Pharmacogenomics of Alcohol Addiction : Personalizing Pharmacologic Treatment of Alcohol Dependence

Alcohol dependence is a serious psychiatric disorder with harmful physical, mental and social consequences, and a high probability of a chronic relapsing course. The fi eld of pharmacologic treatment of alcohol dependence and craving is expanding rapidly; the drugs that have been found to reduce relapse rates or drinking in alcohol-dependent patients and are approved for treatment of alcohol dependence are naltrexone, acamprosate and disulfi ram, whereas also topiramate appears as a promising therapy. For many patients, however, these treatments are not eff ective. Evidence from a number of diff erent studies suggests that genetic variation is a signifi cant contributor to interindividual variation of clinical presentation of alcohol problems and response to a given treatment. The aim of the present review is to summarize and discuss the fi ndings on the association between gene polymorphisms and the response to alcohol dependence treatment medications. It is anticipated that future implementation of pharmacogenomics in clinical practice will help personalize alcohol dependence drug treatment, and development personalized hospital pharmacology.


INTRODUCTION
Alcohol dependence is a serious psychiatric disorder with harmful physical, mental and social consequences, and a high probability of a chronic relapsing course.According to the 2014 global status report on alcohol and health by the World Health Organization, in 2012, about 3.3 million deaths, or 5.9% of all global deaths, and 5.1% of the global burden of disease and injury, were attributable to alcohol consumption [1].Globally, Europe is the region with the highest consumption of alcohol per capita [1].Alcohol dependence is associated with psychiatric conditions such as major depression, dysthymia, mania, hypomania, panic disorder, phobias, generalized anxiety disorder, personality disorders, any drug use disorder, schizophrenia, and suicide [2].On the other hand, psychiatric comorbidity is associated with alcohol-related symptoms of greater severity [2].Long-term relapse prevention in alcohol-dependent patients is based on psychotherapy and pharmacotherapy.Although psychotherapy is in some cases eff ective in reducing alcohol consumption and in maintaining abstinence, without a pharmacological adjunct to psychosocial therapy, the clinical outcome is poor, with up to 70% of patients resuming drinking within 1 year [3][4][5].
Th e fi eld of pharmacologic treatment of alcohol dependence and craving is expanding rapidly [6].To date, the drugs that have been found to reduce relapse rates or drinking in alcohol-dependent patients and are approved for treatment of alcohol dependence are naltrexone, acamprosate and disulfi ram, whereas also topiramate appears as a promising therapy [7].For many patients, however, these treatments are not eff ective.Evidence from a number of diff erent studies suggests that genetic variation is a signifi cant contributor to interindividual variation of clinical presentation of alcohol problems and response to a given treatment.
Pharmacogenomics is the area of medicine that studies the genetic factors that infl uence drug response and toxicity [8,9].In this context, pharmacogenomics paves the path to personalized medicine.Th e rapidly advancing fi eld of pharmacogenomics is a promising area of investigation, focusing on genetic variations in components that aff ect drug pharmacokinetics and pharmacodynamics [10][11][12][13][14][15][16][17] or that are involved in their therapeutic mechanisms and/or cause of their adverse events [18,19].Application of pharmacogenomics explains some of the interindividual variable response to various classes of drugs, such as psychiatric drugs [20,21], antidiabetics [22] and oral coumarinic anticoagulants [23].Eff orts are now focusing on the development of genotype-based guidelines that will help clinicians in incorporating pharmacogenomic knowledge in their routine clinical practice.Among the most solid and recent pharmacogenomic applications is the genotype-guided dosing algorithm of oral coumarinic anticoagulants; results of two large randomised clinical trials conducted in European populations showed that patients who received genotypeguided dosing of the oral coumarinic anticoagulants acenocoumarol, phenprocoumon and warfarin had increased percentage of time in the therapeutic range compared to controls [24,25].
In view of these developments in several pharmacotherapeutic areas it was inevitable that also the fi eld of personalization of alcohol dependence treatment would get a boost from pharmacogenomics.Th e choice of alcohol-dependence treatment may improve by identifying genetic variations that predict individual responses to therapeutic interventions.Data has accumulated suggesting that specifi c genetic polymorphisms govern the therapeutic response, the dose requirements and the risk of experiencing adverse eff ects to the respective therapy [26].Th erefore, pharmacogenomics of alcohol dependence treatment is an emerging fi eld with promising application in psychiatry.Below we discuss evidence for genetic variation in the eff ect of the 4 anti-craving drugs.
