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

描述(申请人提供)：这是一个三中心(PI：博士奥托，波拉克，托林)合作的R01。在这一应用中，我们建议进一步验证和扩展翻译研究的一个明显的显著成功。具体地说，对恐惧消退背后的神经回路的基础研究导致了对d-环丝氨酸的研究，d-环丝氨酸是杏仁核中NMDA受体的一种部分激动剂，能够促进消退学习(Davis等人，2006a；Davis等人，2006b)。在动物实验室成功验证了这一策略后，Ressler等人进行了实验。(2004)表明，在人体暴露模式中，单剂量的d-环丝氨酸(Dcs)可增加恐高症成年人的消光。这一令人兴奋的初步发现被我们的研究团队用于治疗门诊患者的社交焦虑症重复(Hofmann等人，2006年)，我们还完成了一项试点研究，表明类似的益处适用于其他焦虑症的治疗。正如Anderson和Insel(2006)所讨论的，这些发现有可能促进焦虑症治疗方面的重大进步。这项研究代表了分布式控制系统的进一步应用，以增强基于暴露的认知行为疗法(CBT)的效果，目前CBT已被应用于治疗伴有或不伴有广场恐怖症的惊恐障碍。在这项申请中，我们提出了一项在三个治疗地点进行的双盲随机对照试验，以比较与安慰剂相比，增加基于暴露的CBT与DCS对惊恐障碍患者的相对好处。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DCs增强的影响，我们试图确定哪些患者可能对这种简短的联合治疗特别有效。这项研究利用最近在翻译研究中取得的成功，调查了在基于短暂暴露的CBT计划中添加d-环丝氨酸的好处，用于治疗伴有或不伴有广场恐怖症的惊恐障碍。这项研究通过评估干预措施，解决了一个重要的公共卫生问题，该干预措施可能有助于更有效地应用基于经验的心理社会干预措施来治疗恐慌症和其他焦虑症。这种基于暴露的治疗和d-环丝氨酸相结合的新策略在治疗焦虑症患者的令人失望的替代方案中仍然是一个特别有希望的策略，我们的研究也将提供关于CBT疗效的潜在遗传调节剂以及d-环丝氨酸增强这一疗效的有价值的信息。

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.