Safety and tolerability of topiramate and N-acetyl cysteine combination in individuals with alcohol use disorder: a 12 week, randomized, double-blind, pilot study
Safety and tolerability of topiramate and N-acetyl cysteine combination in individuals with alcohol use disorder: a 12 week, randomized, double-blind, pilot study
Topiramate (TPM), a GABA/glutamate modulator, has shown positive results for treating alcohol use disorder (AUD), but causes significant cognitive adverse effects. TPM causes cognitive side effects by reducing glutathione levels in the frontal lobe. N-acetyl cysteine (NAC) increases level of intracellular glutathione. We hypothesized that combining NAC with TPM may mitigate the possible cognitive side effects of TPM, as well as working synergistically in reducing alcohol consumption more efficaciously than using TPM alone. A 12-week, double-blind randomized trial assessing the effects of combining NAC (1200 mg/day) with TPM (200 mg/day) vs TPM alone (i) cognitive side effects caused by TPM, (ii) percentage of heavy drinking days (PHDD) and percentage of days abstinent (PDA) using weekly calendar, and (iii) craving outcomes using the obsessive-compulsive drinking scale. Seventeen participants were randomized into the study (nine received TPM + NAC and eight matching TPM + Placebo). Cognitive adverse events were not significantly different between the treatment arms (P = 0.581). There was no difference in PHDD (P = 0.536) and in PDA over the entire study period (P = 0.892). However, both treatment groups at study end, compared with the baseline, significantly reduced their PHDD and increased their PDA. As for cravings: TPM + NAC group has shown higher level in automaticity of drinking (P = 0.029) and interference due to drinking (P = 0.014) subscales compared with the TPM + Placebo group. No difference was observed between groups in terms of Drinking Obsessions and Alcohol Consumption subscales. This pilot study indicates that combining NAC with TPM is overall safe, but the addition of NAC has no significant benefit over placebo in the incidence of TPM-related cognitive impairment, and alcohol drinking. Furthermore, craving outcomes may become worse with the addition of NAC.
Tryptophan challenge in individuals with schizophrenia and healthy controls: acute effects on circulating kynurenine and kynurenic acid, cognition and cerebral blood flow
Tryptophan challenge in individuals with schizophrenia and healthy controls: acute effects on circulating kynurenine and kynurenic acid, cognition and cerebral blood flow
Cognitive impairments predict poor functional outcomes in people with schizophrenia. These impairments may be causally related to increased levels of kynurenic acid (KYNA), a major metabolic product of tryptophan (TRYP). In the brain, KYNA acts as an antagonist of the of α7-nicotinic acetylcholine and NMDA receptors, both of which are involved in cognitive processes. To examine whether KYNA plays a role in the pathophysiology of schizophrenia, we compared the acute effects of a single oral dose of TRYP (6 g) in 32 healthy controls (HC) and 37 people with either schizophrenia (Sz), schizoaffective or schizophreniform disorder, in a placebo-controlled, randomized crossover study. We examined plasma levels of KYNA and its precursor kynurenine; selected cognitive measures from the MATRICS Consensus Cognitive Battery; and resting cerebral blood flow (CBF) using arterial spin labeling imaging. In both cohorts, the TRYP challenge produced significant, time-dependent elevations in plasma kynurenine and KYNA. The resting CBF signal (averaged across all gray matter) was affected differentially, such that TRYP was associated with higher CBF in HC, but not in participants with a Sz-related disorder. While TRYP did not significantly impair cognitive test performance, there was a trend for TRYP to worsen visuospatial memory task performance in HC. Our results demonstrate that oral TRYP challenge substantially increases plasma levels of kynurenine and KYNA in both groups, but exerts differential group effects on CBF. Future studies are required to investigate the mechanisms underlying these CBF findings, and to evaluate the impact of KYNA fluctuations on brain function and behavior. (Clinicaltrials.gov: NCT02067975).