Information of all gene polymorphisms that have been studied in association with drug response -their chromosome location, eff ect on encoded protein, and the medication they aff ect -is presented in Table 1.To further help the reader in easily assessing the published studies, all currently available data on gene polymorphisms associated with alcohol dependence drug response are briefl y listed in three tables: Table 2 presents gene polymorphisms studied in association with the opioid antagonists naltrexone, nalmofene and naloxone response, Table 4 presents gene polymorphisms studied in association with acamprosate response, Table 5 presents gene polymorphisms studied in association with disulfi ram response and Table 6 presents gene polymorphisms studied in association with topiramate response.Furthermore, given the signifi cance of clinical trials assessing implementation of pharmacogenomics in routine clinical practice, completed and ongoing clinical trials on alcohol addiction pharmacogenomics are listed in Table 3.

Opioid antagonists: Naltrexone, nalmofene and naloxone
Naltrexone is a specifi c opioid antagonist targeting endogenous opioid receptors, particularly μ-receptors.Blocking opioid receptors with naltrexone leads to less alcohol-induced pleasure and, ultimately, less craving and relapse.μ-opioid receptors primarily bind β-endorphin and diff use this binding via Gprotein signaling that alters neuronal fi ring and leads to neuroadaptive changes [27].Other opioid receptor antagonists with similar to naltrexone properties are naloxone and nalefene, however, naltrexone is more commonly prescribed in alcohol addiction therapy.A missense polymorphism in μ-opioid receptor (OPRM1) gene, 118A>G (Asn40Asp), leads to altered β-endorphin binding, function, and receptor levels.Th is substitution has been reported to increase binding of β-endorphin and increase functional activity in vitro.Carriers of 118G (40Asp) allele have 3-fold higher affi nity for β-endorphin binding compared to 118AA (40AsnAsn) individuals (Table 1) [28].Since naltrexone targets the μ-opioid receptor, OPRM1 118A>G gene polymorphism is an attractive candidate to assess the interindividual diff erential response to naltrexone [27].Indeed, results of several studies suggest that 118G carriers respond better to naltrexone treatment.For consistency, throughout the manuscript we refer to OPRM1 polymorphism with nucleotide substitution nomenclature.
Several studies have assessed the potential eff ect of OPRM1A118G polymorphism on altered endogenous response associated with response to alcohol pharmacotherapy (Table 2).Wand and colleagues have tested the hypothesis that OPRM1 A118G polymorphism infl uences the hypothalamic-pituitary-adrenal (HPA) axis activation induced by opioid receptor blockage; opioid receptor antagonists such as naloxone, nalmefene and naltrexone aff ect disinhibition of HPA axis leading to cortisol and adrenocorticotropin hormones release [29].A total of 39 healthy men receiving fi ve doses of naloxone were included in the study.Th e authors have found that carriers of 118G allele had greater cortisol response to receptor blockage and diff erent increase (between 30-90 minutes) and decrease (aft er 90 minutes) rate of adrenocorticotropin [29].Similar results were obtained by Hernandez-Avila and colleagues who also estimated cortisol and adrenocorticotropin response to intravenous naloxone or placebo [30].In a total of 30 healthy participants, carriage of 118G allele was associated with higher cortisol concentration both at baseline and aft er naloxone infusion, with greater peak cortisol response and greater area under the cortisol time curve [30].Th e increased cortisol response to naloxone in 118G carriers was also replicated in the study of Chong and colleagues in a total of 74 participants who received fi ve doses of naloxone [31].In the latter studies, no eff ect on plasma adrenocorticotropin was noticed.In a diff erent study, Ray and colleagues found an association of OPRM1 118G allele with increase of allopregnanolole levels in 32 naltrexone treated heavy drinkers; allopregnanolole is a GABAergic neuroactive steroid that has been associated with naltrexone pharmacotherapy [32].Naltrexone increased allopregnanolole in OPRM1 118G cariers but not in 118AA homozygotes, whereas no eff ect on cortisol levels was present.Based on these results the authors proposed that the enhanced therapeutic response of 118G carriers to naltrexone could be attributed in part to the ability of the drug to increase allopregnanolole levels at least in these individuals [32].Th ese results suggest that OPRM1 A118G polymorphism is associated with diff erential response to physiological processes that are mainly regulated via activation of opioid receptors.
