor in manic relapse of patients with bipolar I disorder was first 
proposed by Hoekstra and colleagues (Hoekstra et al, 2006). The up-regulation of the initiating step of the 
kynurenine pathway has been demonstrated in postmortem anterior cingulate cortex from individuals with 
schizophrenia and bipolar disorder (Miller et al, 2006). A lower plasma tryptophan index, lower neuroprotective 
kynurenic acid and higher tryptophan breakdown has been observed in bipolar patients compared to controls 
(Myint et al, 2007a; Myint et al, 2007b). Our unpublished data also indicates that the kynurenine/tryptophan 
ratio in major depression may serve as an indicator of response to add-on treatment with the cyclooxygenase-2 
inhibitor, celecoxib.    
 
Pro-Inflammatory and Anti-Inflammatory Cytokines 
Endothelial damage leads to the release of pro-inflammatory cytokines, which can induce thrombus formation, 
vascular occlusion, and have been implicated in the pathogenesis of atherosclerosis and cardiovascular disease 
(Koenig et al, 2001; McIntyre et al 2007; Piletz et al, 2000). Endothelial damage of the cerebral vasculature is 
postulated to contribute to the development of an entity referred to as Vascular Depression, which presents with 
many typical symptoms of depression. Studies have shown that pro-inflammatory cytokines are over-expressed 
in many stress-related disorders, including depression (Leonard et al, 1999; Tsao et al, 2006; von Kanel et al 
2006).  
 
Interestingly, depressed patients with or without cardiovascular disease have been shown to exhibit elevations 
in pro-inflammatory biomarkers (Dinan et al, 2009; Koenig et al, 2001; Meyer et al 2008). The pro-
inflammatory cytokines TNFalpha, IL1beta, and IL6 have consistently been found to be elevated in the plasma 
of depressed subjects (Himmerich et al, 2006;Tsao et al, 2006; Tulugu et al, 2003), and elevated IL-6 
concentrations have been associated with an increased prevalence of major depression (O’Brien et al, 2007). 
Interleukin-6 (IL-6) is secreted in response to stress, induces the release of other pro-inflammatory cytokines 
and has been implicated in the pathophysiology of MDD and in the effects of antidepressant treatment (Liciono 
et al, 1999). These observations have led to the postulation that depressive illness is a disease of inflammation 
in response to chronic psychological stress (Koenig et al, 2001).  
 
 
Anti-Inflammatory Therapy in Depression: Existing Studies with Add-On Celecoxib  
The presence of a pro-inflammatory state in bipolar disorder and the usefulness of anti-inflammatory treatment 
was the topic of a recent major review article (Berk et al, 2010). There have been 3 clinical studies describing 
the positive effects of various antidepressant agents with add-on celecoxib therapy. Each study independently 
concluded that administration of a COX inhibitor enhances the efficacy of the antidepressant. In some instances 


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non-responders remitted. All studies underscore the safety of celecoxib when used in doses up to 400 mg/day 
for 8 weeks.   
 
Study No. 1:  In a double-blind, randomized, placebo-controlled study, celecoxib + reboxetine was administered 
to MDD patients to determine if 6 weeks of combination therapy would result in improved outcomes as 
compared to reboxetine monotherapy. Celecoxib was titrated from 200 mg/d to 400mg/d over 3 days. Subjects 
receiving reboxetine + celecoxib showed a significantly greater antidepressant response by week-5 than subjects 
on reboxetine + placebo. Safety issues were assessed by self-reporting. No laboratory measurements were 
performed to assess hematologic or cardiovascular issues that might have arisen with drug combination. 
Mueller et al, 2006.  
 
Study No. 2: In a double-blind, randomized, placebo-controlled study, add-on celecoxib or placebo was 
administered for 6 weeks to non-responsive bipolar patients experiencing depressive or mixed episodes while 
maintained on stable doses of multiple mood stabilizers, atypical antipsychotics, antidepressants, and 
benzodiazepines. A statistically significant improvement (p= 0.03) was noted in the first week of treatment with 
add-on celecoxib in those who completed treatment. This pilot study was limited by small numbers (n=23 for 
completers). The study did not measure drug levels or inflammation biomarkers. The overall finding was a 
better outcome in patients treated with celecoxib add-on. Nery et al, 2008. 
 
Study No. 3:  In a double-blind, randomized, placebo-controlled study, 40 acutely depressed MDD subjects 
were treated with fluoxetine + placebo or fluoxetine + celecoxib for 6 weeks. At 6 weeks of treatment, patients 
receiving combination therapy showed statistically more improvement than patients receiving monotherapy. 
The celecoxib add-on was well-tolerated in study patients. Plasma levels of fluoxetine were monitored and no 
significant drug-drug interactions in metabolism were noted. No inflammation biomarkers were measured. 
Akhondzadeh et al, 2009. 
 
 
Using Celecoxib Instead of Another NSAID   
There are more preliminary reports using CBX as an add-on treatment for depression than any other add-on 
NSAID strategy. Additionally, as a COX-2 inhibitor CBX lacks the substantive anti-platelet effects associated 
with other NSAIDs on the US market which are non-selective mixed COX-1/COX-2 inhibitors, such as aspirin 
(Riondino et al, 2008). Using CBX allows for reasonable confidence that changes (i.e., in biomarkers) could not 
result from indirect effects on platelets or coagulation. Furthermore, due to pharmacokinetic reasons the 
analgesic effects of CBX take effect slower than other NSAIDs. Having a 3-hour interval between medication 
ingestion and effect onset decreased the likeliness that a cue can be perceived by the patient,  thereby breaking 
the blind.  
 
In addition to  these pharmacological issues, the use of CBX also rests on basic science findings linking COX-2 
up-regulation to depression. Pro-inflammatory cytokines are known to activate the HPA axis and exert profound 
effects on central monoaminergic transmission (Besedovsky et al, 1991), and at least three of them (IL-1β, IL-6 
and TNFα) are acted upon by COXs. While there are multiple isoforms of COXs, the main focus of the field has 
been on COX-2 because it is the isoform that is cytokine-induced through NFkappaB-dependent mode 
(Funakoshi-Tago et al, 2008). Stressors such as depression up-regulate transcription factor NFkappaB, which is 
mediator of pro-inflammatory cytokines in monocytes (Miller et al, 2009). Moreover, the predominant reaction 
of COX-2 is conversion of arachidonic acid to prostaglandin E2 (PGE2). Increased PGE2 in saliva, serum, and 
CSF of depressed patients has previously been described (Lieb et al, 1983; Calabrese et al, 1986). Since PGE2 
stimulates IL-6 release, it seems likely that some of the changes observed in depression with IL-6 may be 
related to the COX-2 pathway.  


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The up-regulation of PGE2 has also been described in response to different physical, psychological, or mixed 
trauma experimental paradigms like social crowding, immobilization, or cold restraint stress in animals.  
 
Furthermore, there is evidence that up-regulation of COX-2 can enhance glutamatergic neurotransmission. Sang 
(2007) demonstrated that PGE2 glyceryl ester (PGE2-G), a major COX-2 oxidative metabolite of 2-
arachidonoyl-glycerol, enhances hippocampal glutamatergic synaptic transmission, inducing neuronal injury 
and death. This supports the fact that COX-2 has also been implicated in the pathogenesis of neurodegenerative 
disorders such as Parkinsonism, Multiple Sclerosis, Alzheimer’s disease and traumatic brain injury. According 
to contemporary theories, depressive states are also neurodegenerative (Lieb et al, 1983; Calabrese et al, 1986; 
Yang et al, 2008). Taken together, there is a strong body of literature suggesting that COX-2 up-regulation in 
depression may pose a serious risk not only for the mood disorder itself, but also for the emergence of 
neurodegeneration at later time points in life. 
 
Pro-Inflammatory Biomarkers: Anticipated Effect of Celecoxib Add-On 
CBX inhibits COX-2 and its end-products (i.e. PGE2). Funakoshi-Tago et al. (2008) demonstrated that CBX 
significantly inhibits TNFα-induced NF-kappaB activation by preventing the nuclear translocation of the p65 
NF-kappaB subunit. In a study of patients with osteoarthritis randomized to either CBX or aceclofenac, CBX 
potently inhibited PGE2 concentrations and down-regulated both COX-2 mRNA and protein expression at the 
synovial membrane (Alvarez-Soria et al, 2006). In a double-blind, placebo-controlled, crossover trial of CBX 
(200 mg BID) of patients with severe coronary artery disease undergoing stable background therapy with 
aspirin and statins, 2 weeks of treatment with CBX led to a marked reduction in two pro-inflammatory agents: 
CRP and oxidized LDL (Chenevard et al, 2003). Muller et al (2004) used add-on CBX (400 mg/d) with an 
antipsychotic, risperidone. Their study monitored soluble TNFα receptor levels before and during 5 weeks of 
treatment. CBX add-on led to significantly better-than-placebo responses in the total PANSS scores for 
schizophrenia improvement at weeks 2, 3, and 4 (Leonard et al, 1999). Finally, there are no major drug-drug 
interactions expected between CBX and ESC based on having common cytochrome P450 enzymes.  
 
Pro-Inflammatory Biomarkers: Predictive Value with Respect to Antidepressant Response  
Studies indicate that plasma levels of pro-inflammatory biomarkers could be predictive of treatment response or 
non-response. Lanquillon et al (2000) studied MDD inpatients before and after treatment with amitriptyline. 
Untreated MDD patients had overall higher levels of plasma CRP, TNFα, and IL6 than control patients. MDD 
patients fell into three groups during treatment: responders, non-responders, and drop-outs. Non-responders had 
the highest IL-6 values before treatment.  
 
O’Brien et al (2007) compared patients at the end of a failed 6-week trial on an SSRI with patients who had 
previously failed an SSRI but were euthymic at time of blood drawing (due to switch to venlafaxine or SSRI 
augmentation with lithium). This study found SSRI-resistant patients have significantly higher levels of TNFα 
and IL6 compared to euthymic treatment responders.  
 
Yoshimura et al (2009) compared TNFα and IL6 levels before and after treatment in antidepressant treatment 
responders and non-responders. High IL6 levels before and after treatment was indicative of non-responders, 
regardless of the agent used.  
 
