Risk Factor For Alcohol Dependence Research Articles

Causal effect of physical activity and sedentary behavior on the risk of alcohol dependence: A bidirectional Two-sample Mendelian randomization study

BackgroundAlcohol dependence, influenced by physical activity (PA) and sedentary behavior, lacks clear causal clarity. This study aims to clarify causal relationships by estimating these effects using bidirectional two-sample Mendelian randomization (MR). MethodsA bidirectional multivariable two-sample MR framework was employed to assess the causal effects of PA and sedentary behavior on alcohol dependence. Summarized genetic association data were analyzed for four PA-related activity patterns—moderate to vigorous physical activity (MVPA), vigorous physical activity (VPA), accelerometer-based physical activity with average acceleration (AccAve), and accelerometer-based physical activity with accelerations greater than 425 milli-gravities (Acc425)—and three sedentary behavior patterns—sedentary, TV watching, and computer use. The study was expanded to include the examination of the relationship between sedentary behavior or PA and general drinking behavior, quantified as drinks per week (DPW). We obtained summarized data on genetic associations with four PA related activity patterns (MVPA, VPA, AccAve and Acc425) and three sedentary behavior related behavior patterns (sedentary, TV watching and computer use). ResultsMR analysis found AccAve inversely associated with alcohol dependence risk (OR: 0.87; 95% CI: 0.80–0.95; p < 0.001), MVPA positively associated (OR: 2.86; 95%CI: 1.45-5.66; p = 0.002). For sedentary behavior and alcohol dependence, only TV watching was positively associated with the risk of alcohol dependence (OR: 1.43; 95%CI: 1.09-1.88; p = 0.009). No causal links found for other physical or sedentary activities. Reverse analysis and sensitivity tests showed consistent findings without pleiotropy or heterogeneity. Multivariate MR analyses indicated that while MVPA, AccAve and TV watching are independently associated with alcohol dependence, DPW did not show a significant causal relationship. ConclusionsOur results suggest that AccAve is considered a protective factor against alcohol dependence, while MVPA and TV watching are considered risk factors for alcohol dependence. Conversely, alcohol dependence serves as a protective factor against TV watching. Only TV watching and alcohol dependence might mutually have a significant causal effect on each other.

Evaluation of the Relationship Between Dopamine Receptor D2 Gene TaqIA1 Polymorphism and Alcohol Dependence Risk.

Several studies are published, that investigated dopamine receptor 2 (DRD2) gene TaqIA polymorphism as a risk factor for alcohol dependence (AD) with positive and negative associations. To derive a more precise estimation of the relationship, a meta-analysis of case-control studies that examined the association between DRD2 gene Taq1A polymorphism and alcohol dependence was performed. Eligible articles were identified through a search of databases including PubMed, Science Direct, Springer link, and Google Scholar. The association between the DRD2 TaqIA polymorphism and AD susceptibility was conducted using odds ratios (ORs) and 95% confidence intervals (95% CIs) as association measures. A total of 69 studies with 9125 cases and 9123 healthy controls were included in the current meta-analysis. Results of the present analysis showed significant association between DRD2 TaqIA polymorphism and AD risk using five genetic modes (allele contrast model-OR 1.22, 95% CI 1.13-1.32, p < 0.0001; homozygote model-OR 1.35, 95%CI 1.18-1.55; p ≤ 0.0001; dominant model-OR 1.29; 95% CI 1.20-1.39; p < 0.0001; recessive model-OR 1.21; 95% CI 1.08-1.36; p = 0.0006). There was no significant association found in subgroup analysis, TaqIA polymorphism was not significantly associated with AD risk in the Asian population under all genetic models, but in the Caucasian population, TaqIA polymorphism was significantly associated with AD risk. Overall, results support the hypothesis that DRD2 Taq1A polymorphism plays a role in alcohol dependence.

Incidence of and risk factors for alcohol dependence in bipolar disorder: A population-based cohort and nested case-control study.

