Clinical trial NCT00463580: A Study of Infliximab for Treatment Resistant Major Depression
Official title: An Evaluation of the Efficacy of the Tumor Necrosis Factor-alpha Antagonist Infliximab in Treatment Resistant Major Depression: Mechanisms and Mediators
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Depression
Keywords: depression
TNF-alpha antagonist
infliximab
treatment resistant depression
major depressive disorder (MDD)
bipolar I disorder
bipolar II disorder
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2007-04-20
Enrollment: 60
Sex: ALL
Minimum age (years): 25
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Males or females ages 25-60. Must be able to read and understand English.
2. Currently meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-IV) criteria for a major depressive episode. (History of either unipolar major depression (depressive episodes only) or bipolar I disorder (history of manias and depressions) or bipolar II disorder (hypomanias and depressions), current episode depressed acceptable).
3. Must meet criteria for "treatment resistant" depression defined by failure to respond to, or intolerance of, at least 2 treatment trials (antidepressants or ECT) during the current episode.
4. All subjects will be fully ambulatory and in good medical health.
5. Are required to either be antidepressant free for 2 weeks prior to study entry (4 weeks for fluoxetine secondary to long half-life) or be on a fixed psychotropic medication regimen for at least 4 weeks. Subjects and their primary care providers must agree to continue their status (i.e. without antidepressant or on a fixed regimen) until the 12-week assessment is complete.
6. Pre-menopausal female subjects must not be pregnant and must be willing to use adequate contraception during the study period.

Exclusion Criteria:

1. Current or history of psychotic symptoms.
2. Active suicidal ideation (defined as a score of ≥3 on Hamilton Depression Rating Scale (HDRS) suicide item).
3. Prior use of a TNF-alpha antagonist (i.e. etanercept, infliximab, adalimumab) and use of any other immunosuppressant agent (i.e. systemic corticosteroids or anti-proliferative agents such as methotrexate) within one year of study entry.
4. Current use of aspirin, non-steroidal anti-inflammatory agents (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors during the study. Acetaminophen will be allowed.
5. History of any of the following conditions: Congestive heart failure, abnormal electrocardiogram, malignancy, schizophrenia, neurological disease, auto-immune condition (e.g. rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, lupus), chronic infection (e.g. human immunodeficiency virus, hepatitis B or C), and hematologic, renal or hepatic abnormality.
6. Subjects will be excluded for a positive anti-double stranded DNA antibody test.

Primary outcomes:
measure: Hamilton Depression Rating Scale 17 (HDRS-17) Scores
timeFrame: Baseline, Weeks 1, 2, 4, 6, 8, 10 and 12
Secondary outcomes:
measure: Number of Participants With a 50% Reduction in Hamilton Depression Rating Scale (HDRS) Scores
timeFrame: Week 12
measure: Number of Remitted Patients During Treatment
timeFrame: Week 12
measure: Inventory of Depressive Symptomatology-Self-Report (IDS-SR) Scores
timeFrame: Baseline, Weeks 1, 2, 4, 6, 8, 10 and 12
measure: Plasma Concentrations of Interleukin-6 (IL-6)
timeFrame: Baseline, Week 12
measure: Plasma Concentrations of CRP
timeFrame: Baseline, Week 12
measure: Plasma Concentrations of Tumor Necrosis Factor (TNF)-Alpha
timeFrame: Baseline, Week 12
measure: Sleep Efficiency
timeFrame: Baseline, Week 8
measure: Sleep Efficiency in High (CRP>5mg/L) Versus Low (CRP < or =5mg/L) Infliximab-treated Patients
timeFrame: Baseline, Week 8
measure: Change in Hamilton Depression Rating Scale 17 (HDRS-17) Scores Subgrouped by Baseline Hs-CRP.
timeFrame: Baseline, Week 12
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory Clinic, Emory University Hospital
state: Georgia
Study officials:
affiliation: Emory University
name: Andrew H. Miller, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013 Jan;70(1):31-41. doi: 10.1001/2013.jamapsychiatry.4.
citation: Weinberger JF, Raison CL, Rye DB, Montague AR, Woolwine BJ, Felger JC, Haroon E, Miller AH. Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation. Brain Behav Immun. 2015 Jul;47:193-200. doi: 10.1016/j.bbi.2014.12.016. Epub 2014 Dec 18.
citation: Mehta D, Raison CL, Woolwine BJ, Haroon E, Binder EB, Miller AH, Felger JC. Transcriptional signatures related to glucose and lipid metabolism predict treatment response to the tumor necrosis factor antagonist infliximab in patients with treatment-resistant depression. Brain Behav Immun. 2013 Jul;31:205-15. doi: 10.1016/j.bbi.2013.04.004. Epub 2013 Apr 25.