Alcohol Dependence in Taiwan From Epidemiology to Biomedicine

(1)

REVIEW ARTICLE

Alcohol Dependence in Taiwan: From Epidemiology to Biomedicine

Ming-Chyi Huang

1,2

, Chiao-Chicy Chen

2,3 *

1_{Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan}

2_{Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan} 3_{Department of Psychiatry, Mackay Memorial Hospital, Taipei, Taiwan}

a r t i c l e i n f o

Article history: Received: Jan 12, 2012 Revised: Jan 16, 2012 Accepted: Jan 17, 2012 KEY WORDS: alcohol dependence; epidemiology; genetic; neuroadaptation; oxidative stress

Alcohol-related problems cause a tremendous social and public health burden worldwide. Alcohol dependence (AD) is a common, chronic and relapsing psychiatric disorder, with prevalence varying among different ethnic populations, and determined by a combination of genetic and environmental factors. The heritability of AD is estimated roughly as 50%e60%. Until recently, the only genes established to affect the risk AD, were those encoding several alcohol metabolizing enzymes such as ADH1B and ALDH2. However, we are still in the early stages of understanding the physiology of other risk gene loci. Both ADH1B*2 and ALDH2*2, found more frequently in Asians compared to Caucasians, are considered as protective alleles, potentially explaining a lower prevalence of AD in Taiwanese people. Alcohol intake produces a long-lasting neuroadaptation, which is involved in developing and maintaining AD. Toxicity, such as oxida-tive damage associated with chronic alcohol consumption, also contributes to the addiction process. Emerging evidenceprovides an insight into the understanding of the mechanisms of how alcohol disrupts the synergistic homeostasis of bodily systems, and results in behavioral and physiological dysfunction.

1. Introduction

Alcohol dependence (AD) is a global issue. According to the Global Status Report on Alcohol by the World Health Organization (WHO) in 2007,1the prevalence of AD among adult populations of Euro-pean and American countries are signiﬁcantly high, ranging from 7.0% to 12.2%. Although not as high as seen in Western countries, the prevalence of AD is also high in Asian countries, ranging from 4.1% to 7.3%. The causes of alcohol-related problems are compli-cated, and associated with a combination of genetic, physical, psychological, social, and environmental factors.2 In addition, alcohol policy, availability of alcohol, as well as cultural background andﬁnancial conditions of individual countries, also contribute to the variations of prevalence. For example, the prevalence of alcohol dependence among aboriginal people in Taiwan is 10 folds higher than that of Han people.3,4

Taiwanese people, with a low prevalence of AD, have long been thought to be the ethnicity immune to AD.4 However evidence revealed that the alcohol problem is severe in Taiwan. For example, the total consumption of pure alcohol in Taiwan, is as high as that in many Asian countries.5 Therefore, the problem of alcohol is of a greater concern nowadays in Taiwan. In this article, we will

review alcohol research in Taiwan, focusing on its psychiatric epidemiology and biomedicine.

2. Epidemiology of AD in Taiwan

Three nationwide psychiatric epidemiological studies in Taiwan were conducted from the end of World War II to the 1980s.6,7The ﬁrst survey, which was conducted between 1946 and 1948, found only two cases of AD (0.01%) among Taiwanese communities. From 1949 to1953, a survey was conducted in 11,442 individuals from four Taiwanese aboriginal tribes (Atayal, Paiwan, Saisiat, and Ami). In this study, only 13 cases (0.11%) were found to have AD. Among these, 8 drank actively during the survey period, while 5 were abstinent. Later in the 1980s, Hwu et al reported a 100-fold increase in prevalence (of 1.5% AD in the Taiwanese community, and 10% in Aboriginal tribes).4,8 The ﬁndings of the drastic increase in AD prevalence, caused academic debate concerning the issue of methodology, like interviewers’ reliability and Chinese version’s validity. A further hospital-based survey by psychiatrists, showed that the prevalence of AD was 6.6%, 5 times higher among inpatient s than community samples.9 In 1995, Cheng and Chen further showed that the prevalence of AD is 17%e32% among various aboriginal tribes.3A more recent survey, conducted in a medical center, revealed that 12.6% inpatients have AD.10Although so far there is a lack of nationwide prevalence of AD among Taiwanese Han populations, 3% is a reasonable prevalence estimate based on the data of the inpatient survey.