Proof of concept: Detection of cell free RNA from EDTA plasma in patients with lung cancer and non-cancer patients
Proof of concept: Detection of cell free RNA from EDTA plasma in patients with lung cancer and non-cancer patients
Nucleic acid sequencing technologies have advanced significantly in recent years, thereby allowing for the development of liquid biopsies as new means to detect cancer biomarkers and cancer heterogenicity. Most of the assays available, clinically, focus on cell free DNA (cfDNA), however, cell free RNA (cfRNA) is also present. cfRNA has the potential to complement and improve cancer detection especially in cancers like lung cancer, which are usually only diagnosed at late stages and therefore have poor long-term survival outcomes.
Peripheral blood transcriptomic profiling indicates molecular mechanisms commonly regulated by binge-drinking and placebo-effects
Peripheral blood transcriptomic profiling indicates molecular mechanisms commonly regulated by binge-drinking and placebo-effects
Molecular changes associated with alcohol consumption arise from complex interactions between pharmacological effects of alcohol, psychological/placebo context surrounding drinking, and other environmental and biological factors. The goal of this study was to tease apart molecular mechanisms regulated by pharmacological effects of alcohol - particularly at binge-drinking, from underlying placebo effects. Transcriptome-wide RNA-seq analyses were performed on peripheral blood samples collected from healthy heavy social drinkers (N=16) enrolled in a 12-day randomized, double-blind, cross-over human laboratory trial testing three alcohol doses: Placebo, moderate (0.05g/kg (men), 0.04g/kg (women)), and binge (1g/kg (men), 0.9g/kg (women)), administered in three 4-day experiments, separated by minimum of 7-day washout periods. Effects of beverage doses on the normalized gene expression counts were analyzed within each experiment compared to its own baseline using paired-t-tests. Differential expression of genes (DEGs) across experimental sequences in which each beverage dose was administered, as well as responsiveness to regular alcohol compared to placebo (i.e., pharmacological effects), were analyzed using generalized linear mixed-effects models. The 10% False discovery rate-adjusted DEGs varied across experimental sequences in response to all three beverage doses. We identified and validated 22 protein coding DEGs potentially responsive to pharmacological effects of binge and medium doses, of which 11 were selectively responsive to binge dose. Binge-dose significantly impacted the Cytokine-cytokine receptor interaction pathway (KEGG: hsa04060) across all experimental-sequences that it was administered in, and during dose-extending placebo. Medium dose and placebo impacted pathways hsa05322, hsa04613, and hsa05034, in the first two and last experimental sequences, respectively. In summary, our findings add novel, and confirm previously reported data supporting dose-dependent effects of alcohol on molecular mechanisms and suggest that the placebo effects may induce molecular responses within the same pathways regulated by alcohol. Innovative study designs are required to validate molecular correlates of placebo effects underlying drinking.
A Pilot Analysis of Circulating cfRNA Transcripts for the Detection of Lung Cancer
A Pilot Analysis of Circulating cfRNA Transcripts for the Detection of Lung Cancer
Lung cancers are the leading cause of cancer-related deaths worldwide. Studies have shown that non-small cell lung cancer (NSCLC), which constitutes the majority of lung cancers, is significantly more responsive to early-stage interventions. However, the early stages are often asymptomatic, and current diagnostic methods are limited in their precision and safety. The cell-free RNAs (cfRNAs) circulating in plasma (liquid biopsies) offer a non-invasive detection of spatial and temporal changes occurring in primary tumors since the early stages. To address gaps in the current cfRNA knowledge base, we conducted a pilot study for the comprehensive analysis of transcriptome-wide changes in plasma cfRNA in NSCLC patients. Total cfRNA was extracted from archived plasma collected from NSCLC patients (N = 12), cancer-free former smokers (N = 12), and non-smoking healthy volunteers (N = 12). Plasma cfRNA expression levels were quantified by using a tagmentation-based library preparation and sequencing. The comparisons of cfRNA expression levels between patients and the two control groups revealed a total of 2357 differentially expressed cfRNAs enriched in 123 pathways. Of these, 251 transcripts were previously reported in primary NSCLCs. A small subset of genes (N = 5) was validated in an independent sample (N = 50) using qRT-PCR. Our study provides a framework for developing blood-based assays for the early detection of NSCLC and warrants further validation.
