STUDY OF CYSTEAMINE BITARTRATE IN TREATMENT-RESISTANT MAJOR DEPRESSION

半胱胺酒石酸氢盐治疗难治性重度抑郁症的研究

• 批准号: 7953728
• 负责人: FATIH OZBAY
• 金额: $ 0.46万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953728
• 关键词: Acute; Affect; Aftercare; Alzheimer' s Disease; Antidepressive Agents; Autopsy; Brain-Derived Neurotrophic Factor; Cerebrospinal Fluid; Chronic; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Cysteamine; Cystinosis; Dementia; Funding; General Population; Grant; Human; Huntington Disease; Institution; Lysosomal Storage Diseases; Major Depressive Disorder; Measures; Memory; Morbidity - disease rate; Neuraxis; Neurodegenerative Disorders; Neurons; Neuropsychological Tests; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Public Health; Recurrence; Research; Research Personnel; Resistance; Resources; Role; Selective Serotonin Reuptake Inhibitor; Serum; Source; Tissues; Transglutaminases; United States National Institutes of Health; cell growth; cognitive function; depression; depressive symptoms; improved; inhibitor/antagonist; mortality; novel; open label; polypeptide; pre-clinical

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 4/1/2008 Major depressive disorder (MDD) is a chronic, disabling illness affecting about 17% of the general population. Despite advances in treatment, about two-thirds of patients fail to respond to an initial trial of pharmacotherapy. As MDD continues to pose a significant public health problem, with high rates of morbidity and mortality, well-tolerated new treatments are necessary. Brain-derived neurotrophic factor (BDNF), a polypeptide found naturally in the central nervous system, is responsible for promoting cell growth and survival. Neurodegenerative illnesses such as Huntington's disease (HD), cause a decrease in release of BDNF, and thereby affect neuronal viability. Defective BDNF pathways have also been associated with psychiatric illnesses, such as Alzheimer's dementia and MDD. A multitude of studies have shown low levels of BDNF in subjects with MDD, which have normalized after treatment with an antidepressant. It is presumed that traditional antidepressants such as serotonin reuptake inhibitors increase BDNF via an indirect cascade pathway. Cysteamine is a transglutaminase inhibitor approved for treatment of cystinosis, a lysosomal storage disease. In a preclinical and postmortem study of HD, cysteamine has been shown to increase BNDF in neuronal tissue, and stimulate cell growth. Cysteamine has already been investigated in humans as a potential treatment for HD. Given the ample evidence of decreased levels in major depression, and subsequent increase post-treatment with antidepressants, BDNF may play a key role in developing a novel pathway of treatment for patients who have failed in trials with conventional agents. Therefore, drugs that can demonstrably increase central BDNF, such as cysteamine, may have great use as antidepressant medications. The primary purpose of the study is to assess the acute efficacy of cysteamine, a transglutaminase inhibitor, given in an open-label fashion to patients with recurrent or chronic unipolar major depression without psychotic features. This will be achieved by measuring the mean change in the Montgomery-¿sberg Depression Rating Scale (MADRS) total score from baseline to the score at the end of 8 weeks of therapy. Hypothesis: Our primary hypothesis is that patients receiving therapy with cysteamine will have decreased symptoms of depression (as evidenced by mean reduction in MADRS score of >25%) at study end point (8 weeks) as compared to baseline. Our first exploratory secondary aim is to explore whether patients with major depression receiving open treatment with cysteamine will manifest improved cognitive function, especially memory. This will be measured by change in neuropsychological test battery scores from baseline to the end of treatment. Our second is to explore whether patients receiving cysteamine openly for eight weeks will demonstrate an increase in serum and cerebrospinal fluid (CSF) concentrations of brain derived neurotrophic factor (BDNF) from pre-treatment to the end of treatment.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 2008年4月1日 重度抑郁症（MDD）是一种慢性残疾疾病，影响了约17％的普通人群。尽管有治疗的进步，但大约三分之二的患者未能对初始试验进行药物治疗的反应。随着MDD继续构成重大的公共卫生问题，发病率和死亡率很高，因此需要良好的新疗法。脑衍生的神经营养因子（BDNF）是一种自然存在于中心神经退行性疾病（例如亨廷顿氏病）（HD）的多肽，会导致BDNF释放的释放降低，从而影响神经元的生存能力。有缺陷的BDNF途径也与精神病疾病有关，例如阿尔茨海默氏症和MDD。大量研究表明，MDD受试者的BDNF水平较低，MDD的受试者用抗抑郁药治疗后已归一化。据表明，诸如5-羟色胺再摄取抑制剂之类的传统抗抑郁药通过间接级联途径增加了BDNF。 cysteamine是一种批准用于治疗溶酶体储存疾病的囊这症治疗的转谷氨酸酶抑制剂。 在HD的临床前和验尸研究中，cysteamine已被证明会增加神经元组织中的BNDF，并刺激细胞生长。 cysteamine已经在人类中被研究为HD的潜在治疗方法。鉴于大量抑郁症水平降低以及随后用抗抑郁药的治疗增加的证据，BDNF可能在开发新的治疗途径的途径中为与常规药物试验未能通过的患者发挥着关键作用。因此，可以有效增加中央BDNF的药物（例如cysteamine）可能充分用作抗抑郁药。 该研究的主要目的是评估cysteamine（一种经云丁胺抑制剂）的急性效率，该抑制剂以开放标签的方式给予反复发作或慢性单极重大抑郁症患者而没有精神病性特征。这将通过测量蒙哥马利 - Sberg抑郁评分量表（MADRS）从基线到分数在8周结束时得分的平均变化来实现。 假设： 我们的主要假设是，与基线相比，在研究终点（8周）接受抑郁症症状的患者将降低抑郁症状（如MADRS评分的平均降低> 25％）。 我们的第一个探索性次要目的是探索大抑郁症患者接受西构氨酸开放治疗的患者是否会表现出改善的认知功能，尤其是记忆。这将通过从基线到治疗结束的神经心理测试电池评分的变化来衡量。我们的第二个是探索接受cysteamine八周的患者是否表明血清和脑脊液（CSF）的脑部衍生神经营养因子（BDNF）的浓度从治疗结束到治疗结束。