Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings.
Biochemical Pharmacology Volume 75, Issue 1, 1 January 2008, Pages 34-56

The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)-approved medications naltrexone and acamprosate have shown mixed results in clinical trials.

Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome.

Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious.

Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study.

Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision.

Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials.

Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic.

As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.

Read Full Abstract

Request Reprint E-Mail: bankolejohnson@virginia.edu
_________________________________________________________________

Computational models of ethanol-induced neurodevelopmental toxicity across species: Implications for risk assessment
Birth Defects Research Part B: Developmental and Reproductive Toxicology
Early View Published online 26 December 2007

Computational, systems-based approaches can provide a quantitative construct for evaluating risk in the context of mechanistic data. Previously, we developed computational models for the rat, mouse, rhesus monkey, and human, describing the acquisition of adult neuron number in the neocortex during the key neurodevelopmental processes of neurogenesis and synaptogenesis.

Here we apply mechanistic data from the rat describing ethanol-induced toxicity in the developing neocortex to evaluate the utility of these models for analyzing neurodevelopmental toxicity across species.

Our model can explain long-term neocortical neuronal loss in the rodent model after in utero exposure to ethanol based on inhibition of proliferation during neurogenesis.

Our human model predicts a significant neuronal deficit after daily peak BECs reaching 10-20 mg/dl, which is the approximate BEC reached after drinking one standard drink within one hour. In contrast, peak daily BECs of 100 mg/dl are necessary to predict similar deficits in the rat.

Our model prediction of increased sensitivity of primate species to ethanol-induced inhibition of proliferation is based on application of in vivo experimental data from primates showing a prolonged rapid growth period in the primate versus rodent neuronal progenitor population.

To place our predictions into a broader context, we evaluate the evidence for functional low-dose effects across rats, monkeys, and humans.

Results from this critical evaluation suggest subtle effects are evident at doses causing peak BECs of approximately 20 mg/dl daily, corroborating our model predictions.

Our example highlights the utility of a systems-based modeling approach in risk assessment.

Read Full Abstract


Request Reprint E-Mail: faustman@u.washington.edu
________________________________________________________

GABA-A2 receptor subunit gene (GABRA2) polymorphisms and risk for alcohol dependence.
Journal of Psychiatric Research
Volume 42, Issue 3, February 2008, Pages 184-191

Gamma-aminobutyric acid (GABA) A receptors are believed to mediate some of the physiological and behavioral actions of ethanol. Recent studies have suggested that genetic variants of the GABA-A receptor alpha2 subunit gene (GABRA2) are associated with alcohol dependence.

The aim of this study is to confirm and extend the role of GABRA2 haplotypes in the liability to alcohol dependence.

One genetic variant was detected to significantly differ between alcohol-dependent subjects and controls. Two common 8 SNP haplotypes and their complementary alleles were identified containing this SNP and were present in 89.9% of controls and 93.4% of the alcohol-dependent individuals.

One of the haplotypes (T-C-A-C-A-T-T-C) was significantly associated with alcohol dependence and characteristics of alcohol withdrawal and severity of alcohol dependence (delirium tremens, withdrawal seizures).

These findings support and extend the three previous studies implicating a GABA-A receptor subunit as contributing to the genetic risk for alcohol dependence. Possible implications of these findings are discussed.

Read Full Abstract

Request Reprint E-Mail: michael.soyka@med.uni-muenchen.de
________________________________________________________________

News Release - Researchers Show that Fibrosis can be Stopped, Cured and Reversed

December 27, 2007

Modified Protein Developed by UC San Diego Researchers May Lead to First Cure for Cirrhosis of the Liver

University of California, San Diego researchers have proven in animal studies that fibrosis in the liver can be not only stopped, but reversed. Their discovery, to be published in PLoS Online on December 26, opens the door to treating and curing conditions that lead to excessive tissue scarring such as viral hepatitis, fatty liver disease, cirrhosis, pulmonary fibrosis, scleroderma and burns.
. . . . . .

Read Full News Release

_________________________________________________________________

A Ribosomal S-6 Kinase–Mediated Signal to C/EBP-β Is Critical for the Development of Liver Fibrosis
PLoS ONE 2(12): e1372

In response to liver injury, hepatic stellate cell (HSC) activation causes excessive liver fibrosis. Here we show that activation of RSK and phosphorylation of C/EBPβ on Thr217 in activated HSC is critical for the progression of liver fibrosis.

