Novel Interventions for Adults with Obsessive-Compulsive Disorder

描述（由申请人提供）：强迫症（OCD）是导致疾病相关残疾的主要原因。迫切需要更有效、副作用更少、起效更快的治疗方法。认知行为疗法非常有效，但不容易传播，对许多患者来说难以执行。5 -羟色胺再摄取抑制剂（SRIs）在一些患者中只有中等效果，并且在症状减轻前有很长的滞后时间（610周）。SRIs通常也会导致性功能障碍，这是患者停药的主要原因。唯一被证明可以增加SRIs的药物是抗精神病药物的添加，它可以帮助多达三分之一的患者；然而，体重增加和镇静的副作用也导致高停药率。我的目标是整合最新的基础科学和疾病的病理生理学，并利用这些知识来识别和测试针对强迫症和相关疾病的潜在神经生物学机制的新药。我在本次指导患者导向研究职业发展奖（K23）期间的重点是谷氨酸系统，因为最近的人类和动物数据表明强迫症患者的皮质-纹状体回路中存在异常的谷氨酸功能。此外，被认为可以调节谷氨酸系统的药物已在公开标签试验中显示出前景。职业发展计划将重点发展：1)强迫症现象学和神经生物学方面的专业知识，以确定新的治疗目标；2)设计、实施和分析临床试验以测试新化合物的技能；3)深入了解磁共振波谱（MRS）方法，以测试治疗对大脑的影响。该研究计划将在强迫症中测试两种假定的谷氨酸调节剂：项目1是二甲胺四环素的随机试验，被认为通过神经胶质机制起作用，以增加强迫症患者的SRIs。试点数据表明，该药耐受性良好，某些患者的症状可能显著减轻。米诺环素的优点是成本低，FDA批准儿童用药12（用于长期治疗痤疮），而且副作用比抗精神病药物小。目的是检查二甲胺四环素作为SRIs辅助治疗的效果，以确定二甲胺四环素是否值得在R01应用中进行。项目2：氯胺酮（一种谷氨酸受体拮抗剂）是一项随机试验，用于之前SRI试验失败的无药强迫症患者。目的是确定氯胺酮治疗强迫症的安全性和可行性，并探讨氯胺酮对强迫症症状和前扣带皮层谷氨酸水平的影响。这些项目将有助于研究谷氨酸系统在强迫症中的作用，并探索强迫症的新治疗方法；来自这两个项目的有希望的数据将导致未来的R01研究。在这个过程中，我将获得必要的技能和经验，以启动我作为一个独立的，以病人为导向的研究人员的职业生涯。本研究通过测试强迫症的新干预措施（策略3.1）和探索治疗反应的潜在标记（策略1.3）来促进NIMH战略计划。

DESCRIPTION (provided by applicant): Obsessive compulsive disorder (OCD) is a leading cause of illness related disability. More effective treatments with fewer side effects and faster onset of action are desperately needed. Cognitive behavioral therapy is highly effective, but not easily disseminated and difficult for many patients to execute. Serotonin reuptake inhibitors (SRIs) are only moderately effective in some patients and have a long lag time (610 weeks) before symptom reduction. SRIs also commonly cause sexual dysfunction, a major reason for patient discontinuation. The only medications proven to augment SRIs is the addition of antipsychotics, which help up to a third of patients; however, the side effects of weight gain and sedation also lead to high rates of discontinuation. My goal is to integrate the latest basic science and pathophysiology of disease and to use that knowledge to identify and test new drugs directed at underlying neurobiological mechanisms of OCD and related disorders. My focus during this Mentored PatientOriented Research Career Development Award (K23) is the glutamate system because recent human and animal data implicate abnormal glutamatergic functioning in cortico-striatial circuits in OCD. Moreover, medications thought to modulate the glutamate system have shown promise in open label trials. The Career Development Plan will focus on developing: 1) expertise in the phenomenology and neurobiology of OCD to identify novel treatment targets; 2) skill in the design, conduct, and analysis of clinical trials to test novel compounds; 3) in-depth knowledge of magnetic resonance spectroscopy (MRS) methods to test the effects of treatments on the brain. The Research Plan will test two putative glutamate modulators in OCD: Project #1 is a randomized trial of minocycline, thought to act through glial mechanisms, to augment SRIs in OCD patients. Pilot data suggest that it is well tolerated and may have dramatic symptom reduction in some patients. Advantages of minocycline are low cost, FDA approval in children e12 (for long-term treatment of acne), and less side effects than antipsychotics. The goal is to examine the effects of minocycline as an adjunct to SRIs to determine if minocycline is worth pursuing in an R01 application. Project #2: is a randomized trial of ketamine, a glutamate receptor antagonist, in drug free OCD patients who have failed prior SRI trials. The goal is to determine safety and feasibility of ketamine in OCD and to explore ketamine effects on OCD symptoms and on glutamate measures in the anterior cingulate cortex. Together these projects will help examine the role of the glutamatergic system in OCD and explore novel treatments for OCD; promising data from either project will lead to future R01 studies. In the process, I will acquire skills and experience necessary to launch my career as an independent, patient oriented researcher. This study promotes the NIMH strategic plan by testing novel interventions for OCD (Strategy 3.1) and exploring a potential marker of treatment response (Strategy 1.3).