German Guidelines on Screening, Diagnosis, and Treatment of Alcohol Use Disorders: Update 2021.

INTRODUCTION: Alcohol consumption in Germany is associated with considerable health and economic consequences. In addition to prevention, the early detection and differential treatment of those affected play an important role. The guideline "Screening, Diagnosis, and Treatment of Alcohol Use Disorders" forms the basis of this care for people suffering from alcohol use disorders. Regular updates integrate the current state of research evidence and clinical expertise. METHODS: Under the auspices of the German Society for Psychiatry, Psychotherapy, Psychosomatics, and Neurology and the German Society for Addiction Research and Addiction Therapy e.V. (DG-Sucht), the 2019-2020 S3 guideline on alcohol was revised by eight working groups. Thirty-five professional societies participated in a structured consensus process to deliberate the recommendations. Potential conflicts of interest were examined in advance, documented, and taken into account during the voting on the recommendations. RESULTS: The guideline provides recommendations on screening and brief interventions for different groups of people, as well as on treatment of individuals in the acute and post-acute phases of withdrawal. Special emphasis was placed on the treatment of comorbid somatic and psychological disorders. In addition, recommendations for specific groups of people (e.g., children and adolescents, pregnant women) have been made and adapted to the German care landscape.

Colocalization analysis of pancreas eQTLs with risk loci from alcoholic and novel non-alcoholic chronic pancreatitis GWAS suggests potential disease causing mechanisms.

BACKGROUND: Previous genome-wide association studies (GWAS) identified genome-wide significant risk loci in chronic pancreatitis and investigated underlying disease causing mechanisms by simple overlaps with expression quantitative trait loci (eQTLs), a procedure which may often result in false positive conclusions. METHODS: We conducted a GWAS in 584 non-alcoholic chronic pancreatitis (NACP) patients and 6040 healthy controls. Next, we applied Bayesian colocalization analysis of identified genome-wide significant risk loci from both, our recently published alcoholic chronic pancreatitis (ACP) and the novel NACP dataset, with pancreas eQTLs from the GTEx V8 European cohort to prioritize candidate causal genes and extracted credible sets of shared causal variants. RESULTS: Variants at the CTRC (p = 1.22 × 10-21) and SPINK1 (p = 6.59 × 10-47) risk loci reached genome-wide significance in NACP. CTRC risk variants colocalized with CTRC eQTLs in ACP (PP4 = 0.99, PP4/PP3 = 95.51) and NACP (PP4 = 0.99, PP4/PP3 = 95.46). For both diseases, the 95% credible set of shared causal variants consisted of rs497078 and rs545634. CLDN2-MORC4 risk variants colocalized with CLDN2 eQTLs in ACP (PP4 = 0.98, PP4/PP3 = 42.20) and NACP (PP4 = 0.67, PP4/PP3 = 7.18), probably driven by the shared causal variant rs12688220. CONCLUSIONS: A shared causal CTRC risk variant might unfold its pathogenic effect in ACP and NACP by reducing CTRC expression, while the CLDN2-MORC4 shared causal variant rs12688220 may modify ACP and NACP risk by increasing CLDN2 expression.

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

OBJECTIVE: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. DESIGN: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. RESULTS: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). CONCLUSION: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.

Recovery from alcohol dependence: Do smoking indicators predict abstinence?

BACKGROUND AND OBJECTIVES: There is inconsistent evidence about the potential influence of smoking on recovery from alcohol dependence. Our study aimed at assessing the impact of smoking-behavior on relapse during a 12 months follow-up period following a detoxification in patients with Alcohol Use Disorder (AUD). METHODS: Three hundred Patients with AUD (74.9% smoking) were recruited from two inpatient detoxification units in psychiatric hospitals in Germany and their alcohol consumption was prospectively followed for 1 year. Data on different indicators of smoking behavior was gathered. Cox regression model was used to evaluate potential risk factors on time to relapse of alcohol consumption. Two hundred seventy-nine participants (n = 279) were included in the final analysis. RESULTS: Smoking increased the risk for alcohol relapse (hazard ratio = 3.962, 95% CI 1.582-9.921). However, this increased risk is slightly reduced with higher numbers of daily consumed cigarettes (hazard ratio per cigarette = .986, 95% CI .976-.995). CONCLUSION: Smoking reduced the probability of maintaining alcohol abstinence significantly, whereas higher number of cigarettes smoked daily diminished the increased risk of alcohol relapse in alcohol-dependent patients. SCIENTIFIC SIGNIFICANCE: Coordinated psychiatric and substance abuse interventions for different subgroups of patients with AUD in the post-acute treatment phase are necessary. Individualized treatment planning is especially important in smoking patients with AUD who are vulnerable for a relapse to alcohol drinking and for somatic complications. Our findings might support individualized treatment plans. (Am J Addict 2017;26:366-373).