A diff erent approach was followed by Ray and colleagues who have tested the hypothesis that individuals who have a genetic predisposition to greater feelings of euphoria aft er consuming alcohol due to OPRM1 A118G polymorphism also present with more successful response to the medication that reduces feelings euphoria [33].In 38 students with a moderate or heavier drinking pattern who intravenously received alcohol, feelings of euphoria were recorded.Carriers of 118G allele reported greater feelings of intoxication, higher increases in alcohol-induced stimulation and higher increases in state happiness compared to 118AA homozygotes [33].Results were replicated by the same research team in 40 participants who underwent the same alcohol challenge [34].Similarly to their previous report, carriers of 118G allele reported higher alcohol-induced euphoria compared to 118AA homozygotes [34].
Studies that assess the potential association of OPRM1 A118G polymorphism with naltrexone response, analyze several drinking outcomes such as craving, relapse and abstinence, and recruit participants who are alcohol-dependent, treatment-or non-treatment seeking.First in vivo evidence on association of OPRM1 A118G polymorphism with naltrexone response was published in 2003.Oslin and colleagues have analyzed the association between OPRM1 A118G genotype and drinking outcomesin 71 alcohol-dependent individuals of European descent [35].Additionally to naltrexone treated individuals (treated with naltrexone 50 or 100 mg for 12 weeks), a placebo treated group of 59 individuals was also included in the study.Th e authors have shown that, compared to 118AA individuals, carriers of 118G allele had a greater chance not to return to heavy drinking (OR=3.52)and also had signifi cantly longer time to fi rst relapse (OR=2.79)[35].Ray and colleagues have tested the hypothesis that OPRM1 A118G polymorphism acts as modulator of naltrexone eff ects on alcohol sensitivity and have found that naltrexone reduced self-reported alcohol-induced euphoria in participants with at least one 118G allele [34].Similarly, in the pharmacogenetic arm of the clinical trial NCT00006206, the researchers examined the role of OPRM1 A118G polymorphism as a predictor of naltrexone treatment response [36].Among individuals initially recruited, 300 were randomized on naltrexone therapy.Alcohol dependent patients who were treated with naltrexone and had at least one 118G allele showed an increasing trend in abstinent days over time and fewer heavy drinking days over time, while additionally they also had the best outcome [36].
During the last fi ve years, there has been an increase in publications on the association of OPRM1 A118G polymorphism with naltrexone response, and the majority of the studies support the hypothesis that carriers of 118G allele have enhanced response to naltrexone.In 2009, Ooteman and colleagues have tested the hypothesis that naltrexone primarily exerts its eff ects in patients characterized by genetic variation in opioidergic system whereas acamprosate primarily exerts its eff ects in patients characterized by variations in glutamatergic system [37].A total of 52 naltrexone treated and 56 acamprosate treated alcohol dependent patientswere included in genetic analyses.Th e authors have found that naltrexone outperformed acamprosate in OPRM1 118G allele carriers, whereas acamprosate outperformed naltrexone in the OPRM1 118AA group [37].Th ese results support a role of OPRM1 A118G genotyping prior of therapy choice.Results on the association of genetic factors with acamprosate response are discussed in detail in Acamprosate section that follows.Oroszi and colleagues have also found an association of 118G allele and good clinical response to naltrexone [38].In 146 alcohol dependent patients the authors have used a haplotype-based procedure and have showed that higher percentage of naltrexone-treated patients carrying the haplotype consisted by 118G allele had good clinical outcome compared to non-carriers [38].It should be noted that the sole haplotype that was associated with naltrexone response was the one carrying the 118G allele.In a diff erent prospective study in 63 alcohol-dependent Korean patients treated with naltrexone 25mg/day for fi rst 3 days and 50mg/day for the remaining days ofa 12-week treatment, Kim and colleagues have found that patients with at least one 118G allele took signifi cantly longer time to relapse than 118AA homozygotes [39].Th ese results highlight that the association of OPRM1 A118G polymorphism with naltrexone responseoutscales potential ethnic diff erences.In a following study in 40 social drinkers administered naltrexone 25mg for fi rst day and 50mg for the rest 5 days of the 6-days follow-up, Setiawan and colleagues analyzed the association of OPRM1 A118G polymorphism with subjective eff ects of alcohol [40].Carriers of 118G allele reported experiencing decreased euphoria during naltrexone treatment aft er seeing and drinking alcohol [40].Results of a double-blinded, randomized, placebo-controlled laboratory trial on naltrexone that included 35 non-treatment seeking Asian Americans heavy drinkers have also showed that 118G carriers experience greater alcohol-induced sedation and subjective intoxication, and lower alcohol craving compared to 118AA [41].OPRM1 118G allele was also associated with increased percentage of non-hazardous drinking in a study that included 112 European problem drinkers treated with naltrexone 100mg/day for 12 weeks [42].
