The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study

Abstract

Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress- and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol-dependent patients in early abstinence. Fifty-four anxious alcohol-dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo-controlled study with pexacerfont (300 mg/day for 7 days, followed by 100 mg/day for 23 days). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcohol-related cues, neuroendocrine responses to these stimuli, and functional magnetic resonance imaging (fMRI) responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in cerebrospinal fluid (CSF) that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans.

Trial registration: ClinicalTrials.gov NCT00896038.

Figures

Figure 1

Timeline for procedures and data collection during challenge sessions used to provoke alcohol craving, subjective distress, and neuroendocrine responses used as biomarkers in this experimental medicine study. Upper panel: sessions utilizing guided imagery induced by auditory scripts; lower panel: sessions utilizing a combination of a social stress task and presentation of physical alcohol cues (‘Trier/CR').

Figure 2

Alcohol-craving response to the guided imagery challenge session. (a) Effect of script type on alcohol craving. Covariates in the model included gender, years of education, and the total score from the ASI. The + indicates a significant difference between the 5 min and −15 min points (Tukey, p<0.05), whereas the * indicates a significant difference from the neutral script for both the alcohol and stress scripts (Tukey, p<0.05) at the 5-min time point. The sample size for this analysis was reduced due to missing data from the ASI for some of the subjects. (b) Effect of pexacerfont treatment on craving response to the stress script. Gender was a covariate in the model. (c) Effect of pexacerfont treatment on craving response to the alcohol cue script. Gender was a covariate in the model.

Figure 3

Subjective stress response to the guided imagery challenge session. (a) Effect of script type on subjective stress. Covariates in the model included gender, ADS score, and the total score from the ASI. The + indicates a significant difference between the 5 min and −15 min points (Tukey, p<0.05), whereas the * indicates a significant difference from the neutral script for both the alcohol and stress scripts (Tukey, p<0.05) at the 5-min time point. (b) Effect of pexacerfont treatment on subjective stress to the stress script. Covariates in the model included gender, ADS score, and the total score from the ASI. (c) Effect of pexacerfont treatment on subjective stress to the alcohol cue script. Covariates in the model included gender, ADS score, and the total score from the ASI.

Figure 4

(a) Effect of pexacerfont treatment on craving response to the Trier/CR. Gender was a covariate in the model. The + indicates a significant difference between the 40 min and −15 min time points (Tukey p<0.05). (b) Effect of pexacerfont treatment on subjective stress to the Trier/CR. Covariates in the model included gender, neuroticism, and the total score from the ASI. The + indicates a significant difference between the 20 min and −15 min time points (Tukey p<0.05). The sample sizes for the analyses of subjective stress were reduced due to missing data from the ASI for some of the subjects. (c) Effect of pexacerfont treatment on cortisol response to the Trier/CR. Covariates in the model included gender, race, and number of heavy drinking days from the TLFB. The + indicates a significant difference between the 20 min and −15 min time points (Tukey p<0.05). (d) Effect of pexacerfont treatment on ACTH response to the Trier/CR. Covariates in the model included gender, race, ADS score, and family history density from the FTQ. The + indicates a significant difference between the 20 min and −15 min time points (Tukey p<0.05).

Figure 5

Linear contrast of fMRI BOLD responses to fearful vs neutral faces. (a) In the placebo group, there was a predicted activation to fearful faces within the right amygdala (circled in red) (p<0.015, uncorrected). (b) A comparison between the pexacerfont and the placebo group did not reveal significant differences in activation of the amygdala or other brain regions.