Cognitive Remediation with D-cycloserine to Improve Smoking Cessation Outcomes

描述（由申请人提供）：五分之一的美国人吸烟。每年，美国有超过44万人、全世界有500万人死于与吸烟有关的疾病，而且全球死亡人数还在上升。药物治疗戒烟具有很高的成本效益，但复发率很高，只有不到20%的戒烟尝试成功。在完成戒烟治疗后，最近戒烟的吸烟者面临反复的环境提示，往往会引发复发。线索暴露疗法旨在减少对这些线索的渴望，但迄今为止，这些策略的效果有限。现在，一种新的策略可以加强提示暴露方法的有效性。基础研究已经确定了d-环丝氨酸（DCS）， NMDA受体的部分激动剂，作为一种能够增强灭绝学习的药物。在动物模型上取得成功后，DCS首次应用于增强消退学习以治疗恐高症。正在进行的研究进一步支持了单剂量DCS应用的有效性，以增强基于暴露的治疗在焦虑障碍中的疗效，可能是通过增强成功暴露会话的记忆。在药物成瘾的线索暴露模型中，也有类似的基于灭绝的学习分割的令人鼓舞的证据。在这个应用中，我们建议研究DCS增强提示暴露作为戒烟复发预防策略的应用。具体而言，我们建议在一项随机、双盲、安慰剂对照、平行组设计试验中评估两次单剂量DCS联合线索暴露治疗（CET）间隔一周的效果。本治疗将作为一种预防复发的策略，提供给在完成我们中心提供的标准开放标签7周戒烟治疗后戒烟的吸烟者。结果将是在第二次CET后2天进行的消退后评估中线索反应性和渴望的急性变化，并在6周的随访期间维持戒断。因此，提出的研究有可能支持一种新的认知修复策略，以增强提示暴露治疗对维持戒烟的功效。

DESCRIPTION (provided by applicant): One in five Americans smoke tobacco. Each year over 440,000 people in the US and 5 million worldwide die from smoking-related illness, and the global mortality toll is rising. Pharmacotherapy for smoking cessation is highly cost effective, but relapse rates are high, and fewer than 20% who attempt cessation are successful on a given attempt. After completion of smoking cessation treatment, recently abstinent smokers face repeated environmental cues that often trigger relapse. Cue exposure therapies are directed at reducing cravings in response to such cues, but these strategies have had only limited efficacy to date. Now, a novel strategy for strengthening the efficacy of cue exposure approaches is at hand. Basic research has identified d-cycloserine (DCS), a partial agonist of the NMDA receptor, as an agent capable of enhancing extinction learning. Following success in animal models, DCS was first applied to the enhancement of extinction learning for the treatment of acrophobia. Ongoing study has further supported the efficacy of single-dose applications of DCS to enhance the efficacy of exposure based treatments across the anxiety disorders, presumably by enhancing the memory of successful exposure sessions. There is also encouraging evidence for the similar segmentation of extinction based learning in cue exposure models of drug addiction. In this application, we propose to study DCS enhancement for cue exposure as applied as a relapse prevention strategy for smoking cessation. Specifically, we propose to assess the effects of two sessions of single dose DCS combined with cue-exposure treatment (CET) conducted one week apart in a randomized, double-blind, placebo-controlled, parallel group design trial. This treatment will be offered as a relapse-prevention strategy for smokers who are abstinent upon completing a standard open label 7-week smoking cessation treatment offered in our center. Outcomes will be acute changes in cue-reactivity and craving at a Post-Extinction Assessment conducted 2 days after the second CET session and maintenance of abstinence over a 6-week follow-up period. Accordingly, the proposed study has the potential of supporting for a novel cognitive remediation strategy to enhance the efficacy of cue exposure treatments for the maintenance of smoking cessation. PUBLIC HEALTH RELEVANCE: Based on successful trials in anxiety disorders and promising early data in addiction, the proposed R21 project aims to discover whether a potential novel strategy to prevent relapse to tobacco smoking is effective, and, in so doing, would advance in our understanding of neurobiological mechanisms of addiction and relapse.