Brain Ion Homeostasis, Lithium and Bipolar Disorder.

描述（由申请人提供）：双相情感障碍（BPD）是最使人衰弱和最难治疗的精神疾病之一，它影响着美国约4.4%的人口。BPD的治疗包括情绪稳定药物和心理治疗的联合使用。在用于治疗BPD的情绪稳定药物中，碳酸锂是该疾病不同阶段的首选治疗药物。锂是第一种成功用于治疗精神疾病的药物。它非凡的情绪调节特性是在60年前偶然发现的，至今仍知之甚少。锂有危险的副作用，包括内分泌和神经系统疾病。这些最初可能难以识别，有时在急性情况下是致命的（约15%的受试者）。因此，锂治疗需要持续监测血清锂浓度（SLC），以确保SLC保持在0.6 - 1.2mM的狭窄治疗范围内。然而，使用这一治疗范围仅在不到50%的受试者中导致成功的结果。脑锂浓度（BLC）被认为是比SLC更好的治疗反应预测指标。锂离子具有核磁共振活性，因此，当使用全脑核磁共振时，可以用磁共振波谱（MRS）测量。然而，使用全脑MRS采集导致BLC的准确性和可重复性较低，它低估了药物的峰值浓度，不能提供有关药物空间积累的至关重要的信息。该建议旨在开发一种使用磁共振成像（MRI）进行体内三维锂成像的方法，并确定锂给药后BLC的增加是否可以通过监测其诱导的脑钠浓度（BSC）正常化来间接观察。由于BSC的正常化很容易通过MRI定量测量，因此该方法可以为更好地管理疾病和了解其在大脑中的作用机制提供工具。所提出的方法的有效性将在通过匹兹堡大学西方精神病学研究所和诊所的临床基础设施招募的BPD受试者中进行测试。

DESCRIPTION (provided by applicant): Bipolar Disorder (BPD) is one of the most debilitating and difficult to treat mental illnesses and it affects an estimated 4.4% of the population in the United States. Treatment of BPD involves the combined used of mood stabilizing drugs and psychotherapy. Among the mood stabilizing drugs used to treat BPD, Lithium Carbonate is an established treatment of first choice for different stages of the disease. Lithium was the first medication successfully used to treat mental illnesses. Its remarkable mood regulating properties were accidentally discovered 60 years ago and remain poorly understood to this date. Lithium has dangerous side effects that include endocrine as well as neurological ailments. These could be difficult to recognize at first and sometimes lethal in the acute setting (about 15% of subjects). Consequently, lithium treatment requires constant monitoring of serum lithium concentration (SLC) to ensure that SLC remains in the narrow therapeutic range of 0.6 to 1.2mM. However, use of this therapeutic range only leads to a successful outcome in less than 50% of the subjects. Brain Lithium Concentration (BLC) is accepted to be a better predictor of therapeutic response than SLC. The lithium ion is NMR active and, therefore, measurable with magnetic resonance spectroscopy (MRS) when whole-brain MRS is used. Use of whole-brain MRS acquisitions, however, leads to lower accuracy and reproducibility for BLC, it underestimates the peak concentration of the drug and cannot provide critically important information about the spatial accumulation of the drug. This proposal is aimed at developing a methodology for in vivo three dimensional lithium imaging using magnetic resonance imaging (MRI) and establishing if the increase in BLC that follows lithium administration can be indirectly observed by monitoring the normalization of brain sodium concentration (BSC) that it induces. Because the normalization of BSC is easily measurable in a quantitative fashion with MRI, this methodology could provide a tool for better management of the disease and understanding its mechanisms of action in the brain. The effectiveness of the proposed methodology is to be tested on BPD subjects recruited through the clinical infrastructure of the Western Psychiatric Institutes and Clinic at the University of Pittsburgh. PUBLIC HEALTH RELEVANCE: This proposal aims to develop a methodology for improving the management of Bipolar Disease Subjects using MRI technology. The goal is to develop a technique that allows the measurement of lithium accumulation in the brain with MRI as this is accepted to be a better predictor of outcome than the serum lithium content (which is a critical clinical variable currently used to manage the disease).