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This article was downloaded by: [The University of British Columbia] On: 26 November 2012, At: 11:14 Publisher: Routledge Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Substance Abuse Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/wsub20 Prevention of Alcohol Dependence: Strategies for Selective, Indicated, and Universal Prevention Narayana Manjunatha DPM, MD a, Sahoo Saddichha BA, MBBS, DPM, MD a, Christoday R. J. Khess MD b, Pratima Murthy DPM, MD a & Mohan K. Isaac DPM, MD, FRCPsych c a National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India b Central Institute of Psychiatry, Ranchi, India c School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia Version of record first published: 08 Jun 2011. To cite this article: Narayana Manjunatha DPM, MD, Sahoo Saddichha BA, MBBS, DPM, MD, Christoday R. J. Khess MD, Pratima Murthy DPM, MD & Mohan K. Isaac DPM, MD, FRCPsych (2011): Prevention of Alcohol Dependence: Strategies for Selective, Indicated, and Universal Prevention, Substance Abuse, 32:3, 135-143 To link to this article: http://dx.doi.org/10.1080/08897077.2011.562736 PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.

Substance Abuse, 32:135 143, 2011 Copyright c Taylor & Francis Group, LLC ISSN: 0889-7077 print / 1547-0164 online DOI: 10.1080/08897077.2011.562736 Prevention of Alcohol Dependence: Strategies for Selective, Indicated, and Universal Prevention Narayana Manjunatha, DPM, MD Sahoo Saddichha, BA, MBBS, DPM, MD Christoday R. J. Khess, MD Pratima Murthy, DPM, MD Mohan K. Isaac, DPM, MD, FRCPsych ABSTRACT. Study of the chronology of criteria of dependence in alcohol dependence syndrome (ADS) can enable us to design strategies for the prevention for ADS, which takes into account primary prevention (indicated, selective, and universal prevention) approaches and aims at reducing the occurrence of ADS. The objective of this work is to study the age-wise and order-wise chronologies of International Classification of Diseases Tenth Revision Diagnostic Criteria for Research (ICD-10 DCR) dependence criteria in individuals with ADS. Consecutively admitted and consenting inpatients with ICD-10 DCR diagnosis of ADS were evaluated in a structured interview after detoxification using Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA)-II. The total sample size was 81. The mean ages at the first onset of alcohol use, development of the first criterion, and ICD-10 dependence was 18.72 years (SD: 6.84), 24.33 years (SD: 9.21), and 27.51 years (SD: 9.28), respectively. In age-wise chronology, tolerance, loss of control, and craving were present in 97.53%, 80.24%, and 79%, respectively, of our study sample. In order-wise chronology, either craving (16%) or tolerance (71.6%) was present as the first criterion and the presence of craving (16%), tolerance (21%), or loss of control (18.5%) was observed as the first criterion in 55.5% of the subjects. Indicated prevention may be attempted by enquiring about craving, tolerance, and loss of control and use of anticraving medications or behavioral strategies. Selective prevention by using naltrexone for those genetically inclined and universal prevention by use of clinical labeling on alcoholic beverages can also be attempted. KEYWORDS. Alcohol dependence, indicated prevention, selective prevention, universal prevention Narayana Manjunatha, Sahoo Saddichha, and Pratima Murthy are affiliated with the National Institute of Mental Health & Neurosciences (NIMHANS), Bangalore, India. Christoday R. J. Khess is affiliated with the Central Institute of Psychiatry, Ranchi, India. Mohan K. Isaac is affiliated with the School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia. Address correspondence to: Dr. Sahoo Saddichha, Department of Psychiatry, National Institute of Mental Health & Neurosciences (NIMHANS), Hosur Road, Bangalore 560029, India (E-mail: saddichha@ gmail.com). The authors acknowledge the help of Dr. Victor Hesselbrock, PhD, University of Connecticut, Framington, who provided and permitted the authors to use the SSAGA-II. SSAGA-II has been developed by the Collaborative Study on the Genetics of Alcoholism (COGA), supported by National Institute of Health (NIH) grant U10AA08401 from the National Institute of Alcohol And Alcoholism (NIAAA). The authors also thank the entire COGA team and lastly, but not the least, the patients who made this study possible.

