The effects of drug dependence on social systems has helped shape the generally held view that drug dependence is primarily a social problem, not a health problem. In turn, medical approaches to prevention and treatment are lacking. We examined evidence that drug (including alcohol) dependence is a chronic medical illness. A literature review compared the diagnoses, heritability, etiology (genetic and environmental factors), pathophysiology, and response to treatments (adherence and relapse) of drug dependence vs type 2 diabetes mellitus, hypertension, and asthma. Genetic heritability, personal choice, and environmental factors are comparably involved in the etiology and course of all of these disorders. Drug dependence produces significant and lasting changes in brain chemistry and function. Effective medications are available for treating nicotine, alcohol, and opiate dependence but not stimulant or marijuana dependence. Medication adherence and relapse rates are similar across these illnesses. Drug dependence generally has been treated as if it were an acute illness. Review results suggest that long-term care strategies of medication management and continued monitoring produce lasting benefits. Drug dependence should be insured, treated, and evaluated like other chronic illnesses.

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Drug Dependence, a Chronic Medical Illness: Implications for Treatment, Insurance, and Outcomes Evaluation

Background: Patterns of comorbidity suggest that the common psychiatric and substance use syndromes may be divisible into 2 broad groups of internalizing and externalizing disorders. We do not know how genetic and environmental risk factors contribute to this pattern of comorbidity or whether the etiologic structure of these groups differ in men and women. Methods: Lifetime diagnoses for 10 psychiatric syndromes were obtained at a personal interview in more than 5600 members of male-male and female-female twin pairs ascertained from a population-based registry. Multivariate twin modeling was performed using the program Mx. Results: We first fit models to the following 7 syndromes: major depression, generalized anxiety disorder, phobia, alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder. The full model, which could be constrained to equality in male and female subjects, identified 2 genetic factors. The first had strongest loadings on alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder; the second, on major depression, generalized anxiety disorder, and phobia. Alcohol dependence and drug abuse/dependence had substantial disorder-specific genetic risk factors. Shared environmental factors were most pronounced for conduct disorder and adult antisocial behavior. No clear internalizing/externalizing structure was seen for the unique environmental common factors. We then fit models to 5 internalizing syndromes. The full model, which could also be constrained to equality in men and women, revealed one genetic factor loading most heavily on major depression and generalized anxiety disorder and another loading most strongly on animal and situational phobia. Conclusions: The underlying structure of the genetic and environmental risk factors for the common psychiatric and drug abuse disorders in men and women is very similar. Genetic risk factors predispose to 2 broad groups of internalizing and externalizing disorders. Within the internalizing disorders, 2 genetic factors are seen that predispose to disorders dominated by anxious-misery and fear. Substance use disorders have disorder-specific genetic risks. The externalizing disorders of conduct disorder and adult antisocial behavior are significantly influenced by the shared environment. The pattern of lifetime comorbidity of common psychiatric and substance use disorders results largely from the effects of genetic risk factors. Arch Gen Psychiatry. 2003;60:929-937

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/207813/YOA20695.pdf

The Structure of Genetic and Environmental Risk Factors for Common Psychiatric and Substance Use Disorders in Men and Women

The addictions are common chronic psychiatric diseases that today are prevented and treated using relatively untargeted and only partially effective methods. The addictions are moderately to highly heritable, which is paradoxical because these disorders require use; a choice that is itself modulated by both genes and environment. The addictions are interrelated and related to other psychiatric diseases by common neurobiological pathways, including those that modulate reward, behavioural control and the anxiety or stress response. Our future understanding of addictions will be enhanced by the identification of genes that have a role in altered substance-specific vulnerabilities such as variation in drug metabolism or drug receptors and a role in shared vulnerabilities such as variation in reward or stress resiliency.

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The genetics of addictions: Uncovering the genes

Psychological researchers typically distinguish five major domains of individual differences in human behavior: cognitive abilities, personality, social attitudes, psychological interests, and psychopathology (Lubinski, 2000). In this article we: discuss a number of methodological errors commonly found in research on human individual differences; introduce a broad framework for interpreting findings from contemporary behavioral genetic studies; briefly outline the basic quantitative methods used in human behavioral genetic research; review the major criticisms of behavior genetic designs, with particular emphasis on the twin and adoption methods; describe the major or dominant theoretical scheme in each domain; and review behavioral genetic findings in all five domains. We conclude that there is now strong evidence that virtually all individual psychological differences, when reliably measured, are moderately to substantially heritable.

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Genetic and environmental influences on human psychological differences.

