Richard Feinn

Meta‐analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence

The neurotransmitter serotonin (5‐HT) has been shown to regulate alcohol consumption in both animals and humans. Since activity of the 5‐HT transporter protein (5‐HTT) regulates 5‐HT levels, the gene encoding this protein may contribute to the risk of alcohol dependence (AD). Studies of the association to AD of a functional insertion‐deletion polymorphism in the 5‐HTT‐linked promoter region (5‐HTTLPR) have yielded inconsistent results. We conducted a meta‐analysis of data from 17 published studies (including 3,489 alcoholics and 2,325 controls) investigating the association between 5‐HTTLPR alleles and AD. The frequency of the short (S) allele at 5‐HTTLPR was significantly associated with AD [odds ratio (OR) = 1.18, 95% CI = 1.03–1.33). Moreover, a greater association with the S allele was seen among individuals with AD complicated by either a co‐morbid psychiatric condition or an early‐onset or more severe AD subtype [OR = 1.34 (95% CI = 1.11–1.63)]. Allelic variation at 5‐HTTLPR contributes to risk for AD, with the greatest effect observed among individuals with a co‐occurring clinical feature.

GABRA2 alleles moderate the subjective effects of alcohol, which are attenuated by finasteride

GABAA receptors are involved in the subjective effects of alcohol. Endogenous neuroactive steroids interact with GABAA receptors to mediate several behavioral effects of alcohol in rodents. Based on a haplotypic association of alcohol dependence with the gene encoding the GABAA receptor α-2 subunit (GABRA2), we examined whether GABRA2 alleles are associated with the subjective response to alcohol. We also examined whether finasteride (a 5-α steroid reductase inhibitor), which blocks the synthesis of some neuroactive steroids, reduces the subjective response to alcohol. In all, 27 healthy social drinkers (15 males) completed a randomized, double-blind, placebo-controlled study of high-dose finasteride. After being pretreated with study drug, subjects consumed three alcoholic drinks. Subjective effects were measured repeatedly over the ascending blood alcohol curve. To examine the moderating role of genetic variation in GABRA2, a single-nucleotide polymorphism that was informative in association studies was included as a factor in the analysis. Subjects homozygous for the more common A-allele (n=7) showed more subjective effects of alcohol than did individuals with one or two copies of the alcohol dependence-associated G-allele (n=20, including two homozygotes). Among the A-allele homozygotes, there was a greater reduction in several subjective effects during the finasteride session compared to the placebo session. These findings provide preliminary evidence that the risk of alcoholism associated with GABRA2 alleles may be related to differences in the subjective response to alcohol. The effects of finasteride provide indirect evidence for a mediating role of neuroactive steroids in some of the subjective effects of alcohol.

Effects of Ondansetron in Early‐ Versus Late‐Onset Alcoholics: A Prospective, Open‐Label Study

BACKGROUND Early-onset alcoholics (EOAs) have a greater familial loading for alcoholism, more severe progression of the disorder, a greater severity of comorbid psychopathology, and a poorer response to treatment than late-onset alcoholics (LOAs). Ondansetron, a 5-hydroxytryptamine-3 antagonist, was found to be superior to placebo in the treatment of EOAs, but not of LOAs. This study compared the tolerability and potential efficacy of an oral solution of ondansetron in EOAs versus LOAs. METHODS Forty outpatients with alcohol dependence (67.5% male; 87.5% European American; 20 EOAs; 20 LOAs) received an oral solution of ondansetron at a dosage of 4 microg/kg twice daily for 8 weeks, together with weekly relapse-prevention therapy. RESULTS EOAs had a significantly greater decrease in drinks per day, drinks per drinking day, and alcohol-related problems than LOAs. Changes in the level of carbohydrate-deficient transferrin were consistent with changes in self-reported drinking behavior. CONCLUSIONS An oral solution of ondansetron seems suitable for the treatment of alcohol dependence, yielding findings consistent with evidence from a placebo-controlled trial that ondansetron, at a dosage of 4 microg/kg twice daily, is of value in the treatment of EOAs.

Topiramate treatment for heavy drinkers: moderation by a GRIK1 polymorphism.