* Corresponding author. Chiao-Chicy Chen, Department of Psychiatry, Mackay Memorial Hospital, 92, Sec. 2, Chong-Shan N. Rd., Taipei 10449, Taiwan.

E-mail: Chiao-Chicy Chen <cchen@tmu.edu.tw>

Contents lists available atSciVerse ScienceDirect

Journal of Experimental and Clinical Medicine

j o u r n a l h o m e p a g e : h t t p : // w w w . j e c m - o n l i n e . c o m

(2)

3. Are Han Taiwanese immune to AD?

Despite the dramatic increase of prevalence of AD in Taiwan, the AD prevalence of the Taiwanese is significantly lower than that of Caucasian counterparts and neighboring countries, as well as the Formosan aborigines. Hence, Han Taiwanese are speculated to be immune to AD. Several socio-cultural factors have been proposed to account for the low AD incidence among the Taiwanese society. For example, alcohol is only consumed during ceremonial occasions, or primarily at meals and drunkenness is viewed as bad manners. In the 1970s, it wasfirst reported the alcohol sensitivity may exist among different ethnicities, which implied that the low AD prev-alence among the Taiwanese may be linked to the biological mechanism.11_{In the 1980s, it was further revealed that the lack of} the alcohol metabolizing enzyme, aldehyde dehydrogenase (ALDH) in particular, may cause aversive reactions to alcohol drinking.12,13A series of phenotypic studies, conducted in Taiwan and Japan, confirmed that ALDH deficiency and a flush response after drinking, are significantly correlated with AD prevalence among different ethnic groups in Asia.14,15

4. AD and alcohol-metabolizing enzymes genes 4.1. Genetic factors of AD

That AD runs in families is well-recognized.16 Family, twin, and adoption studies indicate that susceptibility to AD is more likely caused by genetic factors, which carries 50%e60% of the liability of risk. Therefore, genetic factors17,18are considered to be essential for the development of AD. However, AD is not a Mendelian trait with a simple pattern of inheritance, nor is it deterministic. AD is a complex trait like most psychiatric diseases and other common diseases, with both genetic and environmental factors affecting the risk. Numerous functional and positional candidate genes have been postulated with notable successes.

4.2. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes

In contrast to the complex effects of alcohol in the central nervous system (CNS), the hepatic metabolism of alcohol by ADH and ALDH is well-understood. Functional effects of the related genes on the activity of the enzymes have been reported. Alcohol is metabolized by ADH to acetaldehyde, which is further metabolized primarily by ALDH. Acetaldehyde produces a“ﬂushing reaction” characterized by a set of uncomfortable symptoms. Genetic variants which impede ALDH function and increased ADH function, are thought to be protective against the development of AD.

For ADH, three different alleles, ADH1B*2, ADH1B*3and ADH1*C, have been shown to alter the enzymatic activity of ADH, with ADH1B*2 and ADH1B*3 altering the activity more than 30-fold.19 Hence, individuals carrying these alleles presumably have higher levels of acetaldehyde, and therefore are at lower risk of AD development. However, the frequencies of the three alleles vary extremely between different ethnic populations. Speciﬁcally, ADH1B*2 is commonly found in Asians but rare in other ethnic populations, and ADH1*C is also higher in Han Chinese (90%) than Europeans (55%e90%).20_{A meta-analysis revealed that ADH1B*2} has protective properties decreasing the risk of AD by a factor of 3, compared to the ADH1B*1 allele.21

Work with ALDH2 provides an instructive insight into searching the candidate genes for AD. Among the nine gene families encoding for human ALDH, only ALDH1 and ALDH2 play a major role in the acetaldehyde oxidation. The ALDH2*2 allele is particularly associ-ated with enzyme inactivity resulting in symptoms of acetaldehyde

syndrome. Although the allele is rare in Caucasian and African populations, it is commonly found in Asian populations.22Studies examining the association between ALDH2*2 and alcoholism show that ALDH2*2 can reduce the risk of AD by a factor of 10,23e25an effect greater than that from ADH1B and ADH1C.23,24 Taken together, risk variants are likely to be population-speciﬁc. For instance, the meta-analysis by Luczak et al. indicated that ADH1B and ALDH2 can robustly modify the AD risk in Asian populations,26 i.e, ALDH2*2 allele carriers have only a 25% risk of developing AD compared with ALDH2*2 non-carriers.

