A Study of Infliximab for Treatment Resistant Major Depression
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. 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.
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.