Ulrich C. Lutz

A genotype-controlled analysis of plasma dopamine β-hydroxylase in healthy and alcoholic subjects: evidence for alcohol-related differences in noradrenergic function

BACKGROUND Norepinephrine and dopamine mediate important aspects of alcoholism and alcohol withdrawal. Dopamine-beta-hydroxylase (DbetaH) converts dopamine to norepinephrine. A recent study demonstrated a strong association between variance in plasma DbetaH activity and a novel polymorphism (DBH-1021C-->T) at the structural locus (DBH) encoding DbetaH protein. METHODS Our study investigated whether the DBH-1021C-->T polymorphism and plasma DbetaH activity were associated with alcoholism or with delirium tremens (DT) during alcohol withdrawal by analyzing 207 German alcoholic and 102 healthy control subjects. We also examined the influence of the polymorphism on enzyme activity. RESULTS Mean (+SD) plasma DbetaH activity measured in alcoholic subjects abstinent was significantly lower than that observed in control (27.7 + 16.7 vs. 35.6 + 18.8; p =.01). It did not differ between subjects with DT during withdrawal and subjects with mild withdrawal symptoms. The T allele of the DBH-1021C-->T polymorphism was significantly associated with lower plasma DbetaH activity. None of the alleles or genotypes were associated with alcoholism or DT. CONCLUSIONS The data indicate that the alcoholism-related reduction in plasma DbetaH activity is independent of genotype at DBH-1021C-->T and replicate the finding that DBH-1021C-->T is strongly associated with plasma DbetaH activity in a native Western European population.

How smoking affects sleep: a polysomnographical analysis.

OBJECTIVE Subjective quality of sleep is impaired in smokers compared with non-smokers, but there is only limited evidence from methodologically sound studies about differences in polysomnography (PSG) sleep characteristics. Therefore, this study used PSG to evaluate sleep in smokers and non-smokers while controlling for other parameters that affect sleep. METHODS After an adaptation night, PSG sleep laboratory data were obtained from 44 smokers (29 men and 15 women, median age 29.6 years) and compared with PSG data from 44 healthy, sex- and age-matched never smokers. Exclusion criteria were alcohol or other substance abuse, psychiatric or endocrine diseases, and treatment with any kind of psychotropic medication. Nicotine and cotinine plasma levels were measured (in the smoking group) and subjective sleep quality assessed in both groups. RESULTS The smokers had a Fagerström tolerance score of 6.4, consumed an average of 21.2 cigarettes per day and had been smoking for 13.1 years (median). Smokers had a shorter sleep period time, longer sleep latency, higher rapid eye movement sleep density, more sleep apneas and leg movements in sleep than non-smokers. There were no differences regarding parameters of spectral analysis of the sleep electroencephalogram as well as in the sleep efficiency measured by PSG. Nevertheless smokers rated their sleep efficiency lower on the Pittsburgh Sleep Quality Index compared with non-smoking individuals, but no differences were detected on the SF-A. Plasma cotinine level correlated negatively with slow wave sleep in the smoking group. CONCLUSIONS Smokers showed a number of insomnia-like sleep impairments. The findings suggest that it is important for sleep researchers to control smoking status in their analyses. Further research should focus on the causes and consequences of impaired sleep during tobacco cessation, as sleep disturbances are a known risk factor for early relapse after initial tobacco abstinence.

Severity of alcohol withdrawal symptoms and the T1128c polymorphism of the neuropeptide Y gene

Summary. Neuropeptide Y (NPY) modulates ethanol drinking in rodents. The C-allele of the T1128C polymorphism of the human NPY gene has been previously associated with elevated alcohol consumption in a Finn population study. The present study tested the hypothesis that the T1128C polymorphism is associated with the diagnosis of alcoholism or with severe forms of alcohol withdrawal and with the daily consumption of alcohol in alcoholic patients. After PCR-RFLP genotyping, two groups of alcoholics with severe withdrawal symptoms (delirium tremens, n = 83; withdrawal seizures, n = 65) were compared to alcoholics with mild withdrawal symptoms (n = 97). An elevated frequency of the C-allele in the individuals with severe withdrawal symptoms was found, however not reaching statistical significance. Further a group of healthy controls (n = 102) was compared to all included alcoholics (n = 216) revealing no significant result. Alcoholics carrying the C-allele reported a non significantly elevated daily consumption of alcohol compared to alcoholics with the TT genotype. All alcohol dependent subjects with severe withdrawal symptoms revealed a significantly elevated daily consumption of alcohol compared to alcoholics with only mild withdrawal symptoms. More studies on different ethnic groups are needed to further elucidate the influence of the NPY gene on alcoholism.