Recently, researchers attempted to focus on candidate genes which map within linkage peaks. Two different regions of chro-mosome 4 are best characterized in the AD risk loci map: an ADH gene cluster in the long arm and a GABAAreceptor subunit gene

cluster in the short arm. Using a range of methods, including Hardy-Weinberg disequilibrium analysis, structured association, and family based association, ADH4 has been shown to have a signi ﬁ-cant association with AD risk in the gene cluster.27,28

4.3. Dopamine (DA) receptor gene

Dopamine (DA) is the neurotransmitter which has been classically associated with the reinforcing effects of drugs of abuse, and may have a key role in triggering neurobiological changes in the reward system. Alcohol can stimulate DA release in the nucleus accumbens through the mesolimbic dopaminergic pathway, to increase self-rewarding. Previous studies indicate that the DRD2 receptor is involved in DA-mediated reinforcing effects of alcohol. Therefore, the DA receptor gene (DRD2) has been considered a candidate gene to be implicated in AD.29However, the results of the association between DRD2 gene variants and AD are indeed mixed across studies.30 Several possible explanations might account for these conﬂicting results; one of these may be that haplotypes, rather than single nucleotide polymorphisms (SNPs) of the DRD2 gene, play a more important role in the association with AD.31For instance, in Mexican Americans, the exon 8 genotype in combination withﬁve other SNP genotypes, Taq 1A, promotor gene, Taq 1B, intron 6, and exon 7 are associated with AD.32

The distribution of allele frequencies of various DRD2 genotypes differs between populations to a noteworthy extent.31In the Han Chinese population, the genetic variants of DRD2 are found to have equivocal associations with AD risks.33,34 It has been widely accepted that some disease-relevant genes may affect a range of genetically inﬂuenced intermediate characteristics (also called “endophenotypes”) which subsequently affect the risk for alcohol-related problems. As such, DRD2 genotypes are reported to be associated with anxiety/depression in alcoholism33and alcoholism with conduct disorder.35In a case-control study in an independent Han Taiwanese population (number of AD subjects: 320; number of non-AD individuals¼ 314), we did not ﬁnd any genotypic or hap-lotypic association with AD (MC Huang and C.C. Chen, unpublished data).

5. Oxidative stress associated with the metabolism of alcohol The multi-organ toxicity caused by alcohol is related to its metabolism by forming free radicals or interacted compounds. In addition to ADH and ALDH, a minor pathway for alcohol metab-olism is ethanol-inducible cytochrome P450 2E1 (CYP2E1). However this pathway may play an important role in the range of high alcohol levels, as well as in chronic alcoholics. CYP2E1-mediated metabolism induced by alcohol generates more toxic metabolites, including reactive oxygen species (ROS, containing superoxide anion and hydrogen peroxide) as well as ethanol-derived (hydroxyethyl) free radicals. These products cause DNA

(3)

damage, generate protein adducts, and initiate lipid peroxidation. Among them, malondialdehyde (MDA) is a reliable marker of oxidative damage, and reﬂects the extent of interaction between oxygen molecules and polyunsaturated fatty acids. However, several antioxidant defense mechanisms exist, which are involved in the elimination of ROS, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX). SODs catalyze superoxide radicals to hydrogen peroxide and thus are critical for prevention from further toxic oxidative radicals. CAT and GPX are responsible for further metabolizing hydrogen peroxide to water and oxygen.

5.1. Elevated lipid peroxidation and weakened antioxidant defenses in AD patients

A host of studies have investigated the effect of alcohol on oxidative stress in humans. In comparison to controls, MDA levels are increased significantly in alcoholics.36,37_{Antioxidant activities are} generally decreased in chronic alcoholics. After withdrawal, SOD and GPX activities are reduced, while CAT activity is unchanged from the baseline levels.38,39Our data have also shown that MDA levels and activities of SOD and GPX in the blood in alcoholic patients are significantly different from those in healthy con-trols.40e42In AD individuals, MDA levels are found to be signi fi-cantly higher than those in controls; they gradually normalize after 2 weeks of detoxification. Meanwhile, a remarkable and persistent lowering of SOD and GPX activities is found throughout the 2-week withdrawal period. CAT activity is no higher than that in controls at baseline, but is decreased markedly afterwards, and even levels lower than those in controls after 2 weeks of detoxification. We suggest that alcoholic patients have enhanced lipid peroxidation and depressed antioxidative mechanisms.

