A Study of Infliximab for Treatment Resistant Major Depression
Condition: Depression
MeSH terms: Depression; Depressive Disorder
Intervention: Infliximab; Placebo
Intervention description: 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)
Intervention MeSH terms: Infliximab
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 60.0
Sex: All
Minimum age: 25 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: depression; TNF-alpha antagonist; infliximab; treatment resistant depression; major depressive disorder (MDD); bipolar I disorder; bipolar II disorder

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.
    

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.