Gerhard A. Wiesbeck

Phosphatidylethanol as a sensitive and specific biomarker: comparison with gamma-glutamyl transpeptidase, mean corpuscular volume and carbohydrate-deficient transferrin.

Phosphatidylethanol (PEth), a direct ethanol metabolite, is detectable in blood for more than 2 weeks after sustained ethanol intake. Our aim was to assess the usefulness of PEth [comparing sensitivity, specificity and the area under the curve (AUC)] as compared with carbohydrate‐deficient transferrin (CDT), gamma‐glutamyl transpeptidase (GGT) and mean corpuscular volume (MCV), calculating the results from sober patients against those from alcohol‐dependent patients during withdrawal. Fifty‐six alcohol‐dependent patients (ICD‐10 F 10.25) in detoxification, age 43 years, GGT 81 U/l, MCV 96.4 fl, %CDT 4.2, 1400 g ethanol intake in the last 7 days (median), were included in the study. Over the time of 1 year, 52 samples from 35 sober forensic psychiatric addicted in‐patients [age 34 years, GGT 16 U/l, MCV 91 fl, CDT 0.5 (median)] in a closed ward were drawn and used for comparison . PEth was measured in heparinized whole blood with a high‐performance liquid chromatography method. GGT, MCV and %CDT were measured using routine methods. A receiver operating characteristic curve analysis was carried out, with ‘current drinking status’ (sober/drinking) as the state variable and PEth, MCV, GGT and CDT as test variables. The resulting AUC was 0.974 (P < 0.0001, confidence interval 0.932–1.016) for PEth. At a cut‐off of 0.36 µmol/l, the sensitivity was 94.5% and specificity 100%. The AUC for CDT, GGT and MCV were 0.931, 0.894 and 0.883, respectively. A significant Spearman’s rank correlation was found between PEth and GGT (r = 0.739), CDT (r = 0.643), MVC (r = 0.639) and grams of ethanol consumed in the last 7 days (r = 0.802). Our data suggest that PEth has potential to be a sensitive and specific biomarker, having been found in previous studies to indicate longer lasting intake of higher amounts of alcohol.

Phosphatidylethanol: normalization during detoxification, gender aspects and correlation with other biomarkers and self-reports.

Phosphatidylethanol (PEth) is a direct ethanol metabolite, and has recently attracted attention as biomarker of ethanol intake. The aims of the current study are: (1) to characterize the normalization time of PEth in larger samples than previously conducted; (2) to elucidate potential gender differences; and (3) to report the correlation of PEth with other biomarkers and self‐reported alcohol consumption. Fifty‐seven alcohol‐dependent patients (ICD 10 F 10.25; 9 females, 48 males) entering medical detoxification at three study sites were enrolled. The study sample was comprised of 48 males and 9 females, with mean age 43.5. Mean gamma glutamyl transpeptidase (GGT) was 209.61 U/l, average mean corpuscular volume (MCV) was 97.35 fl, mean carbohydrate deficient transferrin (%CDT) was 8.68, and mean total ethanol intake in the last 7 days was 1653 g. PEth was measured in heparinized whole blood with a high‐pressure liquid chromatography method, while GGT, MCV and %CDT were measured using routine methods. PEth levels at day 1 of detoxification ranged between 0.63 and 26.95 µmol/l (6.22 mean, 4.70 median, SD 4.97). There were no false negatives at day 1. Sensitivities for the other biomarkers were 40.4% for MCV, 73.1% for GGT and 69.2% for %CDT, respectively. No gender differences were found for PEth levels at any time point. Our data suggest that PEth is (1) a suitable intermediate term marker of ethanol intake in both sexes; and (2) sensitivity is extraordinary high in alcohol dependent patients. The results add further evidence to the data that suggest that PEth has potential as a candidate for a sensitive and specific biomarker, which reflects longer‐lasting intake of higher amounts of alcohol and seemingly has the above mentioned certain advantages over traditional biomarkers.

Benzodiazepine prescribing to the Swiss adult population: results from a national survey of community pharmacies.

