THE PSYCHOLBIOLOGY AND TREATMENT OF OBESSIVE COMPULSIVE DISORDER IN ADULTS

成人强迫症的心理生物学和治疗

• 批准号: 6111090
• 负责人: Dennis L Murphy
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6111090
• 关键词: adult human (21+); anticonvulsants; basal ganglia; behavioral genetics; brain electrical activity; clinical research; combination chemotherapy; fluoxetine; genetic polymorphism; genetic promoter element; hormone regulation /control mechanism; human subject; human therapy evaluation; magnetic field; mental disorder chemotherapy; obsessive compulsive disorder; pathologic process; psychobiology; serotonin transporter

This project involves clinical research in obsessive- compulsive disorder (OCD) directed towards (1) enhancement of our understanding of OCD pathogenesis, and (2) investigating potential new treatments for this major neuropsychiatric disorder. Our studies use pharmacological probes, neuroimaging, and transcranial magnetic stimulation to investigate pathophysiology in OCD and mechanisms underlying its pharmacological treatment. Other studies assess the relevance of neurotransmission-related candidate genes to OCD and to personality dimensions which are potentially relevant to the illness. Using the "paired-pulse" transcranial magnetic stimulation (TMS) technique first established as a probe of cortical physiology, we found that intracortical inhibition, thought to be GABA-modulated, was defective in OCD patients. This finding is interesting in view of preclinical data indicating important interactions between brain GABAergic and serotonergic circuits and our preliminary evidence that gabapentin, a GABA-modulator, improves the response to serotonin reuptake inhibiting antidepressants in OCD. A controlled study of gabapentin augmentation, which includes TMS measures to determine if corticol excitability changes after gabapentin treatment, is underway. Impaired intracortical inhibition, which is also found in the OCD-related illness, Tourette's Syndrome, could be due to intracortical dysfunction or basal ganglia pathology. Our preliminary finding of structural abnormalities in the basal ganglia of OCD patients using magnetic resonance relaxometry is consistent with theories of striatal pathology in OCD. In an MRI volumetric study we are also testing the hypothesis that basal ganglia abnormalities are associated with OCD by performing volumetric studies of the basal ganglia in OCD. Our most recent neuroanatomical approach to OCD is a collaborative project using diffusion tensor MRI to assess the therapeutic relevance of changes in white matter anatomy after gamma-knife capsulotomy in treatment-refractory patients performed by our colleagues at Brown University. Finally, we are actively pursuing associations between candidate genes affecting central neurotransmission and OCD. Some candidate genes of potential interest, such as functional genetic variants in the promoter regions of genes affecting monoaminergic neurotransmission, are being identified in our ongoing studies of the genetics of anxiety- and depression-related personality dimensions. In one such dimensional phenotype study, we have recently found that the association between functional allelic variation in the serotonin transporter promoter region and heritable personality traits related to depression and anxiety that we had seen previously in a large, mainly male cohort was replicated in a large primarily female population sample. Preliminary analysis suggests an association between allelic variation at the serotonin transporter promoter region polymorphism and OCD, some of the first evidence that genetic differences in serotonin systems may predispose to OCD.

该项目涉及强迫症的临床研究 - 针对（1）增强的强迫症（OCD） 我们对强迫症发病机理的理解，以及（2）研究 这种主要神经精神疾病的潜在新疗法。 我们的研究使用药理学探针，神经影像学和 经颅磁刺激以研究病理生理学 强迫症和其药理治疗基础的机制。 其他研究评估与神经传递相关的相关性 候选基因到强迫症和性格维度 可能与疾病有关。 使用“配对脉冲” 首次建立的经颅磁刺激（TMS）技术 作为皮质生理学的探针，我们发现心脏内部 抑制作用，被认为是GABA调制的，在OCD中有缺陷 患者。鉴于临床前数据，这一发现很有趣 表明脑gabaergic和 血清素能电路和我们的初步证据，即加巴喷丁， GABA调制器，改善对5-羟色胺再摄取的反应 强迫症中抑制抗抑郁药。加巴喷丁的对照研究 增强，其中包括TMS措施来确定是否是否 加巴喷丁治疗后皮质醇的兴奋性改变是 进行。心脏内抑制受损 强迫症相关疾病，图雷特综合症，可能是由于 心脏内功能障碍或基底神经节病理学。我们的 初步发现结构异常的基底神经节 使用磁共振松弛计的强迫症患者是一致的 OCD中的纹状体病理学理论。在MRI体积中 研究我们还测试了基底神经节的假设 异常与OCD相关，通过执行体积 OCD中基底神经节的研究。我们最近的 OCD神经解剖学方法是一个协作项目 扩散张量MRI评估变化的治疗相关性 在伽马刀囊切开术后的白质解剖学中 我们的同事在布朗进行的治疗难治性患者 大学。最后，我们正在积极追求 影响中央神经传递和强迫症的候选基因。 一些潜在感兴趣的候选基因，例如功能 影响基因启动子区域的遗传变异 单胺能神经传递，正在我们的 正在进行的有关焦虑和抑郁有关的遗传学的研究 个性维度。在一项这样的维表型研究中， 我们最近发现功能之​​间的关联 5-羟色胺转运蛋白启动子区域的等位基因变异和 我们的性格特征与我们的抑郁和焦虑有关 以前在一个大的，主要是男性队列中看到的 主要是女性人口样本。初步分析 提示5-羟色胺的等位基因变异之间存在关联 转运蛋白启动子区域多态性和强迫症，其中一些 第一个证据表明5-羟色胺系统的遗传差异可能 易感强迫症。