OBJECTIVE Topiramate has been shown to reduce drinking and heavy drinking in individuals with alcohol dependence whose goal was to stop drinking. The authors evaluated the efficacy and tolerability of topiramate in heavy drinkers whose treatment goal was to reduce drinking to safe levels. METHOD A total of 138 individuals (62.3% men) were randomly assigned to receive 12 weeks of treatment with topiramate (N=67), at a maximal daily dose of 200 mg, or matching placebo (N=71). Both groups received brief counseling to reduce drinking and increase abstinent days. It was hypothesized that topiramate-treated patients would be better able to achieve these goals, and it was predicted that based on prior research, the effects would be moderated by a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the kainate GluK1 receptor subunit. RESULTS The rate of treatment completion was 84.9% and equal by treatment group. Topiramate treatment significantly reduced heavy drinking days and increased abstinent days relative to placebo. Patients receiving topiramate also had lower concentrations of the liver enzyme γ-glutamyl transpeptidase and lower scores on a measure of alcohol-related problems than the placebo group. In a European American subsample (N=122), topiramates effect on heavy drinking days was significantly greater than that for placebo only in rs2832407 C-allele homozygotes. CONCLUSIONS These findings support the use of topiramate at a daily dose of 200 mg to reduce heavy drinking in problem drinkers. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment and provide an important personalized treatment option. The pharmacogenetic findings also implicate the kainate receptor in the mechanism of topiramates effects on heavy drinking.

Nicotine Gum for Pregnant Smokers A Randomized Controlled Trial

OBJECTIVE: To estimate the safety and efficacy of treatment with 2-mg nicotine gum for smoking cessation during pregnancy. METHODS: Pregnant women who smoked daily received individualized behavioral counseling and random assignment to a 6-week treatment with 2-mg nicotine gum or placebo followed by a 6-week taper period. Women who did not quit smoking were instructed to reduce the number of cigarettes smoked by substituting with gum. Measures of tobacco exposure were obtained throughout the study. RESULTS: Participants in the nicotine (nequals;100) and placebo (nequals;94) groups were comparable in age, race/ethnicity, and smoking history. Biochemically validated smoking-cessation rates were not significantly higher with nicotine gum compared with placebo (after 6 weeks of treatment: 13% compared with 9.6%, P=.45; at 32–34 weeks of gestation: 18% compared with 14.9%, P=.56). Using a completer analysis, nicotine gum significantly reduced the number of cigarettes smoked per day (nicotine gum: −5.7 [standard deviation (SD)=6.0]; placebo: −3.5 [SD=5.7], P=.035), and cotinine concentration (nicotine gum: −249 ng/mL [SD=397]; placebo: −112 ng/mL [SD=333]; P=.04). Birth weights were significantly greater with nicotine gum compared with placebo (3,287 g [SD=566] and 2,950 g [SD=653], respectively, P<.001). Gestational age was also greater with nicotine-replacement therapy than with placebo (38.9 weeks [SD=1.7] and 38.0 weeks [SD=3.3], respectively; P=.014). CONCLUSION: Although nicotine gum did not increase quit rates, use of nicotine gum increased birth weight and gestational age, two key parameters in predicting neonatal wellbeing. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT00115687 LEVEL OF EVIDENCE: I

Dehydroepiandrosterone Combined with Exercise Improves Muscle Strength and Physical Function in Frail Older Women

OBJECTIVES: To investigate the effects of dehydroepiandrosterone (DHEA) combined with exercise on bone mass, strength, and physical function in older, frail women.

Targeted naltrexone for early problem drinkers.

Most published studies of the efficacy of naltrexone for alcohol treatment have focused on daily medication for relapse prevention among abstinent alcoholics. The present study compared the effects of naltrexone with those of placebo in a sample of early problem drinkers who received study medication either daily or targeted to situations identified by the patients as being high risk for heavy drinking. Patients (n = 153; 58% male) were randomly assigned to receive naltrexone (50 mg) or placebo on a daily or targeted basis, yielding comparable numbers of patients in each of four treatment groups. Patients were trained to use structured nightly diaries in which they recorded their alcohol consumption and medication intake. Analysis was conducted with hierarchical linear modeling. Irrespective of whether they received naltrexone or placebo, patients in the targeted condition showed a reduced likelihood of any drinking. There was a reduced likelihood of heavy drinking, both for patients who received naltrexone and for patients who were in the targeted groups (either naltrexone or placebo), although these effects diminished as the number of tablets available to the targeted groups was reduced over the 8-week treatment period. Although the effect was a modest one, daily naltrexone reduced the risk of heavy drinking in this patient group. Furthermore, use of a targeted approach to medication treatment appears to be a useful strategy for reducing both drinking and heavy drinking. Efforts to replicate these findings are warranted, since they suggest that schedules of medication administration other than daily should be evaluated for treatment of problem drinking.

