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

Phase 2

Completed

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

Interventions: Other: Placebo
Drug: Pentoxifylline
Behavioral: Standard Treatment

Registration Number: NCT01625845

Lead Sponsor: Indiana University

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pentoxifylline + Standard Treatment	Standard Treatment	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.
Placebo + Standard Treatment	Placebo	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.
Placebo + Standard Treatment	Standard Treatment	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.
Pentoxifylline + Standard Treatment	Pentoxifylline	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.

Primary Outcome Measures

Name	Time	Method
Change in Brachial Flow-Mediated Dilation (FMD) From Pre- to Post- Treatment	0 and 12 weeks	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
Change in Depressive Symptoms Severity (Hopkins Symptom Checklist Depression Scale; SCL-20) From Pre- to Post- Treatment	0 and 12 weeks	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.

Secondary Outcome Measures

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