Enhancing Extinction Learning in PTSD

描述（由申请人提供）：本临床试验研究了记忆增强药物亚甲基蓝（MB）在慢性创伤后应激障碍（PTSD）治疗中的使用，以促进长时间暴露疗法（PE）。各种暴露疗法，特别是长时间暴露疗法的疗效，在对经历过各种创伤性事件的男性和女性进行的研究中得到了证实（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PTSD，稍多的（30-40%）患者未能达到良好终态功能的严格标准（Foa等人，1999；Rothbaum等人，2005），还有一些患者未能完成治疗（20.3%，Hembree等人，2003）。因此，PTSD的治疗效果还有进一步改善的空间。记忆增强药物亚甲基蓝在消退训练后急性给予可以改善大鼠的恐惧消退学习（Gonzalez-Lima & Bruchey, 2004; Wrubel et al., 2007）。MB是一种代谢促进剂，被认为可以刺激线粒体氧化代谢（Sakata等人，2005；Callaway等人，2004），并且是fda的祖父级药物，当以低剂量口服时，多年来一直安全使用，在人体中没有明显的副作用（Meissner等人，2005；Naylor等人，1986;1987;1988；Peter等人，2000）。强有力的动物研究，结合已建立的安全性和显示mb在人类中增强灭绝的试点数据，为将这项工作扩展到基于灭绝的创伤后应激障碍治疗（如PE）提供了坚实的基础。我们寻求进行下一阶段的转化，通过进行小型可行性试验，将基于恐惧的亚甲基蓝在大鼠中的灭绝增强转移到人类的临床实践中。具体来说，这项临床试验将检查亚甲基蓝与安慰剂（PBO）在促进图像暴露后的消退学习治疗慢性创伤后应激障碍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。患有慢性创伤后应激障碍的男性和女性将被随机分配到三种情况中的一种：图像暴露加MB，图像暴露加匹配的安慰剂，或等待名单。260mg MB或PBO将在每日5次影像学暴露后给予。生理和主观唤醒以及药物副作用将被监测。将评估创伤后应激障碍和其他创伤相关症状的前、后和短暂随访变化，包括消退学习的泛化。

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.