The purpose of the study was to assess prevalence of benzodiazepine use in the Swiss adult population and to assess on benzodiazepine prescription patterns of physicians in domiciliary practice. Study designA retrospective, population-based cross-sectional study with 520 000 patients covering a 6-month period. MethodsWe estimated the prevalence, amount and duration of benzodiazepine use using a pharmacy dispensing database. ResultsOf all patients, 9.1% (n=45 309) received at least one benzodiazepine prescription in the 6-month period. Most persons receiving benzodiazepine prescriptions were women (67%), and half of all patients were aged 65 or older. Of 45 309 patients with benzodiazepine prescriptions, 44% (n=19 954) had one single prescription, mostly for a short period (<90 days) and in lower than the recommended dose range. Fifty-six percent (n=25 354) had repeated benzodiazepine prescriptions, mostly for a long time period (>90 days), and in lower than the recommended or within the recommended dose range. In patients with long-term use (n=25 354), however, 1.6% had benzodiazepine prescriptions in extremely high doses. The sample of patients with repeated prescriptions allowed an estimation of a benzodiazepine use of 43.3 daily defined doses per 1000 inhabitants in Switzerland. ConclusionsBenzodiazepine prescriptions were appropriate for most patients and thus were prescribed in therapeutic doses, as indicated in the treatment guidelines. On the other hand, our survey showed that 1.6% of the patients had prescriptions for long time periods at very high doses, indicating an abuse or dependence on benzodiazepines in this subgroup.

Personality Traits Predict Treatment Outcome in Alcohol-Dependent Patients

Personality traits are important individual characteristics modifying responses to therapy in various diseases. The aim of this study was to identify personality traits that may predict treatment outcome in alcohol-dependent patients. The present analysis was based on a total of 146 alcohol-dependent patients (109 male, 37 female) after detoxification. The variable of interest was treatment outcome (abstinence/relapse) after a 1-year follow-up. To identify personality traits as predictors of treatment outcome, 5 personality questionnaires (NEO 5-Factor Inventory, Temperament and Character Inventory, Eysenck Personality Questionnaire, Eysenck Impulsiveness-Venturesomeness-Empathy Scale and Sensation-Seeking Scale) were applied. Data analysis was performed by using a classification and regression tree analysis (CART; a nonparametric technique for data with a complex structure) in order to find a decision rule to predict treatment outcome from personality traits. The CART model identified psychoticism and persistence as the 2 most relevant discriminatory parameters, of which psychoticism was used as the first node in the model, classifying 64% of the patients correctly as relapsed and 12% correctly as abstinent. In addition, the risk of relapse was even higher in patients with a substantial score in psychoticism and a low score in persistence. When comparing relapsed and abstinent patients, further variables, such as scores for novelty seeking (20.9 ± 5.5 vs. 18.5 ± 5.9) and impulsiveness (8.4 ± 3 vs. 7.2 ± 3.5), showed significance. In addition, relapsed patients lived alone more often than abstinent patients (52 vs. 25%, p = 0.004). In conclusion, this analysis demonstrated that specific personality characteristics, namely psychoticism and persistence, are usable predictors for the risk of relapse in alcohol-dependent patients.

Alcohol dependence, family history, and D2 dopamine receptor function as neuroendocrinologically assessed with apomorphine

Fifteen alcohol dependent men with an alcohol dependent first degree relative (i.e. family history positive or FHP), 15 well matched alcohol dependent men without a family history for alcohol dependence (i.e. family history negative or FHN), and 15 healthy controls (CONTR) participated in this study. The three groups were compared according to their postsynaptic D2 dopamine receptor function as assessed by growth hormone release after stimulation with the dopamine receptor agonist apomorphine. Statistical evaluation was done by planned comparisons within a one-way ANOVA. Alcohol dependent subjects significantly differed from CONTRs as long as family history was not taken into account (t(42) = 2.38; P = 0.022*). When differentiating according to family history, both FHPs and FHNs maintained a blunted growth hormone response. However, the difference between FHNs and CONTRs, though present, dropped out of statistical significance (t(42) = 1.65; P = 0.105); at the same time, the difference between FHPs and CONTRs became slightly stronger (t(42) = 2.47; p = 0.017*). In conclusion, our data give neuroendocrinological support to the assumption that a reduced D2 dopamine receptor function in alcohol dependent men is not only a state marker of residual heavy drinking but also a genetically determined trait marker.

