Symposium 19 Monday Sept. 24th 6.30 pm–8.00 pm; Room: Lecture Hall 3
Genes, environment, pharmacotherapy: interactions and targets: Chairpersons: Kiefer F (Germany), Franck J (Sweden)
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Presentation S19-1
Treatment targets in pharmacological anti-craving therapy of alcoholism: an overview
Kiefer F (Germany)
Aims. Addiction is a chronic disorder that develops on a genetic, psychosocial and environmental background. Whereas withdrawal treatment is widely accepted as a pharmacotherapeutic domain, anti-craving and relapse prevention treatment in clinical practice up to now is mainly based on psychosocial and psychotherapeutic interventions.
Methods. New therapies have been developed due to the knowledge of the biological mechanisms of alcohol dependence.
Results. Especially co-morbid depressive- and anxiety disorders seem to require a rational pharmacotherapeutic treatment regime.
Conclusions. The presentation will focus on the neurobiological background of addiction treatment, will interpret very recent data from clinical trials and will translate these results into relevant information for clinical ‘bedside’ treatment.
Presentation S19-2
Evidence for a gene x environment interaction of the human CRH receptor 1 and alcohol risk drinking in adolescents
Schumann G, Blomeyer D, Laucht M (UK and Germany)
Introduction Genetic and environmental influences are both known to be causal factors in substance use disorders. One of the most relevant environmental risk factors for alcoholism is stress which is regulated by HPA-axis activity. We will present data on association of genetic variations of the corticotropin-releasing-hormone (CRH)-receptor1 with human alcohol drinking patterns and its possible contribution to alcohol dependence.
Methods. We analysed two independent samples. One adolescent sample, which consisted of individuals from the ‘Mannheim Study of Risk Children’ who had little previous exposure to alcohol and a sample of alcohol dependent adults which met DSM-IV criteria of alcohol dependence. Following determination of allelic frequencies of 14 polymorphisms of the hCRHR1 gene two htSNPs discriminating between haplotypes with a frequency of >0.7% were identified. Samples were genotyped and systematically analysed for association with the htSNPs of hCRHR1.
Results. In the adolescent sample significant group differences in genotypes were observed in lifetime prevalence of alcohol intake, lifetime prevalence of drunkenness, maximal amount of alcohol intake per occasion and binge drinking. The association of a CRHR1 htSNP with risk drinking behaviour is dependent on a high number of adverse life events (high psychosocial stress) in adolescents. The sample of adult, alcohol dependent patients showed association with high amount of drinking.
Discussion. This study is the first to provide evidence in humans that genetic variation in CRHR1 moderates the impact of stress on heavy drinking, revealing an effect of negative life events only among individuals carrying a particular genotype of this gene.
Presentation S19-3
Effects of dopaminergic candidate genes on response to smoking cessation pharmacotherapy
R Munafo M, C Johnstone E, David PS, Aveyard P, Murphy MFG (UK)
Aims. The neurobiological basis for smoking behaviour and nicotine addiction is becoming increasingly well-understood. As this understanding develops, putative candidate genes related to key neurotransmitter and metabolic pathways have begun to be investigated in relation to various aspects of smoking behaviour and nicotine addiction. Genes regulating the dopamine pathway appear to show promise in predicting smoking cessation and response to smoking cessation pharmacotherapy. This suggests the possibility of tailoring pharmacotherapy by genotype.
Methods. We report data on the association of DRD2 Taq1A (C32806T) polymorphism and smoking cessation in three large, randomised clinical trials, one a placebo-controlled study of transdermal nicotine patch, one a placebo-controlled study of bupropion efficacy, and one a trial of behavioural support and transdermal nicotine patch. In all cases, biochemically-verified continuous abstinence at end-of-treatment and six month follow-up were assessed, with participants lost to follow-up treated as having relapsed to smoking (intent to treat analysis).
Results. Possession of one or more copies of the A1 (32806T) allele was associated with relatively improved response to transdermal nicotine patch (study 1), and worse response to bupropion (study 2). The association of the A1 allele with response to transdermal nicotine patch was confirmed in a separate cohort (study 3). The A1 allele has been reported to be associated with reduced striatal D2 receptor density relative to A2 (C32806) homozygotes, and our findings are broadly consistent with other studies of variants in the DRD2 gene.
Conclusions. These data suggest that candidate genes in the dopamine pathway may predict response to smoking cessation pharmacotherapy, with variants associated with increased function predictive of relatively enhanced response to bupropion, and those associated with reduced function predictive of relatively enhanced response to transdermal nicotine patch. These results are discussed in the context of future genetic tailoring for smoking cessation pharmacotherapy. The question of whether such tailoring is likely to be cost-effective is also explored.
Presentation S19-4
Effects of acamprosate on cue-induced alcohol craving: a placebo-controlled trial
Franck J, Hammarberg A (Sweden)
Aims. Acamprosate significantly reduces the risk of relapse to alcohol drinking in patients with alcohol dependence, although the precise mechanism remains largely unknown. The aim of the present study was to examine if acamprosate reduces cue-induced alcohol craving.
Methods. In a double-blind, parallel groups design, 56 alcohol dependent patients were randomized to 21 days of either acamprosate (1998 g/day) or placebo. On the 22nd day, patients were tested for physiological and subjective responses to a set of alcohol specific or neutral cues. In the alcohol cue session, different types of alcohol drinks were presented, followed by a 90s DVD with a complex mixture of auditory and visual alcohol cues. The patients opened the preferred alcohol bottle, poured out 3–4 cl in a glass and sniffed the content. The neutral cue session followed a similar procedure. In the priming dose session, patients were provided with an alcohol drink of their own choice (0.20 gr. EtOH/kg body weight). In the alcohol choice session, subjects were given a hypothetical choice to have a 2nd drink or earn a monetary reward up to SEK120 (EUR13). Here, the patients indicated the value above which a monetary reward would be preferred over another alcohol drink. Subjective and physiological measurements were recorded before and after each session throughout the testing day. Lastly, patients underwent a debriefing procedure to reduce any alcohol craving. Primary outcome measure was the difference in subjective alcohol craving (as measured by the Desire for Alcohol Questionnaire; DAQ) after 1) exposure to alcohol-related vs non-alcohol related cues, and after 2) the alcohol priming dose sessions.
Results. Patients reported higher subjective alcohol craving after alcohol cue exposure compared to non-alcohol cue exposure (p< 0.05), but with no differences between treatment groups. Further, patients reported higher alcohol craving post-alcohol priming compared to pre-alcohol priming (p< 0.05). This result was qualified by an interaction effect of treatment in that only placebo treated patients showed a statistically significant increase in alcohol craving after priming, while acamprosate treated patients showed no change in alcohol craving. Placebo treated patients showed a significant increase in blood cortisol levels post alcohol priming while acamprosate treated patients showed no increase (p< 0.05).
Conclusions. The results suggest that acamprosate attenuates subjective and physiological measures of alcohol-induced alcohol craving after 22 days of treatment.