Psychometric properties of the Short Index of Problems as a measure of recent alcohol-related Problems

BACKGROUND The Drinker Inventory of Consequences (DrInC) measures overall consequences of drinking and yields five subscale scores. A short form of the DrInC, the Short Index of Problems (SIP), was developed for use when time does not permit completion of the DrInC. This study investigates the psychometric properties of the SIP. METHODS The study sample consisted of 153 problem drinkers who were participants in a placebo-controlled trial of naltrexone and brief counseling. RESULTS The SIP showed good internal consistency, good concurrent validity, and adequate stability. Four of the five SIP subscales contributed unique variance beyond general drinking consequences. CONCLUSIONS The SIP is useful for measuring drinking consequences in a sample of problem drinkers, and the subscale scores can be interpreted clinically. Further research on the SIP in other populations is warranted.

A Double-blind, Randomized Trial of Sertraline for Alcohol Dependence: Moderation by Age of Onset and 5-HTTLPR Genotype

Late-onset/low-vulnerability alcoholics (LOAs) appear to drink less when treated with a selective serotonin reuptake inhibitor than placebo, whereas early-onset/high-vulnerability alcoholics (EOAs) show the opposite effect. We conducted a 12-week, parallel-group, placebo-controlled trial of the efficacy of sertraline in alcohol dependence (AD). We compared the effects in LOAs versus EOAs and examined the moderating effects of a functional polymorphism in the serotonin transporter gene. Patients (N = 134, 80.6% male, 34.3% EOAs) with Diagnostic and Statistical Manual of Mental Disorders-IV AD received up to 200 mg of sertraline (n = 63) or placebo (n = 71) daily. We used urn randomization, and patients were genotyped for the tri-allelic 5-hydroxytryptamine transporter protein linked promoter region polymorphism. Planned analyses included main and interaction effects of medication group, age of onset (≤25 years vs >25 years), and genotype (L&vprime;/L&vprime; vs S&vprime; carriers) on drinking outcomes. Results showed that the moderating effect of age of onset on the response to sertraline was conditional on genotype. There were no main or interaction effects among S&vprime; allele carriers. However, in L&vprime; homozygotes, the effects of medication group varied by age of onset (P = 0.002). At the end of treatment, LOAs reported fewer drinking and heavy drinking days when treated with sertraline (P = 0.011), whereas EOAs had fewer drinking and heavy drinking days when treated with placebo (P < 0.001). The small cell sizes and high rate of attrition, particularly for L&vprime; homozygotes, render these findings preliminary and their replication in larger samples necessary. Because AD is common, particularly in medical settings, and selective serotonin reuptake inhibitors are widely prescribed by practitioners, these findings have potential public health significance and warrant further evaluation.

Using daily interactive voice response technology to measure drinking and related behaviors in a pharmacotherapy study

BACKGROUND Interactive voice response technology (IVR) allows investigators to collect daily measures of drinking, medication adherence, mood, and other treatment-relevant variables that may change day to day during a clinical trial. Despite these advantages, no published studies have used IVR in alcohol pharmacotherapy trials. METHODS Subjects provided daily data via IVR during the 12-week treatment period. Seven subjects completed the trial. RESULTS We found a high level of participant adherence to the IVR protocol, higher levels of drinking reported by IVR than by a commonly used recall method, and distinct within-day associations between daily mood and alcohol consumption: these could not be obtained through traditional assessment methods. CONCLUSIONS IVR seems to be feasible for the collection of daily indicators of treatment outcomes and processes in pharmacotherapy studies among problem drinkers.