A Study of Infliximab for Treatment Resistant Major Depression
Condition: Depression
MeSH terms: Depression; Depressive Disorder
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Infliximab; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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)
Other intervention name(s): Remicade; Normal saline
Intervention MeSH terms: Infliximab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: depression; TNF-alpha antagonist; infliximab; treatment resistant depression; major depressive disorder (MDD); bipolar I disorder; bipolar II disorder