Urge to drink has also been analyzed as an outcome of naltrexone response.
McGeary and colleagues have analyzed the association of OPRM1 A118G polymoprhism with the urge to drink alcohol in a total of 90 individuals consisting a mixed of population of non treatment seeking alcohol dependent individuals and non alcohol dependent individuals; 42 of them were treated with naltrexone 50mg/ day for 3 weeks [43].Th e authors have found that OPRM1 118G carriers showed greater urge to drink when receiving naltrexone compared with placebo.Urge to drink alcohol may become more salient when one is attempting to avoid drinking and may be a marker for the eff ort required to abstain from drinking.Since this urge may be more predictive of drinking among treatment seekers, the authors mention that their results cannot be generalized to alcohol dependent individuals in treatment [43].Similar results were presented by Kranzler and colleages, who analyzed the association of OPRM1 A118G polymorphism with desire to drink in 81 problem drinkers who received naltrexone 50mg/day [44].In this study, registered as NCT00369408 in ClinicalTrials.gov,carriers of 118G allele showed a stronger evening drinking desire and were at greater risk of drinking more than 118AA homozygotes, which was attenuated by naltrexone [44].
It is widely recognized that, in all fi elds of medicine, pharmacogenomic applica-tion has the greater possible impact on clinical practice when multiple gene analyses are carried out and that once a gene has been documented to be clearly associated with a drug response, then studies of other genes should include the previous genes in analyses [16,45].Th is approach has been applied by Ashenhurst and colleagues; in 40 heavy drinkers who underwent an intravenous alcohol challenge paradigm aft er receiving 50mg of naltrexone, the researchers analyzed the pharmacogenetic eff ect of delta and kappa opioid receptor gene polymorphisms on subjective responses to alcohol aft er controlling for OPRM1 A118G polymorphism [46].Th e authors have found that OPRK1 rs997917 and OPRD1 rs4654327 gene polymorphisms were associated with response to alcohol and this eff ect remained signifi cant aft er controlling for OPRM1 A118G polymorphism [46].Anton and colleagues have analyzed both OPRM1 A118G and dopamine transporter (DAT) 9 and 10 VNTRs in 83 nontreatment seeking alcohol dependent individuals receiving either placebo or naltrexone 25mg for 2 days and 50mg for 5 days for a week [47].Th e authors did not fi nd a role of OPRM1 A118G polymorphism alone with response to naltrexone, but they report an epistasis between OPRM1 and DAT genes.In non-carriers of 118G allele, carriers of DAT 9 VNTR had more stimulation to alcohol or medication treatment and in these individuals naltrexone reduced the number of drinks consumed per day [47].Schacht and colleagues have also reported a similar interaction of OPRM1 and DAT genes [48].In the study, a total of 74 non treatment seeking alcohol dependent individuals treated with naltrexone 50mg or placebo for 1 week were included.Results of fMRI alcohol cue reactivity task performed on day 6 showed that OPRM1 A118G polymorphism did not have a main eff ect on medication, however, 118G carriers who also carried DAT 10VNTR had less stimulation than 9 VNTR carriers [48].More recently, in a cohort of 43 alcohol dependent individuals, the interaction of OPRM1 with DAT was replicated [49].OPRM1 118G carriers and DAT 10 VNTR homozygotes reported steeper increase in stimulation and positive mood across rising alcohol concentration [49].Th e consistency in OPRM1-DAT interaction results suggests that opioidergic and dopaminergic systems interact and determine the reinforcing properties of alcohol.