5.2. Enhanced oxidative DNA damage following chronic alcohol consumption

As mentioned before, radical-driven products through alcohol metabolism can induce oxidation of various cellular biomolecules, including lipids, proteins, and DNA, and cause oxidative damage. Among ROS, the highly active hydroxyl radical can cause strand breaks in DNA and base modifications, by reacting with the C-8 position of the guanine base on DNA through hydroxylation, and generating 8-hydroxy-2’-deoxyguanosine (8-OHdG).43_{In addition,} nitrous oxide (NO) can also react with superoxide to form perox-ynitrite, to produce 8-OHdG by a “hydroxyl-radical like” mecha-nism.44 8-OHdG is considered to be a sensitive biomarker to estimate the ROS-induced DNA damage in vivo45and has gained much attention because of its mutagenic potential as well as its relevance to cancer, aging, and neurodegeneration. Of note, we found that a significant increase of serum 8-OHdG levels exists in AD patients compared with normal controls. While serum MDA levels are normalized after alcohol detoxification treatment, serum 8-OHdG levels remain elevated in the same period. Thisfinding suggests that a heightened oxidative DNA damage would not recover during early alcohol withdrawal.46

5.3. Oxidative stress contributes to alcohol withdrawal and addiction

During prolonged exposure to alcohol, individuals with AD will experience the alcohol withdrawal syndrome (AWS) when they abruptly reduce or discontinue alcohol consumption. The over-excitation of N-methyl-D-aspartate (NMDA) glutamate receptors has long been implicated in the mechanisms underlying AWS. Due to the characteristics of high oxygen consumption, rich

polyunsaturated fatty acids, and poor SOD and CAT activity, the brain is highly susceptible to alcohol-induced ROS generation which promotes neuronal damage. Therefore, oxidative stress plays an important role in the manifestations of AWS by interacting with glutamate overactivation.47

Consistently, our clinical study has also shown that the AWS may be a possible reﬂection of excessive oxidative damage in the CNS.40 We found that AWS severity is correlated more robustly with 8-OHdG and MDA levels.46The phenomenon suggests that AWS, a manifestation of central glutamate overexcitation, is inter-woven with oxidative damage which presumably contributes to mechanisms of addiction.

6. Neuroadaptation for alcohol dependence

The neuroadaptation theory has long been implicated in the mechanisms underlying addiction. Brain-derived neurotrophic factor (BDNF) is the most abundant member of the nerve growth factors in the brain. It promotes neuronal survival and differentia-tion, modulates the activity of neurotransmitters, and participates in plasticity mechanisms. Activity dependent activation of BDNF is associated with the neuroadaptation of neurons in brain reward circuitry and takes part in addiction.48,49

6.1. Brain-derived neurotrophic factor (BDNF) and AD

The acute effect of alcohol produces changes in signaling pathways altering gene expression, such as BDNF.49 BDNF expression is increased both in vitro and in vivo following acute alcohol exposure. The BDNF elevation is postulated to be an endogenous neuro-protective response against alcohol-induced disequilibrium to maintain the“homeostatic pathway”or to counteract the rewarding effects of alcohol.49However, the opposing adaptation (i.e., neu-roadaptation) accompanied by chronic alcohol exposure, causes a reduction in BDNF expression. Additionally, alcohol directly dampens BDNF expression and signaling.50Therefore, the role of BDNF in counteracting addiction is attenuated after long-term alcohol consumption,49causing an increase in drinking behavior. In animal studies, chronic alcohol exposure is shown to decrease BDNF and NGF expression.51Consistently, our human studies also found that individuals with AD have lower BDNF levels in the blood.52,53

