UC San Diego UC San Diego Previously Published Works Title Consensus paper of the WFSBP task force on biological markers: biological markers for alcoholism. Permalink https://escholarship.org/uc/item/32r0d1jm Journal The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 14(8) ISSN 1562-2975 Authors Hashimoto, Eri Riederer, Peter Franz Hesselbrock, Victor M et al. Publication Date 2013-12-01 DOI 10.3109/15622975.2013.838302 Peer reviewed eScholarship.org Powered by the California Digital Library University of California The World Journal of Biological Psychiatry ISSN: 1562-2975 (Print) 1814-1412 (Online) Journal homepage: https://www.tandfonline.com/loi/iwbp20 Consensus paper of the WFSBP task force on biological markers: Biological markers for alcoholism Eri Hashimoto, Peter Franz Riederer, Victor M. Hesselbrock, Michie N. Hesselbrock, Karl Mann, Wataru Ukai, Hitoshi Sohma, Florence Thibaut, Marc A. Schuckit & Toshikazu Saito To cite this article: Eri Hashimoto, Peter Franz Riederer, Victor M. Hesselbrock, Michie N. Hesselbrock, Karl Mann, Wataru Ukai, Hitoshi Sohma, Florence Thibaut, Marc A. Schuckit & Toshikazu Saito (2013) Consensus paper of the WFSBP task force on biological markers: Biological markers for alcoholism, The World Journal of Biological Psychiatry, 14:8, 549-564, DOI: 10.3109/15622975.2013.838302 To link to this article: https://doi.org/10.3109/15622975.2013.838302 Published online: 18 Nov 2013. Submit your article to this journal Article views: 254 View related articles Citing articles: 14 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iwbp20 The World Journal of Biological Psychiatry, 2013; 14: 549–564 CONSENSUS PAPER Consensus paper of the WFSBP task force on biological markers: Biological markers for alcoholism ERI HASHIMOTO 1 , PETER FRANZ RIEDERER 2 , VICTOR M. HESSELBROCK 3 , MICHIE N. HESSELBROCK 3 , KARL MANN 4 , WATARU UKAI 1 , HITOSHI SOHMA5 , FLORENCE THIBAUT 6 , MARC A. SCHUCKIT 7 & TOSHIKAZU SAITO 1 1 Department of Neuropsychiatry, Sapporo Medical University School of Medicine, Sapporo, Japan, 2 Laboratory for Clinical Neurobiology, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of W ü rzburg, Wü rzburg, Germany, 3 Department of Psychiatry, University of Connecticut School of Medicine,CT, USA, 4 CIMH Mannheim, University of Heidelberg, Germany, 5 Department of Educational Development, Sapporo Medical University Center for Medical Education, Sapporo, Japan, 6 Department of Psychiatry, Rouen University Hospital, Rouen, France, 7 Department of Psychiatry, University of California, San Diego, CA, USA Abstract Objectives. This article presents an overview of the current literature on biological markers for alcoholism, including mark- ers associated with the pharmacological effects of alcohol and markers related to the clinical course and treatment of alcohol-related problems. Many of these studies are well known, while other studies cited are new and still being evaluated. Methods. In this paper we fi rst describe known biomarkers of alcohol-related disorders, review their features and the prob- lems involved in their use. We then consider future developments on biomarkers and their possible impact on the fi eld. Results. More recent fi ndings cited include the work on type 7 adenylcyclase (AC) polymorphism and its lower expression levels in female alcoholics. Neuroimaging studies involving biomarkers have also reported brain volume reductions of gray and white matter, including amygdala and subcortical regions in alcoholic patients, while a high association between the copy number variations (CNVs) in 6q14.1/5q13.2 and alcohol dependence has more recently been identifi ed in genetic studies. Conclusions . In addition to their possible importance for diagnosis, biomarkers may have utility for predicting prognosis, progression of the disorder, the development of new treatments, and monitoring treatment effects. Although such fi ndings should be verifi ed in independent studies, the search for new biomarkers is continuing. Several potential candidate biomarkers have been found recently in blood, imaging, and genetic studies with encouraging results. Key words: alcohol , biochemical markers , abuse , alcohol dependence , alcohol use disorder Introduction effects. The identifi cation of biochemical substances Alcohol (ethanol) is one of the most widely mis- in the body suggesting the repeated use of heavy used drugs in the world. Humans respond to low doses of alcohol as possibly part of an alcohol use doses of ethanol with euphoria, but with disinhibi- disorder and the identifi cation of genetic suscepti- tion, incoordination and lethargy at high doses. bility factors for