Th e need to draw fi rm conclusions on the association of gene polymorphisms with response to a given pharmacotherapy has led to a type of studies called meta-analysis; a statistical procedure that integrates the results of several independent studies that were conducted analyzing the same outcome [50].Currently, only one meta-analysis on the eff ect of OPRM1 A118G polymorphism on naltrexone response has been published [51].Meta-analysis included a total of 6 studies that assessed the pharmacogenetic eff ect of OPRM1 A118G polymorphism on naltrexone response in alcohol-dependent patients.Overall the results support the evidence that naltrexone treated patients carrying 118G allele have lower relapse rates than those who are 118AA homozygous (OR=1.97),but similar abstinence rates [51].
Th e abovementioned results on the association of OPRM1 A118G polymorphism with naltrexone response were not replicated in all studies.Gelernter and colleagues have assessed the association of OPRM1 A118G polymorphism with naltrexone response in 215 alcohol-dependent male subjects treated with naltrexone 50mg/day for 3 to 12 months [52].Th e authors did not fi nd an association of OPRM1 polymorphisms with rate of and time to relapse [52].Similarly, Mitchell and colleagues did not fi nd a contribution of OPRM1 gene polymorphism on naltrexone eff ect estimated by self reported ethanol consumption [53].Th is study included a total of 25 subjects treated with naltrexone 50mg/day [53].O'Malley and colleagues have also analyzed the association of OPRM1 A118G polymorphism with naltrexone response in 101 alcohol-dependent Alaskians treated for 16 weeks with placebo, naltrexone 50mg monotherapy or naltrexone 50mg and sertraline 100mg combined therapy [54].OPRM1 genotyping was successful for 92 participants, however, all further analyses were restricted in 75 participants who were 118AA homozygous, of whom 52 were treated with naltrexone as monotherapy or combined therapy.When the eff ect of treatments were compared within this subgroup, the pattern of OPRM1 polymorphism association was similar to the results in the total sample, suggesting that OPRM1 polymorphism is not associated with enhanced response to naltrexone [54].In 2008, Tidey and colleagues analyzed the association of OPRM1 A118G polymorphism with drink data, urge levels and subjective eff ects on alcohol consumption in 180 heavy drinkers, 63% of whom were alcohol-dependent [55].88 individuals received naltrexone 50mg/day for 3 weeks.Naltrexone signifi cantly decreased percent drinking days, however, OPRM1 A118G polymorphism was not a moderator of naltrexone response [55].Similarly, Coller and colleagues examined prospectively in 100 alcohol dependent patients treated with naltrexone 50mg for 12 weeks the association of OPRM1 A118G polymorphism with several clinical outcomes of naltrexone treatment, such as time to fi rst relapse and craving [56].Th e authors found no evidence of association of OPRM1 A118G polymorphism and treatment success on any of the outcome measures [56].Similar results were reported by Arias and colleagues in a cohort of alcohol dependent patients treated with nalmefene, a specifi c and potent opioid receptor antagonist that has affi nity for the three opioid receptor subtypes (OPRM1, OPRD1 and OPRK1) [57].In a total of 166 nalmefene treated alcohol dependent patiemts, the authors found no association of genetic variants, including OPRM1 A118G, with moderated response to nalmefene [57].Th e lack of association reported in the latter study could be attributed to the fact that even though nalmefene is structurally similar to naltrexone, it diff ers in binding affi nity for opioid receptors.Th e association of OPRM1 gene polymorphisms with naltrexone response is the subject of several clinical trials (Table 3).Clinical trial NCT00920829 assesses the effect of OPRM1 A118G gene polymorphism on treatment response to naltrexone in treatmentseeking alcohol dependent patients treated with 25 or 50 mg naltrexone.Response will be measured by the percent of heavy drinking days and days of abstinence.Additional primary outcome is the potential diff erence in the naltrexone dampening of the alcohol cue-induced brain activation dependent on OPRM1 genotype.Medication compliance and side effects based on OPRM1 genotype will also be assessed.In clinical trial NCT02026011 the pharmacogenomic eff ects of OPRM1 A118G genepolymorphism on biobehavioral and neural markers of response to naltrexone (50mg/ day) in individuals of East Asian descent is assessed.Clinical trials NCT01738867 and NCT00817089 have been completed but results have not been annotated yet.In clinical trial NCT01738867 at least 48 healthy subjects with a history of social drinking would be recruited and genetically be stratifi ed to result in equal numbers of A118G'AA' homozygotes and A118G'G' carriers for a 5 days treatment with placebo, naltrexone or GSK1521498, a novel opioid antagonist being investigated as a candidate treatment for behavioral and substance addictions.In naltrexone treatment arm, individuals would receive 25mg for the fi rst two days and 50mg for the rest 3 days.Outcomes include functional brain response to alcohol, plasma cortisol and subjective response to an ethanol challenge.In clinical trial NCT00817089, males of European or Asian decent following two inpatient alcohol challenge sessions along with 12 weeks of outpatient treatment using random assignment to either naltrexone (100mg/day) or placebo, were recruited.Th e relationship between OPRM1 A118G polymorphism and the subjective/objective measures to alcohol among alcohol dependent patients treated with naltrexone was OPRM1 A118G polymorphism is associated with naltrexone response with a high degree of reproducibility and has emerged as a useful genetic marker in personalizing naltrexone treatment.Results from prospective, randomized clinical trials on the association of OPRM1 A118G polymorphism with naltrexone response will enable the clinical application of naltrexone pharmacogenomics in routine clinical practice.