Validation of serotonin transporter mRNA as a quantitative biomarker of heavy drinking and its comparison to ethyl glucuronide/ethyl sulfate: A randomized, double-blind, crossover trial
Validation of serotonin transporter mRNA as a quantitative biomarker of heavy drinking and its comparison to ethyl glucuronide/ethyl sulfate: A randomized, double-blind, crossover trial
The serotonin transporter (SERT) mRNA was previously reported to be a quantitative and pathophysiology-based biomarker of heavy drinking in 5HTTLPR:LL genotype-carriers treated with ondansetron. Here, we validated the potential use of SERT mRNA for quantitative prediction of recent alcohol consumption (in the absence of treatment) and compared it with the known biomarkers ethyl glucuronide (EtG) and ethyl sulfate (EtS).
A randomized, double-blind, placebo-controlled, pharmacogenetic study of ondansetron for treating alcohol use disorder
A randomized, double-blind, placebo-controlled, pharmacogenetic study of ondansetron for treating alcohol use disorder
In a previous study, ondansetron, a serotonin 5-HT receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European-ancestry (EA) participants with moderate-to-severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4) and 5-HT (HTR3A), and 5-HT (HTR3B) receptors. We tested whether (1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA), and (2) that reductions in DPDD are greatest among ondansetron-treated individuals with population-specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B.
A randomized, double-blind, placebo-controlled trial of ondansetron for the treatment of cocaine use disorder with post hoc pharmacogenetic analysis
A randomized, double-blind, placebo-controlled trial of ondansetron for the treatment of cocaine use disorder with post hoc pharmacogenetic analysis
Cocaine use disorder (CUD) has significant consequences and there remain no FDA-approved pharmacotherapies. Ondansetron is an indirect dopaminergic modulator that has shown efficacy in alcohol use disorder, particularly in phenotypic and genotypic subgroups, and was found to be efficacious in a pilot dose-finding trial for CUD.
Mobile Telemedicine for Buprenorphine Treatment in Rural Populations With Opioid Use Disorder
Mobile Telemedicine for Buprenorphine Treatment in Rural Populations With Opioid Use Disorder
The demand for medications for opioid use disorder (MOUD) in rural US counties far outweighs their availability. Novel approaches to extend treatment capacity include telemedicine (TM) and mobile treatment on demand; however, their combined use has not been reported or evaluated.
Clinical and genetic validity of quantitative bipolarity
Clinical and genetic validity of quantitative bipolarity
Research has yet to provide a comprehensive understanding of the genetic basis of bipolar disorder (BP). In genetic studies, defining the phenotype by diagnosis may miss risk-allele carriers without BP. The authors aimed to test whether quantitatively detected subclinical symptoms of bipolarity identifies a heritable trait that infers risk for BP. The Quantitative Bipolarity Scale (QBS) was administered to 310 Old Order Amish or Mennonite individuals from multigenerational pedigrees; 110 individuals had psychiatric diagnoses (20 BP, 61 major depressive disorders (MDD), 3 psychotic disorders, 26 other psychiatric disorders). Familial aggregation of QBS was calculated using the variance components method to derive heritability and shared household effects. The QBS score was significantly higher in BP subjects (31.5 ± 3.6) compared to MDD (16.7 ± 2.0), other psychiatric diagnoses (7.0 ± 1.9), and no psychiatric diagnosis (6.0 ± 0.65) (all p < 0.001). QBS in the whole sample was significantly heritable (h = 0.46 ± 0.15, p < 0.001) while the variance attributed to the shared household effect was not significant (p = 0.073). When subjects with psychiatric illness were removed, the QBS heritability was similar (h = 0.59 ± 0.18, p < 0.001). These findings suggest that quantitative bipolarity as measured by QBS can separate BP from other psychiatric illnesses yet is significantly heritable with and without BP included in the pedigrees suggesting that the quantitative bipolarity describes a continuous heritable trait that is not driven by a discrete psychiatric diagnosis. Bipolarity trait assessment may be used to supplement the diagnosis of BP in future genetic studies and could be especially useful for capturing subclinical genetic contributions to a BP phenotype.
