Anti-INFLammatory to Address Mood and Endothelial Dysfunction (INFLAMED)

Study Overview
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Brief Summary
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The objective of this clinical trial is to evaluate whether an anti-inflammatory medication, pentoxifylline, reduces depressive symptoms and improves artery function. Participants in this trial will be older primary care patients (60 years and up) who are depressed but do not have a history of cardiovascular disease. Half of these patients will receive pentoxifylline, and half will receive placebo. In addition, participants in both arms will receive an evidence-based psychological treatment called Beating the Blues®, which is a computerized, cognitive behavioral treatment program for depression. The investigators will use questionnaires to assess change in depressive symptoms and an ultrasound test to measure change in artery function from pre- to post-treatment. It is hypothesized that patients who receive pentoxifylline will show greater improvements in both depression and artery function than patients who receive placebo.

Detailed Description
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Cardiovascular disease is the leading cause of death, and depression is the leading cause of disability in the United States. Previous research suggests that systemic inflammation may play an important role in the development of both depression and cardiovascular disease. Therefore, Aim #1 of this study is to examine whether adding an anti-inflammatory medication (pentoxifylline) to standard depression treatment (cognitive-behavioral therapy) improves both depressive symptoms and endothelial dysfunction, a sign of early cardiovascular disease. Aim #2 is to evaluate candidate mediators of treatment effects by examining whether reductions in multiple markers of systemic inflammation account for treatment-related improvements in depressive symptoms and endothelial dysfunction. To achieve these aims, a clinical trial of older depressed primary care patients free of cardiovascular disease is being conducted. Patients will be randomized to one of two groups: a standard depression treatment (a cognitive-behavioral treatment program) plus pentoxifylline or standard depression treatment plus placebo. The treatment phase of the study will be 12 weeks. At baseline, 6 weeks, and 12 weeks, patients will undergo assessments of depressive symptoms, various inflammatory markers, and endothelial function. Our index of endothelial function is brachial artery flow-mediated dilation, a noninvasive measure of endothelial function. Demonstrating that medications targeting systemic inflammation are effective for concurrently treating late-life depression and reducing CAD risk would place anti-inflammatory approaches in the collection of depression treatment strategies, as well as CAD prevention strategies, of the primary care provider. This change to clinical practice should result in improved management of both late-life depression and cardiovascular risk, which in turn would reduce disability, CAD morbidity, and mortality among older adults.

Official Title
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Targeting Systemic Inflammation to Concurrently Treat Late-Life Depression and Reduce Coronary Artery Disease Risk

Conditions
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Major Depressive Disorder, Depression, Depressive Symptoms, Cardiovascular Disease (CVD), Coronary Artery Disease (CAD), Heart Disease

Intervention / Treatment
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* Drug: Pentoxifylline
* Other: Placebo
* Behavioral: Standard Treatment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary care patients Age ≥ 40 years Clinically significant depressive symptoms, defined as a PHQ-9 score ≥15 English speaking Exclusion Criteria: History of clinical cardiovascular disease History of cardiac arrhythmias or cardiomyopathy History of carotid bruits History of certain chronic disorders (HIV/AIDS, kidney disease, liver disease, systemic inflammatory disease, or past-year cancer) History of bleeding disorder, gastrointestinal ulceration or bleeding, cerebrovascular aneurysm or bleeding, or retinal hemorrhage History of migraine headaches History of Raynaud's phenomenon History of bipolar disorder or psychosis Current use of anticoagulants or vasodilators (Lipid-lowering antihypertensive medications are allowed.) Current use of acetazolamide, anticonvulsants, or thyroid replacements Current use of glucocorticoids - including topical, nasal, or oral steroids - or anabolic steroids (Physiologic testosterone replacement therapy is allowed.) Current use of anti-inflammatory agents (including, but not limited to, plaquenil, infliximab, etanercept, mycophenolate mofetil, sirolimus, tacrolimus, cyclosporine, pentoxifylline, thalidomide) Known allergy or intolerance to pentoxifylline or other methylxanthines, such as , theophylline, caffeine, theobromine Known allergy or intolerance to nitroglycerin. Severe cognitive impairment (≥3 errors on 6-item cognitive screen105) Current alcohol use problem (≥2 on CAGE questionnaire106) Very severe depressive symptoms, defined as a PHQ-9 score ≥24 Acute risk of suicide Vision or hearing problems Unable to lie flat for 30 minutes at a time Therapy for acute infection or other serious medical illnesses within 14 days prior to the pre-treatment visit (Therapy for acute infection or other serious medical illnesses that overlaps with a main study visit will result in postponement of that study visit until the course of therapy is completed; postponement outside of the allowed study visit timeframe will result in study discontinuation.) Creatinine clearance < 50mL/min using a serum creatinine level measured at the pre-treatment visit Hemoglobin < 9.0mg/dL at the pre-treatment visit Alanine aminotransferase (ALT) level or aspartate aminotransferase (AST) > 3 times ULN at the pre-treatment visit Total bilirubin > 2.5 times ULN at the pre-treatment visit Current evidence of abuse of prescription medications Current evidence of illicit drug use