After  6 weeks of SSRI treatment, Dinan et al (2009) divided depressed patients into two groups: SSRI non-
responders and SSRI-responders. Omega-3 fatty acid, eicosapentanoic acid (EPA) was shown to be a state 
marker. EPA competes with arachidonic acid (AA) as a substrate for cyclooxygenase-2 (COX-2). These studies 


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provide evidence that pro-inflammatory biomarkers may be clinically useful in predicting antidepressant 
response. 
 
Genetic Testing 
The association between depressive disease and serotonergic transmission is well established. Similarly, there is 
a compelling link between depression and risk for developing cardiovascular disease. Abnormalities of 
serotonergic mechanisms in depression have been described and reviewed (Leonard 2000 and Mendelson 2000) 
in the literature over the past decades. Studies have reported decreased platelet aggregation in response to 
serotonin, but Shimbo et al. (202) reported a significant increase in platelet reactivity to serotonin in depressed 
patients. Whyte et al. (2001) demonstrated that depressed patients with the serotonin-transporter-linked 
promoter region l/l genotype have increased platelet activation compared to both depressed patients without this 
genotype and non-depressed control subjects. These authors hypothesize that persons with this polymorphism 
are likely to experience higher mortality rates. More recent evidence shows that certain pro-inflammatory 
cytokines (e.g, TNFalpha, IL-6) reduce serotonergic transmission by inducing the enzyme indoleamine 
dioxygenase (IDO) and shunting tryptophan away from the synthesis of serotonin. Taken together, these 
findings strongly indicate that genotyping could be used to identify patients at greater risk of developing 
depression and depression-associated cardiovascular morbidity and mortality (White et al., 2001).  
 
Salivary Cortisol Testing 
Recent evidence suggests that a prolonged inflammatory response can lead to dysregulation of the 
hypothalamic-pituitary-adrenal axis, potentially due to pro-inflammatory modulators such as TNF-a and IL-6 
(Straub et. al, 2011). HPA axis dysfunction has the potential to lead to an overall increase in secretion of 
cortisol and disruption of the well-established diurnal rhythm of cortisol, a glucocorticoid released in response 
to stress (Zunszain et. al, 2011). Evidence suggests that variation of the HPA axis and subsequent alterations in 
cortisol levels may be associated with the depressive phase in bipolar patients (Van der Werf-Eldering et. al, 
2012). Obtaining cortisol through salivary collection has shown to be an effective, non-invasive method for 
evaluating the HPA axis, and research shows that there is a strong correlation between salivary and blood levels 
of cortisol (Marques et. al, 2010). 
 
 
HYPOTHESES AND SPECIFIC AIMS 
 
HYPOTHESIS: The pro-inflammatory state of BPD subjects can delay, diminish or even thwart antidepressant 
monotherapy. Combination therapy of escitalopram + celecoxib will result in improved treatment outcomes 
(faster action, augmented response, and/or higher remission rates) for treatment-resistant BPD subjects. 
Response to antidepressant treatment in BPD subjects will be proportional to the change in pro-inflammatory 
status before and after treatment. 
 
SPECIFIC AIM #1: Determine if combined pharmacotherapy of escitalopram + celecoxib will result in 
improved affective responses compared to escitalopram + placebo. Scores from the Short-Form McGill 
Pain Inventory will be used to control for variation in depression that could be attributed to the relief of 
physical pain resulting from administration of celecoxib.  
 
SPECIFIC AIM #2: Determine whether combined pharmacotherapy of escitalopram + celecoxib 
causes any pharmacokinetic drug-drug interaction or poses safety/tolerability issues in terms of 
gastrointestinal bleeding or cardiovascular health. Clinical and laboratory assessments will be made 
throughout treatment and an adverse events inventory will be completed at each visit.  
 


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SPECIFIC AIM #3: Determine the blood concentration of pro-inflammatory biomarkers of all subjects 
before and after treatment. Determine whether there is a correlation between blood concentration of  
pro-inflammatory biomarkers and the psychiatric effectiveness of the combined treatment.  
 
SPECIFIC AIM #4: Quantify the specific anti-inflammatory action of celecoxib by assaying for 
inhibition of PGE2. PGE2 concentrations will be measured from the blood of all subjects before and 
after treatment. 
 
HYPOTHESIS: A chronic pro-inflammatory state leads to endothelial dysfunction, arterial stiffness, and dis-
regulation of the autonomic nervous system with sustained sympathetic activation and diminished vagal tone.  
 
SPECIFIC AIM #5: Determine whether endothelial dysfunction is present in BPD subjects and if this 
dysfunction will respond favorably to the combined treatment of escitalopram + celecoxib. The detection will 
be accomplished by means of by arterial pulse wave analysis, velocity and heart rate velocity. 
 
HYPOTHESIS: A pathological shunt in the kynurenine pathway exists in BPD patients who fail to remit on 
antidepressant treatment. This shunt interferes with the ability of an antidepressant agent to exert its full 
therapeutic action. 
 
SPECIFIC AIM #6: Determine the nature of the kynurenine pathway in all subjects before and after 
treatment.  
 
 
HYPOTHSESIS:  A genetic polymorphism identified in the 5-HT-transporter-linked promoter region may 
predispose subjects to depression and associated cardiovascular risk. 
 
SPECIFIC AIM #7:  Genotype the serotonin transporter length polymorphic region (5-HTTLPR) on all 
subjects to determine if the 5HTTLPR alleles associate with bipolar depression, inflammation 
biomarkers, heart rate variability and endothelial dysfunction.  
 
 
STUDY ENDPOINTS  
The primary endpoints pertain to the main hypothesized outcome: namely, a significantly better-than-placebo 
mood response for escitalopram + celecoxib that is not related to altered pain perception.  
 
The HAM-D rating scale (17 items from the 21-item scale) will be the main measure of clinical improvement.  
Onset of response is defined as the day of treatment when a 30% decline in the initial (day 0) HAM-D score is 
recorded and is maintained for two consecutive weeks. Treatment response is defined as a 50% reduction in the 
initial HAM-D score occurs. Symptom remission is defined as a HAM-D score of 7 or less.  
 
I. Primary Endpoint 
We seek to establish whether the combination therapy of escitalopram + celecoxib will augment antidepressant 
efficacy compared to escitalopram therapy alone as demonstrated by:  
 a significantly earlier group response (earlier decline in HAM-D scores) 
 a more robust group improvement in HAM-D scores at 8 weeks of treatment 
 more patients with symptom remission than in the escitalopram + placebo group at 8 weeks 
 


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II. Secondary Endpoint 
We seek to determine whether there is a reduction in pro-inflammatory biomarkers at end of treatment in 
patients randomized to receive the combination treatment. Three key pro-inflammatory biomarkers (TNFalpha, 
hsCRP and VEGF) shown to be robustly elevated in depressed patients will be measured. Baseline values will 
be compared to age and sex matched controls from a normative dataset of healthy subjects. We will also attempt 
to subtype BPD patients by a median split into two groups (high and very high) according to their baseline 
biomarker levels.   
 
III. Second Tier Exploratory Endpoints 
Our “second tier endpoints” are exploratory in nature. Our study is not powered for them since existing data in 
the literature is insufficient to calculate an accurate sample size for these endpoints.   
 
1. We will seek to establish whether a specific psychiatric symptom profile may be associated with the 
anticipated differential mood improvement in response to escitalopram + celecoxib or escitalopram + 
PBO. To that end, additional rating instruments have been included (over and above the HAM scales) 
and detailed assessments will be made of symptom profiles obtained from the rating instruments. 
 
2. We will assess the safety and tolerability of the combination treatment by means of an adverse events 
symptom checklist and by relevant laboratory measures (e.g., CBC, PT, PTT). 
 
3. Assessment of the efficacy of celecoxib by measuring PGE2 response to assess the extent of COX-2 
inhibition. 
 
4. An assessment of blood levels of escitalopram and celecoxib will tell us if these two agents interfere or 
promote each other’s uptake and/or clearance. 
 
 
STUDY DESIGN 
 
This is a 10-week, randomized, double-blind, two-arm, placebo-controlled study. The study includes a 
screening visit, a 1-week washout phase, a 1-week placebo run-in phase and an 8-week flexible dose phase. A 
minimum of 70 subjects will be randomized. The randomization code will be created and kept by the 
pharmacist in sealed envelopes for each individual subject. The PI will have access to the randomization code 
through the pharmacist if there is a medical safety issue.  
 
At the screening visit, subjects will undergo a psychiatric interview. The diagnosis of Bipolar Depression (BPD) 
will be established in this examination using portions of the MINI. The study will be explained to all subjects. If 
a subject meets inclusion criteria, he or she will be asked to review the consent form and agree to 
participate. Subjects who meet the screening criteria and sign the IRB-approved consent form will undergo 
comprehensive assessments in order to quantify depression and associated symptoms.   
At the end of the screening visit, subjects will be instructed how to taper the antidepressant they have been 
taking over the course of one week. A one-week taper is sufficient for all antidepressant medications except 
fluoxetine. Subjects taking fluoxetine will undergo a two-week taper/wash-out. After the taper, all subjects will 
return for a second visit to be placed on a 1-week single-blind placebo run-in. At the second screening visit, the 
subject will provide a saliva sample prior to undergoing assessments. Subjects will be instructed how to take 
pills (escitalopram placebo 10mg/day and celecoxib placebo 400mg/day) until the next visit one week later. Due 
to the fact that a one-week placebo run-in may be insufficient for some patients to reliably establish whether or 
not they are placebo responders, there will be an option to extend the placebo run-in for one additional week, at 


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the discretion of the PI.  No increased risks are anticipated with the extension of the placebo phase, as patients 
are evaluated weekly and in close telephone contact.  
 
At the Baseline visit, subjects will be reassessed for depression and associated symptoms. If subjects continue to 
score 18 or higher on the 17-item HAM-D scale, they will be randomized to receive escitalopram + celecoxib, 
or escitalopram + placebo in an assignment ratio 1:1. Subjects will then go on to complete assessments at Week 
1, Week 2, Week 4 and Week 8. If the subject scores below 18 on the 17-item HAM-D scale at Baseline, he or 
she will be terminated from the study and classified as a placebo responder.  At each of these visits,  subjects 
will arrive 30 minutes before their schedule appointment time, rest for 20 minutes in the exam room, and 
provide a saliva sample prior to undergoing any assessments. Terminated subjects will be offered conventional 
care at the same institution.  
 
