NK1 receptor antagonism for treatment of alcohol-dependent patients

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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 is currently being prepared for publication.