6.2. BDNF and alcohol withdrawal syndrome

The disinhibition of BDNF during alcohol withdrawal, is suggested to exert a protective function against neuronal damage through stimulation of sprouting and synaptic reorganization.51 Brain insults such as sustained stress, epileptic, hypoglycemic, ischemic, and traumatic events can trigger BDNF expression. It is postulated that increased glutamate release and calcium inﬂux are responsible for increasing BDNF during the insults. In accordance, over-excitation of glutamate NMDA receptors, implicated in AWS-related neurotoxicity,54 would be expected to promote BDNF elevation to cope with the aggressive NMDA overactivation of AWS. Based on those clinical study observations, we suggest that the BDNF levels are increased after alcohol withdrawal in AD patients,52,53 and that BDNF elevation plays an important role in enhancing the resilience of neuronal cells during withdrawal, which would further contribute to the progressive nature of AD. 6.3. BDNF may be involved in modifying the phenotypes of AD The spectrum of AWS ranges from mild symptoms to severe complications, such as withdrawal seizures and delirium tremens

(4)

(DTs). DTs is the most serious manifestation of AWS and potentially fatal. It is rare, occurring in about 5% of patients hospitalized for AWS treatment,55but is difﬁcult to treat once it develops. Patients with DTs are suggested to be a clinically distinct subgroup among alcohol-dependent individuals, and are associated with a genetic predisposition.56Numerous studies have investigated the potential predictors, including clinical parameters or biological markers, in alcohol-dependent individuals to develop DTs.

With important effects on neurotransmitter modulation, BDNF is implicated in mediating various clinical exhibitions such as DTs. Being compatible with this speculation, our study has shown that there are differential expressions of serum BDNF levels between alcoholic inpatients with DTs and without DTs. Serum baseline BDNF level are signi_{ficantly lowest in patients with DTs, followed by} those without DTs and healthy controls.52The BDNF levels in the DT group remained significantly lower following withdrawal treat-ment. This suggests that more deficient BDNF levels could be related to the incidence of DTs, and are likely to be underlying the fundamentally distinct neuroadaptive responses between the subtypes of AWS.

7. Conclusion

AD is a debilitating psychiatric disorder worldwide which is char-acterized by persistent, compulsive and uncontrolled drinking. A recent study has shown that, among drug-related harm, alcohol is listed as the most harmful drug.57An earlier report also revealed in Taiwan that AD patients are associated with a higher mortality.58In addition, according to the report of the Department of Health in Taiwan, more than 40% of domestic violence is associated with alcohol use. AD is also a potent risk factor for suicide,59and is associated with a higher risk of depressive and anxiety disorders.60 Given the multiple harmful effects associated with AD, we believe that pertinent research can provide a key to a more detailed understanding and develop feasible approaches to deal with the challenging disease.

In this review, we have addressed the long-known relationship of the alcohol-metabolizing enzymes to AD risk in Asian populations, including Taiwanese, who are considered to be immune to the development of AD. ADH and ALDHﬁndings have been replicated across many genes and populations beyond the initial work, although there still exist con_{ﬂicting results in the association of} genes in neurotransmitter systems such as DRD2 with AD risk. In recent years, a technological revolution has occurred to produce a shift from single-locus studies to genome-wide research and to promote our understanding of the mechanisms by which genetic variations alter molecular function and predispose individuals to AD. We also have discussed the biomedicine issue associated with the process of AD. In addition to the notion that chronic alcohol consumption leads to excessive oxidative stress, we also propose that the oxidative stress may be closely linked with alcohol with-drawal severity in clinical samples and contribute to the patho-physiology of AD. On the other hand, prolonged alcohol drinking also dampens the neuroprotective mechanisms which counteract the development of AD. The long-term neuroadaptation following chronic drinking worsens the vicious cycle of addiction, favoring a process of more severe AD. We suggest that BDNF may be involved in modifying the severe phenotype of AD. However, knowledge about the underlying molecular mechanisms is just one part of the complex clinical architecture of AD. Looking ahead, our ability to better map the interactions between genes, biomedicines, and the environment offers strategies for more effective clinical management of AD, by focusing on preventative measures for vulnerable individuals.

References

1. WHO. Expert committee on problems related to alcohol consumption. Second report, vol. 944. World Health Organization Technique Report; 2007. pp. 55e57.