It is our desire to observe the diurnal nature of cortisol levels in saliva by measuring the patient’s salivary 
cortisol levels at a time point prior to treatment and post treatment. At each of these two time points, we would 
collect saliva from the patient at five times during the day: upon awakening, approximately 30 minutes past 
awakening, before lunch, at approximately 3pm, and before bedtime. The patient would be required to do this at 
home and would then store the samples in their refrigerator until their next visit. Subjects will be provided with 
a log to record the exact time of saliva collection.  We will be using salivettes purchased from Sarstedt Inc., and 
our Salivary Assay kits will be purchased from Salimetrics, LLC. 
 
The overall study is powered for 90 subjects. We aim to randomize 70 subjects at LUMC. Approximately 30 
subjects will be randomized by investigators at our sister site in Munich, Germany. At LUMC, 35 subjects will 
be randomized to each arm of the study. Subjects must complete 8 weeks of active medication to be considered 
study completers. We plan to enroll approximately 80 patients in anticipation of a 10% drop-out rate. The drop-
out rate is based on our experience with our patient population over the past 5 years. If a subject drops out or is 
terminated after Week 6, their last observation will be carried forward in the analysis (LOCF). There are no 
healthy controls in this study because we already possess normative, untreated data for comparison. 
 
 
SUBJECT SELECTION  
 
I. Target population 
We propose to study bipolar depressed subjects (BPD) whose depression has failed to remit following one or 
more adequate trials with an antidepressant, or who are experiencing a breakthrough depressive episode in spite 
of being maintained on a mood stabilizer and/or an atypical antipsychotic agent. Manic/hypomanic symptoms 
must have responded adequately to a mood stabilizer other than lithium. Subjects will be maintained on a mood 
stabilizer and/or atypical antipsychotic throughout the proposed study. Subjects who are maintained on lithium 
will not be included since there is a potential adverse interaction with celecoxib.  
 
The following eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate. All relevant medical and non-medical conditions should be taken into consideration when deciding 
whether this protocol is suitable for a particular subject. Re-screenings may be permitted at the discretion of the 
PI.  
 
II. Inclusion Criteria  
 Male or female of any race and 18 - 65 years of age at time of screening visit. 
 Diagnosis of BPD I or II (DSM-IV-TR (296.52, 296.53, 296.89) without significant co-morbid secondary 
medical or psychiatric diagnoses. 


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 Depressive symptoms that failed to remit in response to antidepressant therapy OR current breakthrough 
depressive episode in spite of being maintained on a mood stabilizer and/or an atypical antipsychotic agent. 
 Managed mania/hypomania with a mood stabilizer other than lithium, or an atypical antipsychotic. 
 A minimum score of 18 on the Hamilton Depression Scale (HAM-D), 17-item. 
 Willingness to institute lights-out at 11:00pm hours on the nights before blood drawings. 
 
 
III. Exclusion Criteria  
 Any abnormal findings on the physical exam, ECG, blood/urine or minor infections. 
 Abnormal results on liver or bone marrow function as indicated by liver function or CBC with differential 
blood tests. 
 Any pre-existing physical pain condition, including fibromyalgia. 
 History of peptic ulcer complicated by perforation, hemorrhage, or obstruction; symptoms of peptic ulcer 
within 4 weeks of enrollment date. 
 Substance abuse or dependence during the preceding 12 months. 
 Clinically significant hypertension, anemia, liver disease, kidney disease, arthritis, diabetes, recurrent 
migraines, epilepsy, stroke, gum disease, autoimmune disease. Based on the judgment of the PI, a risk 
assessment should be done if a subject meets any of this clinical criteria but is otherwise suitable.  
 Current use of lithium.  
 Current use of a stimulant. 
 Current use of any anticoagulant agents. 
 Current use of nicotine-containing substances. Subjects who stop using nicotine-containing substances more 
than 1 month prior to assessment may be considered for the study. 
 Certain steroids including use of hormonal birth control and any systemic or topical corticosteroids  
(hormone replacement therapy will be allowed). 
 Unwillingness to refrain from H2 receptor antagonists, non-aspirin NSAIDs, ginko biloba, vitamin E or fish 
oils, or aspirin over 81 mg/day.   
 Sensitivity or allergy to the study medications. 
 Need to receive agents that are contraindicated in combination with celecoxib or escitalopram. 
 Unwillingness to fast and abstain from caffeine on mornings of blood drawings. 
 A sleep disorder other than insomnia or hypersomnia as a distinct symptom of MDD. 
 Inability to commit to the follow-up visits between 8:30am and 12:00pm.  
 
IV. Randomization Criteria 
 Subjects must not have responded or remitted as measured by the HAM-D 17 after 1 week of treatment with 
single-blind placebo.  
 
V. Criteria for Temporary Suspension of Study Participation Pending Clarification 
 HAM-D 17 score of less than 18 at Baseline visit, indicative of a placebo responder.  
 Subject attempts suicide or seriously deteriorates. 
 Develops signs or symptoms suggestive of an ulcer or kidney disease or other serious illness. 
 Develops elevated blood pressure, creatinine, potassium, or decreased hematocrit.  
 Requires corticosteroids, warfarin, ticlopidine, or any anticoagulant. 
 Takes more than 4 doses per week of any of the following: Vitamin E or fish oils (at doses > 600 IU/day), 
non-aspirin NSAIDs or aspirin (>81 mg/day). 
 


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VI. Criteria for Subject Termination 
 Subject attempts suicide or seriously deteriorates; if so, appropriate care will be provided. 
 Develops serious complications of an ulcer, such as gastrointestinal bleeding, perforation, or obstruction.  
 Engages in behaviors or develops any condition that the PI deems makes it medically unsafe or 
inappropriate to remain in the study. 
 
 
 
STUDY TREATMENTS AND COMPLIANCE  
 
Subjects who meet the eligibility criteria will receive one week of single-blinded escitalopram placebo + single-
blinded celecoxib placebo. Subjects who continue to meet eligibility at randomization will receive open-label 
escitalopram (beginning at 10mg/day) + double-blinded treatment of celecoxib (fixed at 400mg/day) or placebo. 
Escitalopram doses may be optimized based on efficacy and tolerability over the 8 weeks of active treatment. 
Subjects will be randomized according to a fixed assignment ratio of 1:1 (escitalopram + celecoxib: 
escitalopram + placebo). Assignment to groups is based on a pharmacy generated randomization code. 
 
I. Compliance  
To ensure compliance, participants be asked to return all unused medication at the following visit. The returned 
capsules will be counted. Additionally, blood concentrations of escitalopram and celecoxib will be determined 
at Baseline, Week 4 and Week 8.  
 
II. Procurement of Compounds  
Escitalopram and celecoxib will be purchased from the pharmaceutical companies that market them. In the US 
celecoxib is marketed by Pfizer and escitalopram is marketed by Forest Laboratories. The pharmacy will 
produce placebo identical in appearance to celecoxib and escitalopram.  
 
 
STUDY PROCEDURES  
 
Schedule of Events 
Procedure 
Screen 
1
Screen 
2
Baseline Week 
1
Week 
2
Week 
4
Week 
8
Consent 
X 
 
 
 
 
 
  
Assign Subject ID 
X 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
  
HAM-D/HAM-A/MADRS 
X* 
X* 
X  
X 
X 
X 
X 
CGI/CSSRS/AdverseEvents/CSULGIE X 
 
X 
X 
X 
X 
X 
Self-Assessment Packet 
 
 
X 
X 
X 
X 
X 
Dispense Study Medication 
 
PBO 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
 
X  
Drug Screen and Pregnancy Test 
X 
 
 
 
 
 
X  
Routine Clinical Labs 
X 
 
 
 
 
 
X  
Research Blood Draw 
 
 
X 
 
 
X 
X 
CBC/PT/PTT Monitoring 
X 
 
 
 
X 
X 
X 
Pulse Wave Analysis 
 
 
X 
 
 
X 
X 


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Heart Rate Variability 
 
 
X 
 
 
 
X 
Albuterol Challenge 
 
 
X 
 
 
 
X 
Pulse Wave Velocity 
  
  
X 
  
  
  
X 
Saliva Sampling 
 
X 
X 
X 
X 
X 
X 
 
*HAM-D only.  
Routine Clinical Labs include complete blood count, complete metabolic panel, lipid profile and thyroid 
function. 
 
The following assessments are included in the self-assessment packet:  
 Beck Depression Inventory (BDI) 
 Beck Anxiety Inventory (BAI) 
 State/Trait Anxiety Inventory (STAI) 
 Spielberger Anger Expression Inventory (STAXI) 
 International Physical Activity Questionnaire (I-PAQ) 
 Quality of Life and Enjoyment Questionnaire (QLES-Q) 
 The Short-Form McGill Pain Inventory (MPI) 
 Perceived Stress Scale (PSS-14) 
 
Subjects will be treated as outpatients for a total of ten weeks. Subjects must complete at least six weeks to be 
regarded as completers. If a subject chooses to withdraw from the study on or after six weeks of treatment, he or 
she will be asked to complete end-of-study assessments at that time. Those results will be carried forward for 
the purpose of data analysis. 
 
Subjects will not receive any other type of therapeutic intervention (e.g., psychotherapy) during participation in 
the study. Such options may be offered to them at the conclusion of the study, if appropriate. 
 
Subjects who complete the study and respond favorably will remain under the care of the LUMC physician, if 
they wish. 
 
 
ASSESSMENTS  
 
I. Psychometric Data Collection Instruments 
Mini International Neuropsychiatric Interview (MINI)   
Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A)  
Beck Depression Inventory (BDI); Beck Anxiety Inventory (BAI)  
MADRS-Montgomery Asberg Depression Rating Scale (MADRS) 
Columbia Suicide Severity Rating Scale (C-SSRS)  
State/Trait Anxiety Inventory (STAI)  
Spielberger Anger Expression Inventory (STAXI) 
Inventory of Clinically Significant Upper and Lower GI events (CSULGIE)  
Short-Form McGill Pain Inventory (MPI) 
Perceived Stress Scale (PSS-14) 
Quality of Life and Enjoyment Questionnaire (QLES-Q) 
International Physical Activity Questionnaire (IPAQ) 
 


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II. Blood Sampling 
Blood samples will be drawn at trough levels after instructing subjects to ensure a 12-hour interval after the last 
dose in the evening preceding the morning blood draw. Plasma, serum and buffy coat will be immediately 
separated and frozen at -80°C for future analysis.  
 
