Exploration of the Impact of Combining Risk Phenotypes on the Likelihood of Alcohol Problems in Young Adults.

AIMS: We tested the hypothesis that high novelty seeking (NS-an externalizing trait), sweet-liking (SL-a phenotype that may reflect processing of hedonic stimuli) and initial insensitivity to the impairing effects of alcohol (SRE-A) act independently and synergistically to increase the likelihood of having alcohol-related problems in young adults. METHODS: A sample of 145 young adults, ages 18-26, balanced for gender and alcohol use disorders identification test (AUDIT) scores <8 or ≥8 were selected from a prior sample. NS, SL and SRE-A were assessed along with AUDIT score and family history of alcoholism (FH). The effect of phenotypes and their interaction on the likelihood of alcohol problems was assessed. RESULTS: All three phenotypes contribute to the total AUDIT score. The best-fitting model explaining 35.8% of AUDIT variance includes all three phenotypes and an interaction between NS and SL/sweet-disliking (SDL) status. The addition of FH to the model explains an additional 4% of variance in both models. Classification and regression tree analysis showed that the main phenotype influencing AUDIT score is NS. The SL/SDL phenotype is a strong modifying factor for high NS. SRE-A was shown to be a weak modifier for individuals with low NS. CONCLUSION: The evidence supports the hypothesis that the presence of multiple alcohol use disorders (AUD) risk phenotypes with different underlying neurobiological mechanisms within an individual (SL, NS and SRE-A) represents a higher likelihood for developing alcohol-related problems and may allow for a graded assessment of risk for AUD and offer the possibility for early intervention strategies.

Efficacy and tolerability of baclofen in a U.S. community population with alcohol use disorder: a dose-response, randomized, controlled trial.

Identification of new medications for alcohol use disorder (AUD) is important for improving treatment options. Baclofen, a GABAB agonist, has been identified as a potential pharmacotherapy for AUD. In a 16-week double-blind, randomized, placebo-controlled trial, we investigated 30 and 90 mg/day of baclofen compared to placebo and examined effects of dose, sex, and level of pretreatment drinking. One hundred and twenty participants with DSM-IV alcohol dependence (age 46.1 (sd = 10.1) years, 51.7% male) were randomized after exclusion for unstable medical/psychiatric illness and/or dependence on drugs other than nicotine. Seventy-three participants completed the trial. A main effect of baclofen was found [%HDD (F(2,112) = 4.16, p = 0.018, d = 0.51 95%CI (0.06-0.95), 13.6 fewer HDD) and %ABST (F(2,112) = 3.68, p = 0.028, d = 0.49 95%CI (0.04-0.93), 12.9 more abstinent days)] and was driven by the 90 mg/day dose. A sex × dose interaction effect was present for both %HDD (F(2,110) = 5.48, p = 0.005) and %ABST (F(2,110) = 3.19, p = 0.045). Men showed a marginally positive effect for 90 mg/day compared to PBO (%HDD t(110) = 1.88, p = 0.063, d = 0.36 95%CI (-0.09-0.80), 15.8 fewer HDD days; %ABST t(110) = 1.68 (p = 0.096, d = 0.32 95%CI (-0.12-0.76), 15.7 more ABST)) with no effect for 30 mg/day. Women showed a positive effect for 30 mg/day (%HDD, t(110) = 3.19, p = 0.002, d = 0.61 95%CI (0.16-1.05), 26.3 fewer HDD days; %ABST t(110) = 2.73, p = 0.007, d = 0.52 95%CI (0.07-0.96), 25.4 more ABST days) with marginal effects for 90 mg/day on %ABST (p = 0.06) with drop-outs/dose reduction from sedative side-effects of 59% in women at 90 mg/day compared to 5% for men. These findings support the hypothesis that baclofen has efficacy in AUD and suggest that dose and sex be further explored as potential moderators of baclofen response and tolerability.

Clinical and biological moderators of response to naltrexone in alcohol dependence: a systematic review of the evidence.

