This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: Bipolar disorder is a severe and debilitating psychiatric illness. The current treatments for this disorder benefit only about 50% of the patients, and there is a sizeable group that does not respond adequately to available alternatives. Bipolar depression often presents a very significant challenge for clinical management, and treatment responses with currently available agents are often inadequate. The pathophysiology of depression is not yet known, but there is evidence suggesting the involvement of an immune inflammatory response. Available studies suggest that abnormalities in the cyclooxygenase type 2 (cox-2) pathway (present in cell membranes, including brain neurons) could be implicated. These findings, although preliminary, provide a very compelling rationale for the involvement of abnormalities in the cox-2 pathway in brain neurons in the pathophysiology of mood disorders, and suggest that the potential therapeutic value of compounds that could modulate the cox-2 pathway should be tested in bipolar patients. RESEARCH PLAN: With the development of new non-steroidal anti-inflammatory medications that are selective inhibitors of cox-2, new agents have become available for potential clinical trials in this field. One of such medications, celecoxib, has recently been approved by the FDA for the treatment of osteoarthritis, rheumatoid arthritis, and familial adenomatous polyposis. This new agent has a side-effect profile that compares very favorably with the side effects of commonly utilized non-steroidal anti-inflammatory agents. These new developments provide the optimal agent for conducting the first controlled trial that will test the potential of a cox-2 inhibitor in the treatment of bipolar disorder. METHODS: We propose to conduct a 6-week double-blind placebo controlled trial with celecoxib (200 mg twice a day, orally) as an add-on treatment to mood stabilizers in refractory bipolar type I and II patients, on a depressive or mixed episode. The 6-week double-blind trial will be followed by a 6-week period of open treatment for patients who responded to the active drug, or patients who did not respond to placebo during the double-blind phase of the study. CLINICAL
This study will allow the investigation of the importance of a potentially novel mechanism of action that could be involved in antidepressant response (cox-2 inhibition), and could result on the development of a new treatment modality for bipolar patients.
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