Measurement of Plasma Pro-Inflammatory Biomarkers 
These measures will be obtained from blood drawn at Baseline, Week 4 and Week 8 using the Randox 
Technologies “Evidence InvestigatorTM” system. This compact Biochip array system is comprised of a super-
cooled Charge Coupled Device (CCD) camera and unique image processing software. This Biochip technology 
has been validated using blood samples from our preliminary studies. Several cytokines, chemokines and 
growth factors can be analyzed simultaneously using microliter volumes of plasma. The results produced by the 
Biochips are impressive and comparable to results obtained by individual ELISAs for each parameter. This 
assay will be completed in an LUMC lab.  
 
Measurement of Serum Kynurenines and the Tryptophan Pathway 
These measures will be obtained from blood drawn at Baseline, Week 4 and Week 8. The measurement of 
tryptophan and kynurenines has been established in the Psychoneuroimmunology (PNI) Laboratory of the 
Psychiatric Hospital of LMU, Munich using Ultra Performance Liquid Chromatography – Mass Spectrometry 
(UPLC-MS) methodology. The method has been standardized by the participation of 6 universities in the 
External Quality Assurance Scheme as a part of the EU collaboration project MOODINFLAME. The measured 
metabolites are: tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranillic acid and 
quinolinic acid. This assay will be completed by collaborating investigators in Munich, Germany. 
 
Measurement of Blood Levels of Celecoxib and Escitalopram 
These measures will be obtained from blood drawn at Baseline, Week 4 and Week 8. Plasma concentrations of 
celecoxib and escitalopram will be measured using a solid phase HPLC method. This measurement will help the 
study team determine whether subjects are compliant, adequately dosed and if celecoxib changes escitalopram 
blood levels, or vice versa. Celecoxib levels will be assayed by collaborating investigators in Munich, Germany. 
Escitalopram levels will be assayed by collaborating investigators in Charleston, SC.  
 
Measurement of COX-2 Inhibitory Level in Blood via PGE2 Activity 
These measures will be obtained from blood drawn at Baseline, Week 4 and Week 8 using an EIA kit from 
Cayman Chemical Inc. This fast and reliable method uses LipoPolySaccharide (LPS) stimulation and a special 
Cremophor EL-EtOH vehicle to solubilize and assay PGE2. The method is rapid and eliminates COX-1 activity 
artifact using aspirin and an available thromboxane synthase inhibitor (TXBSI). This assay will be completed in 
an LUMC lab.  
 
Monitoring of Possibility of Bleeding Diathesis 
These measures will be obtained from blood drawn at Week 2, Week 4, and Week 8. Since the combination of 
an SSRI and a COX-2 inhibitor has the potential to induce bleeding diathesis, a complete blood count (CBC), 
prothrombin time (PT) and partial thromboplastin time (PTT) will be evaluated. Prothrombin Time and aPTT 
testing are performed on the Sysmex CA-7000 analyzer utilizing the scattered light detection method. The 
analyzer irradiates red light (660 nm) onto a mixture of blood plasma and reagent and detects the change in 
turbidity (when the fibrinogen is transformed into fibrin) as the change in scattered light. A curve is generated, 
plotting time against the amount of scattered light. This sample will be processed by LUMC Clinical 
Laboratories.  
 
III. SphygmoCor® Assessments 


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All SphygmoCor® measures will be obtained using the non-invasive SphygmoCor® device (SCOR-Vx, AtCor 
Medical Pty, Ltd) equipped with the most recent software (v9.0, AtCor Medical, West Ryde, Australia). 
Brachial blood pressure will be recorded at the same session using a standard method. 
 
Pulse Wave Analysis to Quantify Arterial Stiffness 
Subjects will undergo the Pulse Wave Analysis at Baseline, Week 4 and Week 8. Pulse-wave analysis (PWA) is 
a non-invasive, FDA-approved technique that allows for the assessment of arterial stiffness. Pulse wave 
measurements have been established as prognostic markers of cardiovascular morbidity and mortality 
(Papaioannou et al, 2007; Weber et al, 2007). These wave indices may also serve as prognostic markers of 
response to therapy (Weber et al, 2007; Williams et al, 2006). A portable tonometric probe is positioned over 
the maximal arterial pulse of the artery under study. A minimum of twenty sequential pressure waveforms must 
be recorded. SphygmoCor® Software generates mean peripheral and corresponding central and aortic pressure 
waveforms using a validated transfer function. Intra- and inter- observer reproducibility of these measures has 
been established in various populations (Papaioannou et al, 2007; Wilkinson et al, 2002).  Resting wave form 
will be recorded using standard PWA technique, as described by Nutt et al (2006) and Rybakowski et al (2006). 
 
Albuterol Challenge to Assess Endothelial Function 
Subjects will undergo the Albuterol Challenge at Baseline and Week 8 to assess endothelium-dependent 
vasodilation. Albuterol (2 x 200μg) will be given by inhalation with a spacer device. The subject will be asked 
to slowly inhale for 50 seconds, and then hold breath for 10 seconds. After a 30 second rest, the procedure will 
be repeated. Albuterol induces vasodilation by way of receptors on the endothelium through a nitric oxide 
pathway (Hayward et al, 2002; Wilkinson et al, 2002). Pulse Wave Analysis will be performed at 0, 5, 10 and 
15 minutes after albuterol treatment. Responses to the Albuterol Challenge will be defined as the maximum 
possible difference between Baseline augmentation index and post-treatment augmentation index.    
 
Pulse Wave Velocity 
Subjects will undergo the Pulse Wave Velocity assessment at Baseline and Week 8. The assessment involves 
the measurement of pulse waves at the common carotid artery and on the femoral artery using the 
aforementioned probe. A 3-lead ECG will be used to simultaneously obtain heart rate values. ECG recording 
during measurements is necessary for synchronization of carotid and femoral pulse wave times. The distance 
from the sternal notch to the femoral location and from sternal notch to the carotid location are measured 
manually and entered into the program, transit time between carotid and femoral pressure waves is calculated 
and Pulse Wave Velocity is PWV computed by the software.  
 
Heart Rate Variability 
Subjects will undergo the Heart Rate Variability assessment at Baseline and Week 8. This technique allows for 
the assessment of sympathetic/parasympathetic imbalance in depression, which may be central to the 
development of cardiovascular disease secondary to depression. HRV is a natural physiological function of a 
healthy heart capable of responding and adapting to changing demands of life circumstances.  
 
IV. Safety Assessments and Adverse Events Monitoring 
A complete physical examination with clinical laboratory assessments will be performed at enrollment and 
termination. Bleeding diathesis monitoring will be completed with higher frequency, as outlined in the schedule 
of events. Any negative clinically significant changes from the entry examination will be recorded as adverse 
events.  
 


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Adverse event (AE) monitoring will formally occur after weeks 1, 2, 4, and 8 of treatment. Subjects will be 
asked to describe health concerns since the last visit. Suicidality will be assessed at each visit by direct 
questioning and the Columbia Suicide Severity Rating Scale (C-SSRS). 
 
All adverse events will be monitored until stable regardless of when the event takes place. If the event occurs at 
the end of the study, it will be referred to the subject’s primary care physician and/or psychiatrist for continued 
treatment and/or follow-up.   
 
 
ADVERSE EVENTS REPORTING 
 
All AEs will reported, regardless of whether the event seems related to the study drugs escitalopram and/or 
celecoxib. Study staff will also report AEs spontaneously reported by the patient and/or observed by the staff. 
Information that will be collected includes: 
 
 A description of the event 
 Start and stop date 
 Action taken with regards to investigational product 
 Outcome 
 If the AE causes the patient to discontinue the study 
 A statement reporting if the AE meets criteria for a Serious Adverse Event or not (see below) 
 The investigator’s assessment of the causal relationship between the event and the study drug 
 Intensity of the AE 
o mild (awareness of sign or symptom, but easily tolerated) 
o moderate (discomfort sufficient to cause interference with normal activities) 
o severe (incapacitating, with inability to perform normal activities) 
 
All serious adverse events (SAE) will be documented and reported to appropriate regulatory bodies. All adverse 
events will be summarized in a report at intervals requested by the IRB and the Data Safety Monitoring Board.  
 
 
ETHICS AND EVALUATION OF RISKS 
 
I. Consent Process Overview 
Each subject will be presented the Informed Consent Form after meeting criteria for inclusion. Subjects will be 
asked to read the Informed Consent Form carefully. Subjects will be told about the effects of celecoxib and 
escitalopram. Subjects will be told that their participation in this study could benefit patients with BPD in the 
future. Subjects will also be informed of potential risks and discomforts. Any subject who appears incapable of 
providing informed consent (e.g., due to cognitive impairment) will not be enrolled. Subjects will be informed 
that they can decline to participate in the study without penalty or loss of treatment. Subjects will also be 
informed may withdraw from the study prior to analysis of their data. Following a thorough resolution of any 
questions, the subject will be asked to sign the consent form if he or she agrees to participate. 
 
II. Evaluations of Benefits and Risks/Discomforts 
Each subject will be given a medical and psychiatric evaluation. Subjects who receive active treatment may 
experience greater improvement or possible remission of their mood disorder, as well as improved biomarker 


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levels and arterial compliance as measured by PWA. To compensate for time spent and inconvenience 
experienced during the study, a predetermined compensation fee will be given.  
     
Physical risks to subjects are minimal. Discomfort may result from the blood drawing. There may be bruising at 
the needle site. Certain individuals may feel light-headed during venipuncture. Venipuncture will be performed 
when the subjects are sitting or recumbent to avoid injury. Discomfort may be experienced due to tedious 
questionnaires and interviews. 
 
Side effects listed in the Physician’s Desk Reference for albuterol include hoarseness, headache, tremors, and 
palpitations. A hypersensitivity reaction to the drug has been reported in very rare cases.  To avoid this risk, 
subjects will be asked if they have had previous exposure to albuterol, and if they displayed a hypersensitivity 
reaction.  If any adverse reactions are noted after the first administration, the subject will receive no further 
exposure to the drug. 
 
