Behaviors and Mental Disorders

All Conditions

Symptoms and General Pathology

Depression

Depressive Disorder

Necrosis

Depressive Disorder, Major

Depressive Disorder, Treatment-Resistant

Behavioral Symptoms

Mood Disorders

Mental Disorders

Psychotic Disorders

Anti-Inflammatory Agents

Antirheumatic Agents

Dermatologic Agents

Gastrointestinal Agents

All Drugs and Chemicals

Infliximab

Tumor Necrosis Factor Inhibitors

Participants in this arm will receive an infusion of infliximab.

Participants in this arm will receive an infusion of normal saline.

Participants will receive three infusions 5mg/kg of infliximab (at Baseline, Week 2 and Week 6)

Participants will receive three infusions of a placebo (at Baseline, Week 2 and Week 6)

Placebo

Andrew H. Miller, MD

Major depression is increasingly recognized to be a chronic and highly recurrent condition, which results in significantly increased health problems. One possible mechanism that may contribute to treatment resistance is increased production and release of chemicals called proinflammatory cytokines in patients with major depression. These chemicals mediate the body's response to infectious agents like bacteria and have been shown to be increased by psychological stress. They produce the symptoms that we associate with being sick, including fever, malaise and changes in sleep and appetite. Several lines of evidence indicate that proinflammatory cytokines may contribute to the development of major depression and may thus represent a novel target for the pharmacological treatment of the disorder.

The TNF-alpha antagonist, Infliximab (Remicade®), is an infusion style drug approved by the FDA for the treatment of inflammatory conditions like Crohns disease and rheumatoid arthritis. The researchers are conducting a study to see if the infliximab (Remicade®) is more effective than placebo in acutely reducing symptoms of depression in patients who have elevated proinflammatory markers and have not responded to, or been unable to tolerate, at least two previous treatments in the current depressive episode. Proinflammatory markers are measured by a simple blood test for C-Reactive Protein (CRP) levels in the body.

After appropriate screening to determine eligibility, 64 subjects with treatment resistant depression will be randomized to receive three infusions of either infliximab (Remicade®) or placebo (salt water) in the Emory Infliximab Infusion Center in the Division of Digestive Diseases, Emory University School of Medicine. Subjects will be followed for 12 weeks with evaluations at weeks 0 (baseline), 1, 2, 3, 4, 6, 8, 10 and 12. The first infliximab (Remicade®) infusion will occur at the first (Baseline) visit. The second infusion will occur at Study Week 2 (the third visit). The third infusion will occur at Study Week 6 (Visit 6). The choice of three infusions, and the infusion schedule, is based on current recommendations for the use of infliximab (Remicade®) in conditions for which it has received FDA approval. Subjects will be evaluated for twelve weeks by trained clinicians for changes in depression symptoms and improvements in quality of life. In addition, a physician will evaluate subjects each visit to make sure they are remaining healthy. Blood will be drawn at baseline prior to infusion and all subsequent visits to check labs for safety but also to evaluate potential relationships between changes in inflammatory activity and therapeutic response. After Study Week 12, participants will be monitored by phone, every 4 weeks during the 22-Week Post Study Follow-up Phase to assess physical and psychiatric symptoms in the period following the final infusion. At the baseline and Week 8 visits, subjects will be admitted to the Atlanta Clinical Translational Science Institute (ACTSI), a research unit in the Emory Hospital, for an extended evaluation. The purpose of coming to the ACTSI will be for researchers to evaluate whether treatment with infliximab improves endocrine function, inflammation, sleep and thinking abilities in people who are depressed. For all other visits (Week 1, 2, 4, 6, 10 and 12), participants will come for an office visit in the Winship Cancer Institute.

