Lithium's Molecular Mechanism of Action and the Pathology of Bipolar Disorders

描述(申请人提供)：双相情感障碍(BPD)是一种脑部疾病，以反复发作的躁狂和严重抑郁发作为特征，一年的患病率在1-2%之间。1在19992年度残疾调整生命年的丧失原因方面，BPD排名第20位，与高达19%的终身自杀风险有关。3 BPD的主要疾病负担是抑郁症。5-羟色胺(5-羟色胺)功能缺陷被认为是抑郁发作的基础，但很少有研究检验BPD患者大脑中5-羟色胺神经传递的指标。人们普遍认为，目前在双相抑郁的识别和治疗方面存在重大差距。5-8更好地了解BPD的神经传递缺陷可能有助于诊断、识别生物标记物和治疗靶点，以促进治疗的发展，并最终帮助治疗选择。我们与[11C]DASB的初步数据显示，BPD的结合较低。我们建议使用正电子发射断层扫描(PET)来确定非药物治疗的双相I型抑郁症患者体内5-HTT结合异常的程度和性质。我们假设与对照组相比，BPD的5-HTT结合较低。我们还将研究5-羟色胺对BPD的影响，锂是一种常见的治疗方法。几十年前发现的锂仍然是BPD为数不多的有效治疗方法之一，有证据表明它具有稳定情绪、抗抑郁、抗自杀甚至神经保护的作用，被认为是一线治疗方法。锂对5-羟色胺指数的作用可能是其抗抑郁和抗自杀特性的核心。我们假设锂下调突触前5-HT1a受体结合，上调突触后5-HT1a结合，上调5-HTT结合，这些分子效应将与临床改善有关，无论是抑郁还是自杀。5-HT1A结合电位将使用[11C]方法100635测定。我们建议在38名无药物治疗的BPD I受试者中进行[11C]DASB和[11C]Way 100635扫描，并在38名健康志愿者中比较5-HTT和5-HT1A的结合潜力。我们还将通过以相同的方式研究10名单相抑郁受试者来检验锂反应的诊断特异性。我们将通过研究BPD受试者中的拉莫三嗪来检验锂的药理特异性。最后，我们还将评估基线扫描预测治疗反应的能力。所有BPD受试者都将接受锂治疗，并用两种放射性示踪剂进行重复扫描。许多患有BPD的人不能忍受锂的副作用负担，而且它的治疗窗口很窄。在此授权期内，我们将确定5-羟色胺蛋白(S)锂在哪一处发挥其抗抑郁和抗自杀特性。最终，这可以带来耐受性更好的新疗法。我们将独立推进我们对BPD的分子病理生理学的理解，以及锂的作用机制的表征。

DESCRIPTION (provided by applicant): Bipolar disorder (BPD) is a brain disorder characterized by recurrent manic and major depressive episodes with a one year prevalence rate between 1-2%.1 BPD ranked 20th in terms of causes of loss of disability- adjusted life-years in 19992 and is associated with a life time suicide risk of up to a 19%.3 The main burden of illness in BPD is in the depressive pole. A deficiency of serotonin (5-HT) function has been postulated to underlie depressive episodes yet few studies have examined indices of 5-HT neurotransmission in the brain in BPD. It is widely acknowledged that there are significant gaps in the current identification and treatment of bipolar depression.5-8 Better understanding of the neurotransmission deficits in BPD may aid diagnosis, identification of biomarkers and treatment targets to facilitate treatment development and ultimately to assist in treatment selection. Our preliminary data with [11C]DASB shows lower binding in BPD. We propose to determine the extent and nature of abnormalities of 5-HTT binding in vivo using positron emission tomography (PET) in medication-free bipolar I depression. We hypothesize that BPD has lower 5-HTT binding compared to controls. We will also investigate the 5-HT effects of a common treatment for BPD, lithium. Discovered decades ago, lithium remains one of the few effective treatments in BPD, with evidence of mood stabilizing, antidepressant, antisuicidal, and even neuroprotective qualities and is considered to be first line treatment. The actions of lithium on 5-HT indices may be central to its antidepressive and antisuicidal properties. We hypothesize that lithium downregulates presynaptic 5-HT1A receptor binding, upregulates postsynaptic 5-HT1A binding, upregulates 5-HTT binding, and these molecular effects will be related to clinical improvement, both in depression and suicidality. 5-HT1A binding potential will be determined using [11C]WAY 100635. We propose to perform [11C]DASB and [11C]WAY 100635 scans in 38 medication free BPD I subjects during a major depressive episode and compare 5-HTT and 5-HT1A binding potential in 38 healthy volunteers. We will also examine the diagnostic specificity of lithium response by studying 10 unipolar depressed subjects in an identical manner. We will examine the pharmacological specificity of lithium by studying lamotrigine in BPD subjects. Finally, we will also assess the ability of baseline scanning to predict treatment response. All BPD subjects will be treated with lithium and have repeat scans with both radiotracers. Many with BPD do not tolerate lithium's side effect burden, and it has a narrow therapeutic window. In this grant period we will determine at which 5-HT protein(s) lithium exerts its antidepressant and antisuicidal properties. Ultimately this can lead to novel therapeutics that are better tolerated. We will independently advance our understanding of the molecular pathophysiology of BPD as well as characterize the mechanisms of action of lithium.