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 depression, the depressive phase of bipolar disorder (BD), is a major therapeutic challenge and frequent cause of chronic impairment. Patients suffering from bipolar depression are often non-responsive to various therapeutic interventions. Abnormalities in fronto-limbic brain (FLB) mechanisms could account for their pathophysiology and relate to treatment response. We propose to test specific hypotheses about the involvement of FLB circuits in bipolar depression in BD type I patients, and the relationship of FLB abnormalities to symptom remission and treatment response to mood stabilizing agents. RESEARCH PLAN: Ninety (90) untreated depressed DSM-IV BD type I patients will undergo MRI and MRS scans at entry to the study, and after 4 and 16 weeks of medication treatment. 60 matched healthy controls will undergo MRI/MRS scan at entry, of which 20 will repeat these measures at weeks 4 and 16. The BD patients will be stratified into 3 groups, based on their responsiveness to treatments (50% improvement in HAMD-21 item scores) during the 16-week period: (i) those who improve following 4 weeks of monotherapy with lithium, and remain improved until the end of the 16-week follow-up period, (ii) monotherapy non-responders who subsequently are responsive to an additional 12 weeks of combination treatment lithium lamotrigine and lithium, and (iii) patients with bipolar depression who do not respond to either monotherapy or combination therapy. METHODS: In vivo brain imaging methods (magnetic resonance imaging, MRI, and MR-spectroscopy, MRS) will be utilized to measure and compare regional brain volumes and regional levels of N-Acetyl Aspartate (NAA), a non-specific marker of neuronal viability and function, in prefrontal cortex and medial temporal lobe regions. CLINICAL
Our proposed study will examine the role of FLB abnormalities in the mechanisms involved in bipolar depression and treatment response. It will be the first controlled longitudinal study to investigate the relevance of morphometric and neurochemical FLB abnormalities in course of illness and response to treatment with mood stabilizers in BD patients. The elucidation of involved mechanisms could begin to shed light into the specific processes underlying treatment response and refractoriness in bipolar depression. These studies have considerable potential to elucidate the pathophysiology of BD and ultimately contribute to the development of novel and more effective treatments for this severe psychiatric illness.
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