The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects.
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.
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
Melanie L
ML
Schwandt
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.|Center for Social and Affective Neuroscience, Linköping University, Linköping, Sweden.
Carlos R
CR
Cortes
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
Laura E
LE
Kwako
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
David T
DT
George
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
Reza
0000-0002-7624-9676
R
Momenan
The Yale Stress Center, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
Rajita
R
Sinha
Neurocrine Biosciences, San Diego, CA, USA.
Dimitri E
DE
Grigoriadis
Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
Emilio Merlo
EM
Pich
Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
Lorenzo
L
Leggio
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.|Center for Social and Affective Neuroscience, Linköping University, Linköping, Sweden.
Markus
M
Heilig
D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000328:Adult; D000368:Aged; D000437:Alcoholism / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D000818:Animals; D001007:Anxiety / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology; D053961:Azabicyclo Compounds / Q000627:therapeutic use*; D066249:Craving / Q000187:drug effects; D004195:Disease Models, Animal; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007091:Image Processing, Computer-Assisted; D019018:Imagery, Psychotherapy; D008875:Middle Aged; D010069:Oxadiazoles / Q000627:therapeutic use*; D010100:Oxygen / Q000097:blood; D011569:Psychiatric Status Rating Scales; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D016037:Single-Blind Method; D055815:Young Adult; D000099052:CRF Receptor, Type 1
D053961:Azabicyclo Compounds; C556497:NBI 77860; D010069:Oxadiazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D010100:Oxygen; D006854:Hydrocortisone