NK1 receptor antagonism for treatment of alcohol-dependent patients

酒精依赖与焦虑症高度并存。饮酒的冲动与伴随而来的自我报告的焦虑程度密切相关。P物质在杏仁核对压力的反应中释放，作用于神经激肽1(NK1)受体，介导应激引起的焦虑效应。阻断NK1受体亚型代表了一种减少应激诱导的负面影响的新方法。从NK1零突变动物身上获得的初步数据显示，自愿饮酒的人数减少了。 这项研究对50名被诊断为酒精依赖的住院患者进行了焦虑(由斯皮尔伯格特质焦虑评分39定义)。使用了一周的安慰剂导入期。在此期间，进行了基线的非药物酒精线索反应会议，以排除安慰剂应答者和没有报告对酒精线索做出反应的渴望的受试者。在基线治疗过程中有治愈反应的受试者被随机分成双盲研究，参与者接受50毫克的NK1拮抗剂或安慰剂。积极治疗的持续时间约为3周。用于测试药物疗效的结果变量包括：1)焦虑和渴望的评分表；2)对临床上出现的酒精提示的反应，以及fMRI扫描仪中酒精和非酒精饮料图像与阳性或阴性IAPS图像的配对；以及3)对心理(Trier测试)和生理应激源(美托拉酮测试)的反应。 这项研究已经完成，分析表明，一些措施可以预测临床疗效。基于这项研究结果的手稿已发表在《科学》杂志上。

Alcohol dependence is highly co-morbid with anxiety disorders. Urges to drink are closely correlated with concomitant levels of self-reported anxiety. Substance P, released in the amygdala in response to stress, acts at neurokinin 1 (NK1) receptors to mediate the anxiogenic effects of stress. Blockade of the NK1 receptor subtype represents a novel approach to reduce stress-induced negative affect. Preliminary data obtained from NK1 null-mutant animals shows a decrease in voluntary intake of alcohol. The study was carried out in 50 anxious (defined by a Spielberger Trait Anxiety Score of >39) inpatients with a diagnosis of alcohol dependence. A one week placebo lead-in was used. During this time, a baseline, unmedicated alcohol cue reactivity session was carried out to exclude placebo responders and subjects who did not report craving in response to the alcohol cue. Subjects who were cure-reactive on the baseline session were randomized into the double-blind study, in which participants received either 50 mg of an NK1 antagonist or placebo. The duration of active treatment was approximately 3 weeks. Outcome variables designed to test drug efficacy included: 1) rating scales for anxiety and craving; 2) response to alcohol cues presented in the clinic as well as alcohol and non-alcohol containing beverage images paired with positive or negative IAPS images in the fMRI scanner; and 3) response to psychological (Trier Test) and physiological stressors (Metyrapone Tests). This study has been completed and analyses show that a number of the measures are predictive of clinical efficacy. A manuscript based on the findings of the study has been published in Science.