Enhancing Extinction Learning in PTSD

描述(申请人提供)：这项临床试验考察了记忆增强药物亚甲蓝(MB)在慢性创伤后应激障碍(PTSD)治疗中的使用，以促进长期暴露疗法(PE)。在对经历过各种创伤事件的男性和女性进行的研究中，各种暴露疗法，特别是长期暴露的有效性得到了重复(例如，医学研究所，2007年)。尽管PE非常有效，但大约20-30%的治疗完成者仍被诊断为创伤后应激障碍，略多的人(30-40%)未能达到良好终端功能的严格标准(Foa等人，1999年；Rothbaum等人，2005年)，有些未能完成治疗(20.3%，Hembree等人，2003年)。因此，有进一步改善创伤后应激障碍治疗结果的空间。记忆增强药物亚甲蓝在灭绝训练后剧烈使用，可改善大鼠的恐惧消退学习(Gonzalez-Lima&Bruceh，2004；Wrubel等人，2007)。甲基溴是一种新陈代谢增强剂，被认为可以刺激线粒体的氧化代谢(Sakata等人，2005年；Callaway等人，2004年)，是FDA的祖辈药物，当口服低剂量时，多年来一直在人类身上安全使用，没有明显的副作用(Meissner等人，2005年；内勒等人，1986；1987；1988；Peter等人，2000年)。强有力的动物研究，再加上已建立的安全性和试点数据显示，甲基溴增强了人类的消亡，为将这项工作扩展到基于消亡的PTSD治疗方法，如PE，提供了坚实的基础。我们寻求进行下一阶段的翻译，通过进行一项小型可行性试验，将使用亚甲基蓝在大鼠身上进行的基于恐惧的消亡增强方法转移到人类的临床实践中。具体地说，这项临床试验将检验亚甲基蓝与安慰剂(PBO)在促进慢性创伤后应激障碍(PTSD)治疗后的消退学习方面的初步安全性和相对有效性。我们将进行双盲随机可行性试验。患有慢性创伤后应激障碍的男性和女性将被随机分配到三种情况之一：想象暴露加MB，想象暴露加匹配的安慰剂，或等待名单。260 mg MB或PBO将在每天五次想象暴露疗程后给予。将监测生理和主观唤醒以及药物副作用。将评估创伤后应激障碍和其他创伤相关症状的前、后和短暂的后续变化，包括对消退学习的概括。 公共卫生相关性：该项目建议使用记忆增强药物亚甲基蓝(MB)来促进慢性创伤后应激障碍(PTSD)的长期暴露治疗。甲基溴如果被证明是暴露治疗的有益补充，将通过减少治疗疗程的次数、促进更快的治疗反应、减少治疗辍学以及随着时间的推移使治疗收益更持久，从而使暴露治疗成为更具成本效益的治疗方法。

DESCRIPTION (provided by applicant): This clinical trial examines the use of the memory-enhancingdrug methylene blue (MB) to facilitate prolonged exposure therapy (PE) in the treatment of chronic posttraumatic stress disorder (PTSD). The efficacy of variants of exposure therapy and, in particular, prolonged exposure, has been replicated across studies with men and women who have experienced a wide range of traumatic events (e.g., Institute of Medicine, 2007). Although PE is highly efficacious, approximately 20-30% of treatment completers continue to have a PTSD diagnosis, slightly more (30-40%) fail to achieve a stringent criterion for good end-state functioning (Foa et al., 1999; Rothbaum et al., 2005), and some fail to complete treatment (20.3%, Hembree et al., 2003). Thus, there is room to further improve PTSD treatment outcomes. The memory-enhancing drug methylene blue administered acutely after extinction training improves fear extinction learning in rats (Gonzalez-Lima & Bruchey, 2004; Wrubel et al., 2007). MB is a metabolic enhancer that is thought to stimulate mitochondrial oxidative metabolism (Sakata et al., 2005; Callaway et al., 2004) and is an FDA-grandfathered drug that, when administered orally in low doses, has been used safely and without significant side effects in humans for years (Meissner et al., 2005; Naylor et al., 1986; 1987; 1988; Peter et al., 2000). Strong animal research, in combination with established safety and pilot data showing MB-enhanced extinction in humans, provides a firm foundation to extend this work to extinction-based therapies for PTSD such as PE. We seek to pursue the next phase of translation, moving fear-based extinction augmentation using methylene blue in rats to clinical practice in humans by conducting a small feasibility trial. Specifically, this clinical trial will examine the initial safety and relative efficacy of methylene blue in comparison to placebo (PBO) in facilitating extinction learning following imaginal exposure for the treatment of chronic PTSD. We will conduct a double-blind randomized feasibility trial. Males and females with chronic PTSD will be randomly assigned to one of three conditions: imaginal exposure plus MB, imaginal exposure plus matched placebo, or waitlist. 260mg MB or PBO will be administered following five daily imaginal exposure sessions. Physiological and subjective arousal and medication side effects will be monitored. Pre-, post-, and brief follow-up changes in PTSD and other trauma-related symptoms will be assessed, including generalization of extinction learning. PUBLIC HEALTH RELEVANCE: This project proposes to use the memory-enhancing drug, methylene blue (MB), to facilitate prolonged exposure therapy for chronic posttraumatic stress disorder (PTSD). MB, if shown to be a useful adjunct to exposure treatments, will render exposure therapy a more cost-efficient treatment by decreasing the number of treatment sessions, promoting a quicker treatment response, reducing treatment dropout, and making treatment gains more durable over time.