A Study of Infliximab for Treatment Resistant Major Depression
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. We 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 withdrawn 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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||An Evaluation of the Efficacy of the Tumor Necrosis Factor-alpha Antagonist Infliximab in Treatment Resistant Major Depression: Mechanisms and Mediators|
- (Study Endpoint): Mean (SD) Hamilton Depression Rating Scale 17-item (HAM-D-17) Scores at Baseline and Each Post Baseline Time Point. [ Time Frame: baseline and treatment weeks 1, 2, 4, 6, 8, 10 and 12 ] [ Designated as safety issue: No ]Hamilton Depression Rating Scale-17 item; Minimum score= 0 Maximum score= 54; Higher scores represent greater symptom severity
- Number of Patients With a 50% Reduction in HDRS Scores at Any Study Point [ Time Frame: At any study point ] [ Designated as safety issue: No ]
- Between Group Difference in Percentage of Remitted Patients During Treatment (HDRS ≤7 or CGI of 1) [ Time Frame: At any study point ] [ Designated as safety issue: No ]
- Between Group Differences in Self-reported Depression Scores Measured by the IDS—SR [ Time Frame: At any study point ] [ Designated as safety issue: No ]
- The Correlation Coefficient Between Changes in HDRS Symptom Score(Measured Numerically and as the Ratio of Change Score to Baseline Score) and Changes in the Plasma Concentrations of TNF-alpha, IL-6 and CRP. [ Time Frame: Between baseline and any study point ] [ Designated as safety issue: No ]
- Between-group Differences (Mean ±SD) in the Change of Cortisol and ACTH Slope, p.m. Cortisol, Diurnal Plasma Cytokine and Cytokine Receptor Concentrations and Sleep Efficiency Between Baseline and Study Week 8. [ Time Frame: Between baseline and study week 8. ] [ Designated as safety issue: No ]
- Correlation Coefficients Between Changes in HDRS Symptom Score and Changes in Diurnal Slope of Cortisol and ACTH, p.m. Cortisol Plasma Concentrations, Diurnal Plasma Concentrations of Inflammatory Cytokines and Their Receptors and Sleep Efficiency [ Time Frame: Measured numerically and as the ratio of change score to baseline score ] [ Designated as safety issue: No ]
- CRP, IL-6, TNF-alpha, TNFR 1 and 2 [ Time Frame: Baseline ] [ Designated as safety issue: No ]Investigate the effects of baseline CRP (and IL-6, TNF-alpha, TNFR 1 and 2) on reduction in depressive symptoms in patients in the two treatment groups.
|Study Start Date:||November 2008|
|Study Completion Date:||June 2011|
|Primary Completion Date:||June 2011 (Final data collection date for primary outcome measure)|
Experimental: infliximab (Remicade)
Drug: infliximab (remicade)
Three infusions across a 12 week period. (Baseline, week 2 and week 6)
Other Name: Remicade
Placebo Comparator: Placebo
Placebo 3 infusions across a 12 week period (Baseline, Week#2 and Week#6)
Other Name: Normal saline
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00463580
|Principal Investigator:||Andrew H. Miller, MD||Emory University|