Although alcohol dependence is highly prevalent in patients with bipolar disorder, the causal relationship is not yet well-established. This study estimated the incidence of alcohol dependence in a nationwide bipolar disorder cohort and examined risk factors for alcohol dependence. Patients aged 15-65 years with consistent bipolar disorder who had their first psychiatric admission between 1999 and 2012 (n = 21,791) were enrolled from the National Health Insurance Research Database in Taiwan. We calculated the adjusted incidence rate ratio of alcohol dependence in the bipolar cohort relative to the general population after stratification by age and sex. In the nested case-control study, we included patients with incident alcohol dependence as cases and four age- and sex-matched controls for each case to analyze health care utilization, comorbidities and concomitant medications between them. We identified 1261 patients with bipolar disorder with incident alcohol dependence. Relative to the general population, the adjusted incidence rate ratio of alcohol dependence was 9.20 in the bipolar cohort. All adjusted incidence rate ratios were high across all age subgroups. Cases had higher psychiatric and nonpsychiatric health care utilization than did controls. Multivariate analysis revealed that cases tended to have cardiovascular disease, diabetes mellitus, chronic hepatic disease, pneumonia and delirium before alcohol dependence diagnosis. Cases had higher psychiatric comorbidities, namely drug-induced mental disorders, anxiety disorder, personality disorder, adjustment disorder and sleep disorder. The bipolar cohort had a higher incidence of alcohol dependence. We identified specific groups with a high risk of alcohol dependence. Additional strategies for early detection, treatment and intervention for alcohol dependence should be developed.

LRRK2 Gene Variants Associated With a Higher Risk for Alcohol Dependence in Multiethnic Populations.

Background: Genetics influence the vulnerability to alcohol use disorders, and among the implicated genes, three previous studies have provided evidences for the involvement of LRRK2 in alcohol dependence (AD). LRRK2 expression is broadly dysregulated in postmortem brain from AD humans, as well as in the brain of mice with alcohol dependent-like behaviors and in a zebrafish model of alcohol preference. The aim of the present study was to evaluate the association of variants in the LRRK2 gene with AD in multiethnic populations from South and North America.Methods: Alcohol-screening questionnaires [such as CAGE and Alcohol Use Disorders Identification Test (AUDIT)] were used to determine individual risk of AD. Multivariate logistic regression analyses were done in three independent populations (898 individuals from Bambuí, Brazil; 3,015 individuals from Pelotas, Brazil; and 1,316 from the United States). Linkage disequilibrium and conditional analyses, as well as in silico functional analyses, were also conducted.Results: Four LRRK2 variants were significantly associated with AD in our discovery cohort (Bambuí): rs4768231, rs4767971, rs7307310, and rs1465527. Two of these variants (rs4768231 and rs4767971) were replicated in both Pelotas and US cohorts. The consistent association signal (at the LRRK2 locus) found in populations with different genetic backgrounds reinforces the relevance of our findings.Conclusion: Taken together, these results support the notion that genetic variants in the LRRK2 locus are risk factors for AD in humans.

Catechol-O-methyltransferase (COMT) Val158Met Polymorphism and Susceptibility to Alcohol Dependence.

Catechol-O-methyl transferase (COMT) enzyme catalyzes the metabolism of dopamine and other catechols in the brain. Several articles investigated catechol-O-methyltransferase (COMT) Val158Met polymorphism as risk factor for alcohol dependence (AD) but the results were inconclusive. The aim of present meta-analysis was to evaluate the association of Val158Met (COMT) polymorphism with AD. Authors performed keyword search of the 4 electronic databases-Pubmed, Google Scholar, Springer Link and Science Direct databases up to December 31, 2019. Total eighteen studies that investigated the association of Val158Met polymorphism with AD were retrieved. The pooled results from the meta-analysis (2278 AD cases and 3717 healthy controls) did not show association with AD using all 5 genetic models (allele contrast model: OR = 1.02, 95% CI = 0.90-1.14, p = 0.03; homozygote model: OR = 1.06, 95% CI = 0.81-1.38, p = 0.69; dominant model: OR = 0.99, 95% CI = 0.85-1.14, p = 0.87; co-dominant model: OR = 0.97, 95% CI = 0.86-1.11, p = 0.71; recessive model: OR = 1.05;95% CI = 0.85-1.29, p = 0.61). Results of subgroup analysis showed that Val158Met is not risk for AD in Asian and Caucasian population. In conclusion, COMT Val158Met is not a risk factor for alcohol dependence.

