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

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

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.

Study Overview

• Status: Completed
• Conditions: Depression; Depressive Symptoms; Heart Disease; Major Depressive Disorder; Coronary Artery Disease (CAD); Cardiovascular Disease (CVD)
• Intervention / Treatment: Drug: Pentoxifylline; Behavioral: Standard Treatment; Other: 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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University-Purdue University Indianapolis (IUPUI)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pentoxifylline + 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.	Drug: Pentoxifylline; Pentoxifylline 400 mg p.o. t.i.d. for 12 weeks; Other Names: Trental; Pentoxil; Pentopak; Behavioral: Standard Treatment; 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.; Other Names: Computer-Based Cognitive Behavioral Therapy (CBT); Computer-Based Psychotherapy
Placebo Comparator: Placebo + 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.	Behavioral: Standard Treatment; 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.; Other Names: Computer-Based Cognitive Behavioral Therapy (CBT); Computer-Based Psychotherapy; Other: Placebo; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Indiana University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Jesse C Stewart, PhD, Indiana University School of Medicine

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: June 19, 2012
• First Submitted That Met QC Criteria: June 20, 2012
• First Posted (Estimate): June 21, 2012

Study Record Updates

• Last Update Posted (Estimate): December 3, 2015
• Last Update Submitted That Met QC Criteria: October 30, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Depression; Inflammation; Endothelial Function; Major Depressive Disorder; Heart Disease; Depressive Symptoms; Cardiovascular Disease (CVD); Coronary Artery Disease (CAD)
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Vascular Diseases; Mood Disorders; Arteriosclerosis; Arterial Occlusive Diseases; Heart Diseases; Depression; Depressive Disorder; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Cardiovascular Diseases; Depressive Disorder, Major; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline
• Other Study ID Numbers: 1110007119; R24MH080827 (U.S. NIH Grant/Contract); 1737 (Other Identifier: Indiana Clinical Research Center)