Discontinuation of subjects’ current antidepressant medication is unlikely to lead to worsening of depression or 
suicidal thoughts because eligible participants are only those who are already depressed whose depression has 
not responded despite attempts to treat depressive symptoms with antidepressant medication.  Subjects will be 
seen one week after beginning the wash-out phase and one week after beginning the placebo run-in, allowing 
study staff  to frequently assess the subjects’ mental status while not on any antidepressant therapy in the 
unlikely event that subjects begin to feel more depressed or suicidal.  Subjects will also be encouraged to 
contact study staff throughout the duration of the study if they notice any changes in their mental or physical 
health.  If in the opinion of the investigator the patient develops serious suicide risks, the patient will be 
withdrawn from the study and provided treatment as appropriate.  Should this occur the subject will be 
responsible for the costs of treatment.   
 
III. Adequacy of Protection Against Risks 
The rights to privacy for participation in this research and safety of confidential information are paramount.  
These rights will firstly be protected through coding of data and storage of research records in a locked room.  
Records that contain identifiable subject information will be stored either in locked cabinets or on a locked 
computer in secure electronic files.  These records will be kept confidential to the fullest extent permitted by 
law. 
 
 
OTHER STUDY DRUG CONSIDERATIONS  
 
I. Safety Issues of Celecoxib and SSRIs 
There are potential risks associated with taking escitalopram. The most commonly reported side effects of 
escitalopram are dizziness, drowsiness, and light-headedness.  Less commonly reported side effects include: 
headache, dry mouth, constipation, change in appetite, sweating, palpitations, upset stomach, abdominal pain, 
weight gain, dyslipidemia, insulin resistance, muscle twitching, and abnormal movements of the face.  At the 
doses we are using, most of the side effects experienced by patients taking escitalopram should be mild to 
moderate and go away with continued treatment.   
 
 
Celecoxib is the only coxib available in the US, but carries a FDA-mandated black-box warning for increased 
cardiovascular risk. The FDA issued this warning based on numerous observational studies and randomized 
clinical trials on cardiovascular risks associated with all COX-2 inhibitors, but the degree of this risk varies 
substantially among the different COX-2 inhibitors. Rofecoxib was removed from the market several years ago, 


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but celecoxib only received a black box warning. Celecoxib is still used widely because it appears at least as 
safe as other marketed NSAIDs. The full explanation of why celecoxib appears to be safe while other COX-2 
inhibitors are not is an area of active research. A review of the literature shows this may relate to the fact that 
celecoxib possesses a number of artery-positive off-setting affinities compared to rofecoxib, a more pure COX-
2 inhibitor. Whatever the reason, celecoxib appears safe at the dose regimen we will prescribe.  
 
II. Co-Prescription of Celecoxib and Escitalopram at Loyola Medical Center in 2009 
There is no evidence that celecoxib and escitalopram interact in any way. As far as we know, their biomolecular 
targets (COX-2 and serotonin transporter) do not have shared affinities. Escitalopram has low potential for 
clinically significant interactions. Studies in vitro have shown that the biotransformation of escitalopram to its 
demethylated metabolites depends on three parallel pathways (cytochrome P450 (CYP) 2C19, 3A4 and 2D6).  
Celecoxib, on the other hand, is metabolized by 2D6. Nevertheless, since we know it is common practice to 
combine celecoxib with antidepressants, mostly in non-psychiatric settings, we conducted an internal review of 
all prescriptions of celecoxib in combination with an antidepressant throughout Loyola Medical Center during 
2009. The results are presented in summary form below. As shown, escitalopram represented 19.2 % of all 
prescriptions of an antidepressant co-prescribed with celecoxib. No adverse events were recorded in a total of 
224 cases receiving the combination at our institution. 
 
 
Situations Resulting in Combination 
No. Cases 
Serious Adverse 
Events from Combo 
Primary treatment of mood disorder  
21 
0 
Primary treatment was the antidepressant for 
other than mood disorder  
17 
0 
Primary treatment for pain (2nd depression?) 
28 
0 
Post-surgery 
6 
0 
Cardiovascular disease present 
38 
0 
GI disease present 
10 
0 
Reason unspecified for combination treatment 104 
0 
Total  
224* 
0 
 
*Of all the incidents of antidepressant co-prescriptions with celecoxib in 2009, escitalopram was the agent co-
prescribed 19.2 % of the time.  There were no serious adverse events reported due to any antidepressant in 
combination with celecoxib at Loyola Medical Center in 2009. 
 
NSAIDs are known to carry a risk of gastrointestinal bleeding. However, this is mostly a property of COX-1 
inhibitors. Escitalopram may also impose a minor risk of prolonged bleeding through its platelet serotonin 
depletion property. Because of this property, we will monitor platelets during treatment. However, the risk of 
bleeding appears very low when the odds ratios published in a recent review article is considered (Loke 2008). 
The odds ratios of gastrointestinal bleeding were summarized from all prior studies of SSRIs alone, NSAIDs 
alone, and SSRIs + NSAIDs. A meta-analysis was performed on published papers representing a total of 
153,000 patients. The article also obtained 161 potentially relevant private company reports covering four 
SSRIs – fluoxetine, paroxetine, sertraline, and escitalopram – in regard to adverse event frequencies involving 
GI hemorrhage. The article also assembled all post-marketing reports of adverse events submitted to the FDA or 
to the Canadian Adverse Events Database. From this large database they concluded that the odds ratio of 
developing GI bleeding from an SSRI alone was 2.36. By comparison, the odds ratio of developing GI bleeding 
from an NSAID alone was 3.16. Finally, the odds ratio of developing GI bleeding from concomitant use of an 


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SSRI and an NSAID was 6.33. However, it is important to realize this was for all NSAIDs combined. COX-2 
inhibitors were found to be involved in only a fraction of the total NSAID+SSRI adverse event cases producing 
GI bleeding. A much lower rate of bleeding risk is expected in our study because the median ages and durations 
of treatment in the review exceed those of the Loke review (median age 66 years, median length of drug 
exposure 25 weeks). Also, the studies assembled were not limited to the 400 mg/d dose of celecoxib we will 
prescribe. Therefore, developing a bleeding diathesis from the combination treatment should be very low: we 
estimate no more than 1 per 350 cases. 
 
The above graph compiled by the Risk Communicator Institute illustrates the very low risk celecoxib poses for 
GI bleed or heart attack compared to other agents.  It is directly comparable to that of naproxen and lower than 
that of ibuprofen, both of which are sold without prescription. 
 
Another potential risk to subjects concerns confidential information.  It will be explained that our study is not 
designed to produce confidential data of any kind that presents any known risk to the subjects.  However, it will 
be acknowledged in plain language that we cannot guarantee that in some unpredictable way either their 
background information or the samples could become a future liability. 
 
III. Accounting for Pain Perception  
No previous study with an NSAID has considered analgesia as a possible confounding variable in the reported 
augmented antidepressant response to the anti-inflammatory add-on agent. Because NSAIDs possess analgesic 
properties and physical pain can be variably present in depression, the issue must be considered. To underscore 
the point, the Sequenced Treatment Alternatives to Relieve Depression multi-center study found that 80% of 
2,876 outpatients with MDD complain of painful physical symptoms (Pilowsky et al, 1984; Husain et al, 2007; 
Leuchter et al 2009).  None of the previous studies on celecoxib excluded patients with active physical pain or 
sought to quantify the pain dimension during treatment. As a result, we feel it is important to control for and 
evaluate pain perception. Therefore, subjects with a pre-existing pain condition will not be enrolled in the study. 
Furthermore, we will use the Short-Form McGill Pain Inventory to assess the visit-to-visit pain perception of 
subjects.  
 
 


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DATA ANALYSIS AND STATISTICAL METHODS 
 
I.  Statistical Analysis 
Specific Aim 1 is to determine if combined pharmacotherapy of escitalopram + celecoxib will result in earlier 
and/or improved affective responses compared to escitalopram + PBO. Additionally, Specific Aim 1 seeks to 
control for pain perception in this analysis. For this aim, the patients in the two treatment arms will be compared 
on HAM-D, HAM-A, MADRS, BDI, and BAI scores. This will be accomplished with an analysis of covariance 
conducted at weeks 1, 2, 4 and 8. Baseline mood scores and McGill Pain Inventory scores will be used as 
covariates. In addition, the number of patients who are and are not classified as remitters at week 8 (those 
having a HAM-D score of 7 or less) will be tallied and cross-referenced with treatment group (escitalopram + 
celecoxib or escitalopram + PBO). The frequencies in the resulting 2-by-2 contingency table will be analyzed 
with the Pearson Chi-Square Test for Association. 
 
For Specific Aim 2, dealing with treatment safety and tolerability, the numbers of patients who do and do not 
experience adverse events at weeks 1, 2, 4, and 8 will be tallied and cross-referenced with treatment group. The 
frequencies in the resulting 2-by-2 contingency table will be analyzed with the Pearson Chi-Square Test for 
Association. Additionally, to understand whether any pharmacodynamic interaction exists between escitalopram 
and celecoxib, blood levels of escitalopram and celecoxib drawn at weeks 4 and 8 will be compared for patients 
in the two treatment groups with an analysis of covariance using baseline levels as a covariate. If there is no 
pharmacokinetic interaction then we expect that there will be no statistically significant results for these 
analyses. 
 
For Specific Aim 3, determining whether there is a correlation between blood concentration of  pro-
inflammatory biomarkers and the psychiatric effectiveness of the combined treatment, three types of analyses 
will be conducted. First, at the end of treatment we expect that general inflammation will be lower for patients 
taking celecoxib. Hence, the week-8 measures of TNF-alpha and hsCRP for patients in the two treatment groups 
will be compared with an analysis of covariance using baseline values as a covariate. Second, based upon 
information from our previous research, we anticipate that patients with the highest inflammation values, who 
receive celecoxib with escitalopram, will derive the greatest therapeutic benefit. Hence, we expect an 
inflammation-by-study group interaction. Therefore, the association of Week 8 HAM-D scores and baseline 
TNF-alpha values will be examined by way of multiple regression analysis. Week 8 HAM-D scores will be the 
criterion variable. The regression equation will include predictor terms for baseline HAM-D scores (to control 
for pre-existing differences in mood) , baseline TNF-alpha values, a dichotomous variable for study group 
(escitalopram+celecoxib vs. escitalopram+PBO), and the product of baseline TNF-alpha and study group.  It 
will be the statistical significance of the last term (the product) that tests the inflammation-by-study group 
interaction. This analysis will be repeated with hsCRP. Third, the change in inflammation across the eight 
weeks of therapy will be correlated with the change in depression scores. The difference in HAM-D scores from 
week 8 and baseline will be correlated with the difference in TNF-alpha and then hsCRP using the Pearson 
Correlation Coefficient. This will be done for patients in the monotherapy group and then for those in the 
combination therapy group. The same analysis will be repeated using HAM-A, MADRS, BDI and BDI.  
 