Plasma homovanillic acid: a significant association with alcoholism is independent of a functional polymorphism of the human catechol-O-methyltransferase gene.

The central dopamine system seems to influence addictive disorders. Plasma homovanillic acid (HVA) is an indicator of central dopaminergic activity. In this study the hypothesis that plasma HVA is associated with alcoholism or with delirium tremens (DT) during alcohol withdrawal was tested. A functional genetic polymorphism of the enzyme catechol-O-methyltransferase (COMT) that participates in converting dopamine into its final metabolite HVA was investigated for an association with alcoholism or DT during alcohol withdrawal. In addition, a relation between the functional polymorphism of COMT and plasma HVA concentrations was studied. Plasma HVA concentrations and COMT genotypes were determined in 142 German alcoholics and 101 German healthy controls. Alcoholic patients were examined after a minimum of 3 weeks after cessation of drinking. Mean plasma HVA concentrations were significantly lower in alcoholic patients compared to healthy controls. A group of alcoholics with a history of DT during alcohol withdrawal (n=62) did not differ significantly in plasma HVA concentrations from alcoholics with a history of only mild withdrawal symptoms (n=67). The functional polymorphism of the human COMT gene was neither significantly associated with the diagnosis of alcoholism or DT during alcohol withdrawal nor with plasma HVA concentrations.

DBH*444G/A polymorphism of the dopamine-β-hydroxylase gene is associated with alcoholism but not with severe alcohol withdrawal symptoms

Summary.As the enzyme dopamine-β-hydroxylase (DβH) converts dopamine to norepinephrine and both transmitters seem to be involved in the pathology of alcoholism and severe alcohol withdrawal symptoms, the gene encoding DβH (DBH) was applied to explore the genetic background of alcoholism and severe withdrawal symptoms. 102 healthy control subjects and 208 alcoholics, including 97 patients with a history of mild withdrawal symptoms, 57 with a history of alcohol withdrawal seizure (AWS) and 82 with a history of delirium tremens (DT) were genotyped for the DBH*444G/A polymorphism revealing a significantly elevated frequency of genotypes carrying the A-allele (p = 0.02; after Bonferroni adjustment for multiple tests) in alcoholics compared to healthy controls. Frequencies of alleles and genotypes of individuals with mild withdrawal symptoms did not differ significantly from those of patients with DT or AWS.

Olanzapine Treatment During Breast Feeding : A Case Report

Postpartum psychosis constitutes a severe complication that entails risk for both mother and child. Little is known about the use of olanzapine in the treatment of postpartum psychosis. In previous studies, it has been reported on mothers receiving relatively low doses of olanzapine. We report a 38-year-old patient who was admitted to the hospital for an acute psychotic exacerbation. She was breast feeding her 5-month-old child, and she wished to continue breast feeding. Olanzapine treatment was started with a daily dosage of 15 mg. The weight-corrected maternal dose was 270 μg/kg. The olanzapine concentration in the mothers plasma was 24 ng/mL. The analysis of olanzapine in breast milk applying two different high-performance liquid chromatography procedures revealed similar results: 12.2 ng/g without and 11.5 ng/g with additional hydrochloric acid extraction, respectively. In addition, breast milk of an unmedicated mother was used for establishing the analytical procedure so that the validity of the results was better confirmed. The milk-plasma ratio arising from our data was 0.5, and the relative infant dose was 0.3%. The olanzapine concentration was below the limit of detection (<5 ng/mL) in the infants plasma sample. No adverse effects were noticed, and the mother experienced a rapid improvement in her psychopathology during her hospital stay. In future studies, long-term follow-up of both mother and child would be useful.

GENETIC STUDY: The polymorphism GABABR1 T1974C [rs29230] of the GABAB receptor gene is not associated with the diagnosis of alcoholism or alcohol withdrawal seizures

As the inhibitory neurotransmitter gamma aminobutyric acid (GABA) modulates ethanol consumption, alcohol withdrawal symptoms and seizure generation by interacting with the GABAB receptor, the genes encoding for the GABAB receptor can be considered as candidate genes for alcoholism and alcohol withdrawal seizures (AWS). As the polymorphism GABABR1 T1974C[rs29230] of the GABAB receptor gene had been associated with alcoholism and EEG abnormalities in prior studies, the present examination investigated if the polymorphism is associated with the diagnosis of alcoholism or AWS. After genotyping the allele and genotype frequencies of a group of alcoholics with a history of AWS (n = 69) were compared with the results of a group of alcoholics with only mild withdrawal symptoms (n = 97). Additionally a group of healthy controls (n = 101) was compared with individuals with the diagnosis of alcoholism (n = 220). As no significant differences were found between the compared groups, this study gave no further evidence for GABABR1 T1974C[rs29230] as a candidate for alcoholism or AWS.