Methylenetetrahydrofolate reductase (&lt;i&gt;MTHFR&lt;/i&gt;) gene C677T (rs1801133) polymorphism and risk of alcohol dependence: a meta-analysis

Alcohol dependence is a complex neuropsychiatric disorder. Numerous studies investigated association between MTHFR gene C677T (rs1801133) polymorphism and alcohol dependence (AD), but the results of this association remain conflicting. Accordingly, authors conducted a meta-analysis to further investigate such an association. PubMed, Elsevier Science Direct and Springer Link databases were searched for studies on the association between the MTHFRC677T polymorphism and AD. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using the fixed- or random-effects model. Statistical analysis was performed with the software program MetaAnayst and MIX.A total of 11 articles were identified through a search of electronic databases, up to February 28, 2020. The results of the present meta-analysis did not show any association between MTHFR C677T polymorphisms and AD risk (for T vs. C: OR = 1.04, 95% CI = 0.88–1.24; CT vs. CC: OR = 1.02, 95% CI = 0.62–1.68; for TT+CT vs. CC: OR = 1.10, 95% CI = 0.94–1.29; for TT vs. CC: OR = 1.01, 95% CI = 0.66–1.51; for TT vs. CT+CC: OR = 0.97, 95% CI = 0.66–1.40). Results of subgroup analysis showed no significant association between MTHFR C677T polymorphism with AD in Asian as well as in Caucasian population. In conclusion, C677T polymorphism is not a risk factor for alcohol dependence.

Evaluation of childhood traumatic experience as a risk factor for alcohol use disorder in adulthood

BackgroundWe aimed to investigate the effect of early-age (prenatal, infant, and childhood) trauma on adulthood alcohol use disorder.MethodsA total number of 1534 subjects who were born and live in the city of Tangshan were selected. The subjects were divided into three age groups. General demographic data, conditions of the mothers during pregnancy, and condition of the babies at birth, were collected. The diagnosis of alcohol use disorder was based on Structured Clinical Interviews for DSM-IV Axis Disorders (patient version) (SCID). The childhood trauma questionnaire short form (CTQ-SF) [1] and the Lifetime of Experience Questionnaire (LTE-Q) [2] were used to evaluate stress in childhood and adulthood, respectively.ResultsOnly male subjects were diagnosed with lifelong alcohol abuse and alcohol dependence. There was no statistically significant difference in the prevalence of lifetime alcohol use disorder (X2 = 4.480, P = 0.345), current alcohol abuse, and current alcohol dependence among the three groups (X2abuse = 2.177, X2depedence = 2.198, P > 0.05). However, higher prevalence of lifetime alcohol use disorders was found in group with higher scores of CTQ (X2 = 9.315, P = 0.009), emotional abuse (X2 = 8.025, P = 0.018), physical abuse (X2 = 20.4080, P < 0.001), but not in the group with higher scores of emotional neglect (X2 = 1.226, P = 0.542), sexual abuse (X2 = 2.779, P = 0.249), physical neglect (X2 = 3.978, P = 0.137), LTE-Q (X2 = 5.415, P = 0.067), and PSQI (X2 = 5.238, P = 0.073). Protective factor for alcohol abuse for men was identified to be heavy drinking (OR = 0.085, 95%CI: 0.011–0.661), and the risk factors for alcohol abuse were identified to be frequent drinking (OR = 2.736, 95%CI: 1.500, 4.988), and consumption of low liquor (OR = 2.563, 95%CI: 1.387, 4.734). Risk factors for alcohol dependence in males were identified to be consumption of low liquor (OR = 5.501, 95%CI: 2.004, 15.103), frequent drinking (OR = 2.680, 95%CI: 1.164, 6.170), and childhood physical abuse (OR = 2.310, 95% CI: 1.026, 5.201).ConclusionTraumatic experience during infant and prenatal periods does not have a strong statistical correlation with alcohol use disorders for male adults. However, subjects with high CTQ scores, experience of emotional abuse and physical abuse show a statistically higher prevalence of lifetime alcohol use disorders. Several risk factors including consumption of low liquor, frequent drinking, and childhood physical abuse contribute to alcohol dependence in male adults.