Chronic treatment with the hepatotoxin CCl₄ induced severe liver fibrosis in C/EBPβ^+/+ mice but not in mice expressing C/EBPβ-Ala217, a non-phosphorylatable RSK-inhibitory transgene. C/EBPβ-Ala217 was present within the death receptor complex II, with active caspase 8, and induced apoptosis of activated HSC.

The C/EBPβ-Ala217 peptides directly stimulated caspase 8 activation in a cell-free system. C/EBPβ^+/+ mice with CCl₄-induced severe liver fibrosis, while continuing on CCl₄, were treated with a cell permeant RSK-inhibitory peptide for 4 or 8 weeks. The peptide inhibited RSK activation, stimulating apoptosis of HSC, preventing progression and inducing regression of liver fibrosis.

We found a similar activation of RSK and phosphorylation of human C/EBPβ on Thr266 (human phosphoacceptor) in activated HSC in patients with severe liver fibrosis but not in normal livers, suggesting that this pathway may also be relevant in human liver fibrosis.

These data indicate that the RSK-C/EBPβ phosphorylation pathway is critical for the development of liver fibrosis and suggest a potential therapeutic target.

Download Article (PDF)

_______________________________________________________________

The DRAM, 3(11) - Childhood Sexual Abuse, Age of First Drink, and Onset of Alcohol Dependence
December 26, 2007

Studies linking childhood sexual abuse (CSA) to higher likelihood of alcohol dependence (AD) later in life (i.e., Dinwiddie et al., 2000; Fergusson, Horwood, & Lynskey, 1996; Kendler et al., 2000; Kilpatrick et al., 2000; Molnair, Buka, & Kessler, 2001; Nelson et al., 2002) might lack adequate control for environmental and genetic factors that influence the relationship between CSA and AD.

These studies are also inconclusive because an earlier age of first drink is associated with later AD regardless of CSA status (DeWit, 2000).

This week’s DRAM reviews a study that controls for the influence of environmental and genetic characteristics, as well as the influence of drinking at an early age using a sample of twins
. . . . . .

Read Full Article
_______________________________________________________________

Let’s Raise a Glass to Fairness

By DAVID LEONHARDT
Published: December 26, 2007


“We are fortunate to be living in a time when there is a lot of good wine from around the world,” Philip Cook was telling me the other day.
. . . . .
The main cause of this golden age of inexpensive wine is the obvious one: globalization. Once confined to a small part of Europe, the making (and exporting) of great wine is now done across the globe.

But there is also another factor that gets less attention. Since the early 1990s, the federal tax on wine — $1.07 a gallon — hasn’t budged. The taxes on beer and liquor haven’t changed either, which means that, in inflation-adjusted terms, alcohol taxes have been steadily falling.

Each of the three taxes is now effectively 33 percent lower than it was in 1992. Since 1970, the federal beer tax has plummeted 63 percent. Many states taxes have also been falling.

At first blush, this sounds like good news: who likes to pay taxes, right? But taxes serve a purpose beyond merely raising general government revenue. Taxes on a given activity are also supposed to pay the costs that activity imposes on society. And for all that is wonderful about wine, beer and liquor, they clearly bring some heavy costs.
. . . . .

Mr. Cook, besides being a wine lover, has been thinking about the costs and benefits of alcohol for much of his career, and he has come up with a blunt way of describing the problem. “Do you think we should be subsidizing alcohol?” he asks. “Because that’s what we’re doing.”

. . . . And if it were somehow possible to tax only those people who were going to drive drunk in the future, it would be a wonderful idea. (Then again, we might just want to take away their driver’s licenses.) Barring clairvoyance, though, raising alcohol taxes from their current lows seems to be the fairest solution.

Mr. Cook has written a wonderful little book, “Paying the Tab,” making this case. In it, he draws on history, political philosophy and straight economics to point out that higher alcohol taxes would fit squarely in the American tradition.
. . . . .

Read Full Article

_________________________________________________________________

News Release - Cognitive, genetic clues identified in imaging study of alcohol addiction
University of North Carolina at Chapel Hill
Public release date: 25-Dec-2007

People with clinical addictions know first-hand the ravages the disease can take on almost every aspect of their lives. So why do they continue addictive behaviors, even after a period of peaceable abstinence"

Some answers appear rooted in regions of the brain active during decision making.