For Specific Aim 4, the effectiveness of celecoxib in inhibiting PGE2 will be analyzed by comparing PGE2 
scores at week-8 for patients in the two treatment groups with an analysis of covariance using baseline PGE2 
scores as a covariate. We anticipate that the adjusted mean for PGE2 at week-8 will be lower for patients 
receiving celecoxib than that for patients receiving PBO. 
 
An approach for statistical analysis of Specific Aims 5, 6, and 7 is currently under development.   
 


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All statistical analyses will be conducted using the latest version of SPSS software for Windows.  If a subject 
drops out after completing 6 weeks on active medication (after randomization), we will use the last observation 
carried forward (LOCF method) to analyze the data.  If a subject has completed at least one week on active 
medication after randomization, but drops out of the study at any time between week-1 and week-8, s/he will be 
included in the intent-to-treat analysis. Since this project seeks to provide proof-of-concept in bipolar 
depression, and is therefore exploratory in nature, we propose the tests of significance use a 0.05 alpha level. 
However, if this proposal develops further we may adjust our desired level of statistical significance to be in 
line with the number of tests so that the family wise Type I error rate could be held at 5%. This issue will be 
considered in the future.  
 
II.  Determination of Sample Size 
Although a number of tests of statistical significance are planned for the proposed study, our required sample 
size is being based upon the primary outcome of treatment effect (Specific Aims 1).  In looking at differences in 
mean HAM-D scores from the studies by Akhondzadeh et al. 5 and Mueller et al. 6 we found that the effect 
sizes of an antidepressant + anti-inflammatory agent over an antidepressant + placebo at week 3 of treatment 
were 0.53 and 0.52, respectively.  In the proposed research we anticipate that the effect size will be slightly 
higher due to the fact that variation in depression scores attributable to baseline levels and pain perception will 
be eliminated in an analysis of covariance.  Hence, we anticipate that the effect size will be about 0.60 for 
escitalopram + celecoxib over escitalopram + PBO.  As noted earlier, we anticipate that the drug combination 
will lead to a therapeutic response that is earlier than what is normally seen at week-3 of treatment. We thus 
expect to see a treatment effect at week-2 of therapy, and expect that the magnitude of the effect will increase 
over the course of the study. The increasing separation between the different treatment groups is similar to what 
was found in the studies mentioned above which observed rising treatment effects during the course of therapy. 
From this, our computations indicate that a sample size of 45 patients per group will provide 80% power for an 
analysis of covariance to detect an effect size of 0.60 at week-2 of therapy using a 0.05 level of significance. 
Thus, a total of 90 patients completing treatment will be acquired for the proposed work. 30 of the total patients 
will be enrolled and randomized at our sister site in Munich, Germany. Given that the therapeutic effect size is 
expected to increase over time, the proposed sample size will be adequate throughout the course of the study. 
Subjects lost to attrition will be replaced.  
 
 
References 
Adams, MD. et al. Complementary DNA sequencing: expressed sequence tags and human genome project. 
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inflammatory signaling pathways 6 months later. Psychosom Med 71, 57-62 (2009).19073750 
 
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schizophrenia. Eur Arch Psychiatry Clin Neurosci 255(2): 149-151. 
 
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ICF_001.pdf: 
 
Document ID #: 203368ar6.111616 
Version Date: 11/16/2016 
 
1
IRB NUMBER:  203368021611 
 
 
LOYOLA UNIVERSITY MEDICAL CENTER 
 
MAYWOOD, ILLINOIS 
 
DEPARTMENT OF PSYCHIATRY 
 
 
 
INFORMED CONSENT 
 
Participant’s Name: _______________________________________________________ 
 
Medical Record Number: ___________________________________________                            
                                                               
PROJECT TITLE:  Cyclooxygenase-2-Inhibitor Combination Treatment for Bipolar 
Depression: Role of Inflammation and Kynurenine Pathway Biomarkers. 
 
THE APPROVAL FOR THIS PROJECT EXPIRES ON 11/16/2017. 
 
 
Participant Information 
 
PRINCIPLES CONCERNING RESEARCH:  You are being asked to take part in a research 
project.  It is important that you read and understand the principles that apply to all individuals 
who agree to participate in the research project described below: 
 
1. Taking part in the research is entirely voluntary. 
 
2. We do not know if you will benefit directly from taking part in the research but the 
knowledge obtained may help others. 
 
3. You may withdraw from the study at any time without anyone objecting and without 
penalty or loss of any benefits to which you are otherwise entitled. 
 
4. If during your participation in the research project, new information becomes available 
which would affect your being in the research project (such as better treatments or the 
side effects of the treatments), your doctor will discuss this new information with you and 
will help you make a decision about your continuing in the research. 
 
The purpose of the research, how it is to be done, and what your part in the research will be, is 
described below.  Also described are the risks, inconveniences, discomforts and other important 
information which you need to make a decision about whether or not you wish to participate.  
You are urged to discuss any questions you have about this research with the staff members. 
 
PURPOSE OF STUDY:  You are being asked to participate in a research project because you 
suffer from Bipolar Disorder and the doctors recommend treatment for your condition.  
 
 
In bipolar disorder, the depressive symptoms are more common than manic symptoms; and, it is 


 
Document ID #: 203368ar6.111616 
Version Date: 11/16/2016 
 
2
depression that most adversely affects the quality of life.  Depressive symptoms suffered by 
bipolar patients are more difficult to treat than manic symptoms, and the suicide rate is highest in 
patients with bipolar disorder.   
 
Patients suffering from depression also show elevated levels of chemicals in the blood, called 
biomarkers that indicate ongoing inflammation.  This inflammation found in patients suffering 
from depression may reduce the effectiveness of antidepressant medications.  Furthermore, 
inflammation likely contributes to the increased risk of depressed patients to develop serious and 
potentially life-threatening complications, such as heart disease and stroke.   
 
The purpose of this research is to determine if treating depression with an antidepressant 
(Escitalopram-Lexapro) and an anti-inflammatory medication (Celecoxib-Celebrex) increases 
the effectiveness of treating the depressive symptoms of Bipolar Disorder.  The related purpose 
is also to see if this treatment reduces the levels of inflammatory biomarkers in the blood that 
suggest patients might be at risk for developing life-threatening conditions like heart disease and 
stroke.  The combination of escitalopram with celecoxib to treat your condition is research. 
 
Approximately 70 participants will participate in this project.  This study is being funded by the 
Stanley Medical Research Institute.   
 
DESCRIPTION AND EXPLANATION OF PROCEDURES:  If you agree to participate,  
you will be asked to come to Loyola University Medical Center up to 8 times during this study. 
These visits will take place between 8:30am and 12:00pm. Additional visits may be necessary if 
you report any adverse events or if an unscheduled dose adjustment is necessary. You should be 
fasting for 12 hours prior to any visit during which a routine blood chemistry blood draw is 
scheduled. 
 
Screening - Visits 1 and 2 
During the Screening (Visits 1 and 2) the following procedures will take place:  
 
Blood draw for routine clinical lab tests. No more than 3 teaspoons will be drawn. 
 
Urine sample collection for drug testing and pregnancy screening, if appropriate. 
 
Medical history including family background history. 
 
A physical examination including a brief gum exam. 
 
A psychiatric interview to assess your level of anxiety and depression. 
 
A saliva sample will be taken for cortisol analysis. 
 
The physical exam and collection of specimens will only take place after your eligibility has 
been confirmed in the psychiatric interview.  
 
During the psychiatric interview portion of these two study visits, the psychiatrist will complete 
the following scales to assess your mood and level of depression:  
 
Hamilton Rating Scales for Depression (HAM-D) 
 
Portions of the Diagnostic Interview for Genetic Studies (DIGS) 
 
The Mini-International Neuropsychiatric Interview (MINI)  
 
Meeting with the psychiatrist will require up to 2 hours of your time during each visit in the 


 
Document ID #: 203368ar6.111616 
Version Date: 11/16/2016 
 
3
Screening process.  
 
You will also be asked to complete the following self-assessments regarding your mood as you 
perceive it:  
 
Patient Health Questionnaire (PHQ-9)  
 
Beck Depression Inventory (BDI) 
 
Beck Anxiety Inventory (BAI) 
 
State/Trait Anxiety Inventory (STAI) 
 
Spielberger Anger Expression Inventory (STAXI) 
 
International Physical Activity Questionnaire (I-PAQ) 
 
Quality of Life and Enjoyment Questionnaire (QLES-Q) 
 
The Short-Form McGill Pain Inventory (MPI) 
 
Perceived Stress Scale (PSS-14) 
 
Completing the above self-assessments will take between 20 and 30 minutes.  
 
If the tests show that you qualify to participate, you will be scheduled for another visit. You will 
be instructed by the psychiatrist on how to taper off of the antidepressant medication you may 
have been taking. Completing all of these assessments may take up to 4 hours in total. If the 
amount of time it takes to complete these assessments and procedures exceeds the allotted time 
of the scheduled visit due to late arrival, waiting time, etc., the assessments and procedures 
mentioned above may be completed over the course of two visits.  
 
More information on Screening Visit 2 
If you are on an antidepressant upon enrolling in the study, you will be instructed on how to 
taper off the medication as mentioned above. If this wash-out step is necessary, Visit 2 will also 
include a second administration of the HAM-D to assess your level of depression and anxiety 
after having stopped taking your antidepressant. If you are still eligible to participate in the 
study, you will begin taking study pills after this visit. You will be given a one week supply of 
study pills at the end of Visit 2.   
 
Baseline – Visit 3 
During the Baseline visit (Visit 3)  you will meet with the psychiatrist again. The following 
instruments will be used to assess your mood, depression and anxiety:  
 
Hamilton Rating Scales for Depression (HAM-D) 
 
Hamilton Rating Scales for Anxiety (HAM-A) 
 
Montgomery Asberg Depression Rating Scale (MADRS) 
 
Clinical Global Impression Severity and Improvement Scales (CGI) 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Inventory of Clinically Significant Upper and Lower GI events (CSULGIE) 
 
Meeting with the psychiatrist will take approximately 1 hour. You will be asked to complete the 
following self-assessment regarding your level of depression, anxiety, and mood:   
 
Beck Depression Inventory (BDI) 
 
Beck Anxiety Inventory (BAI) 


 
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 
State/Trait Anxiety Inventory (STAI) 
 
Spielberger Anger Expression Inventory (STAXI) 
 
International Physical Activity Questionnaire (I-PAQ) 
 
Quality of Life and Enjoyment Questionnaire (QLES-Q) 
 
The Short-Form McGill Pain Inventory (MPI) 
 
Perceived Stress Scale (PSS-14) 
 
Completing the above self-assessments will take between 20 and 30 minutes.  
 