Assessment of Alcohol Use Among Methadone Maintenance Patients by Direct Ethanol Metabolites and Self‐Reports

BACKGROUND Heavy alcohol consumption may accelerate the progression of hepatitis C (HCV)-related liver disease and/or limit efforts at antiviral treatment. As most of the patients in methadone maintenance treatment (MMT) suffer from hepatitis C infection, this study was conducted to identify the alcohol intake among these patients at a Swiss Psychiatric University Clinic by self-reports and direct ethanol metabolites as biomarkers of ethanol consumption. PATIENTS AND METHODS A convenience sample of 40 MMT patients (15 women, 25 men; median age 39 years) of the total 124 patients was asked and consented to participate in this study. This sample was not different in age, gender distribution, and rate of hepatitis C infection from the total sample. The Alcohol Use Disorders Identification Test (AUDIT) and self-reported ethanol intake during the previous 7 days were assessed. In addition, ethyl glucuronide (EtG) in urine, and fatty acid ethyl esters (FAEEs) and EtG in hair were determined using LC-MS/MS and gas chromatograph/mass spectrometer. The limit of quantitation for UEtG, HEtG, and FAEEs were 0.1 mg/l, 2.3 pg/mg, and 0.1 ng/mg, respectively. RESULTS Fourteen participants reported abstinence from alcohol for the previous 7 days. AUDIT scores were > or =8 in 15 male and >5 in 5 female participants. Direct ethanol metabolites were as follows (median, min, max, standard deviation): UEtG (19 positives; 9.91, 1.38 to 251, 62.39 mg/l); the values of HEtG were 17.65, 0 to 513, 105.62 pg/mg [in 2 cases no material, 8 abstinent (up to 7 pg/mg), 15 social drinkers (up to 50 g per day), and 15 excessive users (>50/60 g/d)]. For the 13 cases, where enough material for additional determination of HFAEEs was available, the values were 0.32, 0 to 1.32, 0.44 ng/mg. Among the 30 HEtG-positive participants, 20 had not reported the corresponding ethanol intake using question 1 (frequency) and 2 (quantity) of the AUDIT. Of the 14 participants reporting no alcohol intake during the previous 7 days, 4 were UEtG-positive. HEtG and AUDIT correlated significantly (r = 0.622, p < 0.0001), but this was not the case for UEtG and self-reported ethanol intake during the previous 7 days. CONCLUSION (1) HEtG identified 20 cases of daily ethanol intake of more than 20 g, that would have been missed by the sole use of question 1 (frequency) and 2 (quantity) of the AUDIT. (2) Using the total score of the AUDIT, HEtG confirmed 10 more cases positive for alcohol intake. (3) Episodic heavy drinking is with 22.5% more frequent than in general population, and (4) of the 14 participants who reported no alcohol intake during the previous 7 days, 4 were UEtG positive. Improved detection of alcohol consumption, which is hazardous or harmful in the context of HCV and opiate dependence, would allow for earlier intervention in this population which is at particular risk of liver disease and fatal respiratory-depressed overdose. The combined use of self-reports and direct ethanol metabolites seems promising.

Cortisol concentrations, stress-coping styles after withdrawal and long-term abstinence in alcohol dependence.

Alcohol‐dependent patients face a substantial risk of relapse after detoxification. A major risk factor for relapse is stress which is reflected biologically by various physiological changes that include an activation of the hypothalamic‐pituitary‐adrenal (HPA) axis and release of glucocorticoids. The prospective study examined cortisol concentrations and stress‐coping styles in relation to abstinence 1 year following discharge from treatment. Cortisol concentrations were measured in the plasma of 46 alcohol‐dependent patients (12 women) on initial presentation for treatment (day 1), and again in plasma and in cerebrospinal fluid (CSF) after 6 weeks of abstinence (day 40). These results were compared with those of 26 age‐ and sex‐matched, healthy control subjects. After withdrawal, the patients completed a comprehensive baseline assessment including a stress‐coping questionnaire (Stressverarbeitungsfragebogen SVF120) and were monitored for 1 year after discharge. Negative stress‐coping styles (e.g. flight, resignation) positively correlated with higher cortisol concentration in plasma and in CSF after withdrawal (day 40). Compared with relapsers after 1 year, abstainers had significantly lower levels for cortisol in CSF, whereas the stress‐coping styles did not differ between abstainers and relapsers in this sample. These findings suggest that relatively stable personality traits like stress‐coping styles have no measurable influence on abstinence. The lower cortisol concentration in CSF as an indicator for HPA axis functioning is associated with long‐term abstinence in detoxified alcoholics.

