Enhancing Extinction Learning in PTSD

描述（由申请人提供）：本临床试验检查了记忆增强药物亚甲蓝（MB）在慢性创伤后应激障碍（PTSD）治疗中促进延长暴露疗法（PE）的使用。暴露疗法的变体，特别是延长暴露的疗效，在对经历过各种创伤事件（例如，医学研究所，2007年）。尽管PE是高度有效的，但是大约20-30%的治疗完成者继续具有PTSD诊断，略微更多（30-40%）未能实现良好终末状态功能的严格标准（Foa等人，1999; Rothbaum等人，2005），并且一些未能完成治疗（20.3%，Hembree等人，2003年）。因此，有进一步改善PTSD治疗结果的空间。在消退训练后急性施用的记忆增强药物亚甲蓝改善了大鼠的恐惧消退学习（Gonzalez-Lima & Bruchey，2004; Wrubel等人，2007年）。MB是被认为刺激线粒体氧化代谢的代谢增强剂（Sakata等人，2005; Callaway等人，2004），并且是一种FDA-祖父级药物，当以低剂量口服给药时，多年来在人类中安全使用并且没有显著的副作用（Meissner et al.，2005; Naylor等人，1986; 1987; 1988; Peter等人，2000年）。强有力的动物研究，结合已建立的安全性和试验数据，显示MB增强了人类的灭绝，为将这项工作扩展到基于预防的PTSD治疗（如PE）提供了坚实的基础。 我们寻求寻求下一阶段的翻译，通过进行一个小型的可行性试验，将基于恐惧的灭绝增强在大鼠中使用亚甲蓝转移到人类的临床实践中。具体而言，该临床试验将检查亚甲蓝与安慰剂（PBO）相比在促进慢性PTSD治疗的想象暴露后的消退学习方面的初始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PTSD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将在每日5次影像暴露后给药。将监测生理和主观唤醒以及药物副作用。将评估PTSD和其他创伤相关症状的前、后和短暂随访变化，包括消退学习的泛化。 公共卫生相关性：本项目建议使用记忆增强药物亚甲蓝（MB），以促进慢性创伤后应激障碍（PTSD）的长期暴露治疗。MB，如果被证明是一个有用的辅助暴露治疗，将使暴露治疗更符合成本效益的治疗减少治疗疗程的数量，促进更快的治疗反应，减少治疗脱落，并使治疗收益随着时间的推移更持久。

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.