| City: |
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Atlanta |
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State:
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GA |
| Zip Code: |
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30322 |
| Conditions: |
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Depression - Major Depressive Disorder |
| Purpose: |
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This is a preliminary evaluation to explore whether the TNF-alpha antagonist infliximab
holds promise as a therapeutic intervention for treatment resistant depression. Twenty
subjects with treatment resistant depression will be randomized in a double-blind fashion to
receive a single infusion of either infliximab (5 mg/kg) or placebo (normal saline).
Subjects will be followed for 12 weeks post-infusion, with evaluations at weeks 1, 2, 3, 4,
6, 8 and 12. Subjects who do not respond to the initial infusion (response defined as >50%
reduction in Hamilton Depression Rating Scale score at any assessment in 8 weeks following
the infusion) will be blindly crossed over to receive whichever condition (infliximab or
placebo) they did not receive in the initial infusion. Subjects who are crossed over will be
followed an additional 12 weeks in a manner identical to the protocol for the first 12
weeks. The choice of a single infusion is based both upon our clinical experience that
improvements in mood and energy occur rapidly and on trials suggesting that therapeutic
effects on disease states directly related to inflammatory activity (i.e. skin condition in
psoriasis), as well as improvements in mood and energy, are apparent within the first
several weeks following an initial infusion. Our decision to wait 8 weeks prior to
crossing-over in non-responders is based on evidence suggesting that a single infusion of
infliximab can have long lasting effects on disease states for which it has FDA approval.
Hypothesis #1: A single infusion of infliximab will be superior to placebo (saline infusion)
in reducing depressive symptoms as assessed by differences between groups in symptom score
change on the 24-item Hamilton Depression Rating Scale (HDRS) as well as percentage of
responders (30% and 50% decrease in HDRS)and remitters (HDRS less than or equal to 7 or a
Clinical Global Impression Scale Score of 1).
Hypothesis #2: In subjects receiving infliximab, decreases in inflammatory indices during
treatment will correlate with a decrease in depressive symptom scores as assessed by the
HAM-D.
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| Study summary: |
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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.35 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. |
| Criteria: |
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Inclusion Criteria:
1. Males or females ages 18-65. Must be able to read and understand English.
2. Currently meets 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.
7. Subjects are required to have a plasma high-sensitivity C-reactive protein (CRP) of
greater than 3.
Exclusion Criteria:
1. Current or history of psychotic symptoms.
2. Active suicidal ideation (defined as a score of ≥3 on HDRS suicide item).
3. Prior use of a TNF-alpha antagonist (i.e. etanercept, infliximab, adalimimub) 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 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. |
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If you are interested in this clinical trial please use the contact information above. If you would like to get additional information about this clinical trial please visit ClinicalTrials.gov.
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| Data Source: |
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ClinicalTrials.gov |
| Date Processed: |
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March 15, 2010 |
Modifications to
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above to view all information about this clinical trial. |
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