GABAB receptor ligands for the treatment of alcohol use disorder: preclinical and clinical evidence.

The present paper summarizes the preclinical and clinical studies conducted to define the "anti-alcohol" pharmacological profile of the prototypic GABAB receptor agonist, baclofen, and its therapeutic potential for treatment of alcohol use disorder (AUD). Numerous studies have reported baclofen-induced suppression of alcohol drinking (including relapse- and binge-like drinking) and alcohol reinforcing, motivational, stimulating, and rewarding properties in rodents and monkeys. The majority of clinical surveys conducted to date-including case reports, retrospective chart reviews, and randomized placebo-controlled studies-suggest the ability of baclofen to suppress alcohol consumption, craving for alcohol, and alcohol withdrawal symptomatology in alcohol-dependent patients. The recent identification of a positive allosteric modulatory binding site, together with the synthesis of in vivo effective ligands, represents a novel, and likely more favorable, option for pharmacological manipulations of the GABAB receptor. Accordingly, data collected to date suggest that positive allosteric modulators of the GABAB receptor reproduce several "anti-alcohol" effects of baclofen and display a higher therapeutic index (with larger separation-in terms of doses-between "anti-alcohol" effects and sedation)

Non-specialist health workers to treat excessive alcohol consumption and depression

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Use of pharmacological treatments by a sample of Italian patients affected by alcohol use disorders

Title: USE OF PHARMACOLOGICAL TREATMENTS BY A SAMPLE OF ITALIAN PATIENTS AFFECTED BY ALCOHOL USE DISORDERS Author name(s): R. Agabio; E.M. Diana; D. Grazzini; R. Pirastu; G.L. Gessa Institution: Department of Biochemical Sciences, Section of Neuroscience, Preclinical and Clinical Pharmacology, University of Cagliari, Italy Text Background: It has often been reported that the majority of patients affected by Alcohol Use Disorders (AUDs) do not receive any pharmacological treatment. This study was aimed at investigating the use of the medications available in Italy (disulfiram, naltrexone, acamprosate, and γ-hydroxybutyric acid) by a sample of outpatients affected by AUDs. Methods: Four trained psychologists interviewed outpatients affected by AUDs in an area of Sardinia, Italy, of approximately 550.000 adult inhabitants. Results: A total sample of 208 outpatients affected by AUDs was interviewed (~1/3 of total outpatients affected by AUDs of that area). Their main features were: 166 males (79.5%); mean age=48.6±0.6 year; duration of AUDs=15.8±0.7 years; number of drinks per drinking days=19.4±1.3; number of criteria of DSM-IV-Tr=5.8±0.1. Before the admission into specific services, 13 patients (6.2%) had already received medication for AUDs; 7 patients (3.4%) had received disulfiram and 6 patients (2.9%) γ-hydroxybutyric acid. Over the same period, 22 patients (10.6%) had already attended self-help groups and 4 patients (1.9%) had received thiamine (Vitamine B1). After the admission into specific medical settings for the treatment of AUDs, 113 patients (54.3%) received medication for AUDs: 58 patients (27.9%) received disulfiram, 65 patients (31.2%) γ-hydroxybutyric acid, 2 patients (1.0%) naltrexone, and 6 patients (2.9%) acamprosate. In the same period, 54 patients (26.0%) frequented self-help associations, and 21 patients (10.1%) received thiamine. Conclusions: The results of this study confirm that the number of patients who receive a treatment for AUDs continues to be surprisingly low. Despite the long duration and the high level of severity of the AUDs, the majority of patients affected by AUDs did not receive any treatment before their admission in specific medical settings for the treatment of AUDs (10% of patients frequented self-help groups, 6% received a medication for AUDs, and 2% thiamine). After the admission into specific medical settings, the number of patients who received a treatment increased: 26% frequented self-help associations, 54% received a specific medication, and 10% received thiamine. However, approximately half of the patients did not receive any pharmacological treatment even if they frequented medical settings for the treatment of AUDs. Additional work is needed to understand the reasons of such a scarce use of treatments. Acknowledgements: This study was supported by a grant from Regione Autonoma della Sardegna

