Victor M. Karpyak

Sex and gender-related differences in alcohol use and its consequences: Contemporary knowledge and future research considerations.

AIMS To review the contemporary evidence reflecting male/female differences in alcohol use and its consequences along with the biological (sex-related) and psycho-socio-cultural (gender-related) factors associated with those differences. METHODS MEDLINE, PubMed, Web of Science, SCOPUS, PsycINFO, and CINAHL databases were searched for relevant publications, which were subsequently screened for the presence/absence of pre-specified criteria for high quality evidence. RESULTS Compared to men, more women are lifetime abstainers, drink less, and are less likely to engage in problem drinking, develop alcohol-related disorders or alcohol withdrawal symptoms. However, women drinking excessively develop more medical problems. Biological (sex-related) factors, including differences in alcohol pharmacokinetics as well as its effect on brain function and the levels of sex hormones may contribute to some of those differences. In addition, differences in alcohol effects on behavior may also be driven by psycho-socio-cultural (gender-related) factors. This is evident by variation in the magnitude of differences in alcohol use between countries, decreasing difference in the rates of alcohol consumption in recent generations and other findings. Evidence indicates that both sex and gender-related factors are interacting with alcohol use in complex manner, which differentially impacts the risk for development of the behavioral or medical problems and alcohol use disorders in men and women. CONCLUSIONS Discovery of the mechanisms underlying biological (sex-related) as well as psycho-socio-cultural (gender-related) differences in alcohol use and related disorders is needed for development of personalized recommendations for prevention and treatment of alcohol use disorders and related problems in men and women.

Functional Role of the Polymorphic 647 T/C Variant of ENT1 (SLC29A1) and Its Association with Alcohol Withdrawal Seizures

Background Adenosine is involved in several neurological and behavioral disorders including alcoholism. In cultured cell and animal studies, type 1 equilibrative nucleoside transporter (ENT1, slc29a1), which regulates adenosine levels, is known to regulate ethanol sensitivity and preference. Interestingly, in humans, the ENT1 (SLC29A1) gene contains a non-synonymous single nucleotide polymorphism (647 T/C; rs45573936) that might be involved in the functional change of ENT1. Principal Findings Our functional analysis showed that prolonged ethanol exposure increased adenosine uptake activity of mutant cells (ENT1-216Thr) compared to wild-type (ENT1-216Ile) transfected cells, which might result in reduced extracellular adenosine levels. We found that mice lacking ENT1 displayed increased propensity to ethanol withdrawal seizures compared to wild-type littermates. We further investigated a possible association of the 647C variant with alcoholism and the history of alcohol withdrawal seizures in subjects of European ancestry recruited from two independent sites. Analyses of the combined data set showed an association of the 647C variant and alcohol dependence with withdrawal seizures at the nominally significant level. Conclusions Together with the functional data, our findings suggest a potential contribution of a genetic variant of ENT1 to the development of alcoholism with increased risk of alcohol withdrawal-induced seizures in humans.

Changes in heart rate variability associated with acute alcohol consumption: Current knowledge and implications for practice and research

Alcohol consumption is associated with a broad array of physiologic and behavioral effects including changes in heart rate. However, the physiologic mechanisms of alcohol effects and the reasons for individual differences in the cardiac response remain unknown. Measuring changes in resting heart rate (measured as beats/min) has not been found to be as sensitive to alcohols effects as changes in heart rate variability (HRV). HRV is defined as fluctuations in interbeat interval length which reflect the hearts response to extracardiac factors that affect heart rate. HRV allows simultaneous assessment of both sympathetic and parasympathetic activity and the interplay between them. Increased HRV has been associated with exercise and aerobic fitness, while decreased HRV has been associated with aging, chronic stress, and a wide variety of medical and psychiatric disorders. Decreased HRV has predictive value for mortality in general population samples and patients with myocardial infarction and used as an indicator of altered autonomic function. A significant inverse correlation was found between HRV and both the severity of depression and the duration of the depressive episode. HRV analysis provides insights into mechanisms of autonomic regulation and is extensively used to clarify relationships between depression and cardiovascular disease. This article will review the methodology of HRV measurements and contemporary knowledge about effects of acute alcohol consumption on HRV. Potential implications of this research include HRV response to alcohol that could serve as a marker for susceptibility to alcoholism. At present however there is almost no research data supporting this hypothesis.

Alcohol craving as a predictor of relapse.