136 SUBSTANCE ABUSE INTRODUCTION Alcohol dependence syndrome (ADS) has gained public health importance and has stimulated research after Edwards and Gross (1) described typical behavioral clusters of ADS. The same criteria are used to diagnose ADS across the world in both International Classification of Diseases Tenth Revision (ICD-10) and Diagnostic and Statistical Manual of Mental Diseases Fourth Edition (DSM-IV), with some variations. In ICD-10, the presence of minimum 3 out of 6 criteria is required to diagnose ADS (2). After diagnosis, the management follows the established algorithms of secondary and tertiary prevention. However, it is quite likely that the person has had contact with a primary health care setup before the development of ADS, where he may have received treatment for other alcohol-related conditions such as gastritis, hepatitis, etc. (3), and may be targeted for prevention of alcohol dependence. This category of patients has been termed diagnostic orphans by Kaczynski and Martin (4) and others have adopted it (5, 6). These persons may have high risk to develop ICD-10 dependence syndrome and eventually present with 3 or more criteria (5). Moreover, diagnostic orphans are more likely to seek help for alcoholrelated problems before developing full-fledged dependence syndrome (7). It becomes pertinent, therefore, to know whether intervention strategies may help in progression to dependence in this group, and the best time to implement such strategies. Research on alcohol diagnostic orphans is scant when compared to ADS (8), although there have been some recent attempts to address this gap (4 6). This may be because of difficulties inherent in definition, terminology, measurement, and extent of causation for alcohol-related problems (9). Further, the experience of dependence criteria has also been noted to be varying across the world (10). Because alcohol-related problems are more common in nondependent drinkers than in dependent drinkers (11), it becomes essential to study the natural progression of ADS to formulate effective strategies of prevention in alcohol diagnostic orphans and for those alcohol users without any dependence criteria. Secondary and tertiary prevention are currently the predominating issues in the management of ADS, i.e., detoxification, relapse prevention, etc. However, there are obstacles towards primary prevention of ADS, such as the social acceptance of alcohol use (12), cardioprotective benefit (13), legal and free availability (14), statistically significant prevention programs (15), and an assumption that prevention is not possible due to unknown etiology of alcohol dependence (16). These obstacles indicate that it is impossible to think of an alcohol-free society although long-term alcohol use has been associated with many physical problems, e.g., myocardial infarction, strokes, etc. (13). Although an alcohol-free society may be an impossibility, primary prevention of dependence syndrome is both realistic and feasible. There is, therefore, a need to develop effective prevention strategies, for which identifying the right factors and duration between onset and development of dependence in our population is required. There is very little research on primary prevention of ADS. Ehlers et al. (17) carried out a community-based study on clinical course of alcoholism with targeting the preventive strategies, but not formulated any preventive plan. A systematic study and analysis of chronology of dependence criteria has not been comprehensively carried out to date, although some attempts have been made to do so (18), including an earlier paper of ours (19). This might be helpful in designing a strategy for the prevention of ADS, and lowering the incidence of ADS. We report here a systematic study of the chronology (age-wise and order-wise) and the prevalence of each criterion of ICD-10 ADS of in-patients, which may be helpful in designing strategies of primary prevention for ADS and to better identify the at-risk population, especially in routine primary care practice. METHODS The exact methodology has been detailed in an earlier paper (20). Briefly, patients admitted consecutively into Centre for Addiction Psychiatry, Central Institute of Psychiatry, Ranchi, and