Does binge drinking between the age of 18 and 25 years predict alcohol dependence in adulthood? A retrospective case–control study in France

ObjectiveA retrospective case–control study was conducted to evaluate whether frequent binge drinking between the age of 18 and 25 years was a risk factor for alcohol dependence in adulthood.SettingThe Department...

HPA axis stress reactivity and hair cortisol concentrations in recently detoxified alcoholics and healthy controls with and without childhood maltreatment.

Childhood maltreatment (CM) is a strong risk factor for alcohol dependence (AD) and is associated with a more severe course of the disease. Alterations of the hypothalamic-pituitary-adrenal (HPA) axis may play an important role in this relationship. The aim of the present study was to systematically investigate potential alterations in HPA functioning associated with AD diagnosis and CM. Four study groups were recruited: AD patients with (n=29; 10♀) and without (n=33; 8♀) CM and healthy controls with (n=30; 20♀) and without (n=38; 15♀) CM. Cumulative cortisol secretion was measured by hair cortisol concentration (HCC). To measure HPA axis response to the Trier social stress test (TSST), saliva and blood samples were analysed for adrenocorticotropic hormone (ACTH) and cortisol. In the AD groups, the period of hair growth covered acute alcohol consumption and withdrawal. The TSST was scheduled after completion of withdrawal. Irrespective of CM, higher HCCs and reduced ACTH and cortisol levels before and after TSST were observed in AD patients. The analyses did not reveal any differences between AD patients with and without CM. Healthy controls with CM had lower plasma cortisol levels compared with those without CM. The results suggest that AD is strongly related to HPA axis functioning, which may superimpose possible differences between AD patients with and without CM. Future studies should investigate whether biologically different subtypes of AD with and without CM can be identified in earlier stages or before the development of AD.

Glycogen synthase kinase 3 beta regulates ethanol consumption and is a risk factor for alcohol dependence.

Understanding how ethanol actions on brain signal transduction and gene expression lead to excessive consumption and addiction could identify new treatments for alcohol dependence. We previously identified glycogen synthase kinase 3-beta (Gsk3b) as a member of a highly ethanol-responsive gene network in mouse medial prefrontal cortex (mPFC). Gsk3b has been implicated in dendritic function, synaptic plasticity and behavioral responses to other drugs of abuse. Here, we investigate Gsk3b in rodent models of ethanol consumption and as a risk factor for human alcohol dependence. Stereotactic viral vector gene delivery overexpression of Gsk3b in mouse mPFC increased 2-bottle choice ethanol consumption, which was blocked by lithium, a known GSK3B inhibitor. Further, Gsk3b overexpression increased anxiety-like behavior following abstinence from ethanol. Protein or mRNA expression studies following Gsk3b over-expression identified synaptojanin 2, brain-derived neurotrophic factor and the neuropeptide Y Y5 receptor as potential downstream factors altering ethanol behaviors. Rat operant studies showed that selective pharmacologic inhibition of GSK3B with TDZD-8 dose-dependently decreased motivation to self-administer ethanol and sucrose and selectively blocked ethanol relapse-like behavior. In set-based and gene-wise genetic association analysis, a GSK3b-centric gene expression network had significant genetic associations, at a gene and network level, with risk for alcohol dependence in humans. These mutually reinforcing cross-species findings implicate GSK3B in neurobiological mechanisms controlling ethanol consumption, and as both a potential risk factor and therapeutic target for alcohol dependence.

Religiosity, Guilt, Altruism and Forgiveness in Alcohol Dependence: Results of a Cross-sectional and Prospective Cohort Study.