We will use an approved non-invasive device called the SphgymoCor® apparatus to measure 
your blood pressure waveforms and obtain heart rate information. You will lie down comfortably 
for 10 minutes. Then, a probe tonometer – about the size of a ballpoint pen – will be gently 
applied to the surface of your skin overlying the artery in your wrist. The output from the 
tonometer is viewed in real time on a nearby computer. This is called pulse-wave analysis 
(PWA). PWA is a measure of the function and stiffness of your blood vessels when reclining.  
This procedure will take approximately 15 minutes total. 
 
During this visit, further assessments will be completed using the SphygmoCor® machine. You 
will be asked to recline for at least 10 minutes in the exam room before the following 
assessments are performed.  
 
A 3-lead electrocardiogram (ECG) will record your heart rate for 15 minutes.  
 
PWV will be recorded by taking your pulse over arteries in your neck and groin. 
 
PWA will be recorded as it was during Screening.  
 
Two puffs of albuterol will be administered to you through an aerosol and spacer. 
 
PWA will then be recorded at 0, 5, 10, and 15 minutes after albuterol inhalation.   
 
More information about the SphygmoCor procedures: 
Albuterol is a safe medication commonly used for asthma. The effects of albuterol only last 
about 45 minutes, allowing your blood vessels to relax and your air passages to open. You 
should not experience any pain or difficulty breathing during this procedure, but you might 
become light-headed if suddenly rising to walk. Two puffs of albuterol will be inhaled by you 
through an aerosol sprayer with the aid of a spacer. You will inhale once slowly for 50 seconds, 
and then hold your breath for 10 seconds. After a 30 second pause, the second puff will be given 
in like manner. Pulse waves will then be recorded with the tonometer placed gently on your 
wrist. This albuterol step will only be performed during the baseline visit and at the last study-
visit.    
 
During this visit, a blood draw of about 8 teaspoons will be completed. We will freeze this blood, 
and use it later to measure the chemicals that are thought to be responsible for inflammation and 
the development of cardiovascular disease. Also, DNA (genes/heredity) will be isolated and 
genetic testing will be done using your DNA. The purpose of this genetic testing is to learn more 
about the genetic basis of heart disease and depression. The genetic testing results will be kept 
confidential. 
 
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provide a saliva sample after 20 minutes of rest in the exam room.  
 
You will continue taking study pills after this visit. You will be given a one week supply of study 
pills at the end of the Baseline visit.  
 
Your escitalopram dosing will remain at the discretion of your study psychiatrist. You will be 
assigned by lottery to receive either celecoxib (Celebrex) or a placebo along with the 
escitalopram.  Your chances of receiving celecoxib or placebo are equal.  A placebo is a 
harmless, inactive substance. Neither you nor your doctor know whether you are taking 
celecoxib (Celebrex) or placebo. In the event of a medical emergency, the principal investigator 
of the study will be notified if you are taking celecoxib (Celebrex) or placebo.  
 
All patients participating in this research will receive a placebo at some time during the study. 
 
This visit will last approximately 3 hours. 
 
Week 1 – Visit 4 
At Week 1 (Visit 4), the following scales will be completed:  
 
Hamilton Rating Scales for Depression (HAM-D) 
 
Hamilton Rating Scales for Anxiety (HAM-A) 
 
Montgomery Asberg Depression Rating Scale (MADRS) 
 
Clinical Global Impression Severity and Improvement Scales (CGI) 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Inventory of Clinically Significant Upper and Lower GI events (CSULGIE) 
 
Meeting with the psychiatrist will take approximately 1 hour. You will be asked to complete the 
following self-assessment regarding your level of depression, anxiety, and mood:   
 
Beck Depression Inventory (BDI) 
 
Beck Anxiety Inventory (BAI) 
 
State/Trait Anxiety Inventory (STAI) 
 
Spielberger Anger Expression Inventory (STAXI) 
 
International Physical Activity Questionnaire (I-PAQ) 
 
Quality of Life and Enjoyment Questionnaire (QLES-Q) 
 
The Short-Form McGill Pain Inventory (MPI) 
 
Perceived Stress Scale (PSS-14) 
 
A survey on side effects 
 
You will also provide a saliva sample at the beginning of this visit, after 20 minutes of rest in the 
exam room. You will also be asked about possible adverse events or side effects from the 
medication.  You will be given a one week supply of study pills at the end of your Week 1 visit. 
This visit will last approximately 2 hours. You will be scheduled to return to the clinic in 1 week.  
 
Week 2 – Visit 5 
At Week 2 (Visit 5), you will complete the same rating scales you completed in Week 1 to assess 
your condition. You will be asked about possible adverse events from the medication.  


 
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You will also provide a saliva sample at the beginning of this visit, after 20 minutes of rest in the 
exam room. You will be given a one week supply of study pills at the end of your Week 1 visit. 
This visit will last approximately 2 hours. You will be scheduled to return to the clinic in 2 
weeks.  
 
Week 4 – Visit 6 
At Week 4 (Visit 6), about 8 teaspoons of blood will be drawn to run clinical labs for safety 
monitoring and measure drug levels and biomarkers. You will complete the same rating scales 
you completed in Week 1 to assess your condition. You will also provide a saliva sample at the 
beginning of this visit, after 20 minutes of rest in the exam room.  You will be asked about 
possible adverse events from the medication and given a refill for your medication. PWA will be 
performed. You will be scheduled to return to the clinic in 4 weeks. This visit will last 
approximately 2 hours. 
 
Week 8 – Visit 7 
At Week 8 (Visit 7), you will undergo the same SphygmoCor procedures, psychiatric 
assessments and rating scales that were administered at the Baseline visit.  
 
You will also provide a saliva sample at the beginning of this visit, after 20 minutes of rest in the 
exam room. 
 
You should be fasting for 12 hours prior to this visit.  Up to 11 teaspoons of blood drawn from 
your arm. The blood will be used to measure drug level, biomarker levels, and routine chemistry 
analyses. You will be asked about possible adverse events from the medication. This visit will 
last approximately 3 hours.   
 
Throughout the course of treatment, approximately 25-28 teaspoons of your blood will be taken. 
This includes blood for routine blood chemistry draws, biomarker draws, and drug level draws.  
At this point, your study participation will be completed. After your participation in the study is 
over, our doctor will discuss continuing treatment options with you.   
 
There are certain medicines that you cannot take while participating in this project.  Your doctor 
will discuss them with you before you sign this consent form and you will be given a list of the 
medicines that you cannot take while participating in this project, upon your request.  
 
For confidentiality reasons, when your data is reviewed outside of the patient-doctor relationship, 
your identity will not be revealed and all information about you, including your blood samples, 
will only be known by a code.  The code and the key to the code will be kept in a secure and 
locked location. Your blood will be processed and stored for later testing in our laboratory. Since 
this is a research study and the clinical meaning of the results we obtain may not be immediately 
understood or known, neither you nor your doctor will be notified of the results of the research 
tests.    
 
Your blood will only be used for purposes of this research and will be destroyed when the 
project is completed.  Your blood will not be sold. 


 
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At two time points: prior to the Baseline visit, and prior to the Week 8 visit, we will have you 
collect your saliva at five times during the day: upon awakening, approximately 30 minutes past 
awakening, before lunch, at approximately 3pm, and before bedtime. You will be required to do 
this at home and store the samples in your refrigerator until your next visit. You will be provided 
with a log to document the exact time at which you collected your samples.  
 
RISKS/DISCOMFORTS: Escitalopram (Lexapro) may not help with your depression.  The 
treatment you are randomly assigned to receive may be less effective or may be associated with 
more problems than the treatment other participants may be randomly assigned to receive in this 
study. 
 
The most commonly reported side effects of escitalopram (Lexapro) are: nausea, insomnia, 
problems with ejaculation, sleepiness, increased sweating, fatigue, decreased sexual desire, and 
anorgasmia (inability to have an orgasm). Much less common side effects have also been 
reported: headache, nervousness or anxiety, nausea, diarrhea, dry mouth, changes in appetite or 
weight, sleepiness or insomnia, and decreased sex drive. Most of the side effects experienced by 
patients taking this medication are mild to moderate and go away with continued treatment, and 
usually do not cause patients to stop taking escitalopram (Lexapro). If you experience any of 
these side effects, contact your physician.  
 
Suicidality and Antidepressant Drugs 
Depression is associated with increased risk of suicide. Short-term studies have shown that 
antidepressants like escitalopram (Lexapro) increase the risk of suicidal ideations and behavior in 
young adults between the ages of 18 and 24 with major depressive disorder, compared to a 
placebo. Similar studies have shown no such increase in the risk of suicidality with 
antidepressants in adults beyond age 24, and there is a reduction in risk with antidepressants 
compared to placebo in adults aged 65 and older. Patients of all ages who are started on 
antidepressant therapy should be monitored closely for clinical worsening, suicidality, or unusual 
changes in behavior. Families are advised of the need for close observation and communication 
with the prescriber. 
 
Non-Steroidal Anti-Inflammatory Drugs 
Celecoxib (Celebrex) may cause an increased risk of heart attacks and strokes. This can be fatal. 
All non-steroidal anti-inflammatory drugs (NSAIDs) may have a similar risk. This risk may 
increase with duration of use. Patients with cardiovascular disease or risk factors for 
cardiovascular disease may be at greater risk. 
 
NSAIDs, including celecoxib, cause an increased risk of serious gastrointestinal adverse events 
including bleeding, ulceration, and perforation of the stomach or intestines. This can be fatal. 
These events can occur at any time during use and without warning symptoms. Elderly patients 
are at greater risk for serious gastrointestinal events. 
 