Manjunatha et al. 137 meeting a clinical diagnosis of ADS as per ICD- 10 and who gave written informed consent were recruited for this study. The study protocol was approved by the Institute s Ethics Committee. Subjects who met criteria for other substance dependence, those who had other comorbid psychiatric disorders or general medical conditions, and patients with Mini-Mental Status Examination (MMSE) (21) screening scores of less than 24 were excluded from the study. Patients who fulfilled study criteria were interviewed using the alcohol section of Semi- Structured Assessment for the Genetics of Alcoholism-II (SSAGA-II) (22), after detoxification. SSAGA-II is a polydiagnostic instrument developed by Collaborative Study on the Genetics of Alcoholism team designed to assess the physical, psychological, and social manifestations of alcohol and other substances as well as other psychiatric disorder according to ICD-10 and DSM-IV. It also has items related to each criterion of dependence of ICD-10. Reliability and validity of SSAGA has been established (22, 23). The alcohol section of SSAGA-II contains 45 multipart items. SSAGA has good concordance with Schedule for Clinical Assessment in Neuropsychiatry (24) and has good kappa value (κ =.63) for alcohol dependence (23). SSAGA-II permits detailed evaluation of first onset of each criterion of dependence according to ICD-10. Since it was retrospective study, questions were framed individually to trigger the recall using anchor questions to personal and impersonal or important social events and defining the technical terms (25). Relevant information of patients was also corroborated from their respective case records completed at the time of admission. In case of discrepancy of any items, it was discussed with patient for consensus. At the end of interview, data were transferred to the ICD-10 tally sheet of respective items in the alcohol section of SSAGA-II. Among the first age(s) of appearance of items of each criterion, we considered the earliest age of appearance of any item as age of first appearance of the respective criterion of dependence (ICD-10 Diagnostic Criteria for Research [DCR]). We considered the age of development of ICD-10 dependence syndrome as the age of onset of a third consecutive criterion, with the simultaneous presence of other 2 criteria (among the 6 criteria of ICD-10). The criteria of ICD-10 ADS (2) are (a) a strong desire or sense of compulsion to take alcohol (craving); (b) difficulties in controlling alcohol-taking behavior in terms of onset, termination, or levels of use (loss of control); (c) physiological withdrawal state; (d) tolerance; (e) progressive neglect of alternative pleasures or interests (salience), and (f) persistent use despite overt physical or psychological harm. The key words (in italics) of each criterion are used in discussion of this study. RESULTS Total sample size of present study was 81. All subjects were males, with mean age 35.16 years (SD: 10.20). Mean years of formal education was 11.69 years (SD: 3.98). A 49.4% (N = 40) were engaged in skilled and semiskilled jobs, 27.2% (N = 22) were professionals, 8.6% (N = 7) were students, 8.6% (N = 7), were unemployed and 6.2% (N = 5) were not in active employment. A 70.4% (N = 57) subjects were married, 27.2% (N = 22) were single, and 1.2% each (N = 1) were separated and divorced. Mean monthly income was INR 8451.23 (SD: 7901.03) (approximately $187.8 [SD: $175.6]) and their residence status were of urban 75.3% (N = 61) and rural 24.7% (N = 20) origins. A 77.8% (N = 63) of our study samples had family history of alcohol dependence. This study analyzed the 2 types of chronology of ICD-10 dependence: age-wise chronology (for all criteria) and order-wise chronology (up to only the third criterion, because it met the threshold criteria to diagnose ICD-10 dependence). The age-wise chronology was analyzed for better understanding of course and progression of the disorder, given as ages at which patients experienced the first onset of each criterion of dependence and its frequencies (Table 1). The order-wise chronology of each criterion is summarized as its frequencies in their order of appearance of the first, second, and third criteria at their life-time first appearance (Table 1). However, age-wise chronology of each criterion has important shortcomings. Firstly, not every

