CRF1 Antagonist GSK561679 in Alcoholism

Objective: To evaluate GSK561679, an orally available, brain penetrant selective CRH1 antagonist for its ability to reduce alcohol craving in recently detoxified alcohol dependent women in response to stress or alcohol-associated stimuli. Study population: Up to 60 anxious, alcohol dependent women, aged 21-65 years will be enrolled to complete the study in 50 patients. Design: Subjects will be inpatients and enter the present protocol once withdrawal treatment, if needed, is completed. One week of single blind placebo will be followed by randomized double blind treatment with active medication or placebo for approximately 3 weeks. Spontaneous craving for alcohol and ratings of psychopathology will be obtained twice weekly throughout the study. During the placebo lead-in week, a diurnal cortisol curve will be obtained, and a baseline dexamethasone-CRH test may be carried out. These measures will be repeated after 10-14 days of randomized treatment. Around this time, craving responses will also be assessed in a challenge session that combines a social stressor and exposure to physical alcohol cues. During the final week, three sessions of guided imagery will be carried out, on separate days and in a counter-balanced order, exposing the subject to personalized stress-, alcohol- or neutral condition associated stimuli. An fMRI session will be carried out last. Subjects will remain hospitalized throughout the study, and will remain on the unit for a 3 day post-medication monitoring period. Outcome measures: The primary outcome will be craving for alcohol on guided imagery challenge sessions. Secondary outcomes will include craving as measured in the combined social stress alcohol cue challenge session, spontaneous craving and psychopathology ratings repeatedly measured on the inpatient unit over time. Exploratory blood biomarkers and brain responses to positive and negative affective stimuli on the fMRI session will also be obtained.