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 has a lifetime prevalence of approximately 1.5% in the general population. It is related to substantial morbidity and mortality, and its pathophysiology is still not known. Bipolar depression, the depressive phase of the illness, has been increasingly recognized as a major challenge in the management of bipolar patients and is the frequent cause of chronic impairment.
The specific aims of the proposed study are: (1) Investigate the presence of anatomical and neurochemical brain abnormalities in fronto-limbic brain regions involved in mood regulation in depressed bipolar type II patients; (2) Examine whether treatment with a mood stabilizer (lamotragine) has a pronounced antidepressant effect and is related to improvement or reversal of identified brain changes in bipolar type II depression; and (3) Examine whether clinical response to lamotrigine treatment is related to specific brain abnormalities in depressed bipolar type II patients. RESEARCH PLAN: The study will examine specific abnormalities in fronto-limbic brain structures involved in mood regulation in a group of depressed bipolar type II patients and healthy controls, and it will begin to investigate the effects of illness phase and treatment on identified abnormalities. We will utilize in vivo anatomical and neurochemical brain measurements with magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). We will conduct an in vivo investigation of brain morphology and regional levels of N-Acetyl Aspartate (NAA), a non-specific marker of neuronal viability/function, in the prefrontal cortex and medial temporal lobe. METHODS: The specific hypotheses that will be examined in this study are: (1) There are specific morphometric and neurochemical abnormalities in fronto-limbic brain regions involved in mood regulation in depressed bipolar type II patients; specifically, we predict a reduction in NAA levels in dorsolateral prefrontal cortex, and an enlargement of the amygdala, indicating impairment of these two structures, similarly to what has been described in bipolar type I patients; (2) Enlargement of amygdala, and decreased levels of NAA in dorsolateral prefrontal cortex will reverse after lamotrigine treatment; (3) Patients who respond to lamotrigine treatment will have less pronounced anatomical and neurochemical brain abnormalities at baseline compared to ones who do not respond to treatment. We will recruit 30 depressed bipolar type II subjects and 30 matched healthy controls over a 3-year period. Subjects will be diagnosed according to the DSM-IV criteria, as established in a SCID-IV interview. All patients will undergo a brain MRI/MRS scan at the time of entry in the study, and will then be treated openly with lamotrigine up to 200 mg/day for a period of 12 weeks, as monotherapy. At the end of the treatment period, another MRI/MRS scan will be completed. CLINICAL
The study will examine the role of fronto-limbic abnormalities in mechanisms involved in bipolar type II depression and treatment response. 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 bipolar disorder and ultimately contribute to the development of novel and more effective treatments for this severe psychiatric illness.
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