Major depression has become a health crisis of epidemic proportions in the modern world. The prevalence of major depression has risen over the last several generations in every country examined, and age of symptom onset has decreased. Currently the fourth leading health burden worldwide, major depression will rank second after cardiac disease as a cause of international medical morbidity by the year 2020. One in six individuals in the United States will experience an episode of major depression in his or her lifetime, and the risk of subsequent episodes rises dramatically once a person has been depressed. Indeed, depression is now recognized to be a highly chronic and recurrent illness. On average, patients with major depression are symptomatic 60% of the time, even when receiving community-standard antidepressant treatment. Recent estimates place the economic burden of depression in the United States at 83 billion dollars a year.

Depression is associated with greater disability than are most other chronic illnesses and is a risk factor for mortality. Suicide ranks among the top ten causes of death in the United States, and best estimates suggest that 60-70% of people who kill themselves are clinically depressed. Between 10-15% of severely depressed people eventually commit suicide. In addition, many studies indicate that depression significantly increases all-cause mortality independently of suicide. Depression predicts the later development of a number of medical conditions, including cardiac and cerebrovascular disease, hypertension,diabetes,obesity and the metabolic syndrome,dementia, and cancer. Depression also markedly increases mortality in patients who are medically ill and has been associated with decreased responses to pharmacological treatments for cancer and hepatitis C.

Unfortunately, most patients with depression do not experience a complete resolution of symptoms with antidepressant treatment and 10-20% of patients are refractory to all currently available modalities, including electroconvulsive shock (ECT) therapy. ECT is often effective in patients who have failed adequate trials of multiple antidepressants, but is associated with the risk of anesthesia and with significant short term memory impairment. Responses to ECT are short-lived, and many patients who respond subsequently relapse, even when on maintenance antidepressants. In addition to efficacy issues, many patients are unable to tolerate side effects associated with antidepressants or ECT. The risks of not responding to (or tolerating) treatment have been highlighted by recent studies documenting that partial-but incomplete-response is associated with an increased risk of full symptomatic relapse (even when on therapy) and a worse long term disease course, as well as with significantly impaired quality of life. Treatment resistance also results in a six times increase in direct health care costs. These factors highlight the tremendous need to identify novel treatment strategies, especially for depressed patients who are unresponsive to conventional therapies.

One possible mechanism that may contribute to treatment resistance is increased proinflammatory cytokine production and release. Several lines of evidence indicate that proinflammatory cytokines participate in the pathophysiology of major depression and may thus represent a novel target for the pharmacological treatment of the disorder. First, a high percentage of patients who receive cytokine therapies (such as interferon-alpha for malignant melanoma or hepatitis C infection) develop depressive symptoms, and many patients meet full criteria for major depression. Interferon-alpha-induced depressive symptoms can be ameliorated by pre-treatment with an antidepressant and respond to antidepressants once they have emerged. Second, many studies report that, as a group, medically healthy patients with depression exhibit elevated measures of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 and IL-6. Moreover, a positive relationship between serum concentrations of proinflammatory cytokines and severity of depressive symptoms has been recently reported. Third, antidepressants have been shown to have anti-inflammatory activity and may work-at least in part-by reducing inflammatory activity, given evidence that clinical response is associated with reductions in cytokine levels. These data raise the possibility that cytokine antagonists, such as the chimeric anti-TNF-alpha antibody infliximab, might have antidepressant efficacy. Of special relevance to this proposal, patients who are treatment resistant have been shown to exhibit increased inflammatory activity (as reflected by increased plasma concentrations of interleukin \[IL\]-6 and the soluble IL-6 receptor \[sIL-6R\]), suggesting that cytokine antagonists might be especially effective in these patients.

Providing care to patients with inflammatory bowel disease has given us the clear clinical impression that infliximab rapidly improves mood and energy levels in many patients prior to any demonstrable changes in bowel pathology. This impression is in line with a growing body of evidence suggesting that TNF-alpha antagonists improve emotional functioning and fatigue in patients receiving these agents for rheumatoid arthritis and inflammatory bowel disease. These findings in patients with inflammatory diseases are consistent with the notion that TNF-alpha antagonists such as infliximab might provide acute symptomatic relief for medically healthy patients with treatment-resistant major depression and that symptom improvement might result from decreased inflammatory activity. Moreover, medically healthy depressed patients with increased inflammatory activity may be most likely to benefit from anti-TNF-alpha therapy.

