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

恐慌症中的 3/3 暴露 D-环丝氨酸增强剂和遗传调节剂

• 批准号: 7616448
• 负责人: MARK H POLLACK
• 金额: $ 27.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-24 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616448
• 关键词: Acute; Address; Adult; Adverse event; Aftercare; Agonist; Agoraphobia; Amygdaloid structure; Anxiety Disorders; Basic Science; Brain-Derived Neurotrophic Factor; Combined Modality Therapy; Cycloserine; Dose; Double-Blind Method; Employee Strikes; Extinction (Psychology); Fostering; Fright; Genes; Genetic; Genetic Enhancement; Glutamates; Height; Impairment; Individual; Intervention; Laboratory Animals; Lead; Long-Term Effects; Mediating; N-Methyl-D-Aspartate Receptors; NTRK2 gene; Neurobiology; Outpatients; Panic Disorder; Patients; Pilot Projects; Placebos; Public Health; Randomized Controlled Trials; Relative (related person); Research; Safety; Severities; Site; Symptoms; System; Translational Research; Treatment Efficacy; Treatment outcome; Validation; alternative treatment; base; cognitive behavior therapy; conditioned fear; exposed human population; follow up assessment; follow-up; learning extinction; neural circuit; novel strategies; pill; programs; psychosocial; response; social; success; treatment program; treatment response; treatment site

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.

描述（由申请人提供）：这是一个 3 中心（PI：Otto、Pollack、Tolin 博士）合作的 R01。在本申请中，我们建议进一步验证和扩展转化研究的一项明显的惊人成功。具体来说，对恐惧消退神经回路的基础研究导致了对 d-环丝氨酸（杏仁核 NMDA 受体的部分激动剂）的检查，作为一种能够增强消退学习的药物（Davis 等，2006a；Davis 等，2006b）。在动物实验室成功验证这一策略后，Ressler 等人。 (2004) 表明，在人体暴露范例中，单剂量的 d-环丝氨酸 (DCS) 可以增强患有身高恐惧症的成年人的灭绝。我们的研究团队在门诊社交焦虑症的治疗中重复了这一令人兴奋的初步发现（Hofmann 等，2006），并且我们还完成了一项试点研究，表明治疗其他焦虑症也有类似的益处。正如 Anderson 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。本研究代表了 DCS 的进一步应用，以增强基于暴露的认知行为疗法 (CBT) 的效果，该疗法现在应用于治疗伴有或不伴有广场恐惧症的惊恐障碍。在本申请中，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，以比较使用 DCS 增强基于暴露的 CBT 与安慰剂相比对惊恐障碍患者的相对益处。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 DCS 增强的效果，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来调查在基于短暂暴露的 CBT 计划中添加 d-环丝氨酸对于治疗伴有或不伴有广场恐惧症的恐慌症的益处。这项研究通过评估干预措施来解决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个体的令人失望的替代方案中仍然是一种特别有前途的策略，我们的研究还将提供关于 CBT 功效的潜在遗传调节因素以及 d-环丝氨酸增强这种功效的有价值的信息。