Significant impact of MTHFR C677T polymorphism on plasma homovanillic acid (HVA) levels among alcohol-dependent patients.

The enzyme 5,10‐methylenetetrahydrofolate reductase (MTHFR) synthesizes 5‐methyltetrahydrofolate. It plays a critical role in homocysteine metabolism. A high impact of MTHFR C677T polymorphism on plasma homocysteine levels has been observed among alcoholics. Recent studies indicate that homocysteine has toxic effects on dopaminergic neurons. Thus it lowers levels of homovanillic acid (HVA) in the striatal region in rats. Alcoholics had significantly lower plasma HVA concentrations compared with healthy controls. Aim of this study is to elucidate whether HVA plasma levels in alcoholics are influenced by MTHFR C677T polymorphism. A total of 142 alcohol‐dependent patients and 101 healthy controls were examined regarding plasma HVA concentration and MTHFR C677T genotype. Blood samples of alcoholics were obtained after a minimum of 22 days of abstinence. Among alcohol‐dependent patients MTHFR C677T polymorphism was significantly associated with plasma HVA levels: carriers of MTHFR C677T T‐allele had significantly lower HVA plasma levels compared with homozygote carriers of C‐allele: 11.9 ng/ml versus 14.4 ng/ml (χ2: 5.39; P = 0.02). In healthy control subjects plasma HVA levels did not differ significantly between MTHFR C677T T‐allele carriers and homozygote carriers of C‐allele: 15.1 ng/ml versus 15.3 ng/ml (χ2: 0.04; P = 0.82). The data suggest an influence of MTHFR C677T polymorphism on plasma HVA among alcohol‐dependent patients. This might be due to neurotoxic effects of homocysteine on the dopaminergic system or direct impairment of monoamine metabolism. Future studies should try to elucidate whether this effect is reversible during alcohol abstinence.

Therapie der Nikotinabhängigkeit

ZusammenfassungDas Rauchen ist nach Einschätzung der WHO das größte vermeidbare Gesundheitsrisiko. Der Tabakkonsum führt zu gesundheitsbedingten Risiken und Folgeerkrankungen, die die Konsequenzen des Konsums anderer Suchtmittel bei weitem übertreffen. In Deutschland rauchen ca. 27% der erwachsenen Bevölkerung. Der Anteil tabak- bzw. nikotinabhängiger Raucher wird auf bis zu 60% geschätzt. Viele dieser Raucher haben zahlreiche vergebliche Abstinenzversuche hinter sich. Eine professionelle Unterstützung des entwöhnungswilligen Rauchers erhöht dessen Abstinenzchancen. Aktuelle Behandlungsleitlinien schlagen eine Kombination psychotherapeutischer Techniken (motivierende Gesprächsführung, verhaltenstherapeutisch orientierte Unterstützung im Einzel- oder Gruppensetting) mit einer medikamentösen Begleitbehandlung (Nikotinsubstitution, Bupropion oder Vareniclin) vor. Einzelne Subgruppen (schwangere Raucherinnen, jugendliche Raucher und insbesondere Raucher mit einer psychiatrischen Komorbidität) bedürfen einer intensiveren psychotherapeutischen und gegebenenfalls auch medikamentösen Unterstützung.SummaryThe World Health Organisation (WHO) considers smoking to be the biggest avoidable health risk. The consumption of tobacco leads to health hazards and resulting diseases, the consequences of which are far more serious than those emanating from other addictive substances. Approximately 27% of the German adult population smoke regularly and the proportion of smokers addicted to tobacco or nicotine is estimated to be around 60%. Many of these smokers have undertaken numerous unsuccessful attempts at abstinence. A professional support for smokers who are motivated to give up smoking enhances the chances of success. The current treatment guidelines recommend a combination of psychotherapeutic techniques (e.g. motivational interviewing, behavioural therapy-oriented support either individually or in groups) together with pharmacological support (e.g. nicotine replacement therapy, bupropione or varenicline). Certain subgroups (e.g. pregnant smokers, juvenile smokers and, in particular, smokers with a psychiatric co-morbidity) require a more intense psychotherapy and when necessary pharmacotherapeutic support.The World Health Organisation (WHO) considers smoking to be the biggest avoidable health risk. The consumption of tobacco leads to health hazards and resulting diseases, the consequences of which are far more serious than those emanating from other addictive substances. Approximately 27% of the German adult population smoke regularly and the proportion of smokers addicted to tobacco or nicotine is estimated to be around 60%. Many of these smokers have undertaken numerous unsuccessful attempts at abstinence. A professional support for smokers who are motivated to give up smoking enhances the chances of success. The current treatment guidelines recommend a combination of psychotherapeutic techniques (e.g. motivational interviewing, behavioural therapy-oriented support either individually or in groups) together with pharmacological support (e.g. nicotine replacement therapy, bupropion or varenicline). Certain subgroups (e.g. pregnant smokers, juvenile smokers and, in particular, smokers with a psychiatric co-morbidity) require a more intense psychotherapy and when necessary pharmacotherapeutic support.

