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

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.

该项目涉及强迫症 (OCD) 的临床研究，旨在 (1) 增强我们对 OCD 发病机制的理解，以及 (2) 研究这种主要神经精神疾病的潜在新疗法。 我们的研究使用神经影像学和配对脉冲经颅磁刺激来研究强迫症的病理生理学及其药物治疗的机制。其他研究评估了神经传递相关候选基因与强迫症以及与该疾病潜在相关的人格维度的相关性。使用最初作为 GABA/谷氨酸介导的皮质生理学探针而建立的“配对脉冲”经颅磁刺激 (TMS) 技术，我们发现 TMS 阈值异常。 鉴于临床前数据表明大脑 GABA 能和血清素能回路之间存在重要的相互作用，并且我们的初步证据表明加巴喷丁（一种 GABA 调节剂）可改善强迫症患者对血清素再摄取抑制抗抑郁药的反应，因此这一发现很有趣。一项加巴喷丁增强对照研究即将完成，其中包括通过 TMS 测量来确定加巴喷丁治疗后皮质醇兴奋性是否发生变化。我们使用磁共振松弛测量法初步发现强迫症患者基底神经节的结构异常，这与强迫症患者纹状体病理学的理论是一致的。在 MRI 体积研究中，我们还通过对强迫症中的基底神经节和其他大脑区域进行体积研究来检验基底神经节异常与强迫症相关的假设。我们最近针对强迫症的神经解剖学方法是一个合作项目，使用扩散张量 MRI 来评估我们在布朗大学的同事对难治性患者进行伽玛刀囊切开术后白质解剖结构变化的治疗相关性。最后，我们正在积极寻找影响中枢神经传递的候选基因与强迫症之间的关联。在我们正在进行的与焦虑和抑郁相关的人格维度的遗传学研究中，已经确定了一些潜在感兴趣的候选基因，例如影响单胺能神经传递的基因启动子区域的功能性遗传变异。在一项这样的维度表型研究中，我们最近发现，血清素转运蛋白启动子区域的功能性等位基因变异与抑郁和焦虑相关的可遗传人格特征之间的关联，我们之前在一个大型的、主要是男性的队列中看到过，并且在一个大型的队列中得到了复制。主要是女性人口样本。此外，最近的一项研究发现，血清素转运蛋白启动子区域多态性的等位基因变异与强迫症之间存在关联，这是第一个和最近复制的证据，表明血清素系统的遗传差异可能导致强迫症。