William H. Zywiak

Association of the 5-HTT gene-linked promoter region (5-HTTLPR) polymorphism with psychiatric disorders: review of psychopathology and pharmacotherapy.

Serotonin (5-HT) regulates important biological and psychological processes including mood, and may be associated with the development of several psychiatric disorders. An association between psychopathology and genes that regulate 5-HT neurotransmission is a robust area of research. Identification of the genes responsible for the predisposition, development, and pharmacological response of various psychiatric disorders is crucial to the advancement of our understanding of their underlying neurobiology. This review highlights research investigating 5-HT transporter (5-HTTLPR) polymorphism, because studies investigating the impact of the 5-HTTLPR polymorphism have demonstrated significant associations with many psychiatric disorders. Decreased transcriptional activity of the S allele (“risk allele”) may be associated with a heightened amygdala response leading to anxiety-related personality traits, major depressive disorder, suicide attempts, and bipolar disorder. By contrast, increased transcriptional activity of the L allele is considered protective for depression but is also associated with completed suicide, nicotine dependence, and attention deficit hyperactivity disorder. For some disorders, such as post-traumatic stress disorder and major depressive disorder, the research suggests that treatment response may vary by allele (such as an enhanced response to serotonin specific reuptake inhibitors in patients with major depressive disorder and post-traumatic stress disorder with L alleles), and for alcohol dependence, the association and treatment for S or L alleles may vary with alcoholic subtype. While some studies suggest that 5-HTTLPR polymorphism can moderate the response to pharmacotherapy, the association between 5-HTTLPR alleles and therapeutic outcomes is inconsistent. The discovery of triallelic 5-HTTLPR alleles (LA/LG/S) may help to explain some of the conflicting results of many past association studies, while concurrently providing more meaningful data in the future. Studies assessing 5-HTTLPR as the solitary genetic factor contributing to the etiology of psychiatric disorders continue to face the challenges of statistically small effect sizes and limited replication.

The Important People Drug and Alcohol Interview: Psychometric Properties, Predictive Validity, and Implications for Treatment

Research with the Important People instrument has shown that social support for abstinence is related to alcohol treatment outcomes, but less work has been done on the role of network support in drug treatment outcomes. A drug and alcohol version of the Important People instrument (IPDA) was developed and administered to 141 patients in residential treatment for cocaine dependence. Three components were found, all with acceptable internal consistency: (a) substance involvement of the network, (b) general/treatment support, and (c) support for abstinence. These components and three fundamental network characteristics (size of daily network, size of network, and importance of the most important people) were investigated as correlates of pretreatment and posttreatment alcohol and drug use. The general/treatment support component and network size were inversely related to pretreatment days using drugs, whereas network substance involvement positively correlated with pretreatment drinking frequency. Size of the daily network predicted less drinking, less drug use, and less problem severity during the 6 months after treatment, whereas general/treatment support and support for abstinence did not predict outcome. Network substance involvement decreased for patients who stayed abstinent but not for those who later relapsed. Results suggest that increasing the number of people the patient sees daily while replacing substance-involved with abstinent-supportive people may improve treatment outcomes. Treatment programs may use the IPDA to identify clients most likely to benefit from changes in their social networks.

Intravenous Ghrelin Administration Increases Alcohol Craving in Alcohol-Dependent Heavy Drinkers: A Preliminary Investigation

BACKGROUND There is a need to identify novel pharmacologic targets to treat alcoholism. Animal and human studies suggest a role for ghrelin in the neurobiology of alcohol dependence and craving. Here, we were the first to test the hypothesis that intravenous administration of exogenous ghrelin acutely increases alcohol craving. METHODS This was a double-blind, placebo-controlled human laboratory proof-of-concept study. Nontreatment-seeking, alcohol-dependent, heavy-drinking individuals were randomized to receive intravenous ghrelin 1 mcg/kg, 3 mcg/kg or 0 mcg/kg (placebo), followed by a cue-reactivity procedure, during which participants were exposed to neutral (juice) and alcohol cues. The primary outcome variable was the increase in alcohol craving (also called urge) for alcohol, assessed by the Alcohol Visual Analogue Scale. RESULTS Out of 103 screenings, 45 individuals received the study drug. Repeated measures of analysis of covariance revealed a group effect across ghrelin doses in increasing alcohol craving (p < .05). A dose-specific examination revealed a significant effect of ghrelin 3 mcg/kg versus placebo in increasing alcohol craving (p < .05) with a large effect size (d = .94). By contrast, no significant ghrelin effect was found in increasing either urge to drink juice or food craving (p = ns). No significant differences in side effects were found (p = ns). CONCLUSIONS Intravenous administration of exogenous ghrelin increased alcohol craving in alcohol-dependent heavy-drinking individuals. Although the small sample requires confirmatory studies, these findings provide preliminary evidence that ghrelin may play a role in the neurobiology of alcohol craving, thus demonstrating a novel pharmacologic target for treatment.

