Pharmacogenetic approaches to the treatment of alcohol addiction

• Published in: Nature reviews. Neuroscience Vol. 12; no. 11; pp. 670 - 684
• Main Authors: Heilig, Markus, Goldman, David, Berrettini, Wade, O'Brien, Charles P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2011; Nature Publishing Group
• Subjects: 692/700/565/1436/434; ACTH; Addiction; Addictions; Alcohol use; Alcoholism; Alcoholism - drug therapy; Alcoholism - genetics; Analgesics, Opioid - therapeutic use; Animal Genetics and Genomics; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Care and treatment; Chronic illnesses; Clinical outcomes; Drug therapy; GABA; Genetic aspects; Health aspects; Health risk assessment; Humans; Narcotics; Neurobiology; Neurosciences; Pharmacogenetics; Physiological aspects; Polymorphism, Single Nucleotide; Receptors, Opioid - genetics; review-article; Risk factors; United States; United States > US; Maryland
• DOI: 10.1038/nrn3110
• ISSN: 1471-003X; 1471-0048

Key Points Addictive disorders are common, account for a tremendous disease burden and are in need of improved medical treatments. Alcohol use accounts for more disease burden than any other addictive drug with the exception of nicotine. The discovery of naltrexone as a medication for alcoholism was conceptually groundbreaking, because it demonstrated the feasibility of pharmacotherapy for an addictive disorder using a mechanism other than replacement therapy. Overall, however, the effect size of naltrexone turned out to be small, and despite its evidence base, this medication has not gained widespread clinical use. Clinical experience and meta-analyses have long indicated that clinical response to naltrexone is remarkably variable. Over a decade ago, functional genetic variation was discovered at the locus encoding the target for naltrexone, the mu-opioid receptor (MOR), and this was shortly followed by the suggestion that efficacy of naltrexone may be restricted to carriers of the minor allele at this locus. Recently, a series of translational studies in humans, non-human primates and humanized mice has provided consistent support for the notion that alcohol reward is in part mediated by an alcohol–endogenous opioid–dopamine cascade, that this cascade is more vigorously activated by alcohol in carriers of the minor allele at the OPRM1 gene locus that encodes the MOR, and that these subjects are thereby rendered particularly or maybe selectively sensitive to naltrexone. Alcohol reinforcement is mediated by multiple systems, among which opioids and dopamine are but two, and are mostly involved in pleasurable, positively reinforcing alcohol effects experienced mostly in earlier stages of the addictive process. As patients continue heavy alcohol use, a pathological activation of brain stress systems occurs, and sets the scene for negatively reinforced alcohol use — that is, alcohol use aimed at eliminating anxiety and dysphoria that emerges during abstinence. Corticotropin-releasing factor (CRF), the hypothalamic release factor for pituitary adrenocorticotropic hormone (ACTH), is also widely expressed in extrahypothalamic networks that mediate behavioural and emotional stress responses. Recent work has shown that the CRF system becomes activated following a prolonged history of brain alcohol exposure, and its activity is key to negatively reinforced alcohol seeking and use. Genetic variation that influences the functional activity of the CRF system has been found in rats, non-human primates and humans, and has been shown to be associated with various alcohol use phenotypes in all three species. This suggests that pharmacogenetic effects may need to be considered when CRF receptor 1 (CRF 1 ) antagonists are developed for the treatment of alcoholism. GABAergic and serotonergic transmission are also involved in the pathophysiology of alcoholism, and pharmacogenetic effects of variants within both these systems have also been suggested. A potential implication of these findings is that pharmacogenetic effects may turn out to be the rule rather than the exception, and that much more attention will have to be paid to personalizing pharmacotherapy of addictive disorders. Current addiction pharmacotherapies have limited success. Focusing on alcohol addiction, Heilig and colleagues review the evidence that genetic heterogeneity in the opioid, corticotropin-releasing factor, GABA and serotonin systems may underlie differential treatment responses, and that personalized therapies tailored to patient genotype may lead to more successful treatment for alcohol addiction. Addictive disorders are partly heritable, chronic, relapsing conditions that account for a tremendous disease burden. Currently available addiction pharmacotherapies are only moderately successful, continue to be viewed with considerable scepticism outside the scientific community and have not become widely adopted as treatments. More effective medical treatments are needed to transform addiction treatment and address currently unmet medical needs. Emerging evidence from alcoholism research suggests that no single advance can be expected to fundamentally change treatment outcomes. Rather, studies of opioid, corticotropin-releasing factor, GABA and serotonin systems suggest that incremental advances in treatment outcomes will result from an improved understanding of the genetic heterogeneity among patients with alcohol addiction, and the development of personalized treatments.