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）是一种以反复躁狂和重度抑郁发作为特征的脑部疾病，1年患病率为1- 2%。19992年，BPD在残疾调整生命年损失原因方面排名第20位，与高达19%的终生自杀风险相关.3 BPD的主要疾病负担在抑郁极。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，以促进治疗开发并最终帮助治疗选择。我们对[11 C]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）在无药物治疗的双相I型抑郁症中确定体内5-HTT结合异常的程度和性质。我们假设BPD与对照组相比具有较低的5-HTT结合。我们还将研究5-HT的影响，一个共同的治疗BPD，锂。几十年前发现，锂仍然是BPD中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作用，被认为是一线治疗。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-HT 1A受体结合，上调突触后5-HT 1A结合，上调5-HTT结合，这些分子效应将与抑郁症和自杀倾向的临床改善相关。将使用[11 C]WAY 100635测定5-HT 1A结合潜力。我们建议在38名无药物BPD I受试者中进行[11 C]DASB和[11 C]WAY 100635扫描，并在38名健康志愿者中比较5-HTT和5-HT 1A结合潜力。我们还将通过以相同的方式研究10名单极抑郁受试者来检查锂反应的诊断特异性。我们将通过研究拉莫三嗪在BPD受试者中的药理学特异性来检查锂。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。在本资助期内，我们将确定锂在哪种5-HT蛋白质下发挥其抗抑郁和抗自杀特性。最终，这可以导致更好耐受的新疗法。我们将独立地推进我们对BPD的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.