To compare religious denomination, religiosity, guilt, altruism and forgiveness between alcohol-dependent patients and healthy control subjects and to prospectively investigate their relationship to the disorder's 24-month course following in-patient withdrawal treatment. This study in Franconia (a mainly Christian protestant region of southern Germany) applied six questionnaires to evaluate religiosity, guilt, altruism and forgiveness in 166 alcohol-dependent in-patients during withdrawal and compared findings with that of 240 healthy controls. Compared to controls religious denomination was more frequently reported by the patients (OR = 1.72, P = 0.014) and patients showed higher guilt (P < 0.001). The subjective attainability of altruism was lower in patients than in controls (P = 0.015). Higher scores on scale of inter-religious private practice predicted earlier (Rho = -0.184, P = 0.021) and more frequent alcohol-related readmissions during the follow-up (Rho = 0.207, P = 0.009). Higher religious affiliation was related to earlier (Rho = -0.214, P = 0.008) and more frequent alcohol-related readmissions (Rho = 0189, P = 0.020). Lower values of subjective attainability of altruism predicted a worse outcome (earlier [Rho = 0.231, P = 0.003] and more frequent readmissions [Rho = -0.223, P = 0.004]). The sex-specific analyses show that some of the associations are stronger in women and others are stronger in men; however, these gender differences are small and possibly biased by multiple hypothesis testing. We identified religious denomination, private religious practice, religious affiliation, guilt and reduced attainability of altruism as risk factors for alcohol dependence and a worse follow-up outcome. Our findings may help to establish future preventive and therapeutic strategies.

Spicy Food Preference and Risk for Alcohol Dependence in Korean

ObjectivePrevious studies have reported that both preference for spicy food and drinking behavior are associated with the activity of the opioid system in the central nervous system. The relationship between the preference for spicy food and the risk of alcohol dependence by comparing spicy food preference in alcohol-dependent patients vs. healthy controls was investigated. Also the association between the preference for spicy food and OPRM1 A118G was studied.MethodsA total of 150 Korean male patients with alcohol dependence and 100 normal male control subjects were included in this study. Preference for spicy food was measured using the Food Preference Scale (FPS). DNA analysis was conducted to detect the A118G polymorphism.ResultsThe mean FPS score was significantly higher in the alcohol-dependent patients (61.2±24.2) than in the normal control subjects (53.0±22.0). FPS scores differed significantly between alcohol-dependent patients and normal control subjects who had the G allele in OPRM1 A118G, but not between the two groups with the AA genotype.ConclusionA strong preference for spicy food can be assumed to be a risk factor for alcohol dependence, particularly in those carrying the G allele in OPRM1 A118G.

Variation in the Serotonin Transporter Gene and Alcoholism: Risk and Response to Pharmacotherapy.

SLC6A4, the gene encoding the serotonin transporter protein (5-HTT), has been extensively examined as a risk factor for alcohol dependence (AD). More recently, variability in the transporter gene was identified to be a potential moderator of treatment response to serotonergic medications such as ondansetron and sertraline. There is an insertion-deletion polymorphism in the promoter region (5-HTTLPR) of the SLC6A4, with the most common alleles being a 14-repeat short (S) allele and a 16-repeat long (L) allele. The S allele has often been associated with AD. By contrast, the L allele has been associated with pharmacological responsiveness in some individuals with AD. Differences in clinical phenotype may determine the utility of the 5-HTTLPR polymorphism as a moderator of pharmacological interventions for AD. We review the AD typology and disease onset in the context of pharmacogenetic and genomic studies that examine the utility of 5-HTTLPR in improving treatment outcomes.

Gene-based and pathway-based genome-wide association study of alcohol dependence.