Sex-specific role for adenylyl cyclase type 7 in alcohol dependence.

BACKGROUND: Alcohol has been shown to critically modulate cyclic adenosine-3',5' monophosphate (cAMP) signaling. A number of downstream effectors that respond to the cAMP signals (e.g., protein kinase A, cAMP response element binding protein) have, in turn, been examined in relation to alcohol consumption. These studies did not, however, delineate the point at which the actions of alcohol on the cAMP cascade might translate into differences in drinking behavior. To further understand the role of cAMP synthesis in alcohol drinking and dependence, we investigated a specific adenylyl cyclase isoform, adenylyl cyclase (AC) Type 7, whose activity is selectively enhanced by ethanol. METHODS: We measured alcohol consumption and preference in mice in which one copy of the Adcy7 gene was disrupted (Adcy7(+/-)). To demonstrate relevance of this gene for alcohol dependence in humans, we tested the association of polymorphisms in the ADCY7 gene with alcohol dependence in a sample of 1703 alcohol-dependent individuals and 1347 control subjects. RESULTS: We show that Adcy7(+/-) female mice have higher preference for alcohol than wild-type mice, whereas there is little difference in alcohol consumption or preference between Adcy7(+/-) male mice and wild-type control subjects. In the human sample, we found that single nucleotide polymorphisms in ADCY7 associate with alcohol dependence in women, and these markers are also associated with ADCY7 expression (messenger RNA) levels. CONCLUSIONS: These findings implicate adenylyl cyclase Type 7 as a critical component of the molecular pathways contributing to alcohol drinking and the development of alcohol dependence.

A functional polymorphism in the promoter region of the monoamine oxidase A gene is associated with the cigarette smoking quantity in alcohol-dependent heavy smokers.

Tobacco smoking represents a leading cause of morbidity and mortality with a strong dose-response relation between the amount of smoking and the risks of tobacco-related diseases and death. The quantity that is smoked is determined predominantly by genetic factors. The present study examined whether there is an association between the quantity of cigarettes smoked and length variation of a functional 30-bp repeat polymorphism in the promoter region of the monoamine oxidase A (MAO-A) gene. The number of 30-bp repeats, which is associated with enzyme activity was assessed in 121 Caucasian men suffering from both alcohol and tobacco dependence. Analysis revealed that the highly active long allele (4 repeat) is associated with a significantly greater amount of cigarette smoking in comparison with the less active short allele (3 repeat). In a logistic regression model (dichotomized), smoking quantity was significantly predicted by MAO-A genotype while no other variable (age, height, body weight, frequency of smoking, quantity and frequency of alcohol consumption) met the significance level. Since tobacco smoke is a potent inhibitor of MAO-A, this result could be regarded as a genotype-related dosage effect. Taken together, in alcohol-dependent heavily smoking men there is evidence for a MAO-A gene-associated effect on the quantity that is smoked as reflected by the daily number of cigarettes consumed.

[Use of cigarettes, alcohol and drugs by adolescents--a questionnaire survey among 9th grade students]. / Konsum psychoaktiver Substanzen durch Jugendliche--Eine Erhebung bei Schülern der 9. Klassen.

INTRODUCTION: For the planning of further substance abuse prevention programs it is necessary to obtain data about the patterns of region-specific substance use in adolescents. METHOD: In 2002 a questionnaire survey on substance use among the 9 (th) graders of all school types in the city and in the county of Regensburg was carried out (mean age 15,3 years, N = 1580). RESULTS: The first substance ever used by adolescents are cigarettes, starting at an average age of 12.2 years. 30 % of the students are current daily smokers with 43 % fulfilling criteria of nicotine dependence. When used several times per week 53 % regard the use of spirits being very dangerous, whereas the same rate considers the danger of drinking wine or beer at the same frequency being rather small. The level of information about institutions offering help for substance abuse and dependence problems is being considered as poor or zero by 67 %. DISCUSSION: The primary prevention of smoking as early as possible should be a priority of school-based prevention programs. The study also reveals a deficit of information on substances and institutions offering help for substance abuse and dependence problems which should be faced in school lessons.

