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: 6432771
• 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/6432771
• 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; 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 neuroimaging and paired pulse 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 GABA/glutamate-mediated cortical physiology, we found that TMS threshold was abnormal. This finding was 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 nearing completion. 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 and other brain regions 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, have been 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. In addition, a recent study found an association between allelic variation at the serotonin transporter promoter region polymorphism and OCD, some of the first and recently replicated evidence that genetic differences in serotonin systems may predispose to OCD.

该项目涉及针对（1）增强我们对OCD发病机理的理解的强迫症（OCD）的临床研究，以及（2）研究这种主要神经精神疾病的潜在新疗法。 我们的研究使用神经影像学和配对的脉搏经颅磁刺激来研究强迫症和药理治疗基础的机制中的病理生理学。其他研究评估了神经传递相关的候选基因与强迫症的相关性以及可能与疾病相关的人格维度。使用“配对脉冲”经颅磁刺激（TMS）技术，该技术最初是作为GABA/谷氨酸介导的皮质生理学的探针建立的，我们发现TMS阈值异常。 鉴于临床前数据表明，这一发现很有趣，表明脑GABA能和5-羟色胺能回路之间的重要相互作用以及我们的初步证据，即GABA调制剂Gabapentin改善了对OCD中抑制抗抑郁药的羟色胺再摄取的反应。 Gabapentin增强的对照研究包括TMS措施，以确定Gabapentin治疗后皮质醇的兴奋性是否发生了变化。我们使用磁共振松弛计在强迫症患者基底神经节中对结构异常的初步发现与OCD中纹状体病理学理论一致。在MRI体积研究中，我们还测试了以下假设：基底神经节异常与OCD相关，通过对OCD中基底神经节和其他大脑区域进行体积研究。我们对强迫症的最新神经解剖学方法是一个合作项目，使用扩散张量MRI来评估我们同事在布朗大学同事执行的治疗治疗患者中γ-刀胶质切开术后白质解剖学变化的治疗相关性。最后，我们正在积极追求影响中枢神经传递和强迫症的候选基因之间的关联。一些潜在感兴趣的候选基因，例如影响单胺能神经传递基因的启动子区域的功能遗传变异，在我们正在进行的对与焦虑和抑郁相关人格维度的遗传学的研究中已经鉴定出来。在一项这样的维表型研究中，我们最近发现，在羟色胺转运蛋白启动子区域的功能等位基因变异与与抑郁症和焦虑有关的可遗传性格特征之间的关联是我们以前在大型男性队列中看到的，这是在大型女性人群中复制的。此外，最近的一项研究发现5-羟色胺转运蛋白启动子区域多态性的等位基因变异与OCD之间存在关联，这是一些最早的也是最近复制的证据，表明5-羟色胺系统的遗传差异可能会使OCD倾向于OCD。