2. Chen CC, Yin SJ. Alcohol abuse and related factors in Asia. Int Rev Psychiatry 2008;20:425e33.

3. Cheng AT, Chen WJ. Alcoholism among four aboriginal groups in Taiwan: high prevalences and their implications. Alcohol Clin Exp Res 1995;19:81e91. 4. Hwu HG, Yeh YL, Wang JD, Yeh EK. Alcoholism among Taiwan aborigines

deﬁned by the Chinese Diagnostic Interview Schedule: a comparison with alcoholism among Chinese. Acta Psychiatr Scand 1990;82:374e80.

5. Chen CH. Epidemiology of alcohol consumption. Taiwan: NHRI Forum Taipei: National Health Research Institute; 2004.

6. Lin TY. A study of the incidence of mental disorder in Chinese and other cultures. Psychiatry 1953;16:313e36.

7. Lin TY, Rin H, Yeh EK. Mental disorders in Taiwan:ﬁfteen years later. In: Caudill W, Lin TY, editors. Mental health research in Asia and the Paciﬁc, Hon-olulu. East-West Center Press; 1969.

8. Hwu HG, Yeh EK, Chen CC, Lin TY, Tseng WS, Yeh EK. Alcoholism in Taiwan: the Chinese and Aborigines. In: Chinese societies and mental health. New York: Oxford University Press; 1995. p. 181e96.

9. Chen CC, Yeh EK, Hwu HG, Lin SK, Lee CT, Wang JJ, Yeh YL. Drinking problem in inpatients of a general hospital: lifetime prevalence of alcohol abuse and dependence. Chinese Psychiatry 1987;1:166e72.

10. Chen CH, Chen WJ, Cheng AT. Prevalence and identiﬁcation of alcohol use disorders among nonpsychiatric inpatients in one general hospital. Gen Hosp Psychiatry 2004;26:219e25.

11. Ewing JA, Rouse BA, Pellizzari ED. Alcohol sensitivity and ethnic background. Am J Psychiatry 1974;131:206e10.

12. Agarwal DP, Goedde HW. Pharmacogenetics of alcohol metabolism and alco-holism. Pharmacogenetics 1992;2:48e62.

13. Goedde HW, Agarwal DP, Harada S, Meier-Tackmann D, Ruofu D, Bienzle U, Kroeger A, et al. Population genetic studies on aldehyde dehydrogenase isozyme deficiency and alcohol sensitivity. Am J Hum Genet 1983;35:769e72. 14. Chen CC, Hwu HG, Yeh EK, Morimoto K, Otsuki S. Aldehyde dehydrogenase deficiency, flush patterns and prevalence of alcoholism: an interethnic comparison. Acta Med Okayama 1991;45:409e16.

15. Ohmori T, Koyama T, Chen CC, Yeh EK, Reyes Jr BV, Yamashita I. The role of aldehyde dehydrogenase isozyme variance in alcohol sensitivity, drinking habits formation and the development of alcoholism in Japan, Taiwan and the Philippines. Prog Neuropsychopharmacol Biol Psychiatry 1986;10:229e35. 16. Cotton NS. The familial incidence of alcoholism: a review. J Stud Alcohol

1979;40:89e116.

17. McGue M. Phenotyping alcoholism. Alcohol Clin Exp Res 1999;23:757e8. 18. Prescott CA, Kendler KS. Genetic and environmental contributions to alcohol

abuse and dependence in a population-based sample of male twins. Am J Psychiatry 1999;156:34e40.

19. Bosron WF, Magnes LJ, Li TK. Human liver alcohol dehydrogenase: ADH Indi-anapolis results from genetic polymorphism at the ADH2 gene locus. Biochem Genet 1983;21:735e44.

20. Shen YC, Fan JH, Edenberg HJ, Li TK, Cui YH, Wang YF, Tian CH, et al. Poly-morphism of ADH and ALDH genes among four ethnic groups in China and effects upon the risk for alcoholism. Alcohol Clin Exp Res 1997;21:1272e7. 21. Whitﬁeld JB, Nightingale BN, Bucholz KK, Madden PA, Heath AC, Martin NG.

ADH genotypes and alcohol use and dependence in Europeans. Alcohol Clin Exp Res 1998;22:1463e9.