[Treatment of tobacco dependence: a responsibility of psychiatry and addiction medicine].

ZusammenfassungDas Rauchen ist nach Einschätzung der WHO das größte vermeidbare Gesundheitsrisiko. Der Tabakkonsum führt zu gesundheitsbedingten Risiken und Folgeerkrankungen, die die Konsequenzen des Konsums anderer Suchtmittel bei weitem übertreffen. In Deutschland rauchen ca. 27% der erwachsenen Bevölkerung. Der Anteil tabak- bzw. nikotinabhängiger Raucher wird auf bis zu 60% geschätzt. Viele dieser Raucher haben zahlreiche vergebliche Abstinenzversuche hinter sich. Eine professionelle Unterstützung des entwöhnungswilligen Rauchers erhöht dessen Abstinenzchancen. Aktuelle Behandlungsleitlinien schlagen eine Kombination psychotherapeutischer Techniken (motivierende Gesprächsführung, verhaltenstherapeutisch orientierte Unterstützung im Einzel- oder Gruppensetting) mit einer medikamentösen Begleitbehandlung (Nikotinsubstitution, Bupropion oder Vareniclin) vor. Einzelne Subgruppen (schwangere Raucherinnen, jugendliche Raucher und insbesondere Raucher mit einer psychiatrischen Komorbidität) bedürfen einer intensiveren psychotherapeutischen und gegebenenfalls auch medikamentösen Unterstützung.SummaryThe World Health Organisation (WHO) considers smoking to be the biggest avoidable health risk. The consumption of tobacco leads to health hazards and resulting diseases, the consequences of which are far more serious than those emanating from other addictive substances. Approximately 27% of the German adult population smoke regularly and the proportion of smokers addicted to tobacco or nicotine is estimated to be around 60%. Many of these smokers have undertaken numerous unsuccessful attempts at abstinence. A professional support for smokers who are motivated to give up smoking enhances the chances of success. The current treatment guidelines recommend a combination of psychotherapeutic techniques (e.g. motivational interviewing, behavioural therapy-oriented support either individually or in groups) together with pharmacological support (e.g. nicotine replacement therapy, bupropione or varenicline). Certain subgroups (e.g. pregnant smokers, juvenile smokers and, in particular, smokers with a psychiatric co-morbidity) require a more intense psychotherapy and when necessary pharmacotherapeutic support.The World Health Organisation (WHO) considers smoking to be the biggest avoidable health risk. The consumption of tobacco leads to health hazards and resulting diseases, the consequences of which are far more serious than those emanating from other addictive substances. Approximately 27% of the German adult population smoke regularly and the proportion of smokers addicted to tobacco or nicotine is estimated to be around 60%. Many of these smokers have undertaken numerous unsuccessful attempts at abstinence. A professional support for smokers who are motivated to give up smoking enhances the chances of success. The current treatment guidelines recommend a combination of psychotherapeutic techniques (e.g. motivational interviewing, behavioural therapy-oriented support either individually or in groups) together with pharmacological support (e.g. nicotine replacement therapy, bupropion or varenicline). Certain subgroups (e.g. pregnant smokers, juvenile smokers and, in particular, smokers with a psychiatric co-morbidity) require a more intense psychotherapy and when necessary pharmacotherapeutic support.