A Study of Infliximab for Treatment Resistant Major Depression

An Evaluation of the Efficacy of the Tumor Necrosis Factor-alpha Antagonist Infliximab in Treatment Resistant Major Depression: Mechanisms and Mediators

The HDRS is a 17-item survey asking respondents to rate the degree of depressive symptoms they are feeling on a scale of 0 to 2-4, where 0 means the symptom is absent and 2-4 means the symptom is very strong. Total scores can range from 0 to 52 where higher scores represent greater symptom severity. Scores of 0-7 are considered normal, scores of 8-16 indicates mild depression, scores of 17-23 indicate moderate depression, and scores of 24 and greater indicate severe depression.

The number of participants with a 50% reduction in Hamilton Depression Rating Scale (HDRS) scores at any study point are presented here. The HDRS is a 17-item survey asking respondents to rate the degree of depressive symptoms they are feeling on a scale of 0 to 2-4, where 0 means the symptom is absent and 2-4 means the symptom is very strong. Total scores can range from 0 to 52 where higher scores represent greater symptom severity. Scores of 0-7 are considered normal, scores of 8-16 indicates mild depression, scores of 17-23 indicate moderate depression, and scores of 24 and greater indicate severe depression.

The number of participants achieving depression remission are presented here. Depression remission is defined as an HDRS score of ≤7 or a Clinical Global Impression-Improvement (CGI-I) score of 1. The HDRS is a 17-item survey asking respondents to rate the degree of depressive symptoms they are feeling on a scale of 0 to 2-4, where 0 means the symptom is absent and 2-4 means the symptom is very strong. Total scores can range from 0 to 52 where higher scores represent greater symptom severity. Scores of 0-7 are considered normal, scores of 8-16 indicates mild depression, scores of 17-23 indicate moderate depression, and scores of 24 and greater indicate severe depression. The CGI-I scale includes a single item where a health care provider rates the participant's level of clinical improvement on a scale of 1 to 7 where 1 = very much improved since initiation of treatment and 7 = very much worse since initiation of treatment.

The Inventory of Depressive Symptomatology-Self-Report (IDS-SR) is a 30-item questionnaire asking respondents about symptoms of depression that they have experienced in the past 7 days. Each item is scored on a 4-point scale where 0 means that the symptom is absent and 3 means that the symptom is very strongly felt. Total scores can range between 0 and 84 and higher scores indicate more severe symptoms of depression.

This study collected blood samples to assess inflammatory markers. IL-6 is a proinflammatory cytokine that is elevated during times of inflammation, infection, illness, and in patients with mood disorders. IL-6 is not present or is low in healthy individuals and exact reference ranges vary by lab, with an example normal reference range of 0.31 to 5.00 picograms per milliliter (pg/mL).

This study collected blood samples to assess inflammatory markers. CRP increases when inflammation is present and can be measured with a high sensitivity-CRP (hs-CRP) test. Hs-CRP values \<1 milligram per liter (mg/L) indicate low inflammation while values \>10mg/L indicate inflammation.

This study collected blood samples to assess inflammatory markers. Tumor necrosis factor (TNF)-alpha values are invalid due to the administration of infliximab which interferes with the assay procedure.

Sleep efficiency is the percentage of time in bed spent sleeping (total sleep time/sleep period time x 100). A sleep efficiency of 80% or greater is considered normal. This outcome measures examines sleep efficiency between study treatment groups.

Sleep efficiency is the percentage of time in bed spent sleeping (total sleep time/sleep period time x 100). A sleep efficiency of 80% or greater is considered normal. This outcome measure examines sleep efficiency between participants with high or low baseline CRP.

