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

锂的分子作用机制和双向情感障碍的病理学

• 批准号: 8663953
• 负责人: Ramin V. Parsey
• 金额: $ 84.87万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-12 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663953
• 关键词: Adverse effects; Affect; Aftercare; Amygdaloid structure; Animals; Anterior; Antidepressive Agents; Binding; Biological; Biological Assay; Biological Markers; Bipolar Depression; Bipolar Disorder; Bipolar I; Brain; Brain Diseases; Brain imaging; Brain region; Chronic; Clinical; Data; Depressed mood; Depression and Suicide; Diagnosis; Diagnostic Specificity; Disease remission; Feeling suicidal; Functional disorder; Grant; Hamilton Rating Scale for Depression; Hippocampus (Brain); Hormonal; Human; Imaging technology; Lateral; Lead; Life; Lithium; Manic; Measurement; Measures; Mental Depression; Midbrain structure; Molecular; Molecular Mechanisms of Action; Molecular Target; Mood stabilizers; Moods; Nature; Noise; Organ; Pathology; Patients; Pharmaceutical Preparations; Pharmacotherapy; Positron-Emission Tomography; Prefrontal Cortex; Prevalence; Property; Proteins; Publications; Publishing; Rattus; Recurrence; Risk; Scanning; Selection for Treatments; Serotonin; Serotonin Receptor 5-HT1A; Signal Transduction; Specificity; Synapses; System; Temporal Lobe; Thalamic structure; Therapeutic; Time; Toxic effect; Unipolar Depression; WAY 100635; Work; base; burden of illness; cingulate cortex; common treatment; depressive symptoms; disability-adjusted life years; effective therapy; entorhinal cortex; frontal lobe; healthy volunteer; in vivo; indexing; interest; lamotrigine; neurotransmission; novel therapeutics; postsynaptic; presynaptic; putamen; radiotracer; receptor binding; response; serotonin transporter; sex; single episode major depressive disorder; suicidal risk; therapy development; treatment response

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.

描述（由申请人提供）：双相情感障碍（BPD）是一种脑部疾病，其特征是躁狂和主要的抑郁发作，一年的患病率在1-2％1-2％.1 BPD在19992年的残疾调整年度丧失的原因中排名第20位，这是1999年在1999年的自杀型自杀风险与19％的抑制作用相关联。据推测，羟色胺（5-HT）功能的缺乏是抑郁发作的基础，但很少有研究检查了BPD中大脑中5-HT神经传递的指标。人们普遍承认，当前的双相抑郁症的鉴定和治疗存在很大的差距。5-8更好地了解BPD中神经传递的缺陷可能有助于诊断，生物标志物和治疗靶标的鉴定，以促进治疗的发育并最终有助于治疗选择。我们使用[11C] DASB的初步数据显示BPD中的结合较低。我们建议在无药物的双极I抑郁症中使用正电子发射断层扫描（PET）在体内的5-HTT结合的异常程度和性质。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BPD锂的常见治疗方法的5-HT效应。几十年前发现的锂仍然是BPD中为数不多的有效治疗方法之一，表明情绪稳定，抗抑郁药，抗杀虫剂甚至神经保护品质，被认为是第一线治疗。锂对5-HT指数的作用可能是其抗抑郁和抗命特性的核心。我们假设锂会下调突触前5-HT1A受体结合，上调突触后5-HT1A结合，上调5-HTT结合，并且这些分子作用将与临床改善有关，无论是在抑郁症和自杀性方面。 5-HT1A结合势将使用[11C]方式100635确定。我们建议在重大抑郁发作中执行[11C] DASB和[11C] Way 100635扫描100635扫描，并比较38位健康志愿者的5-HTT和5-HT1和5-HT1A结合潜力。我们还将通过以相同的方式研究10个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BPD受试者中的拉莫三嗪来检查锂的药理特异性。最后，我们还将评估基线扫描预测治疗反应的能力。所有BPD受试者将用锂处理，并用两种放射性示例进行重复扫描。许多带有BPD的人不容忍锂的副作用负担，并且具有狭窄的治疗窗口。在此赠款期间，我们将确定哪种5-HT蛋白锂施加其抗抑郁药和抗杀菌特性。最终，这可能会导致新颖的治疗剂，这些治疗疗法得到更好的耐受性。我们将独立提高对BPD分子病理生理学的理解，并表征锂的作用机理。