Social Factors but Not Stress-Coping Styles Predict Relapse in Detoxified Alcoholics

Alcohol-dependent patients face a substantial risk of relapse after detoxification. Though psychosocial stress and coping strategies are regarded as major contributing factors in returning to drinking, the direct effects of coping styles on relapse are not clear. In this treatment outcome study, a mixed gender sample of 130 detoxified and well-characterized alcohol-dependent patients (37 women) was followed up over a period of 12 months after 6 weeks of inpatient treatment. Patients had completed a comprehensive baseline assessment, including a stress coping questionnaire (SVF120). We hypothesized that these individual stress coping styles would contribute to treatment outcome. A logistic regression analysis was used to evaluate the impact of stress coping styles, as well as the effect of pretreatment drinking and social characteristics on relapse. Approximately half the patients (49%) relapsed within 1 year after treatment. In contrast to our hypothesis, stress coping styles did not predict relapse. However, significant predictors of relapse were social factors related to living situation (living alone), marital status (being separated from the spouse) and pretreatment frequency of alcohol intake. These findings suggest that a partnership is more relevant for the risk of relapse than stress coping styles.

Sensation seeking, alcoholism and dopamine activity

Sensation seeking scale (SSS) scores were determined in 15 alcohol dependent men with a positive family history for alcoholism (FHP), in 15 alcohol dependent men with a negative family history for alcoholism (FHN) and in 15 well-matched healthy male controls (CONTR). Both FHPs and FHNs suffered from longlasting alcohol dependence meeting ICD-10 and DSM-III-R diagnostic criteria. Dopamine activity was neuroendocrinologically assessed by measuring the amount of growth hormone released after stimulation with the dopamine receptor agonist apomorphine. Planned comparisons within a one-way ANOVA yielded significantly elevated levels of boredom susceptibility (BOS) in both FHPs and FHNs against CONTRs. SSS total scores, while approaching statistical significance, were elevated in FHPs only. Partial correlations (controlling for age, body weight, alcohol intake and duration of dependence) were calculated to examine the relationship between SSS and dopamine activity. Among the SSS subtraits, BOS revealed the highest correlation in each group. However, only in CONTRs did the relationship between BOS and dopamine activity reach statistical significance.

No association of dopamine receptor sensitivity in vivo with genetic predisposition for alcoholism and DRD2/ DRD3 gene polymorphisms in alcohol dependence

This study sought to examine dopamine receptor sensitivity among alcoholics in vivo and to explore whether this sensitivity might be associated with functional variations of dopamine D2 (DRD2) and D3 (DRD3) receptor genes along with a genetic predisposition for alcoholism as reflected by an alcohol‐dependent first‐degree relative. We analyzed the −141C Ins/Del polymorphism in the promoter region of the DRD2 gene and the Ser9Gly (BalI) polymorphism in exon 1 of the DRD3 gene in 74 alcohol‐dependent Caucasian men with or without genetic predisposition for alcoholism. In vivo dopamine receptor sensitivity was assessed by measuring apomorphine‐induced growth hormone release. A three‐way analysis of variance revealed no significant effects of DRD2, DRD3 genotypes and genetic predisposition on dopamine receptor sensitivity. Given the explorative and preliminary character of this investigation, we cannot provide evidence that in alcohol‐dependent Caucasian men a genetic predisposition for alcoholism along with functional variants of the DRD2 and DRD3 genes are associated with differences in dopamine receptor sensitivity.