The effects of baseline high-sensitivity C-reactive protein (hs-CRP) on reduction in depressive symptoms were investigated by examining the least squares mean change in the HDRS score from baseline to week 12 (infliximab minus placebo) among participants with baseline CRP of \>1 mg/L, \>3 mg/L, and \>5 mg/L. A negative change score favors infliximab. The HDRS is a 17-item survey asking respondents to rate the degree of depressive symptoms they are feeling on a scale of 0 to 2-4, where 0 means the symptom is absent and 2-4 means the symptom is very strong. Total scores can range from 0 to 52 where higher scores represent greater symptom severity. Scores of 0-7 are considered normal, scores of 8-16 indicates mild depression, scores of 17-23 indicate moderate depression, and scores of 24 and greater indicate severe depression.

National Institute of Mental Health (NIMH)

Emory University

Professor

Participants receiving 5mg/kg of Infliximab at Baseline, Week 2, and Week 6.

Participants receiving normal saline at Baseline, Week 2, and Week 6.

Participants receiving a placebo of normal saline at Baseline, Week 2, and Week 6.

Total

Age, Continuous

Sex: Female, Male

White

Black

Other

Race/Ethnicity, Customized

United States

Region of Enrollment

Hamilton Depression Rating Scale-17 item; Minimum score= 0 Maximum score= 54; Higher scores represent greater symptom severity

Hamilton Depression Rating Scale-17 item (HDRS-17)

This study was underpowered to adequately test placebo response typically reported for treatment resistant depression. Also, no direct measures of the effect of either infliximab or placebo on the central nervous system (CNS) were obtained.

Andrew H. Miller

Baseline

Week 1

Week 2

Week 4

Week 6

Week 8

Week 10

Week 12

All participants beginning the study are included in this analysis.

Hamilton Depression Rating Scale 17 (HDRS-17) Scores

Number of Participants With a 50% Reduction in Hamilton Depression Rating Scale (HDRS) Scores

Number of Remitted Patients During Treatment

Inventory of Depressive Symptomatology-Self-Report (IDS-SR) Scores

Baseline IL-6

Week 12 IL-6

Plasma Concentrations of Interleukin-6 (IL-6)

Baseline hs-CRP

Week 12 hs-CRP

Plasma Concentrations of CRP

TNF-alpha values were invalid due to the administration of infliximab interfering with processing TNF-alpha.

Plasma Concentrations of Tumor Necrosis Factor (TNF)-Alpha

This analysis includes participants having complete polysomnography data at baseline and study week 8, and who did not exhibit sleep apnea or periodic limb movement disorder (PLMD).

Sleep Efficiency

Participants with a baseline CRP measurement of greater than 5 mg/L, who were treated with infliximab.

CRP Greater Than 5 mg/L

Participants with a baseline CRP measurement of less than or equal to 5 mg/L, who were treated with infliximab.

CRP Less Than or Equal to 5 mg/L

This analysis includes participants having complete polysomnography data at baseline and study week 8, who did not exhibit sleep apnea or {LMD, and who were treated with infliximab.

Sleep Efficiency in High (CRP>5mg/L) Versus Low (CRP < or =5mg/L) Infliximab-treated Patients

All Participants

Participants with a baseline hs-CRP value greater than 1 mg/L.

Baseline Hs-CRP of >1 mg/L

Participants with a baseline hs-CRP value greater than 3 mg/L.

Baseline Hs-CRP of > 3

Participants with a baseline hs-CRP value greater than 5 mg/L.

Baseline Hs-CRP of >5 mg/L

This analysis includes all study participants in the first group then progressively limits participants in subsequent groups based on baseline hs-CRP concentrations.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study of Infliximab for Treatment Resistant Major Depression	NCT00463580	Depression	Infliximab Placebo	25 Years - 60 Years	Emory University
A Study of Infliximab for Treatment Resistant Major Depression	NCT00463580	Depression	Infliximab Placebo	25 Years - 60 Years	Emory University

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