TABLE 1. Results of Present Study and Comparison with Ehlers et al. (2004) Ehlers et al., 2004 (17) Present study (N = 81) Age at which the criterion was Patients Age at which the first experienced who experi- the criterion was Patients who (age-wise Order-wise chronology of each criterion enced the first experienced experienced chronology) criterion (years) the criterion (years) First Second Third ICD-10 criteria of dependence n % Mean SD n % Mean SD n % n % n % Craving 70 29 21.39 5.92 64 79.00 26.71 8.05 13 16.0 13 16.0 16 19.8 Tolerance 211 87 20.41 5.99 79 97.53 25.15 9.37 58 71.6 17 21.0 2 02.5 Loss of control 197 81 21.09 6.40 65 80.24 27.76 9.39 3 03.7 15 18.5 22 27.2 Salience 106 44 20.78 5.98 31 38.27 29.67 7.73 0 1 01.2 9 11.1 Withdrawal symptoms 81 33 23.12 7.31 75 92.6 27.04 9.78 6 07.4 29 35.8 21 25.9 Persist use despite harm 33 14 24.09 6.60 71 87.65 27.61 7.73 1 01.2 6 07.4 11 13.6 138

Manjunatha et al. 139 TABLE 2. Notable Age of Onset of Different Chronology of Present Study Criteria Age of onset (in years) (mean ± SD) Age at onset of alcohol use 18.72 ± 6.84 Age at onset of first criterion 24.33 ± 9.21 Age at onset of second criterion 25.86 ± 9.45 Age at onset of ICD-10 dependence 27.51 ± 9.28 Duration from onset of alcohol use to first 5.61 ± 6.2 criterion Duration from onset of alcohol use to 8.78 ± 6.7 dependence Duration from first criterion to 3.17 ± 3.23 dependence patient experiences each criterion of dependence, which is evident in the present study as well as in other studies (18), and secondly, the age of onset of dependence may not be the appearance of any criterion of dependence (18). The order-wise chronology of each criterion is very important in overcoming the shortcomings of age-wise chronology. The ages of life-time first appearance of the first, second, and third criteria as a whole and the time duration between important milestones that are important in formulating the prevention plan of ADS are given in Table 2. This can help in better understanding of individual criterion in alcoholic diagnostic orphans for the purposes of primary prevention of ADS. DISCUSSION The time-gap between onset of alcohol use and appearance of the first criterion and from onset of alcohol use to ICD-10 dependence was 5.61 years (SD: 6.2) and 8.78 years (SD: 6.7), respectively (Table 2). On an average, a person uses alcohol for about 6 years before developing the first criterion of dependence. Thus, criterionfree (or social) drinking lasts for 6 years approximately, and if alcohol use continues, then in about 3 to 4 years, ICD-10 dependence develops clinically. This time frame can be useful for instituting strategies for prevention in this population (Figure 1). Indicated Prevention Indicated prevention is directed at the population not just with high risk but with minimal and detectable symptoms that do not meet the diagnostic criteria (26). In our study, the ages at onsets of the first criterion and ICD- 10 dependence were 24.33 years (SD: 9.21) and 27.51 years (SD: 9.28) (Figure 1). Duration between onset of the first criterion and ICD-10 dependence was 3.17 years (SD: 3.23). A person therefore uses alcohol for about 3 to 4 years from the appearance of the first criterion to development of ICD-10 dependence. These persons are referred to as alcoholic diagnostic orphans, as has been mentioned before, and are therefore the best target for indicated prevention of ADS (27), because these groups are relatively more motivated for intervention at this stage (7) and can be targeted individually by a clinician. At this stage, analyzing the data of both agewise and order-wise chronologies can give us a path towards indicated prevention by determining the questions to be asked. In orderwise chronology, either craving or tolerance was present in 87.6% as first criterion and presence of either of craving (16%), tolerance (21%), or loss of control (18.5%) was seen as second criterion in 55.5% of the subjects. Moreover, in age-wise chronology, tolerance, loss of control, and craving were present in 97.53%, 80.24%, and 79% of our study sample, respectively. In both age-wise as well as order-wise chronologies, craving, tolerance, andloss of control emerged as the most frequently occurring criteria during predependence stage of alcohol