Exploratory findings from the Reasons for Drinking Questionnaire.

Marlatt and Gordons (1985) relapse prevention therapy has received widespread interest and application. The categorization of relapse precipitants was one of the original central features of this model. In more recent iterations of this therapy, increasing emphasis has been placed on coping strategies. In the present article, exploratory findings from a prospective naturalistic alcohol treatment study employing the Reasons for Drinking Questionnaire are reported. A relapse precipitants scoring algorithm is presented allowing relapses to be categorized as either negative affect relapses, social pressure relapses, or craving/cued relapses. Exploratory findings suggest that social pressure relapses are more likely to repeat, and that negative affect and craving/cued relapses are more severe. Perhaps most interestingly, craving/cued relapses appear to subside during the first 6 months following treatment initiation, but subsequent risk for this type of relapse returns if the client has relapsed. However, these findings are still early in a continuing exploration of these issues in relapse prevention.

A human laboratory pilot study with baclofen in alcoholic individuals.

Preclinical and clinical studies show that the GABA(B) receptor agonist baclofen may represent a pharmacotherapy for alcohol dependence (AD). However, the mechanisms by which baclofen affects drinking are not well characterized; thus this pilot study investigated possible baclofens biobehavioral mechanisms. The design was a double-blind controlled randomized human laboratory pilot study. Fourteen non-treatment seeking alcohol-dependent heavy drinking subjects received either baclofen 10mg t.i.d. or an active placebo (cyproheptadine 2mg t.i.d., to control for sedation) for a 7-day period. At day 8, participants performed an alcohol cue-reactivity (CR) followed by an alcohol self-administration (ASA). Additionally, we explored possible moderators that might guide future larger studies, i.e. anxiety, family history and onset of alcoholism, and D4 dopamine receptor (DRD4) and 5-HTTLPR polymorphisms. The main results were a significant effect of baclofen for increasing stimulation (p=.001) and sedation (p<.01). Furthermore, when drinking during the ASA and the 2 days before was analyzed as a composite variable, there was a significant effect of baclofen to reduce alcohol consumption (p<.01). As for the exploratory analyses, baclofens effects to increase alcohol sedation and to reduce alcohol consumption were limited to those individuals with DRD4 ≥7 repeats (DRD4L). Yet, baclofens effects on alcohol consumption were also moderated by 5-HTTLPR LL genotype. In conclusion, baclofens ability to reduce alcohol drinking may be related to its effects on the biphasic effects of alcohol, but larger studies are needed to confirm these preliminary findings.

A Within‐Group Design of Nontreatment Seeking 5‐HTTLPR Genotyped Alcohol‐Dependent Subjects Receiving Ondansetron and Sertraline

BACKGROUND Serotonergic mechanisms are associated with the development of alcohol dependence (AD), however, studies evaluating serotonergic medications have produced conflicting results. One hypothesis suggests that differential response may be due to a functional polymorphism of the 5-HTTLPR promoter region of the serotonin re-uptake transporter (5-HTT). The L/L genotype is postulated to be associated with early onset alcoholism and the S/S or S/L genotypes associated with late onset alcoholism. The aim of this study was to match and mismatch L/L, S/S, or S/L genotypes with administration of ondansetron and sertraline. METHODS Fifteen nontreatment seeking alcohol-dependent individuals were randomized to 1 of 2 counterbalanced arms to receive either 200 mg/d of sertraline or ondansetron 0.5 mg/d for 3 weeks followed by an alcohol self-administration experiment (ASAE), then received placebo for 3 weeks followed by a second ASAE. Participants then received the alternate drug for 2 weeks followed by a third ASAE. RESULTS At the first ASAE compared to sertraline, ondansetron significantly improved drinking outcomes for the L/L genotype for the ASAE volume consumed (100% reduction based on between-subjects comparison, t = 2.35), and for drinks per drinking day during the 7 days prior to the ASAE (79% reduction and t = 4.34). Compared with ondansetron for S/S or S/L genotypes, outcomes at ASAE 1 for sertraline and S/S or S/L genotypes are opposite than hypothesized. Overall, subjects reduced drinking across their participation in the trial, as there appears to be an order effect. CONCLUSION This study suggests that ondansetron may reduce alcohol consumption in alcohol-dependent individuals who have the L/L genotype as measured naturalistically and during the ASAE. By contrast there was no support that sertraline reduces alcohol use in individuals who have S/S or S/L genotypes. Evidence in the literature suggests that AD in some individuals may be influenced by a gene by socio-environmental interaction making pharmacological treatment with serotonergic drugs complex. Research must consider that typologies may predict successful treatment of AD in future trials.