Celecoxib (Celebrex) may cause heart or circulation problems, such as chest pain, weakness, 
shortness of breath, slurred speech, or problems with vision or balance. Celecoxib (Celebrex) can 
also increase your risk of serious effects on the stomach or intestines, including bleeding or 


 
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perforation (forming of a hole). These conditions can be fatal and gastrointestinal effects can 
occur without warning at any time while you are taking celecoxib (Celebrex). Older adults may 
have an even greater risk of these serious gastrointestinal side effects. 
 
Blood drawing may be associated with mild and brief lasting pain from the stick. There is also a 
possibility of bruising and infection. Since we conduct fasting blood draws, you will be asked 
not to eat or drink anything, except water, after midnight prior to your Baseline visit and Week 8. 
At these times, you should not drink alcohol or take any medications not previously allowed by 
the physician for at least 12 hours prior to the blood draw procedure. 
 
Side effects for albuterol include hoarseness, headache, tremors, and palpitations, fast heart rates 
and nervousness. Some people can be allergic to albuterol. You will be asked if you have had 
previous exposure to albuterol, and if you have had any problems with it. If you develop any 
problems due to the albuterol while participating in this research, you will not have any more 
exposure to albuterol.    
 
You may become uncomfortable or feel bored when completing the questionnaires and rating 
scales. 
 
In order to meet the goals of the research study, we will collect information on you, your test 
results, and how you do.  The information will be coded to remove information that could be 
used to identify you and collected by Dr. Halaris, the principal investigator, other physicians, the 
research nurses, data administrators, and secretaries. This information will then be stored in a 
locked room, either in locked cabinets or on a locked computer in secure electronic files. 
However, there is the possibility that there could be a loss of confidentiality regarding your 
health information.   
 
There could also be unknown risks. 
 
REPRODUCTIVE AND SEXUAL ACTIVITY INFORMATION:  The intervention in this 
study could affect a developing baby. Therefore, you cannot participate in this research project, 
if you are pregnant or breast feeding. If you are a woman of childbearing potential, a pregnancy 
test will be done to make certain that you are not pregnant before beginning the study. 
 
Both men and women who are able to have children must use an effective method of preventing 
pregnancy while participating in this study.  You are encouraged to discuss your preferred 
method with the study doctor.  He/she will answer any questions you have regarding effective 
methods of preventing pregnancy. It is important that you consult with your physician because 
some study medications may affect the effectiveness of various methods of preventing 
pregnancy. 
 
If you become pregnant, or suspect that you have become pregnant, or you have fathered a child 
during the study, notify the study doctor immediately.  
 
BENEFITS: You will not receive additional benefit from participating in this study beyond the 
benefit that you may receive by taking approved treatments for your depression. The information 


 
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9
we obtain from you may help others. 
 
Loyola University Medical Center may benefit from your participation in this project. 
 
ALTERNATIVE TREATMENTS: You do not have to participate in this research project to 
receive care and treatment at Loyola University Medical Center.  There are approved medicines 
that you can receive to treat your condition.  Your doctor has discussed other treatments with you 
along with their risks and benefits. 
 
FINANCIAL INFORMATION: There will be no charge to you for any of the research 
procedures and blood tests. Escitalopram (Lexapro) and celecoxib (Celebrex) will be provided 
free of charge only while participating in this research project.   
 
You will be compensated a total of $360 for your participation in the study. The IRS requires 
that we have a W-9 form on file for all participants who receive compensation. You will be 
asked to complete a W-9 form before your payment can be processed. The payments will be 
distributed as follows: 
 
Visit  
Payment 
Screen 1 – Visit 1 
$25 
Screen 2 – Visit 2 
$25 
Baseline – Visit 3 
$50 
Week 1 – Visit 4 
$30 
Week 2 – Visit 5 
$30 
Week 4 – Visit 6 
$60 
Week 8 – Visit 7 
$140 
 
You will be paid a total of $360 upon completion of all visits. If you terminate your participation 
earlier, you will receive prorated compensation according to the completed visits as per the 
above schedule. If you terminate your participation before completion of the study, it will take at 
least 4 weeks for your payment to be processed and mailed to you. 
 
If you do not qualify for the study after completing all assessments at Visit 1, you will still be 
compensated $25. If the psychiatrist determines that you do not qualify for the study at Visit 1 
before having completed less than 25% of the psychiatric assessments, we will reimburse you for 
your travel fare or parking but you will not receive the $25 payment.  
 
RESEARCH RELATED INJURY:  In the event that you are injured as a direct result of 
participating in this research project, your doctor will take necessary steps to diagnose and treat 
the problem.  You will be financially responsible for the cost of care of the problem. 
 
INFORMATION COLLECTED AND WHAT WILL HAPPEN TO IT:  In order to meet the 
goals of the research study (see Purpose of Research section of this consent), we will collect 
information on you, your test results and how you do.  The information will be collected by Dr. 
Angelos Halaris, the study physician(s), the research nurses, data administrators and secretaries.  
Information about you will be provided to Loyola University of Chicago and data collection and 


 
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study verification agencies and/or government regulatory agencies, such as the Food and Drug 
Administration.   
 
The information we will collect and send: 
 
X____DEMOGRAPHIC INFORMATION E.G., NAME, ADDRESS, PHONE NUMBER, 
SOCIAL SECURITY NUMBER  
X____MEDICAL RECORD (INCLUDING BUT NOT LIMITED TO HISTORY AND 
PHYSICAL EXAM NOTES, CONSULTATION REPORTS, LABORATORY TEST 
RESULTS, OPERATIVE REPORTS) 
X____INFORMATION RELATING TO MENTAL OR BEHAVIORAL HEALTH OR 
PSYCHIATRIC CARE EXCLUDING PSYCHOTHERAPY NOTES    
X____BLOOD SAMPLES 
 
We will collect and provide this information about you for as long as you are in the study 
 
Once the information is disclosed outside of LUMC, it may no longer be protected by federal 
privacy laws. 
 
It is possible that the sponsor, the Stanley Medical Research Institute, ,data collection and/or 
study verification agencies, data administrators or staff of the Food and Drug Administration 
may come to Loyola University Medical Center (“LUMC”) and view the medical record (see 
above for description of content) and the research records.  They may take notes or copy pages of 
the medical record.   
 
The results of this research study may be published in a journal for the purpose of advancing 
medical knowledge.  You will not be identified by name or by any other identifying information 
in any publication or report about this research. 
 
Consent for LUMC to use and disclose your medical information is required in order for you to 
participate in the study.   
 
WITHDRAWAL OF CONSENT: Your consent to use and disclose your medical information 
for the purpose of this research study is completely voluntary.  You can withdraw your consent 
for LUMC to use and disclose your information and your consent to participate in this study at 
any time without affecting your ability to receive care and treatment at LUMC unrelated to the 
research study.  Withdrawal means that all study procedures and follow-up will stop and we will 
not send any more information about you to the sponsor of this research or its designees.  
However, information already used and disclosed to the research sponsor prior to the time of 
your withdrawal from this study may continue to be used and disclosed by LUMC and the 
sponsor. 
 
For your safety we may ask that you return to clinic one more time for a follow up visit.  This 
will be to assess your wellbeing. We will also ask that you return any unused study medication.  
If you withdraw from the study, you will need to contact your physician(s) to discuss what other 
options may be available.   


 
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If you withdraw from the study we will ask that you sign the form attached to this consent and 
send it to Dr. Angelos Halaris MD PhD, or give it to the study staff.  Your withdrawal from the 
study will not have any affect on any actions by LUMC taken before the attached form is 
received by LUMC. 
 
Your study doctor, the Institutional Review Board, or the regulatory authorities may terminate 
the study at any time with or without your consent. Your study doctor may choose to take you 
out of the study because of unexpected or serious side effects, treatment non-compliance or 
because you are not taking the medication as you were instructed. You may also be removed 
from the study if your study doctor feels that you are not benefiting from the treatment. 
 
CONSENT 
 
I have fully explained to ____________________________ the nature and purpose of the above 
described procedure and the risks that are involved in its performance.  I have answered and will 
answer all questions to the best of my ability.  I may be reached at 708-216-3752 
 
________________________________              
_________________ 
(Signature of Investigator) 
 
 
 
 
Date 
 
Dr. Angelos Halaris, who is the principal investigator for this study or his associates will be 
available to answer any questions you may have. They can be reached at 708-216-3752. 
 
If you ever feel that you have been injured by participating in this study or if you have any 
questions concerning your rights as a research participant, you may contact Dr. Kenneth 
Micetich, Chairman, Institutional Review Board for the Protection of Human Subjects-Medical 
Center (708-216-4608).   
 
Although you have the right to revoke this authorization except that such revocation will not 
apply to any uses and disclosures of your information that are described in the Loyola University 
Health System Notice of Privacy Practices or otherwise allowable under any Federal or State 
laws.   
 
You will receive a signed copy of this informed consent document. 
 
You have been fully informed of the above-described research program with its possible benefits 
and risks.  Your signature below indicates that you are willing to participate in this research 
study and agree to the use and disclosure of information about you as described above.  You do 
not give up any of your legal rights by signing this consent document.   
 
 
_________________________________________________Date:_____________ 
(Signature: Participant) 
 
 


 
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_________________________________________________Date:_____________ 
(Signature: Witness) 
 


 
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PROJECT TITLE:  Cyclooxygenase-2-Inhibitor Combination Treatment for Bipolar 
Depression: Role of Inflammation and Kynurenine Pathway Biomarkers. 
 
REVOCATION OF AUTHORIZATION TO RELEASE 
PROTECTED HEALTH INFORMATION (PHI) 
 
 
 
I, _____________________________________, hereby revoke my consent to participate 
in the study, “Cyclooxygenase-2-Inhibitor Combination Treatment for Bipolar Depression: Role 
of Inflammation and Kynurenine Pathway Biomarkers”, at Loyola University Medical Center 
(“LUMC”).  I also revoke my consent to release information I provided to LUMC that allowed 
LUMC to use and disclose my medical information to the Stanley Medical Research Institute,  as 
outlined on the consent form, which I signed on ________________[INSERT DATE CONSENT 
WAS SIGNED ORIGINALLY].  I understand that this revocation does not apply to any action 
LUMC has taken in reliance on the consent I signed earlier.   
 
 
 
___________________________________  
 
______________________ 
Signature:  Participant 
 
 
 
 
Date 
 
 
 
 
 
 
Please return this form to: 
 
Dr. Angelos Halaris 
c/o Paula Olivieri 
Loyola University Medical Center 
2160 South First Avenue 
Bldg 54 Rm 222 
Maywood, Illinois 60153