22. Goedde HW, Agarwal DP, Fritze G, Meier-Tackmann D, Singh S, Beckmann G, Bhatia K, et al. Distribution of ADH2 and ALDH2 genotypes in different pop-ulations. Hum Genet 1992;88:344e6.

23. Chen WJ, Loh EW, Hsu YP, Chen CC, Yu JM, Cheng AT. Alcohol-metabolising genes and alcoholism among Taiwanese Han men: independent effect of ADH2, ADH3 and ALDH2. Br J Psychiatry 1996;168:762e7.

24. Thomasson HR, Crabb DW, Edenberg HJ, Li TK, Hwu HG, Chen CC, Yeh EK, et al. Low frequency of the ADH2*2 allele among Atayal natives of Taiwan with alcohol use disorders. Alcohol Clin Exp Res 1994;18:640e3.

25. Thomasson HR, Edenberg HJ, Crabb DW, Mai XL, Jerome RE, Li TK, Wang SP, et al. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet 1991;48:677e81.

26. Luczak SE, Glatt SJ, Wall TL. Meta-analyses of ALDH2 and ADH1B with alcohol dependence in Asians. Psychol Bull 2006;132:607e21.

27. Luo X, Kranzler HR, Zuo L, Lappalainen J, Yang BZ, Gelernter J. ADH4 gene variation is associated with alcohol dependence and drug dependence in European Americans: results from HWD tests and case-control association studies. Neuropsychopharmacol 2006;31:1085e95.

28. Luo X, Kranzler HR, Zuo L, Yang BZ, Lappalainen J, Gelernter J. ADH4 gene variation is associated with alcohol and drug dependence: results from family controlled and population-structured association studies. Pharmacogenet Genomics 2005;15:755e68.

29. Volkow ND, Fowler JS, Wang GJ, Swanson JM, Telang F. Dopamine in drug abuse and addiction: results of imaging studies and treatment implications. Arch Neurol 2007;64:1575e9.

30. Noble EP. The DRD2 gene in psychiatric and neurological disorders and its phenotypes. Pharmacogenomics 2000;1:309e33.

(5)

31. Kidd KK, Morar B, Castiglione CM, Zhao H, Pakstis AJ, Speed WC, Bonne-Tamir B, et al. A global survey of haplotype frequencies and linkage disequi-librium at the DRD2 locus. Hum Genet 1998;103:211e27.

32. Luo HR, Hou ZF, Wu J, Zhang YP, Wan YJ. Evolution of the DRD2 gene haplotype and its association with alcoholism in Mexican Americans. Alcohol 2005;36:117e25. 33. Huang SY, Lin WW, Ko HC, Lee JF, Wang TJ, Chou YH, Yin SJ, et al. Possible interaction of alcohol dehydrogenase and aldehyde dehydrogenase genes with the dopamine D2 receptor gene in anxiety-depressive alcohol dependence. Alcohol Clin Exp Res 2004;28:374e84.

34. Lee JF, Lu RB, Ko HC, Chang FM, Yin SJ, Pakstis AJ, Kidd KK. No association between DRD2 locus and alcoholism after controlling the ADH and ALDH genotypes in Chinese Han population. Alcohol Clin Exp Res 1999;23:592e9. 35. Guillin O, Diaz J, Carroll P, Griffon N, Schwartz JC, Sokoloff P. BDNF controls

dopamine D3 receptor expression and triggers behavioural sensitization. Nature 2001;411:86e9.

36. Tsai G, Coyle JT. The role of glutamatergic neurotransmission in the patho-physiology of alcoholism. Annu Rev Med 1998;49:173e84.

37. Yuksel N, Uzbay IT, Karakilic H, Aki OE, Etik C, Erbas D. Increased serum nitrite/ nitrate (NOx) and malondialdehyde (MDA) levels during alcohol withdrawal in alcoholic patients. Pharmacopsychiatry 2005;38:95e6.

38. Guemouri L, Lecomte E, Herbeth B, Pirollet P, Paille F, Siest G, Artur Y. Blood activities of antioxidant enzymes in alcoholics before and after withdrawal. J Stud Alcohol 1993;54:626e9.

