NK1 receptor antagonism for treatment of alcohol-dependent patients

酒精依赖与焦虑症高度共病。喝酒的冲动与随之而来的自我报告的焦虑程度密切相关。在应激反应中，杏仁核释放P物质，作用于神经激肽1 （NK1）受体，介导应激的焦虑效应。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NK1零突变动物中获得的初步数据显示自愿饮酒减少。

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.