BACKGROUND AND OBJECTIVES Alcoholism treatment interventions, both psychosocial and pharmacologic, aim to reduce cravings to drink. Yet, the role of craving in treatment outcomes remains unclear. This study evaluated craving intensity measured with the Penn Alcohol Craving Scale (PACS) at admission and discharge from residential treatment as a predictive factor of relapse after treatment. METHODS The study cohort included 314 alcohol-dependent subjects. Associations between relapse after discharge, PACS score, and clinical variables were investigated using time-to-event analyses. The primary analysis, based on the intent-to-treat principle, presumed relapse in those declining follow-up or not responding to contact attempts. Secondary analysis utilized data from 226 subjects successfully contacted after discharge with a median follow-up time of 365 days. RESULTS The intent-to-treat analysis demonstrated that relapse was associated with higher level of craving at admission (p= .002) and discharge (p < .001). The analysis of data from patients successfully contacted after discharge led to similar results. A multivariable analysis indicated that relapse rates increased as PACS scores increased, and a higher discharge PACS score was significantly associated with relapse (p= .006) even after adjusting for covariates. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE This study demonstrates that higher PACS scores at the time of admission and discharge are associated with relapse following residential addiction treatment. These data support the role of craving in relapse and the utility of craving measurement as a clinical guide in assessing relapse risk.

Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate

Acamprosate supports abstinence in some alcohol-dependent subjects, yet predictors of response are unknown. To identify response biomarkers, we investigated associations of abstinence length with polymorphisms in candidate genes in glycine and glutamate neurotransmission pathways and genes previously implicated in acamprosate response. Association analyses were conducted in the discovery sample of 225 alcohol-dependent subjects treated with acamprosate for 3 months in community-based treatment programs in the United States. Data from 110 alcohol-dependent males treated with acamprosate in the study PREDICT were used for replication of the top association findings. Statistical models were adjusted for relevant covariates, including recruitment site and baseline clinical variables associated with response. In the discovery sample, shorter abstinence was associated with increased intensity of alcohol craving and lower number of days between the last drink and initiation of acamprosate treatment. After adjustment for covariates, length of abstinence was associated with the GRIN2B rs2058878 (P=4.6 × 10−5). In the replication sample, shorter abstinence was associated with increased craving, increased depressive mood score and higher alcohol consumption. Association of abstinence length with GRIN2B rs2058878 was marginally significant (P=0.0675); as in the discovery sample, the minor A allele was associated with longer abstinence. Furthermore, rs2300272, which is in strong linkage disequilibrium with rs2058878, was also associated with abstinence length (P=0.049). This is the first report of a replicated association of genetic markers with the length of abstinence in acamprosate-treated alcoholics. Investigation of the underlying mechanisms of this association and its usefulness for individualized treatment selection should follow.

Replication of genome wide association studies of alcohol dependence: support for association with variation in ADH1C.

Genome-wide association studies (GWAS) have revealed many single nucleotide polymorphisms (SNPs) associated with complex traits. Although these studies frequently fail to identify statistically significant associations, the top association signals from GWAS may be enriched for true associations. We therefore investigated the association of alcohol dependence with 43 SNPs selected from association signals in the first two published GWAS of alcoholism. Our analysis of 808 alcohol-dependent cases and 1,248 controls provided evidence of association of alcohol dependence with SNP rs1614972 in the ADH1C gene (unadjusted p = 0.0017). Because the GWAS study that originally reported association of alcohol dependence with this SNP [1] included only men, we also performed analyses in sex-specific strata. The results suggest that this SNP has a similar effect in both sexes (men: OR (95%CI) = 0.80 (0.66, 0.95); women: OR (95%CI) = 0.83 (0.66, 1.03)). We also observed marginal evidence of association of the rs1614972 minor allele with lower alcohol consumption in the non-alcoholic controls (p = 0.081), and independently in the alcohol-dependent cases (p = 0.046). Despite a number of potential differences between the samples investigated by the prior GWAS and the current study, data presented here provide additional support for the association of SNP rs1614972 in ADH1C with alcohol dependence and extend this finding by demonstrating association with consumption levels in both non-alcoholic and alcohol-dependent populations. Further studies should investigate the association of other polymorphisms in this gene with alcohol dependence and related alcohol-use phenotypes.

A retrospective study of gender differences in depressive symptoms and risk of relapse in patients with alcohol dependence.

