The role of brief potent glutamatergic modulation in addressing problem drinking: a randomized, controlled trial

项目摘要： 谷氨酸神经传递的改变被认为是药物治疗的重要靶点， 酒精使用障碍（AUD）氯胺酮的初步研究，氯胺酮是一种谷氨酸调节剂， 前额叶效应，表明亚麻醉剂输注可能有助于行为改变， 解决包括AUD在内的各种物质使用障碍的关键脆弱性。扩展到A 初步研究表明，氯胺酮联合使用可减少重度饮酒天数（HDD） 动机增强疗法（MET），这项为期12周的试验有能力检测比例差异 与我们之前的数据（n=120）一致，旨在评估氯胺酮是否促进HDD的减少 相对于活性对照（咪达唑仑）。我们将随机（1：1）120名寻求AUD治疗的受试者 并且显示高基线问题饮酒至2次氯胺酮或咪达唑仑输注，间隔5次 周（0.71 mg/kg氯胺酮或0.025 m/kg咪达唑仑，持续52 min）。此外，为了更严格地 为了评估行为治疗对氯胺酮疗效的影响，我们将采用一个二乘二的析因 (2x2)设计，每个药物组的参与者随机（1：1）接受标准药物治疗 管理，或动机增强治疗（MET）的手动序列，然后 正念复发预防（MBRP）预计MBRP将有助于预防复发后， 个人在MET期间减少使用或开始禁欲。我们预测，与对照组相比， 咪达唑仑、氯胺酮将显著降低患有HDD的个体比例。重要的二次 一种假设是，那些接受氯胺酮和行为治疗的人会表现得更好， 结果比单独接受氯胺酮的人要好。其他目的涉及氯胺酮对数量的影响 每日饮酒量和饮酒天数;氯胺酮对首次HDD或脱落时间的影响;以及 评价氯胺酮与MET/MBRP联合使用时的额外有效性。如果成功，这个项目 将对AUD的治疗做出重大贡献，新的药物治疗策略 needed.未来的研究可能会使用这里介绍的设计测试其他药物，以及关注 阐明氯胺酮治疗AUD的机制。 !

Project Summary: Alterations in glutamate neurotransmission are recognized as an important target of pharmacotherapy for alcohol use disorder (AUD). Preliminary investigations with ketamine, a glutamate modulator with potent prefrontal effects, suggest sub-anesthetic infusions may work to facilitate behavioral modification by addressing critical vulnerabilities for a variety of substance use disorders, including AUD. Expanding on a preliminary study suggesting that ketamine reduces number of heavy drinking days (HDD) when combined with motivational enhancement therapy (MET), this 12-week trial powered to detect proportional differences consistent with our prior data (n=120) aims to evaluate whether ketamine promotes a reduction in HDDs relative to an active control (midazolam). We will randomize (1:1) 120 participants seeking treatment for AUD and demonstrating high baseline problem drinking to 2 infusions of ketamine or midazolam separated by 5 weeks (0.71 mg/kg ketamine or 0.025 m/kg midazolam over 52 min). Further, in order to more rigorously assess the impact of behavioral treatment on the efficacy of ketamine, we will employ a two by two factorial (2x2) design, with participants in each medication arm randomized (1:1) either to standard medication management, or to a manualized sequence of motivational enhancement therapy (MET) followed by mindfulness-based relapse prevention (MBRP). MBRP is expected to facilitate relapse prevention after individuals have reduced use or initiated abstinence during MET. We predict that, compared to the control midazolam, ketamine will significantly reduce the proportion of individuals with HDDs. An important secondary hypothesis is that those receiving ketamine and behavioral treatment will demonstrate significantly better outcomes than individuals receiving ketamine alone. Other aims pertain to the effects of ketamine on number of daily drinks, and number of drinking days; the impact of ketamine on time to first HDD or drop-out; and the evaluation of added effectiveness when ketamine is combined with MET/MBRP. If successful, this project stands to contribute significantly to the treatment of AUD, for which new pharmacotherapy strategies are needed. Future studies might test other medications using the design introduced here, as well as focus on clarifying the mechanisms by which ketamine addresses AUD. !