BackgroundThe organization of risk genes within signaling pathways may provide clues about the converging neurobiological effects of risk genes for alcohol dependence. Aim Identify risk genes and risk gene pathways for alcohol dependence.MethodsWe conducted a pathway-based genome-wide association study (GWAS) of alcohol dependence using a gene-set-rich analytic approach. Approximately one million genetic markers were tested in the discovery sample which included 1409 European-American (EA) alcohol dependent individuals and 1518 EA healthy comparison subjects. An additional 681 African-American (AA) cases and 508 AA healthy subjects served as the replication sample.ResultsWe identified several genome-wide replicable risk genes and risk pathways that were significantly associated with alcohol dependence. After applying the Bonferroni correction for multiple testing, the ‘cellextracellular matrix interactions’ pathway (p<2.0E-4 in EAs) and the PXN gene (which encodes paxillin) (p=3.9E-7 in EAs) within this pathway were the most promising risk factors for alcohol dependence. There were also two nominally replicable pathways enriched in alcohol dependence-related genes in both EAs (0.015≤p≤0.035) and AAs (0.025≤p≤0.050): the ‘Na+/Cl- dependent neurotransmitter transporters’ pathway and the ‘other glycan degradation’ pathway.ConclusionThese findings provide new evidence highlighting several genes and biological signaling processes that may be related to the risk for alcohol dependence.

Theory of mind among young adult children from alcoholic families.

Given the evidence that several cognitive and emotional functions are impaired in adult alcohol-dependent patients and the possibility that some of these deficits are transmitted to their children, the objective of the present study was to test the hypothesis that the perception of complex mental states would be reduced in young adults from families with a positive family history of alcohol dependence. It was also anticipated that social-perceptual deficits would confer unique predictive ability beyond that shared with other cognitive risk factors for alcohol dependence and/or substance use risk. Data from 301 youth ages 18-21 years, recruited from an ongoing community longitudinal study of alcoholic and matched control families, were analyzed. Family history of alcohol dependence as well as alcohol-dependence diagnosis in the youth was based on diagnostic criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. A substance use risk factor measured early problem alcohol/other drug use. The perception of mental states was measured with the computerized version of the Reading the Mind in the Eyes Test (RMET). Children of alcohol-dependent parents did not show impairment in the mental states perception task, nor did social perception skills predict alcohol dependence in the youth. Correlational analysis performed between RMET and the substance use risk factor showed no significant association between the variables. The study results do not confirm the hypothesis that behaviorally measured social perception impairment is more prevalent in the children of alcohol-dependent parents. In addition, social-perceptual deficits were not a unique marker of either alcohol dependence or high risk for alcohol dependence in this young adult sample.

SAT1 * ALCOHOL DEPENDENCE - FROM RISK TO REALITY (LUNDBECK)