Subgroup Identification in Personalized Treatment of Alcohol Dependence
Subgroup Identification in Personalized Treatment of Alcohol Dependence
Identification of patient subgroups to enhance treatment effects is an important topic in personalized (or tailored) alcohol treatment. Recently, several recursive partitioning methods have been proposed to identify subgroups benefiting from treatment. These novel data mining methods help to address the limitations of traditional regression-based methods that focus on interactions.
Transcriptome profiling and pathway analysis of genes expressed differentially in participants with or without a positive response to topiramate treatment for methamphetamine addiction
Transcriptome profiling and pathway analysis of genes expressed differentially in participants with or without a positive response to topiramate treatment for methamphetamine addiction
Developing efficacious medications to treat methamphetamine dependence is a global challenge in public health. Topiramate (TPM) is undergoing evaluation for this indication. The molecular mechanisms underlying its effects are largely unknown. Examining the effects of TPM on genome-wide gene expression in methamphetamine addicts is a clinically and scientifically important component of understanding its therapeutic profile.
Significant associations of CHRNA2 and CHRNA6 with nicotine dependence in European American and African American populations
Significant associations of CHRNA2 and CHRNA6 with nicotine dependence in European American and African American populations
The direct physiological effects that promote nicotine dependence (ND) are mediated by nicotinic acetylcholine receptors (nAChRs). In line with the genetic and pharmacological basis of addiction, many previous studies have revealed significant associations between variants in the nAChR subunit genes and various measures of ND in different ethnic samples. In this study, we first examined the association of variants in nAChR subunits α2 (CHRNA2) and α6 (CHRNA6) genes on chromosome 8 with ND using a family sample consisting of 1,730 European Americans (EAs) from 495 families and 1,892 African Americans (AAs) from 424 families (defined as the discovery family sample). ND was assessed by two standard quantitative measures: smoking quantity (SQ) and the Fagerström Test for ND (FTND). We found nominal associations for all seven tested SNPs of the genes with at least one ND measure in the EA sample and for two SNPs in CHRNA2 in the AA sample. Of these, associations of SNPs rs3735757 with FTND (P = 0.0068) and rs2472553 with both ND measures (with a P value of 0.0043 and 0.00086 for SQ and FTND, respectively) continued to be significant in the EA sample even after correction for multiple tests. Further, we found several haplotypes that were significantly associated with ND in the EA sample in CHRNA6 and in the both EA and AA samples in CHRNA2. To confirm the associations of the two genes with ND, we conducted a replication study with an independent case-control sample from the SAGE study, which showed a significant association of the two genes with ND, although the significantly associated SNPs were not always the same in the two samples. Together, these findings indicate that both CHRNA2 and CHRNA6 play a significant role in the etiology of ND in AA and EA smokers. Further replication in additional independent samples is warranted.
Topiramate for the treatment of cocaine addiction: a randomized clinical trial
Topiramate for the treatment of cocaine addiction: a randomized clinical trial
No medication has been established as an efficacious treatment for cocaine dependence. We hypothesized that dual modulation of the mesocorticolimbic dopamine system by topiramate-a glutamate receptor antagonist and γ-aminobutyric acid receptor agonist-would result in efficacious treatment for cocaine dependence compared with placebo.