[Repetitiv Transcranial Magnetic Stimulation in Nicotine Dependence] / Transkranielle Magnetstimulation bei Nikotinabhängigkeit.

70 - 80 % of regular smokers fulfill the ICD-10-criteria of dependence. In Germany, approximately 120 000 deaths per year are caused by tobacco-associated diseases. In contrast, therapeutic interventions, such as nicotine substitution or bupropione, yield poor abstinence rates of 30 % after 12 months, at best. In animal experiments, repetitive transcranial magnetic stimulation (rTMS) exhibited modulatory effects on dopaminergic neurotransmission in regions of the so-called reward system. This pilot study should evaluate, if rTMS could modulate subjective craving for tobacco, which quite often leads to relapse to smoking. Therefore, 11 tobacco-dependent cigarette smokers were randomly assigned to a course of verum- and placebo-rTMS on consecutive days. Craving, as measured by a visual analogue scale, is significantly decreased after Verumstimulation compared to placebostimulation intra-individually. This encourages further studies to clarify, if rTMS might be helpful in achieving higher tobacco abstinence rates in smokers willing to quits.

[Neuroleptic therapy of comorbid narcotic dependent patients in ambulatory methadone maintenance]. / Neuroleptikatherapie von komorbiden Opiatabhängigen in der Methadonambulanz.

Methadon maintenance therapy with opiate addicts who suffer from a comorbid schizophrenia in an outpatient treatment setting of a psychiatric hospital is described. We examined five patients looking for periods of inpatient treatment, drug free urine tests, social integration and illegal activities before and after neuroleptic treatment. In comparison with standard neuroleptics patients show under the therapy with atypical neuroleptics better outcome in drug urine tests especially concerning cannabis and benzodiazepines. According to these findings, the best improvements seem to occur with a combination of methadone and clozapine.

[Transcranial magnetic stimulation for nicotine dependence]. / Transkranielle Magnetstimulation bei Nikotinabhängigkeit.

70-80% of regular smokers fulfill the ICD-10-criteria of dependence. In Germany, approximately 120,000 deaths per year are caused by tobacco-associated diseases. In contrast, therapeutic interventions, such as nicotine substitution or bupropione, yield poor abstinence rates of 30% after 12 months, at best. In animal experiments, repetitive transcranial magnetic stimulation (rTMS) exhibited modulatory effects on dopaminergic neurotransmission in regions of the so-called reward system. This pilot study should evaluate, if rTMS could modulate subjective craving for tobacco, which quite often leads to relapse to smoking. Therefore, 11 tobacco-dependent cigarette smokers were randomly assigned to a course of verum- and placebo-rTMS on consecutive days. Craving, as measured by a visual analogue scale, is significantly decreased after Verumstimulation compared to placebo-stimulation intra-individually. This encourages further studies to clarify, if rTMS might be helpful in achieving higher tobacco abstinence rates in smokers willing to quits.

High-frequency repetitive transcranial magnetic stimulation decreases cigarette smoking.

BACKGROUND: The mesolimbic dopaminergic reward system seems to play a crucial role in reinforcing effects of nicotine. Recently, acute high-frequency repetitive transcranial magnetic stimulation (rTMS) of frontal brain regions has been shown to efficiently modulate the mesostriatal and mesolimbic dopaminergic system in both animals and humans. For this reason, we investigated whether high-frequency rTMS would be able to influence nicotine-related behavior by studying rTMS effects on craving and cigarette smoking. METHOD: Fourteen treatment-seeking smokers were included in a double-blind crossover trial, conducted in 2002, comparing single days of active versus sham stimulation. Outcome measures were rTMS effects on number of cigarettes smoked during an ad libitum smoking period and effects on craving after a period of acute abstinence. RESULTS: High-frequency (20-Hz) rTMS of left dorsolateral prefrontal cortex reduced cigarette smoking significantly (p <.01) in an active stimulation compared with sham stimulation. Levels of craving did not change significantly. CONCLUSION: High-frequency rTMS may be useful for treatment in smoking cessation.