Acamprosate
Acamprosate has been approved to maintain abstinence in alcohol dependent individuals who have quit drinking.Acamprosate does not prevent the withdrawal symptoms people may experience when they stop drinking alcohol, but reduces craving for alcohol and relapse after quitting drinking.Th e exact mechanism of action of acamprosate is still unknown, however, it has been suggested that it interferes with the glutamate system, leading to neurotransmitter balance restoration that is disturbed aft er chronic alcohol abuse [58].Overall, the adoption of acamprosate in alcohol addiction treatment is limited [59].Th is might be the major factor that even though only one third of individuals receiving acamprosate remain alcohol abstinent for more than six months, data on acamprosate pharmacogenomics are scarce.Th e potential association of genetic variations with acamprosate response has been assessed only in one study (Table 4); Ooteman and colleagues have tested the diff erential eff ects on acamprosate and naltrexone on reductions in cue-induced craving and physiological cue reactivity for diff erent polymorphisms on the opioid, dopamine, glutamate and γ-aminobutyric acid (GABA) receptors [37].Th e authors have found that acamprosate effi cacy was enhanced in GABRA6 1519C allele carriers and that in GABRB2 1412TT homozygous individuals acamprosate outperformed naltrexone with respect to physiological cue reactivity (heart rate), and in DRD2 A1A1 homozygous acamprosate outperformed naltrexone with respect to craving as measured with a visual analogue scale [37].Th e minor allele frequency of the described gene polymorphisms and their effect on protein are presented in Table 1.Currently, one clinical trial assessing the eff ect of genetic variations on acamprosate response is registered on the ClinicalTrials.gov website (listed in Table 3).Clinical trial NCT00662571, assessing the eff ect of polymorphisms in GRIN1, GRIN2A and GRIN2B genes coding for N-methyl-D-aspartate receptor (NMDA) and type 5 metabotropic glu-tamate receptor (mGluR5) on acamprosate response has been completed; however, the results have not been published yet.

Investigated
Pharmacogenomics may have the potential to guide therapy of acamprosate, by increasing drug therapeutic success and days of abstinence.However, data is still lacking.Th erefore, more studies should be conducted to assess the eff ect of genetic variations on acamprosate response.

Disulfi ram
Disulfi ram reduces alcohol dependence by inhibiting the enzyme aldehyde dehydrogenase leading to increased plasma levels of acetaldehyde upon drinking alcohol, a byproduct of alcohol metabolism that is aversive [60].Disulfi ram also inhibits dopamine beta-hydroxylase (DβH), the enzyme that converts dopamine into norepinephrine and is co-released with catecholamines [61].Polymorphisms in DβH gene aff ect circulating DβH levels.Specifi cally, C-1021T polymorphism, positioned ~1 kb upstream from the initiation codon of the DβH gene, is associated with decreased DβH levels.Individuals that are -1021T allele homozygous have the lowest levels of plasma DβH activity [62].One could speculate that, in individuals with already low levels of DβH enzyme due to C-1021T polymorphism, disulfi ram would be more eff ective in increasing dopamine and decreasing norepinephrine, therefore carriage of -1021T allele can potentially be associated with increased response to disulfi ram therapy.