dependence. These criteria are hence to be enquired from all persons who are alcoholic diagnostic orphans. If these are routinely enquired by all clinicians in all alcohol users, it may help in earlier detection and possible indicated prevention of ADS in diagnostic orphans and reduce the increased risk of progression to dependence from any predependence criteria (28). Possible methods for indicated prevention are use of anticraving medications that may be useful in alcohol diagnostic orphans (as prophylaxis for prevention of ADS rather than as merely for relapse prevention) when craving has developed as first or second criterion, even if the

140 SUBSTANCE ABUSE FIGURE 1. Illustrative graph of chronology of ADS. (Color figure available online.) Onset of use-18.72+6.84 Onset of tolerance-25.15+9.37 Onset of craving-26.71+8.05 Onset of withdrawal symptoms- 27.04+9.78 Onset of persistent use- 27.61+7.73 Onset of LOC-27.76+9.39 Onset of salience-29.67+7.73 Best Prevention Strategy Clinical condition Universal prevention 20 25 30 5.61+6.2 Period of Selective prevention Dependence Free Alcohol Use & family h/o ADS complete syndrome of ADS has not yet developed. Psychopharmacological agents certainly have an important role to play (29), since craving has neurobiological underpinnings involving functional changes and many neurotransmitters and receptors of the brain reward center. In the present study, 16% of subjects had craving as first criterion, as second criterion in 16%, and as third criterion in 19.8%. This is a sizable bulk of future ADS patients, who may benefit from prophylactic anticraving medications even before development of the clinical syndrome of alcohol dependence, as we understand it today. Active community-based, nonpharmacological methods including behavioral interventions are also likely to be useful in this population of diagnostic orphans. Such interventions have the potential to save significant resources and reduce social and economic burden to the individual as well as to the society at large. Moreover, there is evidence to suggest that brief interventions are beneficial to at-risk patients and problem drinker who are not yet alcohol dependent (30). Selective Prevention Selective prevention is aimed at high-risk populations who have not yet developed any symptoms of the disorder, i.e., for alcohol users who do not have any dependence criteria and who have family history of ADS (26, 27). In our 1st criteria-24.33+9.21 2 nd criteria-25.86+9.45 3.17+3.23 Period of Indicated prevention Sub-syndromal dependence 3rd criteria (ICD 10 dependence)-27.51+9.28 Secondary Prevention ADS study, the window of opportunity for selective prevention for those with high risk for developing dependence in future can be determined by examining the mean duration between onsets of alcohol use to appearance of the first criterion, which was 5.61 years (SD: 6.2) (Figure 1). We believe that the factors to be targeted under selective prevention are hereditary and genetic factors. Hereditary factors may play a role in the development of chronology of alcohol dependence, from the age at first use to onset of regular use and in the transition between regular use and ADS (31). Familial genetic factors also play a major role in alcohol dependence (32), including behavioral response of alcohol, i.e., tolerance (33) and lower subjective response to alcohol (34). The higher tolerance to alcohol in children of alcoholics predicts a 4-fold increase in risk of future dependence within 10 years (34). Naltrexone, a prototypal anticraving agent (33), has been shown to cause significant reduction in craving among volunteers with family history of alcoholism (35) as well as in social drinkers (36). Alcoholic patients who drink during naltrexone treatment reported less alcohol high and were less likely to progress to heavy drinking (37). This is further strengthened by the fact that 77.8% of our study samples had family history of ADS. Probably they may not have developed the first criterion of dependence if the intervention had taken place before