# SAT1.1 RISK FACTORS FOR ALCOHOL DEPENDENCE {#article-title-2} Alcohol dependence is a complex genetically influenced brain disease. This lecture reviews the evidence that supports the importance of genetic influences in this condition, and describes one aspect of the search for the genetic and environmental characteristics that contribute to the vulnerability toward heavy drinking and alcohol problems. Most risk factors operate indirectly on the predisposition toward alcohol dependence by affecting how alcohol is metabolized, operate through personality characteristics such as impulsive behaviours that increase the risk for all substance-related problems, relate to several psychiatric disorders, or affect how a person's brain reacts to alcohol. One of the most thoroughly studied of the genetically influenced mechanisms relating to how a person responds to alcohol is a low level of response, or low sensitivity, to alcohol. This characteristic is used to demonstrate how research has identified risk factors, established whether there are genetic influences for these characteristics, discovered environmental characteristics that impact on how the genetically-influenced factor affects the risk for alcohol dependence, identified brain mechanisms that contribute to the vulnerability, and then used these findings to develop and test a prevention approach to decrease the risk for heavy drinking and alcohol problems. # SAT1.2 AN EXTENSION OF THE CURRENT TREATMENT PARADIGM FOR ALCOHOL DEPENDENCE: RESULTS FROM NALMEFENE PHASE III TRIALS {#article-title-3} Treatment for alcohol depends has been focused on total abstinence using psychotherapeutic and pharmacological interventions. However, many alcohol-dependent individuals are not able or inclined to achieve total abstinence, resulting in a medical condition that is under-diagnosed and under-treated. In Europe, only a small fraction (8.3%) of the people diagnosed with alcohol dependence receives treatment. Nalmefene is an opioid system modulator with antagonist activity at the μ and δ opioid receptors and partial agonist activity at the κ opioid receptor. Three multi-centre, double-blind, placebo-controlled Phase III studies, designed to assess the efficacy and safety of nalmefene in reducing alcohol consumption, enrolled close to 2000 patients with alcohol dependence. Nalmefene as-needed has been shown to reduce the total amount of alcohol consumption and number of heavy drinking days and to improve liver functions and clinical status in two 6-month studies (identically designed), and one 1-year study in patients with alcohol dependence. The benefit of nalmefene was further studied in the pooled subgroup of patients from the 6-month studies. The patients in this subgroup were consuming alcohol at a high drinking risk level at the initial assessment (screening) and at the start of treatment (baseline). In this subgroup, identified as most likely to benefit, the net treatment effect over placebo in terms of reduction of alcohol consumption was more pronounced. # SAT1.3 CLINICAL DATA SUPPORTING THE BENEFIT OF A PATIENT-CENTRED APPROACH IN THE TREATMENT OF ALCOHOL DEPENDENCE {#article-title-4} A patient centred approach that offers the choice of reduction of alcohol consumption as part of a continuum of treatment goals and which allows patients to have a say in dosing regimens, may help reduce the barriers to treatment perceived by some individuals. Engaging patients in managing their treatment may also improve adherence. In three phase III studies assessing as-needed nalmefene in reducing alcohol consumption in alcohol dependent patients, it has been shown that alcohol dependent patients understand, accept and adhere to the “as-needed” dosing concept and that nalmefene as-needed reduces the average daily total alcohol consumption (TAC; g/day) and number of heavy drinking days (HDDs). The W.H.O. has defined risk categories for health problems based on the level of daily alcohol consumption. These categories can be used to define response, as a measure of the clinical relevance of the reduction in alcohol consumption at an individual patient level. Drinking variables (TAC and HDDs) were measured using Timeline Follow-Back. Various analyses were used to translate the reduction in alcohol consumption into clinically relevant responses. Response was defined as 1) two-category down-shift in drinking risk level; 2) downward shift to low drinking risk level; 3) 70% reduction in TAC; all at month 6. As-needed nalmefene was associated with each of these clinically relevant responses, supporting that the benefits of a patient-centered approach can be shown in clinical trials.

Extended genetic effects of ADH cluster genes on the risk of alcohol dependence: from GWAS to replication

Alcohol dependence (AD) is a multifactorial and polygenic disorder involving complex gene-to-gene and gene-to-environment interactions. Several genome-wide association studies have reported numerous risk factors for AD, but replication results following these studies have been controversial. To identify new candidate genes, the present study used GWAS and replication studies in a Korean cohort with AD. Genome-wide association analysis revealed that two chromosome regions on Chr. 4q22-q23 (ADH gene cluster, including ADH5, ADH4, ADH6, ADH1A, ADH1B, and ADH7) and Chr. 12q24 (ALDH2) showed multiple association signals for the risk of AD. To investigate detailed genetic effects of these ADH genes on AD, a follow-up study of the ADH gene cluster on 4q22-q23 was performed. A total of 90 SNPs, including ADH1B rs1229984 (H47R), were genotyped in an additional 975 Korean subjects. In case-control analysis, ADH1B rs1229984 (H47R) showed the most significant association with the risk of AD (p = 2.63 × 10(-21), OR = 2.35). Moreover, subsequent conditional analyses revealed that all positive associations of other ADH genes in the cluster disappeared, which suggested that ADH1B rs1229984 (H47R) might be the sole functional genetic marker across the ADH gene cluster. Our findings could provide additional information on the ADH gene cluster regarding the risk of AD, as well as a new and important insight into the genetic factors associated with AD.