"It's perhaps not just that people are slaves to pleasure, but that they have trouble thinking through a decision," said Charlotte Boettiger, an assistant professor of psychology at the University of North Carolina at Chapel Hill, and lead author of a study in the December issue of the Journal of Neuroscience that took a novel tack in addiction imaging research.

"Our data suggest there may be a cognitive difference in people with addictions," Boettiger said. "Their brains may not fully process the long-term consequences of their choices. They may compute information less efficiently."

The study also found that a variant of the COMT gene, which controls the level of the neurotransmitter dopamine in the cortex, was associated with a tendency to make impulsive decisions and with high activity in certain brain areas during decision making.
. . . . .

Read Full News Release

____________________________________________________________

Immediate Reward Bias in Humans: Fronto-Parietal Networks and a Role for the Catechol-O-Methyltransferase 158^Val/Val Genotype
The Journal of Neuroscience, December 26, 2007, 27(52):14383-14391


The tendency to choose lesser immediate benefits over greater long-term benefits characterizes alcoholism and other addictive disorders. However, despite its medical and socioeconomic importance, little is known about its neurobiological mechanisms.

Brain regions that are activated when deciding between immediate or delayed rewards have been identified (McClure et al., 2004, 2007), as have areas in which responses to reward stimuli predict a paper-and-pencil measure of temporal discounting (Hariri et al., 2006). These studies assume "hot" and "cool" response selection systems, with the hot system proposed to generate impulsive choices in the presence of a proximate reward. However, to date, brain regions in which the magnitude of activity during decision making reliably predicts intertemporal choice behavior have not been identified.

Here we address this question in sober alcoholics and non-substance-abusing control subjects and show that immediate reward bias directly scales with the magnitude of functional magnetic resonance imaging bold oxygen level-dependent (BOLD) signal during decision making at sites within the posterior parietal cortex (PPC), dorsal prefrontal cortex (dPFC), and rostral parahippocampal gyrus regions.

Conversely, the tendency of an individual to wait for a larger, delayed reward correlates directly with BOLD signal in the lateral orbitofrontal cortex. In addition, genotype at the Val158Met polymorphism of the catechol-O-methyltransferase gene predicts both impulsive choice behavior and activity levels in the dPFC and PPC during decision making.

These genotype effects remained significant after controlling for alcohol abuse history.

These results shed new light on the neurobiological underpinnings of temporal discounting behavior and identify novel behavioral and neural consequences of genetic variation in dopamine metabolism.

Read Full Abstract

Request Reprint E-Mail: cab@unc.edu
____________________________________________________________
__________________________________________________________

Doctors may soon offer what alcoholics need (if not what they want)

By Melissa Healy, Los Angeles Times Staff Writer
December 24, 2007

British songstress Amy Winehouse, who croons "no, no, no" to rehab, has a lot of American company this time of year -- both in her heavy-drinking ways and her unwillingness to spend weeks in a specialized facility to get sober.

But experts say there may be new hope for rehab refuseniks like Winehouse and an estimated 5.7 million alcoholics in the United States who are not in treatment -- hope that could be as close as the family doctor.

New research and a growing arsenal of medications have set the stage for a major shift in the treatment of alcoholism, from specialized clinic to the "primary care office setting," the Journal of the American Medical Assn. reported in its Dec. 5 issue.
. . . . . .
Read Full Article
____________________________________________________________________

Network Support for Drinking: An Application of Multiple Groups Growth Mixture Modeling to Examine Client-Treatment Matching
J. Stud. Alcohol Drugs 69: 21-29, 2008


The current study re-examined the Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity) hypothesis that individuals with high network support for drinking would have the best treatment outcomes if they were assigned to twelve-step facilitation (TSF).

Drinking consequences, as measured by the Drinking Inventory of Consequences, was the primary outcome measure. Growth mixture models with multiple groups were used to estimate the drinking consequence trajectories of 952 outpatients during the 12 months following treatment for each of the three Project MATCH treatment conditions. Growth factors within latent trajectory classes were regressed on network support for drinking to assess whether treatment condition moderated the relationship between network support for drinking and drinking consequences over time.