Homelessness and Substance Misuse: A Tale of Two Cities

In this article we examine the relationship between alcohol and drug misuse among the literally homeless (those living out of doors and in emergency shelters) in Hartford, Connecticut and Providence, Rhode Island, two northeastern U.S. cities of comparable size. We worked with homeless advocacy organizations in both cities, using a point-in-time census (N = 1058) and random sample (N = 66) in Hartford, and a sampling of clients (N = 82) of six shelters serving residents of Providence (N = 82). We found substance misuse relevant in 47.2% of the homeless in Hartford and in 45.1% of the homeless in Providence. We conclude that there is a great need for substance treatment services inside shelters, soup kitchens, and day centers so that homeless individuals have an opportunity to engage in treatment within their own milieu.

Helping Others and Long-term Sobriety: Who Should I Help to Stay Sober?

Examination of the change strategies associated with successful long-term sobriety remains an understudied area in addiction research. The following study recruited individuals with long-term sobriety (range 16–25 years continuous abstinence). Subjects (n = 11) were surveyed on demographic information, problem history, Alcoholics Anonymous (AA) affiliation, and helping behaviors within several life domains over the course of sobriety. General helping behaviors increased from lower levels in the month prior to getting sober, to moderate levels at 1 year of sobriety, but did not continue to increase with additional years of sobriety. Levels of general help to others at home, work, and 12-step programs were similar at varying lengths of sobriety. Whereas overall levels of general help given to others were similar across settings, helping other alcoholics, as opposed to helping others at home or work, was rated as contributing the most to staying sober. Across time, alcoholics increased participation in helping behaviors specific to 12-step programs. The utility of helping others as a behavioral strategy to maintain successful addictive behavioral change is discussed.

Role of the α1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial.

Evidence suggests that the norepinephrine system represents an important treatment target for alcohol dependence (AD) and the α1‐blocker prazosin may reduce alcohol drinking in rodents and alcoholic patients. The α1‐blocker doxazosin demonstrates a more favorable pharmacokinetic profile than prazosin, but has never been studied for AD. A double‐blind placebo‐controlled randomized clinical trial was conducted in AD individuals seeking outpatient treatment. Doxazosin or matched placebo was titrated to 16 mg/day (or maximum tolerable dose). Drinks per week (DPW) and heavy drinking days (HDD) per week were the primary outcomes. Family history density of alcoholism (FHDA), severity of AD and gender were a priori moderators. Forty‐one AD individuals were randomized, 30 (doxazosin = 15) completed the treatment phase and 28 (doxazosin = 14) also completed the follow‐up. There were no significant differences between groups on DPW and HDD per week. With FHDA as a moderator, there were significant FHDA × medication interactions for both DPW (pcorrected = 0.001, d = 1.18) and HDD (pcorrected = 0.00009, d = 1.30). Post hoc analyses revealed that doxazosin significantly reduced alcohol drinking in AD patients with high FHDA and by contrast increased drinking in those with low FHDA. Doxazosin may be effective selectively in AD patients with high FHDA. This study provides preliminary evidence for personalized medicine using α1‐blockade to treat AD. However, confirmatory studies are required.

Preliminary findings on the use of metadoxine for the treatment of alcohol dependence and alcoholic liver disease

Metadoxine is approved in Europe for alcohol intoxication and is also indicated for alcoholic liver disease (ALD). This study aims to investigate the use of metadoxine as a potential pharmacotherapy for alcohol dependence (AD).