The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects - PubMed (original) (raw)

Randomized Controlled Trial

. 2016 Nov;41(12):2818-2829.

doi: 10.1038/npp.2016.61. Epub 2016 Apr 25.

Affiliations

Randomized Controlled Trial

The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects

Melanie L Schwandt et al. Neuropsychopharmacology. 2016 Nov.

Abstract

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.

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Figures

Figure 1

Figure 1

(a) CONSORT graph for the clinical study. (b) 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 using a combination of a social stress task and presentation of physical alcohol cues (Trier Social Stress/cue-reactivity test ‘Trier/CR'). Lower panel: sessions using guided imagery induced by auditory scripts.

Figure 2

Figure 2

(a) Inhibition of plasma adrenocorticotropic hormone (ACTH) in adrenalectomized rats following a single dose of corticotropin-releasing factor receptor 1 (CRF1) antagonists with slow (NBI-30775, verucerfont) but not fast (CP-316,311, pexacerfont) receptor dissociation rates. Adrenalectomized rats were administered vehicle or the respective antagonist immediately after a baseline sample (_t_=0) was obtained, and plasma ACTH was sampled over the following 6 h. Data points for the different drugs at each time-point have been jittered by±5 min to allow visual separation, and represent covariate adjusted means±S.E.M., with baseline as covariate (_n_=6–7). Non-adjusted baseline means were in the range 820–1215 pg/ml. NBI-30775 and verucerfont suppressed (P<0.01) ACTH at each time-point, both compared with the corresponding time-point for vehicle, and compared with their respective baseline. For detailed statistics, see Results. Blockade of (b) cortisol and (c) ACTH responses to dexamethasone/CRF challenge by verucerfont (_n_=11) but not placebo (_n_=18) in the clinical study. Data points represent mean±S.E.M. Covariates in the model included neuroticism and the total score from the Addiction Severity Index (ASI) for cortisol, and race, neuroticism, and total score from the ASI for ACTH. For detailed statistics, see Results.

Figure 3

Figure 3

Alcohol craving responses to the guided imagery challenge session. (a) Effect of script type on alcohol craving. Data are mean±S.E.M.; _n_=35. Covariates in the model included age, neuroticism score from the NEO, and lifetime diagnosis of post-traumatic stress disorder (PTSD). The ‘+' indicates a significant difference between the 5 min and −15 min time points (Tukey's, P<0.05) for both the alcohol and stress scripts. (b) Effect of verucerfont on craving response to the stress script (verucerfont: _n_=14; placebo: _n_=21). Data points represent mean±S.E.M. Covariates in the model included race, neuroticism score, and total score from the Addiction Severity Index (ASI). (c) Effect of verucerfont on craving response to the alcohol cue script (verucerfont: _n_=14; placebo: _n_=21). Data points represent mean±S.E.M. Covariates in the model included race, average number of drinks per drinking day from the Timeline Follow-Back (TLFB), neuroticism score, and total score from the ASI. For detailed statistics, see Results.

Figure 4

Figure 4

Anxiety response to the guided imagery challenge session. (a) Effect of script type on anxiety. Data points represent mean±S.E.M. Covariates in the model included age, race, years of education, neuroticism, total score on the Addiction Severity Index (ASI), and the trait anxiety score from the Spielberger State Trait Anxiety Inventory-Trait (STAI-Trait) version. One subject was missing the STAI-Trait version score, thus the sample size was reduced to 34 for this analysis. The ‘+' indicates a significant difference between the 5 min and −15 min time points (Tukey's, P<0.05) during the stress script. (b) Effect of verucerfont on anxiety during the stress script (verucerfont: _n_=14; placebo: _n_=21). Data points represent mean±S.E.M. Covariates in the model included age, years of education, Alcohol Dependence Scale (ADS) score, and neuroticism. (c) Effect of verucerfont on anxiety during the alcohol cue script (verucerfont: _n_=14; placebo: _n_=21). Data points represent mean±S.E.M. Age was a covariate in the model. For detailed statistics, see Results.

Figure 5

Figure 5

(a) Effect of verucerfont treatment on craving response to the Trier Social Stress/cue-reactivity test (Trier/CR) (verucerfont: _n_=16; placebo: _n_=21). Data points represent mean±S.E.M. Covariates in the model included race, average number of drinks per drinking day, and the total score from the Addiction Severity Index (ASI). The ‘+' indicates a significant difference between the 40 and −15 min time points (Tukey's P<0.05). The sample sizes for the analyses of craving were reduced owing to missing data from the ASI for one subject, and missing data for race from another subject. (b) Effect of verucerfont treatment on anxiety during the Trier/CR (verucerfont: _n_=18; placebo: _n_=21). Data points represent mean±S.E.M. Covariates in the model included age and neuroticism. The ‘+' indicates an overall significant difference between the 20 and −15 min time points (Tukey's P<0.05); subjects receiving verucerfont showed higher anxiety overall compared with subjects receiving placebo. (c) Effect of verucerfont treatment on cortisol response to the Trier/CR (verucerfont: _n_=15; placebo: _n_=20). Data points represent mean±S.E.M. Covariates in the model included age, race, and total score from the ASI. The ‘+' indicates a significant difference from −15 min time point at both 40 and 50 min (Tukey's P<0.05). (d) Effect of verucerfont treatment on adrenocorticotropic hormone (ACTH) response to the Trier/CR (verucerfont: _n_=17; placebo: _n_=20). Data points represent mean±S.E.M. Covariates in the model included age and total score from the Childhood Trauma Questionnaire (CTQ). The ‘+' indicates a significant difference between the 20 min and −15 min time points (Tukey's P<0.05). For detailed statistics, see Results.

Figure 6

Figure 6

Functional magnetic resonance imaging blood oxygen level-dependent (fMRI BOLD) responses to fearful faces. Upper row: Right amygdala (within green oval) showed the predicted activation in the placebo group (placebo; _n_=20). Middle row: The corresponding activation in the verucerfont group was attenuated (verucerfont; _n_=13). Lower row: On direct comparison, there was a reduction in the verucerfont group, which exceeded the threshold for whole-brain corrected significance (_P_=0.03 family-wise error (FWE)-corrected, 91 voxel cluster size). The whole-brain analysis model included the following covariates: race, ADS (Alcohol Dependence Scale); and CTQ (Childhood Trauma Questionnaire) scores.

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References

    1. Asberg M, Schalling D (1979). Construction of a new psychiatric rating instrument, the Comprehensive Psychopathological Rating Scale (CPRS). Progr Neuro-Psychopharmacol 3: 405–412. - PubMed
    1. Bernstein DP, Fink L, Handelsman L, Foote J, Lovejoy M, Wenzel K et al (1994). Initial reliability and validity of a new retrospective measure of child abuse and neglect. Am J Psychiatry 151: 1132–1136. - PubMed
    1. Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T (2008). A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry 165: 617–620. - PubMed
    1. Bohn MJ, Krahn DD, Staehler BA (1995). Development and initial validation of a measure of drinking urges in abstinent alcoholics. Alcohol Clin Exp Res 19: 600–606. - PubMed
    1. Brandon TH, Vidrine JI, Litvin EB (2007). Relapse and relapse prevention. Annu Rev Clin Psychol 3: 257–284. - PubMed

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