Symposium 20 Monday Sept. 24th 6.30 pm–8.00 pm; Room: Lecture Hall 4
DSM-V and ICD 11 Symposium: Chairpersons: Lesch OM (Austria), Heinz A (Germany)
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Presentation S20-1
Diagnosis of alcoholism in the future: Implications from emerging neurobiology
Heilig M, Ciccocioppo A, Barr CS, Sommer WS, Thorsell A, Hansson A, Cippitelli A (USA)
Aims. The main objective of a diagnosis is to guide treatment. As novel pharmacotherapies emerge, the long debated heterogeneity of ‘alcoholism’ is becoming a biological reality, which can and must inform clinical diagnostic systems. The long term objective should be to arrive at etiologically based diagnostic categories, that can be supported by objectively measurable biomarkers, and successfully match patients to treatments. The aim of this presentation is to review recent progress in work carried out in experimental animals that points to a dichotomy between ‘reward driven/impulsive’, and ‘relief driven/neuroadapted’ alcoholism as a key emerging distinction for coming diagnostic systems to consider.
Methods. Behavioral, molecular genetic and pharmacological studies in non-human primates and rodents.
Results. Acute alcohol reward shows high individual variability. To the extent it occurs, it is mediated by activation of classical brain reward circuitry, through release of endogenus opioid peptides that in turn activate mesolimbic dopaminergic circuitry. In the rhesus macaque, pre-existing susceptibility, encoded by genetic variation at the mu-opioid receptor locus (OPRM1), accounts for variation in psychomotor stimulation by alcohol, alcohol preference and thus presumably alcohol reward. OPRM1 variation interacts with sex such that only male carriers of the variant OPRM1 77G display excessive alcohol reward. Consistent with those findings, in humans, sex, family history, and most importantly an orthologous human OPRM1 variant are determinants of therapeutic response to the opioid receptor antagonist naltrexone. In contrast, rodent studies show that a prolonged history of repeated cycles of alcohol intoxication and withdrawal induces what we have labelled ‘a post-dependent state’. This is characterized by excessive alcohol consumption and increased behavioral sensitivity to stress. Several neurochemical systems share a profile characterized by a lack of influence over initial stages of alcohol consumption, but a recruitment of control over intake and self-administration in the post-dependent state. Recruitment of corticotropin-Releasing Hormone (CRH) and glutamate signalling appear to be key to induction of the post-dependent state, while neuropeptide Y (NPY) and nociceptin (NOP) seem to counteract it.
Conclusions. To adequately guide the use of emerging pharmacotherapies, a diagnosis of alcoholism must distinguish between excessive alcohol use that occurs for positively reinforcing, pleasurable effects of alcohol (‘reward’) in genetically susceptible individuals, or negatively reinforcing alcohol actions (‘relief’) in a neuroadapted, post-dependent state.
Presentation S20-2
Multidimensional Subtypes of Alcohol Dependence
Hesselbrock V, Hesselbrock MN (USA)
Aims. The use of categorical diagnoses, including ‘alcoholism’ has a long history in medicine. Categorical classification systems are easy for clinician's to use and simplify decision making by forcing selection of a cut-point for intervention. However, even before the publication of DSM-I, clinicians and researchers were disenchanted with a categorical approach as it failed to capture many clinically important features of the disorder and often lead to both false positive and false negative diagnoses. This presentation will review several different dimensional and multivariate typologies of alcoholism and alcohol dependence in relation to their clinical utility, with a focus on gender differences.
Methods. Studies using multivariate methods for classifying homogeneous groups of patients/subjects were selected for inclusion. Theoretically-based typologies will not be discussed.
Results. This review of different studies that used a variety of different methods suggests that there may be as many as four homogeneous typologies of alcohol dependence: a chronic/severe type, a depressed/anxious type; an antisocial type; and a mildly affected type. The prevalence of alcohol dependence types varies by gender.
Conclusions. In spite of different samples and assessment methods being used, there is a remarkable similarity across many dimensional typologies of alcohol dependence. Multi-dimensional typologies of alcohol dependence are a potentially valuable tool for the investigation of the etiological pathways into alcohol use disorders, both behavioral and pharmacological therapies, and long term course of alcohol use disorders. Such typologies can also highlight important gender differences.
Presentation S20-3
Serotonergic dysfunction and its behavioral correlates in alcoholics—biomarker for impulsive alcoholism subtype?
Heinz A (Germany)
Impulsive aggressiveness and a low response to alcohol upon initial exposure predispose humans to alcoholism in prospective studies and may be associated with central serotonergic dysfunction. High alcohol intake in a free choice paradigm was correlated with low serotonin turnover (concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid) and transporter availability, a low alcohol response upon first exposure and aggressiveness. Aggressive behavior and a low response to alcohol were correlated with a high availability of brainstem serotonin transporters and a low serotonin turnover rate. In a linear multiple regression analysis, the amount of alcohol intake was associated with serotonin transporter availability, but not tolerance to the acute effects of alcohol intake or aggressiveness. These observations indicate that central serotonergic dysfunction may significantly contribute to the clinical correlations between excessive alcohol intake, alcohol tolerance and aggressive behavior. However, negative mood states such as anxiety were also present in the non-human primates and may mediate the correlation between serotonergic dysfunction and aggressiveness. In alcoholics, this hypothesis was supported by direct correlations between negative mood states and alterations in serotonin transporter availability in alcoholics and patients suffering from major depression. However, serotonergic dysfunction was not limited to early onset (type 2) alcoholism.
Presentation S20-4
Biomarkers and endophenotypes for relapse and treatment prediction
Spanagel R (Germany)
Aims. The first goal is to develop biomarkers that improve diagnosis for abstinence.
Improving the treatment situation is the second goal. In addition to several psychosocial intervention programmes, the maintenance of abstinence remains a challenge and it is believed that anti-relapse medications will be beneficial in this respect. Acamprosate (Campral®) is the only approved anti-relapse medication in Germany, but only about 30–40% of the alcohol dependent patients in actuality benefit from this medication (so-called acamprosate responders). An important step towards individualised medicine in the alcohol field would be the identification of acamprosate responders by novel diagnostic biomarkers and/or the definition of endophenotypes that would help to predict treatment response.
Methods. In this context, we will systematically screen peripheral samples from detoxified alcohol dependent individuals so as to identify diagnostic biomarkers for clinical response (i.e. relapse vs non-relapse). We will utilise multi-analyte profiling in plasma samples that will allow for the simultaneous measurement of multiple markers. The anti-relapse effects of acamprosate are mediated via the glutamatergic system and therefore, in a first step, we will perform gene expression profiling via the application of a ‘Glutamate Chip’ in acamprosate responders vs non-responders. In addition, we are using glutamate spectroscopy in alcohol-depedent animals and humans to define endophenotypes for acamprosate response.
Results. The definition of a marker panel will help identify therapeutically relevant subgroups of alcohol dependent patients and predict the risk of relapse. Relevant transcriptomic information will be translated to the protein level and by the use of reverse phase protein-microarrays we will finally be able to detect alterations in the glutamatergic system, which predict treatment response. The ultimate goal is to develop an antibody based biomarker kit for acamprosate response.
Conclusions. The establishment of diagnostic biomarker kits for relapse prediction and for the prediction of treatment response will improve clinical outcome in the field of alcoholism and will transform DSM and ICD into a neurobiologically orientated medical systems approach.