It has been suggested that individu-als carrying DβH C-1021T TT genotype would respond better to disulfi ram treatment and would need less of a dose whereas CT individuals would need an intermediate dose and those with the CC genotype may need increased concentrations for maximum therapeutic eff ectiveness [63].For disulfi ram, only one study has assessed the eff ect of DβH C-1021T polymorphism on treatment response (Table 5) [64].
In this study, Mutschler and colleagues have recruited -increased risk of adverse events -a trend towards longer cumulative alcohol abstinence [64] Table 5. Human studies on the association of genetic polymorphisms with response to disulfi ram.
the same time.Currently, no clinical trials are registered at ClinicalTrials.gov on DβH genetic variations and disulfi ram response in alcohol dependent patients.
Disulfi ram is currently rarely used for the treatment of alcohol dependence.Further pharmacogenomic studies that will unravel the genetic factors aff ecting disulfi ram response are needed.

Topiramate
Topiramate is an anticonvulsant medication that has recently been identifi ed as a potent therapy of alcohol dependence.Even though topiramate has not yet gained approval for alcohol dependence treatment, several controlled clinical trials have shown its effi cacy in the treatment of alcohol dependence and it has been used in several countries for the treatment of alcohol dependence [65,66].Topiramate may antagonize alcohol rewarding eff ects associated with abuse liability by inhibiting mesocorticolimbic dopamine release.Also, it has been suggested that it enhances the inhibitory function of GABA, antagonizes excitatory glutamate receptors, and inhibits dopamine release [67].However, a major concern and limitation in the use of topiramate has been its adverse eff ects, which are prominent especially during the titration period, appear to be dose-related but usually subside with continued treatment [66].Recently it has been reported that the rs2832407 C>A intron 9 polymorphism of glutamate receptor GluR5 (GRIK1) gene is associated with the severity of topiramate-induced side eff ects and with serum levels of topiramate, thus making it an interesting candidate for therapy personalization [68].
First evidence on the association of GRIK1 polymorphisms with topiramate pharmacokinetics and response were published on 2009 (Table 6).Ray and colleagues have shown that,in a total of 32 alcohol dependent patients treated with topiramate 200-300 mg/day for 5 weeks, GRIK1 rs2832407C>A polymorphismwas associated with topiramate serum levels and the severity of topiramate-induced side eff ects [69].Carriers of rs2832407A al-lele had both higher serum topiramate levels and of greater severity topiramate side eff ects both when compared to placebo and to homozygous topiramate treated CC individuals.Additionally, carriers of rs2832407A allele reported higher mean percentage of heavy drinking days as compared to CC individuals (40.4% vs. 22.2%) [69].More recently, Kranzler and colleagues have analyzed the association of GRIK1 rs2832407C>A polymorphism with topiramate eff ect on heavy drinking days [70].In a total of 138 individuals treated either with topiramate at a maximal dose of 200mg for 12 weeks (67 individuals) or matching placebo (71 individuals), the authors have found that, in a subgroup of 122 European American individuals the eff ect of topiramate on heavy drinking days was signifi cantly greater than that for placebo only in rs2832407CC homozygotes [70].Th e same research team have further analyzed in the subgroup of 122 European American individuals the potential association of GRIK1 rs2832407C>A polymorphism with topiramate eff ect on BMI, but no association was found [71].Finally, Kranzler and colleagues have validated in the subgroup of 122 European American individuals the interactive eff ect of GRIK1 rs2832407C>A polymorphism and topiramate as predictors of drinking level [72].Th e authors have found that topiramatetreated rs2832407CC homozygotes drank less during treatment than those receiving placebo, validating this way their earlier fi ndings, and have also shown that rs2832407CC homozygotes showed the largest decreases in positive alcohol expectancies and desire to drink [72].
Several clinical trials are registered on Clinicaltrials.govwebsite and assess whether topiramate will improve drinking outcomes in alcohol dependent individuals, however, currently, only one clinical trial assesses the association of gene polymorphisms with topiramate eff ect on craving, subjective stimulation and other behavioral eff ects associated with alcohol consumption (Table 3).Th e clinical trial NCT00884884 will recruit 216 healthy, alcohol-dependent volunteers who are not currently seeking treatment for their alcohol dependence to learn more about how topiramate and alprazolam medications may work on alcohol dependence and how gene polymorphisms modulate their action.
