A Study of Infliximab for Treatment Resistant Major Depression

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.