A systematic review of school-based alcohol and other drug prevention programs

Background: Alcohol use in adolescents constitutes a major public health concern. Europe is the heaviest drinking region of the world. Several school-based alcohol prevention programs have been developed but it is not clear whether they are really effective. The present study was aimed at identifying the typology with the best evidence of effectiveness in European studies. Methods: A systematic search of meta-analyses and/or randomized controlled trials (RCTs) on interventions school-based prevention programs aimed at preventing alcohol consumption or changing the attitudes to consume alcohol. Results: A meta-analysis published in 2011 and 12 RCTs more recently published were identified. The meta-analysis evaluated 53 RCTs but only 11.3% of them were conducted in Europe. Globally, 23 RCTs (43.4%) showed some evidence of effectiveness, and 30 RCTs (56.6%) did not find significant difference between the groups. According to the conclusions of the meta-analysis, the Unplugged program should be considered as a practice option in Europe. Among the other 12 RCTs, 42% were conducted in Europe. Globally, 7 studies (58.3%) achieved positive results, and 5 studies (41.7%) did not find significant differences or produced a mixed pattern of results. Three of the 5 European trials (60%) used the Unplugged program with positive results. Conclusion: Even if further studies should be conducted to confirm these results, Unplugged appears to be the prevention project with the best evidence of effectiveness in European studies

Gender Differences among Sardinians with Alcohol Use Disorder

Sardinia is an Italian island in the Mediterranean characterized by secular isolation and the singular genetic characteristics of its inhabitants. Findings obtained in populations with diverse genetic make-up and cultural background indicate gender differences and/or similarities in drinking characteristics of patients with alcohol use disorder (AUD). Knowledge of these characteristics in AUD patients is useful to improve access to treatments. This paper investigated the drinking characteristics of 66 female and 282 male outpatients with AUD, born from 1937 to 1991, living in Sardinia, and compared their characteristics with those of AUD patients living in other countries. Most Sardinian patients were men, approximately 3 years younger than women; women consumed lower amounts of alcohol than men but did not differ from men in the severity of AUD. Men were more often single than women, while a higher proportion of women reported that their mother or spouse was affected by AUD. Anxiety and depression were more prevalent among women while a higher proportion of men were affected by substance use disorders. Women were older than men at the age of first drink, regular drinking, and onset of AUD, and progressed faster than men from regular use to AUD onset. Women did not differ from men in age at first request for care, and in the lapse from AUD onset to first request for care. Women and men waited for more than 8 and 9 years, respectively, before receiving medical treatment. Gender differences progressively decreased among younger patients. Although the scarce number of women in some cohorts limits the strength of these findings, drinking characteristics of Sardinian patients did not vary significantly from those of AUD patients living in other countries. These results suggest that the number of Sardinian women with AUD is increasing and services for treatment of AUD should (a) consider women’s specific needs, and (b) realize effective policies to reduce latency prior to accessing medical treatment for both men and women with AUD

Alcohol-related behaviour in freshmen university students in Sardinia, Italy

This study aims to provide a picture of University of Cagliari students’ alcohol-related behaviour and to explore factors associated with it. Data were collected by administering a questionnaire to 992 freshmen university students from different programs consisting of twelve closed questions, including three questions from the Alcohol Use Disorders Identification Test for Consumption (AUDIT-C short form). Three subgroups of alcohol-related behaviour were distinguished (risky drinkers, social drinkers and abstainers). In order to explore factors associated with patterns of alcohol consumption, a multivariate logistic regression was performed. The prevalence of risky drinkers was 35%. A binge-drinking behaviour at least once in the last twelve months was declared by 65% (more widespread in men and in students living away from their parents). Risky consumption is significantly associated with age of onset of alcohol use, living away from parents’ home, drinking outside meals and attending health courses. Regarding the levels of daily alcohol consumption perceived as a health risk, 66% of men and 88% of women indicate values higher than those recommended. The results underline the need for tailored prevention measures. University could be a promising setting to implement actions according to a health promotion perspective, to empower students to control their alcohol consumption

A DNA methylation biomarker of alcohol consumption.

The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42-76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90-0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10-7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.Medical Research Council (Grant IDs: MC_UU_12015/1, MC_UU_12015/2), Wellcome Trust. Detailed acknowledgements are included in the Supplementary Information that accompanies the paper on the Molecular Psychiatry website