Topiramate appears to be a promising therapy for alcohol dependence.Accumulated data implicate consistently GRIK1 rs2832407C>A as a predictor of topiramate response and adverse drug reactions incidence.Th erefore, upon approval of topiramate as a therapy for alcohol dependence, GRIK1 polymorphisms may have an important role in personalizing topiramate therapy.

Other drugs
So far, as it was already extensively described, the only three drugs that have been approved by FDA for alcohol dependence are naltrexone, acamprosate and disulfi ram, whereas topiramate appears as a promising therapy.Several other compounds have been experimented for the treatment of alcohol dependence and some of them are in clinical development.Describing the exact mechanism of action of these drugs and their potency is beyond the scopes of the present review, therefore we simply list the drugs that have been associated with positive outcomes of alcohol dependence.
In Italy and Austria, sodium oxybate is already approved for alcohol dependence and it is expected to will be soon introduced in Kazakhstan.Sodium oxybate is a short-chain fatty acid, structurally similar to the inhibitory neurotransmitter γ-amino-butyric acid, which exerts an ethanol-mimicking eff ect on GABAB receptors in the central nervous system.Baclofen is a GABAB receptor agonist currently used to control spasticity that was also shown to reduce alcohol consumption.Ondansetron is a 5-HT3 receptor antagonist that is thought to reduce the reward from alcohol.Additionally, other compounds clinically approved for diff erent than alcohol addiction indications, such as pregabalin, oxcarbamazepine, gabapentin, valproic acid, aripiprazole, prazosin, vigabatrin, tiagabine, quetiapine and neurosteroids, seem to be able to reduce alcohol consumption, but further trials should be performed to confi rm their effi cacy in preventing relapse and maintaining complete abstinence [73][74][75].

CONCLUSIONS AND FUTURE PERSPECTIVES
It is anticipated that treating eff ectively alcohol dependence will decrease social and economic burden of this serious disorder.As it was extensively described in the present review, pharmacogenomics of alcohol dependence is a fi eld in which several applications are mature and ready to be implemented in routine clinical practice.OPRM1 A118G polymorphism is highly associated with improved response to naltrexone.Th is gene polymorphism can serve a marker to distinguish individuals who will benefi t the most from naltrexone or who could be administered an alternative drug, such as acamprosate.Additionally, even prior of FDA approval of topiramate for treating alcohol dependence, it has been consistently shown that topiramate response is aff ected by GRIK1 rs2832407C>A polymorphism.As for the other drugs used for alcohol dependence, further studies are needed before any conclusions can be drawn on their utility in personalizing alcohol addiction therapy.
It is expected that in the coming years alcohol dependence pharmacogenomics may be instrumental in personalizing drug addic-tion therapy by guiding the choice of pharmacotherapy.It is hoped that incorporation of pharmacogenomics in routine clinical practice will lead to increased days of abstinence, lower relapse rates and days of heavy drinking, as well as lower incidence of drug adverse events.More importantly, application of pharmacogenomics in the fi eld of alcohol dependence may lead to increased productivity of individuals who are currently addicted to alcohol.Overall, application of personalized medicine approaches on alcohol dependence therapy with the use of pharmacogenomics may provide with benefi ts all the players involved: the patients who may respond faster and more eff ectively to pharmacotherapy, the psychiatrists who -by integrating the latest and most updated scientifi c information in their practice -will increase therapy response rates, and the national health systems in each country as well as the society as a whole as it may help to reduce the fi nancial and social burden of alcoholdependence.
62 alcohol-dependent patients from the specialized disulfi ram outpatient treatment program in Mannheim, Germany.Th e authors have found that carrying DβH-1021T low activity allele is associated with an increased risk of adverse events, but not with disulfi ram response, despite a trend of longer cumulative alcohol abstinence achieved in CT/TT individuals, compared to CC group[64].It should be noted, however, that,currently,disulfi ram is not a treatment of choice for alcohol dependence due to the increased number and fear of the severe and sometimes fatal reaction known as a disulfi ram-alcohol reaction.Disulfi ramalcohol reaction is the result of the build up of a chemical from the alcohol in the body when patients take the medicine and drink alcohol at

Table 1 .
Summary of the genetic locus and gene poly-

Table 2 .
Human studies on the association of genetic polymorphisms with response to the opioid receptor antagonists naloxone and naltrexone.