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

描述（由申请人提供）：双相情感障碍（BPD）是一种以反复发作的躁狂和重度抑郁发作为特征的脑部疾病，一年患病率在1-2%之间1992年，BPD在导致丧失残疾的原因中排名第20位（调整后的生命年），与一生中高达19%的自杀风险相关BPD患者的主要疾病负担是抑郁极。5-羟色胺（5-HT）功能的缺乏被认为是抑郁发作的基础，但很少有研究检查BPD患者大脑中5-HT神经传递的指标。人们普遍认为，目前双相抑郁症的识别和治疗存在重大差距。5-8更好地了解BPD的神经传递缺陷可能有助于诊断、识别生物标志物和治疗靶点，从而促进治疗开发，最终协助治疗选择。我们的初步数据显示[11C]DASB在BPD中的结合较低。我们建议使用正电子发射断层扫描（PET）来确定无药物双相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具有较低的5-HTT结合。我们还将研究5-羟色胺对BPD常见治疗方法锂离子的影响。几十年前发现的锂仍然是BPD的少数有效治疗方法之一，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特性，被认为是一线治疗方法。锂对5-HT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-HT1A结合，这些分子效应将与抑郁和自杀的临床改善有关。使用[11C]WAY 100635测定5-HT1A的结合势。我们建议对38名重度抑郁发作期间无药物治疗的BPD I患者进行[11C]DASB和[11C]WAY 100635扫描，并比较38名健康志愿者的5- httt和5-HT1A结合电位。我们还将以相同的方式研究10名单极抑郁症患者，以检查锂反应的诊断特异性。我们将通过研究拉莫三嗪在BPD患者中的作用来检验锂的药理学特异性。最后，我们还将评估基线扫描预测治疗反应的能力。所有BPD患者将接受锂治疗并使用两种放射性示踪剂进行重复扫描。许多BPD患者无法忍受锂的副作用负担，而且锂的治疗窗口期很窄。在这个资助期，我们将确定5-HT蛋白(s)锂发挥其抗抑郁和抗自杀特性。最终，这将带来耐受性更好的新疗法。我们将独立推进我们对BPD分子病理生理学的理解，并表征锂的作用机制。

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.