2/3-Exposure D-Cycloserine Enhancement and Genetic Modulators in Panic Disorder

描述（由申请人提供）：这是一项3中心（PI：Drs. Otto、Pollack、Tolin）协作研究R 01。在这个应用程序中，我们建议进一步验证和扩展的转化研究的明显惊人的成功之一。具体而言，对恐惧消退背后的神经回路的基础研究导致对d-环丝氨酸（杏仁核中NMDA受体的部分激动剂）作为能够增强消退学习的药剂的检查（Davis等人，2006 a; Davis等人，2006年b）。在动物实验室中成功验证了这一策略后，Ressler等人（2004年）表明，在身高恐惧成年人的人类暴露范例中，单剂量的d-环丝氨酸（DCS）可增强灭绝。这一令人兴奋的初步发现被我们的研究小组复制，用于治疗门诊患者的社交焦虑障碍（Hofmann et al.，2006年），我们还完成了一项试点研究，表明对其他焦虑症的治疗也有类似的好处。正如安德森和Insel（2006）所讨论的，这些发现有可能促进焦虑症治疗的重大进展。目前的研究代表了DCS的进一步应用，以增强暴露为基础的认知行为疗法（CBT）的效果，现在应用于治疗惊恐障碍伴或不伴广场恐怖症。在本申请中，我们提出了一项双盲随机对照试验，在三个治疗地点进行，以比较与安慰剂相比，惊恐障碍患者使用DCS增强基于焦虑的CBT的相对获益。此外，通过研究特定基因位点的变异性作为治疗反应的预测因子，特别是对于DCS增强的影响，我们试图确定哪些患者可能对这种形式的简短联合治疗特别敏感。本研究利用最近在转化研究中取得的成功，研究了将d-环丝氨酸添加到基于短暂性焦虑的CBT治疗伴有或不伴有广场恐怖症的惊恐障碍的方案中的益处。本研究通过评估一种干预措施来解决一个重要的公共卫生问题，这种干预措施可能有助于更有效地应用基于精神病学的心理社会干预措施来治疗恐慌症和其他焦虑症。这种结合基于胰岛素的治疗和d-环丝氨酸的新策略仍然是治疗焦虑症患者的令人失望的替代方案中特别有前途的策略，我们的研究还将提供有关CBT疗效以及d-环丝氨酸增强这种疗效的潜在遗传调节剂的有价值的信息。

DESCRIPTION (provided by applicant): This is a 3-center (PIs: Drs. Otto, Pollack, Tolin) collaborative R01. In this application, we propose to further validate and expand upon one of the apparent striking successes of translational research. Specifically, basic research on the neural circuitry underlying fear extinction led to the examination of d-cycloserine, a partial agonist at the NMDA receptor in the amygdala, as an agent capable of enhancing extinction learning (Davis et al., 2006a; Davis et al., 2006b). Following successful validation of this strategy in the animal laboratory, Ressler et al. (2004) showed that single doses of d-cycloserine (DCS) could enhance extinction in a human exposure paradigm for height phobic adults. This exciting initial finding was replicated by our research team for the treatment of social anxiety disorder in outpatients (Hofmann et al., 2006), and we also have completed a pilot study indicating similar benefits for the treatment of other anxiety disorders. As discussed by Anderson and Insel (2006), these findings have the potential to foster significant advances in the treatment of anxiety disorders. The present study represents the further application of DCS for augmenting the effects of exposure- based cognitive-behavior therapy (CBT), now applied to the treatment of panic disorder with or without agoraphobia. In this application we propose a double-blind randomized controlled trial, conducted at three treatment sites, to compare the relative benefit of augmenting exposure-based CBT with DCS as compared to placebo for patients with panic disorder. In addition, by studying variability at specific gene sites as a predictor of treatment response, particularly for the effects of DCS augmentation, we seek to identify which patients may be particularly responsive to this form of brief, combined treatment. This study capitalizes on the recent successes in translational research to investigate the benefits of the addition of d-cycloserine to a program of brief exposure-based CBT for the treatment of panic disorder with or without agoraphobia. This study addresses an important public health issue by assessing an intervention that may help lead to a more efficient and effective application of empirically-based psychosocial interventions for the treatment of panic disorder and other anxiety disorders. This novel strategy of combining exposure-based treatment and d-cycloserine remains a particularly promising strategy among disappointing alternatives for the treatment of individuals with anxiety disorders, and our research will also provide valuable information on potential genetic moderators of both CBT efficacy as well as d-cycloserine enhancement of this efficacy.