Three latent classes were identified, representing low (n = 154, 16.2%), medium (n = 400, 42%), and high (n = 398, 41.8%) levels of drinking consequences. Classes did not differ across treatment groups. Greater network support for drinking predicted more drinking consequences over time but only for clients assigned to cognitive-behavioral therapy and motivational enhancement therapy, not TSF.

This study provides further support for one of the original Project MATCH matching hypotheses: Clients with social networks supportive of drinking had better outcomes immediately after treatment if they were assigned to TSF.

Because the original Project MATCH studies found this matching effect only at the 3-year follow-up, these results add validity to the network support for drinking matching effect.

The study also provides additional evidence that accounting for heterogeneity in alcohol treatment outcomes is important for accurately estimating treatment effectiveness.

Read Full Abstract

Request Reprint E-Mail: jwu24@uic.edu
___________

Alcohol Consumption in Australia: A Snapshot, 2004-05


This article provides an overview of the level, prevalence and type of alcohol consumption; the health status, risk factors and demographic characteristics of those who drink alcohol at risky or high risk levels; as well as information on mortality and health costs.

This article uses data from the 2004-05 National Health Survey (NHS), the 2004-05 National Aboriginal and Torres Strait Islander Health Survey (NATSIHS) and the Causes of Death Collection.

This article also draws on measures of alcohol consumption from the Apparent Consumption of Alcohol Collection, which uses excise and import trade administrative data to produce an indirect measure of consumption of alcohol, based on a population aged 15 years or more (ABS 2006a).

Data from the 2004 National Drug Strategy Household Survey (NDSHS) are also used in this article (AIHW 2005a).

Both short and long term risk of harm were measured in the 2004-05 NHS (footnote 1). Unless otherwise stated, this article presents NHS information on alcohol consumption for long term risk of harm. Survey respondents were categorised as drinking alcohol at low, risky or high risk levels based on the guidelines of the National Health and Medical Research Council (NHMRC) (footnote 2).

Data were collected in the 2004-05 NHS from those aged 18 years and over, and from those aged 14 and over (with a small sample from 12-13 year olds) in the 2004 NDSHS.

Read Full Report
_______________________________________________________________________

HIDDEN MARKOV MODELS FOR ALCOHOLISM TREATMENT TRIAL DATA
University of Pennsylvania and Syracuse University


In a clinical trial of a treatment for alcoholism, the usual response variable of interest is the number of alcoholic drinks consumed by each subject each day. Subjects in these trials are typically volunteers who are alcoholics, and thus are prone to erratic drinking behaviors, often characterized by alternating periods of heavy drinking and abstinence. For this reason, many statistical models for time series that assume steady behavior over time and white noise errors do not fit alcohol data well.

In this paper, we propose to describe subjects' drinking behavior using a Hidden Markov model (HMM) for categorical data, where the counts of drinks per day are summarized as a categorical variable with three levels, as is the convention in alcohol research.

We compare the HMM's properties to those of other models, focusing on out-of-sample prediction error as well as interpretability; to do this, we analyze data from a clinical trial of the drug Naltrexone using each model.

The HMM performs at a level comparable to the other models with respect to out-of-sample prediction error, and contains unique features that allow for useful clinical interpretations.

Read Full Text (PDF)
__________________________________________________________________

Alcohol Drinking Patterns and Prevalence of Alcohol-Abuse and Dependence in the Israel National Health Survey
Isr J Psychiatry Relat Sci Vol 44 No. 2 (2007) 126–135


Coexistence of disparate religious/cultural mores with regard to alcohol drinking within the changing social milieu of Israel provides an informative environment for investigation of alcohol consumption patternsand alcohol-related mental disorders.

Half of the 4,859 respondents reported any alcohol consumption in the year prior to interview; 5% drink 3 ormore times weekly. DSM-IV criteria for alcohol abuse or dependence (lifetime) were met by 4.3% of respondents. Significantly higher rates were found among males (AOR, adjusted odds ratio=7.3), younger adults (AOR=5.0), immigrants from the former Soviet Union (AOR=2.0), and those who were never married (AOR=1.6).

Under-reporting remains a potential concern in health behavior surveys, particularly in the face of opposing religious norms.

The lifetime prevalence of alcohol abuse in Israel is identical to other European countries while drinking levels are considerably lower, suggesting a biological sensitivity alongside socio-cultural factors.

Read Full Text (PDF)
________________________________________________________________