Background: Although prior family and twin studies have examined the relationship between the genetic and environmental risk factors for pairs of psychiatric disorders, the interrelationship between these classes of risk factors for a broad range of psychiatric disorders remains largely unknown. Methods: An epidemiologic sample of 1030 femalefemale twin pairs with known zygosity, ascertained from the Virginia Twin Registry, were evaluated by a personal interview conducted by mental health professionals, assessing lifetime history of phobia, generalized anxiety disorder, panic disorder, bulimia nervosa, major depression, and alcoholism. Results: A multivariate twin analysis suggested the following: First, genetic, familial-environmental, and individual-specific environmental risk factors each cause a unique pattern of comorbidity among the six disorders. Second, genetic influences on these disorders are best explained by two factors, the first of which loads heavily on phobia, panic disorder, and bulimia nervosa and the second, on major depression and generalized anxiety disorder. Third, unlike other disorders, genetic influences on alcoholism are largely disorder specific. Fourth, familialenvironmental influences on these disorders are best explained by a single factor that substantially influenced liability to bulimia nervosa only. Fifth, individual-specific environmental influences on the risk for these psychiatric disorders are best explained by a single factor, with highest loadings on generalized anxiety disorder and major depression and with large-disorder—specific loadings, especially on phobias, panic disorder, and alcoholism. Conclusions: These results support the following hypotheses: First, each major risk factor domain (genes, family environment, and individual-specific environment) influences comorbidity between these disorders in a distinct manner. Second, genetic influences on these six disorders are neither highly specific nor highly nonspecific. Neither a model that contains a discrete set of genetic factors for each disorder nor a model in which all six disorders results from a single set of genes is well supported. Third, the anxiety disorders are not, from a genetic perspective, etiologically homogeneous. Fourth, most of the genetic factors that influence vulnerability to alcoholism in women do not alter the risk for development of other common psychiatric disorders. These results should be interpreted in the context of both the strengths and limitations of multivariate twin analysis.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=PSYCH&articleId=497078&pdfFileName=archpsyc_52_5_007.pdf

The structure of the genetic and environmental risk factors for six major psychiatric disorders in women. Phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism.

The liver enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), which are responsible for the oxidative metabolism of ethanol, are polymorphic in humans. An allele encoding an inactive form of the mitochondrial ALDH2 is known to reduce the likelihood of alcoholism in Japanese. We hypothesized that the polymorphisms of both ALDH and ADH modify the predisposition to development of alcoholism. Therefore, we determined the genotypes of the ADH2, ADH3, and ALDH2 loci of alcoholic and nonalcoholic Chinese men living in Taiwan, using leukocyte DNA amplified by the PCR and allele-specific oligonucleotides. The alcoholics had significantly lower frequencies of the ADH2*2, ADH3*1, and ALDH2*2 alleles than did the nonalcoholics, suggesting that genetic variation in both ADH and ALDH, by modulating the rate of metabolism of ethanol and acetaldehyde, influences drinking behavior and the risk of developing alcoholism.

Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men.

Low RNA yields from small tissue samples can limit the use of oligonucleotide microarrays (Affymetrix GeneChips®). Methods using less cRNA for hybridization or amplifying the cRNA have been reported to reduce the number of transcripts detected, but the effect on realistic experiments designed to detect biological differences has not been analyzed. We systematically explore the effects of using different starting amounts of RNA on the ability to detect differential gene expression. The standard Affymetrix protocol can be used starting with only 2 micrograms of total RNA, with results equivalent to the recommended 10 micrograms. Biological variability is much greater than the technical variability introduced by this change. A simple amplification protocol described here can be used for samples as small as 0.1 micrograms of total RNA. This amplification protocol allows detection of a substantial fraction of the significant differences found using the standard protocol, despite an increase in variability and the 5' truncation of the transcripts, which prevents detection of a subset of genes. Biological differences in a typical experiment are much greater than differences resulting from technical manipulations in labeling and hybridization. The standard protocol works well with 2 micrograms of RNA, and with minor modifications could allow the use of samples as small as 1 micrograms. For smaller amounts of starting material, down to 0.1 micrograms RNA, differential gene expression can still be detected using the single cycle amplification protocol. Comparisons of groups of four arrays detect many more significant differences than comparisons of three arrays.

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Reproducibility of oligonucleotide arrays using small samples

The human alcohol dehydrogenase 4 gene (ADH4) encodes the human pi-alcohol dehydrogenase (pi-ADH), which can contribute to ethanol metabolism at moderate and high concentrations of ethanol. There are no known structural variants of pi-ADH in humans. We report the first polymorphisms in the ADH4 gene, at three sites in the promoter: -192 bp, -159 bp and -75 bp, respectively. To determine whether these variations affected promoter function, different haplotypes of the ADH4 proximal promoter were subcloned into a luciferase reporter vector, and the relative promoter activity analysed in hepatoma cells. One of the three sites had a dramatic effect on promoter activity, while the others did not detectably affect activity. The -75A allele had promoter activity more than twice that of the -75C allele. Alcohol dehydrogenase activity is rate limiting for ethanol oxidation. We hypothesize that the different ADH4 alleles lead to different amounts of pi-ADH in liver, which affects the risk for alcoholism by modulating alcohol metabolism.

Ronald E. Jerome

Papers

Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men.

Reproducibility of oligonucleotide arrays using small samples

Polymorphism of the human alcohol dehydrogenase 4 (ADH4) promoter affects gene expression.