Association, interaction, and replication analysis of genes encoding serotonin transporter and 5-HT3 receptor subunits A and B in alcohol dependence
Association, interaction, and replication analysis of genes encoding serotonin transporter and 5-HT3 receptor subunits A and B in alcohol dependence
On the basis of the converging evidence showing regulation of drinking behavior by 5-HT3AB receptors and the serotonin transporter, we hypothesized that the interactive effects of genetic variations in the genes HTR3A, HTR3B, and SLC6A4 confer greater susceptibility to alcohol dependence (AD) than do their effects individually. We examined the associations of AD with 22 SNPs across HTR3A, HTR3B, and two functional variants in SLC6A4 in 500 AD and 280 healthy control individuals of European descent. We found that the alleles of the low-frequency SNPs rs33940208:T in HTR3A and rs2276305:A in HTR3B were inversely and nominally significantly associated with AD with odds ratio (OR) and 95 % confidence interval of 0.212 and 0.073, 0.616 (P = 0.004) and 0.261 and 0.088, 0.777 (P = 0.016), respectively. Further, our gene-by-gene interaction analysis revealed that two four-variant models that differed by only one SNP carried a risk for AD (empirical P < 1 × 10(-6) for prediction accuracy of the two models based on 10(6) permutations). Subsequent analysis of these two interaction models revealed an OR of 2.71 and 2.80, respectively, for AD (P < 0.001) in carriers of genotype combinations 5'-HTTLPR:LL/LS(SLC6A4)-rs1042173:TT/TG(SLC6A4)-rs1176744:AC(HTR3B)-rs3782025:AG(HTR3B) and 5'-HTTLPR:LL/LS(SLC6A4)-rs10160548:GT/TT(HTR3A)-rs1176744:AC(HTR3B)-rs3782025:AG(HTR3B). Combining all five genotypes resulted in an OR of 3.095 (P = 2.0 × 10(-4)) for AD. Inspired by these findings, we conducted the analysis in an independent sample, OZ-ALC-GWAS (N = 6699), obtained from the NIH dbGAP database, which confirmed the findings, not only for all three risk genotype combinations (Z = 4.384, P = 1.0 × 10(-5); Z = 3.155, P = 1.6 × 10(-3); and Z = 3.389, P = 7.0 × 10(-4), respectively), but also protective effects for rs33940208:T (χ (2) = 3.316, P = 0.0686) and rs2276305:A (χ (2) = 7.224, P = 0.007). These findings reveal significant interactive effects among variants in SLC6A4-HTR3A-HTR3B affecting AD. Further studies are needed to confirm these findings and characterize the molecular mechanisms underlying these effects.
Determination of allelic expression of SNP rs1880676 in choline acetyltransferase gene in HeLa cells
Determination of allelic expression of SNP rs1880676 in choline acetyltransferase gene in HeLa cells
Recently, we reported that several polymorphisms and haplotypes in the choline acetyltransferase gene (ChAT) are associated with nicotine dependence (ND). Of them, SNP rs1880676 is of particular interest because: (1) it is a non-synonymous variant located in the coding region of an alternatively spliced form of ChAT and (2) it is located in several haplotypes that are significantly associated with ND. The objective of this study was to determine, using an in vitro system, whether the alleles G (coding for aspartic acid) or A (coding for asparagine) of rs1880676 have any allele-specific effect on ChAT expression. We first used site-directed mutagenesis to construct two expression vectors differed in the allelic position of rs1880676 (G/A), which were transfected into HeLa cells. We then measured expression of ChAT associated with each allele. We found significant expression differences for the two alleles, with the G allele being expressed significantly greater than A allele (P<0.01 at both mRNA and protein levels). Further, we validated the ChAT expression of the G allele was significantly higher than that of the A allele by using ELISA assay (P=0.00016). We concluded that rs1880676 is functional and that the allelic variations of this polymorphism are involved in developing ND by altering ChAT expression.
Determination of genotype combinations that can predict the outcome of the treatment of alcohol dependence using the 5-HT(3) antagonist ondansetron
Determination of genotype combinations that can predict the outcome of the treatment of alcohol dependence using the 5-HT(3) antagonist ondansetron
The authors previously reported that the 5'-HTTLPR-LL and rs1042173-TT (SLC6A4-LL/TT) genotypes in the serotonin transporter gene predicted a significant reduction in the severity of alcohol consumption among alcoholics receiving the 5-HT3 antagonist ondansetron. In this study, they explored additional markers of ondansetron treatment response in alcoholics by examining polymorphisms in the HTR3A and HTR3B genes, which regulate directly the function and binding of 5-HT3 receptors to ondansetron.
