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

短暂有效的谷氨酸能调节在解决饮酒问题中的作用：一项随机对照试验

• 批准号: 10241426
• 负责人: Elias Dakwar
• 金额: $ 70.83万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241426
• 关键词: Abstinence; Address; Affinity; Alcohol abuse; Alcohol consumption; Alcohol dependence; Anesthetics; Awareness; Behavior Therapy; Behavioral; Biological; Brain-Derived Neurotrophic Factor; Clinical; Clinical Trials; Cocaine; Cocaine Users; Cues; Data; Dopamine; Double-Blind Method; Dropout; Drug usage; Effectiveness; Evaluation; Future; Glutamates; Goals; Heavy Drinking; Hour; Impairment; Individual; Infusion procedures; Inpatients; Investigation; Ketamine; Lead; Life Style; Medical; Medication Management; Methods; Midazolam; Mindfulness Training; Modeling; Motivation; N-Methyl-D-Aspartate Receptors; Outcome; Participant; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Public Health; Randomized; Randomized Controlled Trials; Regimen; Research; Role; Series; Serum; Signal Transduction; Structure; Substance Use Disorder; Testing; Therapeutic; Time; Visit; Work; active control; alcohol abuse therapy; alcohol intervention; alcohol use disorder; arm; base; cocaine self-administration; craving; design; disorder later incidence prevention; drinking; effective therapy; efficacy trial; eligible participant; expectation; experience; improved; mindfulness; motivational enhancement therapy; neuroadaptation; neurotransmission; novel; pilot trial; reduced alcohol use; relating to nervous system; risk minimization; substance user; therapy development; treatment response; week trial

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. !

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标 酒精使用障碍（AUD）。氯胺酮的初步研究，氯胺酮是一种有效的谷氨酸调节剂 前额叶效应，建议亚动理输注可能有助于通过 解决包括AUD在内的各种药物使用障碍的关键漏洞。扩展 初步研究表明，氯胺酮合并后减少了大量饮酒天数（HDD） 通过动机增强疗法（MET），这项为期12周的试验旨在检测比例差异 与我们先前的数据一致（n = 120），旨在评估氯胺酮是否促进了HDD的减少 相对于主动控制（咪达唑仑）。我们将随机分组（1：1）120名参与者寻求AUD治疗 并显示出高基线问题饮用至2种氯胺酮或咪达唑仑2的输注 几周（0.71 mg/kg氯胺酮或0.025 m/kg咪达唑仑在52分钟内）。此外，为了更严格 评估行为治疗对氯胺酮疗效的影响，我们将采用两个阶乘 （2x2）设计，每个药物臂中的参与者随机分配（1：1） 管理，或者是动手增强疗法（MET）的手动序列 基于正念的预防复发（MBRP）。预计MBRP将促进预防复发 个人在MET期间减少了使用或戒酒。我们预测，与对照相比 氯胺酮将大大减少HDD患者的比例。重要的次要 假设是那些接受氯胺酮和行为治疗的人将表现出明显更好 结果比仅接受氯胺酮的人。其他目的与氯胺酮对数量的影响有关 每日饮料和饮酒天数；氯胺酮准时到达HDD或辍学的影响；和 当氯胺酮与MET/MBRP结合时，评估增加有效性。如果成功，这个项目 对AUD的治疗做出了重大贡献，新的药物治疗策略是 需要。未来的研究可能会使用此处介绍的设计测试其他药物，并关注 阐明氯胺酮解决AUD的机制。 呢