This revised application proposes to conduct a randomized, double blind, placebo-controlled combined laboratory and clinical outcome study to test the efficacy of Prazosin (PZ) in decreasing alcohol craving, anxiety, stress dysregulation and alcohol use outcomes in treatment seeking alcohol dependent (AD) individuals with and without current anxiety disorders (+Anx/-Anx). In previous research we've shown that laboratory exposure to stress and alcohol cues increases alcohol craving, anxiety and stress dysregulation, which in turn, are predictive of subsequent alcohol relapse outcomes. Prazosin, an alpha-1 adrenergic antagonist, known to decrease central norepinephrine and CRF upregulation, decreases stress-induced alcohol reinstatement and alcohol consumption in both dependent rats and in a preliminary study with alcoholic patients. However, the specific mechanisms by which PZ may be decreasing alcohol consumption in humans is not understood. Our preliminary data show that PZ relative to Placebo (PL) decreases stress and cue- induced alcohol craving, anxiety and stress dysregulation in AD individuals, and that such decreases are more pronounced in AD individuals with current anxiety disorders than those without such comorbidity. Thus, in light of previous research and our preliminary findings, we propose a 5-year study that will recruit 150 AD individuals (evenly split by those with and without any current anxiety disorders) to participate in a randomized, double blind, placebo-controlled 12-week clinical laboratory and outcome study. The following specific aims will be addressed: 1) To evaluate the effects of PZ (16 mg, tid) on stress and cue-induced alcohol craving and anxiety, stress dysregulation in the laboratory in AD patients with and without current anxiety disorders; (2)To evaluate the effects of 16mg PZ on alcohol craving, anxiety and stress dysregulation in AD patients with current anxiety disorders as compared to those without anxiety disorders; (3) To determine the efficacy of 12- week PZ treatment on primary alcohol use outcomes, and secondary outcomes including alcohol craving, negative mood symptoms, smoking and sleep; (4) To assess the efficacy of 12-week PZ versus PL treatment on primary alcohol use and secondary outcomes in alcoholics with/without any current anxiety disorders. (5) To examine one-month post-treatment follow-up alcohol use outcomes for enduring short term treatment effects. The role of patient characteristics and laboratory-based craving and stress dysregulation in predicting alcohol treatment outcome will also be explored. If the proposed hypotheses are supported, it will provide evidence for efficacy of Prazosin as a medication for alcoholism, particularly for those with co-morbid anxiety disorders.

Public Health Relevance

Alcoholism is among the top three causes of preventable death and disease in the US (Mokdad et al., 2004; Room et al., 2005) and stress and anxiety disorders play a role in high alcohol relapse risk. The proposed study will test the efficacy of Prazosin, an alpha-1 adrenergic antagonist, versus placebo, in decreasing provoked alcohol craving, normalizing stress dysregulation and reducing alcohol use outcomes in alcoholics with and without anxiety disorders. Findings will have significant implications for developing new treatments for alcoholism, particularly among those with co-morbid anxiety disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA020504-04
Application #
8901730
Study Section
Neuroscience Review Subcommittee (AA)
Program Officer
Falk, Daniel
Project Start
2012-09-01
Project End
2016-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
Zhao, Xiaomei; Wu, Yihong; Song, Guidong et al. (2018) A deep learning model integrating FCNNs and CRFs for brain tumor segmentation. Med Image Anal 43:98-111
Zheng, Qiang; Wu, Yihong; Fan, Yong (2018) Integrating Semi-supervised and Supervised Learning Methods for Label Fusion in Multi-Atlas Based Image Segmentation. Front Neuroinform 12:69
Zhang, Maolei; Zhao, Kun; Xu, Xiaoping et al. (2018) A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun 9:4475
Milivojevic, Verica; Sinha, Rajita (2018) Central and Peripheral Biomarkers of Stress Response for Addiction Risk and Relapse Vulnerability. Trends Mol Med 24:173-186
Goldfarb, Elizabeth V; Sinha, Rajita (2018) Drug-Induced Glucocorticoids and Memory for Substance Use. Trends Neurosci 41:853-868
Blaine, Sara K; Seo, Dongju; Sinha, Rajita (2017) Peripheral and prefrontal stress system markers and risk of relapse in alcoholism. Addict Biol 22:468-478
Tang, Zhenyu; Wu, Yihong; Fan, Yong (2017) Groupwise registration of MR brain images with tumors. Phys Med Biol 62:6853-6868
Milivojevic, Verica; Ansell, Emily; Simpson, Christine et al. (2017) Peripheral Immune System Adaptations and Motivation for Alcohol in Non-Dependent Problem Drinkers. Alcohol Clin Exp Res 41:585-595
Blaine, Sara K; Sinha, Rajita (2017) Alcohol, stress, and glucocorticoids: From risk to dependence and relapse in alcohol use disorders. Neuropharmacology 122:136-147
Seo, Dongju; Ahluwalia, Aneesha; Potenza, Marc N et al. (2017) Gender differences in neural correlates of stress-induced anxiety. J Neurosci Res 95:115-125

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