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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 4/1/2008 重度抑郁症（MDD）是一种慢性致残性疾病，影响约17%的普通人群。 尽管治疗取得了进展，但约三分之二的患者对药物治疗的初步试验没有反应。 由于MDD继续造成严重的公共卫生问题，具有高发病率和死亡率，因此需要耐受性良好的新治疗方法。 脑源性神经营养因子（BDNF）是一种天然存在于中枢神经系统中的多肽，负责促进细胞生长和存活。 神经退行性疾病（例如亨廷顿病（HD））会导致脑源性神经营养因子（BDNF）的释放减少，从而影响神经元的活力。缺陷的BDNF通路也与精神疾病有关，如阿尔茨海默氏痴呆症和MDD。大量研究表明，MDD患者的BDNF水平较低，在抗抑郁药治疗后恢复正常。 据推测，传统的抗抑郁药，如血清素再摄取抑制剂，通过间接级联途径增加BDNF。 半胱胺是一种转氨酶抑制剂，被批准用于治疗胱氨酸病，一种溶酶体贮积病。 在HD的临床前和死后研究中，半胱胺已显示出增加神经元组织中的BNDF，并刺激细胞生长。 半胱胺已经在人类中作为HD的潜在治疗进行了研究。 鉴于有充分的证据表明，重度抑郁症的水平降低，以及抗抑郁药治疗后的水平升高，BDNF可能在为常规药物试验失败的患者开发新的治疗途径方面发挥关键作用。 因此，可以明显增加中枢BDNF的药物，如半胱胺，可能作为抗抑郁药物有很大的用途。 本研究的主要目的是评估半胱胺（一种转氨酶抑制剂）对无精神病特征的复发性或慢性单相重性抑郁症患者以开放标签方式给药的急性疗效。这将通过测量蒙哥马利-<$sberg抑郁评定量表（MADRS）总评分从基线至8周治疗结束时评分的平均变化来实现。 假设： 我们的主要假设是，与基线相比，接受半胱胺治疗的患者在研究终点（8周）时的抑郁症状将减轻（MADRS评分平均降低>25%即可证明）。 我们的第一个探索性次要目标是探索接受半胱胺开放治疗的重度抑郁症患者是否会表现出认知功能的改善，特别是记忆力。 这将通过神经心理学成套测试评分从基线至治疗结束的变化来测量。 我们的第二个目的是探索患者接受半胱胺开放治疗8周后，从治疗前到治疗结束，血清和脑脊液（CSF）中脑源性神经营养因子（BDNF）浓度是否会增加。