Manjunatha et al. 141 becoming alcoholic diagnostic orphans and ultimately preventing ADS. Universal Prevention This is aimed at the general population irrespective of risk, e.g., school programs, mass media campaigns, etc. (26, 27). Innovative strategies may be tried for universal prevention such as detailing criteria of dependence or clinical labeling on the labels of alcoholic beverages in a simple, commonly used language, along with the label that Alcohol is injurious to health. In addition, routine enquiries about alcohol use in terms of criteria of dependence by primary care physicians in all patients irrespective of diagnosis could help in universal prevention. In the authors opinion, the above technique should be combined with routine questions on the use of alcohol, its frequency and quantity, such as Do you drink alcoholic beverages? How often? How much? (38). A recent report of the Institute of Medicine (IOM) recommended that preventive interventions, earlier described as primary prevention, are to be subdivided into 3 subcategories (i.e., universal, selective, and indicated prevention) designed for populations before the onset of full-blown mental disorders (i.e., ADS) that are aimed at reducing the incidence of any mental disorder (39). Therefore, all 3 types of primary prevention (universal, selective, and indicated) may be possible in ADS when we know the chronology of dependence criteria (Figure 1). Among the 3 types of primary prevention, studies of interventions on indicated prevention have shown reduction in the incidence of mental disorders, whereas insufficient data exist on selective and universal prevention on reducing the incidence of mental disorders (15). However, Cuijpers (15) opines that synergistic effect of combining the interventions of all 3 types of primary prevention may be superior to each individual type of prevention alone. We suggest that the term alcohol predependence be used for an alcohol user when there is any evidence of socio-occupational dysfunction in the period of onset of the first criterion to onset of the third criterion. Further, the term subsyndrome alcohol dependence may be used for alcohol relapse and those who have not achieved full dependence, as relapses are very common even after abstinence (40). We also believe that using the prevention approaches will also prevent withdrawal symptoms, especially life-threatening delirium tremens and withdrawal seizure, since withdrawal symptoms are a sure sign of onset of ICD-10 dependence, seen in our study as the near-simultaneous onset of both withdrawal as a criterion and dependence as a syndrome (27.04 and 27.5 years, respectively). Our study findings are also similar to an earlier study (17) in a community sample in terms of tolerance and loss of control. The difference in the prevalence of withdrawal symptoms can be attributed to the origin of the sample hospital versus community population (41). The differences in criteria of persistent use despite harm may be because of cultural variations in attribution of harm to alcohol as appearance of different criteria (10). In spite of these differences, we believe that our findings and suggestions are significant enough to be initiated on a large-scale basis that may form part of the National Mental Health Program in India. Strengths The descriptions of order-wise chronology along with age-wise chronology of each criterion of dependence are unique in this study. To the best of our knowledge, this is the first study conducted on chronologies of dependence criteria. Prevalence of each criterion in our study is more or less consistent with other studies. This is also the first study to discuss a strategy for primary prevention of ADS rather than just alcohol use, which is more realistic in reducing the incidence of ADS in the society at large. Even though this is a retrospective study, adequate care has been taken to minimize the inevitable recall bias, by using more reliable and valid instruments (SSAGA-II), MMSE screening before interview, corroboration from Case Record Form as well as questions in interview being individually framed. Limitations There are inherent limitations in this study design such as inclusion of only male patients,