Serotonin transporter and receptor genes significantly impact nicotine dependence through genetic interactions in both European American and African American smokers
Serotonin transporter and receptor genes significantly impact nicotine dependence through genetic interactions in both European American and African American smokers
Pharmacologic studies implicate a significant role of genes encoding the serotonin transporter (SLC6A4) and the 5-HT3AB subunits HTR3A and HTR3B in nicotine dependence (ND). However, whether they are involved in ND remains largely unknown.
Alcohol-medical drug interactions
Alcohol-medical drug interactions
Concomitant use of alcohol and medications may lead to potentially serious medical conditions. Increasing prescription medication abuse in today's society necessitates a deeper understanding of the mechanisms involved in alcohol-medication interactions in order to help prevent adverse events. Interactions of medications with alcohol result in altered bioavailability of the medication or alcohol (pharmacokinetic interactions) or modification of the effects at receptor or ion channel sites to alter behavioral or physical outcome (pharmacodynamic interactions). The nature of pharmacokinetic or pharmacodynamic interactions involved in alcohol-medication interactions may differ between acute and chronic alcohol use and be influenced by race, gender, or environmental or genetic factors. This review focuses on the mechanisms underlying pharmacokinetic and pharmacodynamic interactions between alcohol and medications and provides examples for such interactions from replicated research studies. In conclusion, further translational research is needed to address several gaps in our current knowledge of alcohol-medication interactions, including those under various pathologic conditions.
Editorial: Harnessing placebo mechanisms
Serotonin transporter genomic biomarker for quantitative assessment of ondansetron treatment response in alcoholics
Serotonin transporter genomic biomarker for quantitative assessment of ondansetron treatment response in alcoholics
Paucity of sensitive biomarkers to quantify transient changes in alcohol consumption level remains a critical barrier for the development of efficacious therapeutic agents to treat alcoholism. Recently, in an 11-week, randomized, placebo-controlled, double-blind trial of 283 alcohol-dependent individuals, we demonstrated that ondansetron was efficacious at reducing the severity of drinking (measured as drinks per drinking day; DDD) in alcoholics carrying the LL compared with the LS/SS genotype of the serotonin transporter gene, 5'-HTTLPR. Using peripheral blood samples from a cohort of 41 of these subjects, we determined whether there was a relationship between mRNA expression level of the 5'-HTTLPR genotypes (measured at weeks 0, 4, and 11) and self-reported alcohol consumption following treatment with either ondansetron (4 μg/kg twice daily; N = 19) or placebo (N = 22). Using a mixed-effects linear regression model, we analyzed the effects of DDD and 5'-HTTLPR genotypes on mRNA expression levels within and between the ondansetron and placebo groups. We found a significant three-way interaction effect of DDD, 5'-HTTLPR genotypes, and treatment on mRNA expression levels (p = 0.0396). Among ondansetron but not placebo recipients, there was a significant interaction between DDD and 5'-HTTLPR genotype (p = 0.0385 and p = 0.7938, respectively). In the ondansetron group, DDD was associated positively with mRNA levels at a greater rate of expression alteration per standard drink in those with the LL genotype (slope = +1.1698 in ln scale). We suggest that the combination of the LL genotype and 5'-HTTLPR mRNA expression levels might be a promising and novel biomarker to quantify drinking severity in alcoholics treated with ondansetron.