39. Lecomte E, Herbeth B, Pirollet P, Chancerelle Y, Arnaud J, Musse N, Paille F, et al. Effect of alcohol consumption on blood antioxidant nutrients and oxidative stress indicators. Am J Clin Nutr 1994;60:255e61.

40. Huang MC, Chen CC, Peng FC, Tang SH, Chen CH. The correlation between early alcohol withdrawal severity and oxidative stress in patients with alcohol dependence. Prog Neuropsychopharmacol Biol Psychiatry 2009;33:66e9. 41. Huang MC, Chen CH, Peng FC, Tang SH, Chen CC. Alterations in oxidative stress

status during early alcohol withdrawal in alcoholic patients. J Formos Med Assoc 2009;108:560e9.

42. Peng FC, Tang SH, Huang MC, Chen CC, Kuo TL, Yin SJ. Oxidative status in patients with alcohol dependence: a clinical study in Taiwan. J Toxicol Environ Health A 2005;68:1497e509.

43. Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: mecha-nisms, mutation, and disease. FASEB J 2003;17:1195e214.

44. Inoue S, Kawanishi S. Oxidative DNA damage induced by simultaneous generation of nitric oxide and superoxide. FEBES Lett 1995;371:86e8. 45. Halliwell B. Why and how should we measure oxidative DNA damage in

nutritional studies? How far have we come? Am J Clin Nutr 2000;72:1082e7. 46. Chen CH, Pan CH, Chen CC, Huang MC. Increased oxidative DNA damage in

patients with alcohol dependence and its correlation with alcohol withdrawal severity. Alcohol Clin Exp Res 2011;35:338e44.

47. Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science 1993;262:689e95.

48. Hall J, Thomas KL, Everitt BJ. Rapid and selective induction of BDNF expression in the hippocampus during contextual learning. Nat Neurosci 2000;3:533e5.

49. McGough NN, He DY, Logrip ML, Jeanblanc J, Phamluong K, Luong K, Kharazia V, et al. RACK1 and brain-derived neurotrophic factor: a homeo-static pathway that regulates alcohol addiction. J Neurosci 2004;24: 10542e52.

50. Davis MI. Ethanol-BDNF interactions: still more questions than answers. Pharmacol Ther 2008;118:36e57.

51. Tapia-Arancibia L, Rage F, Givalois L, Dingeon P, Arancibia S, Beauge F. Effects of alcohol on brain-derived neurotrophic factor mRNA expression in discrete regions of the rat hippocampus and hypothalamus. J Neurosci Res 2001;63:200e8.

52. Huang MC, Chen CH, Liu HC, Chen CC, Ho CC, Leu SJ. Differential patterns of serum brain-derived neurotrophic factor levels in alcoholic patients with and without delirium tremens during acute withdrawal. Alcohol Clin Exp Res 2011;35:126e31.

53. Huang MC, Chen CH, Liu SC, Ho CJ, Shen WW, Leu SJ. Alterations of serum brain-derived neurotrophic factor levels in early alcohol withdrawal. Alcohol Alcohol 2008;43:241e5.

54. Tsai GE, Ragan P, Chang R, Chen S, Linnoila VM, Coyle JT. Increased gluta-matergic neurotransmission and oxidative stress after alcohol withdrawal. Am J Psychiatry 1998;155:726e32.

55. Mayo-Smith MF. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol With-drawal. JAMA 1997;278:144e51.

56. van Munster BC, Korevaar JC, de Rooij SE, Levi M, Zwinderman AH. Genetic polymorphisms related to delirium tremens: a systematic review. Alcohol Clin Exp Res 2007;31:177e84.

57. Nutt DJ, King LA, Phillips LD. Drug harms in the UK: a multicriteria decision analysis. Lancet 2010;376:1558e65.

58. Chen CC, Kuo CJ, Tsai SY. Causes of death of patients with substance depen-dence: a record-linkage study in a psychiatric hospital in Taiwan. Addiction 2001;96:729e36.

59. Conner KR, Duberstein PR. Predisposing and precipitating factors for suicide among alcoholics: empirical review and conceptual integration. Alcohol Clin Exp Res 2004;28:6e17.

60. Hasin DS, Stinson FS, Ogburn E, Grant BF. Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National epidemiologic survey on alcohol and related condi-tions. Arch Gen Psychiatry 2007;64:830e42.