LITHIUM RESPONSIVE BIPOLAR DISORDER AND CNS MYO INOSITOL

双相情感障碍(BD)是一种常见、严重、慢性、危及生命的疾病。锂的功效的发现彻底改变了BD患者的治疗方法，二十多年后，锂仍然是治疗的中流砥柱。一项估计显示，锂的使用减少了相关的医疗成本，恢复了生产力，在最近一年期间为美国节省了40亿美元，这突出了对更广泛社区的影响。然而，尽管锂作为精神病学最重要的治疗方法之一，其作用机制仍有待充分阐明。此外，越来越多的证据表明，相当数量的患者对锂治疗的反应很差，估计有20%到40%的患者对锂没有表现出足够的治疗反应。这样的研究为未来的研究指明了两个重要的和高度临床相关的方向：第一，需要更好地识别可能对锂治疗有反应的患者，第二，需要开发更有效的治疗方案。锂的治疗效果背后最广泛接受的假说是肌醇耗竭假说。这一假说认为，锂在大脑的关键区域产生肌醇(Mi)的相对耗竭，正是这种耗尽了磷酸肌醇第二信使系统的主要前体，最终导致了锂的治疗效果。尽管肌醇耗竭假说很有吸引力，但从未在BD患者中进行过研究。因此，显然有必要确定锂是否降低了BD患者大脑关键区域的水平，以及个体对锂诱导的CNS mI减少的敏感度是否代表了决定锂治疗效果抵抗或敏感性的主要因素。这项拟议的研究将利用非侵入性质子磁共振波谱(MRS)技术来确定锂治疗是否改变了人脑中局部的MI浓度。此外，这项研究将确定大脑MI水平的变化是否与锂的抗抑郁药物效应的反应有关。这项研究不仅有助于确定最有可能对锂治疗有反应的患者，而且还可能促进新型治疗剂的开发。

Bipolar Affective Disorder (BD) is a common, severe, chronic and life-threatening illness. The discovery of lithium's efficacy revolutionized the treatment of patients with BD, and after more than two decades, lithium continues to be the mainstay of treatment. The effect on the broader community has been highlighted by one estimation that the use of lithium saved the United States US4 billion dollars in a recent year period, by reducing associated medical costs and restoring productivity. However, despite its role as one of psychiatry's most important treatments, lithium's mechanisms of action remain to be fully elucidated. Furthermore, increasing evidence suggests that a significant number of patients respond poorly to lithium therapy, with an estimated 20 percent to 40 percent failing to show an adequate therapeutic response to lithium. Studies such as these indicate two important and highly clinically relevant directions for future research: firstly, the need to better identify patients likely to respond to lithium treatment, and secondly, the necessity to develop more effective treatment regimens. The most widely accepted hypothesis underlying lithium's therapeutic efficacy is the inositol depletion hypothesis. This hypothesis posits that lithium produces a relative depletion of myo-inositol (mI) in critical areas of brain and it is this depletion of a major precursor of the phosphoinositide second messenger system which ultimately results in its therapeutic effects. Despite the attractiveness of the inositol depletion hypothesis, it has never been investigated in BD patients. Thus, there is a clear need to determine if lithium reduces the levels of mI critical brain regions of individuals with BD, and if individual differences in susceptibility to lithium-induced CNS mI reductions represent major factors determining resistance or sensitivity to lithium's therapeutic effects. The proposed research will utilize non-invasive proton magnetic resonance spectroscopy (MRS) technology to determine if lithium treatment alters regional mI concentrations in the human brain. In addition, the research will determine if alterations in brain mI levels are associated with responsiveness to lithium's antidepressants effects. This research offers the potential not only to facilitate in the identification of patients most likely to respond to lithium treatment, but may also facilitate the development of novel therapeutic agents.