alcoholism (i.e. “ biomarkers for Alcohol abuse and alcohol dependence signify alco- alcoholics ” ) will provide important tools for future hol use disorders characterized by chronic heavy investigation. drinking, culminating in serious adverse outcomes The goal of this paper is to provide a guide to the and loss of control. Alcohol dependence is charac- optimal application of biomarkers for heavy drinking terized by an unhealthy drive to drink alcohol that and alcohol use disorders, and to facilitate objective leads to an inability to control intake on any given and quantitative data gathering in both clinical and occasion and an increasing tolerance to alcohol’ s research settings. Correspondence: Wataru Ukai, Department of Neuropsychiatry, Sapporo Medical University, School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. Tel: ϩ 81 11 611 2111. Fax: ϩ 81 11 644 3041. E-mail: [email protected] (Received 8 August 2013 ; accepted 22 August 2013 ) ISSN 1562-2975 print/ISSN 1814-1412 online © 2013 Informa Healthcare DOI: 10.3109/15622975.2013.838302 550 E . Ha sh i mot o et a l . Pharmacological effects of alcohol ethanol withdrawal. Chronic alcohol consumption may also augment the sensitivity to NMDA by Many neurochemical systems have been implicated increasing the density of NMDA receptors, thereby in the biology of alcohol intoxication, but two sys- increasing biosynthesis or release of glutamate. tems are the most relevant: (1) gamma-aminobutyric Thus, the effects of ethanol on calcium homeostasis acid (GABA) and its receptors; (2) glutamate and the can have an important impact on the clinical fea- N -methyl- D -aspartic acid (NMDA) receptor ( α glu- tures of alcoholism. tamate receptors) ’ and the opioid systems (Addison and Kurtz 1986). GABA receptors include ion-selec- tive and ligand-gated ion channels, while GABA itself Therapeutic studies in alcoholics is the major inhibitory neurotransmitter in the brain that interacts with a family of receptors that recog- The opioid receptor antagonists naltrexone and nize anxiolytic and sedative drugs. For example, ben- nalmefene have been shown to be effective in reducing zodiazepines, which share bio-behavioural properties alcohol consumption in both animal and human stud- – with alcohol, enhance Cl transport through GABAA ies. Naltrexone ’ s propensity to reduce alcohol intake receptors. Drugs that simulate the effect of GABA may be negatively correlated with baseline beta- enhance and prolong the behavioural effects of alco- endorphin levels as mu-opioid receptor antagonists hol, whereas drugs opposing the effect of GABA attenuate alcohol consumption. Nalmefene also works antagonize alcohols effects. In animal studies, benzo- as an opioid receptor antagonist and is helpful in the diazepine receptor antagonists have been shown to treatment of alcohol dependence. Nalmefene has a block many alcohol-induced cognitive, behavioural longer half-life than naltrexone, better bioavailability, and neurophysiological effects of ethanol. and a more favourable tolerance profi le in achieving Several lines of evidence implicate opioid peptides, its benefi t. Because alcohol is believed to activate the such as beta-endorphin (an endogenous opioid brain reward system by increasing the release of beta- receptor ligand), in both the perception of the endorphin, an endogenous opioid receptor ligand, it rewarding effects of ethanol and in the risk for devel- is possible that some of the rewarding and pleasant oping alcoholism. Alcohol is believed to activate the effects of alcohol related to this physiological effect brain reward system, especially in the mesolimbic promote drinking behaviour. Although the precise dopamine system, in part by increasing beta-endor- mechanisms underlying the actions of nalmefene phin release. The direct mechanism of alcohol’ s remain to be elucidated, endogenous opioid peptides action on dopamine release in the ventral tegmental as well as metabolic by-products of ethanol (e.g., tet- area (VTA) is intriguing and has been widely inves- rahydroisoquinolines and beta-carbolines) may medi- tigated. Recent patch clamp studies suggest that ate these effects and may also involve interactions alcohol excites VTA dopamine neurons, partly by between cannabinoids and the opioid receptor system. increasing ongoing opioid-mediated suppression of These rewarding and pleasant effects are potentially local GABAergic inhibition. associated with both internal and external drinking Glutamate, the major excitatory neurotransmitter cues. Analogous to the concept of negative rein- in the brain, is also believed to be involved in alco- forcement or relief craving (euphoria and