STUDY OF CYSTEAMINE BITARTRATE IN TREATMENT-RESISTANT MAJOR DEPRESSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 4/1/2008 严重抑郁障碍(MDD)是一种慢性致残性疾病，约占总人口的17%。尽管在治疗方面取得了进展，但大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继续构成一个重大的公共卫生问题，发病率和死亡率都很高，因此有必要采用耐受性良好的新疗法。脑源性神经营养因子(BDNF)是一种天然存在于中枢神经系统的多肽，负责促进细胞生长和存活。神经退行性疾病，如亨廷顿病(HD)，会导致BDNF释放减少，从而影响神经元的生存。脑源性神经营养因子通路的缺陷也与精神疾病有关，如阿尔茨海默氏症和MDD。大量研究表明，MDD患者体内脑源性神经营养因子水平较低，经抗抑郁药物治疗后恢复正常。据推测，传统的抗抑郁药物，如5-羟色胺再摄取抑制剂，通过间接级联途径增加BDNF。半胱胺是一种转谷氨酰胺酶抑制剂，被批准用于治疗胱氨酸病，一种溶酶体储存疾病。 在HD的临床前和死后研究中，半胱胺已被证明能增加神经元组织中的BNDF，并刺激细胞生长。半胱胺已经在人类身上作为一种潜在的HD治疗方法进行了研究。鉴于大量证据表明重度抑郁症患者的抑郁水平降低，以及随后抗抑郁药物治疗后水平的上升，BDNF可能在为常规药物试验失败的患者开发一种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，可能在抗抑郁药物方面有很大的用途。 该研究的主要目的是评估半胱胺的急性疗效，半胱胺是一种谷氨酰胺转氨酶抑制剂，以开放标签的方式给予无精神病特征的复发性或慢性单相重度抑郁症患者。这将通过测量蒙哥马利-斯伯格抑郁评定量表(MADRS)总分从基线到治疗8周结束时的平均变化来实现。 假设： 我们的基本假设是，与基线相比，接受半胱胺治疗的患者在研究结束时(8周)抑郁症状减轻(MADRS评分平均降低25%)。 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。这将通过从基线到治疗结束的神经心理测试组合分数的变化来衡量。我们的第二项研究是探讨公开接受半胱胺治疗8周的患者从治疗前到治疗结束期间血清和脑脊液(CSF)脑源性神经营养因子(BDNF)浓度是否升高。

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.