AIM: The goal of this systematic review was to identify moderators of naltrexone efficacy in the treatment of alcohol dependence. METHODS: We searched Pubmed, CINHAL, Embase, PsycINFO and the Cochrane Library from 1990 to April 2012 and reference lists of pertinent review articles, which yielded 622 trial, pooled analysis and review articles. Using pre-established eligibility criteria, two reviewers independently determined whether abstracts contained evidence of demographic or biological characteristics, i.e. moderators, influencing naltrexone response in alcohol dependence. We assessed each publication for risk of bias and evaluated the strength of the body of evidence for each moderator. RESULTS: Twenty-eight publications (on 20 studies) met criteria for data synthesis. These included 26 publications from 12 randomized, placebo-controlled trials, three non-randomized, non-placebo studies and one randomized, non-placebo study. In addition, there were two publications from pooled analyses of four randomized, placebo-controlled trials. Family history of alcohol problems and the Asn40Asp polymorphism of the µ-opioid receptor gene showed a positive association with efficacy in four of five and three of five studies, respectively. Other moderators reported to be associated with efficacy included male sex (two of five studies), pre-treatment drinking (two of two studies) and high craving (two of five studies). However, the overall risk of bias in the published literature is high. CONCLUSIONS: The identification of naltrexone-responsive alcohol-dependent patients is still in development. Studies to date point to two potential moderators-family history and presence of the OPRM1 Asn40Asp polymorphism-as having the strongest evidence. However, the data to date is still insufficient to recommend that any moderator be used in determining clinical treatment.

Intact Hedonic Responses to Sweet Tastes in Autism Spectrum Disorder.

The Sweet Taste Test (STT) is a standardized measure designed to index the ability to detect differences in sweet tastes (sweet taste sensitivity) and hedonic responses to sweet tastes (sweet taste liking). Profiles of response on the STT suggest enhanced hedonic responses to sweet tastes in psychiatric disorders characterized by dysfunctional reward processing systems, including binge-eating disorders and substance use disorders, and a putative mechanism governing STT responses is the brain opioid system. The present study examined STT responses in 20 adults with autism spectrum disorder (ASD) and 38 healthy control adults. There were no differences in sweet taste sensitivity or hedonic response to sweet tastes between the ASD and control groups. Within the ASD sample, ASD symptom severity was associated with sweet taste sensitivity, but not hedonic response to sweet taste. Results may ultimately shed light on brain opioid system functioning in ASD.

Role of feeding-related pathways in alcohol dependence: A focus on sweet preference, NPY, and ghrelin.

Converging research evidence suggests that alcohol and food-seeking behaviors share common neural pathways. There is preclinical and clinical evidence linking the consumption of sweets to alcohol intake in both animals and humans. In addition, a growing body of animal and human literature suggests the involvement of "feeding-related" peptides in alcohol-seeking behavior. In particular, both central and peripheral appetitive peptides have shown a possible role in alcohol dependence. The present mini-review will summarize the literature on the link between sweet preference and alcohol dependence, and on the role of feeding-related peptides in alcohol dependence. Specifically, in an attempt to narrow the field, the present mini-review will focus on 2 specific pathways, the central neuropeptide Y and the peripheral gut peptide ghrelin. Although more research is needed, data available suggest that studying feeding-related pathways in alcohol dependence may have theoretic, biologic, diagnostic, and therapeutic implications.

Efficacy and safety of baclofen for alcohol dependence: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Recent clinical trials and case-reports indicate that baclofen, a GABA(B) agonist, may have efficacy for alcohol dependence. Baclofen has been shown to enhance abstinence, to reduce drinking quantity, to reduce craving, and to reduce anxiety in alcohol-dependent individuals in 2 placebo-controlled trials in Italy. However, the clinical trial data with baclofen is limited. The purpose of the present study was to test the efficacy and tolerability of baclofen in alcohol dependence in the United States. METHODS: The study was a double-blind, placebo-controlled, randomized study comparing 30 mg/d of baclofen to placebo over 12 weeks of treatment and utilizing 8 sessions of BRENDA, a low-intensity psychosocial intervention. One hundred and twenty-one subjects were screened to yield 80 randomized subjects (44 men) with randomization balanced for gender. Percent heavy drinking days was the primary outcome measure with other drinking outcomes, anxiety levels, and craving as secondary outcomes. Tolerability was examined. RESULTS: Seventy-six percent of subjects completed the study. No difference by drug condition was seen in percentage of heavy drinking days where on-average rates were 25.5% (±23.6%) for placebo and 25.9% (±23.2%) for baclofen during treatment (t(73)=0.59, p=0.56). Similarly, no differences were seen by drug condition in percentage of days abstinent, time to first drink, or time to relapse to heavy drinking. Baclofen was associated with a significant reduction in state anxiety (F(1,73)= 5.39, p=0.02). Baclofen was well tolerated with only 2 individuals stopping baclofen because of adverse events. There were no serious adverse events. CONCLUSIONS: Baclofen, a GABA(B) agonist, represents a possible new pharmacotherapeutic approach to alcohol dependence. Despite encouraging preclinical data and prior positive clinical trials with baclofen in Italy, the current trial did not find evidence that baclofen is superior to placebo in the treatment of alcohol dependence. Additional clinical trial work is necessary to establish whether baclofen does or does not have therapeutic efficacy in alcohol dependence and, if it does, what factors are predictive of response.