142 SUBSTANCE ABUSE historical cohort study, recall bias even though it is reduced to great extent, and lack of generalizability (in terms of ages of onset) to a general population. However, our study gives the broad framework for prevention of ADS. Future Directions We suggest future studies in different target populations in different countries in order to formulate individual respective plans for primary prevention of ADS with the help of the broad framework derived in our study, since our findings may not be applicable to other culture in terms of ages of onset of different criteria because of cultural variations of meanings in criteria of dependence such as salience, tolerance, etc. Prospective studies may also concentrate on the effectiveness of preventive interventions of predependence alcohol users. CONCLUSIONS The chronology of dependence criteria gives us an opportunity for intervention as a step towards primary prevention of ADS. Adequate training of primary care personnel and early psychiatric referral may be helpful. All 3 types of primary prevention are possible for ADS. Enquiring about presence of craving, tolerance, withdrawal symptoms, and loss of control routinely in every alcohol user presenting to health care would be beneficial for indicated prevention. Describing criteria of dependence in a simple language as mode of public education in mass media as well as on all alcohol beverages and routine enquiry by primary care physicians about dependence criteria may be useful as strategies of universal prevention. Prospective studies on effectiveness of the suggested interventions in alcohol user are required. REFERENCES 1. Edwards G, Gross MM. Alcohol dependence: provisional description of a clinical syndrome. BMJ. 1976;1:1058 1061. 2. World Health Organization. ICD-10 Classification of Mental and Behavioural Disorders. Diagnostic Criteria for Research (DCR). Geneva: World Health Organization; 1993. 3. Chand PK, Issac MK. Management of substance use disorder in primary care. In: Lal R, ed. Substance Use Disorder Manual for Physicians. New Delhi: National Drug Dependence Treatment Centre, All India Institute of Medical Sciences; 2005:1 12. 4. Kaczynski-Pollock N, Martin CS. Diagnostic orphans: adolescent with alcohol symptoms who do not qualify for DSM IV abuse or dependence diagnoses. Am J Psychiatry 1999;156:897 901. 5. Eng MY, Schuckit MA, Smith TL. A five-year prospective study of diagnostic orphans for alcohol use disorders. J Stud Alcohol. 2003;64:227 234. 6. Hasin D, Paykin A. Dependence symptoms but non-problem drinkers: diagnostic orphans in a 1992 national sample. Drug Alcohol Depend. 1999;53:215 222. 7. Sarr M, Bucholz KK, Phelps DL. Using cluster analysis of alcohol use disorders to investigate diagnostic orphans : subjects with alcohol dependence symptoms but no diagnosis. Drug Alcohol Depend. 2000;60:295 302. 8. Drummond DC. The relationship between alcohol dependence and alcohol-related problems in a clinical population. Br J Addict. 1990;85:357 366. 9. Room R. Measuring alcohol consumption in the United States: methods and rationales. In: Kozlowski LT, Annis HM, Cappell HD, et al., eds. Research Advances in Alcohol and Drug Problems. Vol. 10. New York: Plenum Press; 1990:39 80. 10. Schmidt L, Room R. Cross-cultural applicability in international classifications and research on alcohol dependence. J Stud Alcohol. 1999;60:448 462. 11. Marshall J. Alcohol dependence and alcohol problems. In: Gelder MG, Lopez-Ibor JJ, Andreasen N, eds. New Oxford Textbook of Psychiatry. Oxford, UK: Oxford University Press; 2000:482 488. 12. Park K. Mental health. In: Park K, ed. Park s Textbook of Preventive and Social Medicine. Jabalpur, India: Banarsidas Bhanot Publishers; 2005:632 637. 13. Friedman GD, Klatsky AL. Is alcohol good for your health? N Engl J Med. 1993;329:1882 1883. 14. Room R. Prevention of alcohol-related problems. In: Gelder MG, Lopez-Ibor JJ, Andreasen N, eds. New Oxford Textbook of Psychiatry. Oxford, UK: Oxford University Press; 2000:514 518. 15. Cuijpers P. Examining the effects of prevention programs on the incidence of new cases of mental disorders: the lack of statistical power. Am J Psychiatry. 2003;160:1385 1391. 16. Raphael B. Prevention in psychiatry: Australian contributions. Aust N Z J Psychiatry. 2000;34, S6 S13. 17. Ehlers CL, Wall TL, Betancourt M, Gilder DA. The clinical course of alcoholism in 243 Mission Indians. Am J Psychiatry. 2004;161:1204 1210. 18. Mattoo SK, Basu D. Clinical course of alcohol dependence. Indian J Psychiatry. 1997;39:294 99.

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