Integration of virtual platforms for enhanced conference experience: Data-based evidence from the Society of Interdisciplinary Placebo Studies 2021 conference
Integration of virtual platforms for enhanced conference experience: Data-based evidence from the Society of Interdisciplinary Placebo Studies 2021 conference
The Society of Interdisciplinary Placebo Studies (SIPS) was one of many organizations that hosted a virtual scientific conference in response to the COVID-19 pandemic restrictions. Retaining essential benefits of an in-person conference experience was a primary objective for the SIPS conference planning committee and guided the selection of a virtual platform on which to host the 2021 meeting. This article reports on the methods used to design and analyze an engaging, virtual scientific conference, along with the findings and implications for future meetings.
Preliminary Evidence for cue-induced Alcohol Craving Modulated by Serotonin Transporter Gene Polymorphism rs1042173
Preliminary Evidence for cue-induced Alcohol Craving Modulated by Serotonin Transporter Gene Polymorphism rs1042173
We previously have shown that cue-induced alcohol craving and propensity for higher drinking are modulated by allelic differences in SLC6A4 associated with serotonin transporter (5-HTT) expression level alterations. In an independent study, we characterized another polymorphism, SNP rs1042173, in 3'-untranslated region (3'-UTR) of the same gene, which also altered 5-HTT expression levels; the T allele of rs1042173 was associated with lower mRNA and protein levels. In subsequent analyses, the TT genotype was found to be associated with higher drinking intensity in alcohol-dependent (AD) individuals of Caucasian descent. Building upon these findings, we hypothesized that the low-expressing TT genotype associated with intense drinking would predict higher craving for alcohol in AD individuals. In this pilot study, we sought to test our hypothesis by examining 34 Hispanic AD volunteers (mean age, 34.8 years) for rs1042173 genotype-based [i.e., TT versus TG/GG (Gx)] differences in subjective response to alcohol. We employed a human laboratory paradigm and analyzed the data using a linear mixed-effects model (SAS® PROC MIXED) to assess treatment, cue procedures, and genotype main effects as well as the two-way interaction effects between them. On subjective "urge to drink" and "crave for a drink," we found a significant main effect of the cue experiment (p ≤ 0.01) and an interaction effect between genotype and cue effects (p < 0.05). TT genotype was associated with higher urge to drink (p = 0.002) and crave for a drink (p = 0.005) when exposed to alcohol cue. Our results not only support the hypothesis that rs1042173 is a genetic marker for cue-induced alcohol craving among AD males but also are suggestive of a neurobiological mechanism associated with the rs1042173-TT genotype that triggers a disproportionate craving in response to alcohol consumption, which in turn may lead to more intense drinking. Future studies with larger sample sizes are needed to characterize the interactive effects of the serotonin transporter-linked polymorphic region (5'-HTTLPR)-L-allele reported in our previous study and of the rs1042173-TT genotype on cue-induced alcohol craving.
Advances in Medications and Tailoring Treatment for Alcohol Use Disorder
Advances in Medications and Tailoring Treatment for Alcohol Use Disorder
Alcohol use disorder (AUD) is a chronic heritable brain disorder with a variable clinical presentation. This variability, or heterogeneity, in clinical presentation suggests complex interactions between environmental and biological factors, resulting in several underlying pathophysiological mechanisms in the development and progression of AUD. Classifying AUD into subgroups of common clinical or pathological characteristics would ease the complexity of teasing apart underlying molecular mechanisms. Genetic association analyses have revealed several polymorphisms-small differences in DNA-that increase a person's vulnerability to develop AUD and other alcohol-related intermediate characteristics, such as severity of drinking, age of AUD onset, or measures of craving. They also have identified polymorphisms associated with reduced drinking. Researchers have begun utilizing these genetic polymorphisms to identify alcoholics who might respond best to various treatments, thereby enhancing the effectiveness of currently tested medications for treating AUD. This review compares the efficacy of medications tested for treatment of AUD with and without incorporating genetics. It then discusses advances in pre-clinical genetic and genomic studies that potentially could be adapted to clinical trials to improve treatment efficacy. Although a pharmacogenetic approach is promising, it is relatively new and will need to overcome many challenges, including inadequate scientific knowledge and social and logistic constraints, to be utilized in clinical practice.