Prevalence and correlates of alcohol dependence in adult prisoners vary according to Indigenous status

Objective : To estimate the prevalence and identify independent correlates of alcohol dependence among Indigenous and non-Indigenous adult prisoners in Queensland. Methods : A confidential, cross-sectional survey of 1,155 adult prisoners (n=274 Indigenous, n=881 non-Indigenous) in seven adult prisons in Queensland. The usual alcohol consumption in the year before prison was assessed using the Alcohol Use Disorders Identification Test (AUDIT); scores =20 are considered consistent with alcohol dependence. Results : Indigenous prisoners were significantly more likely than non-Indigenous prisoners to report patterns of alcohol consumption consistent with dependence. Separate multivariable analyses revealed different independent correlates of alcohol dependence according to Indigenous status. Among Indigenous prisoners, significant independent correlates of alcohol dependence included income below the poverty line and daily cannabis use before incarceration. Daily heroin use and history of injecting drug use were protective. Among non-Indigenous prisoners, significant independent correlates included history of mental illness or self harm, and daily tobacco or cannabis use before incarceration. Older age and daily heroin use before incarceration were protective. Conclusions and Implications : The prevalence of risky alcohol use and dependence is high in Australian prisoner populations, particularly among Indigenous prisoners. Risk factors for alcohol dependence differ according to Indigenous status, indicating that separate, culturally appropriate interventions to reduce alcohol-related harm for Indigenous prisoners may be required.

Alcohol impairment of saccadic and smooth pursuit eye movements: impact of risk factors for alcohol dependence

While persons at risk for alcohol dependence by virtue of heavy drinking patterns or family history (FH) of alcohol use disorders have exhibited differential alcohol responses on a variety of measures, few studies have examined alcohol's effects on eye movements in these subgroups. The purpose of this study was to (1) conduct a placebo-controlled, dose-ranging study of alcohol's effects on eye movements and (2) examine the impact of these risk factors on oculomotor response to alcohol. A within-subject, double-blind laboratory study was conducted in N = 138 heavy (HD; n = 78) and light social drinkers (LD; n = 60) with self-reported positive (FH+) or negative (FH-) family history. Subjects participated in three laboratory sessions in which they consumed a beverage containing a high (0.8 g/kg) or low (0.4 g/kg) dose of alcohol or placebo. Smooth pursuit, pro-saccadic, and anti-saccadic eye movements were recorded before and at two intervals after alcohol consumption. Alcohol significantly impaired smooth pursuit gain and pro- and anti-saccade latency, velocity, and accuracy in a dose and time specific matter. HD and LD showed similar impairment on smooth pursuit gain and anti-saccade measures, but HD were less impaired in pro-saccade latency, velocity, and accuracy. FH+ and FH- subjects were equally impaired in nearly all pro- and anti-saccade measures, but FH+ were less impaired in smooth pursuit gain. In sum, alcohol produced systematic impairment on oculomotor functioning, even at a non-intoxicating dose. Furthermore, high- and low-risk drinkers may be vulnerable to select performance deficits relative to eye movement task.

Genetic origins of the association between verbal ability and alcohol dependence symptoms in young adulthood

Cognitive deficits in alcohol dependence (AD) have been observed, poorer verbal ability being among the most consistent findings. Genetic factors influence both cognitive ability and AD, but whether these influences overlap is not known. A subset of 602 monozygotic (MZ) and dizygotic (DZ) twins from FinnTwin16, a population-based study of Finnish twins, was used to study the associations of verbal ability with DSM-III-R diagnosis and symptoms of AD, the maximum number of drinks consumed in a 24-h period, and the Rutgers Alcohol Problem Index (RAPI) scores. These twins, most of them selected for within-pair discordance or concordance for their RAPI scores at age 18.5 years, were studied with neuropsychological tests and interviewed with the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) in young adulthood (mean age 26.2 years, range 23-30 years). All alcohol problem measures were associated with lower scores on the Vocabulary subtest of the Wechsler Adult Intelligence Scale - Revised (WAIS-R), a measure of verbal ability. In bivariate genetic models, Vocabulary and the alcohol problem measures had moderate heritabilities (0.54-0.72), and their covariation could be explained by correlated genetic influences (genetic correlations -0.20 to -0.31). Poorer verbal ability and AD have partly overlapping biological etiology. The genetic and environmental influences on the development of cognitive abilities, alcohol problems and risk factors for AD should be studied further with prospective longitudinal designs.