BACKGROUND AND OBJECTIVES The aim of this study was to investigate potential gender differences in situations associated with heavy alcohol drinking. METHODS Data from 395 alcohol dependent patients participating in the Mayo Clinic Intensive Addiction Program were evaluated. Each participant completed the inventory of drug taking situations (IDTS), Penn alcohol craving scale (PACS), patient health questionnaire (PHQ-9), and/or Beck depression inventory (BDI). Gender differences in IDTS scores representing three domains (negative, positive, and temptation) of situations associated with heavy alcohol use were examined. RESULTS Women with alcohol dependence report a higher frequency of heavy drinking in unpleasant emotional (IDTS negative scores mean ± SD women vs. men: 52.3 ± 22.1 vs. 43.8 ± 21.8; p = .0006), and as a result of temptation (IDTS temptation scores mean ± SD women vs. men: 40.4 ± 23.0 vs. 35.3 ± 20.8; p = .035). Upon admission, women also scored significantly higher on depressive symptoms as measured by the BDI (23.4 ± 11.4 vs. 18.2 ± 9.8, p < .001). After controlling for depressive symptom severity as a covariate, the IDTS gender differences were no longer significant. CONCLUSION AND SCIENTIFIC SIGNIFICANCE Our results suggest that unpleasant or temptation based emotional situations are a vulnerability risk factor for heavy drinking particularly in females. This risk appears to be at least partially driven by depressive symptom burden. Future research is needed to further investigate this finding.

Genetic variability in the NMDA-dependent AMPA trafficking cascade is associated with alcohol dependence

Model studies in mice indicate that the severity of alcohol withdrawal is associated with polymorphic variation and expression of the MPDZ gene. Current knowledge about variation in the human MPDZ gene is limited; however, our data indicate its potential association with alcohol dependence. The multi‐PDZ protein is an important part of the N‐methyl‐D‐aspartate (NMDA)‐dependent α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptor trafficking cascade that controls glutamate‐related excitatory neurotransmission. To investigate association of variation in the NMDA‐dependent AMPA trafficking cascade with alcohol dependence, we performed a gene‐set (pathway) analysis using single nucleotide polymorphism (SNP) data from the Study of Addiction: Genetic and Environment. Rather than testing for association with each SNP individually, which typically has low power to detect small effects of multiple SNPs, gene‐set analysis applies a single statistical test to evaluate whether variation in a set of genes is associated with the phenotype of interest. Gene‐set analysis of 988 SNPs in 13 genes in the pathway demonstrated a significant association with alcohol dependence, with P < 0.01 for the global effect of variation in this pathway. The statistically significant association of alcohol dependence with genetic variation in the NMDA‐dependent AMPA receptor trafficking cascade indicates a need for further investigation of the role of this pathway in alcohol dependence.

Gender differences in the relationship between depressive symptoms and cravings in alcoholism.

This study examines the clinical correlates of alcohol craving in men and women self-referred for addiction treatment. Admission clinical data from patients participating in the Mayo Clinic 1-month Intensive Addictions Program were evaluated. Women had higher BDI and PACS scores compared with men in both the entire cohort and Dual Diagnoses group. Alcohol-dependent females had the most marked correlation between BDI and PACS (rho= .78). Further prospective study is encouraged to evaluate whether depressive symptoms and concomitant alcohol cravings in women are a marker for relief cravings and, as such, a target symptom for treatment intervention.

Characteristics of Heart Rate Variability in Alcohol-Dependent Subjects and Nondependent Chronic Alcohol Users

Heart rate variability (HRV) is an objective and sensitive measure of integrated physiological functioning reflective of heart rhythm responsivity to internal and external demands. Reduced HRV is associated with vulnerability to stress and deterioration of medical and/or psychiatric conditions, while increased HRV is associated with a favorable treatment response and recovery from various medical and/or psychiatric conditions. Our previous review found that acute alcohol consumption caused decreased parasympathetic and increased sympathetic HRV effects in both nonalcoholic and chronic alcohol users. This review investigates the effects of chronic alcohol consumption on HRV in alcohol-dependent subjects and nondependent users. MEDLINE, Scopus, and PubMed were searched for human experimental and clinical trials that measured the effects of chronic alcohol use on HRV. Only publications that included a description of their study designs and clearly stated methodologies for data collections, and outcome measures were reviewed. We have reviewed a total of 24 articles. In nondependent users, low dose (approximating the recommended daily amount of 1 standard drink in women and 2 in men) use is associated with increased HRV parameters compared to those who drink less frequently or abstain altogether. A further increase in consumption is associated with decreased HRV compared to both abstainers and more moderate drinkers. HRV changes during withdrawal generally follow the same negative direction but are more complex and less understood. In dependent subjects, an improvement in HRV was seen following abstinence but remained reduced compared to nonalcoholic controls. This review demonstrates that HRV changes associated with chronic use follow a J-shaped curve. It supports recommendations that limit daily alcohol intake to no more than 2 drinks for men and 1 drink for women. Future studies should investigate HRV as a biomarker of alcoholism development and treatment response as well as the physiological basis for alcohol effects on HRV.