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pentoxifylline + Standard Treatment<br>Pentoxifylline: Pentoxifylline is phosphodiesterase inhibitor that interferes with proinflammatory cytokine signaling and synthesis. Participants will be instructed to take pentoxifylline 400 mg p.o. t.i.d. for 12 weeks. Standard Treatment: Beating the Blues (BtB) is a widely used, empirically supported, computer-based, CBT program for depression designed for use in primary care clinics. BtB utilizes an interactive, multimedia format to deliver and eight 50-minute, weekly therapy sessions. | Drug: Pentoxifylline<br>* Pentoxifylline 400 mg p.o. t.i.d. for 12 weeks<br>* Other names: Pentopak;Behavioral: Standard Treatment<br>* BtB is a widely used, empirically supported, computer-based, CBT program for depression designed for use in primary care clinics. BtB utilizes an interactive, multimedia format to deliver and eight 50-minute, weekly therapy sessions. General topics covered include identifying and challenging automatic thoughts, cognitive errors, core beliefs, and attributional styles; activity scheduling; problem solving; graded exposure; task breakdown; sleep management; and relapse prevention. In addition to session work, patients are assigned homeworks that are customized to their needs and reviewed at the start of each session. A progress report, including whether the patient is experiencing suicidal ideation, is generated at the end of each session.<br>* Other names: Computer-Based Psychotherapy;|
| Placebo Comparator: Placebo + Standard Treatment<br>Placebos: Placebo pills will match the study drug for color, taste, texture, size, and smell. Participants will receive the same instructions as those randomized to pentoxifylline. Standard Treatment: Beating the Blues (BtB) is a widely used, empirically supported, computer-based, CBT program for depression designed for use in primary care clinics. BtB utilizes an interactive, multimedia format to deliver and eight 50-minute, weekly therapy sessions. | Other: Placebo<br>* Placebo pills will match the study drug for color, taste, texture, size, and smell. Participants will receive the same instructions as those randomized to pentoxifylline.<br>Behavioral: Standard Treatment<br>* BtB is a widely used, empirically supported, computer-based, CBT program for depression designed for use in primary care clinics. BtB utilizes an interactive, multimedia format to deliver and eight 50-minute, weekly therapy sessions. General topics covered include identifying and challenging automatic thoughts, cognitive errors, core beliefs, and attributional styles; activity scheduling; problem solving; graded exposure; task breakdown; sleep management; and relapse prevention. In addition to session work, patients are assigned homeworks that are customized to their needs and reviewed at the start of each session. A progress report, including whether the patient is experiencing suicidal ideation, is generated at the end of each session.<br>* Other names: Computer-Based Psychotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Brachial Flow-Mediated Dilation (FMD) From Pre- to Post- Treatment | Patients underwent ultrasound assessment of brachial FMD in accordance with established guidelines at pre- (0 weeks) and post- (12 weeks) treatment. After a 10-minute supine rest, high-resolution baseline images of the brachial artery were obtained from 3 consecutive cardiac cycles. Next, the forearm cuff was inflated to 250 mmHg for 5 minutes and then was rapidly deflated. At 60 and 90 seconds post-deflation, images from 3 consecutive cardiac cycles were acquired. FMD values were computed as the % change in brachial diameter at either 60 or 90 seconds after cuff deflation | 0 and 12 weeks | 
| Change in Depressive Symptoms Severity (Hopkins Symptom Checklist Depression Scale; SCL-20) From Pre- to Post- Treatment | Self-reported depressive symptom severity was measured at pre- (0 weeks) and post- (12 weeks) treatment visits by the 20 depression items from the Symptom Checklist 90 (Hopkins Symptom Checklist depression scale; SCL-20). Each item on the scale ranges from 0 (not at all) to 4 (extremely). Total scores are the average across all response items and range from 0 to 4 with higher scores indicating greater levels of depressive symptoms. | 0 and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Circulating Tumor Necrosis Factor-Alpha (TNF-a) From Pre- to Post-Treatment | A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment. | 0 and12 weeks | 
| Change in Circulating Interleukin-6 (IL-6) From Pre- to Post-Treatment | A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment. | 0 and 12 weeks | 
| Change in Circulating Interleukin-10 (IL-10) From Pre- to Post-Treatment | An anti-inflammatory cytokine measured from blood samples collected at pre- and post-treatment. | 0 and 12 weeks | 
| Change in Interleukin-1ra (IL-1ra) From Pre- to Post-Treatment | A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment. | 0 and 12 weeks | 
| Change in Circulating C-Reactive Protein (CRP) From Pre- to Post-Treatment | A marker of systemic inflammation measured from blood samples collected at pre- and post-treatment. | 0 and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary Artery Disease (CAD), Major Depressive Disorder, Depression, Depressive Symptoms